Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma.

As described in the Focus on Angiogenesis section of this edition of TherapeuticAdvances, renal cell carcinoma (RCC) is a niche cancer that accounts for 2-3% of all solid tumors in the major pharmaceutical markets. Approximately 30,000 patients are diagnosed with the disease each year in the US while RCC accounts for 12,000 deaths annually. The market is currently dominated by the cytokines. Indeed interleukin-2 (IL-2) is the only FDA-approved therapy used to treat renal cell carcinoma in the United States. Patients with RCC who fail IL-2 therapy have a median survival of only six months and furthermore IL-2 produces a response in only 15-20% of patients. Treatment is also associated with serious side-effects.

The FDA's fast track program is designed to facilitate development and expedite review of new drugs or biologicals that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Treatments of RCC are therefore likely to gain fast-track status with the FDA

Wyeth's Temsirolimus (CCI-779), binds to the immunophilin FKBP thus inhibiting mTOR kinase activity. This kinase regulates the protein translation machinery and is central to cell growth; consequently, CCI-779 leads to G1 phase cell cycle arrest effectively inhibiting cell proliferation. There is a body of evidence to suggest that mTOR plays a role in the etiology of RCC and this is reflected by data from a phase I study in which a patient with RCC exhibited a partial tumor response following dosing with CCI-779.

Atkins et al have recently reported the results of a phase II study investigating the effects of multiple doses of CCI-779 on RCC patients. The data published earlier this year in the Journal of Clinical Oncology demonstrated an overall response rate of 7% in heavily pretreated patients administered with 25, 75 or 250mg CCI-779. Clinical responses or stable disease for at least 24 weeks were observed in 50% of patients. Median time to tumor progression was 5.8 months in all treated patients (compared to 4.8 months in patients treated with anti-VEGF antibody or thalidomide for example) and median survival was 15 months, a survival time that was considerably longer than the 6 months expected for patients that fail interleukin therapy. Two-year survival rates were 29%. The most common adverse effects were maculopapular rash, mucositis, asthenia and nausea. The most common grade 3 or 4 adverse effects were hypophospatemia, anemia, hyperglycemia and hypertriglyceridemia. The latter two metabolic adverse effects possibly reflect the involvement of mTOR in insulin signaling.

On the basis of data including the results of this phase II study, CCI-779 gained fast-track status in 2002 for the treatment of patients that failed IL-2 treatment. One of the finding of this study was that the median survival of patients with a poor prognosis was almost twice as long following treatment with CCI-779 compared to previous studies in which interferon alpha, the gold-standard treatment for RCC in the UK, was used as a first-line treatment of patients with a poor prognosis. On the basis of these data Wyeth have changed their strategy developing CCI-779 as a possible first-line treatment of RCC. Consequently a phase III study comparing CCI-779 alone, interferon alpha alone and CCI-779 with interferon alpha was initiated with survival as the primary endpoint. Reflecting this strategy change Wyeth applied to the FDA for an extension of the earlier fast-track approval and in August 2004 this was granted thus expediting the development of CCI-779 as a first-line treatment of poor-prognosis patients with advanced RCC (click here for the press release).

Entry date Sunday, August 29, 2004

Adapted from Atkins et al, J Clin Oncol. 2004 Mar 1;22(5):909-18