Multi-Institutional Randomized Phase II Trial of the Epothilone B Analog Ixabepilone (BMS-247550) With or Without Estramustine Phosphate in
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《临床肿瘤学》
the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Department of Nursing, Memorial Sloan-Kettering Cancer Center and Department of Medicine, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY
University of California, San Francisco, CA
Dana-Farber Partners Cancer Care, Boston, MA
The University of Texas M.D. Anderson Cancer Center, Houston, TX
University of Michigan, Ann Arbor, MI
National Cancer Institute, Bethesda, MD
ABSTRACT
PATIENTS AND METHODS: Patients were randomly assigned to receive ixabepilone (35 mg/m2) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5.
RESULTS: Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of ≥ 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm.
CONCLUSION: Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.
INTRODUCTION
Microtubule targeting agents, including the vinca alkaloids and the taxanes, are among the most active drugs in castrate metastatic prostate cancer. In the early 1990s, preclinical studies suggested that the anticancer effects of these agents could be enhanced with the addition of estramustine phosphate (EMP), which binds complementary sites within the microtubule.5-7 In subsequent randomized phase II studies, combination regimens with EMP did result in significantly higher proportions of patients achieving prostate-specific antigen (PSA) declines, but at the cost of added toxicity.8 A randomized phase III trial demonstrated a trend toward improved survival with vinblastine + EMP compared with vinblastine alone; however, this study was limited by a small sample size and, perhaps, an overestimation of benefits.9 The current study was initiated before the publication of the results of the recent phase III trials involving docetaxel-based therapy, which suggest that any potential contribution of EMP to overall outcomes is likely to be small.3,10
The epothilones are a new class of cytotoxic tubulin polymerization agents obtained from the fermentation broth of the myxobacterium Sorangium cellulosum. These agents have demonstrated antineoplastic activity against a range of solid tumor cell lines and xenografts.11 While their target of action is similar to that of the taxanes, activity has also been shown in taxane-resistant models. In prostate cancer cells lines, epothilone B was the most active epothilone and inhibited growth seven- to 10-fold more effectively than paclitaxel.12-14 Ixabepilone (BMS-247550), an analog of epothilone B, was developed to optimize the antitumor efficacy and therapeutic index of this novel class.15
To expedite the development of ixabepilone for the treatment of patients with progressive castrate metastatic prostate cancer, we designed a two-stage program. First, given the prior experience showing increased activity with the addition of EMP to a second microtubule agent, we performed a dose escalation study to establish a safe dose of ixabepilone to use in combination with EMP. This combination proved to be well tolerated, with promising clinical activity.16 Subsequently, we initiated a multi-institutional (Memorial Sloan-Kettering Cancer Center [MSKCC], Dana-Farber Cancer Institute [DFCI], The University of Texas M.D. Anderson Cancer Center [MDACC], University of California at San Francisco [UCSF], University of Michigan [UM]) randomized phase II trial of ixabepilone, with or without EMP, to rapidly evaluate the clinical activity and safety of the single agent and combination in parallel.
PATIENTS AND METHODS
Exclusion Criteria
Excluded from the study were patients who had received prior palliative radiation therapy to more than 25% of the active bone marrow, as estimated based on the distribution of active bone marrow in the adult17; prior radioisotope therapy with strontium-89 or samarium-153; known brain metastases; a concurrent active malignancy other than nonmelanoma skin cancer; significant cardiovascular disease (New York Heart Association Class III or IV congestive heart failure, active angina pectoris, and/or myocardial infarction within the last 6 months); a bleeding disorder or recent gastrointestinal bleeding that would preclude anticoagulation; a history of hemorrhagic or thrombotic cerebral vascular accident; deep venous thrombosis or pulmonary embolism within 6 months before starting therapy; a history of allergic reactions to compounds of similar composition to the epothilones.
Randomization and Site Coordination
Patients were randomly assigned to treatment with ixabepilone alone or ixabepilone + EMP immediately after registration through the MSKCC Clinical Trials Office. Randomization was accomplished by the method of random permuted block. MSKCC served as the coordinating center for this trial.
Treatment Plan
Treatment arm 1 consisted of ixabepilone 35 mg/m2 administered intravenously over 3 hours on day 2 + EMP 280 mg orally three times daily on days 1 to 5 every 3 weeks. Warfarin 2 mg daily was administered for thromboembolic prophylaxis. Treatment arm 2 consisted of ixabepilone alone (35 mg/m2 administered intravenously over 3 hours every 3 weeks). Because ixabepilone is formulated in polyoxyethilated castor oil (CremophorEL), which can cause a hypersensitivity reaction during infusion, patients were premedicated with diphenhydramine 50 mg and ranitidine 150 mg orally 1 hour before infusion. Premedication with corticosteroids (dexamethasone 20 mg 12 hours and 6 hours before chemotherapy) was indicated only if patients developed a ≥ grade 3 hypersensitivity reaction with a prior administration if ixabepilone. Therapy was continued until disease progression or development of unacceptable toxicities.
Treatment Modifications
Patients received subsequent cycles of therapy every 3 weeks if absolute neutrophil count ≥ 1,500/mm3, platelets ≥ 100,000/mm3, and treatment-related nonhematologic toxicity had resolved to baseline or ≤ grade 1 (except fatigue or alopecia, grade 2). If these criteria were not met, treatment was delayed a maximum of 3 weeks. The dose of ixabepilone was reduced by 5 mg/m2 on subsequent cycles for: grade 4 neutropenia lasting 7 or more days; febrile neutropenia; grade ≥ 3 thrombocytopenia; more than 1 week delay in re-treatment due to drug toxicity; grade 3 nausea/vomiting or diarrhea; and/or grade 2 neuropathy (motor or sensory) lasting more than 7 days or grade 3 neuropathy lasting less than 7 days. Treatment was discontinued for grade 3 neuropathy lasting ≥ 7 days. For other toxicities ≥ grade 3, treatment was adjusted or discontinued as medically indicated after review by the investigator. Estramustine phosphate was held in case of: grade ≥ 2 nausea/vomiting; diarrhea with grade higher than 2; and/or bilirubin elevation of more than 1.5 x the upper normal limits or AST elevation higher than 5 x the upper normal limits. EMP was reintroduced with a 50% dose reduction (140 mg PO tid) after the toxicity resolved. If patients could not tolerate EMP, this could be discontinued, and the patent could continue ixabepilone alone. In case of an otherwise uncomplicated deep venous thrombosis, full anticoagulation was instituted, and patients continued EMP at the investigator's discretion. However, in case of pulmonary embolism or acute myocardial infarction, discontinuation of EMP was mandated.
