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

• Published in: Clinical cancer research 2023-09, Vol.29 (17), p.3329-3339
• Main Authors: Akshintala, Srivandana, Sundby, R Taylor, Bernstein, Donna, Glod, John W, Kaplan, Rosandra N, Yohe, Marielle E, Gross, Andrea M, Derdak, Joanne, Lei, Haiyan, Pan, Alexander, Dombi, Eva, Palacio-Yance, Isabel, Herrera, Kailey R, Miettinen, Markku M, Chen, Helen X, Steinberg, Seth M, Helman, Lee J, Mascarenhas, Leo, Widemann, Brigitte C, Navid, Fariba, Shern, Jack F, Heske, Christine M
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Animals; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Child; Dasatinib - adverse effects; Humans; Insulin-Like Growth Factor I; Maximum Tolerated Dose; Mice; Receptor, IGF Type 1; Rhabdomyosarcoma; src-Family Kinases; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-23-0709

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.