Results of a phase I trial of ganitumab plus dasatinib in patients with rhabdomyosarcoma (RMS).
Authors: Akshintala Srivandana , Bernstein Donna , Glod John , Kaplan Rosandra N. , Shern John Frederick , Yohe Marielle Elizabeth , Gross Andrea M. , Derdak Joanne , Dombi Eva , Palacio-Yance Isabel , Herrera Kailey Rebecca , Levi Abrahm , Miettenen Markku , Steinberg Seth M. , Helman Lee J. , Mascarenhas Leo , Widemann Brigitte C. , Navid Fariba , Heske Christine M 
Published: June 2022

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Background: Antibodies against the insulin-like growth factor type 1 receptor (IGF1-R) have shown transient objective partial responses (PR) in patients with RMS followed by rapid development of resistance. Preclinical data demonstrate that activation of the SRC family kinase YES acts as a bypass resistance mechanism to IGF-1R targeting. Co-targeting IGF-1R and YES results in sustained responses in murine RMS models. We developed a phase I/II trial of the anti-IGF-1R antibody ganitumab combined with the multi-kinase inhibitor dasatinib in patients with RMS (NCT03041701). During the phase II part of the study, ganitumab became unavailable, and the trial was terminated early. We report here the results of the completed phase I study. Methods: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. A 3+3 dose escalation design was used to determine the maximum tolerated dose (MTD), and evaluable patients were assessed for response using RECISTv1.1 criteria. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib was administered orally on a continuous schedule. Dose level (DL)1 was 60 mg/m2/dose (max 100 mg) once daily; DL2 was 60 mg/m2/dose (max 70 mg) twice daily. MTD was determined based on cycle 1 dose-limiting toxicities (DLTs) and responses were assessed every 2 cycles. Results: Thirteen eligible patients (5M, 8F), median age 18 years (range 8-29 years) with embryonal (n = 6) and alveolar (n = 7) RMS were enrolled at DL1 (n = 7) and DL2 (n = 6). Median number of prior systemic therapies was 3 (range 1-6), all had received prior radiation, 5 prior surgery, and 2 prior high dose chemotherapy with stem cell rescue. Of 11 patients evaluable for toxicity, 1/6 had a DLT at DL1 (grade 3 diarrhea) and 2/5 had DLTs at DL2 (grade 3 pneumonitis and grade 3 hematuria) confirming DL1 as MTD. Common non-DLTs at least possibly attributed to dasatinib, ganitumab, or both included thrombocytopenia (n = 12), anemia (n = 10), lymphopenia (n = 8), hypophosphatemia (n = 7), hypocalcemia (n = 6), elevated transaminases (n = 5), fatigue (n = 5), nausea (n = 5), and vomiting (n = 5). The most common grade 3-4 adverse events were cytopenias and electrolyte abnormalities. Of 9 patients evaluable for response, 1 had a confirmed PR at DL2 sustained for 5 cycles, and 1 had prolonged stable disease (SD) for 6 cycles at DL1. Patients received a median of 1.5 cycles (range 0-6). Analysis of correlative biology studies of ctDNA and target expression are ongoing. Conclusions: The combination of dasatinib and ganitumab was safe and tolerable at DL1 in patients with relapsed and refractory RMS. Once daily dasatinib at 60 mg/m2/dose (max 100 mg) combined with 18 mg/kg ganitumab every 2 weeks was determined to be the MTD. PR and SD for > 4 months were observed in this phase I trial suggesting that the addition of a YES-targeting agent may delay the development of acquired resistance to IGF-1R antibody therapy in RMS. Clinical trial information: NCT03041701.