(P 556) EVALUATION OF PALBOCICLIB (IBRANCE®) IN COMBINATION WITH CHEMOTHERAPY IN PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY EWING SARCOMA OR NEUROBLASTOMA

Objective: Palbociclib is an orally administered, highly selective, reversible, small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4 are critical for Ewing sarcoma (EWS) cell-line proliferation. Preclinical studies in EWS patient-derived xenograft models suggested potential antitumor benefit of adding palbociclib to irinotecan/temozolomide (IRN/TMZ) chemotherapy. Preclinical models also showed that palbociclib reduced growth of neuroblastoma (NBL) cell lines, induced G1 cell-cycle arrest, and inhibited the cyclin D1-Rb pathway. The phase 1 portion of the study for pediatric and young adult patients with recurrent/refractory (R/R) solid and central nervous system tumors established the recommended phase 2 dose (RP2D) of palbociclib in combination with IRN/TMZ and in combination with topotecan (TOPO) and cyclophosphamide (CTX). The study is now enrolling 2 cohorts: 1) a randomized, open-label, phase 2 cohort for patients with R/R EWS to determine whether the addition of palbociclib to IRN/TMZ prolongs event-free survival (EFS) and 2) a nonrandomized single-arm cohort for patients with R/R NBL to confirm the safety and evaluate the preliminary antitumor activity of palbociclib with TOPO/CTX.

Methods: R/R EWS Cohort
Patients with R/R EWS are randomly assigned 2:1 to receive either palbociclib with IRN/TMZ or IRN/TMZ alone. The primary efficacy endpoint is EFS per investigator assessment. Secondary efficacy endpoints include EFS by independent review, objective response (OR), progression-free survival (PFS), and overall survival (OS). An interim futility analysis is planned to allow for early stopping of the study due to futility/no signal of activity based on investigator-assessed EFS. Safety and planned interim efficacy data will be assessed by an external Data Monitoring Committee.
Key eligibility criteria include R/R EWS with at-least-evaluable disease in ≥1 site other than bone marrow, molecular confirmation of EWS R1-ETS or FUS-ETS rearrangement or availability of formalin-fixed paraffin-embedded tumor tissue sample for central testing, and age ≥2 and < 21 years at the time of study entry. Patients could have received prior IRN and/or TMZ if their disease did not progress on this regimen.
Patients randomly assigned to the palbociclib with IRN/TMZ arm will receive palbociclib at the RP2D (75 mg/m2) orally (either as a capsule or oral solution) once daily on days 1–14 of each 21-day treatment cycle. IRN (50 mg/m2) will be administered intravenously (IV), and TMZ (100 mg/m2) will be given orally (IV if patient cannot swallow the TMZ capsule), both once daily on days 1–5. Patients randomly assigned to the IRN/TMZ-only arm will receive IRN/TMZ at the same doses and schedule.

NBL Cohort
Patients with R/R NBL will receive palbociclib with TOPO/CTX. The primary efficacy endpoint is objective response, as assessed by investigator using International Neuroblastoma Response Criteria (INRC). Secondary efficacy endpoints include duration of response, PFS, and OS. Preliminary antitumor activity will be evaluated using a modified Simon’s 2-stage optimal design.
Key eligibility criteria include R/R NBL, at-least-evaluable disease as defined by INRC, aged ≥2 and < 21 years at the time of study entry, and an adequate organ function and performance status. Patients could have received prior TOPO and/or CTX if their disease did not progress on this regimen. Prior treatment with a CDK4/6 inhibitor is exclusionary.
Patients will receive palbociclib (75 mg/m2) orally once daily on days 1–14 of each 21-day treatment cycle. CTX (250 mg/m2) followed by TOPO (0.75 mg/m2) will be administered IV once daily on days 1–5. Concurrent radiotherapy or surgery for local disease control will be permitted.

Both Cohorts
Treatment will continue until disease progression, patient and/or legal guardian refusal, unacceptable toxicity, or up to 24 months of treatment, whichever occurs first.
As of June 2023, 45 of 75 patients with R/R EWS have been enrolled in the randomized phase 2 EWS cohort and 4 of 21 patients with R/R NBL have been enrolled in the nonrandomized NBL cohort. Enrollment to both cohorts of the study is ongoing.

Results: Not applicable.

Conclusion: Not applicable.