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Phase 1 Dose-escalating Study of MM-398 (Irinotecan Sucrosofate Liposome Injection) Plus Intravenous Cyclophosphamide in Recurrent or Refractory Pediatric Solid Tumors
This is a Phase 1 study of the combination of two drugs: MM-398 and Cyclophosphamide. The
goal is to find the highest dose of MM-398 that can be given safely when it is used together
with the chemotherapy drug Cyclophosphamide.
• Histologically or cytologically-confirmed Ewing sarcoma, rhabdomyosarcoma,
neuroblastoma, or osteosarcoma
• Disease progression after prior therapy in locally advanced or metastatic setting
• Measurable or evaluable disease based on the Response Evaluation Criteria in Solid
Tumors (RECIST v1.1) criteria
• Age 12 months to <21 years
• Adequate bone marrow reserves, hepatic function, and renal function
• Recovered from effects of any prior surgery or cancer therapy
• Patients 18 years or older will provide written consent. A parent or legal guardian of
a patient <18 years of age will provide informed consent and patients 11 to 18 years
of age will provide written assent or as per participating institutional policy.
Exclusion Criteria:
• Clinically significant gastrointestinal disorders
• NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled
blood pressure
• Active infection or unexplained fever
• Known hypersensitivity to any of the components of MM-398 or other liposomal products
• Recent Investigational therapy
• Pregnant or breast feeding; females of child-bearing potential must test negative for
pregnancy at the time of enrollment
Drug: MM-398 (Irinotecan Sucrosofate Liposome Injection) plus cyclophosphamide
Neuroblastoma, Sarcoma, Ewing Sarcoma, Mycosis Fungoides, Rhabdomyosarcoma, Osteosarcoma, Recurrent or Refractory Solid Tumors, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Hodgkins Lymphoma, Kaposis sarcoma, Other Hematopoietic, Small Intestine, Soft Tissue
Inclusion Criteria-Part A:
Subject must meet all of the following applicable inclusion criteria to participate in this
study:
• Patients must have histologically confirmed advanced RCC (any histology). Collecting
duct tumors and tumors originating from the renal pelvis or upper urinary tract are
considered of urothelial origin and are excluded from this protocol.
• Patients must have at least one measurable site of disease, per RECIST 1.1, that has
not been previously irradiated. If the patient has had previous radiation to the
marker lesion(s), there must be evidence of progression since the radiation.
• Archival tissue of a metastatic lesion obtained within 1 year prior to study
registration (within 4 weeks preferred) and tumor tissue from nephrectomy is required
if available. In addition to archival tissue of a metastatic lesion and nephrectomy,
patients must have at least one site of disease (not including bone metastases)
accessible for biopsy. If biopsy/resection of a new lesion or primary tumor and slow
freezing of fresh tissue for single cell RNAseq study (as specified in the CLM) is not
feasible, the subject is not eligible for the study. All biopsies must be core needle
or excisional. Fine needle aspirate is not acceptable. NOTE: The tissue collected from
a surgical resection or multiple core biopsies of either a metastatic lesion or
primary tumor for the slow freezing of fresh tissue after the patient has signed
consent for the study could also be used for collecting the FFPE specimens.
• ECOG performance status 0-2.
• Age ≥ 18 years.
• Have signed the current approved informed consent form.
• Patients must have adequate organ function within 14 days prior to study entry as
evidenced by screening laboratory values that must meet the following criteria:
• Hematological:
• White blood cell (WBC) ≥ 2000/µL
• Absolute Neutrophil Count (ANC) ≥ 1500/μL
• Platelets (Plt) ≥ 100 x103/μL
• Hemoglobin (Hgb) > 9.0 g/dL (with or without transfusion)
• Renal:
• Serum Creatinine ≤ 1.5 x ULN; if creatinine > 1.5, subject must demonstrate
CrCl as outlined below.
• Calculated creatinine clearance ≥ 40 mL/min using Cockcroft-Gault formula
• Hepatic:
• Bilirubin ≤ 1.5× upper limit of normal (ULN); Except subjects with Gilbert
Syndrome, who can have total bilirubin < 3.0 mg/dL
• Aspartate aminotransferase (AST) ≤ 3 × ULN
• Alanine aminotransferase (ALT) ≤ 3 × ULN
• Patients should not have received prior systemic therapy for metastatic RCC. Prior
radiotherapy must have been completed at least 2 weeks prior to the administration of
study drug. Patients must be 2 weeks from prior major surgery and 1 week from
pre-treatment biopsy. Prior systemic adjuvant therapy (excluding with PD1 or CTLA4
pathway blockers) is allowed if treatment completed > 12 months previously.
• Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months
after the last dose of study drug. NOTE: Contraception is not required for male
participants.
• Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) during screening for
registration purposes. This pregnancy test should be repeated within 24 hours prior to
the start of nivolumab. NOTE: "Women of childbearing potential" is defined as any
female who has experienced menarche and who has not undergone surgical sterilization
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is
defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of
other biological or physiological causes. In addition, women under the age of 55 must
have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/ml.
• Women must not be breastfeeding.
• Be willing and able to comply with this protocol.
Exclusion Criteria:
• Patients are excluded if they have active brain metastases or leptomeningeal
metastases. Subjects with brain metastases are eligible if metastases have been
treated and there is no magnetic resonance imaging (MRI) evidence of progression for 2
weeks of more after treatment is complete and within 28 days prior to the first dose
of nivolumab administration. There must also be no requirement for immunosuppressive
doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2
weeks prior to study drug administration.
• Patients with controlled brain metastases are allowed on protocol if they had solitary
brain metastases that was surgically resected without recurrence or treated with SRS
without progression x 4 weeks.
• Patients should be excluded if they have an active, known or suspected autoimmune
disease. Subjects 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.
• 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.
• As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab
combinations, drugs with a predisposition to hepatoxicity should be used with caution
in patients treated with nivolumab-containing regimen
• Active infection requiring systemic therapy
• Has any other medical or personal condition that, in the opinion of the site
investigator, may potentially compromise the safety or compliance of the patient, or
may preclude the patient's successful completion of the clinical trial
• Patients should be excluded if they are positive test for hepatitis B virus surface
antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating
acute or chronic infection
• Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Allergies and Adverse Drug Reaction
• History of allergy to study drug components
• History of severe hypersensitivity reaction to any monoclonal antibody
• Known additional malignancies within the past 3 years (excluding basal of squamous
cell skin cancers, CIS or localized prostate cancer that has been treated or is being
observed)
Inclusion/Exclusion Criteria- Part B
• Must meet eligibility criteria for initiation of Part A with the exception of being
allowed to have prior nivolumab in Part A of this protocol
• Must have evidence of either RECIST 1.1 defined Disease Progression or Stable Disease
1 year after initiating nivolumab therapy
• Tumor biopsy prior to combination treatment is mandatory. If a biopsy/resection of a
new lesion or primary tumor and slow freezing of fresh tissue for single cell RNAseq
study (as specified in the CLM) is not feasible, the subject is not eligible for the
study. All biopsies must be core needle or excisional. Fine needle aspirate is not
acceptable.
• Must not have had a Grade ≥ 3 irAE on nivolumab monotherapy
• Must not have untreated brain metastases
• Must not have had major surgery or radiation therapy within 14 days of starting study
treatment
• Must not have active autoimmune disease
• Must not have a concurrent medical condition requiring use of systemic corticosteroids
with prednisone >10 mg per day
• Must not have had prior systemic therapy for Stage IV RCC (except for nivolumab as
part of part A of this protocol)
• Prior solid organ or stem cell transplant
Maintenance Chemotherapy With or Without Local Consolidative Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer
This randomized phase II/III trial studies how well giving maintenance chemotherapy with or
without local consolidation therapy works in treating patients with stage IV non-small cell
lung cancer. Drugs used in maintenance chemotherapy, such as docetaxel, pemetrexed disodium,
erlotinib hydrochloride, and gemcitabine work in different ways to stop the growth of tumor
cells, either by killing the cells, by stopping them from dividing, or by stopping them from
spreading. Local consolidation therapy such as radiation/stereotactic body radiation or
surgery may kill cancer cells left after initial treatment. Giving maintenance chemotherapy
and local consolidation therapy together may work better than maintenance chemotherapy alone
in treating patients with stage IV non-small cell lung cancer.
• Patients must have the psychological ability and general health that permits
completion of the study requirements and required follow up
• Women of childbearing potential and men who are sexually active should be willing and
able to use medically acceptable forms of contraception during the trial and for up to
180 days after completion of all treatment to prevent pregnancy or fathering a child.
• Pathologically proven diagnosis of NSCLC, with metastases (stage IV disease) present
prior to registration; this includes patients newly diagnosed with metastatic disease
or those initially diagnosed and treated for stage I-III NSCLC who ultimately develop
metastases
• Appropriate stage for study entry based on the following diagnostic workup:
• History/physical examination within 30 days prior to registration
• Imaging proof of limited metastatic disease and response to therapy/stable
disease, by at least CT chest through the adrenals or PET/CT within 30 days prior
to registration
• Zubrod performance status 0, 1, or 2 within 30 days prior to registration
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of
normal (ULN) or ≤ 5 × ULN with metastatic liver disease
• Total bilirubin ≤ 1.5 × ULN
• Absolute neutrophil count (ANC) ≥ 500 cells/mm^3
• Creatinine clearance ≥ 45 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal
• Platelets ≥ 50,000 cells/mm^3
• Negative serum pregnancy test within one week prior to registration for females of
childbearing potential
• Patients must have received first-line/induction chemotherapy (4 cycles) and achieved
stable disease or a partial response
• Prior systemic chemotherapy as part of concurrent treatment approach for previously
diagnosed stage III NSCLC, as adjuvant therapy for previously resected NSCLC, or for
other previous cancers is permitted
• Prior radiotherapy for patients with brain metastases prior to enrollment is
acceptable
• Patients must have measurable disease at baseline and 3 or fewer discrete,
extracranial metastatic disease sites that are technically amenable to SBRT
• For de novo stage IV NSCLC patients (patients with metastatic disease at first
presentation), primary disease must be treatable with local therapy in the form of
SBRT or hypofractionated radiation; if the primary disease is found in the peripheral
or central lung parenchyma without nodal disease for instance, SBRT may be employed;
if primary disease is more advanced with involvement of the mediastinum (T4 tumor,
N1-N3 disease, etc.), these volumes should be technically treatable with
hypofractionated radiation
• If primary disease in the thoracic cavity was previously treated with local therapy in
the form of surgery, any local/regional disease recurrence should be technically
treatable with SBRT or hypofractionated radiation after induction systemic therapy
• Patients must be registered within 35 days of administration of the last dose of
first-line/induction systemic therapy
• The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry
• Patients with brain metastases are eligible if these lesions have been previously
treated and the patients have no clinical or radiographic evidence of progression
prior to enrollment
Exclusion Criteria:
• Clinical or radiologic evidence of untreated and/or progressive brain metastases
• Cutaneous metastasis of NSCLC
• Metastatic disease invading the esophagus, stomach, intestines, or mesenteric lymph
nodes if not a candidate for surgery for these lesions
• Prior invasive malignancy (except non-melanomatous skin cancer, low or intermediate
risk prostate cancer, or in situ carcinoma of breast, oral cavity, skin, or cervix)
unless disease free for a minimum of one year
• Metastases located within 3 cm of previously irradiated (< 3Gy per fraction)
structures if if not a candidate for surgery for these lesions and if:
• Spinal cord previously irradiated to > 40 Gy
• Brachial plexus previously irradiated to > 50 Gy
• Small intestine, large intestine, or stomach previously irradiated to > 45 Gy
• Brainstem previously irradiated to > 50 Gy
• Lung previously irradiated with prior V20 Gy > 35%
• Patients receiving targeted therapy (non-cytotoxic systemic therapy) for NSCLC in the
first-line setting
• If a patient has progressed in previous areas of primary disease that received
definitive doses of radiation, these patients would require re-irradiation in previous
high dose anatomic areas and are not eligible for this study
• Patients with malignant pleural effusions that do not resolve after first-line
systemic therapy; patients with pleural effusions that have become too small for
thoracentesis at the time of registration would be permitted on study, indicating a
significant response to first-line chemotherapy
• Patients with more than 3 discrete locations of extra-cranial metastatic disease after
first-line systemic therapy requiring more than 3 SBRT plans to cover these distinct
metastatic disease entities
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of
registration
• Patients who are pregnant or nursing
• Participation in any investigational drug study (excluding non-oncology and/or symptom
management studies) within 4 weeks prior to registration
• Known human immunodeficiency virus (HIV) positive with cluster of differentiation 4
(CD4) count < 200 cells/microliter; note that patients who are HIV positive are
eligible, provided they are under treatment with highly active antiretroviral therapy
(HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to
registration; note also that HIV testing is not required for eligibility for this
protocol
• For patients who received immunotherapy during induction, patients on chronic steroids
or who have active autoimmune disease for which they received systemic treatment in
the previous 2 years with corticosteroids, disease modifying agents, or
immunosuppressive drugs are not eligible. Replacement therapy (thyroxine, insulin or
physiological corticosteroid replacement for adrenal or pituitary insufficiency) is
allowed. Patients with active interstitial lung disease or who have a history of
pneumonitis for which they had received glucocorticoids are not eligible
• Prior bevacizumab therapy or other antiangiogenic therapy in first-line or planned
maintenance therapy (due to potential for increased complications from local therapy)
Study of Biomarker-Based Treatment of Acute Myeloid Leukemia
This screening and multi-sub-study Phase 1b/2 trial will establish a method for genomic
screening followed by assigning and accruing simultaneously to a multi-study "Master Protocol
(BAML-16-001-M1)." The specific subtype of acute myeloid leukemia will determine which
sub-study, within this protocol, a participant will be assigned to evaluate investigational
therapies or combinations with the ultimate goal of advancing new targeted therapies for
approval. The study also includes a marker negative sub-study which will include all screened
patients not eligible for any of the biomarker-driven sub-studies.
