Annals of Oncology Advance Access originally published online on February 21, 2008
Annals of Oncology 2008 19(5):977-983; doi:10.1093/annonc/mdm591
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head and neck cancer |
A randomized phase II study of ixabepilone (BMS-247550) given daily x 5 days every 3 weeks or weekly in patients with metastatic or recurrent squamous cell cancer of the head and neck: an Eastern Cooperative Oncology Group study
1 Department of Medical Oncology, Division of Medical Sciences, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111
2 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA
3 Department of Medicine, Thomas Jefferson University, Philadelphia, PA
4 Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA
5 Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA
* Correspondence to: Dr B. Burtness, Department of Medical Oncology, Division of Medical Sciences, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Tel: +1-215-728-3023; Fax: +1-215-728-3639; E-mail: barbara.burtness{at}fccc.edu
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Abstract |
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Ixabepilone is a tubulin-polymerizing agent with potential activity in squamous cell carcinoma of the head and neck (SCCHN). Patients were eligible who had incurable, measurable SCCHN and less than two prior regimens for metastatic/recurrent disease. Eastern Cooperative Oncology Group performance status of less than or equal to one and adequate renal/hepatic/hematological function were required. Patients were randomly assigned to receive ixabepilone 6 mg/m2/day x 5 days every 21 days (arm A) or 20 mg/m2 on days 1, 8, and 15 of a 28-day cycle (arm B). Each arm accrued taxane-naive and -exposed strata in a two-stage design. The primary end point was response. Eighty-five eligible patients entered; there was one response in a taxane-exposed patient among 32 patients on arm A. Five of 35 taxane-naive patients on arm B had partial responses (14%). No taxane-exposed patient on arm B responded. Common grades 3 and 4 toxic effects were fatigue, neutropenia, and sensory/motor neuropathy. Median survival for arm A taxane-naive and taxane-exposed patients is 5.6 and 6.5 months; for arm B, taxane-naive and taxane-exposed patients is 7.8 and 6.5 months. Weekly ixabepilone 20 mg/m2 is active in taxane-naive patients with SCCHN. A high incidence of motor and sensory grade 3 neuropathy resulted at this dose and schedule. Further development of ixabepilone in previously treated head and neck cancer is not warranted on the basis of these data.
Key words: antimicrotubule therapy, epothilone, squamous cell carcinoma of the head and neck
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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More than 34 000 new cases of squamous cell cancer of the head and neck (SCCHN) are anticipated in USA in 2007, and 7500 deaths are likely [1]. Standard therapy for advanced head and neck cancer consists of cisplatin or methotrexate-based therapy [2], and activity has been demonstrated for taxanes as well [3]. The combination of paclitaxel with cisplatin, however, is not superior to the combination of cisplatin and 5-fluorouracil [4]. Taxane resistance is associated with overexpression of the MDR-1 transport gene [5] and with aberrant tubulin expression [6]. The epothilones were identified as a novel class of microtubule-stabilizing agents. Like the taxanes, epothilones bind β-tubulin and result in cell cycle arrest, and there is—in the laboratory—evidence of antitumor activity in cell lines with taxane resistance on the basis of either MDR expression or β-tubulin mutation [7]. Epothilones are macrolides obtained by fermentation of the myxobacterium Sporangium cellulosum, but the natural products are metabolically unstable. Ixabepilone (BNS-247550, NSC #710428, Bristol Myers-Squibb, Princeton, NJ) is a semisynthetic derivative of epothilone B; substitution of a lactam for the natural product’s lactone ring reduces carboxylestrase metabolism and improves stability [8].
Ixabepilone has been studied on a variety of schedules. The maximum tolerated dose (MTD) of ixabepilone when given every 3 weeks is 40 mg/m2 [9]. First cycle dose-limiting toxicities (DLTs) noted include prolonged grade 4 neutropenia and grades 1–2 sensory neuropathy. Daily administration for 3–5 days on an every 3-week schedule has also been evaluated [10, 11]. The MTD for daily x5 administration on an every 3-week basis is 6 mg/m2/day. Neutropenia is also the DLT on this schedule, including in taxane-exposed patients, whereas neuropathy led to treatment discontinuation in only 1 of the 28 patients in the phase I study. Transient distal extremity pain, numbness, tingling, and other dysaesthesiae were described. A phase I study of weekly dosing resulted in a recommended phase II dose of 20 mg/m2/week given as a 1-h infusion for 3 weeks of a 4-week cycle [12].
A novel antitubule agent not susceptible to the same resistance mechanisms as taxanes could represent an important addition to the therapy of head and neck cancer. We wished to determine whether ixabepilone had activity in advanced SCCHN, either in taxane-exposed or taxane-naive patients. The primary end points of the study were to determine the response rate and toxicity of ixabepilone given in two dosing schedules to taxane-naive and taxane-exposed patients and to provide information about the toxicity of ixabepilone in the two dosing schedules.
