IMC-A12 With Mitotane vs Mitotane Alone in Recurrent, Metastatic, or Primary ACC That Cannot Be Removed by Surgery

Phase 2

Terminated

Conditions: Recurrent Adrenocortical Carcinoma
Stage III Adrenocortical Carcinoma
Stage IV Adrenocortical Carcinoma

Interventions: Biological: IMC-A12
Drug: mitotane

Registration Number: NCT00778817

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase II trial is studying mitotane and IMC-A12 to see how well they work compared with mitotane alone in treating patients with recurrent, metastatic, or primary adrenocortical cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as mitotane, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as IMC-A12, 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. It is not yet known whether mitotane is more effective with or without monoclonal antibody IMC-A12 in treating adrenocortical cancer.

Detailed Description: 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.

NOTE: The study was terminated after the safety evaluation phase (i.e., before the randomization phase) due to futility concerns. Thus, patients were only enrolled into ARM II (i.e., mitotate + IMC-A12). Results presented in this report are only given for the safety evaluation phase.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 20

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm II (Mitotane + IMC-A12)	IMC-A12	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.
Arm II (Mitotane + IMC-A12)	mitotane	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.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival Rate at 6 Weeks	6 weeks	Progression-free survival rates were estimated at 6, 12, and 18 weeks by the Kaplan-Meier method. At a given time point, this outcome is defined as the proportion of subjects who had not progressed or died. Disease progression is defined according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). Progression is characterized by a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Progression-free Survival Rate at 12 Weeks	12 weeks	Progression-free survival rates were estimated at 6, 12, and 18 weeks by the Kaplan-Meier method. At a given time point, this outcome is defined as the proportion of subjects who had not progressed or died. Disease progression is defined according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). Progression is characterized by a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Progression-free Survival Rate at 18 Weeks	18 weeks	Progression-free survival rates were estimated at 6, 12, and 18 weeks by the Kaplan-Meier method. At a given time point, this outcome is defined as the proportion of subjects who had not progressed or died. Disease progression is defined according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). Progression is characterized by a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

Name	Time	Method
Number of Patients Exhibiting Decrease in Tumor Size at 12 Weeks	12 weeks	Total number of patients whose tumor size at 12 weeks was smaller than their tumor size recorded at baseline (by any amount).
Number of Patients Exhibiting Decrease in Tumor Size at 18 Weeks	18 weeks	Total number of patients whose tumor size at 18 weeks was smaller than their tumor size recorded at baseline (by any amount).
Number of Patients Exhibiting Decrease in Tumor Size at 48 Weeks	48 weeks	Total number of patients whose tumor size at 48 weeks was smaller than their tumor size recorded at baseline (by any amount).
Response at 12 Weeks	12 weeks	RECIST v1.0 was used to evaluate patient response at each time point. Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter (LD) since the treatment started; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Subjects who were unevaluable for response were classified as having 'Unknown response'. Each patient's 'best response' was the most favorable of all recorded responses across all time points. Proportions of patients with each response as their best response are reported in this outcome.
Response at 18 Weeks	18 weeks	RECIST v1.0 was used to evaluate patient response at each time point. Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter (LD) since the treatment started; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Subjects who were unevaluable for response were classified as having 'Unknown response'. Each patient's 'best response' was the most favorable of all recorded responses across all time points. Proportions of patients with each response as their best response are reported in this outcome.
Response at 48 Weeks	48 weeks	RECIST v1.0 was used to evaluate patient response at each time point. Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter (LD) since the treatment started; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Subjects who were unevaluable for response were classified as having 'Unknown response'. Each patient's 'best response' was the most favorable of all recorded responses across all time points. Proportions of patients with each response as their best response are reported in this outcome.
Number of Patients Exhibiting Decrease in Tumor Size at 6 Weeks	6 weeks	Total number of patients whose tumor size at 6 weeks was smaller than their tumor size recorded at baseline (by any amount).
Best Response Rates	Up to 6 months	RECIST v1.0 was used to evaluate patient response at each time point. Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter (LD) since the treatment started; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Subjects who were unevaluable for response were classified as having 'Unknown response'. Each patient's 'best response' was the most favorable of all recorded responses across all time points. Proportions of patients with each response as their best response are reported in this outcome.
Response at 6 Weeks	6 weeks	RECIST v1.0 was used to evaluate patient response at each time point. Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter (LD) since the treatment started; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Subjects who were unevaluable for response were classified as having 'Unknown response'. Each patient's 'best response' was the most favorable of all recorded responses across all time points. Proportions of patients with each response as their best response are reported in this outcome.

Trial Locations

Locations (8): University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Memorial Medical Center
🇺🇸
Springfield, Illinois, United States
Central Illinois Hematology Oncology Center
🇺🇸
Springfield, Illinois, United States
University of Southern California
🇺🇸
Los Angeles, California, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Decatur Memorial Hospital
🇺🇸
Decatur, Illinois, United States
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
🇺🇸
Columbus, Ohio, United States
Ohio State University Medical Center
🇺🇸
Columbus, Ohio, United States