1 Department of Medicine, Section of Hematology/Oncology and 2 Department of Health Studies, University of Chicago, Chicago, IL; 3 Fort Wayne Medical Center, Fort Wayne, IN; 4 Northern Indiana Cancer Research Consortium, South Bend, IN, USA
Received 17 February 2004; revised 25 February 2004; accepted 26 February 2004
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ABSTRACT |
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The epothilone B analog, BMS-247550, is a non-taxane microtubulin-stabilizing agent with preclinical activity in taxane-resistant cell lines and phase I activity in colorectal cancer. We conducted a phase II study of single-agent BMS-247550 in advanced colorectal cancer patients who had disease progression following treatment with irinotecan5-fluorouracilleucovorin (IFL).
Patients and methods:
Patients were required to have histologically or cytologically confirmed advanced or metastatic colorectal cancer; progressed on or after chemotherapy with IFL; Eastern Cooperative Oncology Group performance status 1; peripheral neuropathy grade
1; and adequate laboratory parameters. BMS-247550 40 mg/m2 was administered intravenously over 3 h every 3 weeks. Patients were evaluated for response every 6 weeks.
Results:
Twenty-five patients were enrolled; all were evaluable for toxicity and 23 were evaluable for response. There were no complete or partial responses. Thirteen patients (56%) had stable disease after two cycles of therapy; five patients (20%) received six or more cycles. The median time to progression was 11 weeks; median overall survival was 36 weeks. There was considerable grade 3/4 hematological toxicity, including neutropenia (48%) and leukopenia (36%). Grade 3/4 non-hematological toxicities included grade 3 hypersensitivity reaction (12%) and peripheral neuropathy (20%).
Conclusions:
Single-agent BMS-247550 (40 mg/m2) administered every 21 days demonstrated no activity in advanced colorectal cancer. Peripheral neuropathy was treatment-limiting.
Key words: colorectal cancer, epothilone, phase II trial
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Introduction |
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The taxanes are microtubulin-stabilizing agents with clinical activity in multiple solid tumors, but not in colorectal cancer. Development of resistance to the taxanes is attributed to the overexpression of the multidrug-resistant efflux pump, p-glycoprotein. The epothilones are non-taxane, tubulin polymerizing agents that have preclinical activity in taxane-resistant cell lines.
The epothilone B analog, BMS-247550, is a semisynthetic drug derived from fermentation of the myxobacterium, Sorangium cellosum. In vitro, it has more potent preclinical activity than paclitaxel, and has demonstrated in vivo activity in taxane-resistant lung, breast, colon and prostate cell lines [5, 6]. Similar to the taxanes, the epothilones result in microtubule stabilization and mitotic cell cycle arrest at the G2/M transition. However, in contrast to paclitaxel, resistance to BMS-247550 may be a result of ß-tubulin mutations rather than overexpression of p-glycoprotein, thus allowing activity in multidrug-resistant cell lines [6, 7].
Myelosuppression was the dose-limiting toxicity in the initial phase I studies of BMS-247550, and the recommended phase II dose was 50 mg/m2 administered over 1 h repeated every 21 days. The single-agent activity profile of BMS-247550 included ovarian, breast, lung and colon cancer [810]. Therefore, we evaluated BMS-247550 in patients with metastatic colorectal carcinoma who developed disease progression following IFL chemotherapy.
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Patients and methods |
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Exclusion criteria included: poorly controlled physical or psychological illness; history of HIV; history of allergic reaction to compounds containing polyoxyethylated castor oil (Cremophor®EL); pregnancy or lactation; and brain metastases. Other exclusion criteria included concurrent investigational drugs or unconventional therapies, food or vitamin supplements containing the CYP3A4 inhibitor, St Johns Wort; cimetidine must have been discontinued for 7 days prior to initiating therapy. Patients with active or previously treated malignancy considered by the treating physician to have a >30% risk of relapse were excluded. All patients provided written informed consent according to federal and institutional guidelines.
Pretreatment evaluation
On study entry, all patients had a history and physical examination including neurological evaluation, assessment of performance status, and laboratory work including negative serum B-HCG pregnancy test, electrocardiogram and serum carcinoembryonic antigen (CEA) within 7 days of beginning treatment. Assessment of measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) was performed within 28 days of starting therapy.
