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

Autor: Shulman DS; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA., Merriam P; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA., Choy E; Massachusetts General Hospital, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA., Guenther LM; St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Cavanaugh KL; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA., Kao PC; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA., Posner A; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA., Bhushan K; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA., Fairchild G; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA., Barker E; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA., Klega K; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA., Stegmaier K; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA., Crompton BD; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA., London WB; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA., DuBois SG; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Cancer medicine [Cancer Med] 2023 Jul; Vol. 12 (14), pp. 15207-15216. Date of Electronic Publication: 2023 Jun 12.
DOI: 10.1002/cam4.6208
Abstrakt: 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.
(© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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