• Adults, age 60 years or older at the time of diagnosis
• Subjects or their legal representative must be able to understand and provide written
informed consent
• Cohort Inclusion Criteria •Group A: Subjects must have previously untreated acute
myeloid leukemia (AML) according to the WHO classification with no prior treatment
other than hydroxyurea. Prior therapy for myelodysplastic syndrome (MDS),
myeloproliferative syndromes (MPD), or aplastic anemia is permitted but not with
hypomethylating agents.
• Cohort Inclusion Criteria •Group B: Subjects must have relapsed or refractory AML
according to the WHO classification. For study purposes, refractory AML is defined as
failure to ever achieve CR or recurrence of AML within 6 months of achieving CR;
relapsed AML is defined as all others with disease after prior remission. (Group B is
not currently recruiting. Expected to begin recruiting in 3rd quarter 2017.)
Exclusion Criteria:
• Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with
AML to enter the study)
• Acute promyelocytic leukemia
• Symptomatic central nervous system (CNS) involvement by AML
• Signs of leukostasis requiring urgent therapy
• Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis
• Patients with psychological, familial, social, or geographic factors that otherwise
preclude them from giving informed consent, following the protocol, or potentially
hamper compliance with study treatment and follow-up
• Any other significant medical condition, including psychiatric illness or laboratory
abnormality, that would preclude the patient participating in the trial or would
confound the interpretation of the results of the trial
A Study of Therapeutic Iobenguane (131-I) and Vorinostat for Recurrent or Progressive High-Risk Neuroblastoma Subjects (OPTIMUM)
The purpose of this study is to evaluate the efficacy and safety of 131I-MIBG in combination
with Vorinostat in patients with Recurrent or Progressive neuroblastoma
1. Subjects with a diagnosis of iobenguane avid, high-risk neuroblastoma based on Revised
INRC criteria at the time of study enrollment with recurrent or progressive disease at
any time prior to enrollment, regardless of overall response to frontline therapy,
where frontline therapy includes a minimum of 4 cycles of induction therapy at any
time prior to enrollment.
2. May have had prior 131I-MIBG therapy, provided:
1. It has been at least 6 months from the date of last 131I-MIBG ;
2. Response was other than progressive disease on first restaging after 131I-MIBG ;
3. Prior 131I-MIBG was given as monotherapy and not in combination with systemic
anticancer agents;
4. Cumulative lifetime dose of 131I-MIBG at enrollment does not exceed 18 mCi/kg.
3. All soft tissue lesions identified on CT/MRI scans must be iobenguane avid lesions on
an (123I)-iobenguane scan, or
1. any progressive non-iobenguane avid lesion is proven by biopsy to be a
non-neuroblastoma lesion.
2. any other non-avid lesion is comprised of a fibrotic or scarred mass as shown by
routine imaging and confirmed by the investigator.
4. Adequate cryopreserved autologous peripheral blood stem cells or bone marrow (at least
2 aliquots of 2.0 × 10exp6 CD34/kg at the time of study enrollment).
5. If a male, must agree to use an adequate contraception method as deemed appropriate by
the Investigator (e.g., vasectomy, condoms) or partner using effective contraception
and to not donate sperm during the study and for 90 days after receiving the last dose
of study drug.
6. If a female of childbearing potential, have a negative serum pregnancy test result
prior to each dosing and, if sexually active, be practicing an effective method of
birth control [e.g., intrauterine device, double-barrier method (i.e., diaphragm, or a
cervical cap) with intravaginal spermicidal foam, cream or gel], or male partner
sterilization throughout the study.
7. Age at study entry ≥1 year.
8. Previous platelet transfusions are permitted, as long as the subject has a platelet
count ≥50,000/μL without transfusion support for at least 1 week.
9. Subjects must have a minimum pulse oximetry measurement of at least 94% at baseline.
10. An absolute neutrophil count ≥750/μL without growth factor for 5 days.
11. Liver function parameter results: total bilirubin ≤2 × upper limit of normal for age,
and Serum alanine aminotransferase (glutamic-pyruvic transaminase) and serum aspartate
aminotransferase (glutamic-oxaloacetic transaminase) ≤ 10 times the upper limit of
normal (for all sites, the upper limit of normal for alanine aminotransferase is
defined as 45 U/L).
12. Normal thyroid function as measured by T4 or TSH or have abnormal results that are not
considered clinically important by the Investigator or may be receiving levothyroxine.
13. Cardiac Function: shortening fraction of ≥ 27% by echocardiogram or ejection fraction
≥ 50% documented by echocardiogram or radionuclide angiogram within 1 month prior to
Visit 1 (Baseline).
14. Karnofsky Performance Status (for subjects >16 years of age) or the Lansky Performance
Status Performance Status (for subjects 1 to 16 years of age) ≥50%.
15. Full recovery from the toxic effects of any prior therapy.
16. Coagulation Function:
1. International Normalized Ratio (INR) < 1.5
2. Partial thromboplastin time (PTT) < 1.5 times upper limit of normal.
Exclusion Criteria:
1. Subjects within 5 half-lives after any antibody-based immunotherapy, or have not
recovered from effects of any biologic therapy.
2. Subjects <12 weeks after myeloablative therapy with autologous stem cell transplant.
3. Subjects who have had an allogeneic stem cell treatment less than 4 months from Visit
1 are excluded. Those who have received allogeneic stem cell treatment more than 4
months from Visit 1 must have recovered and have no active graft versus host disease
(GVHD) to be eligible.
4. Subjects must not have received radiation for a minimum of 2 weeks prior to study
enrollment. Subjects whose only site(s) of disease have been radiated are eligible as
long as the subject has MIBG avidity 2 weeks after completion of radiation. A minimum
of 12 weeks prior to study enrollment is required following prior large field
radiation therapy (ie, craniospinal, whole abdominal, total lung, > 50% marrow space)
5. History of total body irradiation.
6. Subjects do not have adequate renal function defined as GFR ≥ 70 mL/min/1.73 m2 either
by creatinine clearance or radioisotope direct measurement or by calculation with the
Schwartz formula
7. Subjects who are on hemodialysis.
8. Pregnancy or breastfeeding.
9. Significant active infections including active hepatitis B, or hepatitis C infection,
or known infection with human immunodeficiency virus (HIV) (testing for HIV is not
required prior to study entry).
10. Clinically important cardiac, pulmonary, and hepatic impairment.
11. Vorinostat treatment exclusion criteria (subjects, who meet any one of these criteria
and otherwise meet eligibility criteria, are still eligible for 131I-MIBG monotherapy)
1. Since valproic acid has HDAC inhibitory activity, patients must not have received
valproic acid within 30 days of study entry.
2. Since vorinostat may prolong the QT interval, patients must not be receiving
other medications known to prolong the QT interval at the time of study entry .
Pentamidine must not have been received within 1 week of study enrollment.
3. Patients with a history of deep venous thrombosis that was not associated with
the presence of a central venous catheter.
4. Patients who are receiving Coumadin.
Drug: 131I-MIBG, Drug: 131-MIBG + Vorinostat
Neuroblastoma, Neoplasms, Neuroectodermal Tumors, Brain and Nervous System
Basket Study of Neratinib in Participants With Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations (SUMMIT)
This is an open-label, multicenter, multinational, Phase 2 basket study exploring the
efficacy and safety of neratinib as monotherapy or in combination with other therapies in
participants with HER (EGFR, HER2) mutation-positive solid tumors.
• Provide written informed consent
• Histologically confirmed cancers for which no curative therapy exists
• Documented HER2 or EGFR exon 18 mutation
• Participants must agree and commit to use appropriate methods of contraception as
outlined in the protocol
• At least one measurable lesion, defined by RECIST v1.1
Exclusion Criteria:
• Participants harboring ineligible somatic HER2 mutations
• Prior treatment with any HER2-directed tyrosine kinase inhibitor (e.g., lapatinib,
afatinib, dacomitinib, neratinib) is excluded with the following exception: patients
with EGFR exon 18 mutated NSCLC who may have received afatinib, osimertinib, or other
pan HER or EGFR TKIs remain eligible
• Participants who are receiving any other anticancer agents
• Symptomatic or unstable brain metastases
• Women who are pregnant or breast-feeding
There are additional inclusion and exclusion criteria. The study center will determine if
criteria for participation are met.
A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001) (LIBRETTO-001)
This is an open-label, first-in-human study designed to evaluate the safety, tolerability,
pharmacokinetics (PK) and preliminary anti-tumor activity of selpercatinib (also known as
LOXO-292) administered orally to participants with advanced solid tumors, including
rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer
(MTC) and other tumors with RET activation.
For Phase 1:
• Participants with a locally advanced or metastatic solid tumor that:
• Has progressed on or is intolerant to standard therapy, or
• For which no standard therapy exists, or in the opinion of the Investigator, are not
candidates for or would be unlikely to tolerate or derive significant clinical benefit
from standard therapy, or
• Decline standard therapy
• Prior multikinase inhibitors (MKIs) with anti-RET activity are allowed
• A RET gene alteration is not required initially. Once adequate PK exposure is
achieved, evidence of RET gene alteration in tumor and/or blood is required as
identified through molecular assays, as performed for clinical evaluation
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as
appropriate to tumor type
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance
Score (LPS) greater than or equal to (≥) 40 percent (%) (age less than [<] 16 years)
with no sudden deterioration 2 weeks prior to the first dose of study treatment
• Adequate hematologic, hepatic and renal function
• Life expectancy of at least 3 months
For Phase 2: As for phase 1 with the following modifications:
• For Cohort 1: Participants must have received prior standard therapy appropriate for
their tumor type and stage of disease, or in the opinion of the Investigator, would be
unlikely to tolerate or derive clinical benefit from appropriate standard of care
therapy
• Cohorts 1 and 2:
• Enrollment will be restricted to participants with evidence of a RET gene
alteration in tumor
• At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate
to tumor type and not previously irradiated
• Cohorts 3 and 4: Enrollment closed
• Cohort 5:
• Cohorts 1-4 without measurable disease
• MCT not meeting the requirements for Cohorts 3 or 4
• MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with
neuroendocrine features/differentiation, or poorly differentiated thyroid cancers
with other RET alteration/activation may be allowed with prior Sponsor approval
• cfDNA positive for a RET gene alteration not known to be present in a tumor
sample
• Cohort 6: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who
discontinued another RET inhibitor may be eligible with prior Sponsor approval
• Cohort 7: Participants with a histologically confirmed stage IB-IIIA NSCLC and a RET
fusion; determined to be medically operable and tumor deemed resectable by a thoracic
surgical oncologist, without prior systemic treatment for NSCLC
Key Exclusion Criteria (Phase 1 and Phase 2):
• Phase 2 Cohorts 1 and 2: an additional known oncogenic driver
• Cohorts 3 and 4: Enrollment closed
• Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor Notes: Participants
otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval
• Investigational agent or anticancer therapy (including chemotherapy, biologic therapy,
immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5
half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292
(selpercatinib). In addition, no concurrent investigational anti-cancer therapy is
permitted Note: Potential exception for this exclusion criterion will require a valid
scientific justification and approval from the Sponsor
• Major surgery (excluding placement of vascular access) within 2 weeks prior to planned
start of LOXO-292 (selpercatinib)
• Radiotherapy with a limited field of radiation for palliation within 1 week of planned
start of LOXO-292 (selpercatinib), with the exception of participants receiving
radiation to more than 30% of the bone marrow or with a wide field of radiation, which
must be completed at least 4 weeks prior to the first dose of study treatment
• Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the
exception of alopecia and Grade 2, prior platinum-therapy related neuropathy
• Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated
spinal cord compression. Participants are eligible if neurological symptoms and CNS
imaging are stable and steroid dose is stable for 14 days prior to the first dose of
LOXO-292 (selpercatinib) and no CNS surgery or radiation has been performed for 28
days, 14 days if stereotactic radiosurgery (SRS)
• Clinically significant active cardiovascular disease or history of myocardial
infarction within 6 months prior to planned start of LOXO-292 (selpercatinib) or
prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds
(msec)
• Participants with implanted pacemakers may enter the study without meeting QTc
criteria due to nonevaluable measurement if it is possible to monitor for QT
changes.
• Participants with bundle branch block may be considered for study entry if QTc is
appropriate by a formula other than Fridericia's and if it is possible to monitor
for QT changes.
• Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or
inducers and certain prohibited concomitant medications
• Phase 2 Cohort 7 (neoadjuvant treatment): Participant must not have received prior
systemic therapy for NSCLC.
MEDI9447(Oleclumab) Pancreatic Chemotherapy Combination Study
The objective of this study is to evaluate the safety, tolerability, and antitumor activity
of oleclumab (MEDI9447) in combination with or without durvalumab plus chemotherapy in
subjects with metastatic pancreatic cancer.
1. Age ≥ 18
2. Written and signed informed consent must be obtained
3. ECOG Performance Status 0 or 1
4. Weight ≥ 35 kg
5. Subjects must have histologically or cytologically, confirmed pancreatic
adenocarcinoma:
Cohort A: Subjects with previously untreated metastatic pancreatic adenocarcinoma (1st
line metastatic disease) not previously treated with systemic therapies.
