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Study to Assess Enzastaurin + R-CHOP in Subjects With DLBCL With the Genomic Biomarker DGM1™
This randomized, placebo-controlled phase 3 study is planned to enroll approximately 235
treatment-naïve subjects with high-risk Diffuse Large B-Cell Lymphoma (DLBCL). Subjects will
be randomized 1:1 to R-CHOP plus enzastaurin or R CHOP (plus placebo during induction). All
subjects will receive up to 6 cycles (3 weeks per cycle) of treatment. PET/ CT will be used
to assess radiographic response at the end of treatment. Each subject's treatment assignment
will be unblinded after initial phase of treatment. Subjects randomized to the enzastaurin
arm who have a response will be offered maintenance treatment of the study drug for up to 2
additional years.
Inclusion Criteria
1. Male or female at least 18 years of age and able to provide informed consent.
2. Histologically-confirmed diagnosis of CD20-positive DLBCL based on the WHO
classification (2016); the diagnosis must be confirmed at the enrolling site. Subjects
with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements and
high-grade B-cell lymphoma, NOS are eligible.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
4. International Prognostic Index (IPI) score of at least 3.
5. Estimated life expectancy of at least 12 weeks.
6. Adequate organ function as follows (within 14 days prior to randomization):
1. Hepatic: total bilirubin ≤1.5 times upper limit of normal (ULN); alanine
transaminase (ALT) and aspartate transaminase (AST) ≤1.5 times ULN (<5 times ULN
if liver involvement)
2. Renal: creatinine clearance of >50 mL/min by Cockcroft- Gault equation
3. Bone marrow: platelets ≥75 x 109/L, absolute neutrophil count (ANC) ≥1.5 x 109/L,
hemoglobin ≥10 g/dL. (Platelets ≥50 x 109/L, ANC ≥1.0 x 109/L, hemoglobin ≥8 g/dL
permitted if documented bone marrow involvement)
7. Male or female with reproductive potential, must be willing to use an approved
contraceptive method (for example, intrauterine device (IUD), birth control pills, or
barrier device) during and for 3 months after discontinuation of study treatment.
Women of childbearing potential must have a negative serum pregnancy test within 7
days prior to randomization.
1. Men are considered of reproductive potential unless they have undergone a
vasectomy and confirmed sterile by a post-vasectomy semen analysis.
2. Women are considered of reproductive potential unless they have undergone
hysterectomy and/or surgical sterilization (at least 6 weeks following a
bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusive
procedure that has been confirmed in accordance with the device's label) or
achieved postmenopausal status (defined as cessation of regular menses for
greater than 12 consecutive months in women at least 45 years of age).
8. Left ventricular ejection fraction ≥50% by echocardiography or nuclear medicine
multi-gated scan.
9. Must be able to swallow tablets.
10. Must be able to comply with study protocol procedures.
11. Willing to consent to have blood stored for possible future biomarker and disease
analysis.
12. Must have available and willing to submit pre-systemic treatment DLBCL tumor biopsy
tissue/slides for central pathology review.
Exclusion Criteria
1. Received treatment with an investigational drug within the last 30 days.
2. Receiving or has received radiation or any other systemic anticancer treatment for
lymphoma (Up to 7 days of corticosteroids are permitted but must be administered after
eligibility IPI determination and imaging scans).
3. History of indolent lymphoma or follicular Grade 3b lymphoma.
4. Primary mediastinal (thymic) large B-cell lymphoma.
5. B-cell lymphoma, unclassifiable, with features. intermediate between DLBCL and
classical Hodgkin lymphoma.
6. Burkitt lymphoma.
7. Pregnancy or breastfeeding.
8. Known central nervous system (CNS) involvement.
9. Any significant concomitant disorder based on the discretion of the investigator,
including but not limited to active bacterial, fungal, or viral infection,
incompatible with participation in the study.
10. A second primary malignancy (except adequately treated non-melanoma skin cancer);
subjects who have had another malignancy in the past, but have been disease-free for
more than 5 years, and subjects who have had a localized malignancy treated with
curative intent and disease free for more than 2 years are eligible.
11. Use of a strong inducer or moderate or strong inhibitor of CYP3A4 within 7 days prior
to start of study therapy or expected requirement for use on study therapy.
12. Personal or immediate family history of long QT syndrome, QTc interval >450 msec
(males) or >470 msec (females) at screening (recommended that QTc be calculated using
Fridericia correction formula, QTcF: see Section 6.2.1), or a history of unexplained
syncope.
13. Use of any medication that can prolong the QT/QTc interval within 7 days prior to
start of study therapy or expected requirement for use on study therapy.
14. History of severe allergic or anaphylactic reaction to monoclonal antibody therapy.
15. Confirmed diagnosis of progressive multifocal leukoencephalopathy.
16. Ongoing grade 2 or higher peripheral neuropathy.
17. Have any of the following cardiac disorders: uncontrolled hypertension, unstable
angina, myocardial infarction within 8 weeks of Day1, NYHA Grade 2 or higher
congestive heart failure, ventricular arrhythmia requiring medication within 1 year of
Day 1, NYHA Grade 2 or higher peripheral vascular disease.
18. Received a live vaccine within 28 days of study Day 1.
19. HIV positive.
20. Evidence of chronic hepatitis C infection as indicated by antibody to HCV with
positive HCV-RNA.
21. Evidence of chronic hepatitis B infection as indicated by either:
1. HBsAg+ or
2. HBcAb+ with HBV-DNA+ (any detectable amount is considered positive)
Study to Evaluate the Efficacy and Safety of Camidanlumab Tesirine (ADCT-301) in Patients With Relapsed or Refractory Hodgkin Lymphoma
The purpose of this study is to evaluate the clinical efficacy and safety of Camidanlumab
Tesirine (ADCT-301) in participants with relapsed or refractory Hodgkin Lymphoma (HL).
1. Written informed consent must be obtained prior to any procedures.
2. Male or female participant aged 18 years or older. (16 years or older at US based
sites)
3. Pathologic diagnosis of classical Hodgkin lymphoma (cHL).
4. Patients with relapsed or refractory cHL, who have received at least 3 prior lines of
systemic therapy (or at least 2 prior lines in HSCT ineligible patients) including
brentuximab vedotin and a checkpoint inhibitor approved for cHL (e.g., nivolumab or
pembrolizumab). Note 1: Receipt of HSCT to be included in the number of prior
therapies needed to meet eligibility.
5. Measurable disease as defined by the 2014 Lugano Classification.
6. Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block (or minimum
10 freshly cut unstained slides if block is not available).
Note 1: Any biopsy since initial diagnosis is acceptable, but if several samples are
available, the most recent sample is preferred.
Note 2: If a sufficient amount of tissue is not available, a fresh biopsy may be
taken, provided the procedure is not deemed high-risk and is clinically feasible, and
provided it is approved locally.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
8. Adequate organ function as defined by Screening laboratory values within the following
parameters:
1. Absolute neutrophil count (ANC) ≥ 1.0 × 103/μL (off growth factors at least 72
h).
2. Platelet count ≥ 75 × 103/μL without transfusion in the past 2 weeks.
3. ALT, AST, or GGT ≤ 2.5 × the upper limit of normal (ULN) if there is no liver
involvement; ALT or AST ≤ 5 × ULN if there is liver involvement.
4. Total bilirubin ≤ 1.5 × ULN (participants with known Gilbert's syndrome may have
a total bilirubin up to ≤ 3 × ULN with direct bilirubin ≤ 1.5 × ULN).
5. Blood creatinine ≤ 3.0 × ULN or calculated creatinine clearance ≥ 30 mL/min by
the Cockcroft-Gault equation.
Note: A laboratory assessment may be repeated a maximum of two times during the
Screening Period to confirm eligibility.
9. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior
to start of study drug for women of childbearing potential.
10. Women of childbearing potential (WOCBP) must agree to use a highly effective method of
contraception from the time of giving informed consent until at least 6.5 months after
the last dose of Camidanlumab Tesirine. Men with female partners who are of
childbearing potential must agree to use a highly effective method of contraception
from the time of giving informed consent until at least 16 weeks after the
participants receives his last dose of Camidanlumab Tesirine.
Exclusion Criteria:
1. Previous treatment with Camidanlumab Tesirine.
2. Participation in another investigational interventional study. Being in follow-up of
another investigational study is allowed.
3. Known history of hypersensitivity to or positive serum human anti-drug antibody (ADA)
to a CD25 antibody.
4. Allogenic or autologous transplant within 60 days prior to start of study drug.
5. Active graft-versus-host disease (GVHD), except for non-neurologic symptoms as a
manifestation of mild (≤ Grade 1) chronic GVHD.
6. Post-transplantation lymphoproliferative disorders.
7. Active second primary malignancy other than non-melanoma skin cancers, non-metastatic
prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the
breast, or other malignancy that the Sponsor's medical monitor and Investigator agree
and document should not be exclusionary.
8. History of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic
progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjögren's syndrome,
autoimmune vasculitis [e.g., Wegener's granulomatosis]) (subjects with vitiligo, type
1 diabetes mellitus, residual hypothyroidism, hypophysitis due to autoimmune condition
only requiring hormone replacement may be enrolled).
9. History of neuropathy considered of autoimmune origin (e.g., polyradiculopathy
including Guillain-Barré syndrome and myasthenia gravis) or other central nervous
system autoimmune disease (e.g., poliomyelitis, multiple sclerosis).
10. History of recent infection (within 4 weeks of Cycle 1, Day 1 [C1D1]) considered to be
caused by one of the following pathogens: HSV1, HSV2, VZV, EBV, CMV, measles,
Influenza A, Zika virus, Chikungunya virus, mycoplasma pneumonia, Campylobacter
jejuni, or enterovirus D68, or severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2).
Note: An influenza test and a pathogendirected SARS CoV-2 test (such as polymerase
chain reaction) are mandatory and must be negative before initiating study treatment
(tests to be performed 3 days or less prior to dosing on C1D1; an additional 2 days
are allowed in the event of logistical issues for receiving the results on time).
11. Participants known to be or having been infected with human immunodeficiency (HIV)
virus, hepatitis B virus (HBV), or hepatitis C virus (HCV), and require anti-viral
therapy or prophylaxis. Note: Serology testing is mandatory for patients with unknown
status.
12. History of Stevens-Johnson syndrome or toxic epidermal necrolysis.
13. Failure to recover ≤ Grade 1 (Common Terminology Criteria for Adverse Events version
4.0 [CTCAE v4.0]) from acute non-hematologic toxicity (except ≤ Grade 2 neuropathy or
alopecia), due to previous therapy, prior to screening.
14. Hodgkin lymphoma (HL) with central nervous system involvement, including
leptomeningeal disease.
15. Clinically significant third space fluid accumulation (i.e., ascites requiring
drainage or pleural effusion that is either requiring drainage or associated with
shortness of breath).
16. Breastfeeding or pregnant.
17. Significant medical comorbidities, including uncontrolled hypertension (blood pressure
[BP] ≥ 160/100 mmHg repeatedly), unstable angina, congestive heart failure (greater
than New York Heart Association class II), electrocardiographic evidence of acute
ischemia, coronary angioplasty or myocardial infarction within 3 months prior to
screening, severe uncontrolled atrial or ventricular cardiac arrhythmia, poorly
controlled diabetes, or severe chronic pulmonary disease.
18. Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy, within 14
days prior to start of study drug, except shorter if approved by the Sponsor.
19. Use of any other experimental medication within 30 days prior to start of study drug.
20. Any live vaccine within 4 weeks prior to start of study drug and planned live vaccine
administration after starting study drug.
21. Congenital long QT (measure between Q wave and T wave in the electrocardiogram)
syndrome, or a corrected QTc interval of ≥ 480 ms, at screening (unless secondary to
pacemaker or bundle branch block).
22. Any other significant medical illness, abnormality, or condition that would, in the
Investigator's judgment, make the participants inappropriate for study participation
or put the participant at risk.
A Safety and Efficacy Study Evaluating CTX110 in Subjects With Relapsed or Refractory B-Cell Malignancies (CARBON)
This is an open-label, multicenter, Phase 1 study evaluating the safety and efficacy of
CTX110 in subjects with relapsed or refractory B-cell malignancies.
1. For NHL patients: Age ≥18 years. For B cell ALL patients: age ≥18 years to ≤70 years
2. Refractory or relapsed non-Hodgkin lymphoma, as evidenced by 2 or more lines of prior
therapy, or histologically confirmed B cell ALL, refractory or relapsed.
3. Eastern Cooperative Oncology Group performance status 0 or 1.
4. Adequate renal, liver, cardiac and pulmonary organ function
5. Female subjects of childbearing potential and male subjects must agree to use
acceptable method(s) of contraception from enrollment through at least 12 months after
CTX110 infusion.
6. Agree to participate in an additional long-term follow-up study after completion of
this study.
Key
Exclusion Criteria:
1. Treatment with any gene therapy or genetically modified cell therapy, including CAR T
cells.
2. For NHL patients: prior allogeneic HSCT. For B cell ALL patients: prior allogeneic
HSCT within 6 months, and/or any evidence of GvHD.
3. History of central nervous system (CNS) involvement by malignancy
4. History of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia,
cerebellar disease, or any autoimmune disease with CNS involvement.
5. Presence of bacterial, viral, or fungal infection that is uncontrolled or requires IV
anti-infectives.
6. Active HIV, hepatitis B virus or hepatitis C virus infection.
7. Previous or concurrent malignancy, except basal cell or squamous cell skin carcinoma,
adequately resected and in situ carcinoma of cervix, or a previous malignancy that was
completely resected and has been in remission for ≥5 years.
8. For NHL patients: Use of systemic anti-tumor therapy or investigational agent within
14 days or 5 half-lives, whichever is longer, of enrollment. For B cell ALL patients:
Use of systemic antitumor therapy within 7 days of enrollment.
9. Primary immunodeficiency disorder or active autoimmune disease requiring steroids
and/or other immunosuppressive therapy.
10. Women who are pregnant or breastfeeding.
Biological: CTX110
Non-hodgkin Lymphoma, B-cell Malignancy, B-cell Lymphoma, Adult B Cell ALL
CAR T, Non-Hodgkin Lymphoma, NHL, Lymphoma, Allogeneic, Leukemia
Safety and Efficacy of Pembrolizumab (MK-3475) in Children and Young Adults With Classical Hodgkin Lymphoma (MK-3475-667/KEYNOTE-667)
This study will examine the safety and efficacy of pembrolizumab (MK-3475) in combination
with chemotherapy in children and young adults with newly diagnosed classical Hodgkin
Lymphoma (cHL) who are slow early responders (SERs) to frontline chemotherapy.
• Group 1: Must have newly diagnosed, pathologically confirmed cHL at Stages IA, IB and
IIA without bulky disease. Group 2: Must have newly diagnosed, pathologically
confirmed cHL at Stages IIEB, IIIEA,IIIEB, IIIB, IVA and IVB
• Has measurable disease per investigator assessment
• Male participants must agree to use approved contraception during the treatment period
and for at least 120 days (or longer, if required by the drug label of chemotherapy
received by the participant on study) after the last dose of study treatment and
refrain from donating sperm during this period
• Female participants who are not pregnant or breastfeeding, and who are either not a
woman of childbearing potential (WOCBP), or are a WOCBP who agrees to use approved
contraception during the treatment period and for at least 120 days (or longer, if
required by the drug label of chemotherapy received by the participant on study) after
the last dose of study treatment
• Performance status: Lansky Play-Performance Scale ≥50 for children up to and including
16 years of age OR Karnofsky score ≥50 for participants >16 years of age
• Has adequate organ function
Exclusion Criteria:
• Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic
stem cell transplantation within the last 5 years
• WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of
study treatment
• Baseline left ventricular ejection fraction value <50% or shortening fraction of <27%
• Has received prior therapy with an anti-Programmed Death (PD)-1, anti-Programmed
Death-Ligand 1 (PD-L1), or anti-PD-L2 agent or with an agent directed to another
co-inhibitory T-cell receptor or has previously participated in a Merck pembrolizumab
(MK-3475) clinical study
• Has received any prior anti-cancer therapy, monoclonal antibody, chemotherapy, or an
investigational agent or device before the first dose of study treatment, or has not
recovered from AEs due to previously administered agents
• Has received a live vaccine within 30 days prior to the first dose of pembrolizumab
• Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment
• Has a diagnosis of lymphocyte-predominant Hodgkin Lymphoma (HL)
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to the first dose
of pembrolizumab
• Has a known additional malignancy that is progressing or requires active treatment
• Has radiographically detectable central nervous system metastases and/or carcinomatous
meningitis as assessed by local site investigator at the time of diagnosis
• Has severe hypersensitivity (≥Grade 3) to any study therapies including any excipients
• Has an active autoimmune disease that has required systemic treatment in past 2 years
• Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of Hepatitis B or known active Hepatitis C virus infection
• Has a known history of active tuberculosis
• Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's
participation for the full duration of the study, or is not in the best interest of
the participant to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with
cooperating with the requirements of the study
• Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 120 days
(or longer, if required by the drug label of chemotherapy received by the participant
on study) after the last dose of trial treatment
Study of Acalabrutinib Alone or in Combination Therapy in Subjects With B-cell Non-Hodgkin Lymphoma
Part 1: To characterize the safety profile of acalabrutinib alone or in combination with
rituximab in subjects with R/R FL.
Part 2: To characterize the activity of acalabrutinib alone or in combination with rituximab
in subjects with R/R MZL, as measured by ORR.
Part 3: To characterize the safety of acalabrutinib in combination with rituximab and
lenalidomide in subjects with R/R FL
• Men and women ≥ 18 years of age.
