Here are the studies that match your search criteria. If you are interested in participating, please reach out to the contact listed for the study. If no contact is listed, contact us and we'll help you find the right person.
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
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.
Drug: LOXO-292
Lymphoma, Non-Small Cell Lung Cancer, Colon Cancer, Medullary Thyroid Cancer, Any Solid Tumor, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Stomach, Thyroid, Urinary Bladder, Hodgkins Lymphoma, Small Intestine, Soft Tissue
LOXO-292, KIF5B-RET, M918T, CCDC6-RET, RET-PTC1, NCOA4-RET, RET-PTC, RET-PTC3, RET-PTC4, PRKAR1A-RET, RET-PTC2, GOLGA5-RET, RET-PTC5, ERC1-RET, KTN1-RET, RET-PTC8, HOOK3-RET, PCM1-RET, TRIM24-RET, RET-PTC6, TRIM27-RET, TRIM33-RET, RET-PTC7, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, BCR-RET, FGRF1OP-RET, RFG8-RET, RET-PTC9, ACBD5-RET, MYH13-RET, CUX1-RET, KIAA1468-RET, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, G533C, C609F, C609G, C609R, C609S, C609Y, C611F, C611G, C611S, C611Y, C611W, C618F, C618R, C618S, C620F, C620R, C620S, C630R, C630Y, D631Y, C634F, C634G, C634R, C634S, C634W, C634Y, K666E, E768D, L790F, V804L, V804M, A883F, S891A, R912P, CLIP1-RET, Y806C, RET fusion, RET alteration, RET mutation, RET rearrangement, RET translocation, Neoplasms by Site, Neoplasms, Non-Small Cell Lung Cancer, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Cancer of Lung, Cancer of the Lung, Lung Cancer, Neoplasms, Lung, Neoplasms, Pulmonary, Pulmonary Cancer, Pulmonary Neoplasms, Respiratory Tract Neoplasms, Lung Diseases, Respiratory Tract Diseases, Carcinoma, Bronchogenic, Bronchial Neoplasms, Medullary Thyroid Cancer, Papillary Thyroid Cancer, Thyroid Diseases, Thyroid Neoplasms, Cancer of the Thyroid, Cancer of Thyroid, Neoplasms, Thyroid, Thyroid Ademona, Thyroid Cancer, Thyroid Carcinoma, Endocrine System Diseases, Endocrine Gland Neoplasms, Head and Neck Neoplasms, Thoracic Neoplasms, CNS tumor, Primary CNS tumor, Cancer of Colon, Cancer of the Colon, Colon Cancer, Colon Neoplasms, Colonic Cancer, Neoplasms, Colonic, Malignant tumor of Breast, Mammary Cancer, Mammary Carcinoma, Human, Mammary Neoplasm, Human, Neoplasms, Breast, Tumors, Breast, Human Mammary Carcinoma, Malignant Neoplasm of Breast, Breast Carcinoma, Breast Tumors, Cancer of the Breast, Breast Neoplasms, Breast Cancer, RET Inhibitor, MTC, NSCLC, selpercatinib, neo-adjuvant treatment in early stage NSCLC
• 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)
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 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
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
Testicular Tissue Cryopreservation for Fertility Preservation
Testicular tissue cryopreservation is an experimental procedure where a young boy's
testicular tissue is retrieved and frozen. This technique is reserved for young male patients
who are not yet producing mature sperm, with the ultimate goal that their tissue may be used
in the future to restore fertility when experimental techniques emerge from the research
pipeline.
• Be male at any age.
• Be scheduled to undergo surgery, chemotherapy, drug treatment and/or radiation for the
treatment or prevention of a medical condition or malignancy with risk of causing
permanent and complete loss of subsequent testicular function.
• Or, have a medical condition or malignancy that requires removal of all or part of one
or both testicles.
• Have newly diagnosed or recurrent disease. Those who were not enrolled at the time of
initial diagnosis (i.e., patients with recurrent disease) are eligible if they have
not previously received therapy that is viewed as likely to result in complete and
permanent loss of testicular function.
• Have two testicles if undergoing elective removal of all or part of a testicle for
fertility preservation only. Note: removal of both testicles will limit fertility
preservation options.
• Sign an approved informed consent and authorization permitting the release of personal
health information. The patient and/or the patient's legally authorized guardian must
acknowledge in writing that consent for specimen collection has been obtained, in
accordance with institutional policies approved by the U.S. Department of Health and
• Consent for serum screening tests for infectious diseases [HIV-1, HIV-2, Hepatitis B,
Hepatitis C], to be performed at the time of testicular tissue harvesting.
• Undergo a full history and physical examination and obtain standard pre-operative
clearance (based on the most recent ACC/AHA Guideline for Perioperative Cardiovascular
Evaluation for Noncardiac Surgery) as determined by their primary surgeon.
• Participating in long term follow-up is a requirement of the protocol.
Exclusion Criteria:
• Diagnosed with psychological, psychiatric, or other conditions which prevent giving
fully informed consent.
• Diagnosed with an underlying medical condition that significantly increases their risk
of complications from anesthesia and surgery.
Procedure: Testicular biopsy
Lymphoma, Sarcoma, Cancer, Mycosis Fungoides, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Male, Carcinoid Tumor, Cardiovascular, Colon, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Nose, Other Digestive Organ, Other Endocrine System, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Leukemia, Other, Hodgkins Lymphoma, Heart, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Myeloid and Monocytic Leukemia, Non-Hodgkins Lymphoma, Other Hematopoietic, Small Intestine, Soft Tissue, Unknown Sites, Ill - Defined Sites, Autoimmune Disorders
Efficacy and Safety of KD025 in Subjects With cGVHD After At Least 2 Prior Lines of Systemic Therapy
This is a Phase 2, randomized, multicenter study to evaluate the efficacy and safety of KD025
in subjects with Chronic Graft Versus Host Disease (cGVHD) after at least 2 prior lines of
systemic therapy
1. Male and female subjects at least 12 years of age who have had allogenic hematopoietic
cell transplant (HCT).
2. Previously received at least 2 and not more than 5 lines of systemic therapy for cGVHD
3. Receiving glucocorticoid therapy with a stable dose over the 2 weeks prior to
screening
4. Have persistent cGVHD manifestations and systemic therapy is indicated
5. Karnofsky Performance Score of ≥ 60 (if aged 16 years or older); Lansky Performance
Score of ≥ 60 (if aged < 16 years)
6. Weight ≥ 40kg
Exclusion Criteria:
1. Subject has not been on a stable dose / regimen of systemic cGVHD treatments for at
least 2 weeks prior to screening. (Note: Concomitant corticosteroids, calcineurin
inhibitors, sirolimus, MMF, methotrexate, rituximab, and extracorporeal photophoresis
(ECP) are acceptable. Systemic investigational GVHD treatments are not permitted).
2. Histological relapse of the underlying cancer or post-transplant lymphoproliferative
disease at the time of screening.
3. Current treatment with ibrutinib. Prior treatment with ibrutinib is allowed with a
washout of at least 28 days prior to randomization.
Drug: Belumosudil (KD025)
Leukemia, Other, Hodgkins Lymphoma, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Other Hematopoietic, Chronic Graft-versus-host-disease
Posoleucel (ALVR105) for the Treatment of Adenovirus Infection in Pediatric and Adult Participants Receiving Standard of Care Following Allogeneic Hematopoietic Cell Transplantation
This study will assess the safety and efficacy of Posoleucel for the treatment of adenovirus
(AdV) infection in pediatric and adult allo-HCT recipients receiving standard of care (SoC).
• Male or female >1 year of age.
• Has undergone allogeneic cell transplantation ≥21 days prior to randomization and
demonstrated engraftment with an absolute neutrophil count >500/mm^3, AND has one of
the following:
1. AdV viremia DNA ≥10,000 copies/mL at screening, OR
2. Two consecutive and rising AdV viremia DNA results of ≥1,000 copies/mL at
screening, AND
1. has absolute lymphocyte count <180/mm3, OR
2. has received T cell depletion.
• Contraceptive use by men and women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical studies and
refrain from donating sperm or eggs for at least 90 days after treatment completion.
• Willing and able to provide signed informed consent.
• Has an HLA type matching with at least 1 suitably matched and available posoleucel VST
line for infusion.
Exclusion Criteria:
• Grade >2 acute GVHD
• Ongoing therapy with high-dose systemic corticosteroids
• Grade 4 diarrhea
• Uncontrolled viral (other than AdV), bacterial, or fungal infection(s)
• Requirement for fraction of inspired oxygen >0.5 to maintain arterial oxygen
saturation >90% (via pulse oximetry) or need for mechanical ventilation.
• Prior therapy with anti-thymocyte globulin, alemtuzumab (Campath®), or other
immunosuppressive T cell monoclonal antibodies within 28 days prior to randomization.
• Prior donor lymphocyte infusion or CD34+ stem cell infusion within 21 days prior to
randomization.
• Use of vasopressors within 7 days prior to randomization.
• Use of any investigational antiviral agent, including brincidofovir, within 7 days
prior to randomization.
• Lactating female unwilling to discontinue nursing prior to randomization.
• Severe allergy to any component of posoleucel or history of severe prior reactions to
blood product transfusions.
• Positive for SARS-CoV-2 virus at screening.
Safety Study of Cord Blood Units for Stem Cell Transplants
Background:
- Cord blood is blood that is taken from the umbilical cord and placenta of healthy newborns
after childbirth. The cord blood collected from a baby is called a cord blood unit. Cord
blood units are stored frozen in public cord blood banks. About 10,000 cord blood
transplants have been performed in children and adults for blood cancers and other diseases
in the world. These transplants have helped save lives and improve treatments. However, not
all available units of cord blood have been collected, stored, and licensed according to
specific government requirements. These unlicensed units can still be used in transplant,
but they can only be given as part of specific research studies. This study will evaluate
the safety of giving these unlicensed units by recording any problems that may occur during
and after giving the cord blood.
Objectives:
- To test the safety and effectiveness of unlicensed cord blood units in people who need
stem cell transplants.
Eligibility:
- Individuals who are scheduled to have a stem cell transplant.
Design:
- Participants will be screened with a medical history and physical exam.
- Participants will receive the cord blood unit as part of their stem cell transplant
procedure. The transplant will be performed according to the current standard of care
for the procedure.
- After the transplant, participants will be monitored for up to 1 year. Any problems or
side effects from the transplant will be treated as necessary. All outcomes will be
reported to the National Cord Blood Program and to the Center for International Blood
and Marrow Transplant.
• INCLUSION CRITERIA:
• Patients of any age or either gender with indications for receipt of investigational
HPC-CORD BLOOD who are participating in an NIH-IRB approved clinical trial for
unrelated hematopoietic stem cell transplantation.
