Phase II Study of Samotolisib in Children and Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Pathway Alterations: Pediatric MATCH APEC1621D

Authors

Theodore W Laetsch
Kathleen Ludwig
P Mickey Williams
Sinchita Roy-Chowdhuri
David R Patton
Brent Coffey
Joel M Reid
Jin Piao
Lauren Saguilig
Todd A Alonzo
Stacey L Berg
Joyce Mhlanga
Elizabeth Fox
Brenda J Weigel
Douglas S Hawkins
Margaret M Mooney
Naoko Takebe
James V Tricoli
Katherine A Janeway
Nita L Seibel
Donald Williams Parsons

Language

English

Publication Date

9-1-2024

Journal

JCO Precision Oncology

DOI

10.1200/PO.24.00258

PMID

39298693

PMCID

PMC11581706

PubMedCentral® Posted Date

9-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Purpose: Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.

Methods: Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children.

Results: A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), PIK3CA (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m2/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children.

Conclusion: This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.

Keywords

Humans, Child, Adolescent, Female, Male, Young Adult, Child, Preschool, TOR Serine-Threonine Kinases, Infant, Neoplasms, MTOR Inhibitors, Phosphatidylinositol 3-Kinases, Pyrimidines, Bridged Bicyclo Compounds, Heterocyclic

Published Open-Access

yes

Recommended Citation

Laetsch, Theodore W; Ludwig, Kathleen; Williams, P Mickey; et al., "Phase II Study of Samotolisib in Children and Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Pathway Alterations: Pediatric MATCH APEC1621D" (2024). Faculty and Staff Publications. 5142.
https://digitalcommons.library.tmc.edu/baylor_docs/5142