Date: 2013-10-22
Type of information: Initiation of the trial
phase: 1
Announcement: initiation of the trial
Company: Curis (USA) Debiopharm (Switzerland)
Product: Debio 0932 and everolimus (Afinitor®)
Action
mechanism: Debio 0932 is a novel heat shock protein 90 (HSP90) inhibitor, high oral bioavailability and potent anti-proliferative activity against a broad range of cancer cell lines (with a mean IC50 of 220 nmol/L), including many non–small cell lung cancer (NSCLC) cell lines which are resistant to standard-of-care (SOC) agents. It competes with ATP in binding to the N-terminal portion of HSP90 and inactivates the ATPase activity of the chaperone. Inhibition of HSP90 results in an increased degradation of oncogenic proteins resulting in tumor growth inhibition. In several pre-clinical tumor models, Debio 0932 exhibited potent antitumor activity against a broad range of cancers. In renal cell carcinoma (RCC) in vitro tumor models, Debio 0932 combined with sorafenib, sunitinib or everolimus showed significant additive to synergistic activity in different cell lines. These findings were confirmed in vivo. In a patient-derived in vivo RCC xenograft model, Debio 0932 combined with everolimus demonstrated additive to synergistic antitumor activity.
Everolimus Afinitor®) is an inhibitor of mammalian target of rapamycin (mTOR).
Disease: advanced metastatic renal cell carcinoma
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On October 22, 2013, Curis, an oncology focused company developing novel, targeted drug candidates for the treatment of human cancers, and Debiopharm, a Swiss-based global biopharmaceutical group of companies with a focus on the development of prescription drugs that target unmet medical needs have announced the start of an open-label, multicenter Phase I dose-finding study of Debio 0932, a heat shock protein 90 (HSP90) inhibitor in combination with everolimus (Afinitor®), an inhibitor of mammalian target of rapamycin (mTOR) in patients with advanced or metastatic renal cell carcinoma (RCC), who have been previously treated with a VEGF-directed tyrosine kinase inhibitor.
This dose escalation study is designed to determine the safety and maximum tolerated dose of Debio 0932 in combination with everolimus, in previously treated patients with advanced/metastatic RCC. The pharmacokinetic profiles and any potential drug-drug interactions between the two agents will also be assessed. The trial also includes an expansion cohort of 25 patients with metastatic clear cell RCC. While approved monotherapy treatments for RCC, including mTOR inhibitors are active, improved therapies are needed to enhance the depth and duration of response. Several mTOR signaling pathway components such as mTOR, AKT and LKB1 are HSP90 client proteins. Mechanistic data suggest the potential for improved efficacy through dual mTOR and HSP90 inhibition, which may also prevent the development of acquired resistant to this cancer therapy.
