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

Condition(s) targeted: Adrenocortical Carcinoma

Intervention: cixutumumab (Biological); mitotane (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: University of Chicago

Official(s) and/or principal investigator(s):
Gary D. Hammer, MD, PhD, Study Chair, Affiliation: University of Michigan Cancer Center

RATIONALE: 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.

PURPOSE: 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.

Official title: 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.

Study design: Allocation: Randomized, Primary Purpose: Treatment

Primary outcome: Progression-free survival

Secondary outcome:

Objective response rates

Changes in tumor size over time

Overall survival

Detailed description: OBJECTIVES:

Primary

- Compare the progression-free survival 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

- Compare the response rates in these patients using RECIST criteria.

- Compare the change in tumor size from baseline to 12 weeks in these patients.

- Compare the overall trajectories in tumor growth in these patients.

Tertiary

- Define predictive markers of response or insensitivity to IMC-A12.

- Define pharmacodynamic markers of IMC-A12.

- 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 periodically.

PROJECTED ACCRUAL: A total of 122 patients (20 for the safety evaluation phase and 102 [51 per treatment arm] for the randomized phase) will be accrued for this study.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- 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

PATIENT CHARACTERISTICS:

- 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

PRIOR CONCURRENT THERAPY:

- 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

Decatur Memorial Hospital Cancer Care Institute, Decatur, Illinois 62526, United States; Recruiting
Clinical Trials Office - Decatur Memorial Hospital Cancer Care, Phone: 217-876-4750

Central Illinois Hematology Oncology Center, Springfield, Illinois 62701, United States; Recruiting
Edem S. Agamah, MD, MS, Phone: 217-525-2500, Email: ihdn@aol.com

University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0942, United States; Recruiting
Clinical Trials Office - University of Michigan Comprehensive, Phone: 800-865-1125

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210-1240, United States; Recruiting
Ohio State University Cancer Clinical Trial Matching Service, Phone: 866-627-7616, Email: osu@emergingmed.com

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: December 2008
Last updated: September 2, 2010