• Acute Myeloid
• Leukemia
• Acute Lymphoblastic Leukemia
• Mixed Lineage Acute Leukemia
• Mixed Phenotype Acute Leukemia
• Acute Leukemia of Ambiguous Lineage

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), or acute leukemia harboring an MLL rearrangement, NUP98 rearrangement, or NPM1 mutation that have detectable disease in the bone marrow.

1. Phase 1:
   • Arm A: Patients not receiving any strong CYP3A4 inhibitor/inducers or fluconazole.
   • Arm B: Patients receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis.
   • Arm C: Patients receiving SNDX-5613 in combination with cobicistat.
   • Arm D: Patients receiving fluconazole (moderate CYP3A4 inhibitor).
   • Arm E: Patients not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers.
   • Arm F: Patients receiving isavuconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis.
2. 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.
3. White blood cell count below 25,000/ microliter at time of enrollment. Patients may receive cytoreduction prior to enrollment per protocol-specified criteria.
4. Male or female patient aged ≥30 days old.
5. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or Karnofsky/Lansky score ≥40.
6. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.
7. 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).
8. Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stem cell transplant and at least 4 weeks must have elapsed from donor lymphocyte infusion.
9. 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.
10. Myelosuppressive Chemotherapy: At least 14 days, or 5 half-lives, whichever is shorter, since the completion of cytotoxic/myelosuppressive therapy.
11. 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.
12. Biologics: At least 90 days, or 5 half-lives, whichever is shorter, since the completion of therapy with an antineoplastic biologic agent.
13. Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing (equivalent to ≤10 mg prednisone daily) or cytoreductive therapy.
14. Adequate organ function.
15. 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:

Patients meeting any of the following criteria are not eligible for study participation:

1. Active diagnosis of acute promyelocytic leukemia.
2. Isolated extramedullary relapse.
3. Active central nervous system disease (cytologic, such as any blasts on cytospin, or radiographic).
4. 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.
5. Hepatitis B or C.
6. Pregnant or nursing women.
7. 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.- Corrected QT interval (QTc) >450 milliseconds.
8. 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.
9. 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.
10. 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, or concurrent low-grade lymphoma, that is asymptomatic and lacks bulky disease and shows no evidence of progression, and for which the patient is not receiving any systemic therapy or radiation.
11. In Phase 1 and Phase 2: Patients requiring the concurrent use of medications known or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies (eg, diphenhydramine, famotidine, ondansetron, Bactrim) and the azoles permitted in the relevant arms of Phase 1.

Louise Hay
louise.hay@health.wa.gov.au
08 6383 3207

Dr. Carolyn Grove

Syndax Pharmaceuticals

Phase 1 & 2

SNDX-5613

NCT04065399