February 23, 2021 - The first patient in a first-in-human phase 1 study has been dosed with DS-6000, a novel CDH6-directed antibody-drug conjugate.
The first patient in a first-in-human phase 1 study (NCT04707248) has been dosed with DS-6000, a novel CDH6-directed antibody-drug conjugate (ADC), according to a press release from Daiichi Sankyo Company, Limited and Sarah Cannon Research Institute.1
The study is evaluating the agent in patients with advanced renal cell carcinoma (RCC) and ovarian cancer with disease progression following standard treatment.
“Research suggests DS-6000 could play a role as a CDH6-directed therapy in patients with advanced RCC or ovarian cancer that continues to progress following standard treatment,” said Erika Hamilton, MD, director of the Breast Cancer and Gynecologic Cancer Research Program at Sarah Cannon Research Institute. “Working together with Daiichi Sankyo, we are eager to investigate this new targeted approach to further evaluate whether it may serve as a new and effective therapy for patients facing these hard-to-treat cancers.”
DS-6000 is a first-in-class agent that is comprised of a humanized anti-CDH6 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker.
CDH6 is a cadherin family protein that is overexpressed in many tumor types, including kidney and ovarian carcinoma. This overexpression causes tumor growth and proliferation, which in RCC, has been correlated with poor prognosis.
Preclinical studies suggest that DS-6000 is endocytosed when it binds to CDH6 on the surface of cancer cells. Then, lysosomal enzymes break down the linker and release the cytotoxic payload to effectively destroy the cancer cell. Moreover, DS-6000 exhibited tumor growth inhibition and tumor regression in RCC and ovarian cancer cells that express CDH6.
Metastatic RCC and ovarian cancers are common malignancies that have 5-year survival rates around 13% and 30%, respectively. Currently, novel therapies are needed for patients with RCC and ovarian cancer who progress on available treatment options.
The dose-escalation portion of the ongoing, phase 1 study will assess the safety and tolerability of DS-6000, given in increasing doses. Dosing will begin at 1.6 mg/kg of intravenous DS-6000 given on day 1 of 21-day cycles.2
This portion of the study, which is expected to enroll approximately 46 patients with RCC and ovarian cancer, will establish the maximum tolerated dose and/or a recommended dose for expansion (RDE).
The dose-expansion portion of the study will evaluate DS-6000 at the RDE in 2 cohorts: patients with RCC (n ≈ 30) and patients with ovarian cancer (n ≈ 25). Key end points for this portion include overall response rate, duration of response, disease control rate, clinical benefit rate, time to response, progression-free survival, dose-limiting toxicities, and adverse effects. Additionally, end points evaluating pharmacokinetic and exploratory biomarkers will be included.
Eligibility criteria state that patients must have an ECOG performance status of 0 or 1, available tumor tissue samples, left ventricular ejection fraction of 50% or greater by echocardiogram or multigated acquisition scan within 28 days before study start, adequate organ function 7 days before study start, and an adequate treatment wash out period. Additionally, patients with childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study for at least 4 months or 7 months for males and females, respectively, following the last dose of the study drug.
Patients who have had prior treatment with other CDH6-targeted agents, an ADC that consists of a topoisomerase 1 inhibitor, history or current presence of central nervous system (CNS) metastases, among other criteria, are ineligible for enrollment. Notably, patients with CNS involvement who have completed radiation therapy or surgery 2 or more weeks before the start of treatment and have no evidence of disease progression in the CNS and do not require chronic corticosteroid therapy within 2 weeks before the start of treatment may participate.
DS-6000 marks the sixth DXd ADC from Daiichi Sankyo to enter clinical development. Additionally, of these 6 agents, Sarah Cannon Research Institute has collaborated with the pharmaceutical company on 3.1
1. Daiichi Sankyo initiates clinical development of sixth DXd ADC DS-6000 with Sarah Cannon Research Institute. News release. Daiichi Sankyo. February 2, 2021. Accessed February 22, 2021. https://bit.ly/3aIS164.
2. A study of DS-6000a in subjects with advanced renal cell carcinoma and ovarian tumors. ClinicalTrials.gov. Posted January 13, 2021. Updated February 12, 2021. Accessed February 22, 2021. https://clinicaltrials.gov/ct2/show/NCT04707248.