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A Study of SNDX-5613 in R/R Leukemias Including Those With an MLLr/KMT2A Gene Rearrangement or NPM1 Mutation (AUGMENT-101)

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ClinicalTrials.gov Identifier: NCT04065399
Recruitment Status : Recruiting
First Posted : August 22, 2019
Last Update Posted : January 22, 2020
Sponsor:
Information provided by (Responsible Party):
Syndax Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE August 16, 2019
First Posted Date  ICMJE August 22, 2019
Last Update Posted Date January 22, 2020
Actual Study Start Date  ICMJE November 5, 2019
Estimated Primary Completion Date July 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 20, 2019)
  • Occurrence of dose-limiting toxicities (DLTs) (Phase 1) [ Time Frame: Approximately 1 year ]
    Assessed by the NCI CTCAE version 5.0 (Phase 1)
  • Frequency, duration, and severity of treatment-emergent adverse events (TEAEs) (Phase 1) [ Time Frame: Approximately 1 year ]
    Assessed by the NCI CTCAE version 5.0 (Phase 1)
  • Frequency, duration, and severity of treatment-related TEAEs (TRAEs) (Phase 1) [ Time Frame: Approximately 1 year ]
    Assessed by the NCI CTCAE version 5.0 (Phase 1)
  • Frequency, duration, and severity of serious adverse events (SAEs) (Phase 1) [ Time Frame: Approximately 1 year ]
    Assessed by the NCI CTCAE version 5.0 (Phase 1)
  • Cmax (Phase 1) [ Time Frame: Approximately 1 year ]
    Maximum plasma concentration (CMAX) of SNDX-5613 (Phase 1)
  • Tmax (Phase 1) [ Time Frame: Approximately 1 year ]
    Time to observed maximum plasma concentration of SNDX-5613 (Phase 1)
  • AUC0-t (Phase 1) [ Time Frame: Approximately 1 year ]
    Area under the plasma concentration-time curve from time 0 to time of last measurable concentration of SNDX-5613 (Phase 1)
  • AUC0-24 (Phase 1) [ Time Frame: Approximately 1 year ]
    Area under the plasma concentration-time curve from time 0 to 24 hours (Phase 1)
  • CL/F (Phase 1) [ Time Frame: Approximately 1 year ]
    Apparent oral clearance of SNDX-5613 (Phase 1)
  • Vz/F (Phase 1) [ Time Frame: Approximately 1 year ]
    Apparent volume of distribution of SNDX-5613 (Phase 1)
  • t1/2 (Phase 1) [ Time Frame: Approximately 1 year ]
    Terminal phase half-life of SNDX-5613 (Phase 1)
  • Complete remission (CR) rate (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess the CR rate (CR+CRh). (Phase 2)
  • Frequency and severity of adverse events (AEs) (Phase 2) [ Time Frame: Approximately 3 years ]
    Assessed by the NCI CTCAE version 5.0 (Phase 2)
  • Frequency and severity of serious adverse events (SAEs) (Phase 2) [ Time Frame: Approximately 3 years ]
    Assessed by the NCI CTCAE version 5.0 (Phase 2)
  • Frequency, duration, and severity of treatment-emergent adverse events (TEAEs) (Phase 2) [ Time Frame: Approximately 3 years ]
    Assessed by the NCI CTCAE version 5.0 (Phase 2)
  • Frequency, duration, and severity of treatment-related TEAEs (TRAEs) (Phase 2) [ Time Frame: Approximately 3 years ]
    Assessed by the NCI CTCAE version 5.0 (Phase 2)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 20, 2019)
  • Composite definition of complete remission (CRc) Rate (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess the CRc rate. (Phase 2)
  • Complete remission with partial hematologic recovery (CR+CRh) rate after 4 weeks of therapy (Phase 2) [ Time Frame: Approximately 19 months ]
    To assess the CR (CR+CRh) rate after 4 weeks of therapy. (Phase 2)
  • BORR (CRc+ partial remission [PR]). (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess the best overall remission rate (BORR) of SNDX-5613 (Phase 2)
  • Median RFS (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess relapse-free survival of SNDX-5613 (Phase 2)
  • TTR (Phase 2) [ Time Frame: Approximately 34 months ]
    To assess the time to response (TTR) of SNDX-5613 (Phase 2)
  • DOR (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess the duration of response (DOR) of SNDX-5613 (Phase 2)
  • OS (Phase 2) [ Time Frame: Approximately 5 years ]
    To assess overall survival of SNDX-5613 (Phase 2)
  • Cmax (Phase 2) [ Time Frame: Approximately 3 years ]
    Maximum plasma concentration (CMAX) of SNDX-5613 (Phase 2)
  • Tmax (Phase 2) [ Time Frame: Approximately 3 years ]
    Time to observed maximum plasma concentration of SNDX-5613 (Phase 2)
  • AUC0-t (Phase 2) [ Time Frame: Approximately 3 years ]
    Area under the plasma concentration-time curve from time 0 to time of last measurable concentration of SNDX-5613 (Phase 2)
  • AUC0-24 (Phase 2) [ Time Frame: Approximately 3 years ]
    Area under the plasma concentration-time curve from time 0 to 24 hours (Phase 2)
  • CL/F (Phase 2) [ Time Frame: Approximately 3 years ]
    Apparent oral clearance of SNDX-5613 (Phase 2)
  • Vz/F (Phase 2) [ Time Frame: Approximately 3 years ]
    Apparent volume of distribution of SNDX-5613 (Phase 2)
  • t1/2 (Phase 2) [ Time Frame: Approximately 3 years ]
    Terminal phase half-life of SNDX-5613 (Phase 2)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of SNDX-5613 in R/R Leukemias Including Those With an MLLr/KMT2A Gene Rearrangement or NPM1 Mutation
Official Title  ICMJE 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. 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Intervention Model Description:
Phase 1 will employ an accelerated titration design. The dose escalation will follow a modified Fibonacci sequence.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Acute Lymphoblastic Leukemia
  • Mixed Lineage Acute Leukemia
  • Mixed Phenotype Acute Leukemia
  • Acute Leukemia of Ambiguous Lineage
Intervention  ICMJE Drug: SNDX-5613
SNDX-5613 capsules orally
Study Arms  ICMJE Experimental: Experimental: SNDX-5613

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).

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.
Intervention: Drug: SNDX-5613
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 20, 2019)
132
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2024
Estimated Primary Completion Date July 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Susan Brouwer 781-419-1401 sbrouwer@syndax.com
Contact: Sue Fischer 781-795-9419 sfischer@syndax.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04065399
Other Study ID Numbers  ICMJE SNDX-5613-0700
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Syndax Pharmaceuticals
Study Sponsor  ICMJE Syndax Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Galit Rosen, M.D. Syndax Pharmaceuticals, Inc.
PRS Account Syndax Pharmaceuticals
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP