Cixutumumab and Temsirolimus in Treating Younger Patients With Solid Tumors That Have Recurred or Not Responded to Treatment

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00880282
First received: April 10, 2009
Last updated: September 27, 2013
Last verified: September 2013
  Purpose

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


Condition Intervention Phase
Recurrent Childhood Brain Stem Glioma
Recurrent Childhood Brain Tumor
Unspecified Childhood Solid Tumor, Protocol Specific
Biological: cixutumumab
Drug: temsirolimus
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum-tolerated dose and recommended phase II dose based on the incidence of dose-limiting toxicity (DLT) as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Toxicities as assessed by the NCI CTCAE version 4.0 [ Time Frame: Up to 30 days after the last dose of treatment ] [ Designated as safety issue: Yes ]
  • Pharmacokinetics (PK) of cixutumumab [ Time Frame: At end of infusion, at 1, 3, 6, and 24 hours, days 1, 4, 8, 15, 22, and 28 (of course 1), and days 15 and 28 (of course 2) ] [ Designated as safety issue: No ]
    The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

  • Pharmacokinetics of temsirolimus [ Time Frame: At end of infusion, at 15 and 30 minutes, at 1, 3, 6, and 24 hours, days 1, 4, 7, and 28 (of course 1), and days 15 and 28 (course 2) ] [ Designated as safety issue: No ]
    The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).


Secondary Outcome Measures:
  • Disease response according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Reported descriptively.

  • Change IGFR and insulin receptor expression [ Time Frame: From baseline to up to 28 days (of course 1) ] [ Designated as safety issue: No ]
    Summary statistics and descriptive plots will be generated for IGFR expression. The changes will be assessed using paired t-test or Wilcoxon matched pairs signed rank sum test when appropriate.

  • Change in levels of S6K1, AKT, eIF4G, and associated phosphoproteins [ Time Frame: From baseline to up to 28 days (of course 1) ] [ Designated as safety issue: No ]
    Summary statistics and descriptive plots will be generated. The changes will be assessed using paired t-test or Wilcoxon matched pairs signed rank sum test when appropriate.

  • Incidence of IGFR expression as well as mTOR pathway activation [ Time Frame: At baseline ] [ Designated as safety issue: No ]

Enrollment: 40
Study Start Date: April 2009
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (cixutumumab, temsirolimus)
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.
Biological: cixutumumab
Given IV
Other Names:
  • anti-IGF-1R recombinant monoclonal antibody IMC-A12
  • IMC-A12
Drug: temsirolimus
Given IV
Other Names:
  • CCI-779
  • cell cycle inhibitor 779
  • Torisel
Other: pharmacological study
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. 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.

II. To define and describe the toxicities of this regimen. III. To characterize the pharmacokinetics of this regimen in children with refractory cancer.

SECONDARY OBJECTIVES:

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

II. 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).

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

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

OUTLINE:

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.

After completion of study therapy, patients are followed up periodically.

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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
  • 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)
  • 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
  • No other concurrent investigational agents
  • No other concurrent anticancer therapy, including chemotherapy, radiation therapy, immunotherapy, or biologic therapy
  • 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)
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00880282

  Show 22 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Maryam Fouladi Children's Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00880282     History of Changes
Other Study ID Numbers: NCI-2011-01910, NCI-2011-01910, COG-ADVL0813, CDR0000639150, ADVL0813, ADVL0813, U01CA097452
Study First Received: April 10, 2009
Last Updated: September 27, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Brain Neoplasms
Glioma
Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antibodies
Antibodies, Monoclonal
Sirolimus
Everolimus
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on April 17, 2014