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

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 29 Issue 17 Pg. 3329-3339 (09 01 2023) ISSN: 1557-3265 [Electronic] United States
• PMID: 37398992 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: ©2023 American Association for Cancer Research.

Chemical References

• Dasatinib
• ganitumab
• src-Family Kinases
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1

Topics

• Humans
• Animals
• Mice
• Child
• Adolescent
• Young Adult
• Adult
• Dasatinib (adverse effects)
• src-Family Kinases
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1
• Rhabdomyosarcoma
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Maximum Tolerated Dose