An open-label phase 1 study of DCC-2812 monotherapy in patients with advanced genitourinary cancers.

TPS4639 Background: The integrated stress response (ISR) is a major adaptive cellular response pathway that cancer cells depend on to survive in the context of oncogenic pathway activation and high proliferative demand. The ISR is tightly regulated by stress-sensing kinases, including general control nonderepressible 2 (GCN2). Under a controllable level of cellular stress, moderate activation of GCN2 promotes adaptation to nutrient and oxygen deficiency, supporting cancer cell survival. In contrast, excessive GCN2 activation in response to unresolvable stress leads to the induction of pro-apoptotic genes and cancer cell death, making pharmacologic activation of this pathway a promising therapeutic strategy. DCC-2812 is an investigational, potent, and selective activator of GCN2 and the ISR pathway in cancer cells. In preclinical studies, DCC-2812 upregulated the ISR pathway and demonstrated single-agent antitumor activity in a variety of cancer cell lines, including those of renal and urothelial origin. DCC-2812 also inhibited tumor growth in vivo in xenograft models of renal cell carcinoma (RCC) and urothelial cell carcinoma. Here, we describe an ongoing phase 1 study evaluating DCC-2812 as a monotherapy in patients with advanced genitourinary cancers. Methods: This is a multicenter, open-label, phase 1 dose-escalation study evaluating the safety and preliminary antitumor activity of DCC-2812 in adult patients (≥18 years) with histologically or cytologically confirmed advanced or metastatic RCC, urothelial cancer, or castration-resistant prostate cancer (NCT06966024). Eligible patients must have experienced disease progression on or be intolerant of standard-of-care therapies and must have adequate organ function as well as the ability to take oral medication. Individuals will be excluded if they received any anticancer therapy (other than luteinizing hormone–releasing hormone agonists/antagonists for prostate cancer) or investigational therapy within a specified timeframe prior to the first dose of DCC-2812, have impaired cardiac function, or had major surgery within 28 days of the first dose of DCC-2812. Enrolled patients will receive DCC-2812 orally in 28-day cycles. The primary outcome measures are the number of patients with dose-limiting toxicities during cycle 1, treatment-emergent adverse events (TEAEs) and serious adverse events, and dose modifications due to TEAEs. Secondary outcome measures include radiographic objective response rate and radiographic duration of response per Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Working Group 3 criteria, if applicable, as well as pharmacokinetics. The study is currently recruiting patients at multiple sites in the United States. Clinical trial information: NCT06966024 .