First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors

Abstract

BACKGROUND:The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS:This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m 2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m 2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m 2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors.

The potential of PARP as a therapeutic target across pediatric solid malignancies

“…Furthermore, the poor prognostic outlook for patients with relapsed solid tumors urges the development of more targeted treatment approaches, such as PARP inhibition. Currently, there are no clinically approved PARP inhibitors for children, however the results of a recently published phase 1 clinical study evaluating olaparib in pediatric patients with refractory solid tumors were promising and there are multiple ongoing clinical studies to evaluate the safety, dosing and efficacy of PARP inhibitors in children (NCT02392793, NCT04544995, NCT01858168, among others) [30].…”

Genomic and phenotypic stability of fusion-driven pediatric Ewing sarcoma cell lines

“…We next complemented these results by exposing each newly purchased EwS cell line (m0) and their 12-month derivate (m12) to an extended drug library that contained 10 additional compounds (extended library, ntotal=20, Supp. Table 1) to include drugs that had been recently described in EwS preclinical or clinical studies, such elesclomol, olaparib and gemcitabine [8][9][10] . Here, we again observed inter-cell line variability in collective drug response over time that ranged from the least stable A-673, to the remarkably stable TC-71 EwS cell line (Fig 3e).…”