• Signed informed consent (and assent when applicable).
EXCLUSION CRITERIA:
• Patients who are receiving licensed CB products (only)
• Patients who are receiving unlicensed CB products from other CB banks (i.e. NMDP)
Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
The purpose of Phase 1b of this study is to:
- Asses the safety, tolerability and activity of carfilzomib, alone and in combination
with induction chemotherapy, in children with relapsed or refractory acute lymphoblastic
leukemia (ALL).
- Determine the maximum tolerated dose (MTD) and to recommend a phase 2 dose of
carfilzomib in combination with induction chemotherapy.
The purpose of Phase 2 of this study is to compare the rate of complete response (CR) of
carfilzomib in combination with vincristine, dexamethasone, PEG asparaginase, daunorubicin
(VXLD) at the end of induction therapy to an appropriate external control.
1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the
time of study treatment initiation.
2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5% blasts in the
bone marrow (M2 or M3 disease), with or without extramedullary disease.
-To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined
as:
• Early first relapse (< 36 months from original diagnosis) after achieving a CR
(B-ALL) or first relapse any time following the original diagnosis after
achieving a CR (T-ALL)
• First refractory bone marrow relapse occurring any time after original diagnosis
after achieving a CR (ie, ≥1 failed attempt to induce a second remission) OR
• Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2
relapses) OR
• Failing to achieve a CR from original diagnosis after at least 1 induction
attempt
3. Subjects must have fully recovered from the acute toxic effects of all previous
chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit
of normal (ULN) according to age. If serum creatinine level is > 1.5 × ULN, the
subject must have a calculated creatinine clearance or radioisotope glomerular
filtration rate (GFR) ≥ 70 mL/min/1.73 m2.
5. Adequate liver function, defined as both of the following:
• Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert
Syndrome
• Alanine aminotransferase (ALT) ≤ 5 × institutional ULN
6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤
16 years old, respectively.
Phase 2
Inclusion Criteria:
1. Subject's legally acceptable representative has provided informed consent when the
subject is legally too young to provide informed consent and the subject has provided
written assent based on local regulations and/or guidelines prior to any
study-specific activities/procedures being initiated.
2. Age greater than or equal to 1 month to less than 21 years. Subjects greater than or
equal to 18 years must have had their original diagnosis at less than 18 years of age.
3. Subjects must be diagnosed with relapsed or refractory relapsed ALL.
4. Subjects must have a documented first remission, less than or equal to 5% blasts in
the bone marrow (M1 bone marrow) and no evidence of extramedullary disease.
5. T-cell ALL with bone marrow relapse (defined as greater than or equal to 5% leukemia
blasts in bone marrow) or refractory relapse with or without extramedullary disease.
OR B-cell ALL bone marrow relapse or refractory relapse (defined as greater than or
equal to 5% leukemia blasts in bone marrow) after having received a targeted B-cell
immune therapy (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or without
extramedullary disease..
6. Adequate liver function: bilirubin less than or equal to 1.5 x upper limit of normal
(ULN), alanine aminotransferase (ALT) less than or equal to 5 x ULN.
7. Adequate renal function: serum creatinine less than or equal to 1.5 x ULN or
glomerular filtration rate (GFR) greater than or equal to 70 mL/min/1.73 m^2; or for
children less than 2 years of age, greater than or equal to 50 mL/min/1.73 m^2.
8. Adequate cardiac function: shortening fraction greater than or equal to 30% or
ejection fraction greater than or equal to 50%.
9. Karnofsky (subjects greater than or equal to 16 years of age) or Lansky (subjects 12
months to less than 16 years of age) performance status greater than or equal to 50%.
10. Subjects must have fully recovered from the acute toxic effects of all previous
chemotherapy, immunotherapy, or radiotherapy treatment before enrollment (for example:
recovery from gastrointestinal toxicity may occur more rapidly than less reversible
organ toxicities such as sinusoidal obstruction syndrome or non-infectious
pneumonitis, for serious prior toxicities recommended discussion with Amgen medical
monitor).
11. Life expectancy of greater than 6 weeks per investigator's judgement at time of
screening.
Phase 1b Key
Exclusion Criteria:
1. Known allergy to any of the drugs used in the study (Subjects who have had a previous
allergy to PEG-asparaginase and if able, may receive Erwinia asparaginase at the
investigator's discretion)
2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
3. Left ventricular fractional shortening < 30%
4. History of ≥ Grade 2 pancreatitis
5. Active graft-versus-host disease requiring systemic treatment
6. Positive culture for or other clinical evidence of infection with bacteria or fungus
within 14 days of the initiation of study treatment
7. Down Syndrome
8. Prior therapy restrictions:
• Subjects must have completed therapy with granulocyte-colony stimulating factor
(G-CSF) or other myeloid growth factors at least 7 days before study treatment
initiation, or at least 14 days before study treatment initiation, if pegylated
myeloid growth factors were administered.
• Subjects must have completed any type of active immunotherapy (e.g., tumor
vaccines) at least 42 days before study treatment initiation.
• Subjects must have received the last dose of a non-monoclonal antibody biologic
agent at least 7 days before study treatment initiation.
• At least 3 antibody half-lives must have elapsed since the last dose of
monoclonal antibody (e.g., 66 days for rituximab and 69 days for epratuzumab)
before subjects may initiate study treatment.
• Subjects must not have received other antineoplastic agents with therapeutic
intent, excluding hydroxyurea and antimetabolites administered as part of
maintenance chemotherapy, within 7 days prior to study treatment initiation.
9. Hepatitis B infection with positive hepatitis B DNA
Phase 2
Exclusion Criteria:
1. Prior treatment with carfilzomib.
2. Prior treatment with a proteasome inhibitor (other than carfilzomib) within less than
3 months of enrollment or to which a subject did not respond (response is defined as
bone marrow with less than 5% blasts).
3. Treatment with a chemotherapy regimen including a vinca alkaloid, steroid,
L-asparaginase, and anthracycline combination with or without other chemotherapy
agents within 2 months of enrollment (eg VXLD, VPLD, R3).
4. Intolerance, hypersensitivity, or inability to receive any of the chemotherapy
components of the VXLD regimen. An exception is allowed for allergy to asparaginase
products if Erwinia asparaginase is unable to be administered,
5. Autologous HSCT within 6 weeks prior to start of study treatment.
6. Allogeneic HSCT within 3 months prior to start of study treatment.
7. Active GVHD requiring systemic immune suppression.
8. Less than 30 days from discontinuation of immune suppressive therapy administered for
the treatment of acute or chronic GVHD.
9. Isolated extramedullary relapse.
10. Positive bacterial or fungal infection within 14 days of enrollment (except for
documented line infection, line has been removed, and blood culture after line removal
is negative for 5 days prior to first dose of induction therapy). Antibiotics may be
administered for prophylaxis as per institutional standards up to and after
enrollment.
11. Subjects with less than 3 antibody half-lives since the last dose of monoclonal
antibody (eg, 66 days for rituximab, 69 days for epratuzumab, inotuzumab for 36 days),
prior to first dose of investigational product must be discussed with the Amgen
medical monitor and may be allowed to enroll based on extent of disease or evidence of
rapidly rising peripheral or bone marrow blast counts.
12. Cell-based immunotherapy (eg, donor leucocyte infusion, CAR-T cells, tumor vaccines)
within 42 days prior to first dose of investigational product. If the Amgen medical
monitor agrees, an exception may be granted to the 42-day requirement for subjects
with rapidly rising peripheral or bone marrow blast counts.
13. Down's syndrome.
14. Presence of another active cancer.
15. History of grade greater than or equal to 2 pancreatitis within 6 months to screening.
16. Unresolved toxicities from prior anticancer therapy, defined as not having resolved to
CTCAE version 4.03 grade 1 or to levels dictated in the eligibility criteria apart
from alopecia or toxicities from prior anticancer therapy that are considered
irreversible and do not trigger another exclusion criterion (defined as having been
present and stable for greater than 4 weeks).
17. Antitumor therapy (chemotherapy, investigational agents, molecular-targeted therapy)
within 7 days of day 1 of induction. Exception: hydroxyurea to control peripheral
blood leukemic cell counts is allowed until start of investigational product.
18. Active viral infection, including but not limited to cytomegalovirus (CMV), Hepatitis
B infection with positive serum hepatitis surface antigen or hepatitis B DNA, HIV,
Hepatitis C with detectable hepatitis C RNA. Subjects who have previously received a
stem cell transplant must be screened for CMV infection, unless both subject and donor
are known to be CMV negative.
19. Currently receiving treatment in another investigational device or product study, or
less than 14 days since ending treatment on another investigational device or product
study.
20. Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of greater
than 470 msec.
21. History or evidence of any other clinically significant disorder, condition or disease
(with the exception of those outlined above) that, in the opinion of the investigator
or Amgen physician, if consulted, would pose a risk to subject safety or interfere
with the study evaluation, procedures or completion.
22. Female subject is pregnant or breastfeeding or planning to become pregnant or
breastfeed during treatment and for an additional 6 months after the last dose of any
study treatment or for 12 months after last dose of cyclophosphamide if administered
during optional consolidation cycle.
23. Female subjects of childbearing potential unwilling to use 1 highly effective method
of contraception during treatment and for an additional 6 months after the last dose
of any study treatment or for 12 months after last dose of cyclophosphamide if
administered during optional consolidation cycle.
24. Female subjects of childbearing potential with a positive pregnancy test assessed at
Screening by a serum or urine pregnancy test.
25. Male subjects with a female partner of childbearing potential who are unwilling to
practice sexual abstinence (refrain from heterosexual intercourse) or use a condom
with spermicide during treatment and for an additional 6 months after the last dose of
any study treatment, even if they have undergone a successful vasectomy.
26. Male subjects with a pregnant partner who are unwilling to practice abstinence or use
a condom with spermicide during treatment, for duration of pregnancy, and for an
additional 6 months after the last dose of any study treatment.
27. Male subjects unwilling to abstain from donating semen or sperm during treatment and
for an additional 6 months after the last dose of any study treatment.
28. Known allergy to captisol (a cyclodextrin derivative used to solubilize carfilzomib;
for a complete listing of Captisol-enabled drugs, see the Ligand Pharmaceuticals, Inc.
website).
Myeloma-Developing Regimens Using Genomics (MyDRUG) (MyDRUG)
The MyDRUG study is a type of Precision Medicine trial to treat patients with drugs targeted
to affect specific genes that are mutated as part of the disease. Mutations in genes can lead
to uncontrolled cell growth and cancer. Patients with a greater than 25% mutation to any of
the following genes; CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, IDH2 or T(11;14) can be enrolled
to one of the treatment arms. These arms have treatments specifically directed to the mutated
genes. Patients that do not have a greater than 25% mutation to the genes listed can be
enrolled to a non-actionable treatment arm.
