Targeted Antibody Therapy for Metastatic Adrenocortical Carcinoma
Name of the Trial
Phase II Randomized Study of Mitotane with Versus without Anti-IGF-1R Recombinant Monoclonal Antibody IMC-A12 in Patients with Recurrent, Metastatic, or Primary Unresectable Adrenocortical Carcinoma (UCCRC-16402A). See the protocol summary.
Dr. Gary Hammer, University of Michigan Comprehensive Cancer Center
Why This Trial Is Important
Adrenocortical carcinoma (ACC) is a rare type of cancer that forms in the outer layer, or cortex, of the adrenal gland. The only potential cure for this disease is surgical removal (resection) of the affected gland. However, many patients are not diagnosed until the disease has become widespread (metastasized). Moreover, the recurrence rate among patients treated with surgery is high. Patients with advanced or recurrent ACC are often treated with the drug mitotane (Lysodren), which is the only drug currently approved by the FDA to treat the disease. Unfortunately, many patients do not respond to the drug or become resistant to treatment with it. Therefore, doctors are eager to find more effective treatments.
The insulin-like growth factor (IGF) signaling pathway is thought to be important in the development and growth of ACC. The IGF pathway is activated by interactions between the circulating growth factors IGF-1 and IGF-2 and their membrane-bound receptor, IGF-1R. A number of agents are being developed that target this pathway by blocking the ability of IGF-1 and IGF-2 to bind to and activate IGF-1R. One such agent is a monoclonal antibody called IMC-A12 (cixutumumab). Doctors want to know if combining IMC-A12 with mitotane will help stop the growth of recurrent, metastatic, or unresectable ACC. In preclinical studies, this combination was more effective than mitotane alone at inhibiting growth of ACC tumors in animal models. In a phase I clinical trial, patients with metastatic ACC that was unresponsive to other therapies were treated with a different monoclonal antibody that targets IGF-1R; although none of the patients had an objective response, the majority experienced stable disease and minor tumor shrinkage.
In this clinical trial, 20 patients with recurrent, metastatic, or otherwise unresectable ACC who have not been previously treated with systemic therapies will be treated with IMC-A12 and mitotane to determine the safety of the combined therapy. If the combination is safe, an additional 102 patients will be randomly assigned to receive the combined treatment or mitotane alone. Doctors want to see if the combination therapy will improve progression-free survival compared with mitotane alone. They will also try to determine whether either treatment improves quality of life or response rates.
“Research by many investigators including those at the University of Michigan has focused on trying to understand the role of IGF in adrenal cancer, particularly the role of IGF-2, the levels of which can be elevated 90- to 100-fold in some cases,” said Dr. Hammer. “What this research suggests is that, if elevated levels of IGF-2 are part of the etiology of the disease, then that may be a very targetable defect.
“The antibody being tested in this trial has a mechanism of action that involves not just blocking the ability of IGF-2 to bind to IGF-1R, but also causing internalization and degradation of the receptor. So the receptor is simply not there for the growth factor to attach to and stimulate growth of the cancer cell,” he added.