Cohort B: Subjects with metastatic pancreatic adenocarcinoma previously treated with
gemcitabine-based chemotherapy (without exposure to 5-FU, capecitabine, oxaliplatin)
2nd line metastatic disease
6. Subjects must have at least 1 measurable lesion according to RECIST v1.1
7. All subjects must consent to providing archival tumor specimens
Exclusion Criteria:
1. Receipt of any conventional or investigational anticancer therapy within 21 days or
palliative radiotherapy within 14 days prior to the scheduled first dose of study
treatment.
2. Prior receipt of any immune-related therapy
3. Concurrent enrollment in another therapeutic clinical study. Enrollment in
observational studies will be allowed
4. Subjects with a history of venous thrombosis within the past 3 months
5. Subjects with prior history of myocardial infarction, transient ischemic attack, or
stroke in the last 3 months prior to start of treatment
6. Active or prior documented autoimmune or inflammatory disorders within the past 3
years prior to the start of treatment
7. Other invasive malignancy within 2 years.
8. Any history of leptomeningeal disease or cord compression.
9. Current or prior use of immunosuppressive medication within 14 days prior to the first
dose
• Stratum I
• Patients must be less than 18 years of age at the time of diagnosis.
• Patients must have histological verification of the diagnosis of Langerhans cell
histiocytosis according to the criteria described in Section 6.1
• Signed informed consent form
• Stratum II
• Patients of Stratum I who have:
• Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course
• AD intermediate or worse in non-risk organs or AD better in risk organs after 12
weeks (Initial Course 2)
• Disease progression (AD worse) in non-risk organs at any time during continuation
treatment
• Active disease at the end of Stratum I treatment
• Disease reactivation in non-risk organs at any time after completion of Stratum I
treatment
• Stratum III
• Patients from Stratum I who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD
intermediate in risk organs after week 12 (after Initial Course 2).
• Presence of unequivocally severe organ dysfunction at the above mentioned
evaluation points (hematological dysfunction, liver dysfunction, or both of them)
as
• Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency
• PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have
to be fulfilled) AND/OR
• Liver dysfunction (or digestive involvement with protein loss)
• Total protein <55 g/L or substitution dependency
• Albumin <25 g/L or substitution dependency (at least one of the two criteria
to be fulfilled)
• Stratum IV
• Patients from Stratum I or Stratum III who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD
intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I
OR
• AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD
intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND
• Presence of unequivocally severe organ dysfunction at the above mentioned
evaluation points (hematological dysfunction, liver dysfunction, or both of them)
as defined in Table XI (see Section 10.3.1).
• Informed consent: All patients or their legal guardians (if the patient is <18
years of age) must sign an Ethics or institutional Review Board approved consent
form indicating their awareness of the investigational nature and the risks of
this study. When appropriate, younger patients will be included in all
discussions in order to obtain assent.
• Adequate organ function: Patients should have adequate hepatic, renal, cardiac
and pulmonary function to undergo reduced intensity HCT based upon local
institutional guidelines, or at a minimum meet requirements noted in eligibility
checklist Appendix A-VIII_1. However, significant hepatic and pulmonary
dysfunction, if secondary to underlying LCH disease activity, will not exclude
patients from protocol enrollment and should be discussed with the National PI
Coordinator and the Coordinating Principal Investigator.
• Stratum V
• All patients with verified diagnosis of LCH and MRI findings consistent with
ND-CNSLCH irrespective of previous treatments (also those not registered to other
Strata ofLCH-IV).
• Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion
in the hypothalamus-pituitary axis). In patients with already established
diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a
biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion
is needed for inclusion into the study
• Stratum VI
-- Patients with newly diagnosed SS-LCH and localization other than "multifocal
bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
• Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as
consent for longterm follow-up has not been withheld.
Exclusion Criteria:
• Stratum I
• Pregnancy (patients of child-bearing age must be appropriately tested before
chemotherapy)
• LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis,
lung fibrosis, etc.) in the absence of active disease
• Prior systemic therapy
• Stratum II
• Patients with progressive disease in risk organs
• Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without
evidence of active LCH in the same organ or in any other locations
• No written consent of the patient or his/her parents or legal guardian
• Stratum III
• The presence of any of the following criteria will exclude the patient from the
study:
• Isolated sclerosing cholangitis without evidence of active hepatic LCH as the
only evidence of risk organ involvement.
• Inadequate renal function as defined by serum creatinine > 3x normal for age
• Stratum IV
• Pulmonary failure (requiring mechanical ventilation) not due to active LCH.
• Isolated liver sclerosis or pulmonary fibrosis, without active LCH.
• Uncontrolled active life-threatening infection.
• Decreased renal function with a GFR of less than 50ml/1.73m2/min.
• Pregnancy or active breast feeding
• Failure to provide signed informed consent
• Stratum VI
• Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible
for Stratum V),
• Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible
for Stratum I, Group 2)
Hyperpolarized Carbon 13-Based Metabolic Imaging to Detect Radiation-Induced Cardiotoxicity
Patients enrolled in the study will receive standard of care adjuvant or definitive breast,
chest wall or thoracic radiation therapy.Cardiac mitochondrial dysfunction is a hallmark of
radiation-induced cardiac injury. Reactive oxygen species (ROS) produced by ionizing
radiation cause oxidation of mitochondrial proteins and alter oxidative phosphorylation and
pyruvate metabolism(5). The goal of this study is to detect early changes in the
mitochondrial metabolism in situ as a marker for subclinical radiation-induced
cardiotoxicity.
• Tissue diagnosis of benign or malignant tumor of the breast (left-sided only) or
thorax
1. Stage I to III
2. ECOG performance status 0-1
3. The patient must be deemed an appropriate candidate for adjuvant ordefinitive
radiation therapy with or without regional nodal irradiation
4. Radiation therapy planning should be CT scan-based using 3D conformal
radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT) or volumetric arc
therapy (VMAT).
5. 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,
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.
5.1 A female of child-bearing potential is any woman (regardless of sexual
orientation, 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).
5.2. A female of postmenopausal status is defined as patients over 60 or greater
OR patients age 50-59 who meet the following criteria:
• s/p bilateral oophorectomy, OR
• with intact uterus without menses in the past 12 months OR,
• with biochemical confirmation of post-menopausal status (estradiol in the
menopausal range based on local laboratory criteria)
6. Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
1. Prior thoracic radiation therapy
2. Neoadjuvant, adjuvant or prior HER-2 directed therapy
3. Subjects may not be receiving any investigational agents for the treatment of the
cancer under study.
4. Tissue expander placement after mastectomy
5. Diagnosis of connective tissue disorders, including systemic lupus erythematosis,
scleroderma, or dermatomyositis
6. Known metastases
7. 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
8. eGFR <30
9. Any contraindication to MRI (including, but not limited to metal implants and devices
contraindicated at 3T, breast tissue expanders, non-MR compatible IV port,
claustrophobia)
10. History of psychiatric or addictive disorders that would preclude obtaining informed
consent
11. Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
Diagnostic Test: [1-13C]pyruvate along with MRI imaging
Thoracic Cancer, Breast - Female, Cardiovascular, Heart, Left Sided Breast Cancer
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. Chemotherapy drugs, 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 patients and/or their parents or legal guardians must sign a written informed
consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
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 within 1 week (7 days) prior to
the start of systemic protocol therapy.
• 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.
Clinical Trial to Evaluate Zevor-cel (CT053) in Patients With Relapsed and/or Refractory Multiple Myeloma (LUMMICAR STUDY 2)
A phase 1b/2, open label, multi-center, Clinical Study of Chimeric Antigen Receptor T Cells
targeting BCMA in patients with relapsed and or refractory multiple myeloma.
1. Voluntarily signed consent;
2. Age of ≥ 18 and < 80 years;
3. Received sufficient prior lines of myeloma therapy;
4. Received treatment with at least one proteasome inhibitor, one IMiD and CD38 anti
body.
5. The patient must be refractory to the last line of therapy.
6. The patients should have measurable disease per IMWG definition.
7. Estimated life expectancy > 12 weeks;
8. ECOG performance score 0-1;
9. Patients should have reasonable CBC counts, renal and hepatic functions;
10. Sufficient venous access for leukapheresis collection, and no other contraindications
to leukapheresis;
11. Women of childbearing age must undergo a serum pregnancy test with negative results
before screening, and are willing to use effective and reliable method of
contraception for at least 12 months after T cell infusion;
12. Men must be willing to use effective and reliable method of contraception for at least
12 months after T cell infusion.
Exclusion Criteria:
1. Pregnant or lactating women;
2. HIV, active hepatitis C virus (HCV), or active hepatitis B virus (HBV) infection;
3. Any uncontrolled active infection;
4. AEs from previous treatment that have not recovered;
5. Patients who have had anti-BCMA therapy;
6. Patients who have graft versus host disease (GvHD);
7. Patients have received stem cell transplantation one year before leukapheresis;
8. Patients have received any anti-cancer treatment before leukapheresis;
9. Patients have received steroids before leukapheresis or lymphodepletion;
10. Patients have plasma cell leukemia, Waldenström macroglobulinemia, POEMS
(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin
changes) syndrome or clinically significant symptomatic immunoglobulin light chain
(AL) amyloidosis with evidence of end-organ damage;
11. Patients have been administered live attenuated vaccine before leukapheresis or
lymphodepletion;
12. Patients allergic to Flu, Cy, tocilizumab, dimethyl sulfoxide (DMSO) or zevor-cel CAR
BCMA T cell;
13. Patients have clinical significant cardiac conditions that researchers believe that
participating in this clinical trial may endanger the health of the patients;
14. Patients have clinical significant pulmonary conditions;
15. Patients are known to have active autoimmune diseases including but not limited to
psoriasis, rheumatoid arthritis and other needs of long-term immunosuppressive
therapy;
16. Patients with second malignancies in addition to MM are not eligible;
17. Patients have central nervous system (CNS) metastases or CNS involvement;
18. Patients have significant neurologic disorders;
19. Patients are unable or unwilling to comply with the requirements of clinical trial;
20. Patients have received major surgery prior to leukapheresis or prior to
lymphodepletion.
Safety and Efficacy Study of IMSA101 in Refractory Malignancies
Open-label, dose escalation (Phase I) and dose expansion (Phase IIA) study of patients
receiving intra-tumoral IMSA101 alone or in combination with an immune checkpoint inhibitor
(ICI) (Phase I and II)
1. Signed informed consent and mental capability to understand the informed consent
2. Male or female patients > 18 years of age
3. Histologically or cytologically documented locally advanced or metastatic solid tumor
malignancies refractory to or otherwise ineligible for treatment with standard-of-care
agents/regimens, including but not limited to:
• Malignant melanoma
• Hormone receptor negative breast cancer
• Gastro-esophageal cancer
• Non-small cell lung cancer
• Head and neck cancer
• Hepatoma
• Renal cell carcinoma
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
5. Evaluable or measurable disease as follows:
• A minimum of 3 RECIST-evaluable lesions: one that is suitable for injection and
biopsied; one non-injected that will be biopsied for abscopal effect; and one
measurable lesion that will be followed for response only.
• Injectable tumors shall be accessed by intralesional (cutaneous) or percutaneous
injection only, including those lesions that are visible, palpable, or detectable
by standard radiographic or ultrasound methods. Neither surgical procedures nor
endoscopically-guided injections including those to endobronchial, endoluminal,
or endosinusial spaces shall be allowed. While no anatomic locations are required
or disallowed, lesions selected for intratumoral injection must, in the opinion
of the investigator:
• Not be immediately adjacent to blood vasculature or other physiologic landmarks
in such a way that will accrue undue safety risk to the patient
• Have longest diameter ≥ 10 mm and ≤ 50 mm
• Be fully efficacy evaluable per RECIST v1.1 criteria
6. Life expectancy > 3 months (Phase I) and > 6 months (Phase IIA)
7. ECG without evidence of clinically meaningful conduction abnormalities or active
ischemia as determined by the investigator
8. Acceptable organ and marrow function as defined below:
• Absolute neutrophil count > 1,500 cells/μL
• Platelets > 50,000 cells/μL
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤ 2.5 times ULN. If
liver metastases are present, AST/ALT < 5 times ULN
• Serum creatinine < 1.5 mg/dL and a measured creatinine clearance ≥ 50 mL/min
using the Cockcroft-Gault formula
• Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 times ULN
9. Women of child-bearing potential (defined as a female who has experienced menarche and
who has not undergone successful surgical sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as
amenorrhea for at least 12 consecutive months with an appropriate clinical profile at
the appropriate age, e.g., greater than 45 years) must have a negative serum pregnancy
test prior to first dose of study drug
10. Male and female patients with reproductive potential must agree to use two forms of
highly effective contraception throughout the study
11. Phase I combination only: Demonstrated RECIST stable disease through ≥ 4 consecutive
cycles of an approved PD-1 or PD-L1 targeted ICI with no Grade ≥ 3 CTCAE events
considered by the investigator to be drug-related.
Exclusion Criteria:
1. Anti-cancer therapy within 4 weeks or < 5 half-lives of the first dose of study drug.
2. Failure to recover to Grade 1 or less from clinically significant AEs due to prior
anti-cancer therapy.
3. Known untreated brain metastases or treated brain metastases that have not been stable
(scan showing no worsening of central nervous system (CNS) lesion[s] and no
requirement of corticosteroids) ≥ 4 weeks prior to study enrollment
4. Baseline prolongation of QT/QTc interval (QTc interval > 470)
5. 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 opinion of the
investigator would limit compliance with study requirements
6. Women who are pregnant or breastfeeding
7. Phase I combination only: Prior tumor progression through PD-1 or PD-L1 targeted ICI
therapy.
