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

March 22, 2024 updated by: Syndax Pharmaceuticals

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

Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of SNDX-5613 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 SNDX-5613.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Phase 1: Oral SNDX-5613; sequential cohorts of escalating dose levels of SNDX-5613 to identify the MTD and RP2D. Participants will be enrolled in one of six dose-escalation arms:

Arm A: Participants not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers or fluconazole.

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

Arm C: Participants receiving SNDX-5613 and cobicistat.

Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis.

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

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

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 SNDX-5613:

  • Cohort 2A: Participants with KMT2Ar acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia (MPAL)
  • Cohort 2B: Participants with KMT2A AML
  • Cohort 2C: Participants with NPM1m AML

Study Type

Interventional

Enrollment (Estimated)

413

Phase

  • Phase 2
  • Phase 1

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Australia
      • Melbourne, Australia, 3004
        • Recruiting
        • Alfred Hospital
        • Principal Investigator:
          • Shaun Fleming, MD
      • Nedlands, Australia, 6009
        • Recruiting
        • Sir Charles Gairdner Hospital
        • Principal Investigator:
          • Carolyn Grove, MD
      • Saint Leonards, Australia, 2065
        • Recruiting
        • Royal North Shore Hospital
        • Principal Investigator:
          • Matthew Greenwood, MD
    • Victoria
      • Melbourne, Victoria, Australia, 3000
      • Parkville, Victoria, Australia, 3050
        • Recruiting
        • Royal Melbourne Hospital (RMH)
        • Principal Investigator:
          • Ashish Bajel
        • Contact:
  • Canada
      • Toronto, Canada
      • Toronto, Canada, M5G 2M9
        • Recruiting
        • University Health Network
        • Principal Investigator:
          • Andre Schuh, MD
  • France
      • Pierre-Benite, France, 69495
      • Villejuif, France, 94805
        • Recruiting
        • Institut Gustave Roussy-Gustave Roussy Cancer Center -DITEP
        • Contact:
        • Principal Investigator:
          • Stephanie De Botton
  • Germany
      • Essen, Germany, 45147
        • Recruiting
        • Universitaetsklinikum Essen (AoR)
        • Principal Investigator:
          • Dirk Reinhardt
        • Contact:
        • Contact:
        • Principal Investigator:
          • Hanoun Maher
      • Greifswald, Germany, 17475
      • Gutenberg, Germany, 55131
  • Israel
      • Haifa, Israel, 3109601
      • Jerusalem, Israel, 9103102
        • Recruiting
        • Shaare Zedek Medical Center
        • Principal Investigator:
          • Yishai Ofran
        • Contact:
      • Jerusalem, Israel, 9112001
        • Recruiting
        • Hadassah Medical Center- Ein Kerem
        • Principal Investigator:
          • Boaz Nachmias
        • Contact:
          • Leah Greenfeld
        • Contact:
      • Nahariya, Israel, 2210010
        • Recruiting
        • Galilee Medical Center
        • Contact:
        • Principal Investigator:
          • Galia Stemer
      • Petach Tikva, Israel, 4941492
        • Recruiting
        • Rabin Medical Center
        • Contact:
        • Principal Investigator:
          • Ofir Wolach
      • Ramat Gan, Israel, 52621
  • Italy
      • Bologna, Italy, 40138
        • Recruiting
        • IRCCS Azienda Ospedaliero Universitaria di Bologna
        • Principal Investigator:
          • Cristina Papayannidis
        • Contact:
      • Meldola, Italy, 47014
        • Recruiting
        • Istituto Romagnolo per lo Studio dei Tumori Dino Amadori
        • Contact:
        • Principal Investigator:
          • Giovanni Marconi
      • Vicenza, Italy, 36100
  • Lithuania
      • Vilnius, Lithuania, 08661
        • Recruiting
        • Vilnius University hospital Santaros klinikos
        • Contact:
        • Principal Investigator:
          • Andrius Zucenka
  • Netherlands
      • Utrecht, Netherlands, 3584 CS
        • Recruiting
        • Princess Maxima Center for pediatric oncology
        • Contact:
        • Principal Investigator:
          • Michael Zwaan
  • Spain
      • Hospitalet De Llobregat, Spain, 08908
        • Recruiting
        • Institut Catala d'Oncologia (ICO) - Hospital Duran i Reynals
        • Contact:
        • Principal Investigator:
          • Montserrat Arnan Sangerman
      • Seville, Spain, 41013
        • Recruiting
        • Hospital Universitario Virgen del Rocio
        • Contact:
        • Principal Investigator:
          • Eduardo Rodriguez-Arboli
      • Valencia, Spain, 46026
        • Recruiting
        • Hospital Universitari i Politecnic La Fe de Valencia
        • Principal Investigator:
          • Pau Montesinos Fernandez
        • Contact:
  • United States
    • California
      • Duarte, California, United States, 91010
        • Recruiting
        • City of Hope Comprehensive Cancer Center
        • Contact:
      • Los Angeles, California, United States, 90033
        • Recruiting
        • University Of California Care Medical Group - Norris Comprehensive Cancer Center And Hospital
        • Principal Investigator:
          • George Yaghmour
        • Contact:
      • Palo Alto, California, United States, 94305
    • Colorado
    • Florida
      • Sarasota, Florida, United States, 34232
        • Recruiting
        • Florida Cancer Specialists and Research Institute
        • Contact:
      • Tampa, Florida, United States, 33162
        • Completed
        • Moffitt Cancer Center
    • Georgia
      • Atlanta, Georgia, United States, 30329
        • Recruiting
        • Children's Healthcare of Atlanta
        • Contact:
      • Atlanta, Georgia, United States, 30322
        • Recruiting
        • Emory Winship Cancer Institute
        • Contact:
    • Illinois
      • Chicago, Illinois, United States, 60637
        • Recruiting
        • The University of Chicago Medical Center
        • Contact:
          • Howie Weiner, CCRP
          • Phone Number: 773-702-2084
    • Iowa
      • Iowa City, Iowa, United States, 52246
        • Recruiting
        • University of Iowa Hospital
        • Principal Investigator:
          • David Dickens, MD
    • Massachusetts
    • Missouri
      • Saint Louis, Missouri, United States, 63110
    • New Jersey
      • Hackensack, New Jersey, United States, 07601
        • Completed
        • Hackensack University Medical Center
    • New York
      • New York, New York, United States, 10065
        • Recruiting
        • Memorial Sloan Kettering Cancer Center
        • Contact:
      • New York, New York, United States, 10467
    • North Carolina
      • Durham, North Carolina, United States, 27110
        • Recruiting
        • Duke University Medical Center
        • Contact:
        • Principal Investigator:
          • Kris Mahadeo
    • Ohio
      • Cincinnati, Ohio, United States, 45267
      • Columbus, Ohio, United States, 43201
    • Oregon
      • Portland, Oregon, United States, 97239
        • Recruiting
        • Oregon Health & Science University
        • Principal Investigator:
          • Ronan Swords, MD
        • Contact:
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • The University of Texas Md Anderson Cancer Center
        • Contact:
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Completed
        • Huntsman Cancer Institute at The University of Utah