Evaluation
Baseline examinations included a CBC, comprehensive profile (sodium, potassium, chloride, carbon dioxide, calcium, blood urea nitrogen, creatinine, glucose, albumin, alkaline phosphatase, ALT, AST, total bilirubin, and lactate dehydrogenase), partial thromboplastin time and prothrombin time, serum testosterone, and PSA. A chest radiograph, CT scan, or MRI scan of the abdomen and pelvis, and radionuclide bone scan were performed within 4 weeks before starting therapy.
During the study, a weekly CBC was performed. A prothrombin time was done weekly during the first cycle, and then every 3 weeks until the end of the study. A comprehensive profile and PSA were repeated every 3 weeks. Measurable disease, when present, was re-evaluated with a CT scan or MRI scan every 12 weeks (four cycles). Patients with osseous metastases had a bone scan repeated every 12 weeks (four cycles).
Statistical Considerations
The primary objective was to determine the clinical activity and safety of ixabepilone with or without EMP in patients with castrate metastatic prostate cancer. The primary end point was the proportion of patients achieving a ≥ 50% post-therapy decline in PSA. A Simon two-stage design18 was applied separately to each treatment arm. In each arm, 22 patients were enrolled with plans to stop further accrual to that arm if seven or fewer patients achieved a ≥ 50% post-therapy decline in PSA. Both arms failed to meet criteria for early termination, and an additional 24 patients were subsequently enrolled on each arm. The study was designed to detect a post-treatment PSA decline (of ≥ 50%) in ≥ 50% of the study population, compared with the null hypothesis of ≤ 30%, with a significance level of .05 and a power of .90.
Criteria for Evaluation and End Point Definitions
Outcomes were assessed independently using CT or MRI, radionuclide bone scans, and post-therapy changes in serum PSA.19 Post-therapy declines in PSA of ≥ 50% were confirmed by three successive evaluations at least 2 weeks apart. Post-therapy declines of less than 50% were reported as stable. Time to PSA progression was calculated according to the PSA Working Group definition.20
For measurable disease, the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines21 were used, and radiographs were reviewed independently, with the reviewer blinded to clinical status. Bone scans were classified as stable/improved versus progression. A stable/improved bone scan required no new lesions or new pain in an area previously visualized. Progression signified new areas of focal uptake.
Toxicities were graded using Cancer Therapy Evaluation Program Common Toxicity Criteria, version 2.0.
RESULTS
Drug Delivery
Patients treated with ixabepilone + EMP received a median of five cycles (range, one to 16 cycles), while patients treated with ixabepilone alone received a median of four cycles (range, one to 29 cycles). Of the 264 total cycles administered on the combination arm, nine (3%) dose reductions of ixabepilone and three (1%) dose reductions of EMP were required. Of the 268 total cycles administered on the ixabepilone arm, eight (3%) dose reductions were required.
At a follow-up of 12 months, 44 of 45 patients on the combination arm and 46 of 47 patients on the ixabepilone-alone arm have discontinued treatment. Reasons for termination of therapy are presented in Table 2. Progressive disease during treatment occurred in 15 (34%) of 44 and 23 (50%) of 46 patients on the combination and single-agent arms, respectively. Treatment was terminated due to neurotoxicity in eight (18%) of 44 patients on the combination arm and 13 (28%) of 46 patients on the ixabepilone-alone arm.
Notably, nine of (20%) 44 patients on the ixabepilone + EMP arm and two of (4%) 46 patients on the ixabepilone-alone arm had treatment discontinued at the "patient's/physician's discretion." These patients all had received multiple cycles of treatment (median, eight; range, four to 16), achieved a decline in PSA, and developed grade 1-2 peripheral neuropathy.
Toxicities
The overall hematologic and nonhematologic toxicities in the 92 patients accrued to this study are presented in Table 3.
Hematologic toxicity. Neutropenia ≥ grade 3 developed in 13 patients (29%) on the ixabepilone + EMP arm, and 10 (22%) patients on the ixabepilone arm. In the majority of patients with ≥ grade 3 neutropenia (16 of 23), the duration of neutropenia was less than 7 days. There were four episodes (8%) of febrile neutropenia with the combination regimen and two episodes (4%) with single-agent ixabepilone. Thrombocytopenia was limited to ≤ grade 2 on both treatment arms.
Nonhematologic toxicity. Fatigue developed in the majority of patients on both treatment arms but was rarely ≥ grade 3 (9% on both arms). The fatigue was most severe during the week after treatment and improved during the week before initiation of the subsequent cycle. No patients experienced ≥ grade 3 nausea or vomiting. One patient (2%) on the combination arm and two patients (4%) on the ixabepilone arm developed allergic reactions; two of these patients received further therapy with steroid premedications without incident, while the other patient was taken off treatment after cycle 1 owing to additional toxicities. Four patients (8%) on the combination arm and no patients on the ixabepilone arm developed ≥ grade 3 thrombotic events.
Peripheral neuropathy. Peripheral sensory neuropathy developed in 32 patients (73%) on the ixabepilone + EMP arm (grade 1: 36%, grade 2: 30%, grade 3: 7%) and 31 patients (67%) on the ixabepilone arm (grade 1: 26%, grade 2: 28%, grade 3: 13%). The neuropathy was characterized by paresthesias, dysesthesias, or numbness, typically in a stocking-glove distribution, more pronounced in the lower extremities than the upper extremities.
