1. Phase I trial of Ganitumab plus Dasatinib to Cotarget the Insulin-Like Growth Factor 1 Receptor and Src Family Kinase YES in Rhabdomyosarcoma.
- Author
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Akshintala S, Sundby RT, Bernstein D, Glod JW, Kaplan RN, Yohe ME, Gross AM, Derdak J, Lei H, Pan A, Dombi E, Palacio-Yance I, Herrera KR, Miettinen MM, Chen HX, Steinberg SM, Helman LJ, Mascarenhas L, Widemann BC, Navid F, Shern JF, and Heske CM
- Subjects
- Humans, Animals, Mice, Child, Adolescent, Young Adult, Adult, Dasatinib adverse effects, Insulin-Like Growth Factor I, Receptor, IGF Type 1, Antineoplastic Combined Chemotherapy Protocols adverse effects, Maximum Tolerated Dose, src-Family Kinases, Rhabdomyosarcoma
- Abstract
Purpose: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701)., Patients and Methods: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT)., Results: Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response., Conclusions: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months., (©2023 American Association for Cancer Research.)
- Published
- 2023
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