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

NCT04065399

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. 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.

Related Conditions:
  • Acute Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Mixed Phenotype Acute Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: SNDX-5613-0700
  • NCT ID: NCT04065399

Conditions

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

Interventions

DrugSynonymsArms
SNDX-5613Experimental: SNDX-5613

Purpose

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. Patients with R/R acute
      leukemia are to be enrolled in Phase 1 agnostic of genetic mutation status.

      In Phase 2, study subjects 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.
    

Trial Arms

NameTypeDescriptionInterventions
Experimental: SNDX-5613ExperimentalPhase 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). 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.
  • SNDX-5613

Eligibility Criteria

        Inclusion Criteria:

          1. Phase 1: Documented R/R acute leukemia.

          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. No standard available therapeutic options.

          5. Male or female patient aged ≥18 years.

          6. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2.

          7. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with
             the exception of ≤Grade 2 neuropathy or alopecia.

          8. 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).

          9. 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.

         10. 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.

         11. Myelosuppressive Chemotherapy: At least 14 days since the completion of
             cytotoxic/myelosuppressive therapy.

         12. 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.

         13. Biologics: At least 7 days or 5 half-lives, whichever is longer, since the completion
             of therapy with a biologic agent.

         14. Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving
             physiologic dosing (equivalent to ≤10 mg prednisone daily) or cytoreductive therapy.

         15. Adequate organ function.

         16. 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:

               -  Inability to swallow or retain whole capsules.

               -  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 the first dose of SNDX-5613. 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 3 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.

         11. Participation in another therapeutic interventional clinical study within 30 days of
             enrollment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Occurrence of dose-limiting toxicities (DLTs) (Phase 1)
Time Frame:Approximately 1 year
Safety Issue:
Description:Assessed by the NCI CTCAE version 5.0 (Phase 1)

Secondary Outcome Measures

Measure:Composite definition of complete remission (CRc) Rate (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:To assess the CRc rate. (Phase 2)
Measure:Complete remission with partial hematologic recovery (CR+CRh) rate after 4 weeks of therapy (Phase 2)
Time Frame:Approximately 19 months
Safety Issue:
Description:To assess the CR (CR+CRh) rate after 4 weeks of therapy. (Phase 2)
Measure:BORR (CRc+ partial remission [PR]). (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:To assess the best overall remission rate (BORR) of SNDX-5613 (Phase 2)
Measure:Median RFS (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:To assess relapse-free survival of SNDX-5613 (Phase 2)
Measure:TTR (Phase 2)
Time Frame:Approximately 34 months
Safety Issue:
Description:To assess the time to response (TTR) of SNDX-5613 (Phase 2)
Measure:DOR (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:To assess the duration of response (DOR) of SNDX-5613 (Phase 2)
Measure:OS (Phase 2)
Time Frame:Approximately 5 years
Safety Issue:
Description:To assess overall survival of SNDX-5613 (Phase 2)
Measure:Cmax (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:Maximum plasma concentration (CMAX) of SNDX-5613 (Phase 2)
Measure:Tmax (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:Time to observed maximum plasma concentration of SNDX-5613 (Phase 2)
Measure:AUC0-t (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:Area under the plasma concentration-time curve from time 0 to time of last measurable concentration of SNDX-5613 (Phase 2)
Measure:AUC0-24 (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:Area under the plasma concentration-time curve from time 0 to 24 hours (Phase 2)
Measure:CL/F (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:Apparent oral clearance of SNDX-5613 (Phase 2)
Measure:Vz/F (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:Apparent volume of distribution of SNDX-5613 (Phase 2)
Measure:t1/2 (Phase 2)
Time Frame:Approximately 3 years
Safety Issue:
Description:Terminal phase half-life of SNDX-5613 (Phase 2)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Syndax Pharmaceuticals

Trial Keywords

  • AML
  • ALL
  • acute leukemia
  • MLLr
  • KMT2A
  • NPM1

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