Durvalumab vs Placebo Following Stereotactic Body Radiation Therapy in Early Stage Non-small Cell Lung Cancer Patients (PACIFIC-4)
This is a Phase III, randomized, placebo-controlled, double-blind, multi-center study
assessing the efficacy and safety of durvalumab versus placebo following SoC SBRT in patients
with unresected clinical Stage I/II lymph node-negative (T1 to T3N0M0) NSCLC.
1. Age ≥18 years
2. Histologically or cytologically documented Stage I to II NSCLC, with clinical Stage
I/II lymph node-negative (T1 to T3N0M0) disease and planned to receive definitive
treatment with SBRT. Patients may be medically inoperable or are medically operable
and refusing surgery or choosing to have SBRT (Stereotactic Body Radiation Therapy) as
definitive therapy
3. Completion of SoC SBRT as definitive treatment prior to randomization
4. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) PS of 0, 1,
or 2
5. Life expectancy of at least 12 weeks
6. Body weight >30 kg
7. Tumor sample required
8. Adequate organ and marrow function required
9. Patients with central or peripheral lesions are eligible
10. Staging studies must be done within 8 weeks before randomization
Key
Exclusion Criteria:
1. Mixed small cell and non-small cell cancer histology
2. History of allogeneic organ transplantation
3. History of another primary malignancy with exceptions
4. History of active primary immunodeficiency
5. Any unresolved toxicity National Cancer Institute (NCI) CTCAE Grade ≥2 from SBRT
(Stereotactic Body Radiation Therapy)
Drug: Durvalumab, Other: Placebo
Carcinoma, Non-Small-Cell Lung, Lung/Thoracic
NSCLC, Double- Blind, PD-L1, MEDI4736, Durvalumab, PFS, OS
UT Southwestern; Parkland Health & Hospital System
The primary objective of the Phase 1 part of the study is to determine the recommended dose
of APVO436 administered intravenously to patients with AML or MDS. The primary objective of
the Phase 1b part of the study is to evaluate the clinical activity of APVO436 in patients
with AML or MDS.
APVO436 is being studied in this Phase 1b, open-label, multi-center, two-part
dose-escalation/dose expansion study to evaluate the safety, pharmacokinetic/pharmacodynamic
(PK/PD), and clinical activity of APVO436 in patients with AML and MDS. The study will be
conducted in 2 parts. The first part of this Phase 1B study is an open-label, multiple dose
ascending dose escalation phase to determine the recommended dose (RP2D) level of APVO436 for
future Phase 2 studies. The goal of the dose expansion phase of the study (Part 2) is to (i)
evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an
adjunct to the standard of care and (ii) obtain a preliminary assessment of the anti-leukemia
activity of APVO436-containing experimental monotherapy and combination therapy modalities.
Study Objectives for Dose Escalation Phase
- Primary Objectives are to:
1. Determine the RP2D level of APVO436 administered intravenously (IV) in patients
with AML or MDS, and
2. Evaluate the safety and tolerability of APVO436 at the RP2D level when it is used
as an adjunct to the standard of care and obtain a preliminary assessment of the
anti-leukemia activity of APVO436-containing experimental monotherapy and
combination therapy modalities.
- Secondary Objectives are to:
1. Define the safety profile and immunogenicity of APVO436; to determine the PK/PD of
APVO436; to evaluate the clinical activity of APVO436 in AML and MDS patients.
2. Further evaluate the safety profile and immunogenicity of APVO436 and the PK/PD of
APVO436 and the relationship between PK/PD and clinical response.
Study Objectives for Dose Expansion Phase
- Primary Objective is to evaluate the safety and tolerability of APVO436 at the RP2D
level when it is used as an adjunct to the standard of care.
- Secondary Objective is to obtain a preliminary assessment of the anti-leukemia activity
of APVO436-containing experimental monotherapy and combination therapy modalities.
Inclusion Criteria for Part 1: Dose Escalation Phase:
All patients must meet the following criteria prior to the first dose of study drug:
1. Signed informed consent. Consent must be obtained prior to any study-related
procedure.
2. Age ≥ 18 years
3. Histologically confirmed AML or MDS:
1. AML •relapsed or refractory AML and refuses or is not a candidate for intensive
chemotherapy (due to prior failure or not eligible due to expected intolerance)
or allogeneic transplant
2. MDS •relapsed or refractory MDS with > 5% blasts in the marrow or any blasts in
the peripheral blood. Patients must have failed prior treatment with an HMA
(azacitidine, decitabine, or other HMA agent); failure is defined as intolerance
to HMA, lack of response (no CR by at least 6 cycles), or have IWG-defined
progressive disease during or after treatment with an HMA.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
5. Life expectancy of > 2 months in the Investigator's opinion
6. White blood cells (WBC) ≤ 25,000 cells/mm3 (may receive hydroxyurea to bring WBC count
down prior to and during the first cycle of treatment with study drug if necessary)
7. Creatinine ≤ 2 × upper limit of normal (ULN)
8. Adequate liver test parameters: total bilirubin < 2.5 × ULN (if disease related or
secondary to Gilbert's disease, then total bilirubin < 3.5 mg/dL), aspartate
aminotransferase (AST), and alanine aminotransferase (ALT) < 3 × ULN
9. Prothrombin time (PT) / international normalized ratio (INR) and partial
thromboplastin time (PTT) < 1.5 × ULN
10. Patients and partners of childbearing potential must be willing to use adequate
contraception during the study and for 2 months after last study drug administration.
Adequate contraception means less than 1% chance of pregnancy may occur with proper
use of the method(s).
Exclusion Criteria for Part 1: Dose Escalation Phase:
A patient is not eligible to enroll into the study if they have any of the following:
1. Any CNS (cerebral/meningeal) disease related to underlying malignancy
2. History of seizures
3. Acute promyelocytic leukemia
4. Prior anti-CD123 therapy outside of this study
5. Any clinically significant graft-versus-host disease (GVHD) secondary to prior
allogenic transplant. Patients must be > 90 days from transplant and have been on no
immunosuppressive therapy for > 30 days. Topical corticosteroids for minor skin rash
(<5% body surface area) is acceptable. Prior solid organ transplant is acceptable
provided the patient is on no immunosuppressive therapy.
6. Any therapy or experimental treatment for MDS or AML within 7 days of the first dose
of study drug. Must have recovered to Grade ≤ 1 from any Grade 2 to 4 toxicity from
previous treatment. The use of hydroxyurea is acceptable and does not exclude the
patient.
7. Active, uncontrolled infection requiring systemic therapy. If the infection is
controlled or has resolved, maintenance and/or prophylactic systemic antimicrobials
are permitted.
8. Major surgery within 3 weeks prior to first dose of study drug
9. Known to be positive for HIV, hepatitis B virus surface antigen (HBsAg), hepatitis B
core antibody (HBcAb), or hepatitis C virus (HCV)
10. Pregnant or breast feeding
11. Any other active systemic malignancies. Exceptions: noninvasive non-melanoma skin
cancer, in situ carcinoma, cervical intraepithelial neoplasia, and breast or prostate
cancer that is well controlled with anti-hormonal therapy
12. Any current autoimmune disorder requiring immunosuppressive therapy
13. Requires more than a replacement dose of corticosteroids (i.e., > 10 mg/day of
prednisone or equivalent)
14. Any uncontrolled medical condition, including but not limited to:
1. Symptomatic congestive heart failure ≥ Class III (New York Heart Association
Functional Classification)
2. Uncontrolled hypertension
3. Unstable angina
4. Myocardial infarction within previous 6 months
5. Clinically significant arrhythmias not controlled by medication
6. Uncontrolled metabolic disorders such as hypercalcemia
15. Substance use disorder, psychiatric, cognitive, or any other condition that, in the
opinion of the Investigator, would pose a risk to the patient's safety, may compromise
the patient's ability to understand and comply with the protocol or provide informed
consent, or interfere with the study evaluation
16. Any difficulty complying with protocol requirements that may increase the risk
associated with study participation or study drug administration, or may cause a
safety concern for the patient
Inclusion Criteria for Part 2: Dose Expansion Phase
Individuals eligible to participate in this study must meet all of the following:
All patients must meet the following criteria prior to the first dose of study drug:
1. Signed informed consent. Consent must be obtained prior to any study-related
procedure.
2. Age: >18 years
3. Histologically confirmed AML: Subjects must have de novo (primary) AML (any WHO 2016
classification excluding acute promyelocytic leukemia, AML with myelodysplasia-related
features, and Therapy-related secondary AML (except in Cohort 1 or Cohort 2)
4. Cohort 1: Fit primary or secondary AML patients (Age: >18 years) in 1st or 2nd relapse
with last CR <1 year or primary refractory disease; Relapsed patients must have
relapsed a maximum of two times after standard induction therapy for AML;
5. Cohort 2: Poor prognostic but fit primary or secondary AML patients who are
treatment-naïve or in 1st relapse; patients in relapse must have relapsed only once
after induction/consolidation therapy for AML, i.e., they must be in 1st relapse
6. Cohort 3: Fit primary AML patients with FLT3-negative intermediate or adverse risk AML
(including but not limited to: TP53, RUNX1 and ASXL1 mutations and/or complex
cytogenetics) who are treatment-naïve or in 1st relapse with a duration of CR1<1 year
7. Cohort 3: Patients are required to be either not in CR or be in CR is MRD positive
(≥01% level) by MFC (Central Laboratory) post induction/consolidation to be eligible
for APVO436 treatments.
8. Cohort 4: MRD+ (at ≥0.1% level by multicolor-multiparameter flow cytometry [MFC] in
Central Lab) high-risk 1st remission AML patients
9. Cohort 4: Patients must be newly diagnosed AML patients in 1st remission who achieved
their first remission after standard chemotherapy with a standard induction regimen
with or without post-induction consolidation.
10. Cohort 5: Patients must be AML patients who were in 1st relapse and achieved a 2nd
remission after standard chemotherapy with a standard induction regimen with or
without post-induction consolidation.
11. Cohorts 1-5: If patient was treated with Cytarabine-containing induction or
consolidation regimen, a minimum of 21 days must have passed since the last Cytarabine
dose to allow for resolution of the side effects
12. Cohorts 1-3: Patients must have CD123-positive AML as confirmed by flow cytometry in
Central Laboratory
13. Cohorts 4 and 5: Patients archived bone marrow or peripheral blood leukemic blast
cells must be CD123-positive •local laboratory results are acceptable. If cells are
available, the positivity should be confirmed by Central Laboratory.
14. Patients with precedent MDS are not eligible
15. MRD+ AML patients in Cohort 4 or Cohort 5 must be in CR (CR/CRi) for no more than 6
months and be MRD+, as determined by central hematopathology laboratory
16. MRD+ AML patients in Cohort 4 or Cohort 5 must first have an evaluable screening bone
marrow sample confirmed as MRD+ by central hematopathology laboratory
17. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
18. Life expectancy of > 2 months in the Investigator's opinion
19. Creatinine ≤ 2 × upper limit of normal (ULN)
20. Adequate liver test parameters: total bilirubin < 2.5 × ULN (if disease related or
secondary to Gilbert's disease, then total bilirubin < 3.5 mg/dL), aspartate
aminotransferase (AST), and alanine aminotransferase (ALT) < 3 × ULN
21. Prothrombin time (PT) / international normalized ratio (INR) and partial
thromboplastin time (PTT) < 1.5 × ULN
22. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
sterile) may participate, provided they meet the following conditions:
1. Must agree to use physician-approved contraceptive methods (e.g., abstinence,
intrauterine device, oral contraceptive, double barrier device) throughout the
study and for 3 months following the last dose of APVO436; and
2. Must have a negative serum or urine pregnancy test within 7 days prior to
beginning treatment on this study.
23. Males with female partners of child-bearing potential must agree to use
physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy)
throughout the study and should avoid conceiving children for 3 months following the
last dose of APVO436
Exclusion Criteria for Part 2: Dose Expansion Phase
Subjects with any of the following will not be eligible for study participation:
1. Acute promyelocytic leukemia (APL) with t(15;17) translocation
2. Absolute peripheral blood myeloblast count greater than 20,000/mm3 •may receive
hydroxyurea to reduce and control the myeloblast count down prior to and during the
first week of the first cycle of treatment with study drug if necessary if deemed
medically necessary and appropriate by the treating physician
3. Patients with active central nervous system (CNS) involvement by AML will be excluded.
A lumbar puncture does not need to be performed unless there is clinical suspicion of
CNS involvement per investigator judgement. Concurrent therapy for CNS prophylaxis or
continuation of therapy for controlled CNS AML is allowed with the approval of the
sponsor.
4. History of seizures
5. Prior anti-CD123 therapy with APVO436; prior anti-CD123 therapy with bispecific
antibodies, recombinant fusion proteins or antibody-drug conjugates is allowed.
6. Prior allogeneic, unrelated or autologous hematopoietic stem cell transplantation is
allowed only in Cohort 5. The transplant must have been performed more than 100 days
before the date of dosing on this study without any Grade ≥2 graft-versus-host disease
(GVHD) secondary to prior allogenic transplant. Patients must be > 100 days from
transplant and have been on no immunosuppressive therapy for > 30 days. Topical
corticosteroids for minor skin rash (<5% body surface area) is acceptable.
7. Prior allogeneic, unrelated or autologous hematopoietic stem cell transplantation is
not allowed for Cohorts 1 to 4
8. Prior solid organ transplant is acceptable provided the patient is on no
immunosuppressive therapy.
9. Any therapy or experimental treatment for AML within 7 days of the first dose of study
drug. Must have recovered to Grade ≤ 1 from any Grade 2 to 4 toxicity from previous
treatment. The use of hydroxyurea is acceptable and does not exclude the patient.
