Mitotane With or Without IMC-A12 in Treating Patients With Recurrent, Metastatic, or Primary Adrenocortical Cancer That Cannot Be Removed By Surgery

• PFS based on RECIST [ Time Frame: Time from randomization to disease progression or death from any cause ] [ Designated as safety issue: No ]
  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.
  
  

• Objective response rates as assessed by RECIST [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
  Response rates will be compared using chisquare or Fisher exact tests, as appropriate. Ninety-five percent confidence intervals will be generating from the Binomial distribution.
  
  
• Changes in tumor size over time [ Time Frame: From baseline to 12 weeks ] [ Designated as safety issue: No ]
  The change in tumor size, analyzed on a log scale, will be compared between the two groups using a two-sample t-test as described in Karrison, et al. In addition, we will conduct a longitudinal analysis incorporating all of the repeated tumor size measurements using a mixed effects model.
  
  
• Overall survival [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
  Since patients with earlier disease progression constitute a type of informative censoring in this analysis, we will use the joint log-normal survival model due to Schluchter.
  
  

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.