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05.08.2019 | PHASE I STUDIES | Ausgabe 3/2020

Investigational New Drugs 3/2020

Phase I study of the anti-endothelin B receptor antibody-drug conjugate DEDN6526A in patients with metastatic or unresectable cutaneous, mucosal, or uveal melanoma

Investigational New Drugs > Ausgabe 3/2020
Shahneen Sandhu, Catriona M. McNeil, Patricia LoRusso, Manish R. Patel, Omar Kabbarah, Chunze Li, Sandra Sanabria, W. Michael Flanagan, Ru-Fang Yeh, Flavia Brunstein, Denise Nazzal, Rodney Hicks, Vanessa Lemahieu, Raymond Meng, Omid Hamid, Jeffrey R. Infante
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The online version of this article (https://​doi.​org/​10.​1007/​s10637-019-00832-1) contains supplementary material, which is available to authorized users.
Investigational New Drugs

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Background Endothelin B receptor (ETBR) is involved in melanoma pathogenesis and is overexpressed in metastatic melanoma. The antibody-drug conjugate DEDN6526A targets ETBR and is comprised of the humanized anti-ETBR monoclonal antibody conjugated to the anti-mitotic agent monomethyl auristatin E (MMAE). Methods This Phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of DEDN6526A (0.3–2.8 mg/kg) given every 3 weeks (q3w) in patients with metastatic or unresectable cutaneous, mucosal, or uveal melanoma. Results Fifty-three patients received a median of 6 doses of DEDN6526A (range 1–49). The most common drug-related adverse events (>25% across dose levels) were fatigue, peripheral neuropathy, nausea, diarrhea, alopecia, and chills. Three patients in dose-escalation experienced a dose-limiting toxicity (infusion-related reaction, increased ALT/AST, and drug-induced liver injury). Based on cumulative safety data across all dose levels, the recommended Phase II dose (RP2D) for DEDN6526A was 2.4 mg/kg intravenous (IV) q3w. The pharmacokinetics of antibody-conjugated MMAE and total antibody were dose-proportional at doses ranging from 1.8–2.8 mg/kg. A trend toward faster clearance was observed at doses of 0.3–1.2 mg/kg. There were 6 partial responses (11%) in patients with metastatic cutaneous or mucosal melanoma, and 17 patients (32%) had prolonged stable disease ≥6 months. Responses were independent of BRAF mutation status but did correlate with ETBR expression. Conclusion DEDN6526A administered at the RP2D of 2.4 mg/kg q3w had an acceptable safety profile and showed evidence of anti-tumor activity in patients with cutaneous, mucosal, and uveal melanoma. identifier: NCT01522664.

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