Infinity Initiates Randomized Phase II Trial of Novel Hsp90 Inhibitor

Infinity Pharmaceuticals, Inc. recently announced the initiation of a Phase II clinical trial of retaspimycin hydrochloride (HCl), also known as IPI-504, the company’s novel heat shock protein (Hsp90) inhibitor, in combination with docetaxel (also known as Taxotere) in patients with non-small cell lung cancer (NSCLC). This study is supported by encouraging data from a Phase Ib trial in which retaspimycin HCl in combination with docetaxel was well-tolerated and showed clinical activity in NSCLC patients with poor prognoses, including patients with squamous cell carcinoma or with a history of heavy smoking.

The adaptive, randomized, placebo-controlled Phase II trial will evaluate the anti-tumor activity, tolerability, and safety of retaspimycin HCl in combination with docetaxel compared to docetaxel alone in approximately 100 second- or third-line NSCLC patients who are naive to docetaxel treatment. Following an interim analysis to evaluate the relationship between efficacy and certain patient characteristics, including histology, tobacco exposure, and a variety of biomarkers, Infinity may expand the trial in patient populations that respond preferentially to treatment with retaspimycin HCl in combination with docetaxel. The study may be expanded based on overall response rate.

“We are encouraged by the results seen in our Phase Ib trial in which response rates in NSCLC patients with a poor prognosis and limited treatment options were among the highest seen to date,” said Pedro Santabarbara, MD, PhD, Chief Medical Officer at Infinity. “These clinical results suggest that retaspimycin HCl may provide an important therapeutic benefit in specific forms of NSCLC when used as part of combination therapy. We look forward to validating our early findings in a rigorous, adaptive Phase II clinical trial designed to quickly and efficiently identify the patients most likely to benefit from this combination.”

In addition to the Phase II trial of retaspimycin HCl in combination with docetaxel, Infinity plans to begin a second clinical trial of retaspimycin HCl in patients with NSCLC by this summer. The second study is based on preclinical data of retaspimycin HCl as part of combination therapy in a molecularly defined subset of patients.

Infinity also announced it has completed a preliminary review of data from two Phase I dose-escalation trials of IPI-493, its oral Hsp90 inhibitor, in patients with solid tumors and hematological malignancies. Since drug exposure of retaspimycin HCl was superior to IPI-493, Infinity intends to focus its efforts exclusively on retaspimycin HCl.

The Phase Ib study included an expansion cohort of 23 NSCLC patients treated with retaspimycin HCl dosed once weekly in combination with docetaxel administered once every 3 weeks. There were six confirmed objective responses in this NSCLC cohort, for an overall response rate of 26%. Patients with squamous cell carcinoma or with a history of heavy smoking appeared to respond preferentially to the combination, with overall response rates of 43% (N = 3/7) and 33% (N = 6/18), respectively.

The combination of retaspimycin HCl and docetaxel was well-tolerated. Side effects were manageable, and docetaxel pharmacokinetics were unaltered by co-administration of retaspimycin HCl. The most common adverse events observed were Grades 1 and 2, and the most common treatment-related adverse events were fatigue, diarrhea, nausea, vomiting, neutropenia, and anemia.

“In this trial, retaspimycin HCl was well-tolerated, and the clinical activity observed suggests that combination therapy with retaspimycin HCl may be a promising treatment strategy for specific forms of NSCLC,” said Gregory J. Riely, MD, PhD, Assistant Attending Physician, Medical Oncology, Memorial Sloan-Kettering Cancer Center, and the Lead Investigator for the Phase Ib trial.

Cancer cells depend on the heat shock protein 90 (Hsp90) chaperone to maintain many proteins critical for cancer growth, proliferation, and survival in a functional state. Certain anti-cancer therapies may enhance the dependency of cancer cells on the Hsp90 chaperone. Therefore, combining an Hsp90 inhibitor, such as retaspimycin hydrochloride (HCl), with another proven anticancer agent may enhance cancer cell killing.

Infinity is an innovative drug discovery and development company seeking to discover, develop, and deliver to patients best-in-class medicines for difficult-to-treat diseases. Infinity combines proven scientific expertise with a passion for developing novel small molecule drugs that target emerging disease pathways. Infinity’s programs in the inhibition of the Hedgehog pathway, the Hsp90 chaperone system, fatty acid amide hydrolase, and phosphoinositide-3-kinase are evidence of its innovative approach to drug discovery and development.