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

Recurrent Adrenocortical Carcinoma Clinical Trial

Official title:

Multi-Institutional Phase II Study of IMC-A12, a Recombinant Human IgG1 Monoclonal Antibody Directed at the Type I Insulin-Like Growth Factor Receptor IGF1R, in Adrenocortical Carcinoma: IMC-A12 With Mitotane vs Mitotane Alone

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00778817
• Other study ID #: NCI-2009-00291
• Secondary ID: NCI-2009-00291UC
• Status: Terminated
• Phase: Phase 2
• First received: October 22, 2008
• Last updated: March 28, 2014
• Start date: December 2008
• Est. completion date: March 2014

Study information

• Verified date: December 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00810537

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 20
• Est. completion date: March 2014
• Est. primary completion date: May 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adrenocortical Carcinoma
• Carcinoma
• Recurrent Adrenocortical Carcinoma
• Stage III Adrenocortical Carcinoma
• Stage IV Adrenocortical Carcinoma

Intervention

Biological:
• IMC-A12
Given IV

Drug:
• mitotane
Given orally

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Chicago Comprehensive Cancer Center	Chicago	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	Decatur Memorial Hospital	Decatur	Illinois
United States	University of Southern California	Los Angeles	California
United States	Central Illinois Hematology Oncology Center	Springfield	Illinois
United States	Memorial Medical Center	Springfield	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival Rate at 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.	6 weeks	No
Primary	Progression-free Survival Rate at 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.	12 weeks	No
Primary	Progression-free Survival Rate at 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.	18 weeks	No
Secondary	Best Response Rates	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.	Up to 6 months	No
Secondary	Response at 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.	6 weeks	No
Secondary	Response at 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.	12 weeks	No
Secondary	Response at 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.	18 weeks	No
Secondary	Response at 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.	48 weeks	No
Secondary	Number of Patients Exhibiting Decrease in Tumor Size at 6 Weeks	Total number of patients whose tumor size at 6 weeks was smaller than their tumor size recorded at baseline (by any amount).	6 weeks	No
Secondary	Number of Patients Exhibiting Decrease in Tumor Size at 12 Weeks	Total number of patients whose tumor size at 12 weeks was smaller than their tumor size recorded at baseline (by any amount).	12 weeks	No
Secondary	Number of Patients Exhibiting Decrease in Tumor Size at 18 Weeks	Total number of patients whose tumor size at 18 weeks was smaller than their tumor size recorded at baseline (by any amount).	18 weeks	No
Secondary	Number of Patients Exhibiting Decrease in Tumor Size at 48 Weeks	Total number of patients whose tumor size at 48 weeks was smaller than their tumor size recorded at baseline (by any amount).	48 weeks	No