The genetic sequencing of the patient's tumor is required via enrollment to the MMRF002
study: Clinical-grade Molecular Profiling of Patients with Multiple Myeloma and Related
Plasma Cell Malignancies. (NCT02884102).
• Willing to be registered into the pomalidomide (POMALYST®) Risk Evaluation and
Mitigation Strategy (REMS®) program
• Enrolled in the MMRF002 Molecular Profiling Protocol (NCT02884102) with report less
than 120 days old
• Disease free of prior malignancies for ≥ 3 years with exception of currently treated
basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or
breast, or prostate cancer not requiring therapy
• High risk patients with relapsed refractory multiple myeloma (RRMM), who have:
• received at least one prior but no more than 3 prior therapies
• exposed to both a PI and an IMiD
• had early relapse after initial treatment Early relapse as defined by at least
one of the following: (Relapse is defined as the IMWG uniform response)
1. Relapse within 3 years of initiation of induction chemo therapy for post
autologous stem cell transplantation (ASCT) followed by maintenance, or 18
months if unmaintained after ASCT
2. Within 18 months of initial non-ASCT based therapy
• Patients must have progressed after their most recent treatment and require therapy
for myeloma
• Females of reproductive potential must have a negative pregnancy test at baseline, be
non-lactating, and willing to adhere to scheduled pregnancy testing
• Females of reproductive potential and males must practice and acceptable method of
birth control
• Laboratory values obtained ≤ 14 days prior to registration:
• Absolute neutrophil count (ANC) ≥ 1000/ul
• Hemoglobin (Hgb) ≥ 8 g/dl
• Platelet (PLT) ≥ 75,000/ul
• Total bilirubin <1.5 x upper limit of normal (ULN) or if total bilirubin is >1.5
x ULN, the direct bilirubin must be ≤ 2.0 mg/dL
• Aspartate aminotransferase (AST) <3 x ULN
• Creatinine Clearance ≥ 30 mL/min
Measurable disease of Multiple Myeloma (MM) as defined by at least one of the following:
• Serum monoclonal protein ≥ 0.5 g by protein electrophoresis
• ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
• Serum immunoglobulin free light chain (FLC) ≥10 mg/dL AND abnormal serum
immunoglobulin kappa to lambda FLC ratio
• Monoclonal bone marrow plasmacytosis ≥30% (evaluable disease)
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2
• Ability to take aspirin, warfarin, or low molecular weight heparin
Sub-Protocol
Inclusion Criteria:
Refer to each respective Sub Protocol for additional inclusion criteria.
Exclusion Criteria:
Patients will be ineligible for this study if they meet any one of the following criteria:
• Aggressive multiple myeloma requiring immediate treatment as defined by:
• Lactate dehydrogenase (LDH) > 2 times ULN
• Presence of symptomatic extramedullary disease or central nervous system
involvement
• Hypercalcemia >11.5 mg/dl
• Acute worsening of renal function (CrCl < 30 ml/min) directly related to myeloma
relapse
• Any neurological emergency related to myeloma
• Clinical symptoms of hyperviscosity related to monoclonal protein
• Involved serum free light chain > 100 mg/dL (1000 mg/L) in the setting of prior
diagnosis of cast nephropathy
• Infection requiring systemic antibiotic therapy or other serious infection within 14
days of enrolment
• Known hypersensitivity or development of erythema nodosum if characterized by a
desquamating rash while taking thalidomide, lenalidomide, pomalidomide or similar
drug. Known allergy to any of the study medications, their analogues, or excipients in
the various formulations of the agents
• Prior Ixazomib/Pomalidomide/Dexamethasone combination therapy
• Pregnant or breast-feeding females
• Serious medical or psychiatric illness, active alcoholism, or drug addiction that may
hinder or confuse compliance, interfere in the completion of treatment per protocol,
or follow-up evaluation
• Active hepatitis A, B or C viral infection or known human immunodeficiency virus (HIV)
infection
• Concurrent symptomatic amyloidosis or plasma cell leukemia
• POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein (M-protein) and skin changes]
• Residual side effects to previous therapy > Grade 1 prior to initiation of therapy
(Alopecia any grade and/or neuropathy Grade 2 without pain are permitted)
• Prior allogeneic or ASCT within 12 weeks of initiation of therapy. Prior allogeneic
stem cell transplant with active graft-versus-host disease (GVHD)
• Prior experimental therapy within 14 days of protocol treatment or 5 half-lives of the
investigational drug, whichever is longer
• Prior anticancer therapy within 14 days of initiation of protocol therapy
(Dexamethasone/ 40mg/day) for a maximum of 4 days before screening is allowed
• Prior major surgical procedure or radiation therapy within 4 weeks of the initiation
of therapy (this does not include limited course of radiation used for management of
bone pain within 7 days of initiation of therapy).
• Known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that
limit the ingestion or Gastro Intestinal (GI) absorption of drugs administered orally
• Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months
• Other co-morbidity, which would interfere with patient's ability to participate in
trial or that confounds the ability to interpret data from the study
Sub-Protocol
Exclusion Criteria:
Refer to each respective Sub Protocol for additional exclusion criteria.
INTERCEPT Blood System for RBCs Study in Regions at Potential Risk for Zika Virus Transfusion-Transmitted Infections (RedeS)
Stage A: To evaluate the safety and efficacy of red blood cells (RBCs) prepared with the
INTERCEPT Blood System for Red Blood Cells Pathogen Reduction Treatment (PRT) in comparison
to conventional RBCs in patients who require RBC transfusion support.
Stage B: To provide early access to the INTERCEPT pathogen reduction system for RBC in
regions where a substantial proportion of the population has been infected or is at risk of a
transfusion-transmissible infection.
The objectives and design of Stage B will be reassessed on the completion of Stage A, in
consultation with the FDA.
• Age ≥ 4 years.
• Patients who require or are expected to require a transfusion of RBC component(s),
including red cell exchange transfusion
• Signed and dated informed consent form.
• Female patients of child-bearing potential must:
• Have negative serum or urine pregnancy tests prior to study treatment to rule out
pregnancy, and
• Agree to use to use at least one method of birth control that results in a low
failure rate (i.e., less than 1% per year) when used consistently and correctly
such as implants, injectables, combined oral contraceptives, some intrauterine
devices (IUDs), sexual abstinence or vasectomized partner for the duration of
study participation and an additional 28 days.
For 28-day +6-month extension study in chronically transfused patients:
• A diagnosis of a bone marrow failure syndrome requiring repeated RBC transfusion for
congenital or acquired chronic anemia (e.g., sickle cell anemia, thalassemia, other
hemoglobinopathies, myelodysplastic syndrome, aplastic anemia, chemotherapy or stem cell
transplant etc.)
For 28-day +6-month extension study in SCD patients requiring regular repeated RCE.
• Diagnosis of SCD, either HbSS, HbSC or HbSB0 thalassemia, confirmed by Hb
electrophoresis, deoxyribonucleic acid (DNA) analysis or high-performance liquid
chromatography (HPLC)
• Currently participating in an automated RCE transfusion program (for at least 3 months
prior to enrollment) with 3-to-8 week intervals between RCE transfusion episodes
Stage A: Exclusion Criteria
• Confirmed positive baseline serum/plasma antibody specific to IBS RBC (S 303 treated
RBC) as determined by INTERCEPT S 303 antibody screening panel prior to receiving the
first study transfusion
• Pregnant or breast feeding.
• Presence of an RBC warm autoantibody with evidence of active hemolysis.
• Positive DAT as defined below:
• A polyspecific-DAT reaction strength > 2+, or
• A polyspecific-DAT (any strength) in conjunction with pan-reactivity with a
commercial IAT antibody screening panel that precludes the identification of
underlying alloantibodies or indicates the presence of autoantibody.
• Have had an RBC transfusion within 7 days prior to randomization.
• Have received investigational products, including investigational blood products,
pharmacologic agents or imaging materials, within 28 days prior to randomization.
Prior receipt of conventional blood products tested with an investigational NAT test
is not considered ground for exclusion.
• Patients presenting with or expected to have massive hemorrhage (≥10 RBC units within
24 hours) or expected to require massive transfusion protocols. Planned red cell
exchange does not apply.
• Patients who require neonatal transfusions and intrauterine transfusions.
• Pre-existing antibody to RBC antigens that may make the provision of compatible study
RBC components difficult.
• History of transfusion reactions requiring washed RBCs, volume reduced RBC, or RBCs
with additive solution removed.
• Patients with documented IgA deficiency or a history of severe allergic reactions to
blood products.
• For SCD patients to be enrolled into the repeated RCE 28-day +6-month arm of the
study:
• A history of acute chest syndrome in the last 6 months, or hyperhemolysis
syndrome at any time.
• Clinical evidence of splenic hyperfunction or splenic enlargement: ≥18 cm in
longitudinal diameter (diagnosed at the Investigator's discretion according to
the data available, with ultrasound data being preferable).
• Currently receiving chemotherapy for treatment of cancer. Hydroxyurea for SCD is
acceptable if subject has been on stable therapy for 3 months and no changes to
dosage are planned.
• Subject is in active treatment with renal dialysis.
• Any subject for whom a substantial change in the number of RBC components
transfused is anticipated due to anticipated splenectomy, bone marrow transplant,
surgery or other change in clinical status.
• Subject with known G6PD deficiency or requiring treatment with medications that
are known to adversely affect RBC viability or bone marrow function.
Device: INTERCEPT Blood System for Red Blood Cells, Device: Conventional (Control)
Study of Glycerol Phenylbutyrate & Sodium Phenylbutyrate in Phenylbutyrate Naïve Patients With Urea Cycle Disorders
This is a randomized, controlled, open-label parallel arm study to assess the safety,
tolerability, pharmacokinetics and ammonia control, of RAVICTI® as compared to NaPBA in urea
cycle disorder subjects not currently or previously chronically treated with phenylacetic
acid (phenylacetate; PAA) prodrugs. The study design will include: 1) Baseline Period; 2)
Initial Treatment Period; 3) a RAVICTI only Transition Period 4) a RAVICTI only Maintenance
Period; and 5) a RAVICTI only Safety Extension Period. The study will run for approximately
25 weeks.
• Signed informed consent given by the subject or the subject's parent/legal guardian
for those under 18 years of age or the age of consent by local regulation.
• Male and female subjects with a suspected or confirmed UCD diagnosis of any subtype,
except NAGS deficiency.
• Suspected diagnosis is defined as having experienced a HAC or a documented high
ammonia of >=100 µmol/L
• Confirmed diagnosis is determined via enzymatic, biochemical, or genetic testing.