• Part 1: A confirmed diagnosis of FL Grade 1, 2, or 3a, which has relapsed after, or
been refractory to ≥ 1 prior therapy for FL, or subjects who have not previously
received systemic anticancer therapy for FL., and which requires treatment.
• Part 2:Histologically confirmed MZL including splenic, nodal, and extranodal sub-
types
1. Subjects with splenic MZL must have an additional measurable lesion, nodal or
extranodal, as described in inclusion criterion #4;
2. Subjects with gastric mucosa-associated lymphoid tissue (MALT) lymphoma must be
Helicobacter pylori (HP)-negative
• Part 3: For subjects with FL: Pathologically confirmed diagnosis of FL Grade 1, 2, or
3a, which has relapsed after, or been refractory to ≥ 1 prior therapy for FL and which
requires treatment per National Cancer Institute or ESMO clinical practice guidelines.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Agreement to use contraception during the study and for 30 days after the last dose of
study drugs if sexually active and able to bear or beget children.
Exclusion Criteria:
• •A life-threatening illness, medical condition or organ system dysfunction which, in
the investigator's opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk
• Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
congestive heart failure, or myocardial infarction within 6 months of screening, or
any Class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification, or Qtc >480 msec
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory
bowel disease, or partial or complete bowel obstruction.
• Breast feeding or pregnant
Study of Ibrutinib and Rituximab in Treatment Naïve Follicular Lymphoma
The purpose of this study is to evaluate whether the addition of ibrutinib will result in
prolongation of progression-free survival (PFS) when compared with rituximab alone in
treatment naïve subjects with follicular lymphoma.
• Histologically confirmed diagnosis of follicular lymphoma CD20+ (Grade 1, 2 or 3a) Ann
Arbor Stage II, III or IV disease.
• Measurable disease
• Subjects 70 years of age or older; OR subjects 60-69 years of age who have one or more
comorbidities.
• Meets one or more Groupe d'Etude des Lymphomes Folliculaire (GELF) criteria.
• Adequate hematologic function within protocol-defined parameters.
• Adequate hepatic and renal function within protocol-defined parameters.
• ECOG performance status score of 0-2.
Exclusion Criteria:
• Transformed lymphoma
• Prior treatment for follicular lymphoma
• Central nervous system lymphoma or leptomeningeal disease
• Currently active, clinically significant cardiovascular disease
Drug: ibrutinib, Drug: placebo to match ibrutinib, Drug: rituximab, Drug: ibrutinib, Drug: placebo to match ibrutinib, Drug: placebo to match ibrutinib
'Re-Priming' RT After Incomplete Response to CAR-T in R/R NHL
This is a single-arm open-label phase I/II trial studying the safety and efficacy of focal
're-priming' radiation therapy (RT) to FDG-avid residual sites of disease in
relapsed/refractory non-Hodgkin lymphoma (R/R NHL) patients with incomplete response (IR) to
CAR T-cell therapy (CAR-T) by day 30 post-CAR-T PET/CT. We hypothesize that focal
're-priming' RT will be safe (phase I) and improve conversion to metabolic complete response
(CR) by day 90 post-CAR-T PET/CT from 29% (historical control) to 58% (phase II).
1. Age ≥ 18 years.
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening (See
Section 13, Appendix A).
3. Biopsy-proven histological high-grade non-Hodgkin lymphoma, such as diffuse large
B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed
follicular lymphoma.
4. Prior treatment with any CD19-directed CAR T-cell therapy, such as tisagenlecleucel
(tisa-cel, Kymriah), axicabtagene ciloleucel (axi-cel, Yescarta), or lisocabtagene
maraleucel (liso-cel).
5. Incomplete response noted on day 30 PET post-CAR-T, defined as not achieving CR per
Lugano 2014 classification37.
6. Ability to understand and the willingness to sign a written informed consent
7. All men, as well as women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, for the duration of study participation, and for 90 days following completion
of therapy. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.
7.1 A female of child-bearing potential is any woman (regardless of sexual orientation,
marital status, having undergone a tubal ligation, or remaining celibate by choice) who
meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has
had menses at any time in the preceding 12 consecutive months).
Exclusion Criteria:
1. Prior radiation therapy to one or more sites of incomplete response as noted on day 30
post-CAR-T PET/CT scan within the past one year.
2. Intracranial site of incomplete response as noted on day 30 post-CAR-T PET/CT scan or
any active central nervous system involvement by malignancy.
3. Active grade 3 or higher CRS or neurotoxicity related to CAR-T.
4. Patients with prior history of auto-immune disease or other contraindication to RT.
5. Patients with life expectancy < 3 months.
6. Psychiatric illness/social situations that would limit compliance with study
requirements.
7. Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that, in the opinion of the
investigator, would limit compliance with study requirements.
Lisocabtagene Maraleucel (JCAR017) as Second-Line Therapy (TRANSCEND-PILOT-017006)
This is a Phase 2, open-label, multicenter study to determine the efficacy and safety of
lisocabtagene maraleucel (JCAR017) in adult subjects who have relapsed from, or are
refractory to, a single line of immunochemotherapy for aggressive B-cell non-Hodgkin lymphoma
(NHL) and are ineligible for hematopoietic stem cell transplant (based on age, performance
status, and/or comorbidities). Subjects will receive treatment with lisocabtagene maraleucel
and will be followed for 2 years for safety, pharmacokinetics and biomarkers, disease status,
quality of life, and survival.
• Confirmation of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma of the
following histology at relapse: diffuse large B-cell lymphoma (DLBCL), not otherwise
specified (NOS; de novo or transformed follicular lymphoma [tFL]), high-grade B-cell
lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology
(double/triple hit lymphoma [DHL/THL]), and follicular lymphoma Grade 3B per WHO 2016
classification
• Previous treatment must include treatment with a single line of chemoimmunotherapy
containing an anthracycline and a CD20-targeted agent
• Subjects must be deemed ineligible for both high-dose chemotherapy and hematopoietic
stem cell transplant (based on age, performance status and/or comorbidities) while
also having adequate organ function for CAR T cell treatment.
• Positron emission tomography (PET)-positive disease
• Histological confirmation of diagnosis at last relapse. Enough tumor material must be
available for central confirmation of diagnosis, otherwise a new tumor biopsy is
mandated.
• ECOG performance status of 0, or 1, or 2
• Adequate vascular access for leukapheresis procedure (either peripheral line or
surgically-placed line)
• Subjects must agree to use appropriate contraception
• Subjects must agree to not donate blood, organs, semen, and egg cells for usage in
other individuals for at least 1 year following lymphodepleting chemotherapy
Exclusion Criteria:
• Subjects with central nervous system (CNS)-only involvement by malignancy (note:
subjects with secondary CNS involvement are allowed on study)
• History of another primary malignancy that has not been in remission for at least 2
years.
• Previous treatment with CD19-targeted therapy, with the exception of prior
lisocabtagene maraleucel treatment in this protocol for subjects receiving retreatment
• Active hepatitis B or hepatitis C infection at the time of screening
• History of or active human immunodeficiency virus (HIV) infection at the time of
screening
• Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate
antibiotics or other treatment at the time of leukapheresis or lisocabtagene
maraleucel administration
• History of any one of the following cardiovascular conditions within the past 6
months: Class III or IV heart failure as defined by the New York Heart Association,
cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other
clinically significant cardiac disease
• History or presence of clinically relevant CNS pathology
• Pregnant or nursing women
• Subject does not meet protocol-specified washout periods for prior treatments
• Prior hematopoietic stem cell transplant
• Progressive vascular tumor invasion, thrombosis, or embolism
• Venous thrombosis or embolism not managed on stable regimen of anticoagulation
• Uncontrolled medical, psychological, familial, sociological, or geographical
conditions
A Study of Nivolumab + Brentuximab Vedotin in Children, Adolescents, and Young Adults With Classic Hodgkin Lymphoma (cHL) After Failure of First Line Therapy, Followed by Brentuximab Vedotin + Bendamustine for Participants With a Suboptimal Response (CheckMate 744)
The purpose of this study is to determine whether nivolumab + brentuximab vedotin, followed
by brentuximab vedotin + bendamustine for participants with a suboptimal response, is safe
and effective in the treatment of classic Hodgkin lymphoma (cHL) in children, adolescents,
and young adults after failure of first line therapy.
For more information regarding Bristol-Myers Squibb Clinical Trial participation, please
visit www.BMSStudyConnect.com
Inclusion Criteria:
• Classic Hodgkin Lymphoma (cHL), relapsed or refractory
• Minimal limitation on activities of daily living as measured by Karnofsky ≥ 50 for
participants > 16 years of age or Lansky ≥ 50 for participants ≤ 16 years of age.
• One prior anti-cancer therapy that did not work
Exclusion Criteria:
• Active, known, or suspected autoimmune disease or infection
• Active cerebral/meningeal disease related to the underlying malignancy
• More than one line of anti-cancer therapy or no treatment at all
• Received a stem cell transplant for Hodgkin Lymphoma and/or a solid organ transplant
• Prior treatment with any drug that targets T cell co-stimulation pathways (such as
checkpoint inhibitors)
Other protocol defined inclusion/exclusion criteria could apply
Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients (BIANCA)
The purpose of the study is to assess the efficacy and safety of tisagenlecleucel in children
and adolescents with relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). For
pediatric patients who have r/r B-NHL, survival rates are dismal, only ~20-50% subjects are
alive at 2 years with overall response rate (ORR) of 20-30% after conventional salvage
chemotherapy.
• Histologically confirmed pediatric mature B-cell non-Hodgkin lymphoma (B-cell NHL)
including the following subtypes; Burkitt lymphoma/ Burkitt leukemia (BL), diffuse
large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), gray zone
lymphoma (GZL), and follicular lymphoma (FL) Note: Patients with B-cell NHL associated
with Nijmegen breakage syndrome will be allowed.
• Patients <25 years of age and weighing at least 6 kg at the time of screening
• Patients who have relapsed after one or more prior therapies (can include allogeneic
and autologous hematopoietic stem cell transplant) or are primary refractory (have not
achieved a CR or PR after the first line of therapy)
• Measurable disease by radiological criteria in all patients at the time of screening.
Patients with Burkitt leukemia who don't meet radiological criteria must have bone
marrow involvement of >25% by local assessment of bone marrow aspirate and/or biopsy.
• Karnofsky (age ≥16 years) or Lansky (age <16 years) performance status ≥60.
• Adequate bone marrow reserve without transfusions (transfusion >2 weeks prior to
laboratory assessment is allowed) defined as:
1. Absolute neutrophil count (ANC) >1000/mm3
2. Platelets ≥50000//mm3
3. Hemoglobin ≥8.0 g/dl
• Adequate organ function defined as:
1. a serum creatinine (sCR) based on gender/age as follows: Maximum Serum Creatinine
(mg/dL) Age Male Female
1 to <2 years 0.6 0.6 2 to <6 years 0.8 0.8 6 to <10 years 1.0 1.0 10 to <13
years 1.2 1.2 13 to <16 years 1.5 1.4
≥16 years 1.7 1.4
2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 times the
upper limit of normal (ULN) for age
3. Total bilirubin <2 mg/dL (for Gilbert's Syndrome patients total bilirubin <4
mg/dL)
4. Adequate pulmonary function
i. Oxygen saturation of >91% on room air ii. No or mild dyspnea (≤Grade 1)
• Must have a leukapheresis material of non-mobilized cells accepted for manufacturing.
Exclusion Criteria:
• Prior gene therapy or engineered T cell therapy.
• Prior treatment with any anti-CD19 therapy.
• Allogeneic hematopoietic stem cell transplant (HSCT) <3 months prior to screening and
≤4 months prior to infusion.
• Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD)
in patients who received prior allogeneic HSCT.
• Prior diagnosis of malignancy other than study indication, and not disease free for 5
years.
• Clinically significant active infection confirmed by clinical evidence, imaging, or
positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
• Presence of active hepatitis B or C as indicated by serology.
• Human Immunodeficiency Virus (HIV) positive test.
• Active neurological autoimmune or inflammatory disorders not related to B cell NHL
(eg: Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis)
• Active central nervous system (CNS) involvement by malignancy.
• Patients with B-cell NHL in the context of post-transplant lymphoproliferative
disorders (PTLD) associated lymphomas.
Other protocol-defined inclusion/exclusion criteria may apply.
Biological: Tisagenlecleucel
Non-hodgkin Lymphoma, Non-Hodgkins Lymphoma
Tisagenlecleucel, relapsed/refractory B-cell non-Hodgkin lymphoma, pediatric patients, Burkitt lymphoma (BL), Burkitt leukemia (BL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), gray zone lymphoma (GZL), follicular lymphoma (FL), leukapheresis, lymphodepleting chemotherapy (LD), NHL
Inclusion Criteria
Each prospective subject must meet ALL of the following inclusion criteria in order to be
eligible for this study:
1. Signed written informed consent granted prior to initiation of any study-specific
procedures.
2. 18 years of age and older.
3. For the dose escalation cohorts, relapsed or refractory subjects with a diagnosis of
B-cell NHL, CLL/SLL and WM who have received at least two prior systemic therapies .
Subjects must have failed or are intolerant to standard therapies and cannot be a
candidate for standard salvage regimens. Subjects with low grade lymphoma must be
progressing and requiring treatment..
4. For the expansion cohorts, the following criteria must be met:
• Cohort A: Relapsed/Refractory (R/R) CLL/SLL subjects with at least 2 prior
systemic therapies and previously treated with a covalent BTKi who must have a
documented BTK mutation on C481 residue
• Cohort B: R/R CLL/SLL subjects who have failed or were intolerant to a BTKi with
documentation of the absence of BTK mutation on C481 residue. In this study,
intolerance to standard therapy is defined as having experienced a grade 3 or
higher adverse event that was caused by the standard therapy and resulted in
treatment discontinuation.
• Cohort C: Richter's transformation subjects who have failed at least one prior
therapy
• Cohort D: Follicular Lymphoma (FL) subjects who have failed at least 2 prior
systemic therapies and are histology grade 1, 2, or 3A
• Cohort E: Mantle Cell Lymphoma (MCL) subjects who have failed at least 2 prior
systemic therapies
• Cohort F: Marginal Zone Lymphoma (MZL) subjects who have failed at least 2 prior
systemic therapies
• Cohort G: High-grade B-cell lymphoma subjects who have failed at least 2 prior
systemic therapies and have known MYC and BCL2 and/or BCL6 translocations
• Cohort H: Waldenström macroglobulinemia (WM) subjects who have failed at least 2
prior systemic therapies
5. Disease status requirement:
1. For CLL subjects, symptomatic disease that mandates treatment (Hallek et al.
2018).
2. For B-cell NHL subjects, measurable disease by imaging scan.
3. For WM, serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the
upper limit of normal (ULN).
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
7. Good organ function
1. Creatinine clearance of ≥ 60 mL/min as estimated by the Cockcroft-Gault equation
or by 24-hour urine collection.
2. Total bilirubin ≤ 1.5 x institutional ULN (total bilirubin of ≤ 3 x institutional
ULN in subjects with documented Gilbert's syndrome).
3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ×
institutional ULN.
4. Platelet count ≥ 50,000/µL
5. Absolute neutrophil count (ANC) ≥ 1000/µL.
6. Hemoglobin (Hgb) ≥ 8.0 g/dL, stable for ≥ 1 week.
8. For men and women of child-bearing potential, willing to use adequate contraception
(e.g., latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire
duration of the study.
9. Female subjects of child-bearing potential must have a negative serum pregnancy test
within 14 days of the first day of drug dosing.
10. Ability to swallow oral medications without difficulty.
Exclusion Criteria
Potential subjects who meet ANY of the following exclusion criteria are not eligible
for enrollment into this study:
11. Had immunotherapy, radiotherapy, radioimmunotherapy, biological therapy, chemotherapy,
or treatment with an investigational product within 5 half-lives or four weeks
(whichever is shorter) prior to treatment initiation, or oral therapy within 5
half-lives or one week (whichever is shorter) prior to treatment initiation.
12. Transformation of FL to a more aggressive subtype of lymphoma or grade 3b FL
13. Subjects currently being treated with the following drugs:
1. CYP 2C9 substrates with a narrow therapeutic index (such as warfarin, phenytoin)
2. CYP 2C8 substrates with a narrow therapeutic index (such as paclitaxel)
3. CYP 2C19 substrates with a narrow therapeutic index (such as S-mephenytoin)
4. CYP 2D6 substrates with a narrow therapeutic index (such as thioridazine,
pimozide)
5. P-gp substrates with a narrow therapeutic index (such as digoxin) Note: A washout
period of at least 5 times the half-life after the last dose of any of the above
treatments is required for a subject to be eligible for study enrollment.
14. Prior allogeneic bone marrow transplant.
15. Active central nervous system (CNS) involvement.
16. Pregnant or breast-feeding women.
17. Has significant, ongoing co-morbid conditions which would preclude safe delivery of
the study drug.
18. Uncontrolled illness including but not limited to ongoing or active infection,
symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or
IV heart failure), unstable angina pectoris, cardiac arrhythmia, cardiac infarction in
the past six months, and psychiatric illness that would limit compliance with study
requirements.
19. QTc prolongation (defined as a QTc > 450 msecs) or other significant electrocardiogram
(ECG) abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd
degree AV block, or bradycardia (ventricular rate less than 50 beats/min). If the
screening ECG has a QTc > 450 msecs, the ECG can be submitted for a centralized,
cardiologic evaluation.
20. Active human immunodeficiency virus (HIV) infection, Hepatitis B, or Hepatitis C
infection.
21. Other medical or psychiatric illness or organ dysfunction which, in the opinion of the
Investigator, would either compromise the subject's safety or interfere with the
evaluation of the safety of the study agent.
