Purpose: To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety.
Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B).
Results: Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. Ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B).
Conclusions: Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin, with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle.
- phase I
- solid tumors
- combination chemotherapy
- pharmacokinetic analysis
Cytotoxic drugs that act by targeting microtubule structure are now well established for the treatment of many solid tumors. Both the taxanes, which are microtubule-stabilizing agents and the Vinca alkaloids, which promote microtubule disassembly, have a broad spectrum of activity and are routinely used to treat breast, ovarian, and non–small-cell lung cancers, with emerging data of activity in prostate cancer (1–8). Efficacy of these classes of chemotherapeutic agents is limited by the development of drug resistance and also by cumulative side effects, in particular neurotoxicity (9, 10). Continued development of novel microtubule inhibitors is important to improve efficacy in drug-resistant disease and to reduce potential toxicities.
The epothilones are naturally occurring products initially isolated from the fermentation broth of the myxobacterium Sorangium cellulosum (11, 12). The compounds are 16-membered ring macrolides, and both epothilone A and epothilone B promote microtubule stabilization (12). Ixabepilone (Bristol-Myers Squibb) is a semisynthetic lactam analogue of epothilone B with a mode of action similar to paclitaxel. This agent has shown superior in vivo antitumor activity to paclitaxel in both paclitaxel-sensitive and paclitaxel-resistant tumors (13).
Ixabepilone has completed four phase I evaluations as a single agent given as a 1-hour infusion every 3 weeks (14–16). The dose-limiting toxicity (DLT) was neutropenia, and the recommended phase II dose was 40 mg/m2 on this schedule. The most common nonhematologic side effects were fatigue and cumulative sensory neuropathy. No hypersensitivity reactions were reported. When ixabepilone was administered as an i.v. infusion weekly on a 21-day cycle and intermittently on days 1, 8, and 15 of a 28-day cycle, it was well tolerated and had an acceptable safety profile at the maximum tolerated doses of 25 and 20 mg/m2, respectively.6 Grade 3 fatigue was the DLT. Myelosuppression was rare, with no grade 3/4 neutropenia. Ixabepilone, administered i.v., has also been evaluated on a daily schedule for 5 days (17).
The combination of paclitaxel and carboplatin, a regimen that is widely used in the treatment of advanced solid tumors, has shown synergistic efficacy and reduced toxicity (18). Consequently, it was important to establish a recommended dose for the ixabepilone plus carboplatin combination so that the efficacy of this regimen could be investigated further.
We report the results of a phase I dose escalation study that examined two dosing schedules, with the starting dose of ixabepilone at 30 mg/m2 based on phase I data. Carboplatin dosage was calculated using the Calvert formula (19) exploring standard combination treatment AUC of 5 or 6. In schedule A, ixabepilone and carboplatin were both given on day 1 of a 21-day cycle. Schedule B investigated whether splitting the dose of ixabepilone between days 1 and 8, with carboplatin given on day 1, altered the recommended dose or side-effect profile. The study was carried out at two sites in the United Kingdom, with the primary objective of establishing recommended phase II doses for each of the schedules.
Patients and Methods
Eligibility. The study protocol was approved by local ethical assessment committees and by institutional review boards. All patients gave written informed consent before any study-specific procedures were done. Adults (≥18 y) with histologically or cytologically proven advanced solid tumors refractory to conventional treatment or for whom no standard treatment existed were recruited. Additional inclusion criteria were Eastern Cooperative Oncology Group performance status 0 to 1; adequate hematologic function (absolute neutrophil count ≥2,000 cells/mm3, platelet count ≥125,000 cells/mm3, hemoglobin ≥9 g/dL) and hepatorenal function (bilirubin ≤1.5 mg/dL; transaminases ≤2.5 times the upper limit of normal and serum creatinine ≤1.5 times the upper limit of normal); and at least 4 wk since last chemotherapy or radiation therapy (6 wk for nitrosureas or mitomycin C). Women of child-bearing potential were required to have a negative serum or urine pregnancy test within 72 h before starting the study drug.
Exclusion criteria included prior treatment with more than two chemotherapy regimens for metastatic disease or in the adjuvant setting or any platinum-containing treatment; preexisting peripheral neuropathy Common Toxicity Criteria (CTC) grade >1; brain metastases; or a documented history of hypersensitivity to paclitaxel or other therapies containing Cremophor EL.
