Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma

Background: Ewing sarcoma (EWS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. Cyclin-dependent kinase 4 (CDK4) is a genomic vulnerability in EWS that is synergistic with IGF-1R inhibition in preclinical studies. We present the results of a phase 2 study combining palbociclib (CDK4/6 inhibitor) with ganitumab (IGF-1R monoclonal antibody) for patients with relapsed EWS.

Patients and methods: This open-label, non-randomized, phase 2 trial enrolled patients ≥12 years with relapsed EWS. All patients had molecular confirmation of EWS and RECIST measurable disease. Patients initially received palbociclib 125 mg orally on Days 1-21 and ganitumab 18 mg/kg intravenously on Days 1 and 15 of a 28-day cycle. The primary endpoints were objective response (complete or partial) per RECIST and toxicity by CTCAE. An exact one-stage design required ≥4 responders out of 15 to evaluate an alternative hypothesis of 40% response rate against a null of 10%. The study was closed following enrollment of the 10th patient due to discontinuation of ganitumab supply.

Results: Ten evaluable patients enrolled [median age 25.7 years (range 12.3-40.1)]. The median duration of therapy was 2.5 months (range 0.9-10.8). There were no complete or partial responders. Three of 10 patients had stable disease for >4 cycles and 2 had stable disease at completion of planned therapy or study closure. Six-month progression-free survival was 30% (95% CI 1.6%-58.4%). Two patients had cycle 1 hematologic dose-limiting toxicities (DLTs) triggering palbociclib dose reduction to 100 mg daily for 21 days. Two subsequent patients had cycle 1 hematologic DLTs at the reduced dose. Eighty percent of patients had grade 3/4 AEs, including neutropenia (n = 8), white blood cell decreased (n = 7), and thrombocytopenia (n = 5). Serum total IGF-1 significantly increased (p = 0.013) and ctDNA decreased during the first cycle.

Conclusions: This combination lacks adequate therapeutic activity for further study, though a subset of patients had prolonged stable disease.