Cancer Therapy: Clinical

A Phase I and Pharmacokinetic Study of Ixabepilone in Combination with in Patients with Advanced Solid Malignancies Ruth Plummer,1Penella Woll,3 David Fyfe,3 AlanV. Boddy,2 Melanie Griffin,2 Paula Hewitt,4 James Carmichael,3 Fouad Namouni,5 Marvin Cohen,5 and MarkVerrill1

Abstract Purpose: To determine the recommended phase II dose of combination ixabepilone plus carbo- platin based on the maximum tolerated dose, , optimum schedule, and safety. Experimental Design: Patients with advanced solid malignancies were treated with escalat- ing 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-twopatientsweretreatedwithixabepilonedosesrangingfrom30to50mg/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.DLTwas myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. Ixabepilone and carbo- platin 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 q3wplus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3wplus carboplatinAUC6(scheduleB). Conclusions: Data from the present study showthe 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.

Cytotoxic drugs that act by targeting structure are B promote microtubule stabilization (12). Ixabepi- now well established for the treatment of many solid tumors. lone (Bristol-Myers Squibb) is a semisynthetic lactam analogue Both the , which are microtubule-stabilizing agents and of epothilone B with a mode of action similar to . This the Vinca alkaloids, which promote microtubule disassembly, agent has shown superior in vivo antitumor activity to paclitaxel have a broad spectrum of activity and are routinely used to treat in both paclitaxel-sensitive and paclitaxel-resistant tumors (13). breast, ovarian, and non–small-cell lung cancers, with emerg- Ixabepilone has completed four phase I evaluations as a ing data of activity in prostate cancer (1–8). Efficacy of these single agent given as a 1-hour infusion every 3 weeks (14–16). classes of chemotherapeutic agents is limited by the develop- The dose-limiting toxicity (DLT) was neutropenia, and the ment of drug resistance and also by cumulative side effects, in recommended phase II dose was 40 mg/m2 on this schedule. particular neurotoxicity (9, 10). Continued development of The most common nonhematologic side effects were fatigue novel microtubule inhibitors is important to improve efficacy and cumulative sensory neuropathy. No hypersensitivity in drug-resistant disease and to reduce potential toxicities. reactions were reported. When ixabepilone was administered The are naturally occurring products initially as an i.v. infusion weekly on a 21-day cycle and intermittently isolated from the fermentation broth of the myxobacterium on days 1, 8, and 15 of a 28-day cycle, it was well tolerated and (11, 12). The compounds are 16- had an acceptable safety profile at the maximum tolerated membered ring macrolides, and both epothilone A and 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). Authors’ Affiliations: 1Northern Centre for CancerTreatment; 2Northern Institute The combination of paclitaxel and carboplatin, a regimen for Cancer Research, Newcastle upon Tyne, United Kingdom; 3Nottingham City that is widely used in the treatment of advanced solid tumors, Hospital, Nottingham, United Kingdom; 4Bristol-Myers Squibb, Uxbridge, United 5 has shown synergistic efficacy and reduced toxicity (18). Kingdom; and Bristol-Myers Squibb,Wallingford, Connecticut Consequently, it was important to establish a recommended Received 2/25/08; revised 7/10/08; accepted 8/19/08. Requests for reprints: Ruth Plummer, Northern Centre for Cancer Treatment, Westgate Road, Newcastle upon Tyne NE4 6BE, United Kingdom. Phone: 44-191- 2563599; Fax: 44-191-2261170; E-mail: [email protected]. 6 Awada A, et al. Phase I dose escalation study of weekly ixabepilone, an epothilone F 2008 American Association for Cancer Research. analogue, in patients with advanced solid tumors who have failed standard therapy, doi:10.1158/1078-0432.CCR-08-0471 in press, 2008.

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Table 1. Patient demographics

Characteristic Schedule A (day 1, q3w), n = 25 Schedule B (days 1 and 8, q3w), n =27 Age, y (range) Median 58 54 Range (31-74) (31-76) No.patients n =25 n =27 Male/female 12/13 17/10 Performance status 0 10 3 1 13 22 2 22 Tumor type Melanoma 1 3 Breast 3 2 Colorectal 4 4 Non – small-cell lung 2 0 Sarcoma 4 5 Mesothelioma 0 3 Adenocarcinoma 1 Adenocarcinoma—unknown primary 4 4 Neuroendocrine carcinoma 1 Neuroectodermal tumor 1 Renal carcinoma 1 2 GIST 0 1 Unknown primary squamous carcinoma 1 Hepatocellular cancer 0 1 Carcinoid tumor 1 0 Spindle cell carcinoma—unknown primary 1 0 Smooth muscle neoplasm 0 1 Peripheral nerve sheath tumor 0 1 Previous treatment 13 17 1 prior regimen 5 9 2 prior regimens 6 6 3 prior regimens 2 2 Hormonal/immunotherapy 4 1 Radiotherapy 13 10 Surgery 23 23

