A Phase I Study of IMC-A12 in Combination With Temsirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors
Primary Purpose
Brain Stem Neoplasms, Glioma, Pinealoma
Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
IMC-A12
Temsirolimus
Sponsored by
About this trial
This is an interventional treatment trial for Brain Stem Neoplasms focused on measuring Maximum Tolerated Dose, Dose Escalation, Pharmacokinetics, Antitumor Activity, Biologic Activity
Eligibility Criteria
- 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.
Sites / Locations
Outcomes
Primary Outcome Measures
To determine the MTD and recommended Phase II dose of IMC-A12 (anti-IGFR monoclonal antibody) IV once weekly in combination with temsirolimus IV weekly to children with refractory solid tumors.
To define toxicities and characterize pharmacokinetics.
Secondary Outcome Measures
Define in a preliminary fashion antitumor activity, assess biologic activity of IMC-A12 and temsirolimus and assess the incidence of IGFR expression and mTOR pathway activation in recurrent or refractory solid tumors of childhood.
Full Information
NCT ID
NCT01182883
First Posted
August 14, 2010
Last Updated
June 30, 2017
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT01182883
Brief Title
A Phase I Study of IMC-A12 in Combination With Temsirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors
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
Study Type
Interventional
2. Study Status
Record Verification Date
April 4, 2012
Overall Recruitment Status
Withdrawn
Study Start Date
July 28, 2010 (undefined)
Primary Completion Date
April 4, 2012 (Actual)
Study Completion Date
April 4, 2012 (Anticipated)
3. Sponsor/Collaborators
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
5. Study Description
Brief Summary
Background:
- IMC-A12 is an experimental substance designed to inhibit a protein called Type I Insulin-Like Growth Factor Receptor (IGF-1R), which can be found on cancer cells and can promote cancer growth. Temsirolimus is a drug that the U.S. Food and Drug Administration has approved to treat advanced renal cell carcinoma in adults. Researchers do not know if the combination of IMC-A12 and temsirolimus will work in children, but want to determine whether these two drugs may be an effective treatment for recurrent tumors.
Objectives:
To determine the safety and effectiveness of IMC-A12 and temsirolimus in treating children and adolescents with solid tumors.
To determine possible side effects of the combination of IMC-A12 and temsirolimus.
Eligibility:
- Children and adolescents between 12 months and 21 years of age who have solid tumors that have not responded to or have relapsed after standard treatment.
Design:
Participants will be screened with a medical history, physical examination, and imaging studies.
Participants will receive IMC-A12 and temsirolimus in 28-day cycles of treatment. IMC-A12 will be given as an infusion over 1 hour, once a week, for 4 weeks. Temsirolimus will also be given after IMC-A12 over 30 minutes, once a week, for 4 weeks.
Participants may continue to receive IMC-A12 and temsirolimus for up to 2 years unless serious side effects develop or the treatment stops being effective.
Participants will have additional physical exams, blood and urine tests, and imaging studies regularly during each treatment cycle.
Participants will be followed at regular intervals after the end of the study to collect tumor response and progression data....
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain Stem Neoplasms, Glioma, Pinealoma
Keywords
Maximum Tolerated Dose, Dose Escalation, Pharmacokinetics, Antitumor Activity, Biologic Activity
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Intervention Type
Drug
Intervention Name(s)
IMC-A12
Intervention Type
Drug
Intervention Name(s)
Temsirolimus
Primary Outcome Measure Information:
Title
To determine the MTD and recommended Phase II dose of IMC-A12 (anti-IGFR monoclonal antibody) IV once weekly in combination with temsirolimus IV weekly to children with refractory solid tumors.
Title
To define toxicities and characterize pharmacokinetics.
Secondary Outcome Measure Information:
Title
Define in a preliminary fashion antitumor activity, assess biologic activity of IMC-A12 and temsirolimus and assess the incidence of IGFR expression and mTOR pathway activation in recurrent or refractory solid tumors of childhood.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dennis D Hickstein, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
12. IPD Sharing Statement
Citations:
PubMed Identifier
14695208
Citation
Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS, Bassi R, Abdullah R, Hooper AT, Koo H, Jimenez X, Johnson D, Apblett R, Kussie P, Bohlen P, Witte L, Hicklin DJ, Ludwig DL. A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res. 2003 Dec 15;63(24):8912-21.
Results Reference
background
PubMed Identifier
14729632
Citation
Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, Tobler S, Heusser C, O'Reilly T, Stolz B, Marti A, Thomas G, Lane HA. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 2004 Jan 1;64(1):252-61. doi: 10.1158/0008-5472.can-3554-2.
Results Reference
background
PubMed Identifier
15156201
Citation
Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med. 2004 Jun;10(6):594-601. doi: 10.1038/nm1052. Epub 2004 May 23.
Results Reference
background
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A Phase I Study of IMC-A12 in Combination With Temsirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors
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