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patients and methods |
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patient selection
Patients
18 years of age with measurable, histologically confirmed SCCHN, excluding nasopharyngeal primaries, incurable with surgery or radiation therapy because of distant metastases or locoregional recurrence or persistent disease within a radiation portal, were eligible. Baseline tumor measurements must have been obtained 
4 weeks before randomization. Patients may have received up to one prior biological therapy and two prior chemotherapy regimens for recurrent and/or metastatic disease. Prior docetaxel (Taxotere) or paclitaxel (Taxol), but not prior investigational taxane therapy, were permitted. Chemotherapy or radiotherapy must have been completed at least 4 weeks before randomization. Patients must have had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero or one, absolute neutrophil count (ANC) 1500/mm3, platelet count 100 000/mm3, serum creatinine clearance 1.2 mg or creatinine clearance >50 ml/min, total bilirubin level 1.5 mg; asparate aminotransferase, alanine aminotransferase, and alkaline phosphatase 2 x institutional upper limit of normal, and serum calcium within the normal range. Patients must not have had a preexisting peripheral neuropathy more than or equal to grade 2. Patients were excluded if they were pregnant or breast-feeding and women of childbearing potential and sexually active males were required to use contraception. Patients must not have had a known hypersensitivity to castor oil, or agents containing Cremophor EL, or paclitaxel. Patients with a history of grade 1 or uncomplicated, nonrecurrent grade 2 hypersensitivity reactions associated with Cremophor EL were eligible with protocol-specified prophylaxis.
treatments
All patients were premedicated with diphenhydramine 50 mg p.o. or i.v. and cimetidine 300 mg p.o. (or equivalent) 1 h before the administration of ixabepilone. Patients randomly allocated to arm A received ixabepilone 6 mg/m2 administered as a 60-min infusion daily for 5 days every 21 days. Patients randomly allocated to arm B received ixabepilone 20 mg/m2 administered as a 60-min infusion on days 1, 8, and 15 of a 28-day cycle.
Treatment was given only if the ANC was >1200/mm3 and the platelet count was >75 000/m3 on the treatment day. Dose modifications and delays were specified in the protocol. If toxicity persisted in spite of these adjustments, patients discontinued protocol treatment. Dose was modified for grade 2 sensory or motor neuropathy, lasting >7 days or any grade 3 neuropathy: for arm A, from 6 to 5 mg/m2 and then to 4 mg/m2 and for arm B, from 20 to 15 mg/m2 and then to 10 mg/m2. Patients discontinued protocol treatment if they would have needed further dose reductions.
Patients remained on treatment until disease progression, unacceptable toxicity, withdrawal of consent, or medical circumstances which made protocol therapy unadvisable. Patients achieving a complete response (CR) by RECIST [13] could discontinue therapy at the discretion of the treating physician two cycles after CR was documented, if a minimum of six cycles had been administered.
tumor assessments
Tumor assessment was carried out with computed tomography or magnetic resononance imaging utilizing RECIST [13]. Tumor assessment was conducted on an every 6-week schedule on both arms, although cycle length differed by arm, to prevent a bias to longer time to progression for patients treated on an every 4-week cycle.
statistical methods
Taxane-exposed and taxane-naive patients were randomly assigned separately to the two treatment regimens and stratified by PS. Treatment assignments were determined using permuted blocks within strata with dynamic balancing on main institutions plus affiliates. The primary end point of the study was response rate, defined using RECIST [13]. A two-stage design was employed for each stratum (taxane-naive or taxane-exposed) and each dose schedule. A true response rate of 20% was considered worthy of further study, while a response rate of 5% was not of interest. For each group of patients, 14 eligible patients were to be accrued in the first stage. If one response was observed, an additional 18 eligible patients were to be registered. A dose was considered worthy of further study if four or more responses were observed among 32 eligible patients within each stratum/treatment group. This design had a 49% probability of stopping early and 93% probability of declaring the regimen ineffective if the true response rate was 5% (7% type I error) and an 89% probability of declaring the regimen effective if the true response rate was 20% (power).
Response rate was defined as the proportion of patients with CR and partial response (PR) among all eligible treated patients. Patients who were inevaluable for response were included in the denominator. Overall survival (OS), a secondary end point, was defined as the time from registration to death from any cause. Patients who were alive at the time of this analysis were censored as of the date last known alive. Progression-free survival (PFS) was defined as the time from registration to first documentation of disease progression or to death from any cause. Patients who died >2 months after the last disease evaluation or who were alive and free of disease at the time of the analysis were censored as of the date of last disease evaluation. If patients had no follow-up disease evaluations and survived for >2 months, they were excluded from the PFS analysis.
Descriptive statistics were used to characterize patients at baseline. Fisher's exact test was used to explore differences between treatment arms if these appeared to be imbalanced. Exact binomial confidence intervals (CIs) were computed for response rates. The method of Atkinson and Brown [14] was used to compute this CI for the cohort that had two stages of accrual. To examine differences in the distribution of worst degree toxic effects, Mehta’s exact test for ordered categorical data was used [15]. Patients with no toxicity reported or worst degree of grade 1 or 2 were collapsed into a single category for this analysis. Fisher’s exact test was used to compare the rates of lethal toxic effects on the two arms. The method of Kaplan and Meier was used to estimate OS and PFS [16]. All P values are two-sided. A level of 5% was considered statistically significant.
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results |
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patient characteristics
The study accrued 85 eligible patients. Only the taxane-naive stratum of arm B continued to the second stage, although a response was ultimately documented in a taxane-exposed patient in arm A and according to the study design, this would have led to continuation of this stratum of arm A as well, had it been documented before the study closed permanently. The taxane-naive stratum enrolled 17 patients on arm A and 35 on arm B. One patient on arm B was ineligible. One taxane-naive patient on arm A and two on arm B never started assigned therapy. The taxane-exposed stratum enrolled 17 patients onto arm A and 21 onto arm B. Two taxane-exposed patients on arm A and three patients on arm B were ineligible. Two taxane-naive patients on arm A never started assigned therapy, including one who was ineligible. The analyses for response, progression, and survival include the 80 eligible, treated patients. Analysis of toxicity includes all the 85 treated patients. Five patients with prior taxane therapy were stratified incorrectly to the taxane-naive stratum, one on arm A and four on arm B. All patients were analyzed according to their actual prior taxane status, regardless of how they were stratified.
Patient characteristics at baseline are shown in Table 1 for taxane-naive patients and Table 2 for taxane-exposed patients. Median age was 62 (range 40–79 years). Impaired PS was reported for 65%. Approximately 80% were male, and most had a history of smoking. The two arms were well balanced for the presence of metastatic disease in the taxane-naive strata. Among taxane-exposed patients, a higher proportion of patients randomly assigned to receive arm B had metastatic disease, although this was not statistically significant (P = 0.27). Among patients with prior taxane therapy, a higher proportion of patients randomly assigned to receive arm A had experienced response to that prior therapy (nine versus three patients, P = 0.02).
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toxicity
Tables 3 and 4 (taxane naive and taxane exposed, respectively) show adverse events of grade 3 and higher that were possibly related to treatment for all treated patients. Patients randomly assigned to receive weekly treatment had higher grade worst degree toxic effects than patients randomly assigned to receive five daily infusions of 6 mg/m2 (P = 0.03). More sensory and motor neuropathies were noted on arm B among both taxane-naive and taxane-exposed patients. Figure 1 displays time to grade 3 neuropathy by taxane exposure and treatment group. Treatment-related deaths were reported for one patient on arm A (3%) and four on arm B (7%) (P = 0.65). In addition, one patient on arm A and eight patients on arm B had lethal toxic effects not felt to be associated with treatment. Four deaths involving hemorrhage occurred on arm B, all felt to be unlikely or unrelated to treatment. Taking all deaths in all treated patients, there were two deaths among the 31 patients on arm A (7%) and 12 among the 54 patients (22%) on arm B (P = 0.07). There was no significant difference in total deaths by prior taxane exposure: there were 7 deaths among 36 patients with prior taxane exposure (19%) and 7 among 49 patients (14%) who were taxane-naive (P = 0.19).
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response
The primary end point of objective response was evaluated on the basis of all eligible, treated patients. There were no responses among the 16 eligible, treated taxane-naive patients on arm A. There was one response (response rate 7%, 90% CI 0.4% to 30%) among the 14 eligible, treated taxane-exposed patients on arm A. This single response would have constituted evidence for continuing to the second stage of accrual, but it was not documented until after the study had closed to accrual.
There were 5 PRs among the 32 eligible, treated taxane-naive patients on arm B, for a response rate of 16% (90% CI 6% to 30%). Two of these patients had no prior chemotherapy and three had received one prior therapy. There were only three patients with more than one prior chemotherapy, and none of these achieved an objective response. This response rate of 15% exceeded the prospective definition of activity worthy of further study. Among the 18 eligible taxane-exposed patients on arm B, there were no responses.
survival and PFS
The median number of cycles of therapy was 2 (range 1–10) or a median duration of treatment of 1.1 months on arm A and 1.4 months on arm B. Treatment was discontinued for disease progression in 59% of patients. The mean follow-up time among all 80 eligible, treated patients is 39.1 months. Only two patients are still alive, with follow-up times of 19.1 and 41.6 months. Median OS across all cohorts was 7.2 months (95% CI 5.4–8.8 months). Figure 2 shows Kaplan–Meier survival estimates by arm and cohort. Figure 3 shows Kaplan–Meier estimates of survival by prior treatment.