Treatment
BMS-247550 50 mg/m2 was initially administered intravenously (i.v.) as a 1-h infusion repeated every 21 days. In October 2001, the protocol was amended, the dose was reduced to 40 mg/m2 and the duration of the infusion was extended to 3 h in order to decrease the peripheral neuropathy that was observed in other trials of BMS-247550. To prevent hypersensitivity to Cremophor®EL, all patients were required to receive a premedication regimen 1 h prior to treatment consisting of an oral/i.v. H1 blocker (diphenhydramine 50 mg) and an oral H2 blocker (ranitidine 150 mg, nizatidine 150 mg or famotidine 40 mg) or i.v. H2 blocker (ranitidine 50 mg or famotidine 40 mg). If two patients experienced grade 2 or 3 hypersensitivity reactions or one patient experienced a grade 4 hypersensitivity reaction following this premedication regimen, oral/i.v. dexamethasone 20 mg was added. If two additional patients experienced grade 2 or 3 hypersensitivity reactions or one patient experienced a grade 4 hypersensitivity reaction despite oral/i.v. dexamethasone, patients would then be required to receive oral dexamethasone 12 and 6 h before administration of BMS-247550, in addition to the other premedications. If patients developed a grade 2 hypersensitivity reaction despite the measures described as above, patients could be rechallenged at the discretion of the treating physician 24 h after the last BMS-247550 administration; oral/i.v. dexamethasone 20 mg was to be given every 6 h for four doses; and the last dose was to be administered 30 min before BMS-247550 was given, in addition to the standard premedication regimen. Twenty-five per cent of BMS-247550 was to be infused over 2 h, with the remaining dose to be infused over no more than 6 h.
Hormonal therapy, immunotherapy or therapeutic radiation therapy was not permitted while the patient was on study. Colony stimulating factors (CSFs) were not allowed during the first course of therapy. CSFs were allowed in subsequent cycles at the discretion of the treating physician, as recommended by American Society of Clinical Oncology guidelines [12]. Antiemetics were provided at the discretion of the treating physician. Patients received a minimum of two cycles of chemotherapy unless unacceptable toxicity, patient refusal or evident disease progression occurred.
Dose modifications
Toxicities were graded according to the NCI CTC, version 2.0. BMS-247550 was reduced by one dose level (10 mg/m2/cycle decrements) for hematological toxicities, including grade 4 neutropenia lasting >7 days, neutropenic fever or grade 3 thrombocytopenia. Non-hematological toxicities requiring dose reduction included treatment delay >7 days, any grade 3/4 toxicities (including unresolved nausea and vomiting if not amenable to treatment with antiemetics) and grade 2 peripheral neuropathy lasting >7 days. Patients requiring dose reductions below 20 mg/m2 were removed from study, unless the patient had evidence of disease response, in which case they were allowed to continue after approval of the Principal Investigator.
Statistical methods
A standard two-stage Simon design was employed [13]. The primary end point was objective response rate (partial or complete response). A 10% response rate precluded further study, whereas a 25% response rate indicated that further study would be warranted (i.e. P0 = 0.10 and P1 = 0.25 in the Simon terminology). Using and ß errors of 0.10 and 0.10, respectively, 21 patients were enrolled in the first stage, and if two or less responses was observed, the trial was to be terminated. Otherwise, an additional 29 patients were to be enrolled, and if seven or less responses were observed in 50 patients, the agent would not be considered worthy of further study. If eight or more responses were observed, the drug would be considered sufficiently active to warrant further testing. Time to progression and survival were calculated using the method of Kaplan and Meier [14].
Evaluation of response
Evaluation of response was on an intention-to-treat basis. Patients were evaluated for response according RECIST criteria [11]. Patients were reevaluated for radiological response by CT/MRI every 6 weeks or after two successive cycles. Confirmatory CT/MRI scans were to be obtained 4 weeks following initial documentation of objective complete or partial response. Patients remained on study until progression, unacceptable toxicity or patient withdrawal from study. CEA was obtained prior to each treatment cycle for potential indication of response or progression, but required radiological studies for confirmation.
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Results |
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Patient characteristics are summarized in Table 1. The majority of patients were males. Colon cancer was the primary site of disease in 72% of patients, and the liver was the primary site of metastatic disease in 76%. The median ECOG performance status was 1.
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Toxicities
All patients were evaluated for toxicity. Hematological and non-hematological toxicities are presented in Table 2. Significant myelosuppression resulted in grade 3/4 leukopenia (36%), neutropenia (48%) and a single incidence of grade 4 neutropenic fever (4%). The majority of non-hematological toxicities were mild, apart from grade 3 peripheral neuropathy (20%) and perception of pain (20%). Peripheral neuropathy appeared to be cumulative and irreversible. Both patients who had received the original dose of 50 mg/m2 developed grade 3 neutropenia; one patient developed a grade 3 urinary tract infection requiring hospitalization. Three patients experienced a grade 3 hypersensitivity reaction (12%); two patients were successfully rechallenged with additional premedications with no further documented episodes.
