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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 : May 24, 2022
Sponsor:
Information provided by (Responsible Party):
Syndax Pharmaceuticals

Study Description
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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.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Mixed Lineage Acute Leukemia Mixed Phenotype Acute Leukemia Acute Leukemia of Ambiguous Lineage Drug: SNDX-5613 Drug: cobicistat Phase 1 Phase 2

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.
  • Arm C: Patients receiving SNDX-5613 in combination with cobicistat.

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 186 participants
Allocation: N/A
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
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
Actual Study Start Date : November 5, 2019
Estimated Primary Completion Date : July 1, 2022
Estimated Study Completion Date : January 1, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Cobicistat

Arms and Interventions
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Arm Intervention/treatment
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). Patients will be enrolled in one of three 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.
  • Arm C: Patients receiving SNDX-5613 and cobicistat.

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.
 Drug: SNDX-5613
SNDX-5613 orally

Drug: cobicistat
Phase 1 Arm C patients will receive 150 mg cobicistat daily.


Outcome Measures
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Primary Outcome Measures :
  1. Occurrence of dose-limiting toxicities (DLTs) (Phase 1) [ Time Frame: Approximately 1 year ]
    Assessed by the NCI CTCAE version 5.0 (Phase 1)

  2. 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)

  3. 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)

  4. 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)

  5. Cmax (Phase 1) [ Time Frame: Approximately 1 year ]
    Maximum plasma concentration (CMAX) of SNDX-5613 (Phase 1)

  6. Tmax (Phase 1) [ Time Frame: Approximately 1 year ]
    Time to observed maximum plasma concentration of SNDX-5613 (Phase 1)

  7. 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)

  8. AUC0-24 (Phase 1) [ Time Frame: Approximately 1 year ]
    Area under the plasma concentration-time curve from time 0 to 24 hours (Phase 1)

  9. CL/F (Phase 1) [ Time Frame: Approximately 1 year ]
    Apparent oral clearance of SNDX-5613 (Phase 1)

  10. Vz/F (Phase 1) [ Time Frame: Approximately 1 year ]
    Apparent volume of distribution of SNDX-5613 (Phase 1)

  11. t1/2 (Phase 1) [ Time Frame: Approximately 1 year ]
    Terminal phase half-life of SNDX-5613 (Phase 1)

  12. Complete remission (CR) rate (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess the CR rate (CR+CRh). (Phase 2)

  13. Frequency and severity of adverse events (AEs) (Phase 2) [ Time Frame: Approximately 3 years ]
    Assessed by the NCI CTCAE version 5.0 (Phase 2)

  14. 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)

  15. 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)

  16. 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)


Secondary Outcome Measures :
  1. Composite definition of complete remission (CRc) Rate (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess the CRc rate. (Phase 2)

  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)

  3. 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)

  4. Median RFS (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess relapse-free survival of SNDX-5613 (Phase 2)

  5. TTR (Phase 2) [ Time Frame: Approximately 34 months ]
    To assess the time to response (TTR) of SNDX-5613 (Phase 2)

  6. DOR (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess the duration of response (DOR) of SNDX-5613 (Phase 2)

  7. OS (Phase 2) [ Time Frame: Approximately 5 years ]
    To assess overall survival of SNDX-5613 (Phase 2)

  8. Cmax (Phase 2) [ Time Frame: Approximately 3 years ]
    Maximum plasma concentration (CMAX) of SNDX-5613 (Phase 2)

  9. Tmax (Phase 2) [ Time Frame: Approximately 3 years ]
    Time to observed maximum plasma concentration of SNDX-5613 (Phase 2)

  10. 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)

  11. AUC0-24 (Phase 2) [ Time Frame: Approximately 3 years ]
    Area under the plasma concentration-time curve from time 0 to 24 hours (Phase 2)

  12. CL/F (Phase 2) [ Time Frame: Approximately 3 years ]
    Apparent oral clearance of SNDX-5613 (Phase 2)

  13. Vz/F (Phase 2) [ Time Frame: Approximately 3 years ]
    Apparent volume of distribution of SNDX-5613 (Phase 2)

  14. t1/2 (Phase 2) [ Time Frame: Approximately 3 years ]
    Terminal phase half-life of SNDX-5613 (Phase 2)


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
    • Arm C: Patients receiving SNDX-5613 in combination with cobicistat.

  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 >450 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04065399


Contacts
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Contact: Anthony Piscitell 781-492-5716 apiscitelli@syndax.com

Locations
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United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Manjyot Nanhwan       mnanhwan@coh.org   
Stanford Cancer Institute Recruiting
Palo Alto, California, United States, 94305
Contact: Panayota Rigas       prigas@stanford.edu   
United States, Florida
Florida Cancer Specialists and Research Institute Recruiting
Sarasota, Florida, United States, 34232
Contact: Terri Peterson, RN       tpeterson@flcancer.com   
Moffitt Cancer Center Completed
Tampa, Florida, United States, 33162
United States, Georgia
Emory Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Shannon Gleason, MLS, CCRC    404-778-4334 ext 10808    shannon.gleason@emory.edu   
United States, Illinois
The University of Chicago Medical Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Howie Weiner, CCRP    773-702-2084      
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Morgan Johnson    857-215-0238    Morgan_Johnson@DFCI.HARVARD.EDU   
Contact: Lindsay Rae    617-582-9169    Lindsey_Rae@DFCI.HARVARD.EDU   
United States, Missouri
Washington University in St. Louis School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Hannah Hartman    314-273-8628    hannahlhartman@wustl.edu   
Contact: Madeline Stowe       mstowe@wustl.edu   
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Kait Tkachuk    646-608-2783    tkachukk@mskcc.org   
Montefiore Medical Center Recruiting
New York, New York, United States, 10467
Contact: Karen Fehn       KFEHN@montefiore.org   
Contact: Joel Victor       jovictor@montefiore.org   
United States, Ohio
Ohio State University Recruiting
Columbus, Ohio, United States, 43201
Contact: Molly Brandenburg    614-366-7951    molly.brandenburg@osumc.edu   
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Shannon Clark Lewis, BSN RN    215-220-9670    Shannon.Lewis@Pennmedicine.upenn.edu   
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Ghayas Issa, MD       gcissa@mdanderson.org   
United States, Utah
Huntsman Cancer Institute at the University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Jessica Hammond       Jessica.Hammond@hci.utah.edu   
Contact: Catherine Cromar       Catherine.Cromar@hci.utah.edu   
Canada
The Hospital for Sick Children Recruiting
Toronto, Canada
Contact: Aiman Siddiqi       aiman.siddiqi@sickkids.ca   
Netherlands
Princess Maxima Center for Pediatric Oncology Recruiting
Utrecht, Netherlands, 3584 CS
Contact: Secretary Trial and Data Centrum       tdcsecretary@prinsesmaximacentrum.nl   
Sponsors and Collaborators
Syndax Pharmaceuticals
Investigators
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Study Director: Nicole McNeer, M.D. Syndax Pharmaceuticals, Inc.
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Syndax Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04065399    
Other Study ID Numbers: SNDX-5613-0700
First Posted: August 22, 2019    Key Record Dates
Last Update Posted: May 24, 2022
Last Verified: May 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Syndax Pharmaceuticals:
AML
ALL
acute leukemia
 MLLr
KMT2A
NPM1
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Biphenotypic, Acute
Acute Disease
Neoplasms by Histologic Type
Neoplasms
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
 Disease Attributes
Pathologic Processes
Cobicistat
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action