Acute Leukemia of Ambiguous Lineage, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Mixed Lineage Acute Leukemia, Mixed Phenotype Acute Leukemia
Conditions
Keywords
AML, ALL, MPAL, MLAL, ALAL, relapsed leukemia, refractory leukemia, acute leukemia, KMT2A, NPM1
Brief summary
Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of revumenib in participants with acute leukemia. In Phase 2, participants will be enrolled in 4 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of revumenib.
Detailed description
Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib 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 revumenib 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 4 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of revumenib: * 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 * Cohort 2D: Participants with acute leukemia (including KMT2Ar, NPM1m, NUP98r and other acute leukemias expected to have HOX/MEIS upregulation)
Interventions
DRUGrevumenib
revumenib orally
DRUGcobicistat
Phase 1 Arm C participants will receive 150 mg cobicistat daily.
Sponsors
Syndax Pharmaceuticals
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1 will employ an accelerated titration design. The dose escalation will follow a modified Fibonacci sequence.
Eligibility
Sex/Gender
ALL
Age
30 Days to No maximum
Healthy volunteers
No
Inclusion criteria
Key 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 revumenib 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. * Cohort 2D: Documented R/R acute leukemia with a genetic mutation expected to lead to HOX/MEIS upregulation (for example, KMT2Ar, NPM1m, and NUP98r), including participants who are MRD-positive by multiparametric flow cytometry or molecular methods only, and including participants with isolated extramedullary disease. 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. Participants intended to receive SNDX-5613 in combination with cobicistat must weigh ≥35 kilograms (kg). Participants in Cohort 2D must be ≥18 years of age and have a body weight ≥40 kg. 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. Phase 1 and Phase 2 Cohorts 2A-2C only: 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. Phase 2 Cohort 2D only: At least 14 days since any other investigational or commercially available antileukemic therapy, with the following exceptions: 1. Cytoreductive therapy with hydroxyurea, low-dose cytarabine (20 mg/square meter (m\^2)/day subcutaneously \[SC\] for 10 days) or low-dose etoposide (up to 200 mg/day orally for 10 days) may be administered concurrently with SNDX-5613. 2. Intrathecal chemotherapy for CNS prophylaxis is permitted at the treating physician's discretion. 3. Steroids at physiologic dosing (equivalent to ≤10 mg prednisone daily for participants ≥18 years or ≤10 mg/m\^2/day for participants \<18 years) or for cytoreductive therapy. 14. Adequate organ function. 15. If of childbearing potential, willing to use a highly effective method of contraception from the time of enrollment through 120 days following the last study drug dose. Key
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 Cohorts 2A-2C 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 and gastroparesis). * 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. Note: Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with dose-limiting toxicities (DLTs) (Phase 1) | Approximately 1 year | Assessed by the NCI CTCAE version 5.0 (Phase 1) |
| Number of participants with treatment-emergent adverse events (TEAEs) (Phase 1) | Approximately 1 year | Assessed by the NCI CTCAE version 5.0 (Phase 1) |
| Cmax (Phase 1) | Approximately 1 year | Maximum plasma concentration (Cmax) of revumenib and relevant metabolites (Phase 1) |
| Tmax (Phase 1) | Approximately 1 year | Time to observed maximum plasma concentration of revumenib and relevant metabolites (Phase 1) |
| AUC0-t (Phase 1) | Approximately 1 year | Area under the plasma concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) of revumenib and relevant metabolites (Phase 1) |
| CR+CRh rate (Phase 2 [Cohorts 2A-2C]) | Approximately 3 years | To assess the complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate (Phase 2 \[Cohorts 2A-2C\]) |
| Number of participants with TEAEs (Phase 2 [Cohorts 2A-2C]) | Approximately 3 years | Assessed by the NCI CTCAE version 5.0 (Phase 2 \[Cohorts 2A-2C\]) |
| Cmax (Phase 2 [Cohort 2D]) | Approximately 3 years | Cmax of revumenib (Phase 2 \[Cohort 2D\]) |
| AUC0-tau (Phase 2 [Cohort 2D]) | Approximately 3 years | Area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-tau) of revumenib (Phase 2 \[Cohort 2D\]) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Transfusion independence (Phase 2 [Cohorts 2A-2C]) | Approximately 3 years | Transfusion independence is defined as any transfusion-free period lasting for at least 56 consecutive days |
| CRc rate (Phase 2 [Cohorts 2A-2C]) | Approximately 3 years | To assess the composite definition of complete remission (CRc) rate (Phase 2 \[Cohorts 2A-2C\]) |
| ORR (CRc+ morphological leukemia-free state [MLFS] + partial remission [PR]) (Phase 2 [Cohorts 2A-2C]) | Approximately 3 years | To assess the overall response rate (ORR) of revumenib (Phase 2 \[Cohorts 2A-2C\]) |
| TTR (Phase 2 [Cohorts 2A-2C]) | Approximately 34 months | To assess the time to response (TTR) of revumenib (Phase 2 \[Cohorts 2A-2C\]) |
| DOR (Phase 2 [Cohorts 2A-2C]) | Approximately 3 years | To assess the duration of response (DOR) of revumenib (Phase 2 \[Cohorts 2A-2C\]) |
| EFS (Phase 2 [Cohorts 2A-2C]) | Approximately 3 years | To assess the event free survival (EFS) of revumenib (Phase 2 \[Cohorts 2A-2C\]) |
| OS (Phase 2 [Cohorts 2A-2C]) | Approximately 5 years | To assess overall survival (OS) of revumenib (Phase 2 \[Cohorts 2A-2C\]) |
| Cmax (Phase 2 [Cohorts 2A-2C]) | Approximately 3 years | Cmax of revumenib and relevant metabolites (Phase 2 \[Cohorts 2A-2C\]) |
| Tmax (Phase 2 [Cohorts 2A-2C]) | Approximately 3 years | Tmax of revumenib and relevant metabolites (Phase 2 \[Cohorts 2A-2C\]) |
| AUC0-t (Phase 2 [Cohorts 2A-2C]) | Approximately 3 years | AUC0-t of revumenib and relevant metabolites (Phase 2 \[Cohorts 2A-2C\]) |
| Number of participants with TEAEs (Phase 2 [Cohort 2D]) | Approximately 3 years | Assessed by the NCI CTCAE version 5.0 (Phase 2 \[Cohort 2D\])) |
Countries
Australia, Canada, France, Germany, Israel, Italy, Lithuania, Netherlands, Puerto Rico, Spain, United States
Contacts
CONTACTSyndax Pharmaceuticals
STUDY_DIRECTORAngela R Smith, M.D.
Syndax Pharmaceuticals
Outcome results
None listed