This phase I/Ib trial tests the safety and side effects of asparaginase Erwinia chrysanthemi-recombinant-rywn (recombinant Erwinia asparaginase) and venetoclax in combination with blinatumomab and how well the combination works in treating patients with CD19 positive B-cell acute lymphoblastic leukemia (ALL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Asparaginase Erwinia chrysanthemi, a type of protein synthesis inhibitor, is a drug that is made up of the enzyme asparaginase, which comes from the bacterium Erwinia chrysanthemi. It is used in people who cannot take asparaginase that comes from the bacterium E. coli. Asparaginase Erwinia chrysanthemi breaks down the amino acid asparagine and may stop the growth of cancer cells that need asparagine to grow. It may also kill cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Blinatumomab is a drug used to treat certain types of B-cell acute lymphoblastic leukemia that are CD19 positive (expresses the protein CD19). Blinatumomab binds to CD19, which is found on most B cells (a type of white blood cell) and some types of leukemia cells. It also binds to a protein called CD3, which is found on T cells (another type of white blood cell). This may help the immune system kill cancer cells. Blinatumomab is a type of bispecific T-cell engager. Giving asparaginase Erwinia chrysanthemi and venetoclax in combination with blinatumomab may be safe, tolerable, and/or effective in treating patients with relapsed or refractory ALL.
Documented informed consent of the participant and/or legally authorized representative
Age between 12 and 55
Eastern Cooperative Oncology Group (ECOG) ≤ 2 or Karnofsky performance status (KPS) ≥ 70
Patients with relapsed or refractory (R/R) CD19 positive (+) B-cell acute lymphoblastic leukemia (B-ALL) according to World Health Organization (WHO) criteria
Allogeneic hematopoietic cell transplantation (HCT) within 8 weeks prior to the start of protocol-specific therapy. Subjects must be off all immunosuppression for ≥ 2 weeks
Cancer chemotherapy within 2 weeks before the start of protocol-specified therapy with the exception of: intrathecal chemotherapy and/or low-dose maintenance therapy (e.g. vina alkaloids, mercaptopurine, methotrexate, or hydroxyurea etc)
Strong and moderate CYP3A4 inducers and strong CYP3A inhibitors within 7 days prior to day 1 of protocol therapy
Foods/supplements that are strong inhibitors or strong or moderate inducers of CYP3A (such as grapefruit, Seville oranges, starfruit and St. John's wort) within 3 days prior to initiation of and during study treatment
Single group
Asparaginase Erwinia chrysanthemi
DrugGiven IM
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Blinatumomab
Biological/VaccineGiven CIV
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration and biopsy
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow aspiration and biopsy
Cyclophosphamide
DrugGiven cyclophosphamide
Echocardiography Test
Procedure/SurgeryUndergo ECHO
Lumbar Puncture
Procedure/SurgeryUndergo lumbar puncture
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Venetoclax
DrugGiven PO
Vincristine
DrugGiven vincristine
Incidence of adverse events (AEs) (Phase I)
Will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Will be summarized in terms of type (organ affected or laboratory determination), severity, attribution, time of onset, duration, probable association with the study treatment and reversibility or outcome by counts/ rates and 95% Clopper Pearson confidence interval (CI).
Dose-limiting toxicities (DLT) (Phase I)
Will be graded according to NCI CTCAE v 5.0. Will be summarized in terms of type (organ affected or laboratory determination), severity, attribution, time of onset, duration, probable association with the study treatment and reversibility or outcome by counts/ rates and 95% Clopper Pearson CI.
Maximum tolerated schedule (Phase I)
Will be based on the assessment of DLT during cycle 1.
Recommended phase 2 schedule (Phase 1)
Will be selected based on maximum tolerated schedule and a review of cumulative toxicity and tolerability data after cycle 1 and may be lower than the maximum tolerated schedule.
Composite remission rate
The complete remission (CR)/CR with incomplete recovery/CR with partial hematologic recovery and 95% Clopper Pearson binomial CI will be calculated.
Minimal residual disease negativity
Will be defined as residual leukemia \< 0.01% by flow cytometry or Clonoseq in bone marrow biopsy. Clopper Pearson binomial CI will be calculated.
Incidence of adverse events (Expansion Phase)
Will be graded according to NCI CTCAE v 5.0. Will be summarized in terms of type (organ affected or laboratory determination), severity, attribution, time of onset, duration, probable association with the study treatment and reversibility or outcome by counts/ rates and 95% Clopper Pearson CI.
Patients who bridge to transplant directly from the trial therapy
The Clopper Pearson binomial CI will be calculated.
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City of Hope Medical Center
Lead sponsor
National Cancer Institute (NCI)
Collaborator