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 month and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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 SNDX-5613 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: SNDX-5613

Phase 1: Oral SNDX-5613; sequential cohorts of escalating dose levels of SNDX-5613 to identify the MTD and RP2D. Participants will be enrolled in 1 of 6 dose-escalation arms:

  • Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or fluconazole
  • Arm B: Participants receiving any strong CYP3A4 inhibitors for antifungal prophylaxis
  • Arm C: Participants receiving SNDX-5613 and cobicistat
  • Arm D: Participants receiving fluconazole for antifungal prophylaxis
  • Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers
  • Arm F: Participants receiving isavuconazole 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: Participants with KMT2Ar ALL/MPAL
  • Cohort 2B: Participants with KMT2Ar AML
  • Cohort 2C: Participants with NPM1m AML
Drug: SNDX-5613
SNDX-5613 orally
Drug: cobicistat
Phase 1 Arm C participants will receive 150 mg cobicistat daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Occurrence of dose-limiting toxicities (DLTs) (Phase 1)
Time Frame: Approximately 1 year
Assessed by the NCI CTCAE version 5.0 (Phase 1)
Approximately 1 year
Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1)
Time Frame: Approximately 1 year
Assessed by the NCI CTCAE version 5.0 (Phase 1)
Approximately 1 year
Cmax (Phase 1)
Time Frame: Approximately 1 year
Maximum plasma concentration (Cmax) of SNDX-5613 and relevant metabolites (Phase 1)
Approximately 1 year
Tmax (Phase 1)
Time Frame: Approximately 1 year
Time to observed maximum plasma concentration of SNDX-5613 and relevant metabolites (Phase 1)
Approximately 1 year
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 (AUC0-t) of SNDX-5613 and relevant metabolites (Phase 1)
Approximately 1 year
CR+CRh rate (Phase 2)
Time Frame: Approximately 3 years
To assess the complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate (Phase 2)
Approximately 3 years
Number of participants with TEAEs (Phase 2)
Time Frame: Approximately 3 years
Assessed by the NCI CTCAE version 5.0 (Phase 2)
Approximately 3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
TTR (Phase 2)
Time Frame: Approximately 34 months
To assess the time to response (TTR) of SNDX-5613 (Phase 2)
Approximately 34 months
DOR (Phase 2)
Time Frame: Approximately 3 years
To assess the duration of response (DOR) of SNDX-5613 (Phase 2)
Approximately 3 years
Transfusion independence (Phase 2)
Time Frame: Approximately 3 years
Transfusion independence is defined as any transfusion-free period lasting for at least 56 consecutive days
Approximately 3 years
CRc rate (Phase 2)
Time Frame: Approximately 3 years
To assess the composite definition of complete remission (CRc) rate (Phase 2)
Approximately 3 years
ORR (CRc+ morphological leukemia-free state [MLFS] + partial remission [PR]) (Phase 2)
Time Frame: Approximately 3 years
To assess the overall response rate (ORR) of SNDX-5613 (Phase 2)
Approximately 3 years
EFS (Phase 2)
Time Frame: Approximately 3 years
To assess the event free survival (EFS) of SNDX-5613 (Phase 2)
Approximately 3 years
OS (Phase 2)
Time Frame: Approximately 5 years
To assess overall survival (OS) of SNDX-5613 (Phase 2)
Approximately 5 years
Cmax (Phase 2)
Time Frame: Approximately 3 years
Cmax of SNDX-5613 and relevant metabolites (Phase 2)
Approximately 3 years
Tmax (Phase 2)
Time Frame: Approximately 3 years
Tmax of SNDX-5613 and relevant metabolites (Phase 2)
Approximately 3 years
AUC0-t (Phase 2)
Time Frame: Approximately 3 years
AUC0-t of SNDX-5613 and relevant metabolites (Phase 2)
Approximately 3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Syndax Pharmaceuticals

Investigators

  • Study Director: Angela R Smith, M.D., Syndax Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 5, 2019

Primary Completion (Estimated)

December 1, 2024

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

August 16, 2019

First Submitted That Met QC Criteria

August 20, 2019

First Posted (Actual)

August 22, 2019

Study Record Updates

Last Update Posted (Actual)

March 25, 2024

Last Update Submitted That Met QC Criteria

March 22, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SNDX-5613-0700
  • 2020-004104-34 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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