10. Active, uncontrolled infection requiring systemic therapy. If the infection is
controlled or has resolved, maintenance and/or prophylactic systemic antimicrobials
are permitted.
11. Major surgery within 3 weeks prior to first dose of study drug
12. Known to be positive for HIV, hepatitis B virus surface antigen (HBsAg), hepatitis B
core antibody (HBcAb), or hepatitis C virus (HCV)
13. Uncontrolled hypertension, defined as blood pressure ≥ 140/90 mm Hg despite maximum
medical intervention
14. History of congenital long QT syndrome or torsades de pointes
15. Pathologic bradycardia or heart block (excluding first degree heart block)
16. Prolonged baseline QTc, defined as QTcF (Fredericia correction) interval >480 msec
(including subjects with a bundle branch block)
17. History of ventricular arrhythmia (excluding PVCs)
18. Major surgery within 28 days prior to informed consent
19. Unstable angina pectoris within 28 days
20. Myocardial infarction and/or new ST elevation or depression or new Q wave on ECG
within 6 months
21. Any history of stroke
22. Symptomatic congestive heart failure Class III or greater (New York Heart Association
Functional Classification)
23. On full dose anti-coagulation defined as warfarin intended to raise the INR to 2-3
24. Major hemorrhagic event within 28 days requiring transfusion of packed red blood cells
25. Prior history of hypertensive crisis or hypertensive encephalopathy
26. Clinical evidence suggestive of central nervous system (CNS) involvement with leukemia
unless a lumbar puncture was performed to confirm the absence of leukemic blasts in
the cerebrospinal fluid (CSF)
27. Systemic fungal, bacterial, viral, or other infection not controlled (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment)
28. Any open wound
29. Pregnant and nursing subjects are excluded because the effects of APVO436 on a fetus
or nursing child are unknown
30. Treatment with any anticancer therapy (standard or investigational) within the
previous 14 days prior to the first dose of study drug. In addition, subjects must
have fully recovered (NCI CTCAE Grade 1) from the clinically significant toxic effects
of that treatment. The use of hydroxyurea in subjects with rapidly proliferating
disease is allowed only during Cycle 1. Hydroxyurea is allowed prior to starting the
study, and may be used for two weeks after dosing in Cycle 1 (e.g., Days 1-14 dosed
with hydroxyurea)
31. Substance use disorder, psychiatric, cognitive, or any other condition that, in the
opinion of the Investigator, would pose a risk to the patient's safety, may compromise
the patient's ability to understand and comply with the protocol or provide informed
consent, or interfere with the study evaluation, study participation, or follow-up
32. Any difficulty complying with protocol requirements that may increase the risk
associated with study participation or study drug administration, or may cause a
safety concern for the patient
33. Any uncontrolled medical condition, including but not limited to:
1. Uncontrolled hypertension
2. Unstable angina
3. Clinically significant arrhythmias not controlled by medication
4. Uncontrolled metabolic disorders such as hypercalcemia
34. Any other active systemic malignancies. Exceptions: noninvasive non-melanoma skin
cancer, in situ carcinoma, cervical intraepithelial neoplasia, and breast or prostate
cancer that is well controlled with anti-hormonal therapy
35. Any current autoimmune disorder requiring immunosuppressive therapy with more than a
replacement dose of corticosteroids (i.e., > 10 mg/day of prednisone or equivalent)
A Study of Atezolizumab Plus Bevacizumab Versus Active Surveillance as Adjuvant Therapy in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation (IMbrave050)
This study will evaluate the efficacy and safety of adjuvant therapy with atezolizumab plus
bevacizumab compared with active surveillance in participants with completely resected or
ablated hepatocellular carcinoma (HCC) who are at high risk for disease recurrence.
• Participants with a first diagnosis of HCC who have undergone either a curative
resection or ablation (radiofrequency ablation [RFA] or microwave ablation [MVA] only)
within 4-12 weeks prior to randomization
• Documented diagnosis of HCC that has been completely resected or ablated (RFA or MVA
only)
• Absence of major macrovascular invasion (except Vp1/Vp2) and extrahepatic spread
• Absence of extrahepatic spread as confirmed by CT or MRI scan of the chest, abdomen,
pelvis, and head prior to and following curative procedure
• Full recovery from surgical resection or ablation within 4 weeks prior to
randomization
• High risk for HCC recurrence after resection or ablation
• For patients who received post-operative transarterial chemoembolization: full
recovery from the procedure within 4 weeks prior to randomization
• For patients with resected HCC, availability of a representative baseline tumor tissue
sample
• ECOG Performance Status of 0 or 1
• Child-Pugh Class A status
• Adequate hematologic and end-organ function
• For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
a condom, and agreement to refrain from donating sperm
Exclusion Criteria:
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• Evidence of residual, recurrent, or metastatic disease at randomization
• Clinically significant ascites
• History of hepatic encephalopathy
• Prior bleeding event due to untreated or incompletely treated esophageal and/or
gastric varices within 6 months prior to randomization
• Have received more than 1 cycle of adjuvant TACE following surgical resection
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening
chest CT scan
• Significant cardiovascular disease within 3 months prior to Day 1 of Cycle 1, unstable
arrhythmia, or unstable angina
• History of malignancy other than HCC within 5 years prior to screening, with the
exception of malignancies with a negligible risk of metastasis or death
• Active tuberculosis
• Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of an investigational drug, may affect
the interpretation of the results, or may render the patient at high risk from
treatment complications
• Pregnant or breastfeeding, or intending to become pregnant during the study or within
5 months after the final dose of atezolizumab or within 6 months after the final dose
of bevacizumab. Women of childbearing potential must have a negative serum pregnancy
test result within 14 days prior to Day 1 of Cycle 1.
• Co-infection with HBV and HCV
• Co-infection with HBV and hepatitis D viral infection
• Clinical significant uncontrolled or symptomatic hypercalcemia
• Any treatment for HCC prior to resection or ablation, including systemic therapy and
locoregional therapy such as TACE
• Treatment with systemic immunostimulatory or immunosuppressive agents
• Inadequately controlled arterial hypertension
• History of hypertensive crisis or hypertensive encephalopathy
• Significant vascular disease
• Evidence of bleeding diathesis or significant coagulopathy
• Current or recent use of aspirin or full-dose oral or parenteral anticoagulants
• Core biopsy within 3 days of Day 1 of Cycle 1
• History of GI fistula, GI perforation, or intra-abdominal abscess
• Serious non-healing or dehiscing wound
• Major surgical procedure within four weeks
• Chronic daily treatment with a non-steroidal anti-inflammatory drug
Drug: Atezolizumab, Drug: Bevacizumab
Carcinoma, Hepatocellular, Liver
UT Southwestern; Parkland Health & Hospital System
Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma
This phase II trial studies how well the combination of dabrafenib and trametinib works after
radiation therapy in children and young adults with high grade glioma who have a genetic
change called BRAF V600 mutation. Radiation therapy uses high energy rays to kill tumor cells
and reduce the size of tumors. Dabrafenib and trametinib may stop the growth of tumor cells
by blocking BRAF and MEK, respectively, which are enzymes that tumor cells need for their
growth. Giving dabrafenib with trametinib after radiation therapy may work better than
treatments used in the past in patients with newly-diagnosed BRAF V600-mutant high-grade
glioma.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patients must be >= 12 months and =< 21
years of age at the time of enrollment on Step 0
• Note: This age range encompasses pre-screening for all HGG patients. Individual
treatment protocols may have different age criteria
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient is suspected of having
localized newly-diagnosed HGG, excluding metastatic disease
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient and/or their parents or legal
guardians have signed informed consent for eligibility screening on APEC14B1 Part A.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): The specimens obtained at the time of
diagnostic biopsy or surgery must be submitted through APEC14B1 as soon as possible
(ASAP), preferably within 5 calendar days of the procedure.
Please note: See the APEC14B1 Manual of Procedures for a full list of detailed instructions
for submitting required materials and for shipping details
• Patients must be >= 3 years and =< 21 years of age at the time of enrollment
• Patients must have eligibility confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1
• Newly diagnosed high-grade glioma with BRAF^V600-mutation
• Results for H3 K27M by immunohistochemistry (IHC) or sequencing
• Histologically confirmed high-grade glioma (World Health Organization [WHO] grade
III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic
pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG),
glioblastoma (GB), and high-grade astrocytoma, not otherwise specified (NOS)
• Patients must have had histologic verification of a high-grade glioma diagnosis.
Cerebrospinal fluid (CSF) cytology by lumbar puncture must be done if clinically
indicated and determined to be safe prior to study enrollment. If cytology proves
positive, the patient would be considered to have metastatic disease and would,
therefore, be ineligible.
• A pre- and post-operative brain magnetic resonance imaging (MRI) with and without
contrast and a baseline spine MRI with contrast must be obtained prior to enrollment.
The requirement for a post-operative MRI is waived for patients who undergo biopsy
only. If the spine MRI is positive, the patient would be considered to have metastatic
disease and would be ineligible.
• 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.
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
enrollment).
• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
enrollment).
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days
prior to enrollment).
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 (within 7 days prior to enrollment) or
• A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
• Age 3 to < 6 years (Male 0.8 mg/dL, Female 0.8 mg/dL)
• Age 6 to < 10 years (Male 1 mg/dL, Female 1 mg/dL)
• Age 10 to < 13 years (Male 1.2 mg/dL, Female 1.2 mg/dL)
• Age 13 to 16 < years (Male 1.5 mg/dL, Female 1.4 mg/dL)
• Age >= 16 years (Male 1.7 mg/dL, Female 1.4 mg/dL)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment), and
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for
SGPT is 45 U/L.
• Patients with a seizure disorder may be enrolled if their seizures are well controlled
while on non-enzyme inducing anticonvulsants permitted on this study.
• Patients must be enrolled and protocol therapy must be projected to begin no later
than 31 days after definitive surgery (day 0). If a biopsy only was performed, the
biopsy date will be considered the date of definitive surgery. For patients who have a
biopsy or incomplete resection at diagnosis followed by additional surgery, the date
of the last resection will be considered the date of definitive surgery.
• All patients and/or their parents or legal guardians must sign a written informed
consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
Exclusion Criteria:
• Patients with intrinsic brainstem or primary spinal cord tumors will be excluded.
• Patients with metastatic disease (defined as neuraxis dissemination either by imaging
or by cytology) will be excluded.
• Patients must not have received any prior tumor-directed therapy including
chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the
treatment of HGG other than surgical intervention and/or corticosteroids.
• Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK
inhibitor, or an ERK inhibitor.
• Patients with a history of a malignancy with confirmed activating RAS mutation.
• History of allergic reactions attributed to compounds of similar chemical or biologic
composition to dabrafenib, trametinib, and their excipients.
• Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease,
or uncontrolled infection), psychological, familial, sociological, or geographical
conditions that do not permit compliance with the protocol; or unwillingness or
inability to follow the procedures required in the protocol.
• Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel
or large bowel resection) that will interfere significantly with the absorption of
drugs.
• History of hepatitis B virus, or hepatitis C virus infection (patients with laboratory
evidence of cleared hepatitis B virus and/or hepatitis C virus may be enrolled).
• History or current diagnosis of cardiac disease indicating significant risk of safety
for patients participating in the study such as uncontrolled or significant cardiac
disease, including any of the following:
• Recent myocardial infarction (within the last 6 months);
• Uncontrolled congestive heart failure;
• Unstable angina (within last 6 months);
• Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias
(e.g., sustained ventricular tachycardia, and clinically significant second or
third degree atrioventricular [AV] block without a pacemaker) except sinus
arrhythmia within the past 24 weeks prior to the first dose of study treatment;
• Coronary angioplasty or stenting (within last 6 months);
• Intra-cardiac defibrillators;
• Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram.
• Patients with a history or current evidence of retinal vein occlusion (RVO) or central
serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled
glaucoma or ocular hypertension).
• Patients with presence of interstitial lung disease or pneumonitis.
• Female patients who are pregnant are ineligible since there is yet no available
information regarding human fetal or teratogenic toxicities.
• Lactating females are not eligible unless they have agreed not to breastfeed their
infants for the duration of the study and for 4 months following discontinuation of
study therapy.
• Female patients of childbearing potential are not eligible unless a negative pregnancy
test result has been obtained.
• Sexually active patients of reproductive potential (male or female) are not eligible
unless they have agreed to use an effective contraceptive method for the duration of
their study participation and for 4 months following discontinuation of study therapy.
Male patients (including those who have had a vasectomy) taking dabrafenib and
trametinib combination therapy must use a condom during intercourse while on study and
for 16 weeks after stopping treatment, and should not father a child during these
periods. Women of childbearing potential should use effective non-hormonal
contraception during therapy and for 4 weeks following discontinuation of dabrafenib
and at least 4 months following the last dose of trametinib in patients taking
combination therapy. Women should be advised that dabrafenib may decrease the efficacy
of hormonal contraceptives and an alternate method of contraception, such as barrier
methods, should be used.
1. At least 18 years of age. Both men and women and members of all races and ethnic
groups will be included.
2. Willing and able to provide written informed consent
3. Pathologic diagnosis of rectal adenocarcinoma
4. Stage III or Stage II with at least 1 of the following high-risk features:
• Distal (<1cm from anal ring)
• cT4 or within 3mm of MR fascia
• Not candidate for sphincter preservation
• Extramural venous invasion
5. No prior treatment for rectal adenocarcinoma
6. Eastern Cooperative Group (ECOG) performance status of 0-1.
7. Laboratory values supporting acceptable organ and marrow function within 21 days of
eligibility confirmation. Defined as follows:
• WBC ≥ 3,000/mL;
• ANC WBC ≥ 1,500/mL;
• PLT ≥ 100,000/mL;
• T Bili ≤ 1.5 x upper limit of normal (ULN);
• AST/ALT ≤ 2.5 x ULN;
• Creatinine ≤ 1.5 times upper limit of normal or calculated creatinine clearance >
45 mL/min per Cockcroft-Gault equation.