dose for the ixabepilone plus carboplatin combination so that day 1, altered the recommended dose or side-effect profile. The the efficacy of this regimen could be investigated further. study was carried out at two sites in the United Kingdom, with We report the results of a phase I dose escalation study that the primary objective of establishing recommended phase II examined two dosing schedules, with the starting dose of doses for each of the schedules. ixabepilone at 30 mg/m2 based on phase I data. Carboplatin dosage was calculated using the Calvert formula (19) exploring Patients and Methods standard combination treatment AUC of 5 or 6. In schedule A, ixabepilone and carboplatin were both given on day 1of a Eligibility. The study protocol was approved by local ethical 21-day cycle. Schedule B investigated whether splitting the dose assessment committees and by institutional review boards. All patients of ixabepilone between days 1and 8, with carboplatin given on gave written informed consent before any study-specific procedures

Table 2. Dose cohorts and DLTs in phase I (dose escalation)

Schedule (21-d cycle) Dosing No. patients starting No. patients requiring N at this dose dose reduction carboplatin (A) Ixa on day 1 + CBDCA on day 1 Ixa 30 mg/m2 + CBDCA AUC 5; n =3 3 0 Ixa 30 mg/m2 + CBDCA AUC 6; n =6 6 2 Ixa 40 mg/m2 + CBDCA AUC 5; n =14 14 3 Ixa 40 mg/m2 + CBDCA AUC 6; n =2 2 1 (B) Ixa on days 1 and 8 + CBDCA on day 1 Ixa 20 mg/m2 + CBDCA AUC 5; n =9 9 2 Ixa 20 mg/m2 + CBDCA AUC 6; n =15 15 3 Ixa 25 mg/m2 + CBDCA AUC 6; n =3 3 1

Abbreviations: Ixa, ixabepilone; CBDCA, carboplatin.

www.aacrjournals.org 8289 Clin Cancer Res 2008;14(24) December 15, 2008 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2008 American Association for Cancer Research. Cancer Therapy: Clinical were done. Adults (z18 y) with histologically or cytologically proven 5 or more consecutive days or febrile neutropenia (CTC grade 3 or 4); advanced solid tumors refractory to conventional treatment or for thrombocytopenia <25,000 cells/mm3 or a bleeding episode requiring whom no standard treatment existed were recruited. Additional platelet transfusion; CTC grade 3 or 4 nausea and vomiting despite inclusion criteria were Eastern Cooperative Oncology Group perfor- adequate treatment; any other grade 3 or 4 toxicity (except grade 3 mance status 0 to 1; adequate hematologic function (absolute injection site reaction, fatigue, transient arthralgia/myalgia); prolonged neutrophil count z2,000 cells/mm3, platelet count z125,000 cells/ recovery from a drug-related toxicity that delayed re-treatment at mm3, hemoglobin z9 g/dL) and hepatorenal function (bilirubin 3 wk; and omission of day 8 treatment on schedule B due to hema- V1.5 mg/dL; transaminases V2.5 times the upper limit of normal and tologic toxicity. serum creatinine V1.5 times the upper limit of normal); and at least Dose escalation was stopped if two of three to six patients developed 4 wk since last chemotherapy or radiation therapy (6 wk for nitrosureas DLT on the first cycle, and a lower dose level was expanded to a or ). Women of child-bearing potential were required to maximum of nine patients to establish the recommended phase II dose have a negative serum or urine pregnancy test within 72 h before and further characterize pharmacokinetics. starting the study drug. Pretreatment and follow-up studies. Full history; physical examina- Exclusion criteria included prior treatment with more than two tion, including neurologic examination; and routine laboratory tests chemotherapy regimens for metastatic disease or in the adjuvant setting (complete blood count and serum chemistry, including transaminases, or any platinum-containing treatment; preexisting peripheral neurop- bilirubin, urea, and creatinine) were done before every scheduled athy Common Toxicity Criteria (CTC) grade >1; brain metastases; or a treatment. Laboratory tests were repeated weekly during the study. documented history of hypersensitivity to paclitaxel or other therapies Disease was assessed using computed tomography scans, which were containing Cremophor EL. repeated after every two cycles of treatment. Baseline electrocardio- Dosage and