Phase 1/2 Study of SNDX-5613 in Relapsed/Refractory Acute Leukemias with MLL/KMT2A Rearrangement or NPM1 Mutation
- Trial ID
- 2024-513759-34-00
- Protocol
- SNDX-5613-0700
- Sponsor
- Syndax Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 1/2 study is to evaluate the **safety**, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of SNDX-5613 in patients with relapsed or refractory acute leukemias. This is crucial for determining the appropriate dosing regimen that balances efficacy and safety, which is essential for advancing the treatment of these challenging hematologic malignancies. Additionally, the study aims to characterize the pharmacokinetics (PK) parameters of SNDX-5613 and its relevant metabolites, providing insights into the drug's absorption, distribution, metabolism, and excretion.
The secondary objectives include:
- Comparing the PK parameters of SNDX-5613 in tablet versus capsule formulations.
- Assessing postbaseline transfusion independence.
- Evaluating the composite complete remission (CRc) rate, overall response rate (ORR), time to response (TTR), duration of response (DOR), event-free survival (EFS), and overall survival (OS).
- Characterizing the PK parameters of SNDX-5613 and relevant metabolites in further detail.
Participants
The clinical trial involves a total of **159 participants** diagnosed with **relapsed or refractory acute leukemias**. The study population includes both male and female subjects, with an age range starting from 6 months and encompassing various age categories. Participants were selected based on specific inclusion criteria, including the presence of active acute leukemia with certain genetic mutations, such as KMT2A rearrangement or NPM1 mutation, as defined by the National Comprehensive Cancer Network (NCCN) Guidelines. The trial includes individuals with a performance status score of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale for those aged 18 years and older, and equivalent scores on the Karnofsky and Lansky Performance Scales for younger participants. The trial population is considered vulnerable, and participants must have resolved any prior treatment-related toxicities to Grade 1 or lower, except for Grade 2 neuropathy or alopecia. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to medication restrictions related to CYP3A4 inhibitors/inducers. The trial does not specify any particular lifestyle habits or dietary requirements for participants.
Plans and Procedures
The clinical trial is designed to evaluate the safety, tolerability, and efficacy of **SNDX-5613** in patients with relapsed or refractory acute leukemias. This study is structured as a Phase 1/2, open-label, dose-escalation, and dose-expansion cohort trial. The trial aims to determine the maximum tolerated dose and recommended Phase 2 dose of SNDX-5613, as well as to assess the pharmacokinetics of the drug. The study is expected to run from December 2022 to April 2025, with participant involvement varying based on individual response and treatment tolerability.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as diagnosis, prior therapy, and performance level. Following successful screening, participants will enter the treatment phase, which includes regular follow-up visits to monitor safety, drug tolerability, and disease response. These visits will involve assessments such as clinical laboratory tests, electrocardiograms, and performance status evaluations. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination from the study.
The expected length of participant involvement is contingent upon the individual's response to treatment and the occurrence of any dose-limiting toxicities or adverse events. Conditions that may lead to early termination from the study include the development of unacceptable toxicity, disease progression, or withdrawal of consent. The trial's primary endpoints focus on the occurrence of dose-limiting toxicities and the frequency and severity of treatment-emergent adverse events. Secondary endpoints include pharmacokinetic parameters and measures of clinical response, such as complete remission rates and overall survival.
Treatment
The clinical trial involves the administration of **SNDX-5613**, a chemical compound with the active substance **N-ETHYL-2-[4-[7-[[4-(ETHYLSULFONYLAMINO)CYCLOHEXYL]METHYL]-2,7-DIAZASPIRO[3.5]NONAN-2-YL]PYRIMIDIN-5-YL]OXY-5-FLUORO-N-PROPAN-2-YLBENZAMIDE**. This experimental medication is provided in a **capsule** form and is administered **orally**. The frequency and dosage of administration are determined based on the study protocol, with the aim to establish the maximum tolerated dose and recommended Phase 2 dose. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.
Another experimental treatment used in the study is **Revumenib**, which is synonymous with SNDX-5613. Revumenib is available in multiple pharmaceutical forms, including **oral solution** and **tablet**, and is also administered **orally**. The study evaluates the pharmacokinetics and safety profile of Revumenib, with dosing schedules tailored to achieve optimal therapeutic outcomes. Compliance monitoring is integral to the study to ensure accurate assessment of the drug's efficacy and safety.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data. The study focuses on the evaluation of SNDX-5613 and Revumenib, both of which are of chemical origin and are not formulated for pediatric use. The trial is conducted under the sponsorship of Syndax Pharmaceuticals, Inc., and the medications are designated as orphan drugs, indicating their use in treating rare conditions such as relapsed/refractory leukemias with specific genetic mutations.
