Relapsed or Refractory Acute Leukemias MedDRA version: 20.1 Level: LLT Classification code 10024330 Term: Leukemia acute System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: SNDX-5613 25 mg capsule
Pharmaceutical Form: Capsule
INN or Proposed INN: revumenib
CAS Number: 2169919-22-4
Current Sponsor code: SNDX-5613
Other descriptive name: trans N-ethyl-2-((4-(
Sponsors
Syndax Pharmaceuticals, Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Diagnosis: 1. Patients in Arms A and B must have active acute leukemia harboring mixed lineage leukemia (MLL) rearrangement or NPM1c mutation as defined by the NCCN in the NCCN Clinical Practice Guidelines in Oncology for Acute Lymphoblastic Leukemia (Ver 1.2020) and Acute Myeloid Leukemia (Version 3.2020). Patients in Arm C, Arm D, Arm E and Arm F must meet one of the following 2 criteria: • active acute leukemia (bone marrow blasts =5% or reappearance of blasts in peripheral blood) as defined by the guidelines above. • acute leukemia harboring an MLL rearrangement, NUP98 rearrangement, or Nucleophosmin 1 mutation (NPM1c) mutation that have detectable disease in the bone marrow not meeting criterion for active leukemia as described above. 2. Phase 2: Documented R/R acute leukemia: Cohort 2A: Documented R/R acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia (MPAL) with a mixed lineage leukemia-rearranged (MLLr) translocation. Cohort 2B: Documented R/R AML with an MLLr translocation. Cohort 2C: Documented R/R AML with NPM1c. Mutational status is to be reviewed locally to determine patient eligibility in Phase 2 and confirmed centrally. Disease Status: 4. Recurrent or refractory AML/ALL or MPAL, as defined by standardized criteria after standard of care therapy. 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. Refractory or relapsed leukemia is defined by presence of =5% blasts in the bone marrow and/or persistence or reappearance of peripheral blasts. • All patients must have white blood cell (WBC) count below 25,000/µL at time of enrollment. Patients may receive cytoreduction prior to enrollment. Age/Weight: 5. Male or female patient aged =30 days. Patients intend to receive SNDX-5613 in combination with cobicistat must weigh =35 kg. Performance Level: 6. Eastern Cooperative Oncology Group performance status score 0-2 (if aged =18yrs); Karnofsky Performance Scale of =50 (if aged =16yrs and =65 y
Exclusion criteria
Exclusion criteria: Diagnosis: 1. Active diagnosis of acute promyelocytic leukemia. 2. Isolated extramedullary relapse. 3. Active CNS disease. Refer to the protocol for further details. Infection: 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 (defined as hepatitis B virus [HBV] surface antigen positive and HBV core antibody positive, with positive HBV deoxyribonucleic acid [DNA], or HBV positive core antibody alone with reflex to positive HBV DNA. 6. Hepatitis C (defined as positive hepatitis C [HCV] antibody with reflex to positive HCV ribonucleic acid [RNA]). Pregnancy and Breast-Feeding: 7. Pregnant or nursing women. Negative serum pregnancy tests are required during Screening and a negative serum or urine pregnancy test is required within 72 hours prior to receiving the first study drug administration, in females of childbearing potential. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Concurrent Conditions: 8. 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. • QTc using Fridericia’s correction >450 msec. 9. 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. 10. 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. 11. 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. 12. Concurrent malignancy must be in complete remission or no evidence of disease during this timeframe. 13. 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. 15. In Phase 2: Concurrent use of moderate or strong CYP3A4 inhibitors/inducers (except for systemic itraconazole, ketoconazole, posaconazole, or voriconazole). The acceptable azoles should have been started at least 7 days prior to enrollment. Other moderate or strong inhibitors or inducers of CYP3A4 should be discontinued at least 7 days prior to enrollment. 16. 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 prol
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 2 • To evaluate short- and long-term safety and tolerability of SNDX-5613. • To assess the complete remission (CR) rate (CR + complete remission with partial hematologic recovery (CRh)) rate. ;Secondary Objective: Phase 2 • To assess postbaseline transfusion independence. • To assess the composite definition of complete remission (CRc) rate [CR + CRh + complete remission with incomplete hematologic recovery (CRi) + complete remission with incomplete platelet recovery (CRp)]. • To assess the overall response rate (ORR) (CRc + morphological leukemia-free state [MLFS] + partial remission [PR]). • To assess the time to response (TTR), duration of response (DOR), and event free survival (EFS). • To assess overall survival (OS). • To characterize PK parameters of SNDX-5613 and relevant metabolites. ;Primary end point(s): Phase 2: • CR rate (CR+CRh). • Frequency, duration, and severity of TEAEs, TRAEs, and SAEs. • Incidence and shifts of clinically significant clinical laboratory abnormalities. • Change from baseline in other observations related to safety, including ECGs, vital signs, ophthalmologic examination findings, and performance status. For Phase 2, endpoints will be assessed by disease cohort (2A, 2B, and 2C separately) and pooled MLLr population;Timepoint(s) of evaluation of this end point: AEs: BL, C1(Day 3/4, 7/8, 10/11, 14/15, 17/18, 21/22), C2(D1,D15), =C3D1, EoT, f/up ECG: SCR, BL, C1(Day 1, 2, 3/4, 7/8, 14/15, 21/22), C2D15, =C3D1, f/up Holter Monitoring (Phase I): BL Vital signs: SCR, BL, C1(Day 1, 2, 3/4, 7/8, 10/11, 14/15), C2(D1,D15), C3D1, EoT, f/up Ophthalmologic exam: SCR, =C3D1, EoT, f/up Performance Status: SCR, BL, =C2D1, C3D1, f/up Hematology: SCR, BL, C1(D 3/4, 7/8, 10/11, 14/15, 17/18, 21/22), =C2D1, C3D1, EoT, f/up Clinical Chemistry: SCR, BL, C1(Day 2, 3/4, 7/8, 10/11, 14/15, 17/18, 21/22); =C2D1, C3D1, EoT, f/up Urinalysis: BL, C2D1, C3D1, EoT, f/up PK: BL, C1(Day 2, 3/4, 7/8, 14/15), C2D15, =C3D1 Coagulation pa | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 2: • Transfusion independence, defined as any transfusion-free period lasting for at least 56 consecutive days, during which the patient is either on SNDX-5613 therapy or after cessation of SNDX-5613 therapy but prior to the start of new therapy. • CRc rate (ie, CR+CRh+CRi+CRp). • ORR (CRc+MLFs+PR). • Time to response • Duration of response • Event free survival • Overall survival • PK parameters: Cmax, Tmax, AUC0–t, AUC0–24, CL/F, Vz/F, and t1/2. ;Timepoint(s) of evaluation of this end point: Disease assessments: throughout the duration of the study. PK: as above | — |
Countries
Australia, Canada, France, Germany, Israel, Italy, Lithuania, Netherlands, Spain, United States
Contacts
Public ContactMain Telephone Number
Syndax Pharmaceuticals, Inc
Outcome results
None listed