Phase Ib Study of Nivolumab and Dasatinib in Patients With Relapsed/Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Overview
- Phase
- Phase 1
- Intervention
- Dasatinib
- Conditions
- B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1
- Sponsor
- Northwestern University
- Enrollment
- 1
- Locations
- 1
- Primary Endpoint
- Incidence of Dose-Limiting Toxicity (DLT)
- Status
- Terminated
- Last Updated
- 6 years ago
Overview
Brief Summary
The purpose of this research study is to determine the acceptable upper limit dose of nivolumab in combination with dasatinib that may be given to patients with relapsed/refractory philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Nivolumab is currently Food and Drug Administration (FDA) approved for other cancers, but has not yet been investigated in Ph+ ALL. Dasatinib is currently FDA approved for the treatment of Ph+ ALL, but has not yet been investigated in combination with nivolumab for this disease. There is evidence that dasatinib not only blocks the Philadelphia chromosome or breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) mutation, but also increases the activity of cells in your immune system. Nivolumab increases T cells in your immune system, which allows your immune system to attack the cancer. We think the combination of these drugs will be more effective against your leukemia than either drug used alone.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of nivolumab when given in combination with dasatinib in patients with relapsed/refractory Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). SECONDARY OBJECTIVES: I. To evaluate the toxicities and safety profile of nivolumab and dasatinib in patients with relapsed/refractory Ph+ ALL. II. To determine the rate of complete hematologic remission (CR) after three cycles of nivolumab and dasatinib. III. To determine the rate of molecular remission after three cycles of nivolumab and dasatinib. IV. To study the pharmacokinetics of nivolumab and dasatinib. V. To evaluate programmed cell death 1 (PD1) expression levels and saturation in the peripheral blood and bone marrow. VI. To measure peripheral T-cell levels and activation in response to treatment. TERTIARY OBJECTIVES: I. To evaluate the 30 day mortality rate, overall survival (OS), progression free survival (PFS), and duration of remission (DOR) one year after treatment with nivolumab when given in combination with dasatinib in patients with relapsed/refractory Ph+ ALL. II. To compare the OS between patients who receive a hematopoietic stem cell transplant and those who receive no further therapy following remission. III. To evaluate for resistance mutations at the time of disease progression. OUTLINE: Patients receive dasatinib orally (PO) once daily (QD ) on days 1-28 and nivolumab intravenously (IV) over 30 minutes on days 8 and 22 of course 1 and on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression, unacceptable toxicity, or withdrawal from the study for other reasons. After completion of study treatment, patients are followed up at 30 days and then monthly for up to 1 year.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have a histologically confirmed diagnosis of Ph+ ALL
- •Detection of one of the following must be present:
- •t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics
- •Breakpoint cluster region (BCR)-Abelson (ABL) positive status by molecular analysis with qualitative polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH)
- •Patients must have primary refractory ALL based on failure to achieve a hematologic or molecular remission after induction therapy with dasatinib and steroids or dasatinib and chemotherapy, or have relapsed after treatment with a tyrosine kinase inhibitor with or without chemotherapy
- •Note: Prior course of dasatinib and steroid induction therapy should have included dasatinib 140mg PO daily on days 1-84 and prednisone 60mg/m\^2 (capped at 120mg, or equivalent steroid dose) on days 1-28; if patients were unable to tolerate full steroid dose during induction therapy they will still be eligible
- •Note: Patients with refractory or relapsed disease in the central nervous system will be eligible
- •Prior chemotherapy or tyrosine kinase inhibitor (TKI) treatment, aside from dasatinib, must be \>= 7 days before first investigational agent dose
- •Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Patients must have adequate organ and bone marrow function prior to registration, as defined below:
Exclusion Criteria
- •Patients may not be receiving any other investigational agents within 5 half-lives of the drug (if known); if the half-life is not known, investigational agents should not be taken within two weeks
- •Patients are not eligible if they have an intolerance to most recent prior TKI (other than dasatinib) at the lowest possible effective dose, defined as a grade \>= 3 toxicity considered at least possibly related to that TKI; patients are also excluded if they are intolerant or allergic to dasatinib and discontinued prior therapy due to a \>= grade 2 treatment related adverse event
- •Patients must not have a history of a grade 4 anaphylactic reaction to monoclonal antibody therapy or known hypersensitivity reactions to drugs formulated with polysorbate 90
- •Patients must not have had any prior therapy with an anti-PD-1, anti-programmed cell death 1 ligand 1 (PD-L1), anti-programmed cell death 1 ligand 2 (PD-L2), anti-cluster of differentiation (CD)137 or anti-cytotoxic t-lymphocyte-associated protein 4 ligand (CTLA-4) antibody (or any antibody or drug specifically targeting T-cell costimulation or checkpoint pathways; for questions or uncertainties, please contact the PI or quality assurance manager (QAM)
- •Patients who have had allogeneic hematopoietic stem cell transplant (HSCT) are not eligible if they meet any of the following:
- •transplant is within 2 months from cycle 1, day 1 (C1D1)
- •Has clinically significant graft-versus-host disease requiring treatment
- •Has \>= grade 3 persistent non-hematological toxicity related to the transplant
- •Concomitant use of strong inhibitors of the cytochrome p450, family 3, subfamily a, polypeptide 4 (CYP3A4) isoenzyme is not permitted; must have wash-out period of 5 times the half-life of the compound before first dasatinib dose
- •Concomitant use of QT prolonging agents strongly associated with torsades de pointes is not permitted
Arms & Interventions
Treatment (dasatinib, nivolumab)
Patients receive dasatinib PO QD on days 1-28 and nivolumab IV over 30 minutes on days 8 and 22 of course 1 and on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Dasatinib
Treatment (dasatinib, nivolumab)
Patients receive dasatinib PO QD on days 1-28 and nivolumab IV over 30 minutes on days 8 and 22 of course 1 and on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Treatment (dasatinib, nivolumab)
Patients receive dasatinib PO QD on days 1-28 and nivolumab IV over 30 minutes on days 8 and 22 of course 1 and on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Nivolumab
Treatment (dasatinib, nivolumab)
Patients receive dasatinib PO QD on days 1-28 and nivolumab IV over 30 minutes on days 8 and 22 of course 1 and on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Pharmacological Study
Outcomes
Primary Outcomes
Incidence of Dose-Limiting Toxicity (DLT)
Time Frame: Up to 28 days
Determine the maximum tolerated dose (MTD) of nivolumab when given in combination with dasatinib, the MTD will be defined as the highest dose level at which ≤ 1 DLT occurs and will be assessed by the Common Terminology Criteria for Adverse Events version 4.03.
Secondary Outcomes
- Serum Level of Dasatinib(24 hours after the start of cycle 1 and days 8, 15, and 22 prior to treatment during cycle 1)
- PD1 Expression Levels and Saturation Assessed in the Peripheral Blood(Baseline to 28-days after the last dose)
- Rate of Complete Hematologic Remission (CR)(At 84 days (3 cycles))
- Incidence of Adverse Events(Up to 28-days after the last dose)
- Rate of Molecular Remission(At 84 days (3 cycles))
- Serum Level of Nivolumab(Days 8, 15, and 22 prior to treatment during cycle 1)
- PD1 Expression Levels and Saturation in Bone Marrow(Baseline to 28-days after the last dose)
- Peripheral T-cell Levels and Activation in Response to Treatment(At cycle 1 days: 1, 2, 8, 15, & 22 prior to dosing)