• Requires nitrogen-binding agents according to the judgment of the Investigator
• Birth and older.
• All females of childbearing potential and all sexually active males must agree to
use an acceptable method of contraception from signing the informed consent
throughout the study and for 30 days after the last dose of study drug.
Acceptable forms of contraception are (oral, injected, implanted or transdermal),
tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier
methods. Abstinence is an acceptable form of birth control, though appropriate
contraception must be used if the subject becomes sexually active.
Exclusion Criteria:
• Subject has received chronic treatment with an oral phenylbutyrate (RAVICTI, NaPBA,
Pheburane, or other) longer than 14 consecutive days within one year prior to
enrollment.
• Temporary use of NaPBA for acute management of a hyperammonemic crisis in the past is
acceptable.
• Any concomitant illness (e.g., malabsorption or clinically significant liver or
bowel disease) which would preclude the subject's safe participation, as judged
by the Investigator.
• Has undergone liver transplantation, including hepatocellular transplant.
• Subjects on NaBz at Baseline will be excluded if they are viewed by the
Investigator as being unable to undergo NaBz transition to a PAA prodrug during
the Initial Treatment Period.
• Known hypersensitivity to PBA or any excipients of the NaPBA/PBA formulations.
• Pregnant or breast-feeding patients. Women of childbearing potential must have a
pregnancy test performed at the Baseline Visit prior to the start of study drug.
STRATA: Safe Testing of Risk for AsymptomaTic MicrohematuriA
To evaluate the clinical utility associated with the integration of Cxbladder into the
evaluation of subjects presenting with hematuria for evaluation of urothelial carcinoma (UC)
without compromising detection of UC.
• Patient is undergoing investigation of recent confirmed hematuria, as defined by the
AUA/SUFU Guideline (Barocas DA, Boorjian SA, Alvarez RD et al. Microhematuria:
AUA/SUFU guideline, J Urol 2020; 204:778) (by either flexible or rigid
cystoscopy/TURBT), including hematuria subjects referred due to suspicious/positive
imaging, in order to determine the presence of urothelial carcinoma.
• Able to provide a voided urine sample of the required minimum volume
• Able to give written consent
• Able and willing to comply with study requirements
• Aged 18 years or older
Exclusion Criteria
• Prior history of bladder malignancy or pelvic radiotherapy. Prior history prostate or
renal cell carcinoma within the last 5 years.
• Prior genitourinary manipulation (flexible or rigid cystoscopy / catheterisation,
urethral dilation) in the 14 days before urine collection,
• Known current pregnancy
FT516 in Subjects With Advanced Hematologic Malignancies
This is a Phase 1/1b dose-finding study of FT516 as monotherapy in acute myeloid leukemia
(AML) and in combination with CD20 directed monoclonal antibodies in B-cell lymphoma. The
study includes three stages: dose escalation, safety confirmation, and dose expansion.
KEY INCLUSION CRITERIA:
Diagnosis of the following:
Regimen A (FT516 monotherapy):
• Primary Refractory AML
• Relapsed AML defined as not in CR after 1 or more re-induction attempts; if >60 years
of age, prior re-induction therapy is not required
Regimen B (FT516 + rituximab or obinutuzumab):
• Histologically documented B-cell lymphoma expected to express CD20 who have relapsed
after or failed to respond to at least on prior treatment regimen and for whom there
is no available therapy expected to improve survival.
All subjects:
• Provision of signed and dated informed consent form (ICF)
• Age ≥18 years old
• Stated willingness to comply with study procedures and duration
• Presence of measurable disease
KEY EXCLUSION CRITERIA:
All subjects:
• Females of reproductive potential who are pregnant or lactating, and males or females
not willing to use a highly effective form of contraception from Screening through the
end of the study
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≥2
• Evidence of insufficient organ function
• Receipt of therapy within 2 weeks prior to Cycle 1 Day 1 or within five half-lives,
whichever is shorter; or any investigational therapy within 28 days prior to Cycle 1
Day 1
• Currently receiving or likely to require systemic immunosuppressive therapy
• Prior allogeneic HSCT or allogeneic CAR-T within 6 months of Cycle 1 Day 1, or ongoing
requirement for systemic graft-versus-host therapy
• Receipt of an allograft organ transplant
• Known active central nervous system (CNS) involvement by malignancy.
• Clinically significant cardiovascular disease
• Clinically significant infections including: Known HIV infection; Known active
Hepatitis B (HBV) or Hepatitis C (HCV) infection
• Live vaccine <6 weeks prior to start of lympho-conditioning
• Known allergy to human albumin and DMSO
Additional Exclusion Criteria for FT516 monotherapy Regimen: Diagnosis of promyelocytic
leukemia with t(15:17) translocation
Additional Exclusion Criteria for FT516 plus monoclonal antibody Regimens: Diagnosis of
Waldenstrom macroglobulinemia
Heparin Versus Normal Saline in Peripherally Inserted Central Catheter Lines
The study team will be performing a study comparing the use of Heparin Flushes vs. Normal
Saline Flushes in making sure central lines stay open. The participants will be placed in a
group to receive the University of Texas Southwestern Medical Center (UTSW) Standard of Care
(control group) for maintaining central lines, or a group to receive Normal Saline Flushes
only (experimental group) to keep their central line open. The participants electronic
medical record will be reviewed by study team members for the inclusion/exclusion criteria,
the participants central line will be assessed by an 11 Blue BMT nurse every 12 hours, and
they may be asked questions regarding their medical history during their stay on 11 Blue BMT.
If a participant is discharged or transferred off of the 11 Blue BMT unit, they will no
longer be included in the study and their central line maintenance will return to the UTSW
Standard of Care. Participants in this study may be at risk for central line occlusion (a
blood clot) which could require intervention to regain the free flow of fluids and use of the
central line. The study team predicts there will be no increase in the rate of line occlusion
when using Normal Saline Flushes only to maintain the free flow of fluids through
participants central line. The study team also hopes the results of this study will help to
improve patient outcomes by decreasing risk of infection, heparin associated complications,
and costs.
• Oncology patients
• Admitted to 11Blue Bone Marrow Transplant Unit at Clements University Hospital
University of Texas Southwestern Medical Center
• Ages 18-80 years
• Pre-existing or newly placed PICC line
• PICC line with good blood return (defined as: "brisk blood return of 3cc")
• Flushes without difficulty
Exclusion Criteria:
• Patient less than 18 years of age or greater than 80 years of age
• Refused or unable to give consent to the study
• Patient admitted to the 11Blue BMT unit with any line other than a PICC line, or
multiple lines
• Patient admitted to 11Blue BMT for active transplant
• Patient with a coagulopathy diagnosis
• Patient on therapeutic dose of anticoagulants for documented Deep Vein Thrombosis or
Pulmonary Embolism
• Patient on inpatient hospice/comfort care
• Patient transferred off 11B BMT unit onto another floor
Drug: Normal Saline Group, Drug: Heparin Group
Lymphoma, Cancer, Multiple Myeloma, Leukemia, Other, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Myeloid and Monocytic Leukemia
Peripherally Inserted Central Lines, Heparin Flush
Vincristine Sulfate Liposome Injection (Marqibo®) in Combination With UK ALL R3 Induction Chemotherapy for Children, Adolescents, and Young Adults With Relapsed ALL
This is a pilot study utilizing Marqibo® (vincristine sulfate liposome injection) combined
with dexamethasone, mitoxantrone and asparaginase (UK ALL R3) for relapsed acute
lymphoblastic leukemia (ALL).
Inclusion Criteria
Age
-Patients must be ≥ 1 and ≤ 21 years of age at the time of enrollment.
Diagnosis
• Cohort A: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) or
mixed phenotypic acute leukemia with ≥ 5% blasts in the bone marrow (M2 or M3), with
or without extramedullary disease) or a diagnosis of lymphoblastic lymphoma.
• Cohorts B & C: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL),
lymphoblastic lymphoma, or mixed phenotypic acute leukemia with any level of
detectable disease (minimal residual disease level acceptable) with or without
extramedullary disease
Performance Level -Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for
patients ≤ 16 years of age.
Prior Therapy
• Patients must have recovered from the acute toxic effects (≤ Grade 2 or baseline) of
all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study,
unless otherwise specified. Subjects with disease related cytopenias will be eligible.
• Patients must have relapsed or refractory disease after attaining at least a first
remission. They may be in first to third relapse..
• Patients with Philadelphia chromosome t(9;22) positive disease must have received at
least two prior tyrosine kinase inhibitors.
• Patients who have experienced their relapse after a Hematopoietic stem cell
transplantation (HSCT) are eligible, provided they have no evidence of
graft-versus-host disease (GVHD) and are at least 100 days post-transplant at the time
of enrollment.
• Prior anthracycline lifetime cumulative exposure: Patients must have less than 320
mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline
chemotherapy.
1. Cohort A: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior
cardioprotection) lifetime exposure of anthracycline chemotherapy (See Appendix 2
for anthracycline calculation worksheet).
2. Cohorts B & C: There is no limit on prior anthracycline exposure.
• Hematopoietic growth factors: It must have been at least seven days since the
completion of therapy with granulocyte colony-stimulating factor (GCSF) or other
growth factors at the time of enrollment. It must have been at least 14 days since the
completion of therapy with pegfilgrastim (Neulasta®).
• Biologic anti-neoplastic agents: At least seven days after the last dose of a biologic
agent. For agents that have known adverse events occurring beyond seven days after
administration, this period must be extended beyond the time during which adverse
events are known to occur. The duration of this interval must be discussed with the
study chair or vice chair.
• Monoclonal antibodies: At least three half-lives (or 30 days—whichever is longer) of
the antibody must have elapsed after the last dose of monoclonal antibody. (e.g.,
Rituximab = 66 days, Epratuzumab = 69 days)
• Immunotherapy: At least 30 days after the completion of any type of immunotherapy,
e.g. tumor vaccines, chimeric antigen receptor T-cells.
• Recent prior chemotherapy: At least 10 days after standard vincristine and the
completion of any type of chemotherapy induction regimen. At least 3 weeks after
radiation therapy. At least 30 days after the completion of any investigational
neoplastic agent is also required. An investigational agent is defined as any drug
that is not approved and licensed for sale by the FDA for institutions in the United
States, by Health Canada for institutions in Canada and by The Therapeutic Goods
Administration for institutions in Australia.
Exceptions:
• There is no time restriction in regard to prior intrathecal chemotherapy provided
there is complete recovery from any acute toxic effects of such; it is allowable to
enroll a patient that has received IT Cytarabine (ARA-C), IT Methotrexate (MTX) or
triple IT therapy within 14 days of enrollment as part of their evaluation to diagnose
disease relapse. The IT therapy given within 14 days of initiation of protocol
specified chemotherapy, may substitute for the day 1 IT in cohorts A and B
• Subjects with rapidly progressive disease may receive hydroxyurea until they begin
study therapy;
• Patients who relapse while on maintenance-type ALL therapy or are receiving
maintenance therapy for disease stabilization will not require a wash-out period
before entry into this study. However, there must be at least 10 days after any dose
of standard vincristine.
