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

  • Invest New Drugs. 2020 Jun;38(3):844-854. doi: 10.1007/s10637-019-00832-1.
Shahneen Sandhu  1 ,  Catriona M McNeil  2 ,  Patricia LoRusso  3 ,  Manish R Patel  4 ,  Omar Kabbarah  5 ,  Chunze Li  5 ,  Sandra Sanabria  5 ,  W Michael Flanagan  5 ,  Ru-Fang Yeh  5 ,  Flavia Brunstein  5 ,  Denise Nazzal  5 ,  Rodney Hicks  6 ,  Vanessa Lemahieu  5 ,  Raymond Meng  5 ,  Omid Hamid  7 ,  Jeffrey R Infante  8
Affiliations
  • 1. Department of Medical Oncology, Peter MacCallum Cancer Centre, The University of Melbourne, 305 Grattan Street, Melbourne, VIC, 3000, Australia. [email protected].
  • 2. Royal Prince Alfred Hospital, Sydney, Australia.
  • 3. Smilow Cancer Center, Yale University, New Haven, CT, USA.
  • 4. Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, CA, USA.
  • 5. Genentech, Inc., South San Francisco, CA, USA.
  • 6. Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • 7. The Angeles Clinic and Research Institute, California, Los Angeles, USA.
  • 8. Sarah Cannon Research Institute/Tennessee Oncology, PPLC, Nashville, TN, USA.
PMID: 31385109 DOI: 10.1007/s10637-019-00832-1
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 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. ClinicalTrials.gov identifier: NCT01522664.

Keywords
BRAF; Clinical trial; ETBR; Melanoma.
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