FDA Enforces Partial Hold on Trial of Seclidemstat in MDS/CMML

• A partial clinical hold has been placed on a phase 1 trial (NCT04734990) of the combination of seclidemstat (SP-2577) with azacitidine in myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML).
• The hold was placed after a serious and unexpected grade 4 adverse effect (AE) was reported by investigators on the trial at The University of Texas MD Anderson Cancer Center in Houston, Texas.
• No new patients may be enrolled in the study under the partial clinical hold.

The FDA has placed a partial clinical hold on a phase 1 trial evaluating seclidemstat (SP-2577) when given in combination with azacitidine for the treatment of patients with MDS of CMML, following the report of a serious and unexpected grade 4 AE observed in a patient.¹

Seclidemstat is an oral LSD1 inhibitor being tested for the treatment of hematological and solid tumors. The agent has shown to have associations between LSD1 and the maintenance of pluripotency and proliferation genes.

The AE was reported by trial investigators at The University of Texas MD Anderson Cancer Center in Houston. With the partial clinical hold in place, no new patients will be enrolled in the study. Patients already enrolled continue receiving treatment if they are experiencing clinical benefit.

While no details on the nature of the grade 4 AE were disclosed, Salarius said it will support researchers at MD Anderson in assessing the data already available. They will also help with responding to FDA submitted questions.

About the Phase 1 Trial of Seclidemstat

Blood cells : © Dr_Microbe - stock.adobe.com

The phase 1/2 trial is evaluating seclidemstat plus azacitidine in patients with MDS or CMML to determine the best dose.² Patients aged 18 years or older 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 are eligible for enrollment in the study. Additional requirements include having an ECOG performance status of 0 to 2, adequate organ function, disease that did not respond following 6 cycles of treatment with a hypomethylating agent, or disease that relapsed or progressed after any number of cycles.

In the dose-escalation portion of the study, patients were given 75 mg/m² of azacitidine on days 1 to 7 of each 28-day cycle in addition to seclidemstat twice per day at either 150 mg, 300 mg, 450 mg, 600 mg, 900 mg, or 1200 mg.3 Seclidemstat was given once on day 1, then twice per day for the remainder of the cycles during cycle 1, while it was given twice per day on all days of every cycle after.

The primary end points of the study were overall response rate (ORR) and the incidence of AEs. Secondary end points being evaluated consist of overall survival, duration of response, leukemia-free survival, and relapse-free survival.

Data from the phase 1 trial were previously presented at the 2022 American Society of Hematology Annual Meeting. Of the 8 efficacy-evaluable patients with MDS or CMML, the ORR was 50%. This included 1 patient who had a complete response (CR), 1 patient who had a bone marrow CR (mCR) alone, and 2 patients who had mCR and hematologic improvement.³ As of the October 2022 data cutoff, there were no early mortalities and no dose-limiting toxicities seen when seclidemstat was given at doses up to 450 mg twice per day.

Sixty-seven percent of patients experienced reversible elevated creatinine during the first week combining treatment with azacitidine. Additionally, 3 patients had cardiac rhythm or echocardiogram abnormalities.

Looking at safety in the initial 9 patients enrolled in the study, the most common grade 1/2 AEs observed were 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).

At the time of data cutoff, with a median follow-up of 3.9 months (95% CI, 0-10.4), the median number of treatment cycles was 3 (range, 1-7). Two patients discontinued from the study because of disease progression, 1 underwent an allogeneic stem cell transplant, and another 1 patient was off study due to lack of response. Five patients continued with the treatment.

Seclidemstat is being evaluated as a potential treatment for pediatric cancers, sarcomas, and other cancers with limited treatment options.⁴ In addition to this trial in MDS and CMML, seclidemstat is being tested in a phase 1/2 clinical trial for the treatment of patients with relapsed/refractory Ewing sarcoma and select additional sarcomas.

The FDA has granted seclidemstat a fast track designation, orphan drug designation, and rare pediatric disease designation for treating Ewing sarcoma.

REFERENCES:

1. US Securities and Exchange Commission. Form 8-K. Salarius Pharmaceuticals. July 9, 2024. Accessed July 15, 2024. https://tinyurl.com/4ax5puhj

2. 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

3. 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

4. Pipeline. Salarius Pharmaceuticals. Accessed July 16, 2024. https://salariuspharma.com/our-programs/pipeline/