FDA Places Partial Clinical Hold on Phase 1 Trial of Seclidemstat Plus Azacitidine in MDS/CMML

FDA

The FDA has placed a partial clinical hold on a phase 1 trial (NCT04734990) evaluating seclidemstat (SP-2577) in combination with azacitidine (Vidaza) for the treatment of patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML).¹

The decision followed a serious and unexpected grade 4 adverse effect reported by trial investigators at The University of Texas MD Anderson Cancer Center in Houston. Under the partial clinical hold, no new patients are allowed to enroll in the study; however, patients already enrolled are allowed to continue receiving treatment if they are experiencing clinical benefit.

Seclidemstat is an LSD1 inhibitor, and associations have been shown between LSD1 and the maintenance of pluripotency and proliferation genes. Furthermore, inhibiting LSD1 can promote the differentiation of blast cells and produce an antileukemic effect.

Prior data from the phase 1 trial presented at the 2022 ASH Annual Meeting showed that among efficacy-evaluable patients with MDS or CMML (n = 8), the overall response rate (ORR) was 50%, which included 1 patient with a complete response (CR), 1 patient with a bone marrow CR (mCR) alone, and 2 patients with a mCR and hematologic improvement.²

As of the October 2022 data cutoff, the early mortality rate was 0%, and no dose-limiting toxicities were reported at doses of seclidemstat up to 450 mg twice per day. Six patients (67%) experienced reversible elevated creatinine during the initial week of treatment with azacitidine. Three patients had cardiac rhythm/echocardiogram abnormalities.

The study was enrolling patients at least 18 years of age with intermediate-1–, intermediate-2–, or high-risk MDS per the International Prognostic Scoring System, or CMML-1/CMML-2, myeloproliferative CMML, or CMML-0 with high-risk molecular features.³ Patients were required to have disease that did not respond after 6 cycles of treatment with a hypomethylating agent, or disease that relapsed or progressed after any number of cycles. An ECOG performance status of 0 to 2 and adequate organ function were required.²

During dose escalation, patients were receiving 75 mg/m² of azacitidine on days 1 to 7 of each 28-day cycle plus seclidemstat twice per day at 1 of the following 6 dose levels: 150 mg, 300 mg, 450 mg, 600 mg, 900 mg, and 1200 mg.³ Notably, during cycle 1, seclidemstat was given once on day 1, then twice per day for the remainder of the cycles; it was given twice per day on all days of subsequent cycles.

ORR and the incidence of adverse effects are the trial’s primary end points. Secondary end points include overall survival, duration of response, leukemia-free survival, and relapse-free survival.

Additional safety data previously reported for the first 9 patients enrolled in the study showed that the most common grade 1/2 AEs included hypotension (n = 3), atrial fibrillation (n = 1), elevated creatinine (n = 6), nausea (n = 6), constipation (n = 5), vomiting (n = 4), abdominal pain (n = 3), cough (n = 3), diarrhea (n = 3), dizziness (n = 3), dyspnea (n = 3), fatigue (n = 3), myalgia (n = 3), fever (n = 2), right bundle branch block (n = 1), and QT prolongation (n = 1). Grade 3 or higher AEs included infection (n = 3), hypotension (n = 1), and atrial fibrillation (n = 1).²

At data cutoff, and with a median follow-up of 3.9 months (95% CI, 0-10.4,) patients received a median of 3 cycles (range, 1-7) of treatment. Two patients were off study due to disease progression. One patient underwent allogeneic stem cell transplant, and 1 patient was off study due to lack of response. Five patients remained on treatment.

References

1. US Securities and Exchange Commission. Form 8-K. Salarius Pharmaceuticals. July 9, 2024. Accessed July 15, 2024. https://investors.salariuspharma.com/static-files/f29ce3eb-81fb-4257-9ea8-d67b9d502ed6
2. Montalban-Bravo G, DiNardo C, Short N, et al. A phase I/II study of seclidemstat, an LSD1 inhibitor, and azacitidine for patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Blood. 2022;140(suppl 1):9771-9772. doi:10.1182/blood-2022-170138
3. Seclidemstat and azacitidine for the treatment of myelodysplastic syndrome or chronic myelomonocytic leukemia. ClinicalTrials.gov. Updated May 9, 2024. Accessed July 15, 2024. https://clinicaltrials.gov/study/NCT04734990