Efficacy
The efficacy of the clinical trial involving SNDX-5613 will be assessed through a series of primary and secondary endpoints. In Phase 1, the primary endpoints include the occurrence of dose-limiting toxicities (DLTs), the frequency, duration, and severity of treatment-emergent adverse events (TEAEs), treatment-related TEAEs (TRAEs), and serious adverse events (SAEs). Additionally, the incidence and shifts of clinically significant clinical laboratory abnormalities will be monitored, along with changes from baseline in safety observations such as electrocardiograms (ECGs), vital signs, ophthalmologic examination findings, and performance status. Pharmacokinetic (PK) parameters will also be evaluated, including maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma concentration versus time curve (AUC) from time 0 to t (AUC0–t), AUC from time 0 to 24 hours (AUC0–24), apparent oral clearance (CL/F), apparent volume of distribution (Vz/F), and half-life (t1/2).
In Phase 2, the primary endpoints focus on the complete remission (CR) plus complete remission with partial hematologic recovery (CRh) rate, alongside the frequency, duration, and severity of TEAEs, TRAEs, and SAEs. The incidence and shifts of clinically significant clinical laboratory abnormalities will continue to be assessed, as well as changes from baseline in safety observations. Secondary endpoints in Phase 2 include transfusion independence, defined as any transfusion-free period lasting for at least 56 consecutive days, and various response rates such as CRc rate (CR+CRh+CRi+CRp) and overall response rate (ORR, including CRc+MLFS+PR). Time to response, duration of response, event-free survival, and overall survival will also be evaluated. PK parameters will be assessed similarly to Phase 1, with additional focus on the comparison between tablet and capsule formulations.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Diagnosis: Patients in Phase 1 Arm A and Arm B must have active acute leukemia harboring Lysine (K) methyltransferase 2A (KMT2A) rearrangement or Nucleophosmin 1 mutation (NPM1) mutation as defined by the National Comprehensive Cancer Network (NCCN) Guidelines stated in the protocol. Patients in Phase 1 Arm C, Arm D, Arm E and Arm F must meet 1 of the following 2 criteria: •active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts inperipheral blood) as defined by the NCCN Guidelines stated in the protocol. •acute leukemia harboring an KMT2A rearrangement, Nucleoporin 98 (NUP98) rearrangement, or NPM1 mutation that have detectable disease in the bone marrow not meeting criterion for active leukemia as described above.
- Prior Therapy: Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.
- Phase 1 and Phase 2 Cohorts 2A-2C only: Prior Therapy: Radiation Therapy: At least 60 days from prior total body irradiation (TBI), craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14days from local palliative radiation therapy.
- Phase 1 and Phase 2 Cohorts 2A-2C only: Prior Therapy: Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stem cell transplant (HSCT) and at least 4 weeks must have elapsed from donor lymphocyte infusion (DLI).
- Phase 2 Cohort 2D only: At least 14 days since any other investigational or commercially available antileukemic therapy, with the following exceptions: a) Cytoreductive therapy with hydroxyurea, low-dose cytarabine (20 mg/m2 /day SC for 10 days) or low-dose etoposide (up to 200 mg/day PO for 10 days) may be administered concurrently with SNDX-5613. b) Intrathecal chemotherapy for CNS prophylaxis is permitted at the treating physician’s discretion. c) Steroids at physiologic dosing (equivalent to ≤10 mg prednisone daily for patients ≥18 years or ≤10 mg/m2 /day for patients.
- Phase 1 and Phase 2 Cohorts 2A-2C only: Prior Therapy: Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines, and at least 21days since receipt of chimeric antigen receptor therapy or other modified T or Natural KIller (NK) cell therapy.
- Phase 1 and Phase 2 Cohorts 2A-2C only: Prior Therapy: Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy with the exceptions as defined in the protocol.
- Phase 1 and Phase 2 Cohorts 2A-2C only: Prior 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. See protocol for additional inclusion criteria.
- Phase 1: • Arm A: Patients must not be receiving any strong CYP3A4 inhibitor/inducers or fluconazole. Patients who were receiving a strong CYP3A4 inhibitor/inducer or fluconazole must have discontinued the medication at least 7days prior to enrollment. • Arm B: Patients must be receiving itraconazole, ketoconazole, posaconazole, or voriconazole for antifungal prophylaxis for at least 7days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other strong CYP3A4 inhibitors/inducers. • Arm C: Patients must weigh ≥35 kg and be willing to receive daily cobicistat from C1D2 for at least 28 days. Patients must not be receiving any other weak, moderate, or strong CYP3A4 inhibitors/inducers. Patients who were receiving a moderate/strong CYP3A4 inhibitor/inducer must have discontinued the medication at least 7days prior to enrollment. •Arm D: Patients must be receiving fluconazole for at least 7 days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other weak, moderate or strong CYP3A4 inhibitors/inducers. •Arms E: Patients must not be receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers for at least 7 days prior to enrollment and while on SNDX5613 treatment. • Arm F: Patients must be receiving isavuconazole for at least 7 days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other weak, moderate, or strong CYP3A4 inhibitors/inducers.
