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Keywords:

  • ixabepilone;
  • phase 2 trial;
  • urothelial carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Paclitaxel and docetaxel are active agents in advanced urothelial cancer. BMS-247550 (ixabepilone) has activity in preclinical models in paclitaxel resistant models. A phase 2 trial of this epothilone was performed to determine the activity and toxicity of this agent in a multi-institutional setting in patients previously treated with 1 prior chemotherapy regimen.

METHODS.

Forty-five patients with advanced urothelial carcinoma were treated with BMS-247550 40 mg/m2 over 3 hours intravenously on Day 1 of a 21-day cycle and continued therapy until progression or unacceptable toxicity.

RESULTS.

Five patients obtained an objective partial response (PR) among the 42 eligible patients for an overall response rate of 11.9% (90% confidence interval [5.3%, 26.5%]). Median overall survival of the group was 8 months. Toxicity was moderate with granulocytopenia, fatigue, and sensory neuropathy being the most common side effects noted.

CONCLUSIONS.

BMS-247550 (ixabepilone) has very modest activity as a second-line therapy for advanced urothelial cancer. Responses in visceral, nodal, and soft tissues sites were observed. Granulocytopenia without fever, fatigue, and sensory neuropathy was common. Cancer 2007. © 2007 American Cancer Society.

Advanced transitional cell carcinoma is a moderately chemosensitive neoplasm. The M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) regimen, long considered the standard initial regimen for advanced disease, has gradually been replaced by the gemcitabine + cisplatin (GC) doublet based on a phase 3 trial comparing M-VAC to GC that demonstrated comparable activity with a somewhat improved toxicity profile favoring GC.1

Over the last 15 years a large number of new agents and combination regimens have been tested in advanced urothelial cancer. Many of these agents including paclitaxel, pemetrexed, and docetaxel have exhibited activity against advanced transitional cell carcinoma, although none of the doublets/triple combinations studied to date have demonstrated improved survival compared with the M-VAC regimen.2–5

During the past 2 decades a clinically evident stage migration6 has led to earlier appreciation of metastatic disease. Concomitantly there has been an increased utilization of neoadjuvant and adjuvant chemotherapy resulting in an increasing proportion of patients fit enough to be considered for second-line chemotherapy for metastatic disease. Recent phase 2 studies evaluating second-line chemotherapy have demonstrated objective response rates in the 10% to 25% range for a variety of single agents and combination regimens.7–9

The epothilones are novel nontaxane tubulin polymerization agents obtained by fermentation of the myxobacteria Sorangium cellulosum. Aza-epothilone B (BMS-247550; ixabepilone) is a semisynthetic analog of the natural product epothilone B.10 In preclinical models epothilones A and B have broad-spectrum antineoplastic activity as demonstrated against several human cancer xenografts including paclitaxel-resistant tumors.11 In preclinical models (BMS-247550; ixabepilone) paclitaxel-resistant tumor xenografts were also highly susceptible to the antitumor action of BMS-247550.12

Phase 1 trials of BMS-247550 (ixabepilone) tested several different schedules including a 60-minute infusion every 21 days, a daily-times-5 every 21-day schedule, and daily-times-3 every 21-day schedule. Antitumor responses were seen in patients with a variety of epithelial cancers, many previously treated with paclitaxel- or docetaxel-containing regimens. A dosing schedule of 40 mg/m2 once every 3 weeks as a single agent was recommended and adopted for phase 2 testing.13–15

Based on the demonstrated activity of taxanes in advanced urothelial cancer, the Eastern Cooperative Oncology Group (ECOG) investigated BMS-247550 (ixabepilone) therapy in patients with progressive advanced urothelial cancer after front-line chemotherapy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Eligible patients had histologically confirmed transitional cell carcinoma (or mixed histologies containing a component of transitional cell carcinoma) of the urothelium with evidence of progressive, bidimensionally measurable regional or metastatic disease. Patients must have been disease-free from prior malignancies for at least 5 years, with an ECOG performance status of 0 to 2 at entry. Patients must have demonstrated progressive disease after 1 and only 1 prior cisplatin- or carboplatin-containing chemotherapy regimen (minimum of 4 weeks from completion of therapy), which may have been given in the adjuvant, neoadjuvant or metastatic setting and may have included a taxane. Patients must have been at least 4 weeks out from major surgery. Adequate renal and hepatic function were required with a serum creatinine ≤1.5 mg/dL, aspartate aminotransferase (AST) ≤2.5, and bilirubin ≤1.5 times the upper limit of normal. Adequate bone marrow reserve was mandated with a requirement for neutrophils ≥1500 mm3 and a platelet count ≥100,000/μL at entry. Patients with significant congestive heart failure, severe ventricular arrhythmias, or grade 2 or greater peripheral neuropathy were excluded. Written informed consent was obtained from all patients.