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Median PFS across all arms and cohorts was 1.8 months (95% CI 1.5–2.6 months). Figure 4 shows Kaplan–Meier estimates of PFS by arm and cohort. Two patients were excluded from the analysis of PFS because they had no follow-up scans. Seven patients were censored because their last disease evaluation without evidence of progression occurred >2 months before death.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Treatment options in metastatic/recurrent SCCHN remain limited. Taxanes have activity, but have not clearly impacted on survival in the metastatic setting. The advent of epothilone analogs with practical pharmacokinetic profiles and anticancer activity may add to the therapeutic armamentarium in this disease. This phase II study of ixabepilone in patients with SCCHN provides evidence that ixabepilone is an active agent in this disease when given on a weekly schedule in taxane-naive patients.
The response rate of 16% is within the 90% CI for a true response rate of 20% and met the primary end point of the study. This response rate is similar to the 13% reported for paclitaxel in a previous ECOG study in completely treatment-naive patients, although the results may not be strictly comparable because this study evaluated response with RECIST and the earlier study utilized ECOG response criteria [17]. Three of the five responders to weekly ixabepilone in the current study had received prior treatment; in the previous ECOG study of paclitaxel, there were no responses in previously treated patients.
The median PFS reported in this study may have been influenced by the short time to first response evaluation, but at 1.8 months across all cohorts, and 2.0 months for taxane-naive patients treated with weekly ixabepilone, survival is comparable to PFSs reported for second-line therapy with cetuximab [18, 19]. The median OS across all cohorts was 7.2 months, superior to the 6 months reported for cetuximab in chemotherapy-refractory patients [19] and nearly 8 months reported for cisplatin monotherapy in the most recent first-line study conducted within the ECOG [20].
The design of this trial allowed evaluation of ixabepilone given at low dose for 5 days in succession on an every 3-week schedule or given at a higher weekly dose for 3 weeks of a 4-week schedule. Both schedules were evaluated because the optimal schedule is not established for ixabepilone, either with regard to toxicity or efficacy, but there was a concern for increased susceptibility to neuropathy in this population of previously treated patients with SCCHN, many of whom by design were taxane-exposed and many of whom would also have received a platinum analog in the context of initial chemoradiation. It has been hypothesized that higher peak doses increase the risk of ixabepilone neurotoxicity [21]. Changes in neurologic function tests, such as the Jebsen Test of Hand Function and the Grooved Pegboard Test, as measured over the first two cycles of therapy, seemed predictive of neuropathy in a phase II trial of ixabepilone; however, this was an exploratory analysis in a small study, and the study utilized a schedule of ixabepilone administration which ultimately resulted in a low rate of neuropathy. The current study did not utilize neurologic function monitoring. Dose reductions and modifications were guided by neurotoxicity reporting according to the National Cancer Institute—Common Toxicity Criteria.
We also considered the possibility that the activity of the agent, particularly in taxane-exposed patients, might vary by the schedule of administration. The possibility that lower dose administration might have an antiendothelial cell action, and the role of survivin in predicting for resistance to either low- or high-dose ixabepilone, were the subjects of tissue correlative studies which are under way and will be reported separately. Despite the preclinical evidence for ixabepilone activity in taxane-resistant cell lines, little activity for ixabepilone in taxane-refractory disease, however, was demonstrated in this study.
The current study provides evidence that ixabepilone has activity in advanced, taxane-naive SCCHN, producing responses and resulting in PFS and OS that are comparable to other active agents in this setting. Despite this evidence of activity, the study does not yet define a role for ixabepilone in head and neck cancer because of the toxicity profile of the drug in this population. Further studies which attempt to minimize the neurotoxicity—with neuroprotectants, more sophisticated neurologic function monitoring, or more stringent patient selection—would be required to determine whether ixabepilone could be routinely useful in the treatment of previously treated patients with head and neck cancer. Further development of ixabepilone in previously treated head and neck cancer is not warranted on the basis of these data. The drug might be more useful in patients who have not previously been exposed to neurotoxins, such as in the induction setting. Trials of second-line therapy in advanced SCCHN have not been numerous to date, but the activity and median PFS and OS observed here justify further trials of novel agents for this group of patients.
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funding |
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Public Health Service (CA23318, CA66636, CA21115, CA16116, CA39229); National Cancer Institute; National Institutes of Health; Department of Health and Human Services.
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The authors are grateful for the contributions of Dr Dimitrios Colevas and Meredith Goldwasser to the study design, and for the assistance of Wendy Wonson in data management. This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Received for publication July 12, 2007. Revision received December 7, 2007. Accepted for publication December 10, 2007.
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