A Study of SNDX-5613 in R/R Leukemias Including Those With an MLLr/KMT2A Gene Rearrangement or NPM1 Mutation

Brief Title

A Study of SNDX-5613 in R/R Leukemias Including Those With an MLLr/KMT2A Gene Rearrangement or NPM1 Mutation

Official Title

AUGMENT-101: 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

Brief Summary

      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.

      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.
    

Detailed 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 harboring an MLL
      rearrangement or NPM1 mutation:

        -  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.

      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:

        -  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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Occurrence of dose-limiting toxicities (DLTs) (Phase 1)

Secondary Outcome

 Composite definition of complete remission (CRc) Rate (Phase 2)

Condition

Acute Myeloid Leukemia

Intervention

SNDX-5613

Study Arms / Comparison Groups

 Experimental: SNDX-5613
Description:  Phase 1:
Oral SNDX-5613; sequential cohorts of escalating dose levels of SNDX-5613 to identify the maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D). Patients will be enrolled in one of two dose-escalation arms:
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.
Phase 2:
Oral SNDX-5613; Following the determination of the RP2D in Phase 1, 3 indication-specific expansion cohorts will be enrolled 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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

186

Start Date

November 5, 2019

Completion Date

January 1, 2024

Primary Completion Date

July 1, 2022

Eligibility Criteria

        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).

          1. 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.

          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. WBC must be below 50,000/ μL at time of enrollment. Patients may receive cytoreduction
             prior to enrollment.

          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 HSCT and at least 4 weeks
             (from first dose) must have elapsed from donor lymphocyte infusion (DLI) without
             conditioning.

          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 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 7 days or 5 half-lives, whichever is longer, since the completion
             of therapy with a 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. Known CNS involvement (cytologic 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.

             - QTc >450 msec for males and QTc >470 msec for females.

          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. Concurrent malignancy must be in complete remission or no evidence
             of disease during this timeframe.

         11. Participation in another therapeutic interventional clinical study within 30 days of
             enrollment.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Galit Rosen, M.D., 781-419-1400, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04065399

Organization ID

SNDX-5613-0700


Responsible Party

Sponsor

Study Sponsor

Syndax Pharmaceuticals


Study Sponsor

Galit Rosen, M.D., Study Director, Syndax Pharmaceuticals, Inc.


Verification Date

November 2020