- Phase 2: Documented R/R active acute leukemia. • Cohort 2A: Documented R/R ALL/MPAL with a KMT2A rearrangement. • Cohort 2B: Documented R/R AML with a KMT2A rearrangement. • Cohort 2C: Documented R/R AML with NPM1m. • Cohort 2D: Documented R/R acute leukemia with a genetic mutation expected to lead to HOX/MEIS upregulation (eg, KMT2Ar, NPM1m, NUP98r, etc), including patients who are MRD-positive by multiparametric flow cytometry or molecular methods only, and including patients with isolated extramedullary disease.
- Disease Status: 4. Recurrent or refractory AML/ALL or MPAL, as defined by standardized criteria after standard of care therapy, including but not limited to one 1 or 2 cycles of intensive chemotherapy, or venetoclax combinations. Patients with persistent leukemia after initial therapy or with recurrence of leukemia at any time after achieving a response during or after the course of treatment are eligible. Applies only for Phase 2 Cohorts 2A-2C: Refractory or relapsed leukemia is defined by presence of ≥5% blasts in the bone marrow and/or persistence or reappearance of peripheral blasts. Patients who have <5% blasts in the bone marrow at baseline may be replaced to ensure a sufficient number of patients for the efficacy analyses.
- Age/Weight: Male or female patient aged ≥6 months. Patients intended to receive SNDX-5613 in combination with cobicistat must weigh ≥35 kg. See Protocol Section 10.11.3.1 for age of inclusion criteria in Germany. Patients in Cohort 2D must be ≥18 years of age and have a body weight ≥40 kg.
- Performance Level: Eastern Cooperative Oncology Group (ECOG) performance status score 0–2 Karnofsky Performance Scale of ≥50 ; Lansky Performance Score of ≥50 (if aged ≥12 years and <16 years). See Protocol Section 10.11.3.1 for ECOG performance status criteria in Germany.
- See protocol for additional inclusion criteria.
Exclusion Criteria
- Diagnosis: Diagnosis of active acute promyelocytic leukemia.
- Diagnosis: Isolated extramedullary relapse (Phase 2 Cohorts 2A-2C only).
- Diagnosis: Active CNS disease. Refer to the protocol for further details.
- Infection: 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.
- Infection: Hepatitis B (defined as hepatitis B virus [HBV] surface antigen positive and HBV core antibody positive, or positive HBV deoxyribonucleic acid [DNA].
- Infection: Hepatitis C (defined as positive hepatitis C [HCV] antibody with reflex to positive HCV ribonucleic acid [RNA]).
- Pregnancy and Breast-Feeding: Pregnant or nursing women. Negative serum pregnancy tests are required during Screening and a negative serum pregnancy test is required within 72 hours prior to receiving the first study drug administration, in females of childbearing potential.
- Concurrent Conditions: Cardiac Disease: • Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure, life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack. • Corrected QT interval by Fridericia >450 msec.
- Concurrent Conditions: Gastrointestinal (GI) Disease: • Any GI issue of the upper GI tract likely to affect oral drug absorption or ingestion. • Cirrhosis with a Child-Pugh score of B or C.
- Concurrent Conditions: 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.
- Concurrent Conditions: 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 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.
- Concurrent Conditions: Concurrent malignancy must be in complete remission or no evidence of disease during this timeframe.
- Concurrent Conditions: History of or any concurrent condition, therapy, laboratory abnormality, or allergy to excipients that in the Investigator's opinion might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate.
- Concomitant Medications and Interventions: 14. Any commercially available or investigational antileukemic therapy other than SNDX-5613, with exceptions as defined in the protocol.
- Concomitant Medications and Interventions: Please refer to the protocol for the list of exclusion that apply to related to concomitant use of CYP3A4 inhibitors or inducers (Phase 1 and Phase 2).
- Concomitant Medications and Interventions: 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 and the azoles permitted in the relevant arms of Phase 1 and in Phase 2. Please see Appendix 10.7 of the protocol for examples of medications that may be appropriate substitutes for such medications. Please refer to the protocol for additional exclusion criteria.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 22 Dec 2022 | 20 |
 Germany | Recruiting | 22 Dec 2022 | 11 |
 Italy | Recruiting | 22 Dec 2022 | 18 |
 Lithuania | Recruiting | 22 Dec 2022 | 7 |
 The Netherlands | Not Recruiting | 22 Dec 2022 | — |
 Spain | Recruiting | 22 Dec 2022 | 7 |
| Netherlands | — | — | 4 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Revumenib | Test | TABLET | ORAL | — | — | PRD11389272 |
Revumenib | Test | TABLET | ORAL | — | — | PRD11389271 |
SNDX-5613 | Test | CAPSULE | ORAL | — | — | PRD9563453 |
Revumenib | Test | ORAL SOLUTION | ORAL | — | — | PRD11389274 |
Revumenib | Test | TABLET | ORAL | — | — | PRD11389273 |
SNDX-5613 | Test | CAPSULE | ORAL | — | — | PRD9563454 |