Details regarding the course of neuropathy were extracted from the 43 patients treated at MSKCC, as long-term follow-up data on neuropathy were not available from the other participating centers once patients discontinued protocol treatment. Of these 43 patients, 36 developed neuropathy (grade 1: 17, grade 2: 15, grade 3: four). The median time to onset of grade 1 neuropathy was 52 days (range, 21 to 175 days), and the median time to onset of ≥ grade 2 neuropathy was approximately five cycles or 118 days (range, 8 to 248 days). Of the patients who developed ≥ grade 2 neuropathy, the majority (17 to 19 patients) required treatment termination for this reason. At a median follow-up of 413 days (range, 108 to 808 days), neuropathy improved to ≤ grade 1 in 18 (95%) of 19 patients who had experienced significant (grade ≥ 2) neuropathy. The median time to improvement to ≤ grade 1 neuropathy in these patients was 46 days (range, 15 to 259 days). Of the 36 patients who developed any grade neuropathy, the neuropathy resolved completely in 10 patients. However, the latter data are complicated by the fact that many patients with residual grade 1 neuropathy at the end of study went on to receive subsequent chemotherapeutic agents known to be neurotoxic, or were lost to follow-up.
Antitumor Outcomes
Antitumor outcomes for both treatment arms are presented in Table 4. Of note, four patients on the combination arm and two patients on the ixabepilone arm received one to two cycles of treatment, developed side effects, and were taken off study or withdrew consent. In addition, one patient randomly assigned to treatment with ixabepilone + EMP was diagnosed with a deep venous thrombosis on secondary review of his screening CT scan. This patient received one dose of EMP, did not receive ixabepilone, and was taken off study. No antitumor outcome data are available for these patients. However, they are all included in the intent-to-treat outcome analyses.
Post-treatment PSA decline. Thirty-one of 45 patients on the combination arm achieved a ≥ 50% post-treatment decline in PSA (69%; 95% CI, 55% to 82%). Of the 47 patients on the ixabepilone arm, three were not assessable for PSA outcomes due to baseline PSA values of less than 4 ng/mL, and 21 of 44 (48%; 95% CI, 33% to 64%) achieved a ≥ 50% post-treatment decline in PSA. All PSA declines were confirmed by three successive evaluations at least 2 weeks apart. The median time to achieve a ≥ 50% post-treatment decline in PSA was approximately two cycles or 42 days (range, 17 to 231), which was much earlier than the median time to development of significant (grade ≥ 2) neuropathy of approximately five cycles or 106 days (range, 5 to 273 days).
Measurable disease. Twenty-three patients on the combination arm had baseline measurable disease and 11 of 23 (48%; 95% CI, 27% to 68%) achieved an unconfirmed partial response. Of the 25 patients with baseline measurable disease on the ixabepilone arm, eight of 25 (32%; 95% CI, 14% to 50%) achieved an unconfirmed partial response. The majority of partial responses were not confirmed with a CT or MRI scan 1 month later due to lack of reimbursement for repeated scans, patient refusal, or patients lost to follow-up. However, the majority of partial responses (15 of 19) were corroborated by a ≥ 50% post-treatment decline in PSA.
Bone scans. Of the 36 patients with bone metastases on the combination arm, 28 of 36 (78%; 95% CI, 61% to 91%) had stable/improved disease on bone scan for at least 3 months, 15 (42%) of 36 had stable/improved disease for at least 6 months, and three (8%) of 36 had stable/improved disease for at least 9 months. Twenty-four of the 40 patients with bone metastases on the ixabepilone arm (60%; 95% CI, 45% to 75%) had stable/improved disease for at least 3 months, 14 (35%) of 40 had stable/improved disease for at least 6 months, and six (15%) of 40 had stable/improved disease for at least 9 months.
Time to PSA progression. The time to PSA progression TPP for the combination arm was 5.2 months (95% CI, 4.5 to 6.8 months), and the TPP for the ixabepilone-alone arm was 4.4 months (95% CI, 3.1 to 6.9 months).
DISCUSSION
This randomized phase II trial was not intended, nor powered, to directly compare the treatment arms. Rather, this design was chosen to rapidly evaluate the safety and activity of the combination and single agent in parallel. Both regimens have shown noteworthy activity. As expected, the addition of EMP did seem to increase toxicity, particularly nausea, vomiting, and thrombosis. The contribution of EMP to the efficacy of microtubule-based regimens remains controversial. While a large multiarm phase III trial could be considered to definitively address this issue, the results of the recently reported randomized trials involving docetaxel-based therapy suggest that any relative benefit of adding EMP is likely to be small.3,4 Based on these results, this question is likely not worthy of valuable patient resources.
Ixabepilone was generally well-tolerated, but peripheral neuropathy was a prominent side effect. The neuropathy was progressive with continued treatment in most patients, but improved in the vast majority on treatment cessation. Although a higher percentage of patients treated with ixabepilone alone discontinued treatment due to neuropathy, the overall rates of neuropathy on both treatment arms were similar. Prior studies have suggested that the neuropathy may be associated with both the dose and duration of infusion of ixabepilone.16,22 In an effort to reduce neurotoxicity, other schedules of administration, including daily x 5 and weekly dosing, are being explored.23,24 In our study, evidence of antitumor activity was typically observed before the onset of significant (grade ≥ 2) neuropathy. This suggests that an intermittent approach, in which treatment is continued until a plateau in PSA decline is achieved and reinstituted at early evidence of progression, may improve the therapeutic index.
The activity of ixabepilone in our multi-institutional trial is comparable to that achieved in phase II and III trials with docetaxel, the current first-line treatment standard in castrate metastatic prostate cancer.3,4,25,26 To optimally benefit patients, establishing clinical noncross resistance between these agents may be more important than determining which one is superior in the first-line setting. As has been shown in other metastatic solid tumors, incremental gains in survival may be achieved by insuring that patients are eventually exposed to all active non–cross-resistant agents, rather than focusing on the order in which they are administered. In an analysis of patients treated with second-line taxanes after discontinuing treatment with ixabepilone, we have shown that post-treatment declines in PSA (of ≥ 50%) were achieved in 58% (95% CI, 41% to 74%) of patients overall and 38% of patients who discontinued ixabepilone for progressive disease.27 Conversely, ixabepilone has shown activity in patients with metastatic breast cancer and lung cancer who had previously progressed on taxane-based therapy.28,29 The activity of ixabepilone in patients with taxane-refractory metastatic prostate cancer is being evaluated in ongoing prospective clinical trials. A randomized multicenter phase II trial is exploring ixabepilone (administered every 3 weeks) versus mitoxantrone in patients with taxane-refractory disease. The Eastern Cooperative Oncology Group is conducting a phase II trial of weekly ixabepilone in three cohorts of men: chemotherapy-naive, post-taxane therapy, or post–mitoxantrone therapy.
