DS-8201a is a novel antibody-drug conjugate comprised of a humanized HER2 antibody attached by a cleavable peptide-based linker to a topoisomerase I inhibitor; characterized by a high drug-to-antibody ratio of about 8. In an ongoing phase 1 trial, DS-8201a showed high and durable responses across multiple tumors, with a confirmed objective response rate (ORR) of 61.4% in previously T-DM1-treated HER2-positive (IHC 3+ or IHC2+ and ISH+) breast cancer (BC) and 31.6% in HER2 low-expressing (IHC 2+/1+ and ISH–) BC (Oct 2017 cutoff; Modi et al, SABCS 2017). Nivolumab, an anti-PD-1 antibody, is FDA-approved for metastatic urothelial carcinoma (UC) after platinum failure. A xenograft model of HER2-expressing cancer showed significantly increased survival with the combination of DS-8201a with an anti-PD-1 antibody vs either treatment alone (Iwata et al, ASCO 2017).
This phase 1b, multicenter, open-label study will assess the combination of DS-8201a with nivolumab in previously chemotherapy-treated HER2-expressing advanced BC or UC. Previous treatment with anti-PD-1/PD-L1 therapy is an exclusion criterion. A dose escalation (part 1) will identify the recommended dose for expansion (RDE), and dose expansion (part 2) will evaluate efficacy and safety/tolerability of the DS-8201a RDE combination with nivolumab (360 mg IV; q3wk). Part 1 is a 3 + 3+3 design with 3 dose cohorts of DS-8201a (3.2, 5.4, and 6.4 mg/kg q3wk); enrollment will start at 3.2 mg/kg. Following RDE determination, enrollment in part 2 will open (Table); estimated total enrollment is 99–117. ORR is the primary efficacy endpoint; secondary endpoints include overall survival, disease control rate, duration of response, progression-free survival, time to response based on central review, and safety/tolerability. The study is open for enrollment as of May 2018.Table: 370TiP
|Part 2 Cohorts|
|Cohort||Cancer Type||HER2 Status||Approximate Enrollment|
|1||BC||HER2-positive (IHC 3+ or ISH+)||30|
|2||BC||HER2 low-expressing (IHC 2+/1+ and ISH–)||15|
|3||UC||HER2 high-expressing (IHC 3+/2+)||30|
|4||UC||HER2 low-expressing (IHC 1+)||15|
Clinical trial identification
Legal entity responsible for the study
Daiichi Sankyo, Inc.
Daiichi Sankyo, Inc.
Medical writing and editorial support was provided by Stefan Kolata, PhD of AlphaBioCom, LLC (King of Prussia, PA).
S.A. Hurvitz: Grants: Amgen, Bayer, BI Pharma, Genentech, GSK, Lilly, Novartis, Pfizer, Roche, PUMA, Merrimack, Medivation, Dignitana, OBI Pharma, Biomarin, Cacadian, Lilly, Novartis, OBI Pharma, Bayer. M.D. Galsky: Consultancy fees: Genetech, Merck, Novartis, Astellas, AstraZeneca, and BMS; Stock/stock options: Dual Therapeutics. J. Shahidi, G. Zhang, S. Raza: Full time employee: Daiichi Sankyo, Inc. A. Necchi: Personal fees: Roche, Janssen; Grants and personal fees: Merck, AstraZeneca.