BMS-247550 was administered intravenously over 3 hours at a dose of 40 mg/m2 on Day 1 with cycles repeated every 21 days, but were not started until the absolute neutrophil count was ≥1500/μL, the platelet count ≥100,000/μL. Dose modifications of up to 50% were mandated for febrile neutropenia or neurotoxicity.

Before study entry, all patients underwent physical examination and had their ECOG performance status and weight documented. There also were pretherapy complete blood count (CBC) and differential, serum creatinine, BUN, AST, bilirubin, and computed tomograms (CT) of chest and/or abdomen. A CBC and the above chemistries were repeated on the first day of each subsequent therapy cycle. Tumor measurements were performed with each cycle of therapy if determined by physical examination or every other cycle if evaluation required chest radiographs or CT scans.

Each site was required to have approval of this clinical trial by a local Human Investigations Committee in accord with an assurance filed with and approved by the Department of Health and Human Services. All patients provided written informed consent before registration onto this study.

Tumor responses were analyzed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. National Cancer Institute (NCI) common toxicity criteria (CTCAE version 2) were used to analyze toxicity. Patients with objective responses or stable disease were continued on therapy until development of unacceptable toxicity.

At the time the study was designed a response rate of 25% or greater was considered to represent activity that would be of interest. A response rate of 10% would represent an agent not worth further study. The study was designed with 2 stages of accrual. Twenty patients were planned for the first stage of accrual. If 2 or more responses were observed among the first 17 eligible patients the study was planned to accrue up to an additional 25 patients (23 eligible). If 7 or more responses were observed among 40 eligible patients, the treatment would be considered worthy of further study.

Descriptive statistics were used to analyze the characteristics of the patients at study entry. Exact binomial confidence intervals were computed for response rates. The method of Kaplan and Meier16 was used to characterize overall survival and progression-free survival. Overall survival was computed from the time of registration to death. Progression-survival was computed from the time of registration to death or progression, whichever occurred first. For patients who were still alive and progression free, then that patient was censored at the date of last disease assessment.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

From May of 2001 through January of 2005, 45 patients from 17 ECOG institutions were entered to the study and were evaluable for toxicity. Three patients were deemed ineligible, 1 having received 2 previous chemotherapy regimens and 2 patients who did not have baseline disease measurements within 4 weeks of registration. All 42 eligible patients had tumors that were histologically pure or predominantly transitional cell carcinoma. The bladder was the primary site of disease in 33 patients. There were multiple sites involved in 10 patients, with 9 patients each having renal pelvis lesions, 8 ureteral, and 2 urethral disease. Thirty patients underwent primary surgical resection (21 cystectomy, 9 nephrectomy) Three patients had received their initial therapy in the neoadjuvant setting, 17 in the adjuvant setting, and 22 as therapy for metastatic disease. Seventeen (40%) patients had received chemotherapy including a taxane as part of their initial therapy.

The median number of BMS-247550 cycles administered for the entire group was 3 (range, 1–8); for patients who had previously received a taxane-containing regimen the median number was 2 (range, 1–6), in contrast to 3.5 (range, 1–8) for patients without previous taxane exposure. Additional patient characteristics including a breakdown of known prognostic factors are listed in Table 1.17

Table 1. Patient Characteristics
CharacteristicsNo. of patients (%)
  • ECOG indicates Eastern Cooperative Oncology Group; MSK, Memorial Sloan-Kettering.

