A Study of SNDX-5613 in R/R Leukemias Including Those With an MLLr/KMT2A Gene Rearrangement or NPM1 Mutation

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Mixed Lineage Acute Leukemia, Mixed Phenotype Acute Leukemia, Acute Leukemia of Ambiguous Lineage

Intervention / Treatment
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* Drug: SNDX-5613
* Drug: cobicistat


Participation Criteria
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Eligibility Criteria
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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. 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. 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. White blood cell count below 25,000/ microliter at time of enrollment. Participants may receive cytoreduction prior to enrollment per protocol-specified criteria. Male or female participants aged ≥30 days old. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or Karnofsky/Lansky score ≥50. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia. 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). 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. 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. Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy. 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. Biologics: At least 90 days, or 5 half-lives, whichever is shorter, since the completion of therapy with an antineoplastic biologic agent. Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing (equivalent to ≤10 mg prednisone daily) or cytoreductive therapy. Adequate organ function. 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: Active diagnosis of acute promyelocytic leukemia. Isolated extramedullary relapse. Active central nervous system disease (cytologic, such as any blasts on cytospin, or radiographic). 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. Hepatitis B or C. Pregnant or nursing women. 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. 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. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 30 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 will employ an accelerated titration design. The dose escalation will follow a modified Fibonacci sequence.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: SNDX-5613<br>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<br>* SNDX-5613 orally<br>Drug: cobicistat<br>* Phase 1 Arm C participants will receive 150 mg cobicistat daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of dose-limiting toxicities (DLTs) (Phase 1) | Assessed by the NCI CTCAE version 5.0 (Phase 1) | Approximately 1 year | 
| Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1) | Assessed by the NCI CTCAE version 5.0 (Phase 1) | Approximately 1 year | 
| Cmax (Phase 1) | Maximum plasma concentration (Cmax) of SNDX-5613 and relevant metabolites (Phase 1) | Approximately 1 year | 
| Tmax (Phase 1) | Time to observed maximum plasma concentration of SNDX-5613 and relevant metabolites (Phase 1) | Approximately 1 year | 
| AUC0-t (Phase 1) | 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) | 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) | Assessed by the NCI CTCAE version 5.0 (Phase 2) | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transfusion independence (Phase 2) | Transfusion independence is defined as any transfusion-free period lasting for at least 56 consecutive days | Approximately 3 years | 
| CRc rate (Phase 2) | 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) | To assess the overall response rate (ORR) of SNDX-5613 (Phase 2) | Approximately 3 years | 
| EFS (Phase 2) | To assess the event free survival (EFS) of SNDX-5613 (Phase 2) | Approximately 3 years | 
| TTR (Phase 2) | To assess the time to response (TTR) of SNDX-5613 (Phase 2) | Approximately 34 months | 
| DOR (Phase 2) | To assess the duration of response (DOR) of SNDX-5613 (Phase 2) | Approximately 3 years | 
| OS (Phase 2) | To assess overall survival (OS) of SNDX-5613 (Phase 2) | Approximately 5 years | 
| Cmax (Phase 2) | Cmax of SNDX-5613 and relevant metabolites (Phase 2) | Approximately 3 years | 
| Tmax (Phase 2) | Tmax of SNDX-5613 and relevant metabolites (Phase 2) | Approximately 3 years | 
| AUC0-t (Phase 2) | AUC0-t of SNDX-5613 and relevant metabolites (Phase 2) | Approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, ALL, MPAL, MLAL, ALAL, relapsed leukemia, refractory leukemia, acute leukemia, MLLr, KMT2A, NPM1