A Phase 1 Trial of Fimepinostat in Children and Adolescents With Relapsed and Refractory Solid and CNS Tumors.

BACKGROUND

Fimepinostat, an oral dual inhibitor of histone deacetylase (HDAC) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), has shown activity in preclinical models of Myc-driven pediatric malignancies. This Phase 1 trial aimed to determine the recommended pediatric Phase 2 dose (RPP2D), describe the toxicity profile, and evaluate the pharmacokinetics of fimepinostat in children with relapsed and refractory solid and central nervous system (CNS) tumors.

METHODS

This multicenter, Phase 1 study enrolled patients ages 1-21 years with relapsed or refractory solid tumors, CNS tumors, or lymphoma. The dose-escalation phase followed a 3 + 3 design, starting at 27.5 mg/m2 and escalating to 45 mg/m2. Following dose escalation, three expansion cohorts were opened including cohorts for patients with Myc(n)-driven neuroblastoma, Myc-driven extracranial solid tumors, and diffuse large B-cell lymphoma or Burkitt lymphoma. The pharmacokinetics of fimepinostat and its metabolites were studied after the first dose.

RESULTS

Twenty-six patients were enrolled, with 25 receiving treatment. The median age was 13.6 years (range: 4.1-20.9). In the dose-escalation phase, 12 patients were evaluable for DLT assessment. The RPP2D was initially determined to be 45 mg/m2 but was revised to 35 mg/m2 after observing DLTs in the dose-expansion phase. Treatment-related adverse events were primarily hematologic and gastrointestinal. No objective responses were observed in 23 evaluable patients. Three patients had stable disease for over four cycles, including a patient with MYCN amplified neuroblastoma with stable disease for 24 cycles. Pharmacokinetic analysis showed significant interpatient variability and rapid conversion of fimepinostat to its metabolites.

CONCLUSION

Fimepinostat was tolerable at a dose of 35 mg/m2 in children with relapsed and refractory solid and CNS tumors, but lacked significant clinical activity. Discovery of drugs to target Myc continues to be a high priority for childhood cancers.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02909777.