  • *

    Bajorin et al.17

Age, y, median [range]63 [37–81]
Sex
 Men34 (81)
 Women8 (19)
ECOG performance status
 013 (31)
 126 (62)
 23 (7)
Sites of metastases
 Liver17 (26)
 Lung18 (28)
 Bone8 (12)
 Soft tissue/lymph nodes17 (26)
Prognostic factors (MSK)*
 0 risk factors11 (26)
 1 risk factors28 (67)
 2 risk factors3 (7)

Toxicity

Toxicity data were available for all 45 patients, of whom 12 had a worst degree toxicity grade 4 or higher. There was 1 treatment-related death secondary to a febrile neutropenic event. Clinically significant hematologic toxicity manifested primarily as granulocytopenia. Sixteen patients experienced grade 3 or 4 granulocytopenia. However, only 4 patients experienced neutropenic fever. Five patients had grade 3 thrombocytopenia and 1 patient developed grade 3 anemia. Clinically significant (grades 3 and 4) nonhematologic toxicity included 3 patients with sensory neuropathy, 5 patients with grade 3 fatigue, 4 patients with grade 3 dehydration, and 1 each of grade 3 renal failure, supraventricular arrhythmia, and pneumonitis.

Response

Forty-two patients were assessable for response to therapy, with 6 deemed unevaluable (2 died before first evaluation, 4 others had incomplete baseline or follow-up information). Five patients obtained an objective partial response (PR) for an overall response rate of 11.9% (90% confidence interval [CI], 5.3%, 26.5%). Three PRs were observed among patients who had received prior taxane-based therapy. Forty-one patients have progressed or died. The median progression-free survival was 2.7 months, with 1- and 2-year estimates of 5% and 2%, respectively (Fig. 1). At the time of this report, 39 (93%) patients have died. The median follow-up for the 3 remaining patients was 20 months. The median overall survival was 8 months, with 1- and 2-year estimates of 17% and 10%, respectively (Fig. 2).

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Figure 1. Progression-free survival for all patients.

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Figure 2. Overall survival for all patients.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Although there has been only modest progress made in the management of advanced urothelial cancer over the past 15 years, a clinically relevant stage migration has occurred, with patients by and large having improved performance status at diagnosis. In addition, evidence supporting a survival benefit from the use of neoadjuvant chemotherapy18, 19 has significantly increased utilization of perioperative chemotherapy, in turn leading to an enlarging number of patients with metastatic disease having already received front-line chemotherapy. As a consequence, there is an expanding, albeit still modest, number of patients with advanced urothelial cancer fit enough to receive second-line chemotherapy.

A number of phase 2 trials in the salvage setting have been reported.4, 7, 9, 20–22 Among the first trials to evaluate a second line therapy was Witte et al.,7 who conducted a cooperative group multicenter phase 2 trial evaluation of ifosfamide, demonstrating a response rate of 20%, with 5 patients obtaining complete response. The toxicity associated with this therapy was not insignificant, with myelosuppression and renal toxicity being problematic. McCaffrey et al.4 treated 30 patients with residual or progressive disease after cisplatin-based combination therapy with docetaxel at 100 mg/m2 administered on a 3-week schedule. Four (13%) patients achieved a partial response. Sternberg et al.21 treated 41 patients who had previously been treated with cisplatin-based regimens (primarily M-VAC) with gemcitabine and paclitaxel and observed an impressive 60% response rate, with 11 patients achieving a complete response. The median survival in this experience was 14.4 months. Of note, 63% of the patients enrolled had received their initial chemotherapy in either the neoadjuvant or adjuvant settings.

Response rates in phase 2 trials of advanced bladder cancer can be significantly influenced by patient selection, as described by Bajorin et al.17 In the salvage setting other factors in addition to those described by Bajorin et al. will likely influence response rates, including the time to disease progression, the drugs initially received, and the setting of initial chemotherapy, ie, adjuvant/neoadjuvant vs therapy for metastatic disease. Despite variable objective response rates demonstrated in many phase 2 trials of cytotoxics in the salvage setting, the therapeutic goal of treatment in this setting remains palliation of disease-related symptoms, given the lack of evidence that therapy impacts either disease-free or overall survival.

Given the modest activity of BMS-247550 (ixabepilone) noted in this phase 2 trial, the degree of significant myelosuppression including 1 patient death secondary to neutropenic sepsis is problematic. Investigators from the Southwest Oncology Group conducted a phase 2 trial of the same dose and schedule of BMS-247550 (ixabepilone) in 42 chemotherapy-naive patients with advanced prostate cancer. Although interesting antitumor activity was observed, grade 3 and 4 adverse events occurred in 16 and 3 patients, respectively. All grade 4 toxicities were neutropenia or leukopenia.23

In summary, in this clinical setting, BMS-247550 (ixabepilone) has very modest activity at the expense of moderate toxicity, primarily myelosuppression. Further development of this agent in urothelial cancer seems unwarranted.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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