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Study Description

Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of SNDX-5613 in patients with acute leukemia. There are 3 arms in Phase 1 as follows: 

• Arm A: Patients not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/ inducers.
• Arm B: Patients receiving strong cytochrome P450 3A4 (CY3A4) inhibitors for antifungal prophylaxis.
• Arm C: Patients receiving SNDX-5613 in combination with cobicistat.

In Phase 2, patients will be enrolled in 3 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of SNDX-5613. There are 3 cohorts in Phase 2 as follows: 

• Cohort 2A: Patients with MLLr acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia (MPAL).
• Cohort 2B: Patients with MLLr AML.
• Cohort 2C: Patients with NPM1c AML.

Inclusion Criteria

Patients must have active acute leukemia (bone marrow blasts ≥ 5% or reappearance of blasts in peripheral blood) as defined by the National Comprehensive Cancer Network (NCCN) in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020).

• Phase 1: Documented R/R acute leukemia harboring MLL rearrangement or NPM1c mutation.

  • Arm A: Patients not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers.
  • Arm B: Patients receiving strong cytochrome P450 3A4 inhibitors for antifungal prophylaxis.
  • Arm C: Patients receiving SNDX-5613 in combination with cobicistat.

• Phase 2:

  • Cohort 2A: Documented R/R ALL/MPAL with an MLLr translocation.
  • Cohort 2B: Documented R/R AML with an MLLr translocation.
  • Cohort 2C: Documented R/R AML with NPM1c.
• WBC must be below 50,000/ μL at time of enrollment. Patients may receive cytoreduction prior to enrollment.
• Male or female patient aged ≥30 days old.
• Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or Karnofsky/Lansky score ≥40.
• Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.
• Radiation Therapy: At least 60 days from prior total body irradiation (TBI), craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14 days from local palliative radiation therapy (small port).
• Stem Cell Infusion: At least 60 days must have elapsed from HSCT and at least 4 weeks (from first dose) must have elapsed from donor lymphocyte infusion (DLI) without conditioning.
• Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines and checkpoint inhibitors, and at least 21 days since receipt of chimeric antigen receptor therapy or other modified T cell therapy.
• Myelosuppressive Chemotherapy: At least 14 days since the completion of cytotoxic/myelosuppressive therapy.
• Hematopoietic Growth Factors: At least 7 days since the completion of therapy with short-acting hematopoietic growth factors and 14 days with long-acting growth factors.
• Biologics: At least 7 days or 5 half-lives, whichever is longer, since the completion of therapy with a biologic agent.
• Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing (equivalent to ≤10 mg prednisone daily) or cytoreductive therapy.
• Adequate organ function.
• If of childbearing potential, willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose.

Exclusion Criteria

• Active diagnosis of acute promyelocytic leukemia.
• Isolated extramedullary relapse.
• Known CNS involvement (cytologic or radiographic).
• Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Patients with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrollment.
• Hepatitis B or C.
• Pregnant or nursing women.
• Cardiac Disease: Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
  • - QTc >450 msec for males and QTc >450 msec for females.

• Gastrointestinal Disease:

  • Chronic diarrhea or other gastrointestinal issue that might affect oral drug absorption or ingestion (ie, short-gut syndrome, gastroparesis, etc).
  • Cirrhosis with a Child-Pugh score of B or C.
• Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD >Grade 0 within 4 weeks of enrollment. All transplant patients must have been off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks prior to enrollment. Patients may be on physiological doses of steroids.
• Concurrent malignancy in the previous 2 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy. Concurrent malignancy must be in complete remission or no evidence of disease during this timeframe.
• Participation in another therapeutic interventional clinical study within 30 days of enrollment.