22. History of prior cancer within < 1 year, except for basal cell or squamous cell
carcinoma of the skin, cervical cancer in situ or other in situ carcinomas.
Drug: ARQ 531, Drug: ARQ 531
Lymphoma, B-cell, Waldenström Macroglobulinemia, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Follicular Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma, Diffuse Large B Cell Lymphoma, Richter's Transformation, Lymphoid Leukemia
GEN3013 Trial in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma
The trial is an open-label, multi-center safety trial of epcoritamab GEN3013
(DuoBody®-CD3xCD20). The trial consists of two parts: a dose escalation part phase 1,
first-in-human (FIH) and an expansion part phase 2a.
Main Inclusion Criteria Escalation Part
• Documented CD20+ mature B-cell neoplasm
1. Diffuse large B-cell lymphoma •de novo or transformed
2. High-grade B-cell lymphoma
3. Primary mediastinal large B-cell lymphoma
4. Follicular lymphoma
5. Mantle cell lymphoma
6. Small lymphocytic lymphoma
7. Marginal zone lymphoma (nodal, extranodal or mucosa associated)
• Relapsed, progressive and/or refractory disease following treatment with an anti-CD20
monoclonal antibody (e.g. rituximab) potentially in combination with chemotherapy
and/or relapsed after autologous stem cell rescue.
• ECOG performance status 0,1 or 2
• Patients must have measurable disease by CT, MRI or PET-CT scan
• Acceptable renal function
• Acceptable liver function
Main Inclusion Criteria Expansion Part
• Documented CD20 positive mature B cell neoplasm or CD20+ MCL
• Diffuse large B cell lymphoma, de novo or transformed (including double hit or triple
hit)
• Primary mediastinal large B cell lymphoma
• Follicular lymphoma grade 3B
• Histologic confirmed follicular lymphoma
• Marginal zone lymphomas
• Small lymphocytic lymphoma
• Mantle Cell Lymphoma (prior BTKi or intolerant to BTKi)
• At least 2 therapies including an anti CD20 monoclonal antibody containing
chemotherapy combination regimen
• Either failed prior autologous hematopoietic stem cell transplantation or ineligible
for autologous stem cell transplantation due to age or comorbidities
• At least 1 measurable site of disease based on CT, MRI or PET-CT scan with involvement
of 2 or more clearly demarcated lesions and or nodes
Biological: Epcoritamab
Small Lymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma, Non-Hodgkins Lymphoma, High-grade B-cell Lymphoma, Primary Mediastinal Large B-cell Lymphoma
First-in-Human (FIH) Trial of GEN3009 in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas
The aim of this first-in-human trial is to characterize the safety, tolerability,
pharmacokinetic (PK), and pharmacodynamic characteristics of GEN3009 (DuoHexabody®-CD37) in
subjects with relapsed/refractory B-cell Non-Hodgkin Lymphoma (NHL).
1. Be at least 18 years of age.
2. Must sign an informed consent form prior to any screening procedures.
3. Has histologically or cytologically confirmed relapsed and/or refractory B-cell NHL
with no available standard therapy or is not a candidate for available standard
therapy, and for whom, in the opinion of the investigator, experimental therapy with
GEN3009 may be beneficial. All subjects must have received at least two prior lines of
systemic therapy.
4. Has one of the specified subtypes for B-cell NHL for the Dose Escalation and Dose
Expansion parts of the study.
5. Has measurable disease for B-cell NHL or has active disease for Chronic Lymphocytic
Leukemia (CLL).
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
7. Has adequate hepatic, renal, and bone marrow functions.
8. Before the first dose of GEN3009, during the trial, and for 12 months after the last
dose of GEN3009, a woman must be either not of childbearing potential or of
childbearing potential and practicing a highly effective method of birth control, and
must have a negative serum beta-human chorionic gonadotropin (beta-hCG) and urine
pregnancy test at screening.
9. A man who is sexually active with a woman of childbearing potential and has not had a
vasectomy must agree to use a barrier method of birth control.
Exclusion Criteria:
1. Prior treatment with a CD37-targeting agent.
2. Prior allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
3. Autologous HSCT within 3 months before the first dose of GEN3009.
4. Treatment with an anti-cancer biologic including anti-CD20 therapy, radio-conjugated
or toxin-conjugated antibody or chimeric antigen receptor (CAR) T-cell therapy within
4 weeks or 5 half-lives, whichever is shorter, before the first dose of GEN3009.
5. Chemotherapy or radiation therapy within 2 weeks of the first dose of GEN3009.
6. Treatment with an investigational drug or an invasive investigational medical device
within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of
GEN3009.
7. Autoimmune disease or other diseases that require permanent or high-dose
immunosuppressive therapy.
8. Received a cumulative dose of corticosteroids more than the equivalent of 250 mg of
prednisone within the 2-week period before the first dose of GEN3009.
9. Has uncontrolled intercurrent illness.
10. Toxicities from previous anti-cancer therapies have not resolved to baseline levels or
to Grade 1 or less except for alopecia and peripheral neuropathy.
11. Primary central nervous system (CNS) lymphoma or known CNS involvement at screening.
12. Known past or current malignancy other than inclusion diagnosis,
13. Has had major surgery within 3 weeks before screening or will not have fully recovered
from surgery, or has major surgery planned during the time the subject is expected to
participate in the trial (or within 4 weeks after the last dose of GEN3009).
14. Known history/positive serology for hepatitis B.
15. Known medical history or ongoing hepatitis C infection that has not been cured.
16. HIV tested positive at screening.
17. Is a woman who is pregnant or breast-feeding, or who is planning to become pregnant
while enrolled in this trial or within 12 months after the last dose of GEN3009.
18. Is a man who plans to father a child while enrolled in this trial or within 12 months
after the last dose of GEN3009.
A Study of ME-401 in Subjects With CLL/SLL, FL, and B-cell Non Hodgkin's Lymphoma
A Three-Arm Study of ME-401 in Subjects with Relapsed/Refractory CLL/SLL or FL, of ME-401 in
Combination with Rituximab in Subjects with Relapsed/Refractory CLL/SLL or B-cell NHL, and of
ME-401 in Combination with Zanubrutinib in Subjects with Relapsed/Refractory CLL/SLL or
B-cell NHL
Inclusion Criteria MEI-401 Alone:
• Diagnosis of relapsed/refractory CLL and/or relapsed/refractory SLL or FL
• No prior therapy with PI3Kd inhibitors
• No prior therapy with Bruton tyrosine kinase (BTK) inhibitors unless the subject was
intolerant of BTK therapy or subject had disease progression
• Subjects with CLL/SLL must have prior treatment with BTK inhibitor and must have had
progression or recurrence while on treatment of within 12 mos from BTK treatment
• Subject must have failed at least 1 prior systemic therapy
• QT-interval corrected according to Fridericia's formula (QTcF) ≤ 450 milliseconds (ms)
• Left ventricular ejection fraction > 50%
• For subjects, except those with CLL, must have at least one bi-dimensionally
measurable nodal lesion >1.5 cm, as defined by Lugano Classification
• Willingness to participate in collection of pharmacokinetic samples
• A negative serum pregnancy test within 14 days of study Day 0, for females of
childbearing potential
Inclusion Criteria ME-401 in Combination with Rituximab
• Diagnosis of relapsed/refractory CLL SLL or FL, MZL, DLBCL and high-grade B-cell
lymphoma. Subjects must meet the following criteria for relapsed or refractory
disease:
• No prior therapy with PI3Kδ inhibitors
• No prior therapy with Bruton tyrosine kinase (BTK) inhibitors unless the subject was
intolerant of BTK therapy or subject had disease progression
• Subjects with CLL, SLL, FL, and MZL must have a failure of at least 1 prior systemic
therapy and be considered by the investigator a candidate for therapy with a
rituximab-based regimen; subjects with DLBCL and high-grade B-cell lymphoma must have
a failure of at least 2 prior therapies.
• QT-interval corrected according to Fridericia's formula (QTcF) ≤450 milliseconds (ms)
• Left ventricular ejection fraction > 50%
• For subjects, except those with CLL, must have at least one bi-dimensionally
measurable nodal lesion >1.5 cm, as defined by Lugano Classification
• Willingness to participate in collection of pharmacokinetic samples
• A negative serum pregnancy test within 14 days of study Day 0 for females of
childbearing potential
Inclusion Criteria ME-401 in Combination with Zanubrutinib
• Diagnosis of relapsed/refractory CLL or histologically-confirmed relapsed/refractory
SLL or FL, MZL, MCL, DLBCL NOS (germinal center B-cell type or activated B-cell type)
• No prior therapy with PI3Kδ inhibitors
• No prior therapy with BTK inhibitors
• Subjects with CLL, SLL, FL, MCL, and MZL must have a failure of at least 1 prior
systemic therapy, require treatment in the opinion of the investigator, and be
considered by the investigator a candidate for therapy subjects with DLBCL and
high-grade B-cell lymphoma must have a failure of at least 2 prior therapies
• For subjects with SLL, FL, MZL, MCL, DLBCL: At least one bi dimensionally measurable
nodal lesion > 1.5 cm in its longest diameter by CT scan or MRI
• QT-interval corrected according to Fridericia's formula (QTcF) ≤ 450 milliseconds
(msec)
• Left ventricular ejection fraction > 50% as measured by echocardiogram or multigated
acquisition (MUGA) scan
• Willingness to participate in collection of pharmacokinetic samples
• For females of childbearing potential, a negative serum pregnancy test within 14 days
of study Day 0
Exclusion Criteria:
• Known histological transformation from CLL to an aggressive lymphoma
• Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
• Subjects who have tested positive for hepatitis B surface antigen and/or hepatitis B
core antibody
• Positive for hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV)
antibody
• Ongoing drug-induced pneumonitis
• History of clinically significant cardiovascular abnormalities
• History of severe bleeding disorders (ME-401 plus zanubrutinib arm only)
• Known central nervous system (CNS) hemorrhage or stroke within 6 months prior to start
of study drugs (ME-401 plus zanubrutinib arm only)
Drug: ME-401, Drug: Rituximab, Drug: Zanubrutinib
Chronic Lymphocytic Leukemia (CLL), Lymphoid Leukemia, Non-Hodgkins Lymphoma, Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), Marginal Zone B Cell Lymphoma, Diffuse Large B-cell Lymphoma (DLBCL), High Grade Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma (MCL)
Lenalidomide and Blinatumomab for the Treatment of Relapsed Non-Hodgkin Lymphoma
This phase I trial studies the side effects and best dose of lenalidomide and blinatumomab
when given together in treating patients with non-Hodgkin lymphoma that has returned after a
period of improvement (relapsed). Biological therapies, such as lenalidomide, use substances
made from living organisms that may stimulate or suppress the immune system in different ways
and stop cancer cells from growing. Blinatumomab is a monoclonal antibody that may interfere
with the ability of cancer cells to grow and spread.
• Histologically or cytologically confirmed relapsed cluster of differentiation (CD)19+
non-Hodgkin lymphoma (NHL) (included in this category are follicular grade I, II, III,
marginal zone, mantle cell, gray zone, primary mediastinal, Burkitt's, diffuse large B
cell, small lymphocytic lymphoma); patients previously treated with CD19-targeted
therapy (including chimeric antigen receptor T-cells [CAR T]) must have a subsequent
biopsy and/or flow cytometry confirming CD19 positivity
• Karnofsky >= 60%
• Life expectancy of greater than 12 weeks
• Absolute neutrophil count > 1000/mcL
• Platelets >= 50,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal
• AST (SGOT)/ALT(SGPT) (only if elevated liver function tests [LFTs] are due to disease)
=< 5.0 x institutional upper limit of normal
• Body surface area (BSA)-normalized creatinine clearance >= 60 mL/min/1.73 m^2 (using
Cockcroft-Gault creatinine clearance [CrCl])
• Patients must have had at least two prior chemotherapeutic or biologic (e.g. rituximab
alone) regimens and not currently eligible for standard curative options; steroids
alone and local radiation do not count as regimens; radiation to > 1 site and
transplant are considered prior regimens
• Any prior therapy must have been completed at least 4 weeks prior to entry into the
study
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 25 mIU/mL within 10 •14 days prior to and again
within 24 hours of starting lenalidomide and must either commit to continued
abstinence from heterosexual intercourse or begin TWO acceptable methods of birth
control, one highly effective method and one additional effective method AT THE SAME
TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to
ongoing pregnancy testing; men must agree to use a latex condom during sexual contact
with a FCBP even if they have had a successful vasectomy; all patients must be
counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal
exposure
• Patients must have radiographically measurable disease; radiographically measurable
disease is defined as at least one lesion that can be accurately measured in at least
one dimension (longest diameter to be recorded) as > 20 mm with conventional
techniques or as > 10 mm with spiral computed tomography (CT) scan; lesions in
previously irradiated anatomic areas (external beam radiation) cannot be considered
target lesions unless there has been documented growth of those lesions after
radiotherapy
• Ability to understand and the willingness to sign a written informed consent document
• Human immunodeficiency virus (HIV) infected patients are eligible provided they meet
all the other eligibility criteria of the study in addition to the following:
• During prior lymphoma therapy, patients must not have experienced documented
infections attributed to the HIV+ status
• No history of non-adherence to cART and willing to adhere to cART while on study
• Antiretroviral drugs with overlapping or similar toxicity profiles as study
agents not allowed:
• Efavirenz not allowed due to potential central nervous system (CNS) toxicity
• Stavudine not allowed due to potential neuropathic effects
• Zidovudine not allowed due to myelosuppressive effects
• Patients must be willing to be followed at a minimum of approximately every 3
months by physician expert in HIV disease management
• Patients must be willing to be followed at a minimum of approximately every 3 months
by physician expert in HIV disease management
Exclusion Criteria:
• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier
• Patients who are receiving any other investigational agents
• Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events
• History of allergic reactions attributed to compounds of similar chemical or biologic
composition to lenalidomide and blinatumomab or other agents used in study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
• Pregnant women are excluded from this study because lenalidomide is an agent with the
potential for teratogenic or abortifacient effects; because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with lenalidomide, breastfeeding should be discontinued if the mother is
treated with lenalidomide
• Concurrent use of other anti-cancer agents or treatments
• Known active hepatitis, type B or C; patients on suppressive therapy with a negative
viral load and no evidence of hepatic damage are eligible
• Prior treatment with lenalidomide within 8 weeks prior to entering the study
Biological: Blinatumomab, Drug: Lenalidomide
Recurrent Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Non-Hodgkin Lymphoma, Recurrent Non-Hodgkin Lymphoma, Refractory Mantle Cell Lymphoma, Recurrent B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma, Recurrent Burkitt Lymphoma, Refractory B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma, Refractory Burkitt Lymphoma, Recurrent Mediastinal Lymphoma, Refractory Follicular Lymphoma, Refractory Marginal Zone Lymphoma, Refractory Mediastinal Lymphoma, Refractory Small Lymphocytic Lymphoma, Non-Hodgkins Lymphoma, Recurrent Grade 3a Follicular Lymphoma, Recurrent Grade 3b Follicular Lymphoma, Refractory Grade 1 Follicular Lymphoma, Refractory Grade 2 Follicular Lymphoma, Refractory Grade 3 Follicular Lymphoma, Refractory Grade 3a Follicular Lymphoma
A Trial of Temsirolimus With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma
This is a phase I study of temsirolimus (Torisel) combined with dexamethasone,
cyclophosphamide and etoposide in patients with relapsed acute lymphoblastic leukemia (ALL),
lymphoblastic lymphoma (LL) or peripheral T-cell lymphoma (PTL).
INCLUSION CRITERIA
-Patients must be greater than or equal to 12 months and ≤ 21 years of age at the time of
study enrollment.
Patients must have one of the following:
Leukemia
• Patients must have relapsed or refractory acute lymphoblastic leukemia (ALL) with
greater than or equal to 25% blasts in the bone marrow (M3). OR
• Patients may have an M2 marrow (greater than or equal to 5% to < 25% blasts) with an
extramedullary site of relapse; including CNS 2 and CNS 3.
• Refractory disease defined as no more than 1 prior failed salvage attempt following
the current relapse, or no more than 2 additional treatment cycles after initial
induction failure in newly diagnosed patients.
Lymphoma
• Patient must have relapsed or refractory lymphoblastic lymphoma or peripheral T-cell
lymphoma.
• Patient must have histologic verification of disease at original diagnosis.
• Patient must have evaluable or measurable disease documented by clinical or
radiographic criteria or bone marrow disease present at study entry.
• Patients may have CNS 2 or 3 disease, if other sites of involvement.
Karnofsky greater than or equal to 50% for patients > 16 years of age and Lansky greater
than or equal to 50 for patients ≤ 16 years of age.
Patients must have fully recovered from the acute toxic effects of all prior anti-cancer
chemotherapy.
Patients must have had 2 or more prior therapeutic attempts defined as:
• Relapse after going into remission from re-induction for the first or subsequent
relapse (ie: 2nd , 3rd, 4th…relapse), or
• Patients with lymphoma may have refractory disease after first or greater relapse and
a single re-induction attempt.
Patients with leukemia or lymphoma who relapse while receiving maintenance chemotherapy
will not be required to have a waiting period before enrollment onto this study.
At least 14 days must have elapsed after the completion of cytotoxic therapy, with the
exception of hydroxyurea.
Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth
factor (e.g. Neulasta) or 7 days for short-acting growth factor.
Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent.
For agents that have known adverse events occurring beyond 7 days after administration,
this period must be extended beyond the time during which adverse events are known to
occur. The duration of this interval must be discussed with the study chair
Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g.
tumor vaccines. or chimeric antigen receptor T cell (CART) therapy.
Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the
last dose of a monoclonal antibody. (ie: Rituximab = 66 days, Epratuzumab = 69 days).
Patients must have been off blinatumomab infusion for at least 7 days and all drug-related
toxicity must have resolved to grade 2 or lower as outlined in the inclusion and exclusion
criteria
XRT: At least 14 days after local palliative XRT (small port); At least 84 days must have
elapsed if prior TBI, craniospinal XRT or if greater than or equal to 50% radiation of
pelvis; At least 42 days must have elapsed if other substantial marrow radiation.
Stem Cell Infusion: No evidence of active graft vs. host disease and at least 84 days must
have elapsed after transplant or stem cell infusion.
Study specific limitations on prior therapy: Patient may not have received therapy with an
mTOR inhibitor.
Adequate Bone Marrow Function Defined as: Blood counts are not required to be normal prior
to enrollment on trial. However, platelet count must be greater than or equal to
20,000/mm3 to initiate therapy (may receive platelet transfusions). Patients should not be
known to be refractory to red blood cell or platelet transfusions.
Adequate Renal Function Defined as:
• Creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2 or
• Normal serum creatinine based on age and gender.
Adequate Liver Function Defined as:
• Total bilirubin (sum of conjugated + unconjugated) must be less than or equal to 1.5
x normal per institutional normal values for age.
• SGPT (ALT) and SGOT (AST) must be less than 3 x institutional upper limit of normal
(Grade 1 or less per CTCAE 4).
--GGT must be less than 2.5 x institutional upper limit of normal (Grade 1 or less
per CTCAE 4).
• Serum albumin greater than or equal to 2 g/dL.
• The hepatic requirements may be waived for patients with elevations clearly due to
leukemic infiltration after consultation with the Study Chair or Vice Chair.
• Fasting or non-fasting serum triglyceride level ≤ 300 mg/dL and serum cholesterol
level ≤ 300 mg/dL.
Adequate Cardiac Function Defined As:
• Shortening fraction of ≥ 27% by echocardiogram, or
• Ejection fraction of ≥ 50% by gated radionuclide study.
Adequate Pulmonary Function Defined as:
• Pulse oximetry > 94% on room air (> 90% if at high altitude)
• No evidence of dyspnea at rest and no exercise intolerance.
• Baseline chest x-ray with no evidence of active infectious disease or pneumonitis.
Reproductive Function
• Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this
study.
• Male and female patients of child-bearing potential must agree to use an effective
method of contraception approved by the investigator during the study.
• Random or fasting glucose within the upper limits of normal for age. If the initial
blood glucose is non-fasting and above normal limits a fasting glucose can be
obtained and must be within the upper limits of normal for age.
EXCLUSION CRITERIA
• Corticosteroids: Patients receiving corticosteroids who have not been on a stable or
decreasing dose of corticosteroid for at least 7 days prior to enrollment are not
eligible.
• Investigational Drugs: Patients who are currently receiving another investigational
drug are not eligible. The definition of "investigational" for use in this protocol
means any drug that is not licensed by the FDA, Health Canada or the Therapeutic
Goods Administration to be sold in the countries they govern. (United States, Canada
and Australia)
• Anti-cancer Agents: Patients who are currently receiving or may receive while on
therapy, other anti-cancer agents, radiation therapy or immunotherapy are not
eligible [except leukemia patients receiving hydroxyurea, which may be continued
until 24 hours prior to start of protocol therapy]. Intrathecal chemotherapy (at the
discretion of the primary oncologist) may be given up to one week prior to the
initiation of study therapy.
• Anti-GVHD or agents to prevent organ rejection post-transplant: Patients who are
receiving cyclosporine, tacrolimus or other agents to prevent either
graft-versus-host disease post bone marrow transplant or organ rejection post
transplant are not eligible for this trial. At least 3 half-lives must have elapsed
after the last dose of GVHD meds.
• Anticoagulants: Patients who are currently receiving therapeutic anticoagulants
(including aspirin, low molecular weight heparin, and others) are not eligible. At
least 3 half-lives must have elapsed after the last dose of anticoagulants.
• Angiotensin-converting enzyme (ACE) inhibitors: Patients who are currently receiving
ACE inhibitors are not eligible due to the development of angioneurotic edema-type
reactions in some subjects who received concurrent treatment with temsirolimus + ACE
inhibitors. At least 3 half-lives must have elapsed after the last dose of ACE
inhibitors.
• Enzyme inducing Anti-convulsants: Patients who are currently receiving enzyme
inducing anticonvulsants (ie phenytoin, phenobarbitol, or carbamazepine) are not
eligible. Stabilizing on a non-hepatic inducing metabolizing anti-convulsant (ie:
gabapentin or levetiracetam) prior to study entry is acceptable. At least 3
half-lives must have elapsed after the last dose of enzyme inducing anti-coagulants.
• Patients receiving treatment with azoles such as fluconazole or voriconazole which
are potent inhibitors of temsirolimus metabolism. At least 3 half-lives must have
elapsed after the last dose of azoles.
Infection Criteria
Patients are excluded if they have:
• Positive blood culture within 48 hours of study enrollment;
• Fever above 38.2 within 48 hours of study enrollment with clinical signs of
infection. Fever that is determined to be due to tumor burden is allowed if patients
have documented negative blood cultures for at least 48 hours prior to enrollment and
no concurrent signs or symptoms of active infection or hemodynamic instability.
• A positive fungal culture within 30 days.
• Active fungal, viral, bacterial, or protozoal infection requiring IV treatment.
Chronic prophylaxis therapy to prevent infections is allowed.
Patients with Down syndrome and Fanconi Anemia are excluded.
Patients will be excluded if they have significant concurrent disease, illness,
psychiatric disorder or social issue that would compromise patient safety or compliance
with protocol treatment or required observations, interfere with consent, study
participation, follow up, or interpretation of study results.
Patients with known optic nerve and/or retinal involvement (because it may not be possible
to safely delay irradiation) are not eligible. Patients presenting with visual
disturbances by history or physical exam should have an ophthalmological exam and, if
indicated, an MRI to determine optic nerve or retinal involvement.
PK,PD, Safety and Tolerability of Multiple Dose Regimens of MT-3724 With Lenalidomide for the Treatment of Patients With Relapsed/Refractory Diffuse Large B Cell Non-Hodgkin's Lymphoma (MT-3724_NHL_003)
The purpose of this study is to evaluate the safety and tolerability of MT-3724 in
combination with Lenalidomide in subjects with relapsed or refractory B-Cell NHL.
• Subjects must meet ALL the following criteria to be eligible for the study.
1. Be adequately informed about the study and fully consent to participation as
demonstrated by signing the written informed consent form before any screening
procedure.
2. Men or Women , age 18 years or older Have relapsed or refractory B-cell NHL that,
in the investigator's opinion, could benefit from MT-3724+LEN therapy.
3. At least one histology documented relapse of NHL by:
1. Bone marrow biopsy (FNA is not acceptable)
2. Excisional lymph node biopsy or
3. Core biopsy of any involved organ (FNA not acceptable)
4. CD20-positive histology must have been confirmed at any time during NHL
disease course and documented in the medical history.
5. If no histology is available after any relapse the investigator can consult
the medical monitor to discuss if the patient can be included
4. All subtypes of B-cell NHL may be considered for Part 1 (MT-3724 dose
escalation). Only histologically documented DLBCL (including mixed histology) may
be considered for Part 2 (expansion cohort)
5. Have received all available approved therapies for NHL. Those subjects who are
ineligible for approved therapies in the opinion of the investigator, or have
refused such therapies, will be eligible.
6. Have measurable disease by Lugano Classification for NHL (see Appendix 4):
1. >1.5 cm longest diameter (LDi) for lymph nodes
2. >1.0 cm LDi for extra nodal disease.
7. Eastern Cooperative Oncology Group (ECOG) performance score of ≤2
8. Have adequate bone marrow function, as determined by all the following:
1. Absolute neutrophil count (ANC) ≥1,000/mm³
2. Platelet count ≥50,000 mm³
9. Have adequate kidney function, assessed by the estimated glomerular filtration
rate (eGFR) ≥60 mL/min calculated by the CPK-EPI equation.
a. At the investigator's discretion, the eGFR result <60 mL/min may be verified
by measurement of creatinine clearance (CLcr) based on the 24-hour urine
collection. Subjects with CLcr ≥60 mL/min will be eligible irrespective of the
eGFR result.
10. Have adequate hepatic function, as determined by:
1. Total bilirubin ≤1.5 x ULN, or ≤3 x ULN for subjects with Gilbert's
Syndrome) and
2. AST ≤3 x ULN and
3. ALT ≤3 x ULN
11. Have adequate coagulation, as determined by:
1. INR or PT ≤1.5 x ULN
2. PTT ≤1.5 x ULN
12. Have adequate serum albumin, as determined by:
a. Albumin ≥ 3.0 g/dL
13. Women of reproductive potential must have a negative pregnancy test on 2
occasions during the screening period (within 10-14 days and within 24 hours
before the start of treatment). Women not of reproductive potential are female
subjects who are postmenopausal or permanently sterilized (e.g., hysterectomy,
bilateral salpingectomy).
14. Males must agree to always use a latex or synthetic condom during any sexual
contact with females of reproductive potential while taking LEN and for up to 4
weeks after discontinuing LEN, even if they have undergone a successful
vasectomy. Male patients taking LEN must not donate sperm.
15. Subjects of reproductive potential and their partners must agree to either to
abstain continuously from heterosexual intercourse or to use 2 methods of
reliable birth control simultaneously to begin 4 weeks prior to initiating
treatment with LEN until 28 days after the last dose of MT-3724 or LEN. The
investigator or a designated associate should advise the subject how to achieve
adequate contraception. The following birth control methods may be considered:
one highly effective form of contraception •tubal ligation, IUD, hormonal (birth
control pills, injections, hormonal patches, vaginal rings, or implants), or
partner's vasectomy, and one additional effective contraceptive method •male
latex or synthetic condom, diaphragm, or cervical cap.
Exclusion Criteria:
• Subjects who meet any of the following criteria must be excluded from the study.
Medical and surgical history
1. History or current evidence of neoplastic disease that is histologically distinct from
NHL, except cervical carcinoma in situ, superficial noninvasive bladder tumors,
curatively treated Stage I-II non-melanoma skin cancer or any previous cancer
curatively treated >2 years before the start of treatment.
2. Current evidence of new or growing brain or spinal metastases during screening.
Subjects with known brain or spinal metastases may be eligible if they
1. Had radiotherapy or another appropriate therapy for the brain or spinal
metastases
2. Have no neurological symptoms (excluding Grade ≤2 neuropathy)
3. Have stable brain or spinal disease on the CT or MRI scan within 1 month of
enrollment
4. Do not require chronic steroid therapy
3. History of allogeneic hematopoietic stem cell transplant within 180 days before the
start of treatment.
4. Current evidence of acute or chronic Graft versus Host Disease.
5. Current evidence of CTCAE Grade >1 toxicity (except for hair loss, and those
toxicities listed in other eligibility criteria) before the start of treatment.
6. Current evidence of incomplete recovery from surgery before the start of treatment, or
planned surgery at any time during the study until the EoT Visit, except minor
elective interventions deemed acceptable by the investigator.
7. History or current evidence of significant (CTCAE Grade ≥2) infection or wound within
4 weeks before the start of treatment.
8. History or current evidence of significant cardiovascular disease including, but not
limited to the following conditions:
1. Unstable angina (symptoms of angina at rest) or new-onset angina within ≤3 months
before the start of treatment.
2. Arterial thrombosis or pulmonary embolism within ≤3 months before the start of
treatment.
3. Myocardial infarction or stroke within ≤3 months before the start of treatment.
4. Pericarditis (any CTCAE grade), pericardial effusion (CTCAE Grade ≥2), non
malignant pleural effusion (CTCAE Grade ≥2) or malignant pleural effusion (CTCAE
Grade ≥3).
5. Congestive heart failure (NYHA Class III or IV) at screening or LVEF <45%,
assessed by Echo or MUGA scan within 1 month before starting study treatment.
(Echo or MUGA scan performed within 6 months before screening and at least 28
days after the last cancer therapy is acceptable provided the subject has not
received any potential cardiotoxic agents).
6. Cardiac arrhythmia requiring anti-arrhythmic therapy at screening. Subjects
receiving digoxin, calcium channel blockers, or beta-adrenergic blockers are
eligible at the investigator's discretion after consultation with Medical Monitor
if the dose has been stable for ≥2 weeks before the start of treatment. Subjects
with sinus arrhythmia and infrequent premature ventricular contractions are
eligible at the investigator's discretion.
9. QTcF (Fridericia) >480 ms, determined as the average from three QTcF values on the
triplicate ECG obtained at screening.
10. Current evidence of seropositive status for HIV, hepatitis B (positive for HBsAg or
anti-HBsAg and anti-HBcAg antibodies) or hepatitis C (positive for anti-HCV antibody
or HCV-RCV-RNA quantitation) as assessed by the applicable serology testing at
screening.
1. Serology testing is not required if seronegativity is documented in the medical
history and there are no clinical signs suggestive of HIV or hepatitis infection.
2. Subjects with positive HBV serology are eligible if quantitative PCR for plasma
HBV-DNA is negative and the subject will be receiving prophylaxis for potential
HBV reactivation.
3. Subjects with positive HCV serology are eligible if quantitative PCR for plasma
HCV RNA is negative.
11. Women who are pregnant or breastfeeding.
12. History or current evidence of hypersensitivity to any of the study drugs, or of
current hypersensitivity requiring systemic steroids at doses >20 mg/day prednisone
equivalent.
13. History or current evidence of any other medical or psychiatric condition or addictive
disorder, or laboratory abnormality that, in the opinion of the investigator, may
increase the risks associated with study participation, or require treatments that may
interfere with the conduct of the study or the interpretation of study results.
Prior treatments
14. Received anti-CD20 monoclonal antibody (Mab) therapy within the following periods
before the start of treatment
1. Rituximab (Rituxan®): 84 days; if a subject had received rituximab within 37
Weeks before the start of treatment, then a serum rituximab level must be
negative (<500 ng/mL) at screening.
2. Obinutuzumab (Gazyva®): 184 days
3. Ofatumumab (Arzerra®): 88 days
15. Received therapy for NHL (except the anti-CD20 Mab therapies listed above) within 4
weeks before the start of treatment.
16. Any investigational drug treatment from 4 weeks or 5 half-lives of the agent before
the start of treatment, whichever is longer, until the EoT Visit.
17. Received radiotherapy to tumor lesions that would be chosen as target lesions
(measurable disease) within 4 weeks before the start of treatment, unless the lesion
exhibited objective progression between the radiotherapy and the screening according
to the Lugano Classification for NHL.
a. Palliative radiotherapy to non-target lesions is allowed at the investigator's
discretion.
18. Received any vaccines within 28 days of the start of treatment, or likely to require
vaccines at any time from the start of treatment until 28 days after the last dose of
MT-3724. Injectable flu vaccine (inactivated or recombinant) is permitted at the
investigator's discretion.
19. Received systemic immune modulators within 2 weeks before the start of treatment
1. Systemic immune modulators include but are not limited to systemic
corticosteroids at doses >20 mg/day of prednisone equivalent, cyclosporine and
tacrolimus.
2. The use of non-steroidal anti-inflammatory drugs (NSAIDs) is permitted
Drug: MT-3724
Non-hodgkin Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Relapsed Diffuse Large B-Cell Lymphoma, Non-Hodgkins Lymphoma
Venetoclax and Selinexor in Treating Patients With Relapsed or Refractory High Risk Hematologic Malignancies
This phase Ib trial studies the toxicity and dosing of venetoclax in combination with
selinexor, and how well the combination works in treatment of patients with high risk
hematologic malignancies such as diffuse large B-cell lymphoma and acute myeloid leukemia
that has come back (recurrent) or does not respond to initial treatment (refractory).
Venetoclax functions by inhibiting a protein in the body called bcl-2, which is involved in
slowing down the normal process by which old cells in the body are cleared (called
apoptosis). Selinexor functions by trapping "tumor suppressing proteins" within the cell and
causing the cancer cells to die or stop growing. This study examines the effects, if any, of
selinexor and venetoclax on high risk hematologic malignancies and on the body, including any
side-effects.
• Written informed consent in accordance with federal, local, and institutional
guidelines. The patient must provide informed consent prior to the first screening
procedure.
• Age ≥ 18 years
• Life expectancy > 12 weeks.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Histologically confirmed diagnosis of one of the following, in accordance with WHO
diagnostic criteria:
• Escalation:
• Diffuse Large B-cell Lymphoma (DLBCL, including primary mediastinal large B cell
lymphoma, T cell rich B cell lymphoma, and high-grade B cell lymphoma NOS).
Patients with Burkitt's, lymphoblastic lymphoma, follicular lymphoma, and mantle
cell lymphoma are not included. OR
• Acute Myeloid Leukemia (AML)
• Expansion:
• Diffuse Large B-cell Lymphoma and acute myeloid leukemia as above.
• VEN Refractory expansion cohort (Diffuse Large B-cell Lymphoma and acute myeloid
leukemia only): Patients must have previously received and failed venetoclax
therapy (either monotherapy or combination) during their treatment course (i.e.,
patients may receive non-VEN therapy immediately prior to enrollment on this
study). Treatment failure is defined as evidence of disease progression after ≥ 1
cycle (four weeks) of full-intensity venetoclax-based therapy (i.e., 28 days
exclusive of ramp-up. Patients that require dose reductions due to intolerance
may be considered for this cohort after discussion with the sponsor.)
