Multi-institutional Phase II Study of IMC-A12, a Recombinant Human IgG1/λ Monoclonal Antibody Directed at the Type I Insulin-Like Growth Factor Receptor (IGF-1R), in Adrenocortical Carcinoma: A Randomized Trial Comparing the Activity of IMC-A12 With Mitotane Versus Mitotane Alone.
18 Years
N/A
Both
Recurrent Adrenocortical Carcinoma, Stage III Adrenocortical Carcinoma, Stage IV Adrenocortical Carcinoma
Trial Information
Multi-institutional Phase II Study of IMC-A12, a Recombinant Human IgG1/λ Monoclonal Antibody Directed at the Type I Insulin-Like Growth Factor Receptor (IGF-1R), in Adrenocortical Carcinoma: A Randomized Trial Comparing the Activity of IMC-A12 With Mitotane Versus Mitotane Alone.
PRIMARY OBJECTIVES:
I. Compare the progression-free survival (PFS) rate in patients with recurrent, metastatic,
or primary unresectable adrenocortical carcinoma treated with mitotane with vs without
anti-IGF-1R recombinant monoclonal antibody IMC-A12 (IMC-A12).
SECONDARY OBJECTIVES:
I. Compare the response rates in these patients using Response Evaluation Criteria in Solid
Tumor (RECIST) criteria.
II. Compare the change in tumor size from baseline to 12 weeks in these patients.
III. Compare the overall trajectories in tumor growth in these patients.
TERTIARY OBJECTIVES:
I. Define predictive markers of response or insensitivity to IMC-A12. II. Define
pharmacodynamic markers of IMC-A12. III. Determine whether tumor expression of IGF-IR and
activation of downstream signaling in archival tumor tissue samples predict efficacy of
IMC-A12.
OUTLINE: This is a multicenter study that includes a single-arm safety evaluation phase
followed by a randomized phase. Initially, patients are enrolled in the safety evaluation
phase. If ≤ 6 of 20 patients experience a dose-limiting toxicity, then the study may proceed
to the randomized phase.
SAFETY EVALUATION PHASE: Patients receive oral mitotane once or twice daily and anti-IGF-1R
recombinant monoclonal antibody IMC-A12 IV over 1 hour once every 2 weeks in the absence of
disease progression or unacceptable toxicity.
RANDOMIZED PHASE: Patients are stratified according to participating center. Patients are
randomized to 1 of 2 treatment arms.
ARM I: Patients receive oral mitotane once or twice daily in the absence of disease
progression or unacceptable toxicity. Patients with documented disease progression may cross
over and receive treatment on arm II.
ARM II: Patients receive mitotane as in arm I and anti-IGF-1R recombinant monoclonal
antibody IMC-A12 IV over 1 hour once every 2 weeks in the absence of disease progression or
unacceptable toxicity.
Archival frozen tissue blocks, unstained tumor tissue slides from archival paraffin blocks,
plasma samples, and urine samples may be collected and stored for future correlative
biomarker studies.
After completion of study therapy, patients are followed up for 6 months.
