A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation

Recruiting

Trial ID: NCT04065399

Purpose

Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of revumenib 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 revumenib.

Official Title

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

Stanford Investigator(s)

Gabriel Mannis
Gabriel Mannis

Associate Professor of Medicine (Hematology)

Eligibility


Inclusion Criteria:

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 KMT2A rearrangement, NUP98 rearrangement, or NPM1 mutation that
have detectable disease in the bone marrow.

   1. Phase 1:

      - Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or
      fluconazole.

      - Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or
      voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis.

      - Arm C: Participants receiving revumenib in combination with cobicistat.

      - Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor).

      - Arm E: Participants not receiving any weak, moderate, or strong CYP3A4
      inhibitors/inducers.

      - Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for
      antifungal prophylaxis.

   2. Phase 2:

   Documented R/R active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts
   in peripheral blood) as defined by the NCCN Guidelines® for Acute Lymphoblastic
   Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020).

      - Cohort 2A: Documented R/R ALL/MPAL with KMT2A rearrangement.

      - Cohort 2B: Documented R/R AML with KMT2A rearrangement.

      - Cohort 2C: Documented R/R AML with NPM1m.

   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 at least 21 days since receipt of chimeric antigen receptor therapy or other
   modified T or NK 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 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:

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

   1. Diagnosis of active acute promyelocytic leukemia.

   2. Isolated extramedullary relapse (Phase 2 only).

   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.
   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 and in Phase 2.

Intervention(s):

drug: cobicistat

drug: revumenib

Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Panayota Rigas
prigas@stanford.edu

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