Renal and Hepatic Function
• Renal function: Patient's serum creatinine must be ≤ 1.5 x institutional upper limit
of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times
normal, the patient must have a calculated creatinine clearance or radioisotope
glomerular filtration rate (GFR) ≥ 70milliliter/min/1.73m2. Alternatively, a 24-hour
creatinine clearance may also be used.
• Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
must be < 5 x institutional upper limit of norm ULN. Total bilirubin must be ≤ 1.5 x
ULN (except in the case of subjects with documented Gilbert's disease ≤ 5 × ULN).
Cardiac Function
-Patients must have a shortening fraction ≥ 27% or an ejection fraction ≥ 55% by
echocardiogram, cardiac MRI or multigated acquisition scan (MUGA).
Reproductive Function
• Female patients must not be pregnant and those of childbearing potential must have a
negative urine or serum pregnancy test confirmed within one week prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this
study.
• Male and female patients of childbearing potential must agree to use an effective
method of contraception during the study.
Exclusion Criteria
Patients will be excluded if they have isolated testicular disease.
Patients will be excluded if they have previously received Marqibo®.
Patients will be excluded if they have a known allergy to any of the drugs used in the
study, with the exception that patients with an allergy to PEG-asparaginase who can receive
Erwinia asparaginase are eligible. Patients unable to receive any formulation of
asparaginase may only enroll on cohort C
Patients will be excluded if they have active, uncontrolled systemic fungal, bacterial,
viral or other infection despite appropriate antibiotics or other treatment.
Patients who require azole antifungal agents will be excluded. Azoles must be discontinued
at least one week prior to the start of Marqibo®.
Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
radiation therapy, another investigational agent or immunotherapy during the study period.
Patients with pre-existing, persistent grade 2 or greater sensory or motor neuropathy from
any cause will be excluded.
Patients will be excluded if they have, significant concurrent disease, illness,
psychiatric disorder or social issue that would compromise patient safety or adherence with
the protocol treatment or procedures or interfere with consent, study participation, follow
up, or interpretation of study results.Patients with Down syndrome will not be eligible for
enrollment on Cohort A
Patients with a known history of human immunodeficiency virus (HIV) will will be excluded
due to the increased risk of complications such as severe infection and unknown interaction
of Marqibo® with antiretroviral drugs.
Active hepatitis B or C infection as defined by seropositive for hepatitis B (hepatitis B
surface antigen (HBsAg)) or hepatitis C and elevated liver transaminases (defined as above
the ULN per the institution normal ranges).
A Study of Daratumumab Plus Lenalidomide Versus Lenalidomide Alone as Maintenance Treatment in Participants With Newly Diagnosed Multiple Myeloma Who Are Minimal Residual Disease Positive After Frontline Autologous Stem Cell Transplant (AURIGA)
The purpose of this study is to evaluate conversion rate to minimal residual disease (MRD)
negativity following the addition of daratumumab to lenalidomide relative to lenalidomide
alone, when administered as maintenance treatment to anti-cluster of differentiation 38
(CD38) treatment naive participants with newly diagnosed multiple myeloma who are MRD
positive as determined by next generation sequencing (NGS) at screening, following high-dose
therapy (HDT) and autologous stem cell transplant (ASCT).
• Must have newly diagnosed multiple myeloma with a history of a minimum of 4 cycles of
induction therapy, have received high-dose therapy (HDT) and autologous stem cell
transplantation (ASCT) within 12 months of the start of induction therapy, and be
within 6 months of ASCT on the date of randomization
• Must have a very good partial response (VGPR) or better response assessed per
International Myeloma Working Group (IMWG) 2016 criteria at the time of randomization
• Must have archived bone marrow samples collected before induction treatment (that is,
at diagnosis) or before transplant (for example, at the end of induction) or have
existing results on the index multiple myeloma clone based on Adaptive
Biotechnologies' next generation sequencing (NGS)-based minimal residual disease (MRD)
assay. Archived bone marrow samples will be used for calibration of myeloma clonal
cells to facilitate assessment of primary end point by NGS. If an existing result on
index myeloma clone is available from Adaptive Biotechnologies' NGS-based MRD assay,
as part of institutional procedures, an archived bone marrow sample is not required as
long as Adaptive Biotechnologies is able to retrieve historical results on the index
myeloma clone form the clinical database. Any one of the following archived samples
are required: (a) Greater than 1 milliliter (mL) viable frozen bone marrow aspirated
aliquot (preferred) collected in an ethylenediaminetetra-acetic acid (EDTA) tube,
frozen, and stored at a temperature of -80 centigrade (°C), or; (b) Non-decalcified
diagnostic bone marrow aspirate clot sections (block or slides) for MRD assessment:
(i) A formalin fixed paraffin embedded (FFPE) block of bone marrow aspirate clot, or
slides (preferably 5, if available), 5 micrometer each, of non-decalcified bone
marrow, or; (ii) Slides (preferably 5, if available), bone marrow aspirate smear;
(iii) Please note, bone marrow core sections are not acceptable samples for analysis;
(iv) In exceptional circumstances when index myeloma clone cannot be identified from
the archived bone marrow sample, a post-transplant sample can be used to identify
myeloma clone with permission from the sponsor
• Must have residual disease as defined by detectable MRD (Adaptive Biotechnologies' NGS
based MRD assay)
• Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0,
1, or 2
Exclusion Criteria:
• A history of malignancy (other than multiple myeloma) unless all treatment of that
malignancy was completed at least 2 years before consent and the participant has no
evidence of disease before the of date of randomization. Exceptions are squamous and
basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other
non-invasive lesion that in the opinion of the investigator, with concurrence with the
sponsor's medical monitor, is considered cured with minimal risk of recurrence within
3 years
• Must not have progressed on multiple myeloma (MM) therapy at any time prior to
screening
• Have had prior treatment/therapy with: (a) Daratumumab or any other anti-cluster of
differentiation 38 (CD38) therapies, (b) Focal radiation therapy within 14 days prior
to randomization with the exception of palliative radiotherapy for symptomatic
management but not on measurable extramedullary plasmacytoma. Radiotherapy within 14
days prior to randomization on measurable extramedullary plasmacytoma is not permitted
even in the setting of palliation for symptomatic management, or (c) Plasmapheresis
within 28 days of randomization
• Be exhibiting clinical signs of meningeal or central nervous system involvement due to
multiple myeloma
• Have known chronic obstructive pulmonary disease (COPD) with a forced expiratory
volume in 1 second (FEV1) less than (<) 50 percent (%) of predicted normal
• Have known moderate or severe persistent asthma within the past 2 years or current
uncontrolled asthma of any classification
• Have any of the following: (a) Known history of seropositivity for human
immunodeficiency virus (HIV); (b) Seropositive for hepatitis B (defined by a positive
test for hepatitis B surface antigen [HBsAg]. Participants with resolved infection
(that is, participants who are HBsAg negative but positive for antibodies to hepatitis
B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs])
must be screened using real-time polymerase chain reaction (PCR) measurement of
hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded.
EXCEPTION: Participants with serologic findings suggestive of HBV vaccination
(anti-HBs positivity as the only serologic marker) AND a known history of prior HBV
vaccination, do not need to be tested for HBV DNA by PCR; (c) Seropositive for
hepatitis C (anti-hepatitis C virus [HCV] antibody positive or HCV-RNA quantitation
positive), except in the setting of a sustained virologic response, defined as
aviremia at least 12 weeks after completion of antiviral therapy)
Trial of DFP-10917 vs Non-Intensive or Intensive Reinduction for AML Patients in 2nd/3rd/4th Salvage
Phase III, multicenter, randomized study with two arms (1:1 ratio) enrolling patients with
AML relapsed/refractory after 2, 3, or 4 prior induction regimens:
Experimental arm: DFP-10917 14-day continuous intravenous (IV) infusion at a dose of 6
mg/m²/day followed by a 14-day resting period per 28-day cycles.
Control arm: Non-Intensive Reinduction (LoDAC, Azacitidine, Decitabine, Venetoclax
Combination Regimens) or Intensive Reinduction (High and Intermediate Dose Cytarabine
Regimens), depending on the patient's prior induction treatment.
1. Histologically or pathologically confirmed diagnosis of AML based on WHO
classification that has relapsed after, or is refractory to, two, three, or four prior
induction regimens that may have included intensive chemotherapy (e.g., "7+3"
cytarabine and daunorubicin), epigenetic therapy (i.e., azacitidine or decitabine), or
targeted therapy (e.g., FLT-3, IDH-1/2, BCL-2, monoclonal antibody).
(Relapse is defined as reemergence of ≥5% leukemia blasts in bone marrow or ≥1% blasts
in peripheral blood ≥90 days after first CR or CR without complete platelet recovery
(CRp). Refractory AML is defined as persistent disease ≥28 days after initiation of
intensive induction therapy (up to two induction cycles) or relapse <90 days after
first CR or CRp. Refractory disease for patients undergoing hypomethylating agent
induction is defined as lack of remission following at least 2 cycles of epigenetic
therapy without reduction in bone marrow blast status.)
Patients with a history of IPSS-R high or very high risk MDS that transformed to AML
during treatment with hypomethylating drugs and then relapse following or are
refractory to a subsequent AML induction regimen may be enrolled as Second Salvage AML
patients. Additionally, patients with a history of MPN in accelerated phase (MPN-AP)
or high-risk primary myelofibrosis (PMF) that transformed to AML during treatment with
hypomethylating drugs and then relapse following or are refractory to a subsequent AML
induction regimen may be enrolled as Second Salvage AML patients.
2. Aged ≥ 18 years.
3. ECOG Performance Status of 0, 1 or 2.
4. Adequate clinical laboratory values (i.e., plasma creatinine <2.5 x upper limit of
normal (ULN) for the institution, bilirubin <2.5 x ULN, alanine transaminase (ALT) and
aspartate transaminase (AST) ≤2.5 x ULN).
5. Absence of active central nervous system (CNS) involvement by leukemia. Patients with
previously diagnosed CNS leukemia are eligible if the CNS leukemia is under control
and intrathecal treatment may continue throughout the study.
6. Absence of uncontrolled intercurrent illnesses, including uncontrolled infections,
cardiac conditions, or other organ dysfunctions.
7. Signed informed consent prior to the start of any study specific procedures.
8. Women of child-bearing potential must have a negative serum or urine pregnancy test.
9. Male and female patients must agree to use acceptable contraceptive methods for the
duration of the study and for at least one month after the last drug administration.