• Relapsed or refractory following ≥ 1 line(s) of prior therapy
• Patients that relapse ≥ 3 months after allogeneic hematopoietic cell transplantation
(HCT) are eligible.
• Female patients of childbearing potential must agree to use two methods of
contraception (including one highly effective and one effective method of
contraception) and have a negative serum pregnancy test at screening. Male patients
must use an effective barrier method of contraception if sexually active with a female
of childbearing potential. For both male and female patients, effective methods of
contraception must be used throughout the study and for 3 months following the last
dose of study treatment.
• For leukemia and DLBCL with known or suspected marrow involvement, patients must have
at least 10-15 mL of bone marrow aspirate material obtained within 14 days of
beginning treatment on this study. Patients with DLBCL must have 3-5 unstained slides,
or tissue block, available for evaluation within 14 days of study enrollment in the
expansion cohorts. DLBCL patients enrolled during the escalation phase must have
blocks available for submission within 28 days of beginning treatment.
• CBC testing must confirm adequate marrow reserve, as demonstrated by:
• DLBCL: Hgb ≥ 10g/dL, platelets ≥ 75,000 cells/mm3 , ANC ≥ 1,000 cells/mm3
• Adequate organ function, as demonstrated by:
• Total bilirubin < 1.5 x upper limit of normal (ULN) (except patients with
Gilbert's syndrome (hereditary indirect hyperbilirubinemia), who must have a
total bilirubin of < 3 x ULN, and
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to < 2
x ULN
• Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula).
• Patients with laboratory evidence of liver or kidney dysfunction secondary to
underlying disease, that is expected to reverse with treatment, may be enrolled after
discussion with the sponsor/investigator.
Exclusion Criteria:
• Patients who are pregnant or lactating
• Patients who received any systemic anticancer therapy including investigational agents
or radiation ≤3 weeks (or ≤5 half-lives of the drug [whichever is shorter]) prior to
C1D1. Hydroxyurea is permitted for up to 14 days in AML patients
• Inadequate recovery from toxicity attributed to prior anti-cancer therapy. With the
exception of alopecia or fatigue, patients must have recovered to baseline or ≤ Grade
1 (NCI-CTCAE v4.03) residual toxicity prior to first dose of protocol-indicated
treatment.
• Participation in another clinical trial with any investigational drug within 14 days
prior to study enrollment.
• Patients included in the VEN refractory cohort that have discontinued venetoclax
therapy (either monotherapy or combination) due to toxicity or hypersensitivity,
including prior history of grade 3/4 TLS during prior VEN exposure
• In dose expansion cohorts, except venetoclax refractory cohort, no prior treatment
with SINE compounds, another XPO1 inhibitor, or BCL-2 inhibitors.
• Active GVHD requiring calcineurin inhibitors or steroid dosing ≥ 10mg/day prednisone
(or equivalent) or < 3 months from allogenic hematopoietic cell transplant (HCT).
• Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics,
antivirals, or antifungals within one week prior to first dose; however, prophylactic
use of these agents is acceptable even if parenteral.
• Major surgery within 2 weeks of first dose of study drug.
• Any life-threatening illness, medical condition or organ system dysfunction which, in
the investigator's opinion, could compromise the patient's safety.
• Unstable cardiovascular function:
• Symptomatic ischemia, or
• Uncontrolled clinically significant conduction abnormalities (i.e., ventricular
tachycardia on anti-arrhythmia therapy are excluded; 1st degree AV block or
asymptomatic LAFB/RBBB will not be excluded), or
• Congestive heart failure (CHF) of NYHA Class ≥3, or
• Myocardial infarction (MI) within 3 months.
• Known active Hepatitis B or Hepatitis C infection (Hepatitis testing is not required
as part of this study).
• Known human immunodeficiency virus (HIV) infection (HIV testing is not required as
part of this study).
• Subject has received the following ≤ 7 days prior to Cycle 1, Day 1: Strong and
moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's
wort.
• Subject has received the following ≤ 5 days prior to Cycle 1, Day 1: Strong and
moderate CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin.
• Subject has consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or Starfruit ≤ 3 days prior to Cycle 1, Day 1.
• Inability to swallow oral medication; or the presence of a poorly controlled
gastrointestinal disease, disorder, syndrome, or dysfunction that could significantly
affect the absorption of oral study drug •e.g. Crohn's disease, ulcerative colitis,
chronic diarrhea (defined as > 4 loose stools per day), malabsorption syndrome, or
bowel obstruction.
• Inability or unwillingness to take required and recommended medications intended to
prevent and treat potential adverse events of tumor lysis syndrome (TLS), nausea and
vomiting, loss of appetite, and fatigue.
• Patients unwilling to comply with the protocol
Drug: Venetoclax, Drug: Selinexor
Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Diffuse Large B-Cell Lymphoma, Myeloid and Monocytic Leukemia, Non-Hodgkins Lymphoma
A Study of Pembrolizumab (MK-3475) in Pediatric Participants With an Advanced Solid Tumor or Lymphoma (MK-3475-051/KEYNOTE-051)
This is a two-part study of pembrolizumab (MK-3475) in pediatric participants who have any of
the following types of cancer:
- advanced melanoma (6 months to <18 years of age),
- advanced, relapsed or refractory programmed death-ligand 1 (PD-L1)-positive malignant
solid tumor or other lymphoma (6 months to <18 years of age),
- relapsed or refractory classical Hodgkin lymphoma (rrcHL) (3 years to <18 years of age),
or
- advanced relapsed or refractory microsatellite-instability-high (MSI-H) solid tumors (6
months to <18 years of age).
Part 1 will find the maximum tolerated dose (MTD)/maximum administered dose (MAD), confirm
the dose, and find the recommended Phase 2 dose (RP2D) for pembrolizumab therapy. Part 2 will
further evaluate the safety and efficacy at the pediatric RP2D.
The primary hypothesis of this study is that intravenous (IV) administration of pembrolizumab
to children with either advanced melanoma; a PD-L1 positive advanced, relapsed or refractory
solid tumor or other lymphoma; advanced, relapsed or refractory MSI-H solid tumor; or rrcHL,
will result in an Objective Response Rate (ORR) greater than 10% for at least one of these
types of cancer.
• Between 6 months and <18 years of age (or between 3 years and <18 years of age for
rrcHL participants) on day of signing informed consent/assent (the first 3
participants dosed in Part 1 are to be ≥ 6 years of age)
• Histologically- or cytologically-documented, locally-advanced, or metastatic solid
malignancy or lymphoma that is incurable and has failed prior standard therapy, or for
which no standard therapy exists, or for which no standard therapy is considered
appropriate
• Any number of prior treatment regimens
• Tissue (or lymph node biopsy for rrcHL participants) available from an archival tissue
sample or, if appropriate, a newly obtained core or excisional biopsy of a tumor
lesion not previously irradiated
• Advanced melanoma or PD-L1-positive advanced, relapsed, or refractory solid tumor or
lymphoma
• Measurable disease based on RECIST 1.1 (Or based on IWG [Cheson, 2007] [i.e.,
measurement must be >15 mm in longest diameter or >10 mm in short axis] for rrcHL
participants)
• Participants with neuroblastoma with only metaiodobenzylguanidine (MIBG)-positive
evaluable disease may be enrolled
• Lansky Play Scale ≥50 for participants from 6 months up to and including 16 years of
age; or Karnofsky score ≥50 for participants >16 years of age
• Adequate organ function
• Female participants of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication
• Female participants of childbearing potential must be willing to use 2 methods of
contraception or be surgically sterile, or abstain from heterosexual activity for the
course of the study through 120 days after the last dose of study medication
• Male participants of reproductive potential must agree to use an adequate method of
contraception starting with the first dose of study medication through 120 days after
the last dose of study medication
Exclusion Criteria:
• Currently participating and receiving study therapy in, or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the date of allocation/randomization
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form
of immunosuppressive therapy within 7 days prior to the date of
allocation/randomization
• Prior systemic anti-cancer therapy including investigational agent within 2 weeks
prior to study Day 1 or not recovered from adverse events due to a previously
administered agent
• Prior radiotherapy within 2 weeks of start of study treatment
• Known additional malignancy that is progressing or requires active treatment with the
exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin or
carcinoma in situ (eg, breast carcinoma, cervical carcinoma in situ) with potentially
curative therapy, or in situ cervical cancer
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Tumor(s) involving the brain stem
• Severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
• Active autoimmune disease that has required systemic treatment in past 2 years;
replacement therapy (such as thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is acceptable
• Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
• Active infection requiring systemic therapy
• Pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial through 120 days after the last dose of study
medication
• Prior therapy with an anti-programmed cell death (PD)-1, anti-PD-ligand 1
(anti-PD-L1), anti-PD-L2 agent, or any agent directed to another stimulatory or
inhibitory T-cell receptor (eg, cytotoxic lymphocyte associated protein-4 [CTLA-4],
OX-40, CD137)
• Human immunodeficiency virus (HIV)
• Hepatitis B or C
• Known history of active tuberculosis (TB; Bacillus tuberculosis)
• Received a live vaccine within 30 days of planned start of study medication
• Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic
stem cell transplantation within the last 5 years. (Participants who have had an
allogeneic hematopoietic transplant >5 years ago are eligible as long as there are no
symptoms of Graft Versus Host Disease [GVHD].)
• History or current evidence of any condition, therapy, or laboratory abnormality, or
known severe hypersensitivity to any component or analog of the trial treatment, that
might confound the results of the trial, or interfere with the participant's
participation for the full duration of the study
• Known psychiatric or substance abuse disorders that would interfere with the
requirements of the study
A Study to Evaluate the Efficacy and Safety of Daratumumab in Pediatric and Young Adult Participants Greater Than or Equal to (>=)1 and Less Than or Equal to (<=) 30 Years of Age With Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
The purpose of this study is to evaluate the efficacy of daratumumab in addition to standard
chemotherapy in pediatric participants with relapsed/refractory B-cell acute lymphoblastic
leukemia (ALL)/lymphoblastic lymphoma (LL) and T-cell ALL/LL as measured by the complete
response (CR) rate.
• Documented acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) as
defined by the criteria below:
1. B-cell cohort: Stage 1; ALL in second or greater relapse or refractory to 2 prior
induction regimens with greater than or equal to (>=) 5 percent (%) blasts in the
bone marrow and aged 1 to less than (<) 18 years. Stage 2; ALL in second or
greater relapse or refractory to 2 prior induction regimens with (>=) 5% blasts
in the bone marrow and aged 1 to 30 years. LL in second or greater relapse or
refractory to 2 prior induction regimens and biopsy proven and with evidence of
measurable disease by radiologic criteria and aged 1 to 30 years.
2. T-cell cohort: Stage 1; ALL in first relapse or refractory to 1 prior
induction/consolidation regimen with (>=) 5% blasts in the bone marrow and aged 1
to <18 years. Stage 2; ALL in first relapse or refractory to 1 prior
induction/consolidation regimen with (>=) 5% blasts in the bone marrow and aged 1
to 30 years. LL in first relapse or refractory to 1 prior induction/consolidation
regimen biopsy proven and with evidence of measurable disease by radiologic
criteria and aged 1 to 30 years
• Performance status greater than or equal to (>=) 70 by Lansky scale (for participants
less than [<] 16 years of age) or Karnofsky scale (for participants [>=] 16 years of
age)
• Adequate hematology laboratory values at Cycle 1 Day 1 pre-dosing defined as follows:
1. Hemoglobin (>=) 7.5 gram per deciliter (g/dL) ([>=] 5 millimole per liter
[mmol/L]; prior red blood cell [RBC] transfusion is permitted)
2. Platelet count (>=) 10*10^9 per liter (L) (prior platelet transfusion is
permitted)
• Adequate renal function defined as normal serum creatinine for the participant's age
or creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
milliliter per minute per 1.73 square meter (mL/min/1.73 m^2) prior to enrollment
• Adequate liver function prior to enrollment defined as:
1. Alanine aminotransferase level less than or equal to (<=) 2.5* the upper limit of
normal (ULN),
2. Aspartate aminotransferase level (<=) 2.5* ULN, and
3. Total bilirubin (<=) 2* ULN or direct bilirubin level (<=) 2.0* ULN
Exclusion Criteria:
• Received an allogeneic hematopoietic transplant within 3 months of screening
• Active acute graft-versus-host disease of any grade or chronic graft-versus-host
disease of Grade 2 or higher
• Received immunosuppression post hematopoietic transplant within 1 month of study entry
• Philadelphia chromosome positive (Ph+) B-cell ALL eligible for tyrosine kinase
inhibitor therapy
• Has either of the following:
1. Evidence of dyspnea at rest or oxygen saturation (<=) 94 percent (%).
2. Known moderate or severe persistent asthma within the past 2 years, or
uncontrolled asthma of any classification
• Received an investigational drug, was vaccinated with live attenuated vaccines, or
used an invasive investigational medical device within 4 weeks before the planned
first dose of study drug, or is currently being treated in an investigational study
• Known to be seropositive for human immunodeficiency virus (HIV)
• Any one of the following:
1. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Participants with resolved infection (ie, participants who are
HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc]
and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened
using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus
(HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be
excluded
2. Known to be seropositive for hepatitis C (except in the setting of a sustained
virologic response [SVR], defined as aviremia at least 12 weeks after completion
of antiviral therapy)
Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas
This phase II trial studies how well nivolumab with or without varlilumab works in treating
patients with aggressive B-cell lymphomas that have come back (recurrent) or do not respond
to treatment (refractory). Immunotherapy with monoclonal antibodies, such as varlilumab and
nivolumab, may help the body's immune system attack the cancer, and may interfere with the
ability of tumor cells to grow and spread.
