Early results from Children's Oncology Group (COG) ARST08P1: Pilot studies of cixutumumab or temozolomide with intensive multiagent chemotherapy for patients with metastatic rhabdomyosarcoma (RMS)

Background: Data from a previous COG study (ARST0431) showed an early FFS improvement but no long-term survival benefit with intensive interval-compressed chemotherapy in metastatic RMS. ARST08P1 aimed to determine the feasibility of adding cixutumumab (insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody) or temozolomide to an intensive chemotherapy backbone. Methods: A series of non- randomized single-arm pilot studies were conducted. After determining feasibility, pilots were expanded to assess efficacy. Eligible patients were < 50yrs with metastatic RMS. Backbone therapy consisted of blocks of vincristine/irinotecan (weeks 1-6, 20-25, 47-51), interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide (weeks 7-9 and 26-34), and vincristine/actinomycin- D/cyclophosphamide (weeks 38-46). In Pilot 1, patients received cixutumumab (3, 6, or 9 mg/kg) IV once weekly throughout therapy. In Pilot 2, patients received oral temozolomide (100mg/m2) daily x 5 days with irinotecan. Patients received radiation therapy (RT) at weeks 20-25. RT was also permitted at weeks 1-6 or 47-51. Results: 168 eligible patients were enrolled (1/2010 - 7/2013). 71 patients received temozolomide and 97 patients received cixutumumab (19 at 3 mg/kg, 18 at 6 mg/kg, and 60 at 9 mg/kg). Most patients were ≥10 yrs old (73%) with alveolar histology (70%) and with bone and/or bone marrow metastases (59%). Two cases of Grade 4 and one grade 5 sinusoidal obstructive syndrome (SOS) occurred with cixutumumab at 9 mg/kg in combination with the chemotherapy backbone. Otherwise, toxicities were similar to ARST0431. With a median follow-up of 1.6 yrs, 18-month EFS was 68% with cixutumumab and 39% with temozolomide (log rank p- value < 0.001). Conclusions: Addition of cixutumumab or temozolomide to intensive multi-agent chemotherapy for metastatic RMS was safe and feasible. SOS may be a concern with higher doses of cixutumumab combined with intensive chemotherapy. Early FFS was better with cixutumumab than temozolomide. Overall outcome for metastatic RMS remained poor.