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Multi-Institutional Randomized Phase II Trial of the Epothilone B Analog Ixabepilone (BMS-247550) With or Without Estramustine Phosphate in Patients With Progressive Castrate Metastatic Prostate Cancer

From 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

Address reprint requests to Matthew D. Galsky, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: galskym{at}mskcc.org

	ABSTRACT

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PURPOSE: To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer.

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

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The prior assertion that chemotherapy is ineffective in the treatment of prostate cancer has been refuted. In randomized comparisons, cytotoxic agents have now been shown to palliate symptoms^1,2 and prolong life^3,4 in patients with castrate (androgen-independent) metastatic prostate cancer. Despite these advances, with current therapies, response durations are often short, and many patients do not respond. Clearly, additional therapeutic agents are needed.

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

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Inclusion Criteria
Chemotherapy-naive patients with histologically proven adenocarcinoma of the prostate that had progressed despite castration, were eligible for enrollment. Progressive castrate disease was defined as serum testosterone 50 ng/mL and one of the following: a minimum of three consecutive rises in PSA (with the last value 4 ng/mL); new metastatic lesions on bone scan; and/or new or progressive measurable disease on computed tomography (CT) scan or magnetic resonance image (MRI). Patients previously treated with an antiandrogen were required to have disease progression documented after antiandrogen withdrawal. Those who had not undergone orchiectomy were required to continue medical castration with a gonadotropin-releasing hormone analog. Additional eligibility included age 18 years, Karnofsky performance status 70%, and adequate hematologic function (WBC 3,000/µL, absolute neutrophil count [ANC] 1,500/µL, platelet count 100,000/µL), hepatic function (bilirubin level within normal limits, AST and ALT 2.5 x the upper normal limit), and renal function (serum creatinine level 1.5 x the upper limits of normal). The protocol was approved by the institutional review board at each participating institution, and written informed consent was obtained from each patient before study entry.

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

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Patient Characteristics
Ninety-two patients were accrued to this study; 45 were randomly assigned to treatment with ixabepilone + EMP; and 47 were randomized to treatment with ixabepilone alone. The baseline clinical characteristics are summarized in Table 1. The majority of patients (> 66%) had been treated with more than three prior hormonal manipulations, not including antiandrogen withdrawal. No patients had received prior chemotherapy. Accrual across sites was as follows: MSKCC, 43; UCSF, 20; DFCI, 18; MDACC, 10; UM, 1.

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.

Toxicities
The overall hematologic and nonhematologic toxicities in the 92 patients accrued to this study are presented in Table 3.

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.

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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Our program was designed to expedite the development of the epothilone B analog, ixabepilone, in patients with progressive castrate metastatic prostate cancer. This program fulfilled its goal, taking ixabepilone, an agent never before utilized in prostate cancer, through phase I and multicenter phase II testing in 27 months. Ixabepilone, with and without EMP, has exhibited significant clinical activity both with respect to post-treatment PSA decline and regression of measurable disease.

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

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Eric J. Small, Bristol-Myers Squibb; Howard I. Scher, Bristol-Myers Squibb; W. Kevin Kelly, Bristol-Myers Squibb. Research Funding: Howard I. Scher, Bristol-Myers Squibb. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.

	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.

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Submitted September 15, 2004; accepted December 13, 2004.

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