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

• ClinicalTrials.gov Identifier: NCT04065399
• Recruitment Status: Recruiting
• First Posted: August 22, 2019
• Last Update Posted: March 25, 2024
• Sponsor: Syndax Pharmaceuticals
• Information provided by (Responsible Party): Syndax Pharmaceuticals

Tracking Information

• First Submitted Date: August 16, 2019
• First Posted Date: August 22, 2019
• Last Update Posted Date: March 25, 2024
• Actual Study Start Date: November 5, 2019
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 31, 2023)

• Occurrence of dose-limiting toxicities (DLTs) (Phase 1) [ Time Frame: Approximately 1 year ]
  Assessed by the NCI CTCAE version 5.0 (Phase 1)
• 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)
• Cmax (Phase 1) [ Time Frame: Approximately 1 year ]
  Maximum plasma concentration (Cmax) of SNDX-5613 and relevant metabolites (Phase 1)
• Tmax (Phase 1) [ Time Frame: Approximately 1 year ]
  Time to observed maximum plasma concentration of SNDX-5613 and relevant metabolites (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 (AUC0-t) of SNDX-5613 and relevant metabolites (Phase 1)
• 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)
• Number of participants with TEAEs (Phase 2) [ Time Frame: Approximately 3 years ]
  Assessed by the NCI CTCAE version 5.0 (Phase 2)

Original Primary Outcome Measures (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)

Current Secondary Outcome Measures (submitted: March 22, 2024)

• 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
• CRc rate (Phase 2) [ Time Frame: Approximately 3 years ]
  To assess the composite definition of complete remission (CRc) rate (Phase 2)
• 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)
• 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)
• EFS (Phase 2) [ Time Frame: Approximately 3 years ]
  To assess the event free survival (EFS) of SNDX-5613 (Phase 2)
• OS (Phase 2) [ Time Frame: Approximately 5 years ]
  To assess overall survival (OS) of SNDX-5613 (Phase 2)
• Cmax (Phase 2) [ Time Frame: Approximately 3 years ]
  Cmax of SNDX-5613 and relevant metabolites (Phase 2)
• Tmax (Phase 2) [ Time Frame: Approximately 3 years ]
  Tmax of SNDX-5613 and relevant metabolites (Phase 2)
• AUC0-t (Phase 2) [ Time Frame: Approximately 3 years ]
  AUC0-t of SNDX-5613 and relevant metabolites (Phase 2)

Original Secondary Outcome Measures (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)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of SNDX-5613 in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation
• 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

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.

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
• Study Phase: Phase 1; Phase 2

Study Design

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

Condition

• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Mixed Lineage Acute Leukemia
• Mixed Phenotype Acute Leukemia
• Acute Leukemia of Ambiguous Lineage

Intervention

• Drug: SNDX-5613
  SNDX-5613 orally
• Drug: cobicistat
  Phase 1 Arm C participants will receive 150 mg cobicistat daily.

Study Arms

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

Interventions:

• Drug: SNDX-5613
• Drug: cobicistat

Publications *

• Sasca D, Guezguez B, Kuhn MWM. Next generation epigenetic modulators to target myeloid neoplasms. Curr Opin Hematol. 2021 Sep 1;28(5):356-363. doi: 10.1097/MOH.0000000000000673.
• Jimenez JA, Apfelbaum AA, Hawkins AG, Svoboda LK, Kumar A, Ruiz RO, Garcia AX, Haarer E, Nwosu ZC, Bradin J, Purohit T, Chen D, Cierpicki T, Grembecka J, Lyssiotis CA, Lawlor ER. EWS-FLI1 and Menin Converge to Regulate ATF4 Activity in Ewing Sarcoma. Mol Cancer Res. 2021 Jul;19(7):1182-1195. doi: 10.1158/1541-7786.MCR-20-0679. Epub 2021 Mar 19.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 22, 2024): 413
• Original Estimated Enrollment (submitted: August 20, 2019): 132
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility 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 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 30 Days and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Australia, Canada, France, Germany, Israel, Italy, Lithuania, Netherlands, Spain, United States

Administrative Information

• NCT Number: NCT04065399
• Other Study ID Numbers: SNDX-5613-0700; 2020-004104-34 ( EudraCT Number )
• 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

• Plan to Share IPD: No

• Current Responsible Party: Syndax Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Syndax Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Syndax Pharmaceuticals
• Verification Date: March 2024