Studies are also ongoing to define markers predictive of response to epothilones in prostate cancer. Recent in vitro data suggest that mutational status of p53 and phosphorylation status of cdc2 may predict sensitivity to epothilones.30 As therapeutic options increase, predictive markers will be indispensable in the individualization and prioritization of therapies, and further studies are needed.
This trial establishes ixabepilone as an active agent in castrate metastatic prostate cancer. Studies are ongoing and are being planned to further define the role of ixabepilone in the emerging arsenal against this disease.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported in part by a grant from the Cancer Therapy Evaluation Program NIH-CM17105, Prostate Cancer Foundation, and PepsiCo Foundation.
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: Results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol 17:2506-2513, 1999
2. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. J Clin Oncol 14:1756-1764, 1996
3. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004
4. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004
5. Mareel MM, Storme GA, Dragonetti CH, et al: Antiinvasive activity of estramustine on malignant MO4 mouse cells and on DU-145 human prostate carcinoma cells in vitro. Cancer Res 48:1842-1849, 1988
6. Kreis W, Budman DR, Calabro A: Unique synergism or antagonism of combinations of chemotherapeutic and hormonal agents in human prostate cancer cell lines. Br J Urol 79:196-202, 1997
7. Speicher LA, Barone L, Tew KD: Combined antimicrotubule activity of estramustine and taxol in human prostatic carcinoma cell lines. Cancer Res 52:4433-4440, 1992
8. Berry W, Grengurich M, Dakhil S, et al: Phase II randomized study of weekly paclitaxel (Taxol) with or without estramustine phosphate in patients with symptomatic, hormone-refractory, metastatic carcinoma of the prostate. Proc Am Soc Clin Oncol 20:175, 2001 (abstr 696)
9. Hudes G, Einhorn L, Ross E, et al: Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 17:3160-3166, 1999
10. Petrylak D, Tangen C, Hussain M, et al: SWOG 99-16: Randomized phase III trial of docetaxel/estramustine versus mitoxantrone/prednisone in men with androgen independent prostate cancer. Proc Am Soc Clin Oncol 23:2, 2004 (abstr 3)
11. Hofle G, Bedorf N, Steinmetz H, et al: Epothilone A and B- Novel 16-membered macrolides with cytotoxic activity: Isolation, crystal structure, and comformation in solution. Agnew Chem Int Ed Engl 35:1567-1569, 1996
12. Bollag DM, McQueney PA, Zhu J, et al: Epothilones, a new class of microtubule-stabilizing agents with a taxol- like mechanism of action. Cancer Res 55:2325-2333, 1995
13. Sepp-Lorenzino L, Balog A, Su DS, et al: The microtubule-stabilizing agents epothilones A and B and their desoxy- derivatives induce mitotic arrest and apoptosis in human prostate cancer cells: Prostate Cancer Prostatic Dis 2:41-52, 1999
14. Newman RA, Yang J, Raymond M, et al: Antitumor efficacy of 26-fluoroepothilone B against human prostate cancer xenografts. Cancer Chemother Pharmacol 48:319-326, 2001
15. Lee FY, Borzilleri R, Fairchild CR, et al: BMS-247550: A novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7:1429-1437, 2001
16. Smaletz O, Galsky M, Scher HI, et al: Pilot study of epothilone B analog (BMS-247550) and estramustine phosphate in patients with progressive metastatic prostate cancer following castration. Ann Oncol 14:1518-1524, 2003
17. Ellis RE: The distribution of active bone marrow in the adult. Phys Med Biol 5:255-258, 1961
18. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989
19. Scher HI, Mazumdar M, Kelly WK: Clinical trials in relapsed prostate cancer: Defining the target. J Natl Cancer Inst 88:1623-1634, 1996
20. Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: Recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 17:3461-3467, 1999
21. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000
22. Delbado C, Lara PN, Vansteenkiste J, et al: Phase II study of the novel epothilone BMS-247550 in patients with recurrent or metastatic non-small cell lung cancer who have failed first-line platinum-based therapy. Proc Am Soc Clin Oncol 21:303a, 2002 (abstr 1211)
23. Burris H, Awada A, Jones S, et al: Phase I study of the novel epothilone BMS-247550 administered weekly in patients with advanced malignancies. Proc Am Soc Clin Oncol 21:104a, 2002 (abstr 412)
24. Abraham J, Agrawal M, Bakke S, et al: Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days. J Clin Oncol 21:1866-1873, 2003
25. Savarese DM, Halabi S, Hars V, et al: Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: A final report of CALGB 9780—Cancer and Leukemia Group B. J Clin Oncol 19:2509-2516, 2001
26. Petrylak DP: Chemotherapy for androgen-independent prostate cancer. Semin Urol Oncol 20:31-35, 2002
27. Rosenberg JE, Galsky MD, Weinberg V, et al: Response to second-line taxane-based therapy after first-line epothilone B analogue BMS-247550 therapy in hormone refractory prostate cancer. Proc Am Soc Clin Oncol 23:396, 2004 (abstr 4564)
28. Vansteenkiste J, Breton JL, Sandler A, et al: A randomized phase II study of epothilone analog BMS-247550 in patients with non-small cell lung cancer who have failed first-line platinum-based chemotherapy. Proc Am Soc Clin Oncol 22:626, 2003 (abstr 2519)
29. Thomas E, Tabernero J, Fornier M, et al: A phase II study of the epothilone B analog BMS-247550 in patients with taxane-resistant metastatic breast cancer. Proc Am Soc Clin Oncol 22:8, 2003 (abstr 30)
30. Ioffe ML, White E, Nelson DA, et al: Epothilone induced cytotoxicity is dependent on p53 status in prostate cells. Prostate 61:243-247, 2004(Matthew D. Galsky, Eric J)
University of California, San Francisco, CA
Dana-Farber Partners Cancer Care, Boston, MA
The University of Texas M.D. Anderson Cancer Center, Houston, TX
University of Michigan, Ann Arbor, MI
National Cancer Institute, Bethesda, MD
ABSTRACT
PATIENTS AND METHODS: Patients were randomly assigned to receive ixabepilone (35 mg/m2) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5.
