Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Monoclonal antibodies, such as cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of cixutumumab when given together with temsirolimus in treating young patients with solid tumors that have recurred or not responded to treatment.

Further Study Information

OBJECTIVES:

Primary

• To estimate the maximum tolerated dose and recommended phase II dose of cixutumumab administered as an intravenous infusion once weekly in combination with temsirolimus administered intravenously once weekly in children with refractory solid tumors.

• To define and describe the toxicities of this regimen.

• To characterize the pharmacokinetics of this regimen in children with refractory cancer.

Secondary

• To preliminarily define the antitumor activity of this regimen within the confines of a phase I study.

• To assess the biologic activity of cixutumumab by assessing changes in IGFR expression and phosphorylation and insulin-receptor expression and phosphorylation in peripheral blood mononuclear cells (PBMNC).

• To assess the biological activity of temsirolimus by measuring levels of S6K1, AKT, eIF4G, and associated phosphoproteins in PBMNC.

• To assess the incidence of IGFR expression as well as mTOR pathway activation in these patients.

OUTLINE: This is a multicenter study.

Patients receive cixutumumab IV over 60 minutes and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity.

Blood samples are collected periodically for pharmacokinetic, pharmacodynamic, immunogenic, and other correlative studies. Samples are analyzed for IGF-1, IGF-2, IGF-BP3, growth hormone, insulin, C-peptides; S6K1, AKT, and associated phosphoproteins; and IGF-1R and insulin-receptor expression and phosphorylation by immunoprecipitation and western immunoblotting. Tumor tissue studies are conducted to assess the incidence of IGFR expression as well as mTOR pathway activation.

After completion of study therapy, patients are followed periodically.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumor

• Recurrent or refractory disease

• Histologic confirmation may have been made at original diagnosis or relapse

• Histologic confirmation not required for intrinsic brain stem tumors, optic pathway gliomas, or pineal tumors with elevations of serum or CSF alpha-fetoprotein or beta-HCG

• Slides or tissue blocks from either initial diagnosis or relapse must be available

• No known curative therapy or therapy proven to prolong survival with an acceptable quality of life

• Measurable or evaluable disease

• No known bone marrow involvement

• Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled

• Neurologic deficits in patients with CNS tumors must have been clinically stable for ≥ the past week

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 50-100% (patients > 16 years of age) or Lansky PS 50-100% (patients ≤ 16 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

• ANC ≥ 1,000/mm³*

• Platelet count ≥ 100,000/mm³* (transfusion independent)

• Hemoglobin ≥ 8.0 g/dL* (may receive RBC transfusions) NOTE: * Unless due to bone marrow involvement by tumor.

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age/gender as follows:

• 0.6 mg/dL (for patients 1 year of age)

• 0.8 mg/dL (for patients 2 to 5 years of age)

• 1 mg/dL (for patients 6 to 9 years of age)

• 1.2 mg/dL (for patients 10 to 12 years of age)

• 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age)

• 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients ≥ 16 years of age)

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

• ALT ≤ 110 U/L

• Serum albumin ≥ 2 g/dL

• Serum cholesterol and serum triglyceride levels < grade 2

• PT and INR < 1.2 times ULN

• Seizure disorder may be allowed provided well controlled on anticonvulsants

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 3 months after completion of study treatment

• Random or fasting blood glucose normal for age

• No uncontrolled infection

• No known type I or II diabetes mellitus

• No patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cixutumumab or temsirolimus

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• See Patient Characteristics

• Fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy

• At least 2 months since prior stem cell transplant or rescue and no evidence of active graft-versus-host-disease

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

• More than 6 weeks since prior major surgery

• Patients with history of recent minor surgical procedures (e.g., vascular catheter placement, bone marrow evaluation, laparoscopic surgery) are eligible

• At least 7 days since prior hematopoietic growth factors that support platelet or white cell number or function

• At least 7 days since prior therapy with a biologic (antineoplastic) agent

• At least 6 weeks since prior monoclonal antibodies

• Patients receiving corticosteroids must be on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment

• At least 2 weeks since prior local palliative radiation therapy (small port)

• At least 3 months since prior total-body irradiation, craniospinal radiation therapy, or radiation to ≥ 50% of pelvis

• At least 6 weeks since other prior substantial bone marrow radiation therapy

• No prior temsirolimus or monoclonal antibody therapy targeting IGF-1R

• No concurrent systemic warfarin for anticoagulation therapy

• Low-dose warfarin for maintaining patency of central venous catheter allowed

• No concurrent insulin or growth hormone therapy

• No concurrent enzyme-inducing anticonvulsants

• No concurrent potent CYP3A4 inducers or inhibitors (i.e., erythromycin, clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice, or St. John wort)

• No other concurrent investigational agents

• No other concurrent anticancer therapy, including chemotherapy, radiation therapy, immunotherapy, or biologic therapy

Trial Contact Information

Trial Lead Organizations/Sponsors

Children's Oncology Group

Maryam Fouladi

Study Chair

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00880282
Information obtained from ClinicalTrials.gov on November 20, 2012