ABSTRACT

The clinical benefit of molecularly targeted agents used as monotherapy is often limited by escape mechanisms that lead to tumor cell resistance. Rational targeting of multiple pathways implicated in both oncogenesis and resistance to therapy may help improve efficacy. Signaling through the mammalian target of rapamycin (mTOR) pathway is important for the growth and survival of many pediatric tumors. However, single-agent activity of mTOR inhibitors may be limited by upstream activation of Akt through the release of feedback inhibition. This upstream activation is dependent in part on signaling through the insulin-like growth factor-1 receptor (IGF-1R), and antibody blockade of IGF-1R can abrogate this escape pathway and synergize with mTOR inhibitors in preclinical models of pediatric solid tumors.

This Phase II study will assess the activity of the combination of the mTOR inhibitor temsirolimus (CCI-779) and the humanized monoclonal IGF-1R antibody cixutumumab (IMC-A12). Building on the experience of the ADVL0813 Phase I trial of this combination, patients will receive once weekly infusions of both agents. Patients with relapsed or refractory tumors will be accrued in the following disease strata: Ewing sarcoma family of tumors, osteosarcoma, rhabdomyosarcoma, and non-rhabdomyosarcoma soft tissue sarcoma. Additional objectives include further characterization of toxicity, assessment of time to disease progression, and identification of tumor biomarkers that may be correlated with tumor responsiveness to these agents.

EXPERIMENTAL DESIGN SCHEMA

This trial will enroll patients with relapsed or refractory rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, and non-rhabdomyosarcoma soft tissue sarcoma who have measurable disease. Patients will receive weekly doses of cixutumumab as a one-hour intravenous infusion immediately followed by temsirolimus as a 30-minute infusion, using doses established from the recently completed COG Phase I trial ADVL0813. For patients who do not experience significant toxicity during Cycle 1, as described in the protocol, a one-time intrapatient dose escalation of temsirolimus will be administered for the second and subsequent cycles. The trial will use a 2-stage design, accruing a maximum of 19 patients per disease stratum depending on responses seen. One treatment cycle will consist of 4 weekly doses of both agents as shown below, and cycles will be repeated for a total of 25 cycles in the absence of disease progression or dose-limiting toxicity.

Day 1   Cixutumumab  Temisorlimus

Day 8   Cixutumumab  Temisorlimus

Day 15 Cixutumumab  Temisorlimus

Day 22 Cixutumumab  Temisorlimus