RESULTS: Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of ≥ 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm.
CONCLUSION: Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.
INTRODUCTION
Microtubule targeting agents, including the vinca alkaloids and the taxanes, are among the most active drugs in castrate metastatic prostate cancer. In the early 1990s, preclinical studies suggested that the anticancer effects of these agents could be enhanced with the addition of estramustine phosphate (EMP), which binds complementary sites within the microtubule.5-7 In subsequent randomized phase II studies, combination regimens with EMP did result in significantly higher proportions of patients achieving prostate-specific antigen (PSA) declines, but at the cost of added toxicity.8 A randomized phase III trial demonstrated a trend toward improved survival with vinblastine + EMP compared with vinblastine alone; however, this study was limited by a small sample size and, perhaps, an overestimation of benefits.9 The current study was initiated before the publication of the results of the recent phase III trials involving docetaxel-based therapy, which suggest that any potential contribution of EMP to overall outcomes is likely to be small.3,10
The epothilones are a new class of cytotoxic tubulin polymerization agents obtained from the fermentation broth of the myxobacterium Sorangium cellulosum. These agents have demonstrated antineoplastic activity against a range of solid tumor cell lines and xenografts.11 While their target of action is similar to that of the taxanes, activity has also been shown in taxane-resistant models. In prostate cancer cells lines, epothilone B was the most active epothilone and inhibited growth seven- to 10-fold more effectively than paclitaxel.12-14 Ixabepilone (BMS-247550), an analog of epothilone B, was developed to optimize the antitumor efficacy and therapeutic index of this novel class.15
To expedite the development of ixabepilone for the treatment of patients with progressive castrate metastatic prostate cancer, we designed a two-stage program. First, given the prior experience showing increased activity with the addition of EMP to a second microtubule agent, we performed a dose escalation study to establish a safe dose of ixabepilone to use in combination with EMP. This combination proved to be well tolerated, with promising clinical activity.16 Subsequently, we initiated a multi-institutional (Memorial Sloan-Kettering Cancer Center [MSKCC], Dana-Farber Cancer Institute [DFCI], The University of Texas M.D. Anderson Cancer Center [MDACC], University of California at San Francisco [UCSF], University of Michigan [UM]) randomized phase II trial of ixabepilone, with or without EMP, to rapidly evaluate the clinical activity and safety of the single agent and combination in parallel.
PATIENTS AND METHODS
Exclusion Criteria
Excluded from the study were patients who had received prior palliative radiation therapy to more than 25% of the active bone marrow, as estimated based on the distribution of active bone marrow in the adult17; prior radioisotope therapy with strontium-89 or samarium-153; known brain metastases; a concurrent active malignancy other than nonmelanoma skin cancer; significant cardiovascular disease (New York Heart Association Class III or IV congestive heart failure, active angina pectoris, and/or myocardial infarction within the last 6 months); a bleeding disorder or recent gastrointestinal bleeding that would preclude anticoagulation; a history of hemorrhagic or thrombotic cerebral vascular accident; deep venous thrombosis or pulmonary embolism within 6 months before starting therapy; a history of allergic reactions to compounds of similar composition to the epothilones.
Randomization and Site Coordination
Patients were randomly assigned to treatment with ixabepilone alone or ixabepilone + EMP immediately after registration through the MSKCC Clinical Trials Office. Randomization was accomplished by the method of random permuted block. MSKCC served as the coordinating center for this trial.
Treatment Plan
Treatment arm 1 consisted of ixabepilone 35 mg/m2 administered intravenously over 3 hours on day 2 + EMP 280 mg orally three times daily on days 1 to 5 every 3 weeks. Warfarin 2 mg daily was administered for thromboembolic prophylaxis. Treatment arm 2 consisted of ixabepilone alone (35 mg/m2 administered intravenously over 3 hours every 3 weeks). Because ixabepilone is formulated in polyoxyethilated castor oil (CremophorEL), which can cause a hypersensitivity reaction during infusion, patients were premedicated with diphenhydramine 50 mg and ranitidine 150 mg orally 1 hour before infusion. Premedication with corticosteroids (dexamethasone 20 mg 12 hours and 6 hours before chemotherapy) was indicated only if patients developed a ≥ grade 3 hypersensitivity reaction with a prior administration if ixabepilone. Therapy was continued until disease progression or development of unacceptable toxicities.
Treatment Modifications
Patients received subsequent cycles of therapy every 3 weeks if absolute neutrophil count ≥ 1,500/mm3, platelets ≥ 100,000/mm3, and treatment-related nonhematologic toxicity had resolved to baseline or ≤ grade 1 (except fatigue or alopecia, grade 2). If these criteria were not met, treatment was delayed a maximum of 3 weeks. The dose of ixabepilone was reduced by 5 mg/m2 on subsequent cycles for: grade 4 neutropenia lasting 7 or more days; febrile neutropenia; grade ≥ 3 thrombocytopenia; more than 1 week delay in re-treatment due to drug toxicity; grade 3 nausea/vomiting or diarrhea; and/or grade 2 neuropathy (motor or sensory) lasting more than 7 days or grade 3 neuropathy lasting less than 7 days. Treatment was discontinued for grade 3 neuropathy lasting ≥ 7 days. For other toxicities ≥ grade 3, treatment was adjusted or discontinued as medically indicated after review by the investigator. Estramustine phosphate was held in case of: grade ≥ 2 nausea/vomiting; diarrhea with grade higher than 2; and/or bilirubin elevation of more than 1.5 x the upper normal limits or AST elevation higher than 5 x the upper normal limits. EMP was reintroduced with a 50% dose reduction (140 mg PO tid) after the toxicity resolved. If patients could not tolerate EMP, this could be discontinued, and the patent could continue ixabepilone alone. In case of an otherwise uncomplicated deep venous thrombosis, full anticoagulation was instituted, and patients continued EMP at the investigator's discretion. However, in case of pulmonary embolism or acute myocardial infarction, discontinuation of EMP was mandated.
