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

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Summary

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.

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Acknowledgements

We thank the patients and their families who took part in the study, as well as the staff, research coordinators, and investigators at each participating institution. Writing assistance provided by Genentech, Inc.

Funding

This work was supported by Genentech, Inc.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Peter MacCallum Cancer Centre, The University of Melbourne, 305 Grattan Street, Melbourne, VIC, 3000, Australia

    Shahneen Sandhu

  2. Royal Prince Alfred Hospital, Sydney, Australia

    Catriona M. McNeil

  3. Smilow Cancer Center, Yale University, New Haven, CT, USA

    Patricia LoRusso

  4. Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, CA, USA

    Manish R. Patel

  5. Genentech, Inc., South San Francisco, CA, USA

    Omar Kabbarah, Chunze Li, Sandra Sanabria, W. Michael Flanagan, Ru-Fang Yeh, Flavia Brunstein, Denise Nazzal, Vanessa Lemahieu & Raymond Meng

  6. Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia

    Rodney Hicks

  7. The Angeles Clinic and Research Institute, California, Los Angeles, USA

    Omid Hamid

  8. Sarah Cannon Research Institute/Tennessee Oncology, PPLC, Nashville, TN, USA

    Jeffrey R. Infante

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  1. Shahneen Sandhu
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Corresponding author

Correspondence to Shahneen Sandhu.

Ethics declarations

Conflict of interest

SS: Consultant/advisory board member for Roche-Genentech, Novartis, Astra-Zeneca, Bristol Meyers Squibb, Merck Sharp and Dolme and Amgen. Research grant funding from Amgen, Bristol Meyers Squibb, Merck Sharp and Dolme, Merck and Genentech.

CM: None.

PL: None.

MP: Speakers bureau/advisory boards for Pfizer, Exelixis, Pharmacyclics, Celgene, and Bayer.

OK: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd.

CL: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd.

WF: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd.

RY: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd.

FB: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd.

RJH: Advisory board member and stockholder of Telix Pharmaceuticals. Consultant for Endocyte. Research grant funding from Ipsen and ITG.

DN: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd.

VL: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd.

RM: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd.

OH: Consulting for Roche, Amgen, Novartis, BMS, Merck. Speaker for Genentech, BMS, Novartis, Amgen, Sanofi, Array. Contracted research for institution from Roche-Genentech, Amgen, Arcus, Astellas, AstraZeneca, BMS, Celldex, Cytomx, GSK, Immunocore, Incyte, Iovance, Merck, Merck Serono, MedImmune, NextCure, Novartis, Parker, Pfizer, Polynoma, Regeneron.

JI: Consulting for Armo Biosciences, Bio Med Valley Discoveries. Employee of Janssen Pharmaceuticals.

Ethical approval

This study was conducted at 6 institutions in the United States and Australia in accordance with the International Conference on Harmonization E6 Guidelines and the principles of Good Clinical Practice. The study was approved by regulatory and ethics committees at each institution and was registered at Clinicaltrials.gov, NCT01522664. The study was sponsored by Genentech, Inc.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Investigational New Drugs

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Sandhu, S., McNeil, C.M., LoRusso, P. et al. 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 38, 844–854 (2020). https://doi.org/10.1007/s10637-019-00832-1

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