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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
1
Northwestern University
Chicago, Illinois, United States
Incidence of Dose-Limiting Toxicity (DLT)
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.
Time frame: Up to 28 days
Incidence of Adverse Events
To evaluate the toxicity and safety of nivolumab and dasatinib in patients with relapsed/refractory Ph+ ALL. Adverse events will be assessed by number, frequency, and severity and will be graded according to the NCI's common terminology criteria, version 4.03.
Time frame: Up to 28-days after the last dose
Rate of Complete Hematologic Remission (CR)
Determine the rate of complete hematologic remission (CR) after three cycles of nivolumab and dasatinib
Time frame: At 84 days (3 cycles)
Rate of Molecular Remission
Determine the rate of molecular remission after three cycles of nivolumab and dasatinib.
Time frame: At 84 days (3 cycles)
Serum Level of Dasatinib
The serum level of dasatinib will be measured at 24 hours after the start of cycle 1 and on days 8, 15, and 22 prior to treatment during cycle 1.
Time frame: 24 hours after the start of cycle 1 and days 8, 15, and 22 prior to treatment during cycle 1
Serum Level of Nivolumab
The serum level of nivolumab will be measured on days 8, 15, and 22 prior to treatment during cycle 1.
Time frame: Days 8, 15, and 22 prior to treatment during cycle 1
PD1 Expression Levels and Saturation Assessed in the Peripheral Blood
Peripheral blood will be evaluated to measure PD1 expression levels and saturation.
Time frame: Baseline to 28-days after the last dose
PD1 Expression Levels and Saturation in Bone Marrow
Bone marrow will be assessed to measure PD1 expression levels and saturation.
Time frame: Baseline to 28-days after the last dose
Peripheral T-cell Levels and Activation in Response to Treatment
T-cell levels and activation will be measured in the peripheral blood after treatment.
Time frame: At cycle 1 days: 1, 2, 8, 15, & 22 prior to dosing
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