375TiP - A phase I, 2-part, multicenter, first-in-human dose-escalation and dose-expansion study of DS-1103a with trastuzumab deruxtecan (T-DXd) in patients with advanced solid tumors

Background

Immune checkpoint inhibitors have improved outcomes for patients with various cancer types, yet most experience disease progression. Growing evidence supports that myeloid cells, such as macrophages, play a major role in inhibiting tumor progression. Macrophage and cancer cell interaction can be inhibited by the SIRPα-CD47 pathway. Blocking this pathway may restore antitumor immune functions of macrophages and reduce tumor growth. DS-1103a, a recombinant humanized IgG4 anti-SIRPα antibody, blocks this pathway by binding to the major human variants of SIRPα. T-DXd, an antibody-drug conjugate consisting of an anti-HER2 antibody and topoisomerase I inhibitor payload, is approved for various cancers. In nonclinical studies, DS-1103a enhanced the trastuzumab-induced antibody-dependent cellular phagocytosis, suggesting a potential benefit of the combination. This study will assess the preliminary safety and efficacy of DS-1103a + T-DXd in advanced solid tumors.

Trial design

This phase 1, global, multicenter, first-in-human, 2-part, dose-escalation, and dose-expansion study (NCT05765851) plans to enroll up to 78 patients. Part 1 (dose-escalation [based on BOIN design]) will enroll patients with pathologically documented HER2-expressing (IHC1+ or greater) or HER2-mutated (activating mutation) advanced solid tumors not amenable to standard of care. Part 2 (dose-expansion) will enroll patients with HER2-low (IHC2+/ISH- or IHC1+ [ISH- or untested]) breast cancer who received 1-2 prior lines of chemotherapy in the recurrent or metastatic setting. DS-1103a monotherapy will be administered for Cycle 1 of Part 1, DS-1103a + T-DXd for all other 21-day cycles and during Part 2. The evaluation period for dose limiting toxicity will be before Cycle 3 in Part 1. Primary endpoints include the safety and tolerability of the combination in both parts, determining the recommended dose of DS-1103a in combination for expansion in Part 1, and assessing the objective response rate in Part 2. Secondary endpoints include the antitumor activity of DS-1103a + T-DXd, pharmacokinetic profile of DS-1103a, and incidence of antidrug antibodies against DS-1103a.

Clinical trial identification

NCT05765851.

Editorial acknowledgement

Writing support was provided by Kim Caldwell, PhD and Danyang Zhou, PharmD, of Lumanity Communications Inc., and was funded by Daiichi Sankyo, Inc.

Legal entity responsible for the study

Daiichi Sankyo, Inc.

Funding

Daiichi Sankyo, Inc.

Disclosure

L. Cavalcante: Financial Interests, Personal, Advisory Board: Pliant Therapeutics; Financial Interests, Personal, Full or part-time Employment, Employment ended February 2022: Actuate Therapeutics. L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche, Seattle Genetics, Voronoi, Arvinas, Tessa, Navire, Relay Therapeutics, Amgen, Marengo, InterRNA, Medicenna, Hoopika, Coherus, Tubulis, LTZ Therapeutics; Financial Interests, Personal, Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Local PI: Novartis, Bristol Myers Squibb, Pfizer, Boehringer-Ingelheim, Merck, GSK, Roche/Genentech, AstraZeneca, Astellas, Amgen, Shattucks, EMD Serono; Financial Interests, Institutional, Coordinating PI: Bayer, Symphogen, Intensity Therapeutics; Non-Financial Interests, Advisory Role: ICR, Dana Farber Harvard Cancer Center. J. Toso: Financial Interests, Personal, Advisory Board, Employment and equity: Daiichi Sankyo. D. Mires, G. Ayele, Y. Cheng, L. Huang, J.E. Connolly, M. Sue: Financial Interests, Personal, Other, Employment and equity: Daiichi Sankyo. R. Shiga, Y. Ishimoto: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. P.L. Bedard: Financial Interests, Institutional, Local PI: AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Sanofi, Merck, Pfizer, Zymeworks, Nektar Therapeutics, Lilly, SeaGen, Medicenna; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Funding: Servier; Non-Financial Interests, Member of Board of Directors, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND Committee Member, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role: SeaGen, Lilly, Amgen, Merck, BMS, Pfizer, Gilead. All other authors have declared no conflicts of interest.