Exclusion Criteria:
1. The interval from prior treatment to time of study drug administration is < 2 weeks
for cytotoxic agents or < 5 half-lives for noncytotoxic agents. Exceptions: Use of
hydroxyurea is allowed before the start of study and is to be discontinued prior to
the initiation of study treatment. At the investigator's discretion, for patients with
significant leukocytosis that develops during the early treatment cycles, hydroxyurea
may be administered. The hydroxyurea should be discontinued as soon as clinically
appropriate.
2. Any >grade 1 persistent clinically significant toxicities from prior chemotherapy.
3. Inadequate Cardiac (left ventricular ejection fraction ≤40%) function.
4. White blood cell (WBC) count >15,000/μL (Note: Patients considered for possible
venetoclax-containing regimen must have WBC ≤10k/μL prior to initiating venetoclax
treatment).
5. For patients with prior hematopoietic stem cell transplant (HSCT):
1. Less than 3 months since HSCT
2. Acute Graft versus Host Disease (GvHD) >Grade 1
3. Chronic GvHD >Grade 1
6. Any concomitant condition that in the opinion of the investigator could compromise the
objectives of this study and the patient's compliance.
7. A pregnant or lactating woman.
8. Current malignancies of another type. Exceptions: Patients may participate if they
have previously treated and currently controlled prostate cancer, or adequately
treated in situ cervical cancer or basal cell skin cancer, or other malignancies with
no evidence of disease for 2 years or more.
9. Patient has acute promyelocytic leukemia (APL).
10. Patients with known HIV, active HBV or active HCV infection (note: testing for these
infections is not required). For patients with evidence of chronic hepatitis B virus
(HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if
indicated. Patients with a history of hepatitis C virus (HCV) infection must have been
treated and cured. For patients with HCV infection who are currently on treatment,
they are eligible if they have an undetectable HCV viral load.
11. Documented or known clinically significant bleeding disorder.
A Study of CC-99712, a BCMA Antibody-Drug Conjugate, in Participants With Relapsed and Refractory Multiple Myeloma
Study CC-99712-MM-001 is an open-label, Phase 1, dose escalation (Part A) and expansion (Part
B), First-in-Human (FIH) clinical study of CC-99712 in monotherapy or combination with
BMS-986405 in participants with relapsed and refractory multiple myeloma (MM). The dose
escalation part (Part A) of the study will evaluate the safety and tolerability of escalating
doses of CC-99712, administered intravenously (IV) in monotherapy (Arm 1) or combination with
BMS-986405 (Arm 2), to determine the maximum tolerated dose (MTD) of CC-99712 guided by a
Bayesian logistic regression model (BLRM). A modified accelerated titration design will also
be used for Arm 1 and Arm 2. The MTD may be established separately for CC-99712 administered
at Q3W and/ or Q4W schedules. The expansion part (Part B) will further evaluate the safety
and efficacy of CC-99712 in monotherapy (Arm 1) or combination (Arm 2) administered at or
below the MTD in selected expansion cohorts in order to determine the RP2D. One or more doses
or dosing regimens may be selected for cohort expansion. All participants will be treated
until confirmed disease progression per IMWG criteria, unacceptable toxicity, or
participants//Investigator decision to withdraw.
Participants must satisfy the following criteria to be enrolled in the study:
Inclusion
• Participant is ≥ 18 years of age at the time of signing the ICF.
• Participant has a history of multiple myeloma (MM) with relapsed and/or refractory
disease
• Participant must have measurable disease.
• Participant has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of
0 or 1.
Exclusion Criteria
• Participant has symptomatic central nervous system involvement of MM.
• Participant had a prior autologous stem cell transplant ≤ 3 months prior to starting
CC-99712.
• Participant had a prior allogeneic stem cell transplant with either standard or
reduced intensity conditioning ≤ 6 months prior to starting CC-99712 or is on systemic
immunosuppression for graft-versus host disease.
• Subject is a pregnant or lactating female.
• Subject has known human immunodeficiency virus (HIV) infection.
• Subject has active hepatitis B or C (HBV/HCV) infection.
Other protocol-defined inclusion/exclusion criteria apply
Drug: CC-99712, Drug: BMS-986405
Multiple Myeloma
Multiple Myeloma, Relapsed and refractory, CC-99712, BCMA, Antibody drug conjugate, BMS-986405
Study of Venetoclax in Combination With Carfilzomib and Dexamethasone in Participants With Relapsed or Refractory Multiple Myeloma (MM)
A Phase 2, open-label, dose escalation study to evaluate the safety and efficacy of
venetoclax in combination with carfilzomib-dexamethasone (Kd) in participants with relapsed
or refractory MM and have received 1 to 3 prior lines of therapy.
Part 4 of this study is currently enrolling.
• Eastern Collaborative Oncology Group (ECOG) performance score of less than or equal to
2.
• Documented relapsed or progressive Multiple Myeloma (MM) on or after any regimen or is
refractory to the most recent line of therapy.
• Positive for translocation t(11;14) as determined by an analytically validated
Fluorescent In Situ Hybridization (FISH) assay per central laboratory testing.
• Received prior treatment with at least 1 prior line of therapy for MM.
• Measurable disease on Screening per International Myeloma Working Group (IMWG)
criteria.
• Meets absolute neutrophil count, platelet count, hemoglobin, liver and kidney function
laboratory values within 2 weeks prior to first dose of study drug.
Exclusion Criteria:
• Has a pre-existing condition that is contraindicated including.
• Non-secretory or oligo-secretory MM
• Active plasma cell leukemia.
• Waldenström's macroglobulinemia.
• Primary amyloidosis.
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein,
and skin changes).
• Active hepatitis B or C infection based on screening blood testing.
• Known active Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection.
• Significant cardiovascular disease.
• Major surgery within 4 weeks prior to first dose.
• Acute infections requiring antibiotic, antifungal or antiviral therapy within14
days prior to first dose.
• Peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 2 weeks prior to
first dose.
• Uncontrolled diabetes or uncontrolled hypertension within 14 days prior to first
dose.
• Any other medical condition that, in the opinion of the Investigator, would
adversely affect the participant's participation in the study.
• History of other active malignancies, including myelodysplastic syndrome (MDS), within
the past 3 years prior to study entry Other protocol defined inclusion/exclusion
criteria could apply
A Study to Evaluate the Effectiveness and Safety of CAEL-101 in Patients With Mayo Stage IIIa AL Amyloidosis
AL (or light chain) amyloidosis begins in the bone marrow where abnormal proteins misfold and
create free light chains that cannot be broken down. These free light chains bind together to
form amyloid fibrils that build up in the extracellular space of organs, affecting the
kidneys, heart, liver, spleen, nervous system and digestive tract.
The primary purpose of this study is to determine if CAEL-101 improves the overall survival
in Patients with cardiac AL Amyloidosis.
• Each patient must meet the following criteria to be enrolled in this study.
1. Be able to and provide written informed consent and be willing and able to comply
with all study procedures
2. Adult, 18 years and older
3. AL amyloidosis Mayo stage IIIa based on the 2013 European Modification of the
2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement
at the time of Screening
4. Measurable hematologic disease at Screening as defined by at least one of the
following:
1. Involved/Uninvolved Free Light Chain Difference (dFLC) > 4 mg/dL or
2. Involved Free Light Chain (iFLC) > 4 mg/dL with abnormal ratio or
3. Serum Protein Electrophoresis (SPEP) m-spike > 0.5 g/dL
5. Histopathological diagnosis of amyloidosis AND confirmation of AL derived amyloid
deposits by at least one of the following:
1. Immunohistochemistry or
2. Mass spectrometry or
3. Characteristic electron microscopy appearance
6. Cardiac involvement as defined by:
a. Documented clinical signs and symptoms supportive of a diagnosis of heart
failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence
of an alternative explanation for heart failure AND b. At least one of the
following: i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or
ii. Echocardiogram demonstrating a mean left ventricular wall thickness
(calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other
causes (e.g., severe hypertension, aortic stenosis), which would adequately
explain the degree of wall thickening or
iii. Cardiac MRI with gadolinium contrast agent diagnostic or cardiac amyloidosis
7. Planned first-line treatment for plasma cell dyscrasia is a CyBorD-based regimen
administered as Standard of Care (SoC)
8. Adequate bone marrow reserve and hepatic function as demonstrated by:
1. Absolute neutrophil count ≥ 1.0 x 109/L
2. Platelet count ≥ 75 x 109/L
3. Hemoglobin ≥ 9 g/dL
4. Total direct bilirubin ≤ 2 times the upper limit of normal (x ULN) unless
due to Gilbert's syndrome.
5. Aspartate aminotransferase (AST) ≤ 3 x ULN
6. Alanine aminotransferase (ALT) ≤ 3 x ULN
7. Alkaline phosphatase (ALP) ≤ 5 x ULN (except for patients with hepatomegaly
and isozymes specific to liver, rather than bone)
9. Women of childbearing potential (WOCBP) must have a negative pregnancy test
during Screening and must agree to use highly effective physician approved
contraception from Screening to at least 5 months following the last study drug
administration or 12 months following the last dose of her PCD therapy, whichever
is longer
10. Men must be surgically sterile or must agree to use effective physician approved
contraception and refrain from donating sperm from Screening to at least 5 months
following the last study drug administration or 12 months following the last dose
of his PCD therapy, whichever is longer
Exclusion Criteria:
• Patients who meet any of the following criteria will not be permitted entry to the
study.
1. Have any other form of amyloidosis other than AL amyloidosis
2. Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure
of 2 weeks of a CyBorD-based PCD treatment after screening laboratory samples are
obtained and prior to randomization is allowed.
3. Has POEMS syndrome or multiple myeloma defined as clonal bone marrow plasma cells
> 10% or biopsy-proven bony or extramedullary plasmacytoma AND any one or more of
the following CRAB features:
a. Evidence of end organ damage that can be attributed to the underlying plasma
cell proliferative disorder, specifically:
i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the ULN or >
2.75 mmol/L (> 11mg/dL)
ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum
creatinine > 177mol/L (> 2mg/dL)
iii. Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a
hemoglobin value < 100g/L
iv. Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or
PET/CT. If bone marrow has < 10% clonal plasma cells, more than one bone lesion
is required to distinguish from solitary plasmacytoma with minimal marrow
involvement
OR
b. Any one of the following biomarkers of malignancy:
i. 60% or greater clonal plasma cells on bone marrow examination
ii. More than one focal lesion on MRI that is at least 5mm or greater in size
4. Have supine systolic blood pressure < 90 mmHg or symptomatic orthostatic
hypotension, defined as a decrease in systolic blood pressure upon standing of >
30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the
absence of volume depletion
5. Taking prednisone or its equivalent > 10 mg/day
6. Taking doxycycline
7. Receiving dialysis
8. Planned stem cell transplant during the first 6 months of protocol therapy. Stem
cell collection during the protocol therapy is permitted.