8. Female participants of childbearing potential (FOCBP) must have a negative serum or
urine pregnancy test (per institutional standards) within 72 hours prior to the start
of study drug.
FOCBP must agree to use highly-effective method(s) of contraception (Appendix A)
during the study and for 90 days after the last dose of study drugs.
FOCBP are those who have not been surgically sterilized (hysterectomy, bilateral
oophorectomy, or bilateral salpingectomy) or have not been free from menses for >1
year without an alternative medical cause.
9. Male participants must agree to use an adequate method of contraception (Appendix A)
starting with the first dose of study therapy through 90 days after the last dose of
study drugs.
Exclusion Criteria:
1. Distant nodal disease (retroperitoneal nodes) including inguinal nodes, or any
metastatic disease by CT or PET
2. Prior RT to the pelvis.
3. Uncontrolled comorbid illness or condition including an active infection, congestive
heart failure, unstable angina, cardiac arrhythmia, or psychiatric illness that would
limit compliance with the study requirements.
4. Prior treatment with any anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways.
5. Any positive history for HIV/AIDS, HTLV, hepatitis B or hepatitis C virus indicating
acute or chronic infection.
6. Any active known or suspected autoimmune disease. Participants with 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 are permitted to enroll.
7. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalent) or other immunosuppressive medications within 14 days prior to
the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses
up to 10 mg daily prednisone equivalent are permitted (although not encouraged) in the
absence of active autoimmune disease.
8. Malignancy in the past 3 years that required active treatment except locally curable
cancers or cancers deemed by the treating physicians to not impact the subject's
survival duration.
9. Participants receiving any other investigational agent, standard antineoplastic
agents, or immunosuppressive agents.
10. Known history of interstitial lung disease.
11. Received live vaccine within 6 weeks prior to randomization.
12. Psychiatric illness/social situations that would limit consenting and compliance with
study requirements.
13. Participants who are pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
14. Patient is not a candidate for the full treatment regimen.
Drug: APX005M, mFOLFOX, and Radiation Therapy 5Gy x 5 days, Drug: mFOLFOX and Radiation Therapy 5Gy x 5 days
Locally Advanced Rectal Adenocarcinoma, Rectum
UT Southwestern; Parkland Health & Hospital System
Ruxolitinib and Venetoclax in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
This phase I trial studies the side effects and best dose of ruxolitinib when given together
with venetoclax in treating patients with acute myeloid leukemia that has come back
(relapsed) or has not responded to treatment (refractory). Ruxolitinib may stop the growth of
cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax may stop the
growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. This
study is being done to see if the combination of ruxolitinib and venetoclax works better in
treating patients with acute myeloid leukemia compared to standard of care chemotherapy.
• Ability to understand and the willingness to sign a written informed consent document
• Morphologically documented relapsed/refractory acute myeloid leukemia (AML) as defined
by World Health Organization (WHO) criteria after at least 1 prior therapy for AML
with the exception of hydroxyurea. Patients with myelodysplastic syndrome (MDS)
transformed to AML that have been treated with hypomethylating agents may be
considered if they fulfill one or more of the following criteria: 1) patient has a
left ventricular ejection fraction of 45% or less; 2) patient has a serum creatinine
of >= 1.4 gm/dl; 3) patient is age 75 or older
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• Women must not be pregnant or breastfeeding. Women of childbearing potential must have
a negative serum or urine pregnancy test within 14 days prior to start of study drug
administration
• Participants must agree to use an adequate method of contraception
• Must be able to take oral medications
• Creatinine clearance >= 30 mL/min; calculated by the Cockcroft Gault formula or
measured by 24 hours urine collection
• Total serum bilirubin =< 1.5 x upper limit of normal (ULN) unless thought to be due to
leukemic involvement
• Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =< 3.0 x ULN
unless thought to be due to leukemic involvement
Exclusion Criteria:
• Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype)
• Active central nervous system involvement with AML
• Concurrent active malignancy with expected survival of less than 1 year. For example,
candidates with treated skin cancers, prostate cancer, breast cancer, etc. without
metastatic disease are candidates for therapy since their expected survival exceeds
that of relapsed or refractory AML. All subjects with concurrent malignancies will be
reviewed by the principal investigator (PI) prior to enrollment
• Clinically significant graft versus host disease (GVHD) or active GVHD requiring
initiation or escalation of treatment within 28 day screening period
• Participants with rapidly progressive disease (defined by blast count doubles within
48 hours) or organ dysfunction
• Clinically significant coagulation abnormality, such as disseminated intravascular
coagulation
• Participants who are currently receiving any other investigational agents
• Known clinically significant liver disease defined as ongoing drug-induced liver
injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic
liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic
obstruction caused by cholelithiasis, cirrhosis of the liver, portal hypertension, or
history of autoimmune hepatitis
• Untreated human immunodeficiency virus (HIV) or active hepatitis C detectable by
polymerase chain reaction (PCR), or chronic hepatitis B (patients positive for
hepatitis B core antibody who are receiving intravenous immunoglobulin [IVIG] are
eligible if hepatitis [Hep]B PCR is negative)
• Known history of cerebrovascular accident, myocardial infarction, or intracranial
hemorrhage within 2 months of enrollment
• Clinically significant surgery within 2 weeks of enrollment
• Per PI discretion, active infection that is not well controlled by antibacterial or
antiviral therapy
• Participants with known history of tuberculosis (TB; Mycobacterium tuberculosis)
are not eligible for participation. At investigator discretion, latent TB test
should be performed for individuals considered to be at high-risk (e.g., immune
compromised, persons that have traveled to, or emigrated from, regions with high
rates of TB)
• Cancer-directed therapy within 1 week prior to starting treatment, with the exception
of hydroxyurea, which is allowed to control white blood cell count
• Unwillingness to receive infusion of blood products
• Participant on any of the following therapies need to be discussed with the sponsor
investigator:
• Strong and moderate CYP3A inhibitors
• Strong and moderate CYP3A inducers
• Patients with uncontrolled white blood cell count (defined as > 50 K/mm^3 not
controlled with hydroxyurea)
• Patients with known sensitivity to ruxolitinib or venetoclax
Drug: Ruxolitinib, Drug: Venetoclax
Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Refractory Acute Myeloid Leukemia, Recurrent Acute Myeloid Leukemia, Leukemia, Other
A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of Sotorasib (AMG 510) in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100)
Evaluate the safety and tolerability of sotorasib in adult subjects with KRAS p.G12C mutant
advanced solid tumors.
Estimate the maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) in adult
subjects with KRAS p.G12C mutant advanced solid tumors.
• Men or women greater than or equal to 18 years old.
• Pathologically documented, locally-advanced or metastatic malignancy with, KRAS p.G12C
mutation identified through molecular testing.
Exclusion Criteria
• Active brain metastases from non-brain tumors.
• Myocardial infarction within 6 months of study day 1.
• Gastrointestinal (GI) tract disease causing the inability to take oral medication.
Drug: sotorasib, Drug: Anti PD-1/L1, Drug: Midazolam
Study of Adjuvant Cemiplimab Versus Placebo After Surgery and Radiation Therapy in Patients With High Risk Cutaneous Squamous Cell Carcinoma
The primary objective of the study is to compare disease-free survival (DFS) of patients with
high-risk cutaneous squamous cell carcinoma (CSCC) treated with adjuvant cemiplimab, versus
those treated with placebo, after surgery and radiation therapy (RT).
The secondary objectives of the study are:
- To compare the overall survival (OS) of high-risk CSCC patients treated with adjuvant
cemiplimab, versus those treated with placebo, after surgery and RT
- To compare the effect of adjuvant cemiplimab with that of placebo on patients' freedom
from locoregional recurrence (FFLRR) after surgery and RT
- To compare the effect of adjuvant cemiplimab with that of placebo on patients' freedom
from distant recurrence (FFDR) after surgery and RT
- To compare the effect of adjuvant cemiplimab with that of placebo on the cumulative
incidence of second primary CSCC tumors (SPTs) after surgery and RT
- To evaluate the safety of adjuvant cemiplimab and that of placebo in high-risk CSCC
patients after surgery and RT
• For Japan only, men and women ≥21 years old
• Patient with resection of pathologically confirmed CSCC (primary CSCC lesion only, or
primary CSCC with nodal involvement, or CSCC nodal metastasis with known primary CSCC
lesion previously treated within the draining lymph node echelon), with macroscopic
gross resection of all disease
• High risk CSCC, as defined in the protocol
• Completion of curative intent post-operative radiation therapy (RT) within 2 to 6
weeks of randomization
• Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1
• Adequate hepatic, renal, and bone marrow function as defined in the protocol
Key
Exclusion Criteria:
• Squamous cell carcinomas (SCCs) arising in non-cutaneous sites as defined in the
protocol
• Concurrent malignancy other than localized CSCC and/or history of malignancy other
than localized CSCC within 3 years of date of randomization as defined in the protocol
• Patients with hematologic malignancies (eg, chronic lymphocytic leukemia (CLL))
• Patients with history of distantly metastatic CSCC (visceral or distant nodal), unless
the disease-free interval is at least 3 years (regional nodal involvement of disease
in draining lymph node basin that was resected and radiated prior to enrollment will
not be exclusionary)
• Ongoing or recent (within 5 years of randomization date) evidence of significant
autoimmune disease that required treatment with systemic immunosuppressive treatments,
which may suggest risk for immune-related adverse events (irAEs). The following are
not exclusionary: vitiligo, childhood asthma that has resolved, type 1 diabetes,
residual hypothyroidism that required only hormone replacement, or psoriasis that does
not require systemic treatment.
• Has had prior systemic anti-cancer immunotherapy for CSCC
Note: Other protocol defined Inclusion/Exclusion criteria apply
A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)
Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the
maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose
(RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an
ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction.
Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded
Independent Central Review (BICR) of repotrectinib in each subject population expansion
cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene
rearrangement. The secondary objective will include the duration of response (DOR), time to
response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit
rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a
ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on
Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by
protocol specified tests.
2. ECOG PS 0-1.
3. Age ≥18 (or age ≥ 20 of age as required by local regulation).
4. Capability to swallow capsules intact (without chewing, crushing, or opening).
5. At least 1 measurable target lesion according to RECIST version 1.1. CNS-only
measurable disease as defined by RECIST version 1.1 is allowed.
6. Prior cytotoxic chemotherapy is allowed.
7. Prior immunotherapy is allowed.
8. 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.
9. Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
10. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN;
Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present
Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are
present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or
without supplementation
11. Life expectancy ≥ 3 months.
PHASE 2 Key Inclusion Criteria
1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) that harbors a ROS1, or NTRK1-3 gene
fusion.
2. Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based
local testing using either:
1. a next-generation sequencing (NGS) or quantitative polymerase chain reaction
(qPCR) test will be accepted to determine molecular eligibility.
• Adequate tumor tissue needs to be sent to the Sponsor designated central
diagnostic laboratory for retrospective confirmation by a central diagnostic
laboratory test selected by the Sponsor.
OR
2. a fluorescence in situ hybridization (FISH) test AND prospective confirmation of
fusion status by a central diagnostic laboratory test selected by the Sponsor
PRIOR to enrollment will be accepted to determine molecular eligibility.
• Adequate tumor tissue must be sent to the Sponsor designated central
diagnostic laboratory for prospective confirmation by a central diagnostic
laboratory test selected by the Sponsor PRIOR to enrollment.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
4. Age ≥12 (or age ≥ 20 as required by local regulation).
5. Willing and able to provide written institutional review board (IRB)/institutional
ethics committee-approved Informed Consent or an Assent signed by a parent or legal
guardian for subjects age 12 to 17.
6. At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed
by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to
enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST
(v1.1) are eligible.
7. Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3
rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all
inclusion and exclusion criteria are met.
i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based
chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv.
EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+
solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors
8. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
9. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases
(ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline
phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present;
Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without
supplementation
10. Life expectancy ≥ 3 months.
Key Exclusion Criteria PHASE 1 and PHASE 2
1. Concurrent participation in another therapeutic clinical trial.
2. Symptomatic brain metastases or leptomeningeal involvement.
3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the
skin, or any in situ carcinoma that has been completely resected, requiring therapy
within the previous 2 years.
4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy
(except palliative to relieve bone pain) within 2 weeks of study entry. Palliative
radiation (≤10 fractions) must have been completed at least 48 hours prior to study
entry
5. Clinically significant cardiovascular disease (either active or within 6 months prior
to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure (New York Heart Association
Classification Class ≥ II), cerebrovascular accident or transient ischemic attack,
symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac
dysrhythmias of NCI CTCAE grade ≥2
6. 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 (QTcF) > 470 msec obtained from 3
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, hypokalemia, congenital long QT
syndrome, family history of long QT syndrome, or any concomitant medication known to
prolong the QT interval.
7. Known active infections (bacterial, fungal, viral including HIV positivity).
8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact drug absorption.
9. Peripheral neuropathy of CTCAE ≥grade 2.
10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4
interstitial fibrosis or interstitial lung disease including a history of pneumonitis,
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,
obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior
radiation pneumonitis are not excluded.