Dosage and administration. Patients were premedicated with antiemetics, according to the standard protocols of the investigating institution, and with an oral H1 (diphenhydramine) and oral H2 blocker (ranitidine or cimetidine) 1 h before treatment. Ixabepilone for injection (lyophilized cake in 10- or 20-mg vials), supplied by Bristol-Myers Squibb, was diluted in an ethanol/Cremophor EL mixture (1:1, v/v) to achieve a final concentration of 2 mg/mL. This solution was further diluted in Ringer's lactate solution to a final ixabepilone concentration of 0.1 to 0.5 mg/mL. Ixabepilone was infused over 1 h via an infusion pump on both schedules A and B. Carboplatin was supplied as sterile aqueous solution for injection (10 mg/mL in 450-mg vials) and was further diluted in 250 mL of saline for infusion over 30 min. The dose of carboplatin was determined by the modified Calvert formula (19) to a target AUC of 5 to 6. Infusion of carboplatin was started 30 min after completion of the ixabepilone infusion on day 1.
Treatment was planned for a minimum of two courses unless clinical tumor progression or unacceptable toxicity was observed. Response was assessed every two cycles using Response Evaluation Criteria in Solid Tumors criteria, and patients could continue on the study for as long as they benefited from treatment. Toxicity was graded according to the National Cancer Institute CTC version 2.0. Re-treatment was scheduled every 3 wk provided hepatic and renal eligibility criteria were still met, all observed drug-related toxicity had resolved to baseline or CTC grade 1, and hematologic indices of absolute neutrophil count ≥1,500 cells/mm3 and platelet count ≥100,000 cells/mm3 had been achieved.
Following a classic phase I design, three patients were treated at each dose level; the cohort was expanded to six if DLT was observed in the first three patients. DLT was defined as the occurrence of any of the following during cycle 1: absolute neutrophil count <500 cells/mm3 for 5 or more consecutive days or febrile neutropenia (CTC grade 3 or 4); thrombocytopenia <25,000 cells/mm3 or a bleeding episode requiring platelet transfusion; CTC grade 3 or 4 nausea and vomiting despite adequate treatment; any other grade 3 or 4 toxicity (except grade 3 injection site reaction, fatigue, transient arthralgia/myalgia); prolonged recovery from a drug-related toxicity that delayed re-treatment at 3 wk; and omission of day 8 treatment on schedule B due to hematologic toxicity.
Dose escalation was stopped if two of three to six patients developed DLT on the first cycle, and a lower dose level was expanded to a maximum of nine patients to establish the recommended phase II dose and further characterize pharmacokinetics.
Pretreatment and follow-up studies. Full history; physical examination, including neurologic examination; and routine laboratory tests (complete blood count and serum chemistry, including transaminases, bilirubin, urea, and creatinine) were done before every scheduled treatment. Laboratory tests were repeated weekly during the study. Disease was assessed using computed tomography scans, which were repeated after every two cycles of treatment. Baseline electrocardiogram and chest X-ray were also recorded. On discontinuation of the study, patients were followed for at least 30 d or until the resolution of toxicity.
Plasma sampling and analysis. Samples of whole blood (5 mL) were collected during cycle 1 for pharmacokinetic analysis predose, 0.25, 0.5, 0.75, 1 (end of ixabepilone infusion), 1.5, 2, 3, 4, 6, 8, 24, 48, and 72 h after the start of the ixabepilone infusion into K3EDTA tubes. Within 30 min of collection, the plasma was separated by centrifugation at 2,000 × g for 5 min at 0°C to 5°C. Plasma samples were stored at −20°C for further analysis. It has previously been shown that systemic exposure in humans to the two degradation products of ixabepilone (the oxine BMS-249798 and diol BMS-326412) is negligible (14) and, therefore, only ixabepilone (BMS-247550) was analyzed in this study using the published and validated method (14).
At 24 h after carboplatin dosing, an additional blood sample was collected from patients enrolled on schedule B of the study only for analysis of carboplatin pharmacokinetics. The sample was analyzed according to a published method allowing single-sample estimation of AUC (20).
Pharmacokinetic and statistical analyses. Plasma concentration versus time data were analyzed using standard noncompartmental methods. Carboplatin pharmacokinetics were analyzed as described above. All other results are summarized using descriptive statistics.
A total of 55 patients with various solid malignancies were enrolled: 27 on schedule A and 28 on schedule B. Three of the recruited patients were not treated due to unforeseen events (two patients on schedule A, one patient on schedule B). Patient characteristics are summarized in Table 1 . The majority of patients had performance status 1 and had surgery as primary therapy for their disease. Forty-eight percent of patients treated in schedule A and 37% treated in schedule B had not received chemotherapy before their entry into the study. No patients had received prior carboplatin. One patient on each schedule had prior treatment with docetaxel, and one on schedule B had received paclitaxel.