Evaluation
Baseline examinations included a CBC, comprehensive profile (sodium, potassium, chloride, carbon dioxide, calcium, blood urea nitrogen, creatinine, glucose, albumin, alkaline phosphatase, ALT, AST, total bilirubin, and lactate dehydrogenase), partial thromboplastin time and prothrombin time, serum testosterone, and PSA. A chest radiograph, CT scan, or MRI scan of the abdomen and pelvis, and radionuclide bone scan were performed within 4 weeks before starting therapy.
During the study, a weekly CBC was performed. A prothrombin time was done weekly during the first cycle, and then every 3 weeks until the end of the study. A comprehensive profile and PSA were repeated every 3 weeks. Measurable disease, when present, was re-evaluated with a CT scan or MRI scan every 12 weeks (four cycles). Patients with osseous metastases had a bone scan repeated every 12 weeks (four cycles).
Statistical Considerations
The primary objective was to determine the clinical activity and safety of ixabepilone with or without EMP in patients with castrate metastatic prostate cancer. The primary end point was the proportion of patients achieving a ≥ 50% post-therapy decline in PSA. A Simon two-stage design18 was applied separately to each treatment arm. In each arm, 22 patients were enrolled with plans to stop further accrual to that arm if seven or fewer patients achieved a ≥ 50% post-therapy decline in PSA. Both arms failed to meet criteria for early termination, and an additional 24 patients were subsequently enrolled on each arm. The study was designed to detect a post-treatment PSA decline (of ≥ 50%) in ≥ 50% of the study population, compared with the null hypothesis of ≤ 30%, with a significance level of .05 and a power of .90.
Criteria for Evaluation and End Point Definitions
Outcomes were assessed independently using CT or MRI, radionuclide bone scans, and post-therapy changes in serum PSA.19 Post-therapy declines in PSA of ≥ 50% were confirmed by three successive evaluations at least 2 weeks apart. Post-therapy declines of less than 50% were reported as stable. Time to PSA progression was calculated according to the PSA Working Group definition.20
For measurable disease, the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines21 were used, and radiographs were reviewed independently, with the reviewer blinded to clinical status. Bone scans were classified as stable/improved versus progression. A stable/improved bone scan required no new lesions or new pain in an area previously visualized. Progression signified new areas of focal uptake.
Toxicities were graded using Cancer Therapy Evaluation Program Common Toxicity Criteria, version 2.0.
RESULTS
Drug Delivery
Patients treated with ixabepilone + EMP received a median of five cycles (range, one to 16 cycles), while patients treated with ixabepilone alone received a median of four cycles (range, one to 29 cycles). Of the 264 total cycles administered on the combination arm, nine (3%) dose reductions of ixabepilone and three (1%) dose reductions of EMP were required. Of the 268 total cycles administered on the ixabepilone arm, eight (3%) dose reductions were required.
At a follow-up of 12 months, 44 of 45 patients on the combination arm and 46 of 47 patients on the ixabepilone-alone arm have discontinued treatment. Reasons for termination of therapy are presented in Table 2. Progressive disease during treatment occurred in 15 (34%) of 44 and 23 (50%) of 46 patients on the combination and single-agent arms, respectively. Treatment was terminated due to neurotoxicity in eight (18%) of 44 patients on the combination arm and 13 (28%) of 46 patients on the ixabepilone-alone arm.
Notably, nine of (20%) 44 patients on the ixabepilone + EMP arm and two of (4%) 46 patients on the ixabepilone-alone arm had treatment discontinued at the "patient's/physician's discretion." These patients all had received multiple cycles of treatment (median, eight; range, four to 16), achieved a decline in PSA, and developed grade 1-2 peripheral neuropathy.
Toxicities
The overall hematologic and nonhematologic toxicities in the 92 patients accrued to this study are presented in Table 3.
Hematologic toxicity. Neutropenia ≥ grade 3 developed in 13 patients (29%) on the ixabepilone + EMP arm, and 10 (22%) patients on the ixabepilone arm. In the majority of patients with ≥ grade 3 neutropenia (16 of 23), the duration of neutropenia was less than 7 days. There were four episodes (8%) of febrile neutropenia with the combination regimen and two episodes (4%) with single-agent ixabepilone. Thrombocytopenia was limited to ≤ grade 2 on both treatment arms.
Nonhematologic toxicity. Fatigue developed in the majority of patients on both treatment arms but was rarely ≥ grade 3 (9% on both arms). The fatigue was most severe during the week after treatment and improved during the week before initiation of the subsequent cycle. No patients experienced ≥ grade 3 nausea or vomiting. One patient (2%) on the combination arm and two patients (4%) on the ixabepilone arm developed allergic reactions; two of these patients received further therapy with steroid premedications without incident, while the other patient was taken off treatment after cycle 1 owing to additional toxicities. Four patients (8%) on the combination arm and no patients on the ixabepilone arm developed ≥ grade 3 thrombotic events.
Peripheral neuropathy. Peripheral sensory neuropathy developed in 32 patients (73%) on the ixabepilone + EMP arm (grade 1: 36%, grade 2: 30%, grade 3: 7%) and 31 patients (67%) on the ixabepilone arm (grade 1: 26%, grade 2: 28%, grade 3: 13%). The neuropathy was characterized by paresthesias, dysesthesias, or numbness, typically in a stocking-glove distribution, more pronounced in the lower extremities than the upper extremities.
