Daiichi Sankyo, in collaboration with and Sarah Cannon Research Institute, has started the first-in-human, open label, phase I/II study evaluating the safety, tolerability and preliminary activity of DS-7300, a B7-H3 (B7 homologue 3) targeting antibody-drug conjugate (ADC). The investigational drug is tested in adult patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerable to standard treatment or for whom no standard treatment exists.

DS-7300 is an investigational B7-H3 targeting agent using Daiichi Sankyo’s proprietary DXd technology, is comprised of a humanized anti-B7-H3 monoclonal antibody, which is attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker.

B7-H3 is frequently overexpressed in various types of cancers and has been associated with disease progression and poor prognosis in many tumor types. [1]

To date, there are no B7-H3 targeting therapies approved for treatment of any type of cancer.

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B7-H3  is a transmembrane protein which is highly expressed on various types of tumors including lung, head and neck, esophageal, prostate, endometrial and breast cancers,  belonging to the B7 family and plays a role in tumor growth as well as in immune response. [1][2]

In preclinical studies, DS-7300 demonstrated activity in B7-H3 expressing tumors, and activity was associated with target expression levels.

Novel technology
Based on these initial preclinical studies into the construct necessary for optimized safety and efficacy in B7-H3 expressing tumors, DS-7300 was engineered with a new proprietary Daiichi Sankyo technology, DAR-controlled conjugation, to create a drug-to-antibody ratio (DAR) of four.

The same technology has been used to prepare DS-1062, Daiichi Sankyo’s TROP2 ADC under clinical development in patients with NSCLC who have failed standard of care, including immune checkpoint inhibitors.

First-in-human phase I/II study
In late October 2019 researchers at Daiichi Sankyo and Sarah Cannon Research Institute confirmed that a first patient had been dosed in in the first-in-human, open-label, phase I/II study in patients with various advanced solid tumors that have progressed on standard treatments or for whom no standard treatment exists.

The first, dose escalation, part of the study will assess the safety and tolerability of increasing doses of DS-7300 to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE). This portion of the trial will enroll approximately 40 patients with advanced/unresectable or metastatic squamous cell head and neck cancers, squamous cell esophageal cancer, squamous and adenocarcinoma cell non-small cell lung cancer (NSCLC), and other tumor types (ten total).

The second, dose expansion, part of the study will evaluate the safety, tolerability and preliminary activity of DS-7300 at the RDE and assess overall survival. This portion of the trial will include three cohorts of 40 patients each, potentially including patients with advanced/unresectable or metastatic squamous cell head and neck cancers, squamous cell esophageal cancer, and squamous NSCLC. Additional or alternative indications may be added to expansion cohorts based on preliminary signals of activity.

Safety endpoints
The study will also evaluate safety endpoints including adverse events and efficacy endpoints including objective-response rate, duration of response, disease control rate, time to response, progression-free survival, and overall survival. Pharmacokinetic endpoints and exploratory biomarker and immunogenicity endpoints will also be assessed.

A total of approximately 160 patients are expected to be enrolled in this study in the U.S. and Japan.

Strategic oncology partnership
The study evaluating DS-7300 is the first in the strategic oncology partnership announced between Daiichi Sankyo and Sarah Cannon, a clinical research organization conducting community-based clinical trials throughout the United States and United Kingdom. The partnership is focusing on the global clinical development of Daiichi Sankyo’s novel ADCs and other targeted cancer therapies

By combining the operational and scientific expertise of both organizations the researchers are expected to expedite and optimized the trial program.

DS-7300 is the fourth of Daiichi Sankyo’s investigational antibody-drug conjugates in clinical development.

“This first-in-human phase I/II trial will evaluate the potential for DS-7300 to serve as a new mode of targeted therapy for patients with several types of advanced cancers where the B7-H3 protein is overexpressed,” said Antoine Yver, MD, MSc, EVP & Global Head of Oncology Research and Development, Daiichi Sankyo.

Johanna C. Bendell, MD, Chief Development Officer, works closely with the leaders of Sarah Cannon Development Innovations, the organization’s CRO, and clinical operations teams and provides experienced physician leadership to these lines of business.

“Based on our preclinical assessments, the trial will focus initially on patients with non-small cell lung, head and neck, esophageal, and other cancers. We also will continue to conduct important biomarker and translational research to further assess the role this promising therapeutic target may play in treatment of various cancers,” Yver added.

“Given the prevalence of B7-H3 in certain tumors, we hope this unique approach will help us to more effectively target a number of cancer types,” said Johanna Bendell, MD, Chief Development Officer, Sarah Cannon.

“By combining Sarah Cannon’s expertise in developing novel therapies and Daiichi Sankyo’s capabilities in compound development, we have been able to expand our reach to patients across the U.S. and Japan who vitally need advanced treatment options,” Bendell concluded.

Clinical trial
Study of DS-7300a in Participants With Advanced Solid Malignant Tumors – NCT04145622

[1] Zhang X, Fang C, Zhang G, Jiang F, Wang L, Hou J. Prognostic value of B7-H3 expression in patients with solid tumors: a meta-analysis.Oncotarget. 2017 Sep 21;8(54):93156-93167. doi: 10.18632/oncotarget.21114. [Pubmed][Article]
[2] Castellanos JR, Purvis IJ, Labak CM, Guda MR, Tsung AJ, Velpula KK, Asuthkar S. B7-H3 role in the immune landscape of cancer. Am J Clin Exp Immunol. 2017 Jun 15;6(4):66-75.[Pubmed][Article]

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