The FDA has positioned a partial scientific maintain on a section 1 trial (NCT04734990) evaluating seclidemstat (SP-2577) together with azacitidine (Vidaza) for the therapy of sufferers with myelodysplastic syndrome (MDS) or persistent myelomonocytic leukemia (CMML).1
The choice adopted a critical and sudden grade 4 antagonistic impact reported by trial investigators at The College of Texas MD Anderson Most cancers Middle in Houston. Underneath the partial scientific maintain, no new sufferers are allowed to enroll within the research; nonetheless, sufferers already enrolled are allowed to proceed receiving therapy if they’re experiencing scientific profit.
Seclidemstat is an LSD1 inhibitor, and associations have been proven between LSD1 and the upkeep of pluripotency and proliferation genes. Moreover, inhibiting LSD1 can promote the differentiation of blast cells and produce an antileukemic impact.
Prior knowledge from the section 1 trial introduced on the 2022 ASH Annual Assembly confirmed that amongst efficacy-evaluable sufferers with MDS or CMML (n = 8), the general response charge (ORR) was 50%, which included 1 affected person with a whole response (CR), 1 affected person with a bone marrow CR (mCR) alone, and a couple of sufferers with a mCR and hematologic enchancment.2
As of the October 2022 knowledge cutoff, the early mortality charge was 0%, and no dose-limiting toxicities had been reported at doses of seclidemstat as much as 450 mg twice per day. Six sufferers (67%) skilled reversible elevated creatinine in the course of the preliminary week of therapy with azacitidine. Three sufferers had cardiac rhythm/echocardiogram abnormalities.
The research was enrolling sufferers not less than 18 years of age with intermediate-1–, intermediate-2–, or high-risk MDS per the Worldwide Prognostic Scoring System, or CMML-1/CMML-2, myeloproliferative CMML, or CMML-0 with high-risk molecular options.3 Sufferers had been required to have illness that didn’t reply after 6 cycles of therapy with a hypomethylating agent, or illness that relapsed or progressed after any variety of cycles. An ECOG efficiency standing of 0 to 2 and ample organ operate had been required.2
Throughout dose escalation, sufferers had been receiving 75 mg/m2 of azacitidine on days 1 to 7 of every 28-day cycle plus seclidemstat twice per day at 1 of the next 6 dose ranges: 150 mg, 300 mg, 450 mg, 600 mg, 900 mg, and 1200 mg.3 Notably, throughout cycle 1, seclidemstat was given as soon as on day 1, then twice per day for the rest of the cycles; it was given twice per day on all days of subsequent cycles.
ORR and the incidence of antagonistic results are the trial’s main finish factors. Secondary finish factors embody general survival, period of response, leukemia-free survival, and relapse-free survival.
Further security knowledge beforehand reported for the primary 9 sufferers enrolled within the research confirmed that the most typical 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), belly ache (n = 3), cough (n = 3), diarrhea (n = 3), dizziness (n = 3), dyspnea (n = 3), fatigue (n = 3), myalgia (n = 3), fever (n = 2), proper bundle department block (n = 1), and QT prolongation (n = 1). Grade 3 or increased AEs included an infection (n = 3), hypotension (n = 1), and atrial fibrillation (n = 1).2
At knowledge cutoff, and with a median follow-up of three.9 months (95% CI, 0-10.4,) sufferers acquired a median of three cycles (vary, 1-7) of therapy. Two sufferers had been off research attributable to illness development. One affected person underwent allogeneic stem cell transplant, and 1 affected person was off research attributable to lack of response. 5 sufferers remained on therapy.
References
- US Securities and Alternate Fee. Kind 8-Okay. Salarius Prescribed drugs. July 9, 2024. Accessed July 15, 2024. https://buyers.salariuspharma.com/static-files/f29ce3eb-81fb-4257-9ea8-d67b9d502ed6
- Montalban-Bravo G, DiNardo C, Brief N, et al. A section I/II research of seclidemstat, an LSD1 inhibitor, and azacitidine for sufferers with myelodysplastic syndromes and persistent myelomonocytic leukemia. Blood. 2022;140(suppl 1):9771-9772. doi:10.1182/blood-2022-170138
- Seclidemstat and azacitidine for the therapy of myelodysplastic syndrome or persistent myelomonocytic leukemia. ClinicalTrials.gov. Up to date Could 9, 2024. Accessed July 15, 2024. https://clinicaltrials.gov/research/NCT04734990
