Abstract CT233: A first-in-human phase I study of the safety and pharmacokinetic (PK) activity of DEDN6526A, an anti-endothelin B receptor (ETBR) antibody-drug conjugate (ADC), in patients with metastatic or unresectable melanoma
Authors: Infante Jeffrey R. , Sandhu Shahneen K. , McNeil Catriona M. , Kabbarah Omar , Li Chunze , Zhong Wei , Asundi Jyoti , Wood Katie , Chu Yu-Waye , Hamid Omid 
Published: May 2015

Abstract
Background: ETBR, a G-protein coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma compared with normal skin. DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin (MMAE) linked to the humanized IgG1 anti-ETBR monoclonal antibody and represents a novel targeted treatment against melanoma. In preclinical models, DEDN6526A shows dose-dependent anti-tumor activity in ETBR-expressing tumor xenografts.
Methods: DEDN6526A (0.3-2.8 mg/kg) was given intravenously every 3 weeks (q3w) to pts with metastatic or unresectable cutaneous, mucosal, or ocular (uveal) melanoma in a 3+3 design to determine the maximum-tolerated dose, followed by cohort expansion at the recommended phase II dose (RP2D). PK samples were collected, and archival tumor tissue was assessed for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1.
Results: As of 25 November 2013, 28 pts with median age 65 (range 24-82), ECOG PS 0-1, and median 2.5 prior therapies (range 0-5) enrolled in dose escalation and received median 6 doses of DEDN6526A (range 1-28). Based on cumulative safety data, the RP2D of DEDN6526A is 2.4 mg/kg q3w. Three DLTs occurred: G3 infusion-related reaction (IRR) (1.8 mg/kg), G3 transaminitis (2.4 mg/kg), and G3 elevated ALT and AST and transient G2 elevated bilirubin meeting criteria for drug induced liver injury (2.8 mg/kg). The most common treatment-emergent adverse events (AEs) of any grade (G) in ≥ 20% of pts were fatigue (57%), chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), IRRs (25%), asthenia (21%), peripheral sensory neuropathy (21%), and vomiting (21%). The protocol was amended to allow steroid pre-medications prior to DEDN6526A administration, which mitigated the IRRs. Treatment-related G≥3 AEs in ≥ 5% of pts, assessed by investigators, were anemia (11%), neutropenia (11%), leukopenia (7%), and white blood count decreased (7%). Exposures of the conjugate (antibody-conjugated MMAE), total antibody, and unconjugated MMAE increased with dose. Among 19 pts treated at doses ≥ 1.8 mg/kg, there were four confirmed partial responses (21%); 6 pts (32%) had stable disease ≥ 6 months. Clinical benefit in pts did not seem to be associated with melanoma origin (cutaneous/mucosal vs. ocular), tumor BRAF mutation status, and/or progression on prior immune therapies. Correlation of ETBR expression with clinical activity will be presented.
Conclusions: DEDN6526A administered at the RP2D of 2.4 mg/kg q3w is safe and tolerable. There is early evidence of anti-tumor activity in melanoma pts. Enrollment in the expansion cohort is ongoing.
Citation Format: Jeffrey R. Infante, Shahneen K. Sandhu, Catriona M. McNeil, Omar Kabbarah, Chunze Li, Wei Zhong, Jyoti Asundi, Katie Wood, Yu-Waye Chu, Omid Hamid. A first-in-human phase I study of the safety and pharmacokinetic (PK) activity of DEDN6526A, an anti-endothelin B receptor (ETBR) antibody-drug conjugate (ADC), in patients with metastatic or unresectable melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT233. doi:10.1158/1538-7445.AM2014-CT233