Nivolumab and Dasatinib in Treating Patients With Relapsed or Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Condition: 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
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Recurrence; Philadelphia Chromosome
Intervention: Dasatinib; Laboratory Biomarker Analysis; Nivolumab; Pharmacological Study
Intervention description: Given PO; Correlative studies; Given IV; Correlative studies
Intervention MeSH terms: Nivolumab; Dasatinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

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:

               -  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