This is a Phase Ib/II 2 study investigating the safety and efficacy of revumenib in two cohorts of participants with myelofibrosis. COHORT-1 will investigate the safety of revumenib as monotherapy in participants with myelofibrosis previously treated with a JAK inhibitor. Following confirmation of safety in COHORT-1, the study will proceed with enrollment in COHORT-2, which will evaluate the efficacy and safety of revumenib in combination with a JAK inhibitor.
Adults ≥ 18 years of age at time of signing the informed consent
Participants must voluntarily sign informed consent form (ICF) and be willing and able to adhere to the study visit schedule and all protocol requirements.
Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Participants must have a pathologically confirmed diagnosis of PMF, post-ET-MF or post-PV-MF as per the WHO diagnostic criteria, with intermediate-1 or higher risk disease by DIPSS (14.1).
Treatment with any MF-directed therapy (including investigational therapies) within 2 weeks or 5 half-lives, whichever is shorter, of Cycle 1 Day 1
Participants in COHORT-1 should not have received a JAK inhibitor within 14 days prior to Cycle 1 Day 1. Participants who remain on JAK inhibitor at time of screening should be tapered off per investigator discretion.
Hydroxyurea is permitted until the day prior to C1D1, if needed for disease control.
Undergone allogeneic hematopoietic stem cell transplant (allo-HSCT) within the last 6 months prior to enrollment, or with active GVHD and/or on immunosuppressive therapy.
Sequential
Revumenib
DrugDose Level 1: Revumenib 160mg twice daily or 110mg twice daily Dose Level 2: Revumenib 270mg twice daily or 160mg twice daily
Ruxolitinib
DrugPart of routine care. Participants to continue on dosage as prescribed by provider, 5 to 20 mg BID
FEDRATINIB
DrugPart of routine care. Participants to continue on dosage as prescribed by provider, 100 mg to 400 mg daily.
Momelotinib
DrugPart of routine care. Participants to continue on dosage as prescribed by provider, 100 mg to 200 mg daily.
Dose limiting toxicity (DLT)
(COHORT-1) Dose limiting toxicity (DLT) defined as according to the NCI CTCAE v6. AEs attributable to the study agents (possibly / probably / definitely related) will count towards the toxicity stopping boundaries. These include, but not limited to, neutrophil count decreased, thrombocytopenia, and other non-hematologic AEs
Number of Treatment related adverse events (AEs)
(COHORT-1) Number of treatment specific adverse events (AEs) by CTCAE v6.0 (COHORT-2) during dose escalation phase
Overall response rate (ORR) for COHORT-2
(COHORT-2) Overall response rate (ORR) defined as CR, PR, or CI by the revised IWG-MRT and ELN criteria after 6 cycles of therapy (each cycle is one month.)
Overall response rate (ORR) for COHORT 1
(COHORT-1) Overall response rate (ORR) defined as a CR, PR, or CI by the revised IWG-MRT and ELN criteria after 6 cycles of treatment
Number of treatment related grade ≥ 3 AEs
(COHORT-2) AEs and serious adverse events (SAEs), as measured by CTCAE v6.0: Number of grade ≥ 3 AEs using CTCAE v6.0.
Proportion of participants achieving CI
Proportion of participants achieving CI at cycle 3 and cycle 6 by IWG-MRT and ELN criteria: * Anemia response: per IWG-MRT and ELN criteria with screening hemoglobin \< 10 g/dL or transfusion dependency * Spleen response: per IWG-MRT and ELN criteria with baseline spleen volume \> 450 cm3 * Symptom benefit: per IWG-MRT and ELN criteria with baseline MFSAF v4.0 TSS ≥ 10
Change in spleen volume
Spleen volume reduction of ≥35% or ≥25% compared to baseline in patients with baseline spleen volume \>450cm\^3 at completion of cycle 3 and cycle 6
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John Mascarenhas
Lead sponsor
Icahn School of Medicine at Mount Sinai
Sponsor institution
Syndax Pharmaceuticals
Collaborator
National Cancer Institute (NCI)
Collaborator
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