A Phase 1/2, Open-label, Dose-Escalation and Dose-Expansion Cohort Study of SNDX-5613 in Patients with Relapsed/Refractory Leukemias, Including Those Harboring an MLL/KMT2A Gene Rearrangement or Nucleophosmin 1 (NPM1) Mutation
Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase
2 dose (RP2D) of SNDX-5613 in participants with acute leukemia.
In Phase 2, participants will be enrolled in 3 indication-specific expansion cohorts to
determine the efficacy, short- and long-term safety, and tolerability of SNDX-5613.
Participants 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 NPM1c mutation that
have detectable disease in the bone marrow.
1. Phase 1:
- Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or
- Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or
voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis.
- Arm C: Participants receiving SNDX-5613 in combination with cobicistat.
- Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor).
- Arm E: Participants not receiving any weak, moderate, or strong CYP3A4
- Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for
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. Participants
may receive cytoreduction prior to enrollment per protocol-specified criteria.
4. Male or female participants aged ≥30 days old.
5. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or
Karnofsky/Lansky score ≥50.
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. Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, since
the completion of antileukemic 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.
Participants meeting any of the following criteria are not eligible for study
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
4. Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months.
Participants 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:
- any gastrointestinal issue of the upper GI tract that might affect oral drug
absorption or ingestion (that is, gastric bypass, 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 participants must have been off all
systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks
prior to enrollment. Participants 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 (for
example, 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
participant is not receiving any systemic therapy or radiation.
11. In Phase 1 and Phase 2: Participants 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 (for example,
diphenhydramine, famotidine, ondansetron, Bactrim) and the azoles permitted in the
relevant arms of Phase 1.