Phase 2 study to evaluate palbociclib in combination with irinotecan and temozolomide in pediatric patients with recurrent or refractory Ewing sarcoma.

Abstract

TPS11583 Background: Palbociclib (PD-0332991) is a highly selective, reversible, small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6, administered orally. Functional dependence of Ewing Sarcoma (EWS) cell lines and tumor xenografts on Cyclin D1/CDK4 via genetic knockdown has shown both Cyclin D1 and CDK4 as critical dependencies for EWS cell line proliferation. The phase 1 portion of the study established the recommended Phase 2 dose (RP2D) with two chemotherapy backbones in children with solid tumors. The Phase 2 portion of the study now enrolls patients with EWS. The primary objective of this portion of the study is to determine whether the addition of palbociclib to irinotecan (IRN) and temozolomide (TMZ) will prolong event-free survival (EFS) of pediatric and young adult patients with recurrent or refractory EWS. Methods: Patients with recurrent or refractory EWS are randomized 2:1 to receive either palbociclib in combination with IRN and TMZ or IRN and TMZ alone. Randomization is stratified by type and time of disease recurrence (primary refractory or 1st recurrence <2 years vs. 1st recurrence ≥2 years or 2nd or greater recurrence). The primary efficacy endpoint is EFS per investigator assessment. Secondary efficacy endpoints include objective response, progression-free survival and overall survival. An interim futility analysis will be conducted to allow for early stopping of the study due to futility/no signal of activity based on the primary endpoint of EFS. Safety and planned interim efficacy data will be assessed by an Independent Data Monitoring Committee (DMC). Key eligibility criteria include: recurrent or refractory EWS with evaluable disease, no known bone marrow metastases, histopathological confirmation of EWSR1-ETS or FUS-ETS rearrangement or availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing, age ≥2 and <21 years at the time of study entry. Treatment intervention: Patients randomized to palbociclib with IRN and TMZ treatment arm will receive palbociclib at the RP2D of 75 mg/m2 orally (either as a capsule or oral solution) once daily on Days 1-14 of each 21-day treatment cycle. TMZ will be administered orally once daily at 100 mg/m2 on Days 1-5 (intravenously (IV) if patient cannot swallow the TMZ capsule). IRN will be administered IV at 50 mg/m2 on Days 1-5. Patients randomized to the chemotherapy only treatment arm will receive IRN and TMZ at the same doses on Days 1-5 of the 21-day treatment cycle. Treatment will continue until disease progression, patient and/or legal guardian refusal, unacceptable toxicity , or up to 24 months of treatment, whichever occurs first. The Phase 2 enrolment has been initiated and 1/75 patients has been enrolled as of Jan 2022. Clinical trial information: NCT03709680.