Phase I/II Study of Palbociclib + Chemotherapy in Recurrent/Refractory Pediatric Solid Tumors in a Randomly Assigned Cohort With Ewing Sarcoma
Year: 2026
Type: article
Abstract: PURPOSE Pediatric tumor cells, such as Ewing sarcoma (EWS), depend on CDK4/6 and cyclin D1. Palbociclib, a CDK4/6 inhibitor, combined with irinotecan/temozolomide (IRN/TMZ) has demonstrated antitumor activity in patient-derived EWS mouse models. This phase I/II study investigated palbociclib + two chemotherapy combinations for treating relapsed or refractory (R/R) solid tumors, including EWS and neuroblastoma. METHODS The phase I portion was a nonrandomized dose-finding study using a rolling-6 design to determine the recommended phase II dose (RP2D) of palbociclib (once daily on days 1 to 14 of 21-day cycles) combined with IRN (daily at 50 mg/m 2 on days 1 to 5)/TMZ (daily at 100 mg/m 2 on days 1 to 5) or topotecan (TOPO)/cyclophosphamide (CTX) (TOPO [daily at 0.75 mg/m 2 on days 1 to 5]/CTX [daily at 250 mg/m 2 on days 1 to 5]) in pediatric patients with R/R solid tumors. After phase I, a single-arm neuroblastoma-specific cohort was opened. The phase II portion was a randomized study comparing investigator-assessed event-free survival (EFS) of palbociclib + IRN/TMZ versus IRN/TMZ alone in patients with R/R EWS. Safety, pharmacokinetics, and efficacy were assessed in all portions. RESULTS In the phase I portion, RP2D of 75 mg/m 2 once daily palbociclib was established for both combinations in dose-limiting toxicity (DLT)-evaluable patients (n = 58). DLTs (5/58; 9%) were primarily hematologic (neutropenia/thrombocytopenia). No new safety signals emerged, and treatments were tolerable. In the neuroblastoma cohort (stage I; n = 7), only two patients responded to palbociclib + TOPO/CTX. In the phase II portion prespecified interim analysis, median EFS was 1.5 versus 4.4 months in patients with R/R EWS receiving palbociclib + IRN/TMZ (n = 35) versus IRN/TMZ (n = 19), respectively (hazard ratio, 2.0 [95% CI, 0.9 to 4.6]). No clinically meaningful drug-drug interactions were observed between palbociclib and combination chemotherapies. CONCLUSION Palbociclib at RP2D (75 mg/m 2 once daily) with IRN/TMZ or TOPO/CTX was tolerable in pediatric patients with R/R solid tumors. Palbociclib + TOPO/CTX was not promising in R/R neuroblastoma and palbociclib + IRN/TMZ did not improve EFS in R/R EWS versus IRN/TMZ alone. These findings highlight the need to explore alternative treatment strategies in pediatric oncology.
Source: JCO oncology advances.
DOI: 10.1200/oa-26-00050
Authors: Theodore W. Laetsch, Tanya Watt, Fariba Navid, Mustafa Tezer Kutluk, Sameer Rastogi, Hyoung Jin Kang, Margaret E. Macy, Christine A. Pratilas, Joseph G. Pressey, Linda C. Stork, Navin Pinto, Tyler G. Ketterl, Daniel A. Morgenstern, Katarzyna A. Juszczak-Kosela, Zhe Zhang, Charvi Nanavati, Jodi A. Muscal, Neslihan Aslan, Elizabeth Fox, Brenda J. Weigel, Katherine A. Janeway, Douglas S. Hawkins, Anderson B. Collier
Institutions: Children's Hospital of Philadelphia, Abramson Cancer Center, University of Pennsylvania, The University of Texas Southwestern Medical Center, University of Southern California, Children's Hospital of Los Angeles, Hacettepe University, All India Institute of Medical Sciences, Seoul National University, Seoul National University Children's Hospital, Children's Hospital Colorado, University of Colorado Anschutz, Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Oregon Health & Science University, Seattle Children's Hospital, University of Toronto, Hospital for Sick Children, Pfizer (United States), St. Jude Children's Research Hospital, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, University of Washington, Nemours Children's Health System
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7204524197