Dose levels tested, number of patients requiring dose reductions, and DLTs for both schedules are summarized in Table 2 . The tolerability of schedule A was explored first, with patients receiving a median of 4 courses (range, 1-8; total, 94). Nine patients received six or more cycles. Doses were reduced according to protocol; there was a reduction of one dose level for both drugs for grade 4 neutropenia ≥5 days, febrile neutropenia, grade 3 neuropathy, diarrhea, uncontrollable nausea and vomiting, or grade 3 thrombocytopenia with bleeding. A platelet nadir of ≤25,000 mm3 triggered a reduction by AUC 1 of carboplatin alone, with further dose reduction of both drugs if thrombocytopenia occurred again. On schedule A, 5 (20%) patients had ixabepilone reduced and 6 (24%) had carboplatin reduced due to hematologic toxicity. Thirteen patients had a total of 18 course delays: 5 each due to delayed recovery from hematologic and nonhematologic toxicities and 8 for non–drug-related logistical reasons.
After the maximum tolerated dose of schedule A was established, split dosing of ixabepilone on days 1 and 8 of each 21-day cycle was explored to investigate the effect on tolerability (schedule B). Twenty-seven (96%) patients completed a median of 3 treatment cycles (range, 1-6; total, 86), with five patients receiving 6 cycles. Six (22%) patients had ixabepilone and/or carboplatin doses reduced. Twelve patients had a total of 26 course dose delays. The majority of course delays were due to delayed recovery from toxicities (21 of 26). No hypersensitivity reactions due to ixabepilone were observed.
Hematologic toxicity. The most common DLT of ixabepilone plus carboplatin combination is myelosuppression (Table 3 ). All patients (100%) treated with ixabepilone 40 mg/m2 plus carboplatin AUC 6 on schedule A developed grade 4 neutropenia. One patient at the prior dose level (ixabepilone 40 mg/m2 plus carboplatin AUC 5) developed a DLT (febrile neutropenia) and the dose level was expanded to 14 patients. Grade 3/4 neutropenia was observed in 10 (71%) patients, with 2 (14%) cases of febrile neutropenia across any cycle. Dosing with ixabepilone 30 mg/m2 plus carboplatin AUC 6 was associated with reduced hematologic toxicity with no reports of febrile neutropenia.
Hematologic toxicities, primarily neutropenia, were also observed with schedule B and resolved quickly. There was one drug-related toxic death; the patient died of complications from febrile neutropenia at the highest dose level explored, ixabepilone days 1 and 8, 25 mg/m2 plus carboplatin AUC 6. The neutropenia seemed to be dose dependent with both schedules.
Nonhematologic toxicity. The major symptomatic nonhematologic toxicities were cumulative peripheral neuropathy, myalgia, and arthralgia (Table 4 ). Four (29%) patients treated with ixabepilone 40 mg/m2 plus carboplatin AUC 5 on schedule A developed grade 3 neuropathy. Lower incidence and severity of neuropathy were observed after reductions in ixabepilone and/or carboplatin. Eleven patients discontinued treatment because of neurotoxicity (sensory in eight patients, motor in two patients, and unspecified in one patient). All patients developing sensory neuropathy sufficient to be withdrawn from the study had received three or more courses of treatment. Sensory neuropathy was typical, with “glove and stocking” distribution. Motor neuropathy was observed after one course in one patient and after three courses in a second patient. Motor neuropathy resolved on cessation of treatment.
Although myalgia is a common symptom in patients with advanced cancer, 21 of the 52 (40%) patients in this study experienced myalgia, which was the assigned study drug causality by the investigator. Myalgia tended to start 3 to 5 days after ixabepilone infusion and affected primarily large weight-bearing muscle groups. Prophylactic treatment with simple analgesics (paracetamol or nonsteroidal anti-inflammatory drugs) allowed continuation of treatment in the majority of patients.
Response evaluation. Antitumor activity was observed for the ixabepilone plus carboplatin combination. Partial response was observed in a total of 6 (12%) patients, consisting of 2 breast cancer, 1 neuroendocrine tumor, 1 mesothelioma, and 2 adenocarcinomas of unknown origin. The clinical characteristics of the six patients who responded to therapy are summarized in Table 5 . Two of the patients had been heavily pretreated; one of the patients with breast cancer had received prior therapy with paclitaxel, with a partial response. A total of 15 (29%) patients received treatment for six cycles, indicating a clinical benefit with duration of at least 6 months in this poor prognosis and/or treatment-resistant patient population.
Pharmacologic analyses. Samples for pharmacokinetic analysis were collected from the majority of patients during cycle 1. Samples from 43 of 52 (83%) treated patients were suitable for pharmacokinetic analysis. Ixabepilone pharmacokinetics showed that Cmax increased with dose; the plasma half-life was 24 to 40 hours at all doses studied; and there was a large volume of distribution. Table 6 summarizes pharmacokinetic parameters measured for ixabepilone for schedules A and B. Carboplatin pharmacokinetics were analyzed for patients treated on schedule B only. There was no evidence of an alteration in carboplatin pharmacokinetics due to coadministration of ixabepilone. Mean AUC values for those patients with a target of 5 mg/mL min was 5.4 ± 1.0 mg/mL min, and that for a target of 6 mg/mL min was 6.8 ± 2.1 mg/mL min.