9. Have had myocardial infarction, uncontrolled angina, severe uncontrolled
ventricular arrhythmias within 6 months prior to screening or percutaneous
cardiac intervention with recent stent or coronary artery bypass grafting within
4 months prior to screening. Exacerbation of chronic condition or new acute
condition will require discussion and approval by the Medical Monitor.
10. Left Ventricular Ejection Fraction (LVEF) is < 40% by echocardiogram at Screening
11. Have severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area
< 1.0 cm2) or severe congenital heart disease
12. Have history of sustained ventricular tachycardia or aborted ventricular
fibrillation or a history of atrioventricular nodal or sinoatrial nodal
dysfunction for which a pacemaker/implantable cardioverter-defibrillator (ICD) is
indicated but not placed. (Participants who do have a pacemaker or ICD are
allowed in the study.)
13. QT corrected by Fridericia (QTcF) is > 550 msec. Participants who have a
pacemaker may be included regardless of calculated QTc interval.
14. There is evidence of acute ischemia or active conduction system abnormalities
with the exception of any of the following:
1. First degree Atrioventricular (AV)-block
2. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
3. Right or left bundle branch block
4. Atrial fibrillation with a controlled ventricular rate. (An uncontrolled
ventricular rate [i.e., > 110 beats per minute] determined by an average of
three beats in lead II or representative beats in lead II is not allowed)
15. Have had major surgery within 4 weeks of randomization or is planning major
surgery during the study. Patients with surgical procedures conducted under local
anesthesia may participate
16. There is active malignancy (including lymphoma) with the exception of any of the
following:
1. Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ
cervical cancer
2. Adequately treated stage I cancer from which the patient is currently in
remission and has been in remission for > 2 years
3. Low-risk prostate cancer with Gleason score < 7 and prostate-specific
antigen < 10 mg/mL
4. Other localized and/or low risk malignancies may be permitted with Medical
Monitor approval.
17. Have received an investigational drug/device in another clinical investigational
study within 60 days before Screening
18. Hypersensitivity to the study drug
19. Have received a live vaccine within 4 weeks prior to first dose of CyBorD
20. Women who are breast feeding
21. Have any other medical, social or psychological factors that could affect the
patient's safety or ability to consent personally or comply with study
procedures.
POCUS: Hemostatic Potential and Joint Health in Patients With Severe Hemophilia A on Novel Replacement Therapies
This is a prospective, randomized control trial in which each patient will be randomly
assigned to receive either extended half-life factor VIII based replacement therapy or
non-FVIII based replacement therapy, which are both standard of care treatment for persons
with Hemophilia A.
• Subjects with moderate hemophilia A (baseline factor VIII activity 1-5%) or severe
hemophilia A (baseline factor VIII activity <1%) on prophylactic standard half-life
FVIII infusions OR subjects with moderate or severe hemophilia A who have not started
prophylactic treatment
• Less than 18 years of age
Exclusion Criteria:
• Subjects with documented FVIII inhibitor
• Subjects with a history of ≥ 2 target joints
• Subjects with a history of synovectomy
• Currently using medications known to impact bone and mineral metabolism (e.g.,
bisphosphonates, corticosteroids, estrogen, testosterone, calcitonin, thyroid hormone
therapy);
• Disease states known to affect bone integrity (e.g., primary hyperparathyroidism,
Paget's disease, clinically significant liver disease)
Drug: Eloctate, Drug: Adynovate, Drug: Emicizumab
Hemophilia A, Bones and Joints, Other Hematopoietic, Factor VIII
A Study of CC-95266 in Participants With Relapsed and/or Refractory Multiple Myeloma
The purpose of this study is to evaluate the safety and preliminary efficacy of CC-95266 in
participants with relapsed and/or refractory multiple myeloma (R/R MM).
• Age ≥ 18 years
• Participant has a diagnosis of multiple myeloma (MM) with relapsed and/or refractory
disease. Participants must have documented progressive disease on or within 12 months
of completing treatment with the last anti-myeloma treatment regimen, except for
participants with cellular therapy (eg, Chimeric antigen receptor (CAR) T-cell
therapy) as their last treatment, who may enroll beyond 12 months
• Participants must have received at least 3 prior anti-myeloma treatment regimens
(note: induction with or without hematopoietic stem cell transplant (HSCT) and with or
without maintenance therapy is considered one regimen), including:
• Autologous stem cell transplant
• A regimen that included an immunomodulatory agent (eg, thalidomide, lenalidomide,
pomalidomide) and a proteasome inhibitor (eg, bortezomib, carfilzomib, ixazomib),
either alone or combination
• Anti-CD38 (eg, daratumumab), either alone or combination
• Measurable disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate organ function
Exclusion Criteria:
• Known active or history of central nervous system (CNS) involvement of MM
• Active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)
syndrome, or clinically significant amyloidosis
• Active autoimmune disease requiring immunosuppressive therapy
• History or presence of clinically significant CNS pathology such as seizure disorder,
aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar
disease, or psychosis
Other protocol-defined inclusion/exclusion criteria apply
Study of Ravulizumab in Pediatric Participants With HSCT-TMA
This study will evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of
ravulizumab administered by intravenous infusion to pediatric participants, from 1 month to <
18 years of age, with HSCT-TMA. The treatment period is 26 weeks, followed by a 26-week
off-treatment follow-up period.
1. 1 month of age up to < 18 years of age at the time of signing the informed consent.
2. Received HSCT within the past 6 months.
3. Diagnosis of TMA that persists despite initial management of any triggering condition.
4. Body weight ≥ 5 kilograms.
5. Female participants of childbearing potential and male participants with female
partners of childbearing potential must use highly effective contraception starting at
Screening and continuing until at least 8 months after the last dose of ravulizumab.
6. Participants must be vaccinated against meningococcal infections if clinically
feasible, according to institutional guidelines for immune reconstitution after HSCT.
Participants must be re-vaccinated against Haemophilus influenzae type b and
Streptococcus pneumoniae if clinically feasible, according to institutional guidelines
for immune reconstitution after HSCT. All participants should be administered coverage
with prophylactic antibiotics according to institutional post-transplant infection
prophylaxis guidances, including coverage against Neisseria meningitidis for at least
2 weeks after meningococcal vaccination. Participants who cannot receive meningococcal
vaccine should receive antibiotic prophylaxis coverage against Neisseria meningitidis
the entire Treatment Period and for 8 months following the final dose of ravulizumab.
Exclusion Criteria:
1. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin
type 1 motif, member 13' deficiency (activity < 5%).
2. Known Shiga toxin-related hemolytic uremic syndrome.
3. Positive direct Coombs test.
4. Diagnosis or suspicion of disseminated intravascular coagulation.
5. Known bone marrow/graft failure.
6. Diagnosis of veno-occlusive disease.
7. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody
titer).
8. Unresolved meningococcal disease.
9. Presence or suspicion of sepsis (treated or untreated) within 7 days prior to
Screening.
10. Pregnancy or breastfeeding.
11. Hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab.
12. Previously or currently treated with a complement inhibitor.
Drug: Ravulizumab, Other: Best Supportive Care
Brain and Nervous System, Kidney, Leukemia, Other, Hodgkins Lymphoma, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Myeloid and Monocytic Leukemia, Non-Hodgkins Lymphoma, Other Hematopoietic, Thrombotic Microangiopathy
A Study to Evaluate VIP152 in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia or Richter Syndrome
Determine the safety, tolerability, pharmacokinetics, maximum tolerated dose (MTD) and
recommended phase 2 dose (RP2D) of VIP152 in patients with Chronic Lymphocytic Leukemia (CLL)
or Richter Syndrome
• Male or female patients aged >/=18 years
• Patients with a histologically or cytologically:
• Confirmed CLL who are refractory to or have progressed from 2 or more regimens
including BTKi and venetoclax or
• Confirmed CLL transformed to DLBCL (Richter Syndrome) who have relapsed after, or
been refractory, to at least 1 prior line of therapy for the DLBCL and having MYC
overexpression/amplification/translocation
• Adequate bone marrow, liver, and renal functions
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
Exclusion Criteria:
• Active clinically serious infections of Grade > 2; requiring parenteral therapy
• Subjects who have new or progressive brain or meningeal or spinal metastases.
• Anticancer chemotherapy or immunotherapy during the study or within one week prior to
the first dose of study drug
• Major surgery or significant trauma within 4 weeks before the first dose of study drug
• Allogeneic bone marrow transplant or stem cell rescue within 4 months before first
dose of study drug; patients must have completed immunosuppressive therapy before
enrollment
Stereotactic Radiosurgery (SRS) for Brain Metastasis (SRS)
SRS dose escalation for brain metastases in radiation-naïve patients will establish true
tolerable doses, which may exceed the current standard doses. This may lead to an improvement
in local control, patient survival, and/or quality-of life.
Inclusion Criteria
1. Biopsy-proven non-hematopoietic malignancy, except for small cell lung cancer, germ
cell cancer, or unknown primary tumor.
2. Radiographic evidence by MRI (or by CT scan with CT contrast if ineligible or
intolerant of MRI) of brain metastasis. (If patient is unable to tolerate MRI
contrast, an MRI without contrast is acceptable if lesions are visible)
3. All brain metastases must be outside the brain stem (midbrain, pons and medulla).
4. Patient must have 10 or less brain metastases.
5. The maximum diameter of any lesion must be less than or equal to 3.0 cm.
6. Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any
targeted agents are allowed provided that:
• Radiation was not to the brain.
• Surgery to the brain was > 7 days prior to SRS and there remains at least one
additional brain metastasis that can be targeted with SRS
7. Age ≥ 18 years.
8. ECOG Performance Score of 2 or better/Karnofsky Performance Status score of 50-60 or
better.
9. All men, as well as women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately.
A female of child-bearing potential is any woman (regardless of sexual orientation,
marital status, having undergone a tubal ligation, or remaining celibate by choice)
who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
Medically acceptable birth control (contraceptives) includes:
• Approved hormonal contraceptives (such as birth control pills, patch, or ring:
Depo-Provera, Implanon), or
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a
substance that kills sperm)
10. Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria
1. Patients had craniotomy and surgery to the brain within 7 days from the date of SRS.
2. Patients with leptomeningeal metastasis.
NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive
CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal
involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal
enhancement by imaging (MRI) would be considered to have LMD even in the absence of
positive CSF cytology, unless a parenchymal lesion can adequately explain the
neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally
symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would
not be considered to have LMD. In that patient, CSF sampling is not required to
formally exclude LMD, but can be performed at the investigator's discretion based on
level of clinical suspicion.
