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.