Phase I Trial of New Antibody-Drug Conjugate Shows Promise Against All Forms of Melanoma
A small clinical study of a new investigational antibody-drug conjugate called DEDN6526A in patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma has found the drug to be safe and tolerable and demonstrated early evidence of antitumor activity. The findings were presented at the American Association for Cancer Research (AACR) Annual Meeting 2014 in San Diego.
This study is the first phase I clinical trial of DEDN6526A, an anti–endothelin B receptor (ETBR) antibody-drug conjugate. ETBR, a G-protein coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma compared with normal skin. DEDN6526A is an antibody-drug conjugate with the antimitotic agent monomethyl auristatin linked to the humanized IgG1 anti-ETBR monoclonal antibody and represents a novel targeted treatment against melanoma.
Study Method and Results
The researchers enrolled 28 patients with a median age of 65 and median 2.5 prior therapies in a dose escalation phase I study. 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 this dose is being tested in the expansion phase of the trial.
Clinical benefit was observed among 12 of the 19 patients treated at doses of 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 or more months.
In some patients, their melanoma was stable for a prolonged period. For example, one patient is approaching 2 years on the study, according to the researchers. Clinical benefit did not seem to be associated with melanoma origin, tumor BRAF mutation status, and/or progression on prior immune therapies.
The most common treatment-related adverse events were fatigue (57%), chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), infusion-related reaction (25%), asthenia (21%), peripheral sensory neuropathy (21%), and vomiting (21%).
“With the initial findings, we have begun to look at whether clinical activity correlates with ETBR levels on a patient’s tumor,” Jeffrey R. Infante, MD, lead author of the study and Director of the Drug Development Program at Sarah Cannon Research Institute in Nashville, Tennessee, said in a statement. “Patients with all forms of melanoma expressing high levels of ETBR seem more likely to benefit from treatment with DEDN6526A, and we hope that further investigation of this biomarker for response to DEDN6526A will inform future development of this melanoma treatment.”
Enrollment in the expansion of cohorts in this trial is ongoing.
This study was funded by Genentech, developer of DEDN6526A utilizing Seattle Genetics ADC technology. Dr. Infante reported no conflicts of interest.
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