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ccr-23-0709_supplementary_appendix_s1_suppas1.pdf (1.12 MB)

Supplementary Appendix S1 from Phase I trial of Ganitumab plus Dasatinib to Cotarget the Insulin-Like Growth Factor 1 Receptor and Src Family Kinase YES in Rhabdomyosarcoma

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posted on 2023-07-18, 14:00 authored by Srivandana Akshintala, R. Taylor Sundby, Donna Bernstein, John W. Glod, Rosandra N. Kaplan, Marielle E. Yohe, Andrea M. Gross, Joanne Derdak, Haiyan Lei, Alexander Pan, Eva Dombi, Isabel Palacio-Yance, Kailey R. Herrera, Markku M. Miettinen, Helen X. Chen, Seth M. Steinberg, Lee J. Helman, Leo Mascarenhas, Brigitte C. Widemann, Fariba Navid, Jack F. Shern, Christine M. Heske

Supplemental Protocol Information. A: Study Eligibility; B: Dasatinib dosing nomogram; C: Dasatinib dose modifications

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ARTICLE ABSTRACT

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 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). 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. 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.

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