LAUSANNE, Switzerland—Curis Inc., a Lexington, Mass.-based oncology company developing novel, targeted drug candidates for the treatment of cancer, and Debiopharm Group, a Swiss global biopharmaceutical group of companies with a focus on the development of prescription drugs and companion diagnostics that target unmet medical needs, will launch 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.
HSP90 is a highly abundant cytoplasmic molecular chaperone that is involved in the folding, stability and activity of a large number of client oncoproteins. Inhibition of HSP90 results in an increased degradation of misfolded client oncoproteins, which, in turn, results in tumor growth inhibition.
Building on a relationship that began in 2009, the collaborative 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 resistance.
“Tumors are characterized by their increased cellular metabolism necessary to sustain increased signaling by oncoproteins. Cancer cells are also more dependent on HSP90 than normal cells to cope with the folding and stabilization of oncoproteins,” notes a Debiopharm spokesperson. “The combination of everolimus with Debio 0932 is therefore anticipated to show synergistic anti-tumor activities by acting on the cellular metabolism, via everolimus, and on the expression of oncoproteins, via HSP90 inhibition.” Debiopharm acknowledges that synergism suggests a situation where the effect of two-drug combinations is more than additive. “However, true synergism is difficult to demonstrate in complex biological systems and it is therefore more reasonable to speak of additive to synergistic antitumor activity,” the company states.
“We are very pleased that this Phase I study has kicked off and believe that the combination of our compound with everolimus can potentially further improve the outcome for patients suffering from RCC,” said Rolland-Yves Mauvernay, president and founder of Debiopharm Group.
“We continue to be impressed with Debiopharm’s systematic approach in developing Debio 0932 for the treatment of cancers where it is shown to have a strong scientific rationale and supportive preclinical data. We believe that potent inhibition of HSP90 by Debio 0932 with its promising safety profile and convenient oral dosing, in combination with everolimus, has the potential to provide improved benefit for patients with kidney cancers,” said Dr. Ali Fattaey, president and chief operating officer of Curis.
RCC represents approximately two- to three-percent of all adult malignancies and is the seventh most common cancer in men and the ninth most common cancer in women. The European Society of Medical Oncology (ESMO) estimates approximately 209,000 new cases and 102,000 deaths due to renal cell carcinoma each year worldwide. In the United States, according to the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) database, approximately 65,000 new cases and more than 13,500 deaths from kidney and renal pelvic cancers are expected in 2013.
