This was a randomized, multicenter, open-label, phase II study of ixabepilone in patients with NSCLC who had received one prior platinum-containing first-line chemotherapy regimen. The protocol was approved by local ethics committees and conducted in accordance with the US Food and Drug Administration, the International Conference on Harmonization Guidelines for Good Clinical Practice, and the Declaration of Helsinki.

Patients age ≥ 18 years with histologically/cytologically confirmed NSCLC (stage III/IV or metastatic recurrent disease), with bidimensionally measurable disease progression after one prior cisplatin- or carboplatin-based chemotherapy regimen, a performance status of 0 to 1, and life expectancy of ≥ 12 weeks were eligible. Adequate hematologic (absolute neutrophil count ≥ 2,000 cells/μL, platelets > 125,000/μL), hepatic (serum bilirubin ≤ 1.5× institutional upper limits of normal [ULN], ALT ≤ 2.5× ULN [≤ 5× ULN in the presence of hepatic metastases]), and renal function (serum creatinine ≤ 1.5× ULN) were required. Patients were excluded if they had received more than one prior chemotherapy regimen (except [neo]adjuvant chemotherapy); had grade ≥ 2 neuropathy (according to National Cancer Institute Common Toxicity Criteria); or had known brain metastases. All patients provided written informed consent before study entry.

On the basis of phase I studies,^22,23 ixabepilone initially was administered at 50 mg/m² as a 1-hour infusion every 21 days. The study subsequently was modified twice by amendments. The first amendment stopped enrollment into the 50 mg/m² cohort because of neurotoxicity observed in this and other phase II studies. This amendment instituted a randomized enrollment scheme with two arms: 40 mg/m² as a 3-hour infusion on day 1 of a 3-week cycle, or 6 mg/m² as a 1-hour infusion daily for 5 consecutive days every 3 weeks. The latter schedule was pursued based on a phase I trial, which showed a low incidence of neuropathy at the recommended phase II dose.²⁴ The randomization used a permuted block procedure, stratified for prior taxane therapy (therapy v no therapy). However, after 19 patients had been enrolled into the 40 mg/m² cohort, a second amendment reduced the starting dose to 32 mg/m² in this group because of unacceptable rates of mucositis and neutropenia. Patients in arm B were accrued, therefore, while patients in the alternative treatment arm were being enrolled on 40 mg/m² and subsequently 32 mg/m² doses. This report focuses on patients treated with 32 mg/m² (hereafter referred to as arm A), or 6 mg/m² as a 1-hour infusion daily for 5 consecutive days every 3 weeks (arm B), with the aim of identifying the treatment schedule with the best safety-efficacy balance (Fig 1) . Results for the amended 40 and 50 mg/m² cohorts are not presented here.

Treatment continued every 3 weeks for ≤ 18 cycles, unless there was unacceptable toxicity, progressive disease (PD; 25% or greater increase in overall sum of the products of diameters of all target lesions in reference to the smallest sum recorded at or after baseline, or unequivocal progression of existing nontarget lesions overall or presence of new lesions), and/or other discontinuation criteria. Patients with a complete response (disappearance of all clinical and radiological evidence of target lesions and nontarget lesions with no new lesions confirmed on at least two consecutive observations at least 4 weeks apart) received no more than four treatment cycles. Patients with stable disease (failure to observe complete response or partial response, in the absence of any progressive or new lesions, confirmed on at least two consecutive observations at least 4 weeks apart) or partial response (50% or greater decrease in overall sum of the products of diameters of all target lesions in reference to the baseline sum, persistence of one or more nontarget lesions with no new lesions confirmed on at least two consecutive observations at least 4 weeks apart) were treated until PD or for ≤ 18 cycles. All patients were premedicated with oral H₁/H₂ blockers; antiemetics were not administered routinely. Patients were assessed every 3 months after discontinuation.

Dose reduction was permitted in the event of grade 4 neutropenia lasting ≥ 7 days; febrile neutropenia; platelets less than 25,000/μL; grade ≥ 3 thrombocytopenia with bleeding requiring transfusion; more than 1 week delay in re-treatment due to drug toxicity; grade 3 nausea/vomiting, diarrhea, or stomatitis; grade 2 neuropathy (motor or sensory) lasting ≥ 7 days; or grade 3 neuropathy or other grade ≥ 3 toxicities.

Colony-stimulating factors such as granulocyte colony-stimulating factor were used at the discretion of the investigator. Growth factor was not administered for 24 hours before or after cytotoxic chemotherapy, including ixabepilone.

The primary objective was to assess clinical activity of ixabepilone, measured by objective response rate (ORR). Tumor evaluations (physical examination and imaging studies) were performed at baseline and after every two cycles. Response was assessed according to modified WHO criteria,²⁵ with confirmation of responses on two consecutive occasions, ≥ 4 weeks apart. Secondary efficacy objectives were duration of response (calculated for all responders and defined as the period between the first day of treatment and the date PD was first noted, or death); progression-free survival (time from the first day of treatment until the first date of PD or death was reported); and overall survival (OS). Toxicities were evaluated continuously, hematology was evaluated weekly, and serum chemistry was evaluated before each cycle. Safety analyses were conducted on all treated patients who received at least one dose of ixabepilone. Patients who experienced any drug-related toxicities were followed up at least every 4 weeks until all drug-related toxicities were resolved, stabilized, returned to baseline, or deemed irreversible. Toxicity was classified according to the National Cancer Institute Common Toxicity Criteria, version 2.0.