Inclusion Criteria:
- Histologically confirmed adrenocortical carcinoma
- Documented unresectable recurrent, unresectable advanced, or metastatic disease
- At least 1 lesion that can be accurately measured by RECIST criteria as ≥ 20 mm by
conventional radiologic techniques or as ≥ 10 mm by spiral CT scan or MRI
- Patients with disease in an irradiated field as the only site of measurable
disease allowed provided there has been a clear progression of the lesion
- No tumors potentially resectable by surgical excision alone
- No known or suspected leptomeningeal disease or brain metastases
- ECOG performance status 0-2
- Life expectancy ≥ 12 weeks
- ANC ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Hemoglobin ≥ 9 g/dL (transfusion allowed)
- Serum creatinine ≤ 1.5 times upper limit of normal (ULN) OR calculated creatinine
clearance ≥ 60 mL/min
- AST or ALT ≤ 3 times ULN
- Total bilirubin ≤ 1.5 times ULN
- HbA1c < 8 within the past 4 weeks
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 3 months after
completion of study therapy
- Able to take oral medications
- No poor gastrointestinal absorption
- Patients with diabetes mellitus are eligible provided they meet all of the following
criteria:
- Blood glucose is normal (random glucose ≤ 150 mg/dL)
- HgbA1c ≤ 8 within the past 4 weeks
- On a stable dietary or therapeutic regimen for the past 2 months
- No active uncontrolled infection
- No severe disease or condition that, in the judgement of the investigator, would make
the patient inappropriate for study participation, including, but not limited to:
- Bleeding diathesis
- Uncontrolled chronic kidney or liver disease
- Uncontrolled diabetes
- History of cardiac history
- Myocardial infarction within the past 6 months
- Congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Uncontrolled hypertension
- No current malignancy or previous malignancy with a disease-free interval of < 2
years at the time of diagnosis
- Patients with adequately treated basal cell or squamous cell carcinoma of the
skin, carcinoma in situ of the cervix or skin, or stage A low-grade prostate
cancer are eligible
- No known hypersensitivity to monoclonal antibody therapy or mitotane
- No known HIV or hepatitis B or C infection
- No serious medical or psychiatric disorder that would interfere with patient safety
or informed consent
- All significant toxic effects of prior surgery resolved to ≤ grade 1 according to NCI
CTCAE v. 3.0 criteria
- Mitotane for < 8 weeks prior to study entry AND tolerated it well
- No prior IGFR-directed therapy
- No prior systemic antitumor therapy (cytotoxic chemotherapy, biologic, immunotherapy,
or targeted therapy)
- Prior incomplete surgical resections or radiofrequency ablation or radiotherapy
will not be considered as prior therapy provided measurable sites of disease
remain
- Prior adjuvant chemotherapy or mitotane will not be considered as prior
antitumor therapy unless it was completed < 6 months before study enrollment
- No prior radiotherapy to > 20% of bone marrow
- More than 4 weeks since prior and no concurrent radiotherapy
- Radiotherapy for palliation of symptoms related to metastases is permitted
provided that it is > 4 weeks from study initiation, and does not involve
target/measureable lesions that are followed for drug treatment response
evaluation
- No concurrent mitotane ≥ 8 weeks prior to study
- No concurrent tumor resection or tumor-directed surgery
- No other concurrent anticancer or investigational therapy
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
PFS based on RECIST
Outcome Description:
Progression-free survival rates will be estimated by the Kaplan-Meier method. The PFS curves will be compared using the logrank test. Additional analyses, adjusted for major prognostic variables will be performed by fitting Cox proportional hazards regression models. The goodness of fit of the Cox model will be assessed and the appropriate functional form for covariates will be determined through inspection of Schoenfeld and martingale residual plots.
Outcome Time Frame:
Time from randomization to disease progression or death from any cause
Safety Issue:
No
Principal Investigator
Gary Hammer
Investigator Role:
Principal Investigator
Investigator Affiliation:
University of Chicago Comprehensive Cancer Center
Authority:
United States: Food and Drug Administration
Study ID:
NCI-2009-00291
NCT ID:
NCT00778817
Start Date:
December 2008
Completion Date:
Related Keywords:
- Recurrent Adrenocortical Carcinoma
- Stage III Adrenocortical Carcinoma
- Stage IV Adrenocortical Carcinoma
- Carcinoma
- Adrenocortical Carcinoma
- Adrenal Cortex Neoplasms
Name | Location |
|---|---|
| Central Illinois Hematology Oncology Center | Springfield, Illinois 62701 |
| Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center | Columbus, Ohio 43210-1240 |
| Memorial Medical Center | Springfield, Illinois 62781 |
| Ohio State University Medical Center | Columbus, Ohio 43210 |
| Decatur Memorial Hospital | Decatur, Illinois 62526 |
| University of Chicago Comprehensive Cancer Center | Chicago, Illinois 60637-1470 |
| University of Southern California | Los Angeles, California 90033 |
| University of Michigan University Hospital | Ann Arbor, Michigan 48109 |
