SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT02819804

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

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

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.

NCT02819804 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: Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Philadelphia Chromosome
HPO: Leukemia Lymphoid leukemia

4 Interventions

Name: Dasatinib

Description: Given PO

Type: Drug

Treatment (dasatinib, nivolumab)

Name: Laboratory Biomarker Analysis

Description: Correlative studies

Type: Other

Treatment (dasatinib, nivolumab)

Name: Nivolumab

Description: Given IV

Type: Biological

Treatment (dasatinib, nivolumab)

Name: Pharmacological Study

Description: Correlative studies

Type: Other

Treatment (dasatinib, nivolumab)


Primary Outcomes

Description: 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.

Measure: Incidence of Dose-Limiting Toxicity (DLT)

Time: Up to 28 days

Secondary Outcomes

Description: 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.

Measure: Incidence of Adverse Events

Time: Up to 28-days after the last dose

Description: Determine the rate of complete hematologic remission (CR) after three cycles of nivolumab and dasatinib

Measure: Rate of complete hematologic remission (CR)

Time: At 84 days (3 cycles)

Description: Determine the rate of molecular remission after three cycles of nivolumab and dasatinib.

Measure: Rate of molecular remission

Time: At 84 days (3 cycles)

Description: 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.

Measure: Serum level of Dasatinib

Time: 24 hours after the start of cycle 1 and days 8, 15, and 22 prior to treatment during cycle 1

Description: The serum level of nivolumab will be measured on days 8, 15, and 22 prior to treatment during cycle 1.

Measure: Serum level of Nivolumab

Time: Days 8, 15, and 22 prior to treatment during cycle 1

Description: Peripheral blood will be evaluated to measure PD1 expression levels and saturation.

Measure: PD1 expression levels and saturation assessed in the peripheral blood

Time: Baseline to 28-days after the last dose

Description: Bone marrow will be assessed to measure PD1 expression levels and saturation.

Measure: PD1 expression levels and saturation in bone marrow

Time: Baseline to 28-days after the last dose

Description: T-cell levels and activation will be measured in the peripheral blood after treatment.

Measure: Peripheral T-cell levels and activation in response to treatment

Time: At cycle 1 days: 1, 2, 8, 15, & 22 prior to dosing

Other Outcomes

Description: Number and percentage of patients that die within the first 30 days of initiating treatment.

Measure: The 30 day mortality rate

Time: Up to 30 days

Description: OS is defined as the time from the initiation of study treatment until death from any cause, evaluated for up to 1 year.

Measure: Overall survival (OS)

Time: Up to 1 year

Description: PFS is defined as the time from the initiation of study treatment until the time of disease progression or relapse.

Measure: Progression free survival (PFS)

Time: Up to 1 year

Description: Duration of remission is defined as the time from achieving complete response until the time of disease relapse.

Measure: Duration of remission (DOR)

Time: Up to 1 year

Measure: Compare the OS between patients who receive a hematopoietic stem cell transplant and those who receive no further therapy following remission

Time: Up to 1 year

Measure: Presence of resistance mutations in bone marrow at the time of disease progression

Time: Up to 28-days after the last dose

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 T315I

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 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 B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); --- T315I ---

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 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 B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); --- T315I --- --- T315I ---



HPO Nodes


HPO:
Leukemia
Genes 125
MPL RNASEH2B KRAS NPM1 TET2 MYD88 TSR2 RPL26 RPL27 TREX1 EFL1 PIGL SCN11A FLT3 PMS2 RPL35A EVC2 ABL1 CEBPA RARA NRAS WAS WIPF1 ATRX SH2B3 PDGFRA RB1 RNASEH2A PDGFRB CALR ARHGAP26 SH3GL1 RPS7 RPS10 NUMA1 GATA1 GATA2 RPS15A APC NSD1 ETV6 TCIRG1 DNAJC21 EVC SRP54 RPS17 NBN RPS19 SAMHD1 MSH2 RPS24 NUP214 RPS26 RPS27 RPS28 RPS29 MLLT10 RUNX1 XRCC4 CBFB CBL BCR ADAR TRIP13 ADA2 NSUN2 CREBBP PICALM GFI1 F13A1 F13B FANCA FANCC BLM FANCD2 FANCE NUTM1 JAK2 IFIH1 TYROBP MSH6 FANCG LIG4 PTPN11 SAMD9L THPO NF1 STS PIGA BRCA2 DYNC2LI1 PIK3CA SBDS GLI1 PIK3R1 BRD4 SETBP1 RNASEH2C LPP BUB1 BUB1B SCN9A SCN10A TREM2 MLF1 MLH1 ELANE DKC1 ATM HAX1 RPL35 GNB1 BUB3 CEP57 TAL1 KIT TAL2 RPL5 EP300 TP53 RPL11 KIF11 RPL15 DNMT3A RPL18
Lymphoid leukemia