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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 : August 1, 2022
Sponsor:
Information provided by (Responsible Party):
Syndax Pharmaceuticals

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

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

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

Arm C: Patients receiving SNDX-5613 and cobicistat.

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

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

Arm F: Patients receiving isavuconazole (moderate CYP3A4 inhibitor) 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 440 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: 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 : April 30, 2025
Estimated Study Completion Date : April 30, 2026


Arm Intervention/treatment
Experimental: Experimental: SNDX-5613

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

  • Arm A: Patients not receiving any strong CYP3A4 inhibitor/inducers or fluconazole.
  • Arm B: Patients receiving any strong CYP3A4 inhibitors for antifungal prophylaxis.
  • Arm C: Patients receiving SNDX-5613 and cobicistat.
  • Arm D: Patients receiving fluconazole for antifungal prophylaxis.
  • Arm E: Patients not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers.
  • Arm F: Patients 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: 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.




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)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   30 Days and older   (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), or acute leukemia harboring an MLL rearrangement, NUP98 rearrangement, or NPM1 mutation that have detectable disease in the bone marrow.

  1. Phase 1:

    • Arm A: Patients not receiving any strong CYP3A4 inhibitor/inducers or fluconazole.
    • Arm B: Patients receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis.
    • Arm C: Patients receiving SNDX-5613 in combination with cobicistat.
    • Arm D: Patients receiving fluconazole (moderate CYP3A4 inhibitor).
    • Arm E: Patients not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers.
    • Arm F: Patients receiving isavuconazole (moderate CYP3A4 inhibitor) 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. White blood cell count below 25,000/ microliter at time of enrollment. Patients may receive cytoreduction prior to enrollment per protocol-specified criteria.
  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 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 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, or 5 half-lives, whichever is shorter, 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 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 (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. 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. 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.

    - Corrected QT interval (QTc) >450 milliseconds.

  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, or concurrent low-grade lymphoma, that is asymptomatic and lacks bulky disease and shows no evidence of progression, and for which the patient is not receiving any systemic therapy or radiation.
  11. In Phase 1 and Phase 2: Patients 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 (eg, diphenhydramine, famotidine, ondansetron, Bactrim) and the azoles permitted in the relevant arms of Phase 1.

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: David Tamang 781.419.1400 dtamang@syndax.com

Locations
Show Show 19 study locations
Sponsors and Collaborators
Syndax Pharmaceuticals
Investigators
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Study Director: Nicole McNeer, M.D. Syndax Pharmaceuticals, Inc.
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: August 1, 2022
Last Verified: July 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
MPAL
MLAL
ALAL
relapsed leukemia
refractory leukemia
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