• Patients must have a histopathologically confirmed diagnosis of an aggressive B-cell
non-Hodgkin lymphoma that is recurrent or refractory to standard therapy
• For the purpose of this study, aggressive B-cell NHL will be deemed any lymphoma
belonging to one of the following groups according to the 2016 revision of the World
Health Organization (WHO) classification of lymphoid neoplasms
• For the purposes of stratification, diagnoses are grouped into 2 categories:
• Category A
• Burkitt lymphoma
• Burkitt-like lymphoma with 11q aberration
• High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6
rearrangements
• High-grade B-cell lymphoma, not otherwise specified (NOS)
• Category B
• Diffuse large B-cell lymphoma (DLBCL), NOS
• Diffuse large B-cell lymphoma (DLBCL), NOS; germinal center B-cell type
• Diffuse large B-cell lymphoma (DLBCL), NOS; activated B-cell type
• Large B-cell lymphoma with IRF4 rearrangement
• T-cell/histiocyte-rich large B-cell lymphoma
• Primary DLBCL of the central nervous system (CNS)
• Primary cutaneous DLBCL, leg type
• Epstein-Barr virus (EBV)+ DLBCL, NOS
• EBV+ mucocutaneous ulcer
• DLBCL associated with chronic inflammation
• Lymphomatoid granulomatosis
• Primary mediastinal (thymic) large B-cell lymphoma
• Intravascular large B-cell lymphoma
• ALK+ large B-cell lymphoma
• Plasmablastic lymphoma
• Primary effusion lymphoma
• Human herpesvirus (HHV)-8+ DLBCL, NOS
• B-cell lymphoma, unclassifiable, with features intermediate between
DLBCL and classical Hodgkin lymphoma
• Patients must have measurable disease, defined as at least one lesion that is > 15 mm
(1.5 cm) in the longest axis on cross-sectional imaging and measurable in two
perpendicular dimensions per computed tomography (spiral computed tomography [CT]),
positron emission tomography (PET)-CT or magnetic resonance imaging (MRI)
• Patients must have disease that has relapsed after or is refractory to at least 2
lines of standard therapy; the remaining standard treatment options are unlikely to be
effective in the opinion of the treating physician, or patient is felt to be
ineligible for such therapies or the patient refuses such therapies; patients who have
undergone autologous stem cell transplant are eligible as long as they meet all other
criteria
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of greater than 12 weeks
• White blood cell (WBC) >= 2000/mm^3 (within 14 days of registration)
• Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days of registration)
• Platelet count >= 100,000/mm^3 (within 14 days of registration)
• Hemoglobin > 9.0 g/dL (within 14 days of registration)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except patients with Gilbert
Syndrome, who can have total bilirubin < 3.0 mg/dL) (within 14 days of registration)
• Aspartate transaminase (aspartate aminotransferase [AST]) =< 2.5 x ULN (within 14 days
of registration)
• Calculated creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault
formula) (within 14 days of registration)
• Females of child bearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG])
• Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
• Patient has received chemotherapy, targeted agent, or radiotherapy within 4 weeks or
at least 5 half-lives, whichever is longer, prior to registration
• Palliative (limited-field) radiation therapy is permitted, if all of the following
criteria are met:
• Repeat imaging demonstrates no new sites of bone metastases
• The lesion being considered for palliative radiation is not a target lesion
• Patient has received immunotherapy (including monoclonal antibodies) within 4 weeks
prior to registration
• Patients who have not recovered to grade 1 or less from any adverse events due to
agents administered more than 4 weeks earlier (excluding alopecia)
• Patients who are receiving any other investigational agents
• Patients should be excluded if they have had prior treatment with an anti-PD-1,
anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Patients who have received autologous stem cell transplant (ASCT) =< 12 weeks prior to
the first dose of study drug
• Patients with a prior history of allogeneic stem cell or solid organ transplantation
• Patients with evidence of active disease in the central nervous system (CNS) defined
as either the presence of active lesions on MRI obtained within 4 weeks of
registration or progressive neurological decline
• Patients with primary CNS lymphoma who develop systemic recurrence following
standard therapy may be included as long as no active CNS disease is present at
the time or enrollment; similarly, patients with secondary involvement of the CNS
from a systemic lymphoma may be included as long as the CNS disease has been
optimally treated and they demonstrate no evidence of active CNS disease
• History of allergic reactions attributed to compounds of similar chemical or biologic
composition to CDX-1127 (varlilumab) and/or nivolumab
• History of severe hypersensitivity reaction to any monoclonal antibody
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
• Pregnant women are excluded from this study because CDX-1127 (varlilumab) and
nivolumab are agents with the potential for teratogenic or abortifacient effects;
because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with CDX-1127 (varlilumab) or nivolumab,
breastfeeding should be discontinued if the mother is treated with CDX-1127
(varlilumab) or nivolumab
• Patients with human immunodeficiency virus (HIV) are eligible for the study provided
they meet the other protocol criteria in addition to the following:
• Undetectable HIV load by standard polymerase chain reaction (PCR) clinical assay
within 60 days prior to registration
• Absolute CD4 count of >= 200 mm^3 within 60 days prior to registration
• Willing to maintain adherence to combination antiretroviral therapy
• No history of acquired immunodeficiency syndrome (AIDS) defining condition (other
than lymphoma or CD4 cell count < 200 mm^3)
• Likely to have near normal lifespan if not for the presence of
relapsed/refractory lymphoma
• Patients with evidence of hepatitis B virus (HBV) are eligible provided
there is minimal hepatic injury and the patient has undetectable HBV on
suppressive HBV therapy; patient must be willing to maintain adherence to
HBV therapy
• Patients with previously treated and eradicated hepatitis C virus (HCV) who
have minimal hepatic injury are eligible
• Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids, should be excluded; these include but are not
limited to patients with a history of immune related neurologic disease, multiple
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
ulcerative colitis, hepatitis; and patients with a history of toxic epidermal
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
excluded because of the risk of recurrence or exacerbation of disease; patients with
vitiligo, endocrine deficiencies including thyroiditis managed with replacement
hormones including physiologic corticosteroids are eligible; patients with rheumatoid
arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with
topical medication and patients with positive serology, such as antinuclear antibodies
(ANA), anti-thyroid antibodies should be evaluated for the presence of target organ
involvement and potential need for systemic treatment but should otherwise be eligible
• Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger (precipitating event)
• Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration; inhaled or
topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease; patients are permitted to
use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
(with minimal systemic absorption); physiologic replacement doses of systemic
corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief
course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
caused by contact allergen) is permitted
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are
known risk factors for bowel perforation should be evaluated for the potential need
for additional treatment before coming on study
• Patients with other active malignancy =< 3 years prior to registration for which
active treatment is required must be excluded; patients with composite lymphomas that
have a non-B-cell component must be excluded EXCEPTIONS: Non-melanotic skin cancer or
carcinoma-in-situ of the cervix
Biological: Nivolumab, Drug: Varlilumab
Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, Recurrent Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Plasmablastic Lymphoma, ALK-Positive Large B-Cell Lymphoma, Burkitt-Like Lymphoma With 11q Aberration, Diffuse Large B-Cell Lymphoma Activated B-Cell Type, Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation, Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type, EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, EBV-Positive Mucocutaneous Ulcer, Intravascular Large B-Cell Lymphoma, Large B-Cell Lymphoma With IRF4 Rearrangement, Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System, Primary Effusion Lymphoma, Recurrent B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma, Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Burkitt Lymphoma, Recurrent Lymphomatoid Granulomatosis, Refractory B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Burkitt Lymphoma, High Grade B-Cell Lymphoma, Not Otherwise Specified, Lymphoid Leukemia, HHV8-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements, Recurrent High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements, Recurrent Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, Recurrent T-Cell/Histiocyte-Rich Large B-Cell Lymphoma, Refractory High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Refractory High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements, Refractory Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, Refractory T-Cell/Histiocyte-Rich Large B-Cell Lymphoma, Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Refractory Primary Mediastinal (Thymic) Large B-Cell Lymphoma
A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia
This phase III trial studies how well blinatumomab works in combination with chemotherapy in
treating patients with newly diagnosed, standard risk B-lymphoblastic leukemia or
B-lymphoblastic lymphoma with or without Down syndrome. Monoclonal antibodies, such as
blinatumomab, may induce changes in the body's immune system and may interfere with the
ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as vincristine,
dexamethasone, prednisone, prednisolone, pegaspargase, methotrexate, cytarabine,
mercaptopurine, doxorubicin, cyclophosphamide, and thioguanine, work in different ways to
stop the growth of cancer cells, either by killing the cells, by stopping them from dividing,
or by stopping them from spreading. Leucovorin decreases the toxic effects of methotrexate.
Giving monoclonal antibody therapy with chemotherapy may kill more cancer cells. Giving
blinatumomab and combination chemotherapy may work better than combination chemotherapy alone
in treating patients with B-ALL. This trial also assigns patients into different chemotherapy
treatment regimens based on risk (the chance of cancer returning after treatment). Treating
patients with chemotherapy based on risk may help doctors decide which patients can best
benefit from which chemotherapy treatment regimens.
• All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening
(Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement
for B-LLy patients. B-LLy patients may directly enroll on AALL1731.
• Age at diagnosis:
• Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).
• Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).
• Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or
without DS).
• B-ALL patients without DS must have an initial white blood cell count < 50,000/uL
(performed within 7 days prior to enrollment).
• B-ALL patients with DS are eligible regardless of the presenting white blood cell
count (WBC) (performed within 7 days prior to enrollment).
• Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on
a bone marrow (BM) aspirate;
• OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis
can be established by a pathologic diagnosis of B-ALL on a BM biopsy;
• OR a complete blood count (CBC) documenting the presence of at least 1,000/uL
circulating leukemic cells;
• OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without
Down syndrome.
• Note: For B-LLy patients with tissue available for flow cytometry, the criterion
for diagnosis should be analogous to B-ALL. For tissue processed by other means
(i.e., paraffin blocks), the methodology and criteria for immunophenotypic
analysis to establish the diagnosis of B-LLy defined by the submitting
institution will be accepted (diagnostic biopsy for B-LLy must be performed
within 14 days prior to enrollment).
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
• All patients and/or their parents or legal guardians must sign a written informed
consent.
Exclusion Criteria:
• Patient must not have secondary ALL that developed after treatment of a prior
malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior
history of transient myeloproliferative disease (TMD) are not considered to have had a
prior malignancy. They would therefore be eligible whether or not the TMD was treated
with cytarabine.
• With the exception of steroid pretreatment or the administration of intrathecal
cytarabine, patients must not have received any prior cytotoxic chemotherapy for
either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to
initiation of protocol therapy on AALL1731.
• For patients receiving steroid pretreatment, the following additional exclusion
criteria apply:
• Non-DS B-ALL patients must not have received steroids for more than 24 hours in
the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to
initiation of the steroids.
• DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV
steroids within 4 weeks of diagnosis.
• Patients who have received > 72 hours of hydroxyurea.
• B-ALL patients who do not have sufficient diagnostic bone marrow submitted for
APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted
containing > 1,000/uL circulating leukemia cells.
• Patient must not have acute undifferentiated leukemia (AUL).
• Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be
known prior to enrollment).
• Note: DS patients with CNS3 disease are eligible but will be assigned to the
DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior
to administration of any systemic or intrathecal chemotherapy, except for steroid
pretreatment.
• Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular
disease are eligible but will be assigned to the DS-High B-ALL arm).
• For LLy patients, the following additional exclusion criteria apply:
• T-Lymphoblastic Lymphoma.
• Morphologically unclassifiable lymphoma.
• Absence of both B-cell and T-cell phenotype markers in a case submitted as
lymphoblastic lymphoma.
• CNS positive disease or testicular involvement.
• M2 (5% •25% blasts) or M3 (> 25% blasts) marrow.
• Patients with known Charcot-Marie-Tooth disease.
• Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL,
regardless of blast immunophenotype.
• Patients requiring radiation at diagnosis.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. A pregnancy test is required for female
patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation.
An Open-Label Study of JZP-458 (RC-P) in Patients With Acute Lymphoblastic Leukemia (ALL)/Lymphoblastic Lymphoma (LBL)
This is an open-label, multicenter, dose confirmation, and PK study of JZP-458 in patients
(of any age) with ALL/LBL who are hypersensitive to E. coli-derived asparaginases (allergic
reaction or silent inactivation). This study is designed to assess the tolerability and
efficacy of JZP-458 (only in patients who develop hypersensitivity to an E. coli-derived
asparaginase), as measured by asparaginase activity.
1. Pediatric and adult patients with a diagnosis of ALL or LBL.
2. Have had an allergic reaction to a long-acting E. coli-derived asparaginase OR have
silent inactivation.
3. Have 1 or more courses of E. coli-derived asparaginase remaining in his/her treatment
plan.
4. Patients must have, in the opinion of the Investigator, fully recovered from their
prior allergic reaction to E. coli-derived asparaginase.
Exclusion Criteria:
1. Have previously received asparaginase Erwinia chrysanthemi or JZP-458.
2. Have relapsed ALL or LBL.
3. Are concurrently receiving another investigational agent and/or treated with an
investigational device at the same time as JZP-458 (within 48 hours) during Course 1
of JZP-458.
4. Have a history of ≥ Grade 3 pancreatitis.
5. Prior history of asparaginase-associated ≥ Grade 3 hemorrhagic event or
asparaginase-associated thrombus requiring anticoagulation therapy, excluding
catheter-related thrombotic events.
Inotuzumab Ozogamicin in Treating Younger Patients With B-Lymphoblastic Lymphoma or Relapsed or Refractory CD22 Positive B Acute Lymphoblastic Leukemia
This phase II trial studies how well inotuzumab ozogamicin works in treating younger patients
with B-lymphoblastic lymphoma or CD22 positive B acute lymphoblastic leukemia that has come
back (relapsed) or does not respond to treatment (refractory). Inotuzumab ozogamicin is a
monoclonal antibody, called inotuzumab, linked to a toxic agent called ozogamicin. Inotuzumab
attaches to CD22 positive cancer cells in a targeted way and delivers ozogamicin to kill
them.
• Patients must have B-ALL, or previously diagnosed B lymphoblastic lymphoma (B-LL),
with >= 5% (M2 or M3) bone marrow blasts with or without extramedullary disease
• NOTE: Relapsed patients previously diagnosed with B-lymphoblastic lymphoma (B-LL)
are eligible if they have an M2 or M3 marrow at the time of enrollment on this
study
• Patients with ALL or B-LL who have M2 morphology must have local confirmatory testing
showing >= 5% blasts by flow cytometry, fluorescence in situ hybridization (FISH)
testing or other molecular method
• Leukemic blasts must demonstrate surface expression of CD22 at the time of relapse by
local/institutional flow cytometry of a bone marrow aspirate sample; (assessment of
CD22 using a bright fluorophore such as phycoerythrin [PE] is strongly recommended)
• In the case of an inadequate aspirate sample (dry tap) or if bone marrow aspirate
is unable to be performed due to patient clinical status, flow cytometry of
peripheral blood specimen may be substituted if the patient has at least 1,000/uL
circulating blasts; alternatively, CD22 expression may be documented by
immunohistochemistry of a bone marrow biopsy specimen
• Patients with one of the following:
• Second or greater relapse;
• Primary refractory disease with at least 2 prior induction attempts;
• First relapse refractory to at least one prior re-induction attempt
• Any relapse after HSCT (Cohort 1 ONLY)
Patients with Down syndrome are eligible ONLY for Cohort 1 with:
• Any of above disease status, OR
• First relapse with no prior re-induction attempt NOTE: Patients with Down syndrome or
prior HSCT are NOT eligible for Cohort 2 combination therapy
• Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy
attempts including two different tyrosine kinase inhibitors (TKIs)
• Patients must have fully recovered from the acute non-hematologic toxic effects
of all prior anti-cancer therapy, defined as resolution of all such toxicities to
=< grade 2 or lower per the inclusion/exclusion criteria prior to entering this
study
• Myelosuppressive chemotherapy:
• No waiting period will be required for patients receiving standard
"maintenance-like" chemotherapy including oral mercaptopurine, weekly low-dose
oral methotrexate, and intermittent vincristine/steroid pulses; otherwise, at
least 14 days must have elapsed since the completion of cytotoxic therapy, with
the exceptions of hydroxyurea or corticosteroids used for cytoreduction
• Intrathecal cytotoxic therapy: No waiting period is required for patients having
received intrathecal cytarabine, methotrexate, and/or hydrocortisone; intrathecal
chemotherapy given at the time of diagnostic lumbar puncture (LP) to evaluate for
relapse prior to study enrollment is allowed
• At least 7 days must have elapsed since the completion of therapy with a growth
factor; at least 14 days must have elapsed after receiving pegfilgrastim
• At least 7 days must have elapsed since completion of therapy with a biologic agent
(including tyrosine kinase inhibitors); for agents that have known adverse events
occurring beyond 7 days after administration, this period prior to enrollment must be
extended beyond the time during which adverse events are known to occur
• At least 3 half-lives must have elapsed since prior therapy that included a monoclonal
antibody with the exception of blinatumomab; patients must have been off blinatumomab
infusion for at least 3 days and all drug related toxicity must have resolved to grade
2 or lower as outlined in the inclusion/exclusion criteria
• >= 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small
port); >= 3 months must have elapsed if prior cranial or craniospinal XRT was
received, if >= 50% of the pelvis was irradiated, or if total-body irradiation (TBI)
was received; >= 6 weeks must have elapsed if other substantial bone marrow
irradiation was given
• For Cohort 1, at least 90 days must have elapsed since stem cell transplant and at
least 30 days from donor lymphocyte infusion; patient must have had no more than one
previous HSCT and currently have no evidence of active graft versus (vs.) host disease
(GVHD); for Cohort 2, no prior HSCT is allowed
• At least 30 days must have elapsed from the last chimeric antigen receptor (CAR)-T
cell infusion
• Patients must have a performance status corresponding to Eastern Cooperative
Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years
of age and Lansky for patients =< 16 years of age; patients who are unable to
walk because of paralysis, but who are up in a wheelchair, will be considered
ambulatory for the purpose of assessing the performance score
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or
• A serum creatinine based on age/gender as follows:
• 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
• 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
• 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
• 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
• 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
• >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
• Direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5
x ULN for age; for the purpose of this study, the ULN for ALT will be 45 U/L
Exclusion Criteria:
• Patients with any prior history of SOS irrespective of severity
• Patients with isolated central nervous system (CNS), testicular, or any other
extramedullary site of relapse
• Patients who have been previously treated with inotuzumab ozogamicin
• Patients who have previously received HSCT (Cohort 2 only)
• Patients with Down syndrome (Cohort 2 only)
• History of allergic reaction attributed to compounds of similar or biologic
composition to inotuzumab ozogamicin or other agents in the study
• Note: Patients with history of allergy to pegaspargase are eligible for
enrollment on Cohort 2 (dose levels 1 and -1) if asparaginase Erwinia can be
obtained
• If Cohort 2 is enrolling at dose level -2, then patients who cannot receive
asparaginase due to prior allergy, toxicity, or lack of access may enroll
• NOTE: patients on AALL1621 are not eligible to co-enroll on AALL1931
• Patients with active optic nerve and/or retinal involvement are not eligible; patients
who are presenting with visual disturbances should have an ophthalmologic exam and, if
indicated, a magnetic resonance imaging (MRI) to assess optic nerve or retinal
involvement
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving or plan to receive other anti-cancer agents
(except hydroxyurea, which may be continued until 24 hours prior to start of protocol
therapy and intrathecal chemotherapy)
• Anti-GVHD or agents to prevent organ rejection post-transplant; patients who are
receiving cyclosporine, tacrolimus, or other agents to prevent either
graft-versus-host disease post bone marrow transplant or organ rejection
post-transplant are not eligible for this trial; at least 3 half-lives must have
elapsed after the last dose of GVHD medications (meds)
• Patients who are currently receiving or plan to receive corticosteroids except as
described below
• Systemic corticosteroids may be administered for cytoreduction up to 24 hours
prior to the start of protocol therapy, (Cohort 1 only) for all patients,
corticosteroids may be administered as a premedication for inotuzumab ozogamicin
and as treatment for allergic reactions or for physiologic replacement/stress
dosing of hydrocortisone for documented adrenal insufficiency; corticosteroids
are not allowed for other indications
• Patients with known human immunodeficiency virus (HIV), hepatitis B or C infections;
testing to prove negative status is not required for enrollment unless it is deemed
necessary for usual medical care of the patient
• Patients who have an active uncontrolled infection defined as:
• Positive bacterial blood culture within 48 hours of study enrollment;
• Fever above 38.2 degree Celsius (C) within 48 hours of study enrollment with
clinical signs of infection; fever that is determined to be due to tumor burden
is allowed if patients have documented negative blood cultures for at least 48
hours prior to enrollment and no concurrent signs or symptoms of active infection
or hemodynamic instability
• A positive fungal culture within 30 days of study enrollment or active therapy
for presumed invasive fungal infection
• Patients may be receiving IV or oral antibiotics to complete a course of therapy
for a prior documented infection as long as cultures have been negative for at
least 48 hours and signs or symptoms of active infection have resolved; for
patients with clostridium (C.) difficile diarrhea, at least 72 hours of
antibacterial therapy must have elapsed and stools must have normalized to
baseline
• Active viral or protozoal infection requiring IV treatment
• Patients known to have one of the following concomitant genetic syndromes: Bloom
syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachmann
(Shwachmann-Diamond-Blackfan) syndrome or any other known bone marrow failure syndrome
• There have been no human studies of inotuzumab ozogamicin in pregnant women and no
reports of exposure in utero; based on nonclinical safety studies, inotuzumab
ozogamicin has the potential to impair human male and female fertility and to
adversely affect human embryo fetal development; women of childbearing potential
should be advised to avoid becoming pregnant while receiving inotuzumab ozogamicin;
there is no information regarding the presence of inotuzumab ozogamicin in human milk,
the effects on the breast-fed infant, or the effects on milk production; because of
the potential for adverse reactions in breast-fed infants, women should not
breast-feed during treatment with inotuzumab ozogamicin and for at least 2 months
after the final dose
• Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained within 7 days of starting protocol
therapy
• Female patients who are sexually active and of reproductive potential are not
eligible unless they agree to use an effective contraceptive method for the
duration of their study participation and for 8 months after the last dose of
inotuzumab ozogamicin
• Men with female partners of childbearing potential should use effective
contraception during treatment with inotuzumab ozogamicin and for at least 5
months after the last dose of inotuzumab ozogamicin
• Lactating females are not eligible unless they agree not to breastfeed their
infants
Recurrent B Acute Lymphoblastic Leukemia, Recurrent B Lymphoblastic Lymphoma, Refractory B Acute Lymphoblastic Leukemia, Refractory B Lymphoblastic Lymphoma, Leukemia, Other
Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
This is a Phase 1/2, open-label, multicenter study to determine the efficacy and safety of
JCAR017 in adult subjects with relapsed or refractory CLL or SLL. The study will include a
Phase 1 part to determine the recommended dose of JCAR017 monotherapy in subjects with
relapsed or refractory CLL or SLL, followed by a Phase 2 part to further assess the efficacy
and safety of JCAR017 monotherapy treatment at the recommended dose. A separate Phase 1
cohort will assess the combination of JCAR017 and concurrent ibrutinib. In all subjects, the
safety, efficacy, and pharmacokinetics (PK) of JCAR017 will be evaluated.