The aim of this phase I study was to assess the feasibility and tolerability of combination ixabepilone plus carboplatin in patients with a variety of solid tumors and to establish a recommended phase II dose and schedule. Ixabepilone has previously been evaluated as a single agent in multiple phase I (14–17, 21–23) and phase II trials (24–31). It has been studied in combination with estramustine phosphate in prostate cancer (32). Ixabepilone has also been studied in combination with capecitabine in phase II and III trials where it has shown significant improvement in progression-free survival for patients with metastatic breast cancer (33, 34). Overall, myelosuppression has been dose limiting on all schedules investigated, and cumulative sensory neuropathy has been reported to varying degrees in all studies.
In the phase I trial reported here, two dosing schedules were investigated. On schedule A, the maximum tolerated dose was ixabepilone 40 mg/m2 plus carboplatin AUC 5. The most frequent grade 3/4 adverse events with this schedule and dose were neutropenia in 10 (71%) patients and thrombocytopenia and anemia in 2 (14%) patients each. In addition, cumulative grade 3/4 neuropathy occurred in 4 (29%) patients. At the next lower dose level of 30 mg/m2 plus carboplatin AUC 6, no patients developed grade 3/4 neuropathy. Based on the improved safety profile of this dose level, 30 mg/m2 plus carboplatin AUC 6 is chosen as the recommended dose.
Previous single-agent studies suggested that the incidence of neuropathy may be linked to peak concentration of ixabepilone; a consecutive 5-day schedule every 21 days had a lower rate of neuropathy (17). Correlation of neuropathy with peak dose has been observed with other microtubule inhibitors such as paclitaxel; it is known that weekly dosing of this drug allows a higher dose delivery with fewer toxicities (35, 36). Therefore, it was decided to investigate a split-dosing schedule for ixabepilone (schedule B) in combination with carboplatin as a strategy for maintaining dose delivery and reducing potential neurotoxicity.
Schedule B allowed delivery of the selected phase II dose of ixabepilone in combination with a therapeutic dose of carboplatin. The most frequent grade 3/4 adverse events on schedule B were gastrointestinal or hematologic. Ixabepilone doses were reduced on schedule B due to neuropathy and diarrhea, but few were due to hematologic toxicities. All carboplatin dose reductions on schedule B were due to nonhematologic toxicities. All toxicities occurred at doses of ixabepilone that were at or close to the maximum tolerated dose for schedule B 20 mg/m2 plus carboplatin AUC 6.
Pharmacokinetic analysis of ixabepilone was done on the first cycle for most patients. The results were comparable to those already reported in single-agent pharmacokinetic studies (14, 17); consequently, there was no evidence that coadministration of carboplatin affects the pharmacokinetics of this agent. Conversely, there was no evidence of alterations in carboplatin pharmacokinetics when coadministered with ixabepilone.
This study showed that it is possible to deliver the phase II recommended dose of ixabepilone in combination with carboplatin. The combination therapy was well tolerated in the majority of patients. The major toxicities, although dose-limiting in some cases, were primarily sensory neuropathy and neutropenia, both of which were reversible. It is possible that extending the infusion of ixabepilone in the every 21-day schedule to 3 hours, consistent with the recommended schedule in breast cancer, could help reduce the risk of neuropathy associated with this combination; however, confirmation is needed in future studies. There were no new toxicities observed with the combination of ixabepilone plus carboplatin.
The data from the present study show the feasibility and tolerability of ixabepilone, administered both as a single and as a split dose, in combination with carboplatin every 3 weeks. Based on the observed DLTs, the recommended dose for schedule A is ixabepilone 30 mg/m2 (administered on day 1 of a 21-day cycle) plus carboplatin AUC 6. The recommended dose for schedule B is ixabepilone 20 mg/m2 (administered on days 1 and 8 of a 21-day cycle) plus carboplatin AUC 6.
Based on feasibility of combined administration, ixabepilone plus carboplatin is suitable for further investigation in a variety of solid tumors including non–small-cell lung cancer, for which ixabepilone has proven activity as monotherapy (26).
Disclosure of Potential Conflicts of Interest
F. Namouni, M. Cohen, P. Hewitt, employees, Bristol Myers Squibb.
↵6 Awada A, et al. Phase I dose escalation study of weekly ixabepilone, an epothilone analogue, in patients with advanced solid tumors who have failed standard therapy, in press, 2008.
- Received February 25, 2008.
- Revision received July 10, 2008.
- Accepted August 19, 2008.