FDA Places Partial Hold on Trial for Seclidemstat in MDS, CMML

A serious grade 4 adverse effect reported in the phase 1/2 dose-escalation study evaluating seclidemstat combination therapy prompted the partial hold.

The FDA has placed a partial clinical hold on the dose-escalation phase 1/2 study (NCT04734990) assessing the efficacy of the oral LSD1 inhibitor, seclidemstat (SP-2577), in combination with azacitidine (Vidaza) in patients with higher risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), according to a regulatory document published by the United States Securities and Exchange Commission.¹

Due to the occurrence of a grade 4 serious adverse effect (SAE) after treatment with the combination therapy, developer Salarius Pharmaceuticals has paused enrollment of new United States–based patients in the trial until it has met the FDA’s regulatory requirements. Currently enrolled patients are permitted to continue treatment if they are benefitting from the therapy.

Data presented at the 2024 European Hematology Association (EHA) Congress showed that an objective response occurred in 43% (n = 6/14) of evaluable patients, which included a complete response in 1, marrow complete responses in 3, complete responses plus hematological improvement in 1, and hematological improvement in 1. Median follow-up time was 18.9 months (range, 0-48), with median overall survival (OS) and event-free survival (EFS) at 18.5 months (95% CI, 6.1-30.9) and 7.2 months (95% CI, 6.3-8.2), respectively.

Among patients evaluable for toxicity (n = 15), a dose-limiting toxicity was observed in 1 patient in a 750 mg twice daily cohort; this cohort expanded to include 3 additional patients.²

The phase 1 dose-escalation study portion aims to evaluate up to 6 seclidemstat dose levels. Increasing at 150 mg twice daily increments, the fifth cohort will receive 750 mg of seclidemstat, and the sixth and final cohort will receive 900 mg of the agent. The maximum tolerated dose has not been reached, precluding the start of phase 2.

The primary end points of phase 1 are the safety, tolerability, and maximum tolerated dose and overall response rate (ORR) of the combination therapy in adult patients with higher-risk MDS or CMML. Secondary end points include OS, duration of response, and progression-free survival.

Included in the study are adult patients with diagnosed MDS or CMML, serum creatinine at or less than 1.5 times the upper limit of normal (ULN) or creatinine clearance at or more than 50 mL/min for patients with creatinine levels greater than 1.5 times the ULN, and an ECOG performance status of 0 to 2.³ Additional inclusion criteria include adequate hepatic function with total bilirubin less than 2 times the ULN, aspartate aminotransferase or alanine aminotransferase at or less than 3 times the ULN, and prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors.

Exclusion criteria include uncontrolled infection not adequately responding to antibiotics, class III or IV congestive heart failure or left ventricular ejection fraction, and a history of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris.

“We are encouraged by these promising results at this early stage of the study when seclidemstat is combined with azacitidine at doses below what we believe will be the recommended phase 2 dose. Patients who have [progressed on] prior treatments including hypomethylating agents have a poor prognosis and are in desperate need of new treatment options. With a 43% [ORR], median [OS] of 18.5 months and median EFS of 7.2 months, we agree with the investigators that these results show promising early signs of activity in a high-risk MDS and CMML treatment failure population,” said William McVicar, PhD, chairman of the Salarius Pharmaceuticals Board of Directors in a press release on findings from the clinical study presented at EHA 2024.²

References

1. United States Securities and Exchange Commission. Form 8-K. Salarius Pharmaceuticals. Published July 9, 2024. Accessed July 15, 2024. https://tinyurl.com/w32tnpdk
2. Clinical data on Salarius Pharmaceuticals’ seclidemstat in patients with MDS and CMML presented at the 2024 European Hematology Association Annual Meeting. News release. Salarius Pharmaceuticals. Published June 17, 2024. Accessed July 15, 2024. https://tinyurl.com/5szwdbtc
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