A phase 2 study of tipifarnib in children and young adults with tumors harboring HRAS genomic alterations: NCI-COG Pediatric MATCH trial (APEC1621M)

Abstract Background APEC1621 arm M, a subprotocol of the NCI-COG Pediatric MATCH clinical trial, is a phase 2 study evaluating tipifarnib, a farnesyl transferase inhibitor, in patients with relapsed or refractory solid tumors harboring HRAS mutations at codons G12, G13, Q61, or A146 (NCT04284774). Methods Patients identified by the MATCH screening protocol and enrolled to the arm M subprotocol received tipifarnib at 350 mg/m2/dose (maximum 600 mg/dose) orally twice daily on an intermittent dosing schedule (days 1 to 7 and 15 to 21, every 28 days) until disease progression or intolerable toxicity. The primary aim was to determine the objective response rate (ORR) and secondary objectives included estimating progression-free survival (PFS) and assessing the tolerability of tipifarnib on the intermittent dosing schedule in children. Results Seven patients matched to the tipifarnib subprotocol and five patients (71%) enrolled. Two matched patients were ineligible for treatment. Diagnoses for the enrolled patients were rhabdomyosarcoma (n = 4) and angiosarcoma (n = 1). HRAS mutations identified in those tumors included G13R (n = 2) and G12S, G12C, and Q61L (n = 1 each). Treatment was associated with grade 1/2 adverse events (AE) consistent with those expected from prior studies. Grade 3 or higher AEs on treatment were disease progression, dyspnea, and pleural effusion, not related to protocol therapy. One patient had stable disease (SD) at the end of cycle two and remained on protocol therapy for four cycles. There were no objective responses (OR). Conclusions This U.S. cooperative group study was successful at identifying pediatric patients with tumors that harbored oncogenic mutations in HRAS. The frequency of the mutations identified and patients enrolled was lower than anticipated and the study closed before accrual was complete. The adverse effect profile of tipifarnib in pediatric patients on the intermittent dosing schedule was acceptable. Limited single-agent efficacy of tipifarnib was observed in this biomarker-selected cohort of refractory pediatric tumors.