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Response and survival
No objective responses were observed. Both patients who received the original dose of 50 mg/m2 demonstrated disease progression following cycle 2. After a median follow-up of 46 weeks, 13 patients (56%) achieved stable disease after two cycles of treatment. Of the five patients that prematurely withdrew as a result of peripheral neuropathy, three continued to demonstrate stable disease after a median follow up of 50 weeks. Overall, the estimated median time to progression was 11 weeks [95% confidence interval (CI) 617]. The estimated median overall survival was 36 weeks (95% CI 25). Accrual to the study was terminated early due to lack of efficacy as per the Simon two-stage trial design.
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Discussion |
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The principal toxicities of BMS-247550, namely myelosuppression and cumulative peripheral neuropathy, were similar to the taxanes. Peripheral neuropathy was especially problematic, and resulted in the discontinuation of treatment in 20% of patients. Prolonging the duration of infusion has been helpful in decreasing the neurotoxicity of the taxanes, but did not appear to diminish this toxicity in the patients on this study [15]. Other investigators who have evaluated different schedules of BMS-247550, including its administration over 35 days every 21 days, have observed no significant peripheral neuropathy [1618]; these schedules may thus be more appropriate for further development of this agent should clinical activity be observed. We observed no objective responses and limited disease stabilization in this trial. Although 13 patients (56%) continued to demonstrate stable disease following two cycles of BMS-247550, the median time to progression of 11 weeks and median overall survival of 36 weeks suggests that BMS-247550 has limited activity as a single agent in advanced colorectal cancer.
Other epothilones such as epothilone D (KOS-862) are in development, and may result in less peripheral neuropathy than the epothilone B analogs. Preliminary results from a phase I clinical trial of KOS-862 revealed antitumor activity in heavily pretreated testicular, ovarian, breast and pancreatic cancer patients [19]. Although more chemotherapy options are now available to patients with this disease, systemic chemotherapy alone in surgically unresectable advanced colorectal cancer is rarely curative, and requires the continued investigation of other novel agents.
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Acknowledgements |
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FOOTNOTES |
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REFERENCES |
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2. Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 1992; 10: 896903.[Abstract]
3. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343: 905914.
4. Rothenberg ML, Oza AM, Bigelow RH et al. Superiority of oxaliplatin and fluorouracilleucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracilleucovorin: interim results of a phase III trial. J Clin Oncol 2003; 21: 20592069.
5. Altmann KH, Wartmann M, OReilly T. Epothilones and related structuresa new class of microtubule inhibitors with potent in vivo antitumor activity. Biochim Biophys Acta 2000; 1470: M79M91.[CrossRef][ISI][Medline]
6. 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 2001; 7: 14291437.
7. Griffin D, Wittmann S, Guo F et al. Molecular determinants of epothilone B derivative (BMS 247550) and Apo-2L/TRAIL-induced apoptosis of human ovarian cancer cells. Gynecol Oncol 2003; 89: 3747.[CrossRef][ISI][Medline]
8. Calvert P, ONeill V, Twelves C. A phase I clinical and pharmacokinetic study of EPO906 (Epothilone B), given every three weeks, in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2001; 20: (Abstr 429).
9. Trepathi R, Gadgeel S, Wozniak A. Phase I clinical trial of BMS-2347550 (epothilone B derivative) in adult patients with advanced solid tumors. Proc Am Soc Clin Oncol 2002; 21: (Abstr 407).
10. McDaid HM, Mani S, Shen HJ et al. Validation of the pharmacodynamics of BMS-247550, an analogue of epothilone B, during a phase I clinical study. Clin Cancer Res 2002; 8: 20352043.
11. 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 2000; 92: 205216.
12. Ozer H, Armitage JO, Bennett CL et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 2000; 18: 35583585.
13. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 110.[ISI][Medline]
14. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457481.[ISI]
15. Gelderblom H, Mross K, ten Tije AJ et al. Comparative pharmacokinetics of unbound paclitaxel during 1- and 3-hour infusions. J Clin Oncol 2002; 20: 574581.
16. Thambi P, Edgerly M, Agrawal M. A phase I clinical trial of BMS-247550 (NSC 71028), an epothilone B derivative, given daily for 3 days on a 21 day cycle in patients with refractory neoplasms. Proc Am Soc Clin Oncol 2003; 22: (Abstr 540).
17. Vansteenkiste J, Breton J, Sandler A. A randomized phase II study of epothilone analog BMS-247550 in patients (pts) with non-small cell lung cancer (NSCLC) who have failed first-line platinum-based chemotherapy. Proc Am Soc Clin Oncol 2003; 22: (Abstr 2519).
18. 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 2003; 21: 18661873.
19. Piro L, Rosen L, Paron M. KOS-862 (Epothiolone D): A comparison of two schedules in patients with advanced malignancies. Proc Am Soc Clin Oncol 2003; 22: (Abstr 539).