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

NCT02819804 | Terminated Phase 1 Results DMC FDA Drug

• 4 other identifiers: NU 15H13STU00202846P30CA060553NCI-2016-00711
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Incidence of Adverse Events

  Up to 28-days after the last dose

• Rate of Complete Hematologic Remission (CR)

  At 84 days (3 cycles)

• Rate of Molecular Remission

  At 84 days (3 cycles)

• Serum Level of Dasatinib

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

• Serum Level of Nivolumab

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

Other Outcomes (6)

• The 30 Day Mortality Rate

  Up to 30 days

• Overall Survival (OS)

  Up to 1 year

• Progression Free Survival (PFS)

  Up to 1 year

Study Arms (1)

Treatment (dasatinib, nivolumab)

EXPERIMENTAL

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; Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Other: Pharmacological Study

Interventions

Dasatinib DRUG

Given PO

Also known as: BMS-354825, Sprycel

Treatment (dasatinib, nivolumab)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (dasatinib, nivolumab)

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Treatment (dasatinib, nivolumab)

Pharmacological Study OTHER

Correlative studies

Treatment (dasatinib, nivolumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Northwestern University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Dasatinib; Nivolumab

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The study was closed to accrual with only one patient enrolled. It did not meet its accrual goal of 22 patients due to slow accrual and funding issues.

Results Point of Contact

• Title: Shira Dinner, MD
• Organization: Northwestern University

shira.dinner@nm.org

312-695-6180

Study Officials

• Shira Dinner, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2016
• First Posted: June 30, 2016
• Study Start: August 17, 2017
• Primary Completion: August 27, 2017
• Study Completion: August 30, 2018
• Last Updated: February 11, 2020
• Results First Posted: January 31, 2020

Record last verified: 2020-01

Locations

US (1)