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
Shahneen SandhuJeffrey R Infante

Abstract

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 obser...Continue Reading

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Citations

Nov 5, 2019·Hypertension·Matthias Barton, Masashi Yanagisawa
May 27, 2020·Expert Opinion on Drug Discovery·Rajan ChaudhariShuxing Zhang
Nov 10, 2020·Melanoma Research·Trevor S AndersonDevin B Lowe

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