Details regarding the course of neuropathy were extracted from the 43 patients treated at MSKCC, as long-term follow-up data on neuropathy were not available from the other participating centers once patients discontinued protocol treatment. Of these 43 patients, 36 developed neuropathy (grade 1: 17, grade 2: 15, grade 3: four). The median time to onset of grade 1 neuropathy was 52 days (range, 21 to 175 days), and the median time to onset of ≥ grade 2 neuropathy was approximately five cycles or 118 days (range, 8 to 248 days). Of the patients who developed ≥ grade 2 neuropathy, the majority (17 to 19 patients) required treatment termination for this reason. At a median follow-up of 413 days (range, 108 to 808 days), neuropathy improved to ≤ grade 1 in 18 (95%) of 19 patients who had experienced significant (grade ≥ 2) neuropathy. The median time to improvement to ≤ grade 1 neuropathy in these patients was 46 days (range, 15 to 259 days). Of the 36 patients who developed any grade neuropathy, the neuropathy resolved completely in 10 patients. However, the latter data are complicated by the fact that many patients with residual grade 1 neuropathy at the end of study went on to receive subsequent chemotherapeutic agents known to be neurotoxic, or were lost to follow-up.
Antitumor Outcomes
Antitumor outcomes for both treatment arms are presented in Table 4. Of note, four patients on the combination arm and two patients on the ixabepilone arm received one to two cycles of treatment, developed side effects, and were taken off study or withdrew consent. In addition, one patient randomly assigned to treatment with ixabepilone + EMP was diagnosed with a deep venous thrombosis on secondary review of his screening CT scan. This patient received one dose of EMP, did not receive ixabepilone, and was taken off study. No antitumor outcome data are available for these patients. However, they are all included in the intent-to-treat outcome analyses.
Post-treatment PSA decline. Thirty-one of 45 patients on the combination arm achieved a ≥ 50% post-treatment decline in PSA (69%; 95% CI, 55% to 82%). Of the 47 patients on the ixabepilone arm, three were not assessable for PSA outcomes due to baseline PSA values of less than 4 ng/mL, and 21 of 44 (48%; 95% CI, 33% to 64%) achieved a ≥ 50% post-treatment decline in PSA. All PSA declines were confirmed by three successive evaluations at least 2 weeks apart. The median time to achieve a ≥ 50% post-treatment decline in PSA was approximately two cycles or 42 days (range, 17 to 231), which was much earlier than the median time to development of significant (grade ≥ 2) neuropathy of approximately five cycles or 106 days (range, 5 to 273 days).
Measurable disease. Twenty-three patients on the combination arm had baseline measurable disease and 11 of 23 (48%; 95% CI, 27% to 68%) achieved an unconfirmed partial response. Of the 25 patients with baseline measurable disease on the ixabepilone arm, eight of 25 (32%; 95% CI, 14% to 50%) achieved an unconfirmed partial response. The majority of partial responses were not confirmed with a CT or MRI scan 1 month later due to lack of reimbursement for repeated scans, patient refusal, or patients lost to follow-up. However, the majority of partial responses (15 of 19) were corroborated by a ≥ 50% post-treatment decline in PSA.
Bone scans. Of the 36 patients with bone metastases on the combination arm, 28 of 36 (78%; 95% CI, 61% to 91%) had stable/improved disease on bone scan for at least 3 months, 15 (42%) of 36 had stable/improved disease for at least 6 months, and three (8%) of 36 had stable/improved disease for at least 9 months. Twenty-four of the 40 patients with bone metastases on the ixabepilone arm (60%; 95% CI, 45% to 75%) had stable/improved disease for at least 3 months, 14 (35%) of 40 had stable/improved disease for at least 6 months, and six (15%) of 40 had stable/improved disease for at least 9 months.
Time to PSA progression. The time to PSA progression TPP for the combination arm was 5.2 months (95% CI, 4.5 to 6.8 months), and the TPP for the ixabepilone-alone arm was 4.4 months (95% CI, 3.1 to 6.9 months).
DISCUSSION
This randomized phase II trial was not intended, nor powered, to directly compare the treatment arms. Rather, this design was chosen to rapidly evaluate the safety and activity of the combination and single agent in parallel. Both regimens have shown noteworthy activity. As expected, the addition of EMP did seem to increase toxicity, particularly nausea, vomiting, and thrombosis. The contribution of EMP to the efficacy of microtubule-based regimens remains controversial. While a large multiarm phase III trial could be considered to definitively address this issue, the results of the recently reported randomized trials involving docetaxel-based therapy suggest that any relative benefit of adding EMP is likely to be small.3,4 Based on these results, this question is likely not worthy of valuable patient resources.
Ixabepilone was generally well-tolerated, but peripheral neuropathy was a prominent side effect. The neuropathy was progressive with continued treatment in most patients, but improved in the vast majority on treatment cessation. Although a higher percentage of patients treated with ixabepilone alone discontinued treatment due to neuropathy, the overall rates of neuropathy on both treatment arms were similar. Prior studies have suggested that the neuropathy may be associated with both the dose and duration of infusion of ixabepilone.16,22 In an effort to reduce neurotoxicity, other schedules of administration, including daily x 5 and weekly dosing, are being explored.23,24 In our study, evidence of antitumor activity was typically observed before the onset of significant (grade ≥ 2) neuropathy. This suggests that an intermittent approach, in which treatment is continued until a plateau in PSA decline is achieved and reinstituted at early evidence of progression, may improve the therapeutic index.
The activity of ixabepilone in our multi-institutional trial is comparable to that achieved in phase II and III trials with docetaxel, the current first-line treatment standard in castrate metastatic prostate cancer.3,4,25,26 To optimally benefit patients, establishing clinical noncross resistance between these agents may be more important than determining which one is superior in the first-line setting. As has been shown in other metastatic solid tumors, incremental gains in survival may be achieved by insuring that patients are eventually exposed to all active non–cross-resistant agents, rather than focusing on the order in which they are administered. In an analysis of patients treated with second-line taxanes after discontinuing treatment with ixabepilone, we have shown that post-treatment declines in PSA (of ≥ 50%) were achieved in 58% (95% CI, 41% to 74%) of patients overall and 38% of patients who discontinued ixabepilone for progressive disease.27 Conversely, ixabepilone has shown activity in patients with metastatic breast cancer and lung cancer who had previously progressed on taxane-based therapy.28,29 The activity of ixabepilone in patients with taxane-refractory metastatic prostate cancer is being evaluated in ongoing prospective clinical trials. A randomized multicenter phase II trial is exploring ixabepilone (administered every 3 weeks) versus mitoxantrone in patients with taxane-refractory disease. The Eastern Cooperative Oncology Group is conducting a phase II trial of weekly ixabepilone in three cohorts of men: chemotherapy-naive, post-taxane therapy, or post–mitoxantrone therapy.