The Role of 68Gallium PSMA-11 in Enhancing Diagnosis of Primary and Metastatic Prostate Cancer
To goal of this research is to assess the ability of Gallium-68 (68Ga) Prostate-Specific
Membrane Antigen-11 (PSMA-11) positron emission tomography/computed tomography (PET/CT) to
increase diagnostic accuracy in localizing primary and metastatic lesions in patients with
suspected prostate cancer and elevated Prostate Imaging Reporting and Data System (PI-RADS)
scores and Prostate-Specific Antigen (PSA).
• Patients with suspected prostate cancer (e.g., abnormal digital rectal exam, elevated
and/or rising PSA) as determined by referring physician
• Patients must have had a diagnostic, standard of care mpMRI of the prostate with at
least one lesion with a PI-RADS v2.1 score ≥ 4
• In men with PI-RADS v2.1 score 4, PSA should be ≥ 10 ng/mL. In men with at least one
PI-RADS v2.1 score 5 lesion, there is no restriction on PSA level.
• Patients must be scheduled for biopsy or radical prostatectomy
• Patients should not have had any type of curative or palliative therapy for prostate
cancer before enrolling in the study
• Patients must be medically stable as judged by the patient's physician
• Patients must be able to lie still for a total of 60 minutes for the PET/CT scans
• Ability to understand and the willingness to sign a written informed consent
Exclusion Criteria:
• Patients who have had a prior prostatectomy or radiotherapy for prostate cancer cannot
participate in the study
• Patients who have had a prior biopsy for prostate cancer cannot participate in the
study
• Patients who have been treated for cancers other than skin cancers
• Subjects may not be receiving any other investigational agents for the treatment of
the cancer under study
• Patients may not weigh more than the maximum weight limit for the PET/CT scanner table
(>200 kilograms or 440 pounds)
• History of allergic reactions attributed to compounds of similar chemical or biologic
composition to 68Ga PSMA-11 or other agents used in the study such as gadolinium-based
intravenous contrast agent used during the mpMRI
• Prior TURP/BPH procedures, including steam/laser therapies
A Study to Compare Standard Chemotherapy to Therapy With CPX-351 and/or Gilteritinib for Patients With Newly Diagnosed AML With or Without FLT3 Mutations
This phase III trial compares standard chemotherapy to therapy with liposome-encapsulated
daunorubicin-cytarabine (CPX-351) and/or gilteritinib for patients with newly diagnosed acute
myeloid leukemia with or without FLT3 mutations. Drugs used in chemotherapy, such as
daunorubicin, cytarabine, and gemtuzumab ozogamicin, 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. CPX-351 is made up of daunorubicin and cytarabine and is made
in a way that makes the drugs stay in the bone marrow longer and could be less likely to
cause heart problems than traditional anthracycline drugs, a common class of chemotherapy
drug. Some acute myeloid leukemia patients have an abnormality in the structure of a gene
called FLT3. Genes are pieces of DNA (molecules that carry instructions for development,
functioning, growth and reproduction) inside each cell that tell the cell what to do and when
to grow and divide. FLT3 plays an important role in the normal making of blood cells. This
gene can have permanent changes that cause it to function abnormally by making cancer cells
grow. Gilteritinib may block the abnormal function of the FLT3 gene that makes cancer cells
grow. The overall goals of this study are, 1) to compare the effects, good and/or bad, of
CPX-351 with daunorubicin and cytarabine on people with newly diagnosed AML to find out which
is better, 2) to study the effects, good and/or bad, of adding gilteritinib to AML therapy
for patients with high amounts of FLT3/ITD or other FLT3 mutations and 3) to study changes in
heart function during and after treatment for AML. Giving CPX-351 and/or gilteritinib with
standard chemotherapy may work better in treating patients with acute myeloid leukemia
compared to standard chemotherapy alone.
• All patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part
A) prior to enrollment and treatment on AAML1831. Submission of diagnostic specimens
must be done according to the Manual of Procedures
• Patients must be less than 22 years of age at the time of study enrollment
• Patient must be newly diagnosed with de novo AML according to the 2016 World Health
Organization (WHO) classification with or without extramedullary disease
• Patient must have 1 of the following:
• >= 20% bone marrow blasts (obtained within 14 days prior to enrollment)
• In cases where extensive fibrosis may result in a dry tap, blast count
can be obtained from touch imprints or estimated from an adequate bone
marrow core biopsy
• < 20% bone marrow blasts with one or more of the genetic abnormalities
associated with childhood/young adult AML as provided in the protocol
(sample obtained within 14 days prior to enrollment)
• A complete blood count (CBC) documenting the presence of at least 1,000/uL
(i.e., a white blood cell [WBC] count >= 10,000/uL with >= 10% blasts or a
WBC count of >= 5,000/uL with >= 20% blasts) circulating leukemic cells
(blasts) if a bone marrow aspirate or biopsy cannot be performed (performed
within 7 days prior to enrollment)
• ARM C: Patient must be >= 2 years of age at the time of Late Callback
• ARM C: Patient must have FLT3/ITD allelic ratio > 0.1 as reported by Molecular
Oncology
• ARM C: Patient does not have any congenital long QT syndrome or congenital heart block
• ARM C: Females of reproductive potential must agree to use effective contraception
during treatment and for at least 6 months after the last dose of gilteritinib
• ARM C: Lactating women must agree not to breastfeed during treatment with gilteritinib
and for 2 months after the last dose of gilteritinib
• ARM C: Males of reproductive potential must agree to use effective contraception
during treatment and for at least 4 months after the last dose of gilteritinib
• ARM D: Patient must be >= 2 years of age at the time of Late Callback
• ARM D: Patient must have one of the clinically relevant non-ITD FLT3 activating
mutations as reported by Foundation Medicine
• ARM D: Females of reproductive potential must agree to use effective contraception
during treatment and for at least 6 months after the last dose of gilteritinib
• ARM D: Lactating women must agree not to breastfeed during treatment with gilteritinib
and for 2 months after the last dose of gilteritinib
• ARM D: Males of reproductive potential must agree to use effective contraception
during treatment and for at least 4 months after the last dose of gilteritinib
• NEUROPSYCHOLOGICAL TESTING: Patient must be enrolled on Arm A or Arm B. Patients who
transfer to Arm C or Arm D are not eligible
• NEUROPSYCHOLOGICAL TESTING: Patient must be 5 years or older at the time of enrollment
• NEUROPSYCHOLOGICAL TESTING: English-, French- or Spanish-speaking
• NEUROPSYCHOLOGICAL TESTING: No known history of neurodevelopmental disorder prior to
diagnosis of AML (e.g., Down syndrome, fragile X, William syndrome, mental
retardation)
• NEUROPSYCHOLOGICAL TESTING: No significant visual or motor impairment that would
prevent computer use or recognition of visual test stimuli
• All patients and/or their parents or legal guardians must sign a written informed
consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
Exclusion Criteria:
• Fanconi anemia
• Shwachman Diamond syndrome
• Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21
• Telomere disorders
• Germline predispositions known, or suspected by the treating physician to increase
risk of toxicity with AML therapy
• Any concurrent malignancy
• Juvenile myelomonocytic leukemia (JMML)
• Philadelphia chromosome positive AML
• Mixed phenotype acute leukemia
• Acute promyelocytic leukemia
• Acute myeloid leukemia arising from myelodysplasia
• Therapy-related myeloid neoplasms
• Patients with persistent cardiac dysfunction prior to enrollment, defined as ejection
fraction (EF) < 50% (preferred method Biplane Simpson's EF) or if EF unavailable,
shortening fraction (SF) < 24%. *Note: if clinically safe and feasible, repeat
echocardiogram is strongly advised in order to confirm cardiac dysfunction following
clinical stabilization, particularly if occurring in the setting of sepsis or other
transient physiologic stressor. If the repeat echocardiogram demonstrates an EF >=
50%, the patient is eligible to enroll and may receive an anthracycline-containing
Induction regimen
• Administration of prior anti-cancer therapy except as outlined below:
• Hydroxyurea
• All-trans retinoic acid (ATRA)
• Corticosteroids (any route)
• Intrathecal therapy given at diagnosis
• In particular, strong inducers of CYP3A4 and/or P-glycoprotein (P-gp) should be
avoided from the time of enrollment until it is determined whether the patient
will receive gilteritinib. Patients receiving gilteritinib will be required to
avoid strong CYP3A4 inducers and/or strong P-gp inducers for the duration of the
study treatment
• 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
• ARM D: Patient does not have any congenital long QT syndrome or congenital heart block
1. Participant is able and willing to provide informed consent (≥18 years), or informed
consent is obtained by the parent or legal guardian for minor participants, with the
minor providing age appropriate assent, according to local law and regulations;
2. Life expectancy ≥ 12 weeks;
3. Known high-risk neuroblastoma with failure to respond to standard therapy (combination
chemotherapy with or without radiation and surgery), or development of PD at any time;
4. Adequate recovery from acute toxic effects of any prior therapy, as deemed by the
Investigator or treating Sub-Investigator;
5. Adequate liver function as defined by the following laboratory values obtained within
28 days prior to administration of 64Cu-SARTATE: Aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) < 3.0 x upper limit of normal (ULN);
6. Adequate renal function;
7. Adequate laboratory parameters: Absolute neutrophil count > 1.0 x 109/L; Platelet
count > 50 x 109/L; Serum bilirubin <1.5 x ULN;
8. Karnofsky or Lansky performance status ≥50;
9. All participants must have a hematopoietic stem cell product available (minimum CD34+
cell dose is ≥2 x 106 cells/kg);
10. Sexually active participants of reproductive potential must practice an effective
method of birth control while participating on this study, to avoid possible damage to
the fetus. Abstinence is considered acceptable;
11. 64Cu-SARTATE uptake on the 4 hour scan (SUVmax) of any lesion equal to or higher than
that of the liver in order to move on to the therapy phase of the study.
Exclusion Criteria:
1. Participants with disease of any major organ system that would compromise their
ability to tolerate therapy, as deemed by the Investigator or treating
Sub-Investigator;
2. Any other active malignancy, or a history of prior malignancy within the past 3 years;
3. History of cardiac failure as evidenced by: dyspnea at rest, exercise intolerance,
oxygen requirement, clinically significant cardiac dysfunction;
4. Planned administration of chemotherapy, anti-cancer cytokine therapy, immunotherapy,
radiotherapy or other investigational agents within 2 weeks prior to the
administration of 64Cu-SARTATE and 4 weeks prior to the administration of
67Cu-SARTATE;
5. Administration of therapeutic dose of 131I-MIBG within 8 weeks prior to the
administration of 64Cu-SARTATE;
6. EBRT to both kidneys or a single functioning kidney within 12 months prior to the
administration of 64Cu-SARTATE;
7. Administration of any investigational agents within 28 days prior to administration of
64Cu-SARTATE;
8. Treatment with long acting somatostatin analogues (administered within 28 days prior
to the administration of 64Cu-SARTATE), or short acting somatostatin analogues
(administered within 24 hours prior to the administration of 64Cu-SARTATE);
9. Known sensitivity or allergy to somatostatin analogues;
10. Previous PRRT;
11. Female participants who are pregnant or lactating;
12. Participants who are on hemodialysis;
13. QTc interval ≥ 0.45 seconds as measured by Screening ECG;
14. Participants with uncontrolled infection(s);
15. Any medical condition which the Investigator feels may interfere with the procedures
or evaluations of the study;
16. Participants 12 month and younger will be excluded from cohorts where the planned
single or cumulative administered activity is modelled to deliver a radiation dose to
the marrow that exceeds 2 Gy.
Drug: 67Cu-SARTATE, Drug: 64Cu-SARTATE
Neuroblastoma, Refractory Neuroblastoma, Relapsed Neuroblastoma, Brain and Nervous System
A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver)
This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants
with advanced liver cancers. The study is designed with the flexibility to open new treatment
arms as new treatments become available, close existing treatment arms that demonstrate
minimal clinical activity or unacceptable toxicity, modify the participant population, or
introduce additional cohorts of participants with other types of advanced primary liver
cancer.
Cohort 1 will enroll participants with locally advanced or metastatic hepatocellular
carcinoma (HCC) who have not received prior systemic therapy for their disease. Eligible
participants will initially be randomly assigned to one of several treatment arms (Stage 1).
Participants who experience loss of clinical benefit or unacceptable toxicity during Stage 1
may be eligible to receive treatment with a different treatment combination (Stage 2). When a
Stage 2 treatment combination is available, this will be introduced by amending the protocol.
