The investigational drug DEDN6525A, a new antibody-drug conjugate, was safe, tolerable, and showed hints of activity against three forms of melanoma: cutaneous, mucosal, and ocular. These results from a first-in-human phase 1 clinical trial were presented at the American Association for Cancer Research 2014 Annual Meeting, in San Diego, California.
“As one of the first clinical trials to test an antibody-drug conjugate for the treatment of melanoma, we were encouraged by the initial responses,” said Jeffrey R. Infante, MD, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tennessee. “We found DEDN6525A to have a well-tolerated safety profile, and, more importantly, to benefit a substantial proportion of patients. It is particularly promising to see clinical activity in patients with mucosal as well as ocular melanoma, and we hope that patients who are enrolling in the ongoing expansion phase of the trial gain similar benefit.”
Antibody-drug conjugates consist of an antibody attached to a toxic chemotherapy by a special linker that keeps the chemotherapy inactive. In the case of DEDN6525A, the antibody recognizes the protein endothelin B receptor (ETBR) and the toxic chemotherapy is monomethyl auristatin (MMAE).
Infante explained that, when administered to the patient, the antibody portion of DEDN6525A recognizes and attaches to ETBR, which is often present at elevated levels on the surface of tumor cells in patients with melanoma. The cells uptake the whole antibody-drug conjugate and MMAE is released from the linker to become active, killing the melanoma cells. ETBR is expressed at elevated levels on about 50% of melanomas,” said Infante.
Infante and colleagues enrolled patients with metastatic or unresectable melanoma in the dose-escalation phase of the trial. Each patient was administered DEDN6526A intravenously, once every 3 weeks. The initial dose tested was 0.3 mg/kg; the maximum-tolerated dose was determined to be 2.4 mg/kg, and the expansion phase of the trial is testing this dose.
Clinical benefit was observed by the researchers for 12 of the 19 patients who were assigned 1.8 mg/kg of DEDN6526A or more. Four of these patients, two with cutaneous melanoma and two with mucosal melanoma, had confirmed partial responses. The other eight patients, five with cutaneous melanoma, two with ocular melanoma, and one with mucosal melanoma, had stable disease for 6 months or longer. In some cases, disease was stable for a prolonged period; for example, one patient is currently approaching 2 years on the study.
The researchers found that the most specific adverse event related to the study drug was infusion-related reaction, which was mitigated by amending the protocol to allow patients to receive steroids before their DEDN6526A infusion. Other adverse events reported were fatigue, anemia, reduced numbers of immune cells (neutrophils), and neuropathy. Infante stated that these are all side effects that would be expected in patients undergoing treatment with toxic chemotherapy.