Brain Stem NeoplasmsPhase 1NCT01182883
A Phase I Study of IMC-A12 in Combination With Temsirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors
A Phase 1 study testing IMC-A12 and Temsirolimus in people with Brain Stem Neoplasms and Glioma, run by National Cancer Institute (NCI).
Trial 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. Read more about this study
- Who is it for?
- Ages 1 year to 21 years
- Conditions the study is for
- Brain Stem Neoplasms, Glioma, Pinealoma
- What is being tested?
- IMC-A12 and Temsirolimus
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 28 Jul 2010to 4 Apr 2012
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
- 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.
About this study
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
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.
Read more
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....
Read the 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.
- Conditions
- Brain Stem Neoplasms, Glioma, Pinealoma
- Being tested
- IMC-A12, Temsirolimus
- Keywords
- Maximum Tolerated Dose, Dose Escalation, Pharmacokinetics, Antitumor Activity, Biologic Activity
- Medical subject headings
- Brain Stem Neoplasms, Glioma, Pinealoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IMC-A12Drug
TemsirolimusDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
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 outcomes (1)
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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Aug 2010 (estimated)
- Study start28 Jul 2010
- Primary completion4 Apr 2012
- Study completion4 Apr 2012 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Brain Stem NeoplasmsStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Investigators
- Dennis D Hickstein, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01182883
- Sponsor's protocol ID
- 100175
- Other IDs
- 10-C-0175
- Status last verified
- 4 Apr 2012
- First submitted
- 14 Aug 2010
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
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.
PubMed 14695208Boulay 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.
PubMed 14729632Majumder 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.
PubMed 15156201
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01182883
- Acronym / sponsor ID
- 100175
- Conditions
- Brain Stem Neoplasms, Glioma, Pinealoma
- Keywords
- Maximum Tolerated Dose, Dose Escalation, Pharmacokinetics, Antitumor Activity, Biologic Activity
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Withdrawn
- Enrolment
- 0 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 28 Jul 2010
- Primary completion
- 4 Apr 2012 (actual)
- Study completion
- 4 Apr 2012 (estimated)
- First posted
- 17 Aug 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 1 year to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IMC-A12 | Drug | – |
| Temsirolimus | Drug | – |
Primary outcome
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.
1 secondary outcome
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.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 14695208Burtrum 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.
- Background: PubMed 14729632Boulay 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.
- Background: PubMed 15156201Majumder 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dennis D Hickstein, M.D. principal investigator
National Cancer Institute (NCI)
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing IMC-A12 and Temsirolimus in people with Brain Stem Neoplasms and Glioma, run by National Cancer Institute (NCI).
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.. The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01182883, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.