Stage 1
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days
prior to randomization
• Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with
diagnosis confirmed by histology/cytology or clinically by American Association for
the Study of
• Liver Diseases criteria in cirrhotic patients
• Child-Pugh class A within 7 days prior to randomization
• Disease that is not amenable to curative surgical and/or locoregional therapies
• No prior systemic treatment for HCC
• Life expectancy >= 3 months
• Availability of a representative tumor specimen that is suitable for determination of
PD-L1 and/or additional biomarker status via central testing
Stage 1 and Stage 2
• Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1
• Adequate hematologic and end-organ function within 7 days prior to initiation of study
treatment
• Documented virology status of hepatitis, as confirmed by screening tests for hepatitis
B virus •(HBV) and hepatitis C virus (HCV)
• Negative HIV test at screening
• For women of childbearing potential: agreement to remain abstinent or use
contraception and for men: agreement to remain abstinent or use contraception, and
agreement to refrain from donating sperm
Stage 2
• ECOG Performance Status of 0, 1, or 2
• Ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable
toxicity not related to atezolizumab or RO7247669 or loss of clinical benefit as
determined by the investigator while receiving Stage 1 treatment
• Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage
1 (if deemed clinically feasible)
Exclusion Criteria:
Stage 1
• Prior treatment with CD137 agonists or immune checkpoint inhibitors
• Treatment with investigational therapy within 28 days prior to initiation of study
• Treatment with locoregional therapy to liver within 28 days prior to initiation of
study, or non-recovery from side effects of any such procedure
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or
at high risk for bleeding
• Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to
initiation of study
• AEs from prior anti-cancer therapy that have not resolved to Grade <= 1 or better,
with the exception of alopecia of any grade
• Inadequately controlled hypertension
• History of hypertensive crisis or hypertensive encephalopathy
• Significant vascular disease
• History of hemoptysis within 1 month prior to initiation of study
• Evidence of bleeding diathesis or significant coagulopathy
• Current or recent use of asprin (>325 mg/day) or treatment with clopidogrel,
dipyramidole, ticlopidine, or cilostazol
• Current or recent use of full-dose oral or parenteral anticoagulants or thrombolytic
agents for therapeutic (as opposed to prophylactic) purpose
• Core biopsy or other minor surgical procedure within 3 days prior to initiation of
study
• History of abdominal or tracheoesophageal fistula, GI perforation, or intra-abdominal
abscess, intestinal obstruction and/or clinical signs/symptoms of GI obstruction
• Evidence of abdominal free air not explained by paracentesis or recent surgery
• Serious, non-healing/dehiscing wound, active ulcer, or untreated bone fracture
• Grade >=2 proteinuria
• Metastatic disease involving major airways/blood vessels, or centrally located
mediastinal tumor masses of large volume
• History of intra-abdominal inflammatory process
• Radiotherapy within 28 days or abdominal/pelvic radiotherapy within 60 days prior to
initiation of study with the exception of palliative radiotherapy to bone lesions
within 7 days prior to initiation of study
• Major surgery, open biopsy, or significant traumatic injury within 28 days prior to
initiation of study; or abdominal surgery, abdominal interventions or significant
abdominal traumatic injury within 60 days prior to initiation of study; or
anticipation of need for major surgery during study or non-recovery from side effects
of any such procedure
• Chronic daily treatment with NSAID
• Eligible only for control arm
Stage 1 and 2
• Fibrolamellar or sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• History of hepatic encephalopathy
• Moderate or severe ascites
• HBV and HCV coinfection
• Symptomatic, untreated, or actively progressing CNS metastases
• History of leptomeningeal disease
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures
• Uncontrolled or symptomatic hypercalcemia
• Active or history of autoimmune disease or immune deficiency
• History of IPF, organizing pneumonia, drug-induced or idiopathic pneumonitis, or
evidence of active pneumonitis on screening chest CT scan
• Active TB
• Significant CV disease within 3 months prior to initiation of study, unstable
arrhythmia, or unstable angina
• Major surgery, other than for diagnosis, within 4 weeks prior to initiation of study,
or anticipated major surgery during study
• History of malignancy other than HCC within 5 years prior to screening
• Severe infection within 4 weeks prior to initiation of study
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study
• Prior allogeneic stem cell or solid organ transplantation
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study,
or anticipation of need for such a vaccine during atezolizumab treatment or within 5
months after the final dose of atezolizumab
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins
• Known allergy or hypersensitivity to any of the study drugs or any of their excipients
Treatment with systemic immunostimulatory, immunosuppressive agents within 4 weeks or
5 drug-elimination half-lives (whichever is longer) prior to initiation of study
• Treatment with systemic immunosuppressive medication within 2 weeks prior to
initiation of study
• Patients entering Stage 2: immunotherapy-related adverse events that have not resolved
to Grade 1 or better or to baseline at time of consent
This is a Phase 3, randomized, masked, active-controlled, multicenter trial designed to
determine whether early intratracheal administration of a combination of budesonide with
surfactant, as compared to surfactant alone, will reduce the incidence of physiologic
bronchopulmonary dysplasia (BPD) or death by 36 weeks' post-menstrual age in extremely
preterm infants.
Call 214-648-5005 studyfinder@utsouthwestern.edu
Luc Brion
85893
All
up to 48 Hours old
Phase 3
This study is NOT accepting healthy volunteers
NCT04545866
STU-2020-0878
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Inclusion Criteria:
• Liveborn infants 22 0/7 •28 6/7 weeks gestation or 401 •1000 grams (inclusive) birth
weight
• Clinical decision to give surfactant
• Less than or equal to 48 hours postnatal age
Exclusion Criteria:
• Terminal illness (heart rate < 100 beats per minute, unresponsiveness to
resuscitation) or unlikely to survive as judged by the clinician
• Decision to redirect or limit support
• Use of surfactant before enrollment (first dose of surfactant must be study drug)
• Infant received systemic steroids prior to enrollment
• Use of indomethacin, either received by the mother within 24 hours prior to
delivery,received by the infant prior to enrollment, or intent to administer to the
infant for IVH prophylaxis or PDA management from enrollment up to 7 days of final
dose of study drug
• Serious chromosomal abnormalities or major malformations
• Known congenital infections including, but not limited to, confirmed sepsis,
congenital CMV, etc.
• Infants with a permanent neuromuscular condition that affects respiration
• Enrollment in a conflicting clinical trial
Circulating Tumor DNA Testing in Predicting Treatment for Patients With Stage IIA Colon Cancer After Surgery
This phase II/III trial studies how well circulating tumor deoxyribonucleic acid (ctDNA)
testing in the blood works in predicting treatment for patients with stage IIA colon cancer
after surgery. ctDNA are circulating tumor cells that are shed by tumors into the blood.
Finding ctDNA in the blood means that there is very likely some small amounts of cancer that
remain after surgery. However, this cancer, if detected, cannot be found on other tests
usually used to find cancer, as it is too small. Testing for ctDNA levels may help identify
patients with colon cancer after surgery who do benefit, and those who do not benefit, from
receiving chemotherapy.
• The patient must have signed and dated an Institutional Review Board (IRB)-approved
consent form that conforms to federal and institutional guidelines.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Histologically/pathologically confirmed stage IIA adenocarcinoma of the colon (T3, N0,
M0) with at least 12 lymph nodes examined at the time of surgical resection.
• Appropriate for active surveillance (i.e., no adjuvant chemotherapy) at the discretion
of and as documented by the evaluating oncologist based on current practice patterns.
• The distal extent of the tumor must be >= 12 cm from the anal verge on pre-surgical
endoscopy (i.e., excluding rectal adenocarcinomas warranting treatment with
chemoradiation). If the patient did not undergo a pre-surgical endoscopy, then the
distal extent of the tumor must be >= 12 cm from the anal verge as determined by
surgical examination or pre-operative imaging.
• The patient must have had an en bloc complete gross resection of tumor (curative
resection) as definitive surgical cancer treatment within 14 to 60 days of study
randomization. Patients who have had a two-stage surgical procedure to first provide a
decompressive colostomy and then, in a later procedure, to have the definitive
surgical resection, are eligible.
• Availability and provision of adequate surgical tumor tissue for molecular diagnostics
and confirmatory profiling.
• Absolute neutrophil count (ANC) must be >= 1200/mm^3 (within 28 days before
randomization).
• Platelet count must be >= 100,000/mm^3 (within 28 days before randomization); and
• Hemoglobin must be >= 9 g/dL (within 28 days before randomization).
• Total bilirubin must be =< ULN (upper limit of normal) for the lab (within 28 days
before randomization) unless the patient has a chronic grade 1 bilirubin elevation due
to Gilbert?s disease or similar syndrome involving slow conjugation of bilirubin; and
• Alkaline phosphatase must be < 2.5 x ULN for the lab (within 28 days before
randomization); and
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be < 1.5 x
ULN for the lab (within 28 days before randomization).
• Serum creatinine =< 1.5 x ULN for the lab or measured or calculated creatinine
clearance >= 50 mL/min using the Cockcroft-Gault formula for patients with creatinine
levels > 1.5 x ULN for the lab (within 28 days before randomization).
• Pregnancy test (urine or serum according to institutional standard) done within 14
days before randomization must be negative (for women of childbearing potential only).
• Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring
of international normalized ratio (INR) if they are randomized to Arm 2 and receive
capecitabine.
Exclusion Criteria:
• Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma,
sarcoma, lymphoma, squamous cell carcinoma, etc.).
• Pathologic, clinical, or radiologic evidence of overt metastatic disease. This
includes isolated, distant, or non-contiguous intra-abdominal metastases, even if
resected (including the presence of satellite nodules constituting N1c disease in the
absence of lymph node involvement).
• Tumor-related bowel perforation.
• History of prior invasive colon malignancy, regardless of disease-free interval.
• History of organ transplantation.
• Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation
therapy administered as treatment for colorectal cancer (e.g., primary rectal
adenocarcinomas for which treatment with neoadjuvant chemoradiation is warranted are
not permitted).
• Other invasive malignancy within 5 years before randomization. Exceptions are colonic
polyps, non-melanoma skin cancer or carcinoma-in-situ including those of the cervix
and breast (DCIS).
• Synchronous primary rectal and/or colon cancers.
• Antineoplastic therapy (e.g., chemotherapy, targeted therapy, or immunotherapy) within
5 years before randomization. (For the purposes of this study, hormonal therapy is not
considered chemotherapy.).
• Uncontrolled cardiac disease, in the opinion of the treating medical oncologist, that
would preclude the use of any of the drugs included in the GI005 treatment regimen.
This includes but is not limited to:
• Clinically unstable cardiac disease, including unstable atrial fibrillation,
symptomatic bradycardia, unstable congestive heart failure, active myocardial
ischemia, or indwelling temporary pacemaker.
• Ventricular tachycardia or supraventricular tachycardia that requires treatment
with class Ia antiarrhythmic drugs (e.g., quinidine, procainamide, disopyramide)
or class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of
other antiarrhythmic drugs is permitted.
• Second- or third-degree atrioventricular (AV) block unless treated with a
permanent pacemaker.
• Complete left bundle branch block (LBBB) unless treated with a permanent
pacemaker.
• Sensory or motor neuropathy >= grade 2, according to Common Terminology Criteria for
Adverse Events (CTCAE) version (v) 5.0.
• Active seizure disorder uncontrolled by medication.
• Active or chronic infection requiring systemic therapy.
• Known homozygous DPD (dihydropyrimidine dehydrogenase) deficiency.
• Pregnancy or lactation at the time of randomization.
• Co-morbid illnesses or other concurrent disease that, in the judgement of the
clinician obtaining informed consent, would make the patient inappropriate for entry
into this study (i.e., unable to tolerate 6 months of combination chemotherapy or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens or prevent required follow-up).
• Prior testing with any available ctDNA test as part of the management of colon cancer.
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
Trial of Encapsulated Rapamycin (eRapa) for Bladder Cancer Prevention
eRapa (encapsulated rapamycin) will be investigated for secondary prevention in patients with
diagnosed non-muscle invasive bladder cancer (NMIBC) through a phase II double-blind
randomized controlled trial of long-term (one year) prevention with eRapa versus placebo. The
primary hypothesis is that eRapa decreases the risk of cancer relapse for patients with
NMIBC. Secondary hypotheses are that eRapa can improve certain immune parameters and improve
cognition and physical function without adversely affecting patient-reported outcomes and
quality of life.
• Pathologically (histologically) proven diagnosis of non-muscle invasive (Ta, Tis, or
T1) bladder cancer within 90 days prior to enrollment
• Able to give informed consent
• 18 years or older
• Patients must not be taking oral glucocorticoids at the time of registration
• Not have active, uncontrolled infections
• No other prior non-bladder malignancy is allowed except for the following: adequately
treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately
treated Stage I or II cancer from which the patient is currently in complete
remission, or any other cancer from which the patient has been disease free for five
years.
• Patients with localized prostate cancer who are being followed by an active
survelillance program are also eligible.
• Patients must not be pregnant or nursing, as the use of Intravesical BCG is not
recommended during pregnancy. Women/ men of reproductive potential must have agreed to
use an effective contraceptive method. A woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months.
Examples of effective contraception include hormonal contraception, double barrier
method (condom with spermicidal cream, diaphragms with spermicidal cream, or condoms
with diaphragms), Intrauterine device, and/or partner vasectomy. In addition to
routine contraceptive methods, "effective contraception" also includes heterosexual
celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy
prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal
ligation. However, if at any point a previously celibate patient chooses to become
heterosexually active during the time period for use of contraceptive measures
outlined in the protocol, he/she is responsible for beginning contraceptive measures.
Both male and female patients will be required to disclose contraception method during
screening and agree to continue to use that contraception method through the end of
their participation in the study.
• Patients must have had all grossly visible papillary tumors removed within 90 days
prior to registration or cystoscopy confirming no grossly visible papillary tumors
within 90 days prior to registration.
• Patients with T1 disease must have cross-sectional imaging of abdomen/pelvis
demonstrating no evidence of nodal involvement or metastatic disease (MRI or CT scan)
within 90 days prior to registration. Patients with T1 disease must have re-resection
confirming ≤ T1 disease within 90 days prior to registration.
• Patients must no have received prior intravesical BCG
Exclusion Criteria:
• Have muscle-invasive or higher (≥T2) bladder cancer
• Unable to give informed consent
• Age 17 or younger
• Taking oral glucocorticoids at the time of registration
• Another cancer requiring active treatment (except basal cell carcinoma or squamous
cell carcinoma of the skin)
• Patients at risk of pregnancy that are unwilling or unable to take effective
contraception during the study period, or patients that are nursing during the study
period. Women/ Men of reproductive potential must have agreed to use an effective
contraceptive method or will be considered ineligible for study participation.
• Evidence of nodal involvement or metastatic disease (MRI or CT scan) within 90 days
prior to registration
• History of prior intravesical BCG
• History of prior Rapamycin treatment
Drug: eRapa, Drug: Placebos
Urinary Bladder, Non-muscle Invasive Bladder Cancer