Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: A report from the Children's Oncology Group

Abstract

Purpose This phase 2 study was designed to assess the efficacy of single agent cixutumumab (IMC-A12) and gain further information about associated toxicities and pharmacodynamics in children, adolescents, and young adults with recurrent or refractory solid tumors. Patients and Methods Patients with relapsed or refractory solid tumors were treated with 9 mg/kg of cixutumumab as a 1-hour IV infusion once weekly. Strata included: osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma (evaluable disease), neuroblastoma (measurable disease), Wilms tumor, adrenocortical carcinoma, synovial sarcoma, hepatoblastoma, and retinoblastoma. Correlative studies in consenting patients included an assessment of c-peptide, IGFBP-3, IGF-1, IGF-2, hGH, and insulin in consenting patients. Results One hundred and sixteen patients with 114 eligible having a median age of 12 years (range, 2-30) were enrolled. Five patients achieved a partial response: 4/20 with neuroblastoma (evaluable only) and 1/20 with rhabdomyosarcoma. Fourteen patients had stable disease for a median of 10 cycles. Hematologic and non-hematologic toxicities were generally mild and infrequent. Serum IGF-1 and IGFBP-3 increased in response to therapy with cixutumumab. Conclusion Cixutumumab is well tolerated in children with refractory solid tumors. Limited objective single-agent activity of cixutumumab was observed; however, prolonged stable disease was observed in 15% of patients. Ongoing studies are evaluating the toxicity and benefit of cixutumumab in combination with other agents that inhibit the IGF pathway.

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

“…Monotherapy trials of anti-IGF-1R antibodies and TKIs have generally reported disease stabilisation and minor responses, with few objective responses in common cancers [34–38]. There is, however, evidence of activity in heavily pre-treated Ewing sarcoma (EWS), other types of sarcomas, and neuroendocrine tumors, although data in the latter are conflicting [32,39–44]. In addition, IGF-1R antibodies were recently reported to have single agent activity in recurrent ovarian cancer and relapsed thymoma, although thymoma treatment was associated with the development of autoimmune conditions including red cell aplasia [45,46].…”

Adrenocortical carcinoma: The management of metastatic disease

“…Notably, 10 patients with ACC were treated with cixutumumab alone in a phase II study and no objective responses were reported. One patient achieved SD for 7 cycles 83 . In addition, a small-molecule TKI of the IGF-IR (OSI-906) is being investigated.…”

Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

“…Unfortunately, the preclinical anti-RMS activity of targeted agents such as mTOR inhibitors (Hosoi et al 1999) and neutralizing IGF1 receptor antibodies (Mayeenuddin et al 2010) have not translated thus far into durable objective response rates in early-phase clinical trials (Geoerger et al 2012;Pappo et al 2014;Weigel et al 2014). However, improved event-free survival of individuals with relapsed RMS after treatment with the mTOR inhibitor temsirolimus in combination with vinorelbine and cyclophosphamide supports experimental strategies involving combinations of targeted agents and established drugs (Mascarenhas et al 2014).…”