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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 : November 2, 2023
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 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.


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

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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 MLLr acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia (MPAL)
  • Cohort 2B: Participants with MLLr AML
  • Cohort 2C: Participants 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 : December 2024
Estimated Study Completion Date : December 2024


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. 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 MLLr ALL/MPAL
  • Cohort 2B: Participants with MLLr AML
  • Cohort 2C: Participants with NPM1c AML
Drug: SNDX-5613
SNDX-5613 orally

Drug: cobicistat
Phase 1 Arm C participants 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. 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)

  3. Cmax (Phase 1) [ Time Frame: Approximately 1 year ]
    Maximum plasma concentration (Cmax) of SNDX-5613 and relevant metabolites (Phase 1)

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

  5. 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)

  6. 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)

  7. Number of participants with TEAEs (Phase 2) [ Time Frame: Approximately 3 years ]
    Assessed by the NCI CTCAE version 5.0 (Phase 2)


Secondary Outcome Measures :
  1. 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

  2. CRc rate (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess the composite definition of complete remission (CRc) rate (Phase 2)

  3. 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)

  4. EFS (Phase 2) [ Time Frame: Approximately 3 years ]
    To assess the event free survival (EFS) 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 (OS) of SNDX-5613 (Phase 2)

  8. Cmax (Phase 2) [ Time Frame: Approximately 3 years ]
    Cmax of SNDX-5613 and relevant metabolites (Phase 2)

  9. Tmax (Phase 2) [ Time Frame: Approximately 3 years ]
    Tmax of SNDX-5613 and relevant metabolites (Phase 2)

  10. AUC0-t (Phase 2) [ Time Frame: Approximately 3 years ]
    AUC0-t of SNDX-5613 and relevant metabolites (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:

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 an MLL rearrangement, NUP98 rearrangement, or NPM1c 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:

    • 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. 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 checkpoint inhibitors, and at least 21 days since receipt of chimeric antigen receptor therapy or other modified T 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 (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:

Participants 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. 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.

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: Syndax Pharmaceuticals 781-419-1400 clinicaltrials@syndax.com

Locations
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Sponsors and Collaborators
Syndax Pharmaceuticals
Investigators
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Study Director: Angie Smith, M.D. Syndax Pharmaceuticals
Additional Information:
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
2020-004104-34 ( EudraCT Number )
First Posted: August 22, 2019    Key Record Dates
Last Update Posted: November 2, 2023
Last Verified: October 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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