3. Patients with a contraindication to both MRI (with or without contrast) and CT scan
(with contrast)
4. Patients with life expectancy < 3 months.
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 the opinion of the
investigator, would limit compliance with study requirements.
6. Subjects must not be pregnant or nursing at the time of SRS treatment due to the
potential for congenital abnormalities and the potential of this regimen to harm
nursing infants.
Radiation: Stereotactic Radiosurgery
Brain Neoplasms, Adult, Malignant, Lymphoma, Sarcoma, Multiple Myeloma, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Female, Breast - Male, Cardiovascular, 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, Lymphoid Leukemia, Small Intestine, Soft Tissue
UT Southwestern; Parkland Health & Hospital System
Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients (CASSIOPEIA)
This is a single arm, open-label, multi-center, phase II study to determine the efficacy and
safety of tisagenlecleucel in de novo HR pediatric and young adult B-ALL patients who
received first-line treatment and are EOC MRD positive. The study will have the following
sequential phases: screening, pre-treatment, treatment & follow-up, and survival. After
tisagenlecleucel infusion, patient will have assessments performed more frequently in the
first month and then at Day 29, then every 3 months for the first year, every 6 months for
the second year, then yearly until the end of the study. Efficacy and safety will be assessed
at study visits and as clinically indicated throughout the study. The study is expected to
end in approximately 8 years after first patient first treatment (FPFT). A post-study long
term follow-up for lentiviral vector safety will continue under a separate protocol per
health authority guidelines.
1. CD19 expressing B-cell Acute Lymphoblastic Leukemia
2. De novo NCI HR B-ALL who received first-line treatment and are MRD ≥ 0.01% at EOC. EOC
bone marrow MRD will be collected prior to screening and will be assessed by
multi-parameter flow cytometry using central laboratory analysis.
3. Age 1 to 25 years at the time of screening
4. Lansky (age < 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60%
5. Adequate organ function during the screening period:
A. Renal function based on age/gender B. ALT ≤ 5 times ULN for age C. AST ≤ 5 times
ULN for age D. Total bilirubin < 2 mg/dL (for Gilbert's Syndrome subjects total
bilirubin < 4 mg/dL)
E. Adequate pulmonary function defined as:
• no or mild dyspnea (≤ Grade 1)
• oxygen saturation of > 90% on room air F. Adequate cardiac function defined as
LVSF ≥ 28% confirmed by echocardiogram or LVEF ≥ 45% confirmed by echocardiogram
or MUGA within 6 weeks of screening
6. Prior induction and consolidation chemotherapy allowed: 1st line subjects: ≤ 3 blocks
of standard chemotherapy for first-line B-ALL, defined as 4-drug induction,
Berlin-Frankfurt-Münster (BFM) consolidation or Phase 1b, and interim maintenance with
high-dose methotrexate.
Exclusion Criteria:
1. M3 marrow at the completion of 1st line induction therapy
2. M2 or M3 marrow or persistent extramedullary disease at the completion of first-line
consolidation therapy or evidence of disease progression in the peripheral blood or
new extramedullary disease prior to enrollment. Patients with previous CNS disease are
eligible if there is no active CNS involvement of leukemia at the time of screening.
3. Philadelphia chromosome positive ALL
4. Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear evidence
of a hypodiploid clone
5. Prior tyrosine kinase inhibitor therapy
6. Subjects with concomitant genetic syndromes associated with bone marrow failure
states: such as subjects with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or
any other known bone marrow failure syndrome. Subjects with Down syndrome will not be
excluded.
7. Subjects with Burkitt's lymphoma/leukemia (i.e. subjects with mature B-ALL, leukemia
with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3
morphology and /or a MYC translocation)
8. Has had treatment with any prior anti-CD19 therapy 9. Treatment with any prior gene or
engineered T cell therapy
Other protocol-defined inclusion/exclusion may apply.
CTL019, Kymriah, B-Cell Acute Lymphoblastic Leukemia, ALL, tisagenlecleucel, HR B-ALL EOC MRD, Minimal Residual Disease (MRD), Positive at the End of Consolidation (EOC)
PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma
This is a phase 1/2 study of a drug called Ixazomib in combination with cytotoxic
chemotherapy consisting of Vincristine, Dexamethasone, Asparaginase, and Doxorubicin (VXLD).
• Age Patients must be ≤21 years of age at the time of enrollment.
1. Phase 1 •Initial enrollment will be restricted to patients < 18 years of age
until 9 such patients are enrolled
2. Phase 2 •Initial enrollment will be restricted to patients < 18 years of age
until 6 such patients are enrolled
• Diagnosis Patients must have a diagnosis of relapsed/refractory ALL or LLy with or
without extramedullary disease (including CNS2 and CNS3). Patient with mixed phenotype
ALL or mature B (Burkitt-like) leukemia are not eligible.
1. Patients with ALL must have ≥ 5% blasts by morphology.
2. Patients with LLy must have measurable disease documented by clinical, radiologic
or histologic criteria
• Performance Level Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for
patients ≤ 16 years of age.
• Prior Therapy A. Prior therapeutic attempts
• Phase 1 •Any patients with relapsed/refractory ALL or LLy
• Phase 2
1. B-cell ALL/LLy: all patients must have failed two or more therapeutic
attempts.
2. T-cell ALL/LLy: all patients must have failed one or more therapeutic
attempts. B. Recent prior chemotherapy Patients must have fully recovered
from the acute toxic effects of all prior chemotherapy, immunotherapy, or
radiotherapy prior to entering this study.
• Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up
to 24 hours prior to the start of protocol therapy.
• Patients who relapsed while they are receiving cytotoxic therapy At least 14 days
must have elapsed since the completion of the last dose of chemotherapy,except
Intrathecal chemotherapy, and/or maintenance therapy such as vincristine,
mercaptopurine, methotrexate or glucocorticoids. There is no waiting period for
those relapsing on maintenance therapy.
C. Hematopoietic stem cell transplant: Patients who have experienced their relapse after a
HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host
Disease (GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 90 days
post-transplant at the time of enrollment.
D. Hematopoietic growth factors: It must have been at least 7 days since the completion of
therapy with G-CSF or other growth factors at the time of enrollment. It must have been at
least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).
E. Biologic (anti-neoplastic agent): At least 7 days since the last dose of a biologic
agent. For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse events
are known to occur. The duration of this interval must be discussed with the study chair
1. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after
the last dose of monoclonal antibody. (i.e., blinatumomab = 6 hours,44 inotuzumab = 37
days, rituximab = 66 days)
2. Immunotherapy: At least 30 days after the completion of any type of immunotherapy,
e.g., tumor vaccines, CAR T cells.
F. XRT: Craniospinal XRT is prohibited during protocol therapy. No washout period is
necessary for radiation given to any extramedullary site other than CNS; ≥90 days must have
elapsed if prior total body irradiation (TBI) or craniospinal XRT.
G. Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m2 of doxorubicin
equivalents of anthracyclines.
H. Proteasome inhibitors: Patients with a prior exposure to proteasome inhibitors (e.g.,
bortezomib, carfilzomib) are eligible as long as the patient demonstrated at least a
partial response to a proteasome inhibitor with chemotherapy combination.
-Renal and hepatic function
Patients must have adequate renal and hepatic functions as indicated by the following
laboratory values:
A. Adequate renal function defined as: Patient must have a calculated creatinine clearance
or radioisotope GFR 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender
B. Adequate Liver Function Defined as: Direct bilirubin ≤ 1.5 x upper limit of normal (ULN)
for age or normal (except in the presence of Gilbert's syndrome), AND alanine transaminase
(ALT) ≤ 5 x ULN for age. The hepatic requirements are waived for patients with known or
suspected liver involvement by leukemia or lymphoma. This must be reviewed by and approved
by the study chair or vice chair.
• Adequate Cardiac Function Defined as: Shortening fraction of more than or equal to 27%
by echocardiogram, OR ejection fraction of equal to or more than 50% by radionuclide
angiogram (MUGA).
• Reproductive Function A. Female patients of childbearing potential must have a
negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
B. Female patients with infants must agree not to breastfeed their infants while on this
study.
C. Male and female patients of child-bearing potential must agree to use an effective
method of contraception approved by the investigator during the study and for a minimum of
6 months after study treatment.
• Informed Consent Patients and/or their parents or legal guardians must be capable of
understanding the investigational nature, potential risks and benefits of the study.
All patients and/or their parents or legal guardians must sign a written informed
consent. Age appropriate assent will be obtained per institutional guidelines. To
allow non-English speaking patients to participate in this study, bilingual health
services will be provided in the appropriate language when feasible.
• All institutional, FDA, and OHRP requirements for human studies must be met.
Exclusion Criteria:
Patients will be excluded if they have isolated CNS or testicular disease.
Patients will be excluded if they have ≥grade 2 peripheral sensory or motor neuropathy
(defined by the Modified "Balis" Pediatric Scale of Pediatric Neuropathies) at the time of
enrollment (see section 4.7.1.1).
Patients will be excluded if they have a known allergy or intolerance to any of the drugs
used in the study •except for PEG-asparaginase for which erwinia asparaginase may be
substituted
Patients will be excluded if they have a systemic fungal, bacterial, viral or other
infection that is exhibiting ongoing signs/symptoms related to the infection without
improvement despite appropriate antibiotics or other treatment. The patient needs to be off
pressors and have negative blood cultures for 48 hours.
Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
radiation therapy, or immunotherapy during the study period.
Patients will be excluded if they have significant concurrent disease, illness, psychiatric
disorder or social issue that would compromise patient safety or compliance with the
protocol treatment or procedures, interfere with consent, study participation, follow up,
or interpretation of study results.
Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are
excluded.
Patients will be excluded if they have had a lifetime exposure of ≥400 mg/m2 doxorubicin
equivolents of anthracyclines (anthracycline equivalence to doxorubicin conversion see
appendix iv) .
Concomitant medications Investigational drugs: Patients currently receiving another
investigational drug are not eligible.
Anti-GVHD agents post transplant: patients who are receiving cyclosporine, tacrolimus or
other agents to prevent graft-versus-host disease post hematopoetic stem cell transplant
are not eligible.
CYP3A4 agents: patients who are currently receiving drugs that are strong inducers of
CYP3A4 are not eligible. Strong inducers of CYP3A4 should be avoided from 14 days prior to
enrollment to the end of the study. See appendix ii for a list of agents which fall into
this category.
Patients with Ph+ALL and Ph-like ALL who are currently receiving TKI therapy
Infants or Patients with Down Syndrome will be excluded in phase 2 of the study