IMC-A12 in Treating Young Patients With Relapsed or Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor or Other Solid Tumor
IMC-A12 in Treating Young Patients With Relapsed or Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor or Other Solid Tumor
This phase I clinical trial is studying the side effects and best dose of IMC-A12 in treating
 young patients with relapsed or refractory Ewing sarcoma/peripheral primitive neuroectodermal
 tumor or other solid tumors. Monoclonal antibodies, such as IMC-A12, can block cancer growth
 in different ways. Some block the ability of cancer cells to grow and spread. Others find
 cancer cells and help kill them or carry cancer-killing substances to them.
PRIMARY OBJECTIVES:

 I. To estimate the maximum tolerated dose (MTD) or recommended phase II dose of IMC-A12
 (cixutumumab) in children with relapsed or refractory solid tumors using a limited
 dose-escalation strategy.

 II. To define and describe the toxicities of this drug in children with relapsed or
 refractory solid tumors.

 III. To characterize the pharmacokinetics of this drug in children with relapsed or
 refractory solid tumors.

 SECONDARY OBJECTIVES:

 I. To preliminarily define the antitumor activity of this drug in children with relapsed or
 refractory solid tumors within the confines of a phase I study.

 II. To obtain initial phase II efficacy data on the antitumor activity of this drug in
 children with Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET).

 III. To examine change in IGF-IR and insulin receptor (IR) levels and IGF-IR and IR
 activation in lymphocytes as biomarkers of IMC-A12 action and specificity.

 IV. To evaluate the effect of this drug on circulating levels of proteins involved in linear
 growth and glucose homeostasis, including IGF-I, IGF-II, IGF-BP3, growth hormone, insulin,
 and C-peptide.

 V. To develop exploratory data concerning biomarkers of activity.

 OUTLINE: This is a dose-escalation study.

 Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every
 4 weeks for up to 2 years in the absence of unacceptable toxicity or disease progression.

 Patients undergo blood sample collection periodically for pharmacokinetic, immunogenicity,
 and other correlative studies. Samples are analyzed for serum levels of IGF-I, IGF-II,
 IGF-BP3, growth hormone, insulin, and C-peptide; trough concentrations and PK sampling; and
 biomarkers, including IGF-IR expression and phosphorylation and insulin receptor expression
 and phosphorylation via immunoprecipitation and Western immunoblotting. Tumor tissue samples
 from patients with Ewing sarcoma/peripheral PNET are banked for future research.

 After completion of study treatment, patients are followed at 30 days.
Inclusion Criteria:

 -  Histologically confirmed solid tumor

 -  Relapsed or refractory disease

 -  No central nervous system (CNS) tumor or lymphoma

 -  Histological confirmation may have been made at original diagnosis or at relapse

 -  Current disease state must be one for which there is no known curative therapy or
 therapy proven to prolong survival with an acceptable quality of life

 -  Measurable or evaluable disease

 -  Patients with Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET) must
 have tissue blocks or slides available

 -  Study chair must be notified if tissue blocks or slides are not available

 -  Karnofsky performance status (PS) ≥ 50% (patients > 10 years of age) and Lansky (PS) ≥
 50% (patients ≤ 10 years of age)

 -  Patients who are unable to walk because of paralysis, but who are up in a
 wheelchair, will be considered ambulatory for the purpose of assessing the
 performance score

 -  Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on
 age/gender as follows:

 -  1 to < 2 years (males and females 0.6 mg/dL)

 -  2 to < 6 years (males and females 0.8 mg/dL)

 -  6 to < 10 years (males and females 1.0 mg/dL)

 -  10 to < 13 years (males and females 1.2 mg/dL)

 -  13 to < 16 years (males 1.5 mg/dL and females 1.4 mg/dL)

 -  ≥ 16 years (males 1.7 mg/dL and females 1.4 mg/dL)

 -  Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age

 -  SGPT (ALT) ≤ 110 μ/L (for the purpose of this study, the ULN for SGPT is 45 μ/L)

 -  Serum albumin ≥ 2 g/dL

 -  Patients with known bone marrow metastatic disease will be eligible for study but not
 evaluable for hematologic toxicity

 -  Patients must not be known to be refractory to red cell or platelet transfusion

 -  Patients with solid tumors without bone marrow involvement must meet the following
 criteria:

 -  Peripheral absolute neutrophil count ≥ 1,000/μL

 -  Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving
 platelet transfusions within a 7 day period prior to enrollment)

 -  Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception during and for 3 months after
 completion of study therapy

 -  No uncontrolled infection

 -  No known type I or type II diabetes mellitus

 -  Able to comply with the safety monitoring requirements of the study, in the opinion of
 the investigator

 -  No history of allergic reactions attributed to compounds of similar chemical or
 biologic composition to IMC-A12

 -  Fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy,
 or radiotherapy prior to entering this study

 -  At least 7 days since prior and no concurrent hematopoietic growth factors

 -  Growth factors that support platelet or white cell number or function can only be
 administered for culture-proven bacteremia or invasive fungal infection

 -  At least 7 days since prior and no concurrent biologic antineoplastic agents

 -  At least 6 weeks since prior monoclonal antibodies

 -  At least 3 months since prior total body irradiation (TBI), craniospinal external
 radiotherapy (XRT), or ≥ 50% radiotherapy to the pelvis

 -  At least 2 weeks since prior local XRT (small port)

 -  At least 6 weeks since other prior substantial bone marrow radiotherapy

 -  More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea)

 -  More than 7 days since prior and no concurrent systemic corticosteroids

 -  Prior stem cell transplant or rescue allowed provided there has been no evidence of
 active graft-versus-host-disease within the past 2 months

 -  No prior monoclonal antibody therapy targeting the IGF-IR

 -  No concurrent chemotherapy, radiotherapy, or immunotherapy

 -  No concurrent anticancer agents

 -  No concurrent insulin or growth hormone therapy

 -  No other concurrent investigational drugs