Nivolumab and Dasatinib in Treating Patients With Relapsed or Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase Ib Study of Nivolumab and Dasatinib in Patients With Relapsed/Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Conditions
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B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Refractory Adult Acute Lymphoblastic Leukemia, Refractory Childhood Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Dasatinib
* Other: Laboratory Biomarker Analysis
* Biological: Nivolumab
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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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: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2 x institutional upper limit of normal (IULN) Total bilirubin < 2.0 x IULN (unless Gilbert syndrome has been diagnosed); if leukemia infiltration of the liver is suspected to be causing liver function abnormalities the patient will still be eligible with principal investigator (PI) approval Creatinine < 2 x IULN Creatinine clearance > 40 mL/min (measured by Cockroft-Gault) Females of child-bearing potential (FOCBP) must have a negative pregnancy test within 7 days of registration Note: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) Women must not be breastfeeding at the time of study registration Women and men of reproductive potential should agree to use two effective means of birth control For women, contraception should continue for 23 weeks after the last dose of nivolumab and 12 weeks after the last dose of dasatinib to allow complete clearance of drug and its principal metabolites from the body For men, contraception should continue for 31 weeks after nivolumab and 12 weeks after dasatinib Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study 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 Patients who have a known dasatinib-resistant ABL-kinase mutation such as T315I are not eligible; for confirmation, please contact PI Patients who have any serious or uncontrolled medical disorder that would impair the ability of the subject to receive protocol therapy are not eligible; these include, but are not limited to: Active infection that is not well controlled Known pleural or pericardial effusion at baseline Clinically significant gastrointestinal disease or digestive dysfunction compromising absorption of dasatinib Pulmonary arterial hypertension Uncontrolled or significant cardiovascular disease, including: Myocardial infarction within 6 months of enrollment date Uncontrolled angina or congestive heart failure within 3 months of enrollment date Left ventricular ejection fraction (LVEF) < 40% Significant cardiac conduction abnormality, including: History of clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) History of second or third degree heart block (except for second degree type 1) Corrected QT (QTc) interval > 500 msec, unless a cardiac pacemaker is present Prior malignancy active within the previous 3 years, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancers, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast Subjects with active, known or suspected autoimmune disease; (Note: Subjects with vitiligo, type I diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll) Psychiatric illness/social situations that would limit compliance with study requirements Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints Female patients who are pregnant or nursing are not eligible Patients are not eligible if they have a known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (hepatitis C virus [HCV] antibody) indicating acute infection; Note: Patients with evidence of chronic hepatitis B infection will be allowed to enroll if on appropriate suppressive medications under the direction of a hepatologist and with PI approval Patients who are known to be positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are not eligible Patients must not have live vaccine therapies for prevention of infectious diseases within 28 days of first nivolumab dose Patients who are unable to swallow oral medication are not eligible Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater), should be excluded; these include but are not limited to patients with a history of: Immune related neurologic disease Multiple sclerosis Autoimmune (demyelinating) neuropathy Guillain-Barre syndrome Myasthenia gravis Systemic autoimmune disease such as systemic lupus erythematosus (SLE) Connective tissue diseases Scleroderma Inflammatory bowel disease (IBD) Crohn's Ulcerative colitis Patients with a history of toxic epidermal necrolysis (TEN) Stevens-Johnson syndrome Anti-phospholipid syndrome NOTE: Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (dasatinib, nivolumab)<br>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. | Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | At 84 days (3 cycles) | 
| Rate of Molecular Remission | Determine the rate of molecular remission after three cycles of nivolumab and dasatinib. | 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. | 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. | 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. | 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. | 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. | At cycle 1 days: 1, 2, 8, 15, & 22 prior to dosing |