Margaret von Mehren, MD and Johnathan R. Whetstine, PhD
Researchers at Fox Chase Cancer Center are recruiting patients with relapsed or refractory Ewing or Ewing-related sarcomas to a phase-1 clinical trial of a new targeted therapy called seclidemstat, an oral, reversible inhibitor of lysine-specific demethylase 1 (LSD1 or KDM1A) with potential antineoplastic activity (ClinicalTrials.gov NCT03600649).
Ewing sarcomas are a group of cancers that start in the bones or nearby soft tissues and share common genetic causes. The current standards of care include treatment with chemotherapy, radiation therapy, and/or surgery. However, there is an unmet need for effective treatments for relapsed or refractory Ewing sarcoma.
Ewing sarcoma cells highly express and depend on LSD1 for survival. LSD1 overexpression promotes tumor development by contributing to cancer cell proliferation. Seclidemstat works by inhibiting LSD1 demethylase activity and restoring a balanced transcriptional state.
This phase-1 trial is the culmination of a 16-year journey of research on histone demethylation from bench to bedside, according to Johnathan R. Whetstine, PhD, professor and director of Fox Chase’s Cancer Epigenetics Institute.
One of the things Whetstine’s lab investigates is epigenetic mechanisms that regulate the DNA—such as modifications by methylases and demethylases—and whether modulation of these factors can provide novel therapeutic options. Dr. Whetstine was a part of the team of researchers that first showed that LSD1 functions as a histone demethylase and transcriptional corepressor in 2004.
“The concept for this trial is really built on understanding biochemistry and how things work,” Whetstine said. “The whole field of epigenetics is very mechanistically defined. The whole point is understanding how a gene or a protein is functioning and leveraging that to target specific cancer types, such as sarcoma.”
Trial enrollment at Fox Chase will be led by Margaret von Mehren, MD, vice chair and professor, Department of Hematology/Oncology and chief, Division of Sarcoma Medical Oncology. The open-label expansion trial will test single-agent seclidemstat in patients with myxoid liposarcoma, seclidemstat in combination with topotecan and cyclophosphamide in patients with Ewing sarcoma, and single-agent seclidemstat in patients with other sarcomas that share similar chromosomal translocation to Ewing sarcoma (FET-family translocations).
The primary outcome measures are safety and tolerability of seclidemstat as a single agent and as part of a combination therapy. Secondary outcome measures include evaluation of antitumor activity.
To qualify at Fox Chase, patients must be aged 18 or older, have a histologic confirmation of their diagnosis, have received at least one prior course of systemic therapy but no more than three courses of systemic therapy, and have measurable disease by computed tomography or magnetic resonance imaging.
“This therapy is completely novel, and we are trying to treat these cancer cells in a very different way than in the past,” von Mehren said. “We have seen efficacy in cell lines and animal models, but we have to wait to see if that will translate into patients.”
What You Should Know About Seclidemstat
- Seclidemstat has received Fast Track Designation, Orphan Drug Designation, and Rare Pediatric Disease Designation for Ewing sarcoma from the U.S. Food and Drug Administration.
- In data released at ASCO 2021, a subset of patients with advanced FET-rearranged sarcomas treated with single-agent seclidemstat resulted in stable disease (SD) and prolonged time to progression (TTP).