Given that this was a noncomparative randomized phase II trial, no formal statistical comparisons between treatment arms were made. A Simon optimal two-stage design²⁶ was used in both treatment arms to test whether the ORR was of clinical interest. For each arm, an ORR more than 7% was considered of clinical interest. In the first stage, 27 response-assessable patients were to be accrued. If there were no more than two responders at the end of the first stage, enrollment onto the treatment arm was to be terminated. Otherwise, if there were at least three responses, an additional 43 response-assessable patients were to be accrued in the second stage. With this design, there was less than a 10% chance of stopping at the end of the first stage if the true response rate was ≥ 20%. Stopping at the end of the first stage would indicate that ixabepilone administered in the treatment arm was not worth investigating further in this population. A 10% inassessability rate was assumed for a total of about 77 patients to be enrolled onto each treatment arm.

A modification of the method to adjust for the Simon two-stage design was used, in which analyses consisted of the point estimate for ORR and the two-sided exact 95% CI for arms A and B. Discrete variables were summarized, with the number and proportion of patients in each category. Median duration of response, progression-free survival, and OS, with 95% CIs, were calculated for each cohort using the Kaplan-Meier product-limit method.²⁷ Continuous variables were summarized descriptively (median and range). Time to response was presented using univariate statistics (median and range values).

In total, 201 patients were enrolled from 29 study centers (United States, 15; France, five; Spain, four; Canada, three; Belgium, one; and Italy, one center). Of these, 31 patients were enrolled to receive 50 mg/m² ixabepilone, 30 of whom were treated. After the first protocol amendment, 19 patients were randomly assigned to 40 mg/m²; all were treated. After the second protocol amendment (to 32 mg/m²), 77 patients were randomly assigned to arm A, all of whom were treated. Seventy-four patients were randomly assigned to arm B, of whom 69 received treatment. Here we report results for patients receiving 32 mg/m² (arm A), and all patients in 6 mg/m² (arm B), regardless of whether they were randomly assigned concurrently with patients receiving 40 or 32 mg/m² (Fig 1).

Baseline demographic and clinical characteristics are summarized in Table 1. Approximately half of the enrolled patients had received prior radiotherapy; all had received one prior platinum-based regimen either in the metastatic, adjuvant, neoadjuvant, or metastatic and adjuvant setting. Approximately half of patients had received prior taxane therapy in both arms.

Patients in arm A received a median of three cycles (range, one to 17 cycles); median cumulative dose and dose-intensity were 96.2 mg/m² (range, 26.5 to 542 mg/m²) and 10.6 mg/m²/wk (range, 6.9 to 11.1 mg/m²/wk), respectively. Patients in arm B received a median of two cycles (range, one to 14 cycles), and the median cumulative dose and dose-intensity were 61.5 mg/m² (range, 5.9 to 411.3 mg/m²) and 9.9 mg/m²/wk (range, 2.0 to 10.5 mg/m²/wk), respectively. No patient received the maximum permitted number of cycles (18 cycles), although one patient received 17 courses of ixabepilone. Most discontinuations in arms A and B were due to disease progression or relapse (64% and 57%, respectively), or clinical deterioration (9% and 6%, respectively).

The ORR was 14.3% (95% CI, 7.5% to 25.8%) and 11.6% (95% CI, 5.5% to 24.8%) for arms A and B, respectively (Table 2). Of those who responded, the majority did so after two cycles of treatment. Median duration of response was 8.7 months (95% CI, 5.3 to 9.5 months) for arm A and 9.6 months (95% CI, 6.1 to 19.7 months) for arm B. Thirteen of the 19 responders (68%) were without disease progression for more than 6 months, including three patients who were progression-free for more than 12 months.

Median time to progression for assessable patients was 2.1 months (95% CI, 1.4 to 2.8 months) for arm A and 1.5 months (95% CI, 1.4 to 2.8 months) for arm B. Median OS was 8.3 months (95% CI, 5.8 to 11.5 months) for arm A and 7.3 months (95% CI, 5.7 to 11.7 months) for arm B. The 1-year survival rate in both cohorts was 38%. A total of 22 patients (11 in each cohort) survived more than 2 years, nine of whom were responders.

In arm A, 31 patients had received prior taxane therapy in the metastatic setting, four of whom (13%) responded to ixabepilone (Table 3). Moreover, one patient in arm A who received prior adjuvant paclitaxel had a complete response to ixabepilone (Table 3). In arm B, two (6%) of 32 patients previously treated with a taxane in the metastatic setting responded to ixabepilone. Twenty-seven patients in arm A had experienced PD within 1 month of receiving their last dose of platinum-based chemotherapy in the metastatic setting (platinum refractory); of these, four (15%) responded to ixabepilone. Although not considered platinum refractory in this study, of the 18 patients who experienced relapse between 1 and 4 months after receiving platinum-based therapy, three patients (17%) responded to ixabepilone. No patients with prior platinum therapy for metastatic disease in arm B responded to ixabepilone.

On discontinuation of ixabepilone, 50 (65%) of 77 patients in arm A and 39 (57%) of 69 patients in arm B received subsequent chemotherapy. Among the 19 responders, 14 received subsequent chemotherapy, including seven who were treated with agents with demonstrated efficacy in platinum-failed NSCLC: docetaxel (five patients) or pemetrexed (two patients). No responder received subsequent erlotinib treatment, two had radiotherapy only, and three had no additional treatment of any kind reported.