A Phase I Study of IMC-A12 in Combination With Temsirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors

Background

• IMC-A12 is a fully recombinant IgG1monoclonal antibody to the insulin-like growth factor receptor (IGFR). It acts as an antagonist of IGF-1 and IGF-2 ligand binding and blocks ligand binding to IGF-1R and inhibits downstream signaling of the two major insulin-like growth factor pathways: MAPK and PI3K/AKT.
• Temsirolimus is a small molecule inhibitor of mTOR, which like rapamycin and everolimus forms a complex with FK506-binding protein (FKBP)12 and mTOR, inhibiting mTOR and leading to anti-proliferative effects, including G1 phase cell cycle arrest and apoptosis.
• Inhibition of mTOR signaling leads to upregulation of IGF-1R signaling which leads to activation of the PI3K/AKT/mTOR pathway. Pediatric pre-clinical models have demonstrated synergistic anti-tumor effects combining IGF-1R antibodies and mTOR inhibitors.

Objectives

• To determine the maximum tolerated dose (MTD) and recommended Phase II dose of IMC-A12 (anti-insulin growth factor-1 receptor monoclonal antibody) administered as an intravenous infusion once weekly in combination with temsirolimus administered intravenously once weekly to children with refractory solid tumors.
• To define the toxicities of the combination regimen and characterize the pharmacokinetics of IMC-A12 in combination with temsirolimus in this patient population.
• Secondary objectives include defining in a preliminary fashion antitumor activity, assessing biologic activity of IMC-A12 and temsirolimus and assessing the incidence of IGFR expression and mTOR pathway activation in recurrent or refractory solid tumors of childhood.

Eligibility

• Patients > 12 months and less than or equal to 21 years of age with a diagnosis and histologic verification (except patients with intrinsic brain stem tumors, optic pathway gliomas or pineal tumors and elevations of serum or CSF alpha-fetoprotein or beta-HCG) of measureable or evaluable relapsed or refractory solid tumors. Current disease state must be one for which there is no known curative therapy, or therapy proven to prolong survival.
• Must have fully recovered from acute toxic effects from all prior therapy, which has been completed within the specified prior time frame.
• Have adequate organ function as determined by laboratory evaluation including normal random or fasting blood glucose within the upper normal limits for age and grade \< 2 serum cholesterol and triglyceride levels.
• Subjects with uncontrolled infection, known type I or type II diabetes mellitus, known bone marrow involvement or who have received prior monoclonal antibody therapy targeting IGF-1R or temsirolimus are not eligible.

Design

• This is a phase I study of IMC-A12 administered every 7 days as a 1-hour intravenous infusion at a starting dose of 6 mg/kg. Temsirolimus will be administered intravenously over 30 minutes immediately after IMC-A12 on a once weekly schedule, at a starting dose of 15 mg/m(2).
• One cycle of therapy is considered to be 28 days. Therapy may continue for up to 2 years in the absence of progressive disease or unacceptable toxicity.
• All patients will have required trough blood samples for pharmacokinetic analysis of IMC-A12 and temsirolimus and immunogenicity studies collected at the same time as select routine safety labs. Optional participation in additional pharmacokinetic studies and correlative biology studies will be offered.