• Diagnosis of:
1. CLL with an indication for treatment based on the Investigator's opinion and
measurable disease, or
2. SLL (lymphadenopathy and/or splenomegaly and < 5×10^9 CD19+ CD5+ clonal B
lymphocytes/L [< 5000/µL] in the peripheral blood at diagnosis with measurable
disease that is biopsy-proven SLL)
• Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must
have received and failed Bruton tyrosine kinase inhibitor (BTKi) treatment or have
been deemed ineligible for BTKi therapy.
• Subjects (other than those in the ibrutinib + JCAR017 combination therapy cohort) must
have received previous treatment as follows:
1. Subjects with CLL or SLL and high-risk features must have failed at least 2 lines
of prior therapy.
2. Subjects with CLL or SLL and standard-risk features must have failed at least 3
lines of prior therapy.
• Subjects in the ibrutinib + JCAR017 combination therapy cohort must either:
1. be receiving ibrutinib and progressing at the time of study enrollment
2. be receiving ibrutinib for at least 6 months with a response less than complete
response/remission (CR) and have high-risk features as defined in inclusion
criterion 5a
3. have BTK or PLCgamma2 mutations per local laboratory assessment, with or without
progression on ibrutinib
4. have previously received ibrutinib and have no contraindications to restarting
ibrutinib
• Eastern Cooperative Oncology Group performance status of ≤ 1
• Assessed by the Investigator to have adequate bone marrow function to receive
lymphodepleting chemotherapy
• Adequate organ function, defined as:
1. Serum creatinine ≤ 1.5 × age-adjusted upper limit of normal (ULN) OR calculated
creatinine clearance > 30 mL/min
2. Alanine aminotransferase ≤ 5 × ULN and total bilirubin < 2.0 mg/dL (or < 3.0
mg/dL for subjects with Gilbert's syndrome or leukemic infiltration of the liver)
3. Adequate pulmonary function, defined as ≤ Common Terminology Criteria for Adverse
Events (CTCAE) Grade 1 dyspnea and saturated oxygen (SaO2) ≥ 92% on room air
4. Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40% as
assessed by echocardiogram or multiple uptake gated acquisition scan performed
within 30 days prior to determination of eligibility
• Subject either currently has central vascular access or is a candidate to receive
central vascular access or peripheral vascular access for leukapheresis procedure.
• If prior CD19-targeted therapy has been administered, subject must have CD19-positive
disease confirmed by immunohistochemistry or flow cytometry since completing the prior
CD19-targeted therapy.
Exclusion Criteria:
• Subjects with known active central nervous system (CNS) involvement by malignancy.
Those with prior CNS disease that has been effectively treated will be eligible if
treatment was completed at least 3 months prior to enrollment with no evidence of
symptomatic disease and stable abnormalities on repeat imaging.
• History of another primary malignancy that has not been in remission for at least 2
years. (The following are exempt from the 2-year limit: nonmelanoma skin cancer,
completely resected stage 1 solid tumor with low risk for recurrence, curatively
treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous
intraepithelial lesion on Pap smear, and in situ breast cancer that has been
completely resected.)
• Subjects with Richter's transformation
• Prior treatment with any gene therapy product
• Active hepatitis B, active hepatitis C, or active human immunodeficiency virus (HIV)
infection
• Systemic fungal, bacterial, viral, or other infection that is not controlled
• Presence of acute or extensive chronic graft versus host disease (GVHD)
• History of any one of the following cardiovascular conditions within the past 6
months: Class III or IV heart failure as defined by the New York Heart Association
(NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or
other clinically significant cardiac disease
• History or presence of clinically relevant CNS pathology such as epilepsy, generalized
seizure disorder, aphasia, stroke with current neurologic sequelae, severe brain
injuries, dementia, Parkinson's disease, cerebellar disease,cerebral edema, or
psychosis
• Pregnant or nursing (lactating) women
• Use of any of the following medications or treatments within the noted time prior to
leukapheresis:
1. Alemtuzumab within 6 months prior to leukapheresis
2. Allogeneic hematopoietic stem cell transplant within 100 days prior to
leukapheresis
3. Cladribine within 3 months prior to leukapheresis
4. Donor lymphocyte infusions (DLI) within 2 months prior to leukapheresis
5. Radiation including large bone marrow fields such as sternum or pelvis within 6
weeks prior to leukapheresis
6. Fludarabine within 4 weeks prior to leukapheresis
7. GVHD therapies such as calcineurin inhibitors, methotrexate or other
chemotherapeutics, mycophenolate mofetil, rapamycin, or immunosuppressive
antibodies (such as anti-tumor necrosis factor-α [TNFα], anti-interleukin-6
[IL-6], or anti-interleukin-6 receptor [IL 6R]) within 4 weeks prior to
leukapheresis
8. Cyclophosphamide, ifosfamide, bendamustine, chlorambucil, or melphalan within 2
weeks prior to leukapheresis
9. Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or
equivalent) within 7 days prior to leukapheresis
10. Anti-CD20 monoclonal antibodies within 7 days prior to leukapheresis
11. Venetoclax within 4 days prior to leukapheresis
12. Idelalisib or duvelisib within 2 days prior to leukapheresis
13. Lenalidomide within 1 day prior to leukapheresis
14. Experimental agents, including off-label use of approved drugs (with the
exception of acalabrutinib which may be continued up to the day before
leukapheresis), within 4 weeks prior to leukapheresis unless progression is
documented on the experimental therapy and at least 3 half-lives have elapsed
prior to leukapheresis
• Uncontrolled medical, psychological, familial, sociological, or geographical
conditions that do not permit compliance with the protocol, as judged by the
Investigator; or subject unwillingness or inability to follow the procedures required
in the protocol
• Progressive vascular tumor invasion, thrombosis, or embolism
• Deep vein thrombosis or embolism not managed on a stable regimen of anticoagulation
Phase I Trial of IV Fenretinide (4-HPR) Plus IV Safingol for Patients With Relapsed Malignancies
In preclinical studies, the anti-cancer efficacy of fenretinide, a synthetic retinoid that
causes cytotoxicity by mechanisms which include increased intracellular dihydroceramides,
has been shown to be enhanced by safingol, a stereochemical-variant dihydroceramide
precursor. This phase I study represents the first clinical trial employing this promising
combination. The drug administration schedule (fenretinide given on Days 1-5, safingol given
on Days 1-2 of each 21-day cycle) reflects the in vitro observation that tumor cell exposure
to safingol increased fenretinide efficacy both during and after safingol administration.
The total dose of fenretinide, 4600 mg/m2 over 5 days, represents a 30% total dose reduction
from the single agent MTD dose of 1280 mg/m2/day x 5 days determined on the PhI-42 study.
This fenretinide dose is expected to produce plasma levels in the 30?s ?M. This dose
reduction has been employed to reduce the potential for overlapping hepatic toxicities
between these two agents.
The administration of a reduced fenretinide dose on Day 1 (600 mg/m2 on Day 1, escalated to
1000 mg/m2/day on Days 2-5) has been selected due to earlier observations that initial
exposure to the soy bean oil vehicle in the fenretinide emulsion may induce endogenous
lipases, thereby permitting tolerance of higher total doses fenretinide emulsion
subsequently administered. The starting dose of safingol in this study, 210 mg/m2/day x 2
days (420 mg/m2 total), corresponds to 50% of the recommended Phase II safingol dose (bolus)
determined in the Schwartz, et al, Phase I study of safingol plus cisplatin 60 mg/m2 (the
MTD of single-agent, intravenous (emulsion) safingol was not reached in the Phase I safingol
run-in monotherapy portion of this study), and was selected to provide an adequate safety
margin against the potential for overlapping toxicities (such as hepatic transaminitis).
The study has been designed to optimize the safety of this novel combination. Treatment will
be administered in the inpatient setting. Central venous access will be mandated to avoid
the potential for hemolysis and thrombophlebitis associated with the preclinical peripheral
administration of a previous safingol formulation in rats. To reduce the incidence of
hypertriglyceridemia, a revised fenretinide delivery schedule will be employed. Patients
will also be encouraged to maintain a low-fat diet during fenretinide administration. Serum
triglycerides will be monitored every 12 hours. To monitor for cardiac toxicity, which was
noted in canine studies at the highest dose of safingol plus fenretinide tested, serum
troponin T levels will be monitored daily. To limit the potential for hepatotoxicity
resulting from a possible drug interaction observed between intravenous fenretinide,
ceftriaxone and acetaminophen in a pediatric patient, the concurrent administration of
ceftriaxone, or acetaminophen, with the fenretinide emulsion infusion will be prohibited.
Inclusion Criteria •Solid Tumor
1. Patients must have histologically or cytologically confirmed malignancy that is
metastatic or unresectable and for which standard curative or palliative measures do
not exist or are no longer effective.
2. All patients must have measurable disease documented by CT, MRI, or non-measurable
disease documented by Physical Exam within 28 days prior to registration.
3. Age >18 years.
4. ECOG performance status of 0 •2 (Karnofsky > 60%).
5. Life expectancy of greater than 3 months.
6. Patients must have adequate organ and marrow function as defined below:
• absolute neutrophil count ≥ 1,500/μL
• platelets ≥ 100,000/μL
• total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN)
• AST (SGOT) ≤ 2.5 x institutional upper limit of normal (IULN) ≤ 5 x IULN for
patients with liver metastases
• ALT (SGPT) ≤ 2.5 x institutional upper limit of normal (ULN) ≤ 5 x IULN for
patients with liver metastases − creatinine within institutional normal limits
(WNL) OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine
levels above institutional normal
7. Effects of fenretinide and safingol on the developing human fetus are unknown. For
this reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. For women of child-bearing
potential, a negative serum pregnancy test is required within 72 hours prior to
receiving study drug each cycle. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately.
8. Ability to understand and the willingness to sign a written informed consent
document.
9. Patients who have received prior treatment with oral or intravenous fenretinide as a
single agent are eligible, provided they did not experience severe toxicity related
to fenretinide.
Inclusion Criteria •Non-Hodgkin's Lymphoma
1. Patients must have histologically or cytologically confirmed non-Hodgkin's lymphoma
for which standard therapies do not exist or are no longer effective. To be eligible
for this study, lymphoma patients must have no marrow involvement as documented by
routine marrow aspiration and biopsy performed within 30 days of study entry.
2. All patients must have measurable disease documented by CT, MRI, or non-measurable
disease documented by Physical Exam within 28 days prior to registration.
3. Age 18 years or greater.
4. Patients must have adequate organ and marrow function as defined below:
• Absolute neutrophil count (ANC) ≥ 1500, platelets ≥ 100,000, unless due to
direct bone marrow involvement of disease.
• Hemoglobin ≥ 8.0 gm/dL; transfusion permitted to achieve this level
• Serum creatinine ≤ 1.5 x the upper limits of institutional normal (IULN)
• Total bilirubin ≤ 1.5 x the IULN
• AST/ALT ≤ 2.5 x the IULN
• Or ≤ 5 x IULN for patients with liver metastases
5. ECOG performance status of 0 •2 and estimated survival of at least 3 months.
6. Patients must be able to understand and agree to sign an IRB-approved informed
consent form.
7. The effects of fenretinide and safingol on the developing human fetus are unknown.
For this reason,women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control) prior to study entry, for
the duration of study, and for two months after study participation. For women of
child-bearing potential, a negative serum pregnancy test is required within 72hours
prior to receiving study drug each cycle. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately.
8. Patients who have received prior treatment with oral or intravenous fenretinide as a
single agent are eligible, provided they did not experience severe toxicity related
to fenretinide.
Exclusion Criteria:
1. Radiation therapy, chemotherapy, and other investigational agents within 3weeks (6
weeks for nitrosourea or mitomycin C) prior to starting fenretinide + safingol.
Patients must have recovered from toxicities of prior therapy.
2. Concurrent administration of any other investigational agents
3. Uncontrolled intercurrent illnesses including, but not limited to, ongoing or active
systemic infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, coagulation disorders; other major medical illnesses of the
cardiovascular or respiratory systems or psychiatric illness/social situations that
would limit compliance with study requirements.
4. Pregnant women are excluded from this study because the effects of fenretinide and
safingol on the developing human fetus are unknown. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with fenretinide and safingol, breastfeeding must be discontinued.
5. Major surgery in the last three weeks due to unknown effects of fenretinide and
safingol on wound healing.
6. Patients with previously untreated brain metastases (including parenchymal, meningeal
or dural-based CNS lesions) are excluded. However, patients with previously treated
(surgery, radiation or both), clinically inactive brain metastases, who have not
received corticosteroid therapy within three weeks of starting protocol therapy, are
eligible.
7. Known allergy to egg products or soy bean oil.
8. Patients known to be HIV-positive receiving anti-retroviral therapy are excluded from
the study because of possible pharmacokinetic interactions.
9. Baseline fasting triglycerides > 2.5 institutional upper limit of normal (IULN) or
hypertriglyceridemia requiring medication. Patients requiring medication for other
dyslipidemias (i.e., elevated LDL cholesterol) are eligible.
10. Concomitant use of the following drugs (see Concomitant Medications, Section 3.3):
antioxidants; herbal or other alternative therapy medications; vitamin supplements
(especially vitamins A, C, and E) other than a standard dose multivitamin,
acetaminophen, cyclosporine A or analogue; verapamil; tamoxifen or analogue,
ketoconazole, chlorpromazine; RU486; indomethacin; or sulfinpyrazone, tetracycline,
nalidixic acid, nitrofurantoin, phenytoin, sulfonamides, lithium, ceftriaxone, and
amiodarone.
If the patients discontinue usage of the above drugs, they can be eligible for
enrollment into the study after a washout period of four half-lives.
11. Poorly-controlled diabetes mellitus, as defined as fasting serum glucose
concentration over 200 mg/dl or a hemoglobin A1C over 7.5%.
12. Patients with an identified familial hyperlipidemia disorder.
13. Known history of allergic reactions attributed to compounds of similar chemical or
biologic composition to fenretinide, such as 13-cis-retinoic acid, retinol, or
all-trans-retinoic acid.
14. Patients with esophageal cancer with unresected or recurrent primary tumors in the
esophagus are only permitted after discussion of patient with Study Chair due to
concern of tumor necrosis and esophageal perforation.
15. Baseline (pre-treatment) serum troponin T (TnT) ≥ 0.03 ng/mL. Troponin T levels may
be rechecked and therapy given if levels decrease to < 0.03 ng/mL.
16. Baseline (pre-treatment) EKG with any of the following changes consistent with
cardiac ischemia:
• significant ST depression (ST depression of ≥2 mm, measured from isoelectric
line to the ST segment at a point 60 msec from the end of the QRS complex)
• significant ST elevation (> 1mm in limb lead or 2 mm in precordial lead measured
at a point 0.04 sec (1 mm) after the J-point [the end of the QRS complex] and
compared to baseline [line drawn from P start to T end])
Drug: Fenretinide (4-HPR) plus Intravenous Safingol
Clinical Transplant-Related Long-term Outcomes of Alternative Donor Allogeneic Transplantation (BMT CTN 1702)
The purpose of this study is to determine if a search strategy of searching for an
HLA-matched unrelated donor for allogeneic transplantation if possible then an alternative
donor if an HLA-matched unrelated donor is not available versus proceeding directly to an
alternative donor transplant will result in better survival for allogeneic transplant
recipients within 2 years after study enrollment.
Patients fulfilling the inclusion criteria will be eligible for enrollment in this study.
Of those who consent, only patients who lack a suitable HLA-identical or 1 allele or
antigen mismatched related donors are evaluable. Patients with an HLA-identical sibling or
1 allele or antigen mismatched family member donor are evaluable as long as the center
deems the family member donor as unsuitable for other reasons. Patients may co-enroll with
other interventional or observational studies.
