Syndax Pharmaceuticals Moves Forward with Phase 1b Trial of Revumenib for Relapsed or Refractory Metastatic MSS CRC

7 June 2024

Syndax Pharmaceuticals, a clinical-stage biopharmaceutical company, has advanced revumenib, its oral menin inhibitor, into the Phase 1b segment of its ongoing Phase 1/2 trial. This phase tests revumenib as a monotherapy for patients with relapsed or refractory metastatic microsatellite stable (MSS) colorectal cancer (CRC). The company's decision to move forward follows a positive assessment by the trial's Independent Data Monitoring Committee (IDMC) of early data from the Phase 1a portion.

Syndax, stated, "The early data from Phase 1a trials indicate that revumenib maintains a robust safety profile consistent with previous studies. We've seen encouraging efficacy signals, such as a 33% rate of stable disease at 16 weeks with revumenib monotherapy. These results support advancing to Phase 1b. We are excited to further investigate revumenib's potential impact in treating R/R metastatic MSS CRC as we prepare for the possible launches of revumenib and axatilimab later this year."

The Phase 1/2 trial (NCT05731947) is designed to evaluate the safety, tolerability, and anti-tumor activity of revumenib in patients with relapsed or refractory metastatic MSS CRC. In Phase 1a, 19 patients were enrolled, each having undergone a median of four prior therapies. These patients were divided into three dose cohorts: 163 mg, 226 mg, and 276 mg, administered three times daily. Revumenib was well-tolerated across all dose levels, with no Grade 3 or higher treatment-related adverse events (TRAEs) reported. The most common side effects were decreased appetite, dysgeusia, nausea, and fatigue. Preliminary efficacy results suggest that revumenib may effectively manage disease progression in these patients, with 44% showing stable disease at 8 weeks at higher doses, and 33% at 16 weeks. One patient maintained stable disease for 32 weeks, leading to the selection of the 276 mg TID dose for the Phase 1b portion.

Metastatic microsatellite stable colorectal cancer (MSS CRC) is a significant cause of cancer-related deaths in the U.S., with over 55,000 new cases diagnosed annually in the relapsed or refractory setting. The growth of most CRC tumors is driven by the Wnt/β-catenin signaling pathway. The menin-MLL1 complex regulates β-catenin activity, and inhibiting this complex may disrupt tumor growth in CRC, as shown in preclinical studies.

Revumenib is a potent, selective small molecule that inhibits the interaction between menin and KMT2A, being developed for treating KMT2A-rearranged acute leukemias, such as mixed lineage leukemia (MLLr) and mutant nucleophosmin (mNPM1) acute myeloid leukemia (AML). Promising results from the AUGMENT-101 trial in R/R KMT2Ar acute leukemia, which achieved its primary endpoint, were presented at the 65th American Society of Hematology Annual Meeting. Data from the Phase 1 segment of the AUGMENT-101 trial in acute leukemia has been published in Nature. Key results from this trial in R/R NPM1 AML patients are expected in the fourth quarter of 2024. Revumenib has received Orphan Drug Designation from the FDA and the European Commission for AML treatment, as well as Fast Track designation from the FDA for R/R acute leukemias in patients with KMT2A rearrangement or NPM1 mutation. Additionally, the FDA has granted Breakthrough Therapy Designation for treating R/R acute leukemia in patients with a KMT2A rearrangement. The NDA submission for revumenib in R/R KMT2Ar acute leukemia is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) action date of September 26, 2024.