Studies are also ongoing to define markers predictive of response to epothilones in prostate cancer. Recent in vitro data suggest that mutational status of p53 and phosphorylation status of cdc2 may predict sensitivity to epothilones.30 As therapeutic options increase, predictive markers will be indispensable in the individualization and prioritization of therapies, and further studies are needed.
This trial establishes ixabepilone as an active agent in castrate metastatic prostate cancer. Studies are ongoing and are being planned to further define the role of ixabepilone in the emerging arsenal against this disease.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported in part by a grant from the Cancer Therapy Evaluation Program NIH-CM17105, Prostate Cancer Foundation, and PepsiCo Foundation.
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: Results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol 17:2506-2513, 1999
2. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. J Clin Oncol 14:1756-1764, 1996
3. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004
4. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004
5. Mareel MM, Storme GA, Dragonetti CH, et al: Antiinvasive activity of estramustine on malignant MO4 mouse cells and on DU-145 human prostate carcinoma cells in vitro. Cancer Res 48:1842-1849, 1988
6. Kreis W, Budman DR, Calabro A: Unique synergism or antagonism of combinations of chemotherapeutic and hormonal agents in human prostate cancer cell lines. Br J Urol 79:196-202, 1997
7. Speicher LA, Barone L, Tew KD: Combined antimicrotubule activity of estramustine and taxol in human prostatic carcinoma cell lines. Cancer Res 52:4433-4440, 1992
8. Berry W, Grengurich M, Dakhil S, et al: Phase II randomized study of weekly paclitaxel (Taxol) with or without estramustine phosphate in patients with symptomatic, hormone-refractory, metastatic carcinoma of the prostate. Proc Am Soc Clin Oncol 20:175, 2001 (abstr 696)
9. Hudes G, Einhorn L, Ross E, et al: Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 17:3160-3166, 1999
10. Petrylak D, Tangen C, Hussain M, et al: SWOG 99-16: Randomized phase III trial of docetaxel/estramustine versus mitoxantrone/prednisone in men with androgen independent prostate cancer. Proc Am Soc Clin Oncol 23:2, 2004 (abstr 3)
11. Hofle G, Bedorf N, Steinmetz H, et al: Epothilone A and B- Novel 16-membered macrolides with cytotoxic activity: Isolation, crystal structure, and comformation in solution. Agnew Chem Int Ed Engl 35:1567-1569, 1996
12. Bollag DM, McQueney PA, Zhu J, et al: Epothilones, a new class of microtubule-stabilizing agents with a taxol- like mechanism of action. Cancer Res 55:2325-2333, 1995
13. Sepp-Lorenzino L, Balog A, Su DS, et al: The microtubule-stabilizing agents epothilones A and B and their desoxy- derivatives induce mitotic arrest and apoptosis in human prostate cancer cells: Prostate Cancer Prostatic Dis 2:41-52, 1999
14. Newman RA, Yang J, Raymond M, et al: Antitumor efficacy of 26-fluoroepothilone B against human prostate cancer xenografts. Cancer Chemother Pharmacol 48:319-326, 2001
15. Lee FY, Borzilleri R, Fairchild CR, et al: BMS-247550: A novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7:1429-1437, 2001
16. Smaletz O, Galsky M, Scher HI, et al: Pilot study of epothilone B analog (BMS-247550) and estramustine phosphate in patients with progressive metastatic prostate cancer following castration. Ann Oncol 14:1518-1524, 2003
17. Ellis RE: The distribution of active bone marrow in the adult. Phys Med Biol 5:255-258, 1961
18. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989
19. Scher HI, Mazumdar M, Kelly WK: Clinical trials in relapsed prostate cancer: Defining the target. J Natl Cancer Inst 88:1623-1634, 1996
20. Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: Recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 17:3461-3467, 1999
21. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000
22. Delbado C, Lara PN, Vansteenkiste J, et al: Phase II study of the novel epothilone BMS-247550 in patients with recurrent or metastatic non-small cell lung cancer who have failed first-line platinum-based therapy. Proc Am Soc Clin Oncol 21:303a, 2002 (abstr 1211)
23. Burris H, Awada A, Jones S, et al: Phase I study of the novel epothilone BMS-247550 administered weekly in patients with advanced malignancies. Proc Am Soc Clin Oncol 21:104a, 2002 (abstr 412)
24. Abraham J, Agrawal M, Bakke S, et al: Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days. J Clin Oncol 21:1866-1873, 2003
25. Savarese DM, Halabi S, Hars V, et al: Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: A final report of CALGB 9780—Cancer and Leukemia Group B. J Clin Oncol 19:2509-2516, 2001
26. Petrylak DP: Chemotherapy for androgen-independent prostate cancer. Semin Urol Oncol 20:31-35, 2002
27. Rosenberg JE, Galsky MD, Weinberg V, et al: Response to second-line taxane-based therapy after first-line epothilone B analogue BMS-247550 therapy in hormone refractory prostate cancer. Proc Am Soc Clin Oncol 23:396, 2004 (abstr 4564)
28. Vansteenkiste J, Breton JL, Sandler A, et al: A randomized phase II study of epothilone analog BMS-247550 in patients with non-small cell lung cancer who have failed first-line platinum-based chemotherapy. Proc Am Soc Clin Oncol 22:626, 2003 (abstr 2519)
29. Thomas E, Tabernero J, Fornier M, et al: A phase II study of the epothilone B analog BMS-247550 in patients with taxane-resistant metastatic breast cancer. Proc Am Soc Clin Oncol 22:8, 2003 (abstr 30)
30. Ioffe ML, White E, Nelson DA, et al: Epothilone induced cytotoxicity is dependent on p53 status in prostate cells. Prostate 61:243-247, 2004(Matthew D. Galsky, Eric J)