This open-label, multicenter, single-arm, phase 2 study, was designed to assess the safety and efficacy of ixabepilone plus cetuximab in patients with locally advanced pancreatic adenocarcinoma that was not surgically resectable or in patients with distant metastatic disease. The study was conducted in accordance with ethical principles originating in the Declaration of Helsinki and in compliance with Good Clinical Practice and all local regulatory requirements. The study was approved by the Institutional Review Board/Independent Ethics Committee at each site before that site enrolled any patients. All patients provided written informed consent.
Ixabepilone was administered at a dose of 32 mg/m2 via 3-hour IV infusion on day 1 of a 3-week cycle, with cetuximab at an initial loading dose of 400 mg/m2 via 2-hour IV infusion and then weekly at 250 mg/m2 via 1-hour infusion. On days when both drugs were to be administered, ixabepilone was administered before cetuximab. All patients were premedicated before each dose of ixabepilone with an oral H1 antihistamine (diphenhydramine 50 mg or equivalent) and H2 antihistamine (ranitidine 150–300 mg or equivalent) to prevent hypersensitivity reactions. Patients continued to receive treatment with ixabepilone plus cetuximab until disease progression or unacceptable toxicity.
The primary objective was rate of survival at 6 months. Secondary end points were objective tumor response rate (ORR), as defined by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, PFS, OS, duration of response, time to response, and the safety and tolerability of ixabepilone plus cetuximab in all patients that received at least 1 dose of study drug(s).
Men and women aged ≥18 years were eligible for inclusion if they had histologic or cytologic confirmation of pancreatic adenocarcinoma that was locally advanced (unresectable) or metastatic. Patients were required to have measurable disease according to RECIST and had not previously received chemotherapy, immunotherapy, or radiation therapy for advanced pancreatic cancer. Prior adjuvant therapy was allowed if completed ≥6 months earlier. Additional eligibility criteria included adequate recovery from recent surgery (≥1 week after minor surgery or ≥4 weeks after major surgery), Karnofsky performance status of 70% to 100%, and adequate hematologic and hepatic function, including serum creatinine <2 mg/dL. Women of childbearing potential were eligible if they used an adequate method of contraception and were not pregnant or breastfeeding. Patients with serious, uncontrolled medical conditions or who planned to receive any other type of concurrent anticancer treatment were excluded. Patients were also excluded if they had grade 2 or higher peripheral neuropathy, brain and/or leptomeningeal metastases, psychiatric disorders or conditions rendering the patient incapable of protocol compliance; a second malignancy (excluding nonmelanoma skin cancer or carcinoma in situ of the cervix) or known human immunodeficiency viral infection. Prior treatment with an epothilone or epothilone analog, cetuximab, or any other therapy targeting the EGF pathway or the concomitant use of strong CYP3A4 inhibitors was not permitted.
Criteria for Continued Treatment
Treatment with ixabepilone was repeated every 21 days, provided the absolute neutrophil count was ≥1,500 cells/mm3, platelets ≥100,000 cells/mm3, and all treatment-related nonhematologic toxicity attributable to ixabepilone had resolved to lower than grade 2 (except for alopecia or grade 2 fatigue for which resolution was not required and diarrhea for which grade 2 was allowed). Treatment with cetuximab was repeated each week if acne-form rash and diarrhea were grade 2 or lower, and all grade 3 to 4 nonhematologic toxicities attributable to cetuximab had resolved to less than grade 2 (except for anorexia, alopecia, neuropathy, and grade 2 fatigue, for which resolution was not required). If retreatment criteria were not met, treatment with ixabepilone or cetuximab was delayed up to a maximum of 4 weeks. Patients who could not meet retreatment criteria for 1 drug discontinued that drug but were allowed to continue treatment with the other. Upon retreatment, doses of ixabepilone and cetuximab were modified based on tolerability, with a maximum of 2 dose reductions allowed per study drug. Once a dose had been reduced, re-escalation was not permitted.
Patients who had hypersensitivity reactions despite premedication with oral antihistamines in the first cycle received IV premedication with dexamethasone 20 mg, diphenhydramine 50 mg, and ranitidine 50 mg (or their equivalents) approximately 30 to 45 minutes before subsequent doses. Surface area (BSA) was determined at screening, and was recalculated prior to each dose of study drug only when body weight varied by >10% from the last BSA determination.
All patients who received at least 1 dose of study drug were followed up for survival. Patients were evaluated for tumor responses every 6 weeks. Spiral CT scans with contrast were the preferred imaging modality unless the contrast material was contraindicated. Once a tumor was measured at baseline, all subsequent assessments used the same imaging or assessment method, whenever possible. Objective tumor responses were defined according to RECIST guidelines and were considered confirmed if noted on 2 evaluations at least 4 weeks apart. Patients meeting these assessment criteria were defined as response evaluable. Patients who discontinued treatment for reasons other than disease progression were followed every 6 weeks until criteria for progression were met.
Cytological or histological tumor tissue samples, when available, were evaluated for EGFR expression by immunohistochemistry using the DAKO EGFR pharmDx assay, although EGFR expression was not used as an eligibility criterion.
Adverse events were monitored continuously during treatment and evaluated according to the National Cancer Institute's CTCAE, version 3.0. Physical examinations, including neurological assessment, performance status, and evaluation of baseline signs and symptoms, were performed before treatment and then every 3 weeks during treatment. Vital signs were monitored before the dose was administered, every 30 minutes during infusions, at the end of each infusion, and for cetuximab, at 1 hour after infusion. A 12-lead electrocardiogram was recorded at baseline and then as clinically indicated. Complete blood counts including differential were monitored weekly, and serum chemistry was monitored every 3 weeks.
The 6-month survival rate, calculated from the date of the first dose of study treatment, and its exact 2-sided 95% confidence interval (CI) were determined for all treated patients and also estimated using the Kaplan-Meier product limit method.
The study was testing the null hypothesis that the true 6-month survival rate was ≤50% vs. the alternative that the true 6-month survival rate was ≥70%. In order to have 81% power to reject the null hypothesis if the expected 6-month survival rate is 70% at the 2-sided, α = 0.05 level with the exact test, a total of 52 treated patients had to be accrued. With 52 treated patients, the maximum width of the 95% CI is 28% given that the expected 6-month survival rate is within the 50% to 70% range.
ORR and its exact 2-sided 95% CI were determined by the proportion of response-evaluable patients with a best response of partial response (PR) or complete response. Time to response was summarized descriptively for all patients with an objective response, and the duration of response was estimated using the Kaplan-Meier product limit method. PFS and OS were also analyzed by the Kaplan-Meier method for all treated patients. Each time-based variable was summarized by median and 2-sided CI using the method of Brookmeyer and Crowley.18
Safety parameters were analyzed using descriptive statistics for all treated patients.