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Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma
David S Shulman1, Priscilla Merriam2, Edwin Choy3
1Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA.
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.
Insights
This phase 2 trial combining palbociclib and ganitumab for relapsed Ewing sarcoma (EWS) showed no objective responses. The combination therapy demonstrated limited efficacy and significant toxicity in EWS patients.
Area of Science:
- Oncology
- Pharmacology
Background:
- Ewing sarcoma (EWS) is an aggressive cancer with limited treatment options for relapsed cases.
- Cyclin-dependent kinase 4 (CDK4) is a known genomic vulnerability in EWS.
- Preclinical studies suggest synergy between CDK4/6 inhibition and IGF-1R inhibition.
Purpose of the Study:
- To evaluate the efficacy and safety of combining palbociclib (a CDK4/6 inhibitor) with ganitumab (an IGF-1R monoclonal antibody) in patients with relapsed EWS.
- To determine the objective response rate and toxicity profile of this combination therapy.
Main Methods:
- An open-label, non-randomized, phase 2 trial enrolled 10 patients with relapsed EWS.
- Patients received oral palbociclib and intravenous ganitumab on a 28-day cycle.
- Primary endpoints included objective response by RECIST and toxicity by CTCAE.
Main Results:
- No complete or partial responses were observed in the 10 evaluable patients.
- Three patients achieved stable disease for over 4 cycles; two had stable disease at study closure.
- Six-month progression-free survival was 30%. Grade 3/4 adverse events, including neutropenia, occurred in 80% of patients.
Conclusions:
- The combination of palbociclib and ganitumab demonstrated inadequate therapeutic activity for further investigation in relapsed EWS.
- While lacking overall efficacy, a subset of patients experienced prolonged stable disease.
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