Health and Prostate

Ixabepilone (Bristol-Myers Squibb’s BMS-247550, formerly NSC-710428) is an epothilone tubulin inhibitor in Phase II development for CaP and Phase III for breast cancer. An ongoing U.S. Phase II trial, which hopes to recruit 80 patients, is comparing the efficacy of ixabepilone versus mitoxantrone plus prednisone in patients with hormone-refractory CaP who have failed taxane therapy.

A pilot study of ixabepilone plus estramustine (Pfizer’s Emcyt / Estracyt, Nihon Kayaku’s Estracyt, generics) involved 13 chemotherapy-naive patients with metastatic, hormone-refractory CaP. Patients received estramustine 280 mg three times daily for five days plus ixabepilone at one of two dose levels: 35 mg / m² or 40 mg / m². Three of six patients treated at the higher dose developed grade 4 neutropenia, making the lower dose the maximum tolerated dose. A greater than 50% PSA decline was observed in 11 of 12 evaluable patients (92%). Objective responses occurred in 57% of patients with soft tissue metastases and 40% with bone metastases.

At ASCO 2004, investigators presented data from several Phase II trials. A multi-center, randomized Phase II trial involved 92 patients with chemotherapy-naive hormone-refractory CaP . Patients received ixabepilone 35 mg / m² by intravenous infusion over three hours every 21 days or the same dose of ixabepilone plus 280 mg estramustine three times daily for five days. Patients in the ixabepilone-only arm received a median of four cycles of treatment, while those in the combination arm received a median of five cycles. In the combination arm, 69% of patients achieved a greater than 50% decline in PSA and 44% had a partial regression of measurable disease. In the ixabepilone-only arm, 56% achieved a greater than 50% decline in PSA, while 23% had a partial response. Grade 3 or 4 febrile neutropenia occurred in 4% of patients in each arm; grade 1 or 2 neuropathy occurred in 42% of patients in the combination arm and 53% of patients in the ixabepilone-only arm. Grade 3 neuropathy occurred in 4% and 6% of combination-treated patients and ixabepilone-only-treated patients, respectively, and thrombosis in 5% and 2%, respectively.

A retrospective evaluation presented at ASCO 2004 found no apparent cross-resistance between ixabepilone and taxanes . No difference was seen in response to second-line taxane therapy based on whether patients had received ixabepilone as part of their first-line therapy.

A second Phase II trial presented at ASCO 2004 investigated ixabepilone monotherapy in patients with chemotherapynaive, hormone-refractory CaP and performance status 0-2. Patients received 40 mg / m² ixabepilone over three hours every three weeks. Forty-one patients (median age 74) received treatment. At the time of presentation, data were available for 22 patients. Forty-one percent of patients achieved a PSA response. Ten of the 22 patients had measurable disease, and 30% of these patients had an objective response (1 unconfirmed complete response and 2 unconfirmed partial responses). The estimated median progression-free survival was eight months, and the estimated one-year survival was 75%. The most frequent grade 3 toxicities were neutropenia (11 patients), fatigue (3 patients), and sensory neuropathy (3 patients). Grade 4 neutropenia occurred in one patient.

Ixabepilone’s primary shortcomings are grade 1 and 2 neurotoxicity, which occur in about 50% of treated patients, and febrile neutropenia, which occurs infrequently but can be life-threatening.