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A Phase I Study of IMC-A12 (Anti-Insulin-Like Growth Factor-I Receptor Monoclonal Antibody) in Combination With CCI-779 (Temsirolimus) in Pediatric Patients With Recurrent or Refractory Solid Tumors

Phase 1
1 Year
21 Years
Not Enrolling
Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

A Phase I Study of IMC-A12 (Anti-Insulin-Like Growth Factor-I Receptor Monoclonal Antibody) in Combination With CCI-779 (Temsirolimus) in Pediatric Patients With Recurrent or Refractory Solid Tumors



- 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


- 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

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.

Inclusion Criteria


- 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

- 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


- 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


- 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

Type of Study:


Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum-tolerated dose and recommended phase II dose of cixutumumab and temsirolimus

Safety Issue:


Principal Investigator

Maryam Fouladi, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital Medical Center, Cincinnati


United States: Food and Drug Administration

Study ID:




Start Date:

November 2008

Completion Date:

Related Keywords:

  • Unspecified Childhood Solid Tumor, Protocol Specific
  • unspecified childhood solid tumor, protocol specific
  • Neoplasms



Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Children's Hospital of Orange County Orange, California  92668
Children's National Medical Center Washington, District of Columbia  20010-2970
Children's Hospital and Regional Medical Center - Seattle Seattle, Washington  98105
Children's Memorial Hospital - Chicago Chicago, Illinois  60614
St. Jude Children's Research Hospital Memphis, Tennessee  38105-2794
Midwest Children's Cancer Center at Children's Hospital of Wisconsin Milwaukee, Wisconsin  53226
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas Dallas, Texas  75390
Baylor University Medical Center - Houston Houston, Texas  77030-2399
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute Boston, Massachusetts  02115
C.S. Mott Children's Hospital at University of Michigan Medical Center Ann Arbor, Michigan  48109-0286
Masonic Cancer Center at University of Minnesota Minneapolis, Minnesota  55455
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis St. Louis, Missouri  63110
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center New York, New York  10032
Knight Cancer Institute at Oregon Health and Science University Portland, Oregon  97239-3098
Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania  15213
Riley's Children Cancer Center at Riley Hospital for Children Indianapolis, Indiana  46202-5225
UAB Comprehensive Cancer Center Birmingham, Alabama  35294
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office Bethesda, Maryland  20892-1182