1. Patients of all ages with AML, ALL, MDS, NHL, HL, AA, or SCD are eligible.
2. Any planned conditioning regimen and GVHD prophylaxis approach is eligible.
3. Patients must be considered suitable allogeneic transplant candidates at the time of
enrollment based on medical history, physical examination, and available laboratory
tests. Specific testing for organ function is not required for eligibility but, if
available, these tests should be used by the treating physician to judge transplant
suitability.
4. Patient and physician must intend to proceed with allogeneic HCT within the next 6
months if a suitable donor is identified.
5. Center plans to follow the algorithm for alternative donor identification: (a) for
subjects who are Very Likely to find a MUD, attempt to identify a matched unrelated
donor; (b) for a subjects who are Very Unlikely to find a MUD, proceed expeditiously
to a haploidentical, cord blood or mismatched unrelated donor.
6. Signed informed consent, and assent if applicable. Consent may be signed prior to
completion of family typing but patients will only be considered evaluable upon
confirmation that there is no suitable HLA-identical or 1 allele or antigen mismatched
related donor available.
PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma
This is a phase 1/2 study of a drug called Ixazomib in combination with cytotoxic
chemotherapy consisting of Vincristine, Dexamethasone, Asparaginase, and Doxorubicin (VXLD).
• Age Patients must be ≤21 years of age at the time of enrollment.
1. Phase 1 •Initial enrollment will be restricted to patients < 18 years of age
until 9 such patients are enrolled
2. Phase 2 •Initial enrollment will be restricted to patients < 18 years of age
until 6 such patients are enrolled
• Diagnosis Patients must have a diagnosis of relapsed/refractory ALL or LLy with or
without extramedullary disease (including CNS2 and CNS3). Patient with mixed phenotype
ALL or mature B (Burkitt-like) leukemia are not eligible.
1. Patients with ALL must have ≥ 5% blasts by morphology.
2. Patients with LLy must have measurable disease documented by clinical, radiologic
or histologic criteria
• Performance Level Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for
patients ≤ 16 years of age.
• Prior Therapy A. Prior therapeutic attempts
• Phase 1 •Any patients with relapsed/refractory ALL or LLy
• Phase 2
1. B-cell ALL/LLy: all patients must have failed two or more therapeutic
attempts.
2. T-cell ALL/LLy: all patients must have failed one or more therapeutic
attempts. B. Recent prior chemotherapy Patients must have fully recovered
from the acute toxic effects of all prior chemotherapy, immunotherapy, or
radiotherapy prior to entering this study.
• Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up
to 24 hours prior to the start of protocol therapy.
• Patients who relapsed while they are receiving cytotoxic therapy At least 14 days
must have elapsed since the completion of the last dose of chemotherapy,except
Intrathecal chemotherapy, and/or maintenance therapy such as vincristine,
mercaptopurine, methotrexate or glucocorticoids. There is no waiting period for
those relapsing on maintenance therapy.
C. Hematopoietic stem cell transplant: Patients who have experienced their relapse after a
HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host
Disease (GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 90 days
post-transplant at the time of enrollment.
D. Hematopoietic growth factors: It must have been at least 7 days since the completion of
therapy with G-CSF or other growth factors at the time of enrollment. It must have been at
least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).
E. Biologic (anti-neoplastic agent): At least 7 days since the last dose of a biologic
agent. For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse events
are known to occur. The duration of this interval must be discussed with the study chair
1. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after
the last dose of monoclonal antibody. (i.e., blinatumomab = 6 hours,44 inotuzumab = 37
days, rituximab = 66 days)
2. Immunotherapy: At least 30 days after the completion of any type of immunotherapy,
e.g., tumor vaccines, CAR T cells.
F. XRT: Craniospinal XRT is prohibited during protocol therapy. No washout period is
necessary for radiation given to any extramedullary site other than CNS; ≥90 days must have
elapsed if prior total body irradiation (TBI) or craniospinal XRT.
G. Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m2 of doxorubicin
equivalents of anthracyclines.
H. Proteasome inhibitors: Patients with a prior exposure to proteasome inhibitors (e.g.,
bortezomib, carfilzomib) are eligible as long as the patient demonstrated at least a
partial response to a proteasome inhibitor with chemotherapy combination.
-Renal and hepatic function
Patients must have adequate renal and hepatic functions as indicated by the following
laboratory values:
A. Adequate renal function defined as: Patient must have a calculated creatinine clearance
or radioisotope GFR 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender
B. Adequate Liver Function Defined as: Direct bilirubin ≤ 1.5 x upper limit of normal (ULN)
for age or normal (except in the presence of Gilbert's syndrome), AND alanine transaminase
(ALT) ≤ 5 x ULN for age. The hepatic requirements are waived for patients with known or
suspected liver involvement by leukemia or lymphoma. This must be reviewed by and approved
by the study chair or vice chair.
• Adequate Cardiac Function Defined as: Shortening fraction of more than or equal to 27%
by echocardiogram, OR ejection fraction of equal to or more than 50% by radionuclide
angiogram (MUGA).
• Reproductive Function A. Female patients of childbearing potential must have a
negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
B. Female patients with infants must agree not to breastfeed their infants while on this
study.
C. Male and female patients of child-bearing potential must agree to use an effective
method of contraception approved by the investigator during the study and for a minimum of
6 months after study treatment.
• Informed Consent Patients and/or their parents or legal guardians must be capable of
understanding the investigational nature, potential risks and benefits of the study.
All patients and/or their parents or legal guardians must sign a written informed
consent. Age appropriate assent will be obtained per institutional guidelines. To
allow non-English speaking patients to participate in this study, bilingual health
services will be provided in the appropriate language when feasible.
• All institutional, FDA, and OHRP requirements for human studies must be met.
Exclusion Criteria:
Patients will be excluded if they have isolated CNS or testicular disease.
Patients will be excluded if they have ≥grade 2 peripheral sensory or motor neuropathy
(defined by the Modified "Balis" Pediatric Scale of Pediatric Neuropathies) at the time of
enrollment (see section 4.7.1.1).
Patients will be excluded if they have a known allergy or intolerance to any of the drugs
used in the study •except for PEG-asparaginase for which erwinia asparaginase may be
substituted
Patients will be excluded if they have a systemic fungal, bacterial, viral or other
infection that is exhibiting ongoing signs/symptoms related to the infection without
improvement despite appropriate antibiotics or other treatment. The patient needs to be off
pressors and have negative blood cultures for 48 hours.
Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
radiation therapy, or immunotherapy during the study period.
Patients will be excluded if they have significant concurrent disease, illness, psychiatric
disorder or social issue that would compromise patient safety or compliance with the
protocol treatment or procedures, interfere with consent, study participation, follow up,
or interpretation of study results.
Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are
excluded.
Patients will be excluded if they have had a lifetime exposure of ≥400 mg/m2 doxorubicin
equivolents of anthracyclines (anthracycline equivalence to doxorubicin conversion see
appendix iv) .
Concomitant medications Investigational drugs: Patients currently receiving another
investigational drug are not eligible.
Anti-GVHD agents post transplant: patients who are receiving cyclosporine, tacrolimus or
other agents to prevent graft-versus-host disease post hematopoetic stem cell transplant
are not eligible.
CYP3A4 agents: patients who are currently receiving drugs that are strong inducers of
CYP3A4 are not eligible. Strong inducers of CYP3A4 should be avoided from 14 days prior to
enrollment to the end of the study. See appendix ii for a list of agents which fall into
this category.
Patients with Ph+ALL and Ph-like ALL who are currently receiving TKI therapy
Infants or Patients with Down Syndrome will be excluded in phase 2 of the study
A Study of Repotrectinib in Pediatric and Young Adult Subjects Harboring ALK, ROS1, OR NTRK1-3 Alterations
Phase 1 will evaluate the safety and tolerability at different dose levels of repotrectinib
in pediatric and young adult subjects with advanced or metastatic malignancies harboring
anaplastic lymphoma kinase (ALK), receptor tyrosine kinase encoded by the gene ROS1 (ROS1),
or neurotrophic receptor kinase genes encoding TRK kinase family (NTRK1-3) alterations to
estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the
Pediatric Recommended Phase 2 Dose (RP2D).
Phase 2 will determine the anti-tumor activity of repotrectinib in pediatric subjects with
advanced or metastatic malignancies harboring ALK, ROS1, or NTRK1-3 alterations.
1. Documented genetic ALK, ROS1, or NTRK1-3 alteration (point mutation, fusion,
amplification) as identified by local testing in a Clinical Laboratory Improvement
Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab
outside the United States (US) is required.
2. Age <12 years.
3. Prior cytotoxic chemotherapy is allowed.
4. Prior immunotherapy is allowed.
5. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.03 Grade less than or equal to 1.
6. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in
Neuro-Oncology Criteria (RANO) criteria at time of enrollment.
7. Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a
stable or decreasing dose of steroids for at least 14 days prior to enrollment.
8. Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least
50.
9. Life expectancy greater than or equal to 12 weeks.
10. Adequate hematologic, renal and hepatic function.
Phase 2
Inclusion Criteria:
1. Age 12 to <25 years
2. Cohort Specific
Inclusion Criteria:
• Cohort 1: Subjects with NTRK fusion gene positive (NTRK+) advanced solid tumors
(including primary CNS tumors), that are tropomyosin receptor kinase (TRK) TKI
naïve;
• Cohort 2: subjects with NTRK+ advanced solid tumors (including primary CNS
tumors), that are TRK TKI pre-treated;
• Cohort 3: subjects with tumors or ALCL characterized by other ALK/ROS1/NTRK
alterations or NTRK fusions without centrally confirmed measurable disease or not
otherwise eligible for Cohort 1 or 2.
3. Subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by
BICR prior to enrollment.
Key Exclusion Criteria (Phase 1 and Phase 2):
1. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow
aspiration only.
2. Major surgery within 14 days (2 weeks) of start of repotrectinib treatment. Central
venous access (Broviac, Mediport, etc.) placement does not meet criteria for major
surgery.
3. Known active infections (bacterial, fungal, viral including HIV positivity).
4. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact drug absorption.
5. Any of the following cardiac criteria:
• Mean resting corrected QT interval (ECG interval measured from the onset of the
QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained
from three ECGs, using the screening clinic ECG machine-derived QTc value
• Any clinically important abnormalities in rhythm, conduction, or morphology of
resting ECG (e.g., complete left bundle branch block, third degree heart block,
second degree heart block, PR interval > 250 msec)
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, congenital long QT syndrome, family history of long
QT syndrome, or any concomitant medication known to prolong the QT interval
6. Peripheral neuropathy of CTCAE ≥grade 2.
7. Subjects being treated with or anticipating the need for treatment with strong CYP3A4
inhibitors or inducers.
Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
This Pediatric MATCH screening and multi-sub-study phase II trial studies how well treatment
that is directed by genetic testing works in pediatric patients with solid tumors,
non-Hodgkin lymphomas, or histiocytic disorders that have progressed following at least one
line of standard systemic therapy and/or for which no standard treatment exists that has been
shown to prolong survival. Genetic tests look at the unique genetic material (genes) of
patients' tumor cells. Patients with genetic changes or abnormalities (mutations) may benefit
more from treatment which targets their tumor's particular genetic mutation, and may help
doctors plan better treatment for patients with solid tumors or non-Hodgkin lymphomas.
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients with recurrent or
refractory solid tumors, including non-Hodgkin lymphomas, histiocytoses (e.g.
langerhans cell histiocytosis [LCH], juvenile xanthogranuloma [JXG], histiocytic
sarcoma), and central nervous system (CNS) tumors are eligible; patients must have had
histologic verification of malignancy at original diagnosis or relapse except in
patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with
pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers
including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG); in cases where
patient enrolls prior to histologic confirmation of recurrent disease, patient is
ineligible and should be withdrawn from study if histology fails to confirm
recurrence; please note: Patients with Hodgkin lymphoma and plexiform neurofibroma are
not eligible
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must have an
formalin-fixed paraffin-embedded (FFPE) tumor sample available for MATCH study testing
from a biopsy or surgery that was performed at any point after initial tumor
recurrence/progression, or be planned to have a procedure to obtain such a sample that
is considered to be of potential benefit by the treating clinicians; a tumor sample
from a clinically performed diagnostic (pre-treatment) biopsy will be acceptable for
enrollment onto Pediatric MATCH only for children with high-grade gliomas of the
brainstem (diffuse intrinsic pontine gliomas) or thalamus
• Please note: Samples that have been decalcified using standardly utilized
acid-based decalcification methods are not generally suitable for MATCH study
testing; the nucleic acids will have been degraded in the decalcification process
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Karnofsky >= 50% for patients >
16 years of age and Lansky >= 50 for patients =< 16 years of age); note: neurologic
deficits in patients with CNS tumors must have been stable for at least 7 days prior
to study enrollment; patients who are unable to walk because of paralysis, but who are
up in a wheelchair, will be considered ambulatory for the purpose of assessing the
performance score
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must have
radiographically measurable disease; measurable disease based on imaging obtained less
than or equal to 56 days prior to enrollment; patients with neuroblastoma who do not
have measurable disease but have metaiodobenzylguanidine (MIBG) positive (+) evaluable
disease are eligible; measurable disease in patients with central nervous system (CNS)
involvement is defined as tumor that is measurable in two perpendicular diameters on
magnetic resonance imaging (MRI) and visible on more than one slice
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression
post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: NOTE: patient does not need to meet all
subprotocol criteria at time of enrollment onto the APEC1621SC screening protocol, but
will need to meet all criteria prior to enrollment on any assigned treatment
subprotocol. Patients must be enrolled onto a subprotocol within 8 weeks (56 days) of
treatment assignment
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Karnofsky >= 50% for patients > 16 years
of age and Lansky >= 50 for patients =< 16 years of age); Note: neurologic deficits in
patients with CNS tumors must have been stable for at least 7 days prior to study
enrollment; patients who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the performance
score
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of treatment with subprotocol
specified therapy, the patients must have radiographically measurable disease;
patients with neuroblastoma who do not have measurable disease but have MIBG+
evaluable are eligible; measurable disease in patients with CNS involvement is defined
as tumor that is measurable in two perpendicular diameters on MRI and visible on more
than one slice
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression
post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for
RECIST 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of enrollment onto a
subprotocol, the following general criteria for initiation of therapy will be
required:
• Patients must have fully recovered from the acute toxic effects of all prior
anticancer therapy and must meet the following minimum duration from prior
anticancer directed therapy prior to enrollment to the subprotocol; if after the
required timeframe, the numerical eligibility criteria are met, e.g. blood count
criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anticancer agents known to be
myelosuppressive: for agents not listed, the duration of this interval must
be discussed with the study chair and the study-assigned research
coordinator prior to enrollment >= 21 days after the last dose of cytotoxic
or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anticancer agents not known to be myelosuppressive (e.g. not associated with
reduced platelet or absolute neutrophil counts [ANC]): >= 7 days after the
last dose of agent; for agents not listed, the duration of this interval
must be discussed with the study chair and the study-assigned research
coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of
antibody, and toxicity related to prior antibody therapy must be recovered
to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to prior
therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth
factor; for agents that have known adverse events occurring beyond 7 days
after administration, this period must be extended beyond the time during
which adverse events are known to occur; the duration of this interval must
be discussed with the study chair and the study-assigned research
coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total-body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any
stem cell infusion including donor lymphocyte infusion (DLI) or boost
infusion: >= 84 days after infusion and no evidence of graft versus
host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular
therapy (e.g. modified T cells, NK cells, dendritic cells, etc.)
• X-ray therapy (XRT)/External Beam Irradiation including Protons: >= 14 days
after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to
>= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM)
radiation; note: radiation may not be delivered to "measurable disease"
tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42
days after systemically administered radiopharmaceutical therapy
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: For patients with solid tumors without
known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients with known bone marrow
metastatic disease will be eligible for study provided they meet the blood counts (may
receive transfusions provided they are not known to be refractory to red cell or
platelet transfusions); these patients will not be evaluable for hematologic toxicity
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Creatinine clearance or radioisotope
glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on
age/gender as follows:
• Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
• Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1
• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
• Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Bilirubin (sum of conjugated +
unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Serum glutamate pyruvate transaminase
(SGPT) (alanine transferase [ALT]) =< 135 U/L (for the purpose of this study, the ULN
for SGPT is 45 U/L)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients must be able to swallow intact
capsules/tablets, unless otherwise specified in the subprotocol to which they are
assigned
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Agent specific limitations on prior
therapy will be included with specific treatment subprotocols
Exclusion Criteria:
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Pregnant or breast-feeding women will not
be entered on this study due to risks of fetal and teratogenic adverse events as seen
in animal/human studies, or because there is currently no available information
regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in
females who are post-menarchal; males or females of reproductive potential may not
participate unless they have agreed to use an effective contraceptive method
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Concomitant medications
• Corticosteroids: at the time of consent and enrollment to regimen specific
subprotocols, patients receiving corticosteroids who have not been on a stable or
decreasing dose of corticosteroid for at least 7 days prior to enrollment to the
subprotocol will not be eligible; if used to modify immune adverse events related
to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Investigational drugs: patients must meet criteria for prior therapy at the time
of consent and enrollment to a subprotocol; other investigational agents may not
be administered to patients while they are receiving study drug as part of a
subprotocol
• Anticancer agents: patients must meet criteria for prior therapy at the time of
consent and enrollment to a subprotocol; other investigational agents may not be
administered to patients while they are receiving study drug as part of a
subprotocol
• Anti-GVHD agents post-transplant: patients who are receiving cyclosporine,
tacrolimus or other agents to prevent graft-versus-host disease post bone marrow
transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have an uncontrolled
infection are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have had a prior solid organ
transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Additional agent specific criteria will
be included with specific treatment subprotocols