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A Phase 1 Trial of Fimepinostat in Children and Adolescents With Relapsed and Refractory Solid and CNS Tumors
David S Shulman1, Kieuhoa T Vo2, Frank M Balis3
1Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts, USA.
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.
Insights
Fimepinostat showed tolerability in children with relapsed cancers but lacked significant clinical activity. Targeting Myc remains crucial for pediatric cancer drug discovery.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Fimepinostat, a dual inhibitor of histone deacetylase (HDAC) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), demonstrated preclinical activity in Myc-driven pediatric malignancies.
- A Phase 1 trial was conducted to assess fimepinostat in pediatric patients with relapsed/refractory solid and central nervous system (CNS) tumors.
Purpose of the Study:
- Determine the recommended pediatric Phase 2 dose (RPP2D) of fimepinostat.
- Characterize the toxicity profile and pharmacokinetics of fimepinostat in pediatric patients.
- Evaluate the preliminary efficacy of fimepinostat in relapsed/refractory pediatric cancers.
Main Methods:
- A multicenter, Phase 1 dose-escalation study using a 3+3 design enrolled patients aged 1-21 years.
- Dose escalation ranged from 27.5 mg/m² to 45 mg/m², with expansion cohorts for Myc-driven neuroblastoma, extracranial solid tumors, and lymphoma.
- Pharmacokinetic analysis was performed after the first dose; toxicity was assessed via dose-limiting toxicities (DLTs).
Main Results:
- The recommended pediatric Phase 2 dose (RPP2D) was revised from 45 mg/m² to 35 mg/m² due to observed DLTs.
- Treatment-related adverse events were predominantly hematologic and gastrointestinal.
- No objective responses were observed in evaluable patients, though three achieved stable disease, including one with MYCN-amplified neuroblastoma for 24 cycles.
Conclusions:
- Fimepinostat at 35 mg/m² was tolerable in pediatric patients with relapsed/refractory solid and CNS tumors.
- The drug demonstrated limited clinical activity in this patient population.
- Targeting Myc remains a critical area for developing new therapies for childhood cancers.
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