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 1-7 and 15-21, 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 2 and remained on protocol therapy for 4 cycles. There were no objective responses (OR).
Conclusions: This US 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.
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BibTeX
@article{pratilas2026phase,
title = {{A phase 2 study of tipifarnib in children and young adults with tumors harboring HRAS genomic alterations: NCI-COG Pediatric MATCH trial (APEC1621M)}},
author = {Christine A Pratilas and Marielle E Yohe and Paul M Williams and Joel M Reid and Jin Piao and Lauren Saguilig and David R Patton and Brent Coffey and Todd A Alonzo and Alexandria M Thompson and Nicole Arwood and Sinchita Roy-Chowdhuri and Nilsa C Ramirez and Stacey L Berg and Elizabeth Fox and Brenda J Weigel and Douglas S Hawkins and Margaret M Mooney and Naoko Takebe and James V Tricoli and Katherine A Janeway and Nita L Seibel and Donald W Parsons},
journal = {The Oncologist},
year = {2026},
month = oct,
doi = {10.1093/oncolo/oyag401},
url = {https://doi.org/10.1093/oncolo/oyag401},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - A phase 2 study of tipifarnib in children and young adults with tumors harboring HRAS genomic alterations: NCI-COG Pediatric MATCH trial (APEC1621M)
AU - Christine A Pratilas
AU - Marielle E Yohe
AU - Paul M Williams
AU - Joel M Reid
AU - Jin Piao
AU - Lauren Saguilig
AU - David R Patton
AU - Brent Coffey
AU - Todd A Alonzo
AU - Alexandria M Thompson
AU - Nicole Arwood
AU - Sinchita Roy-Chowdhuri
AU - Nilsa C Ramirez
AU - Stacey L Berg
AU - Elizabeth Fox
AU - Brenda J Weigel
AU - Douglas S Hawkins
AU - Margaret M Mooney
AU - Naoko Takebe
AU - James V Tricoli
AU - Katherine A Janeway
AU - Nita L Seibel
AU - Donald W Parsons
PY - 2026
DA - 2026/10/09
JO - The Oncologist
DO - 10.1093/oncolo/oyag401
UR - https://doi.org/10.1093/oncolo/oyag401
AB - 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 1-7 and 15-21, 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 2 and remained on protocol therapy for 4 cycles. There were no objective responses (OR). Conclusions: This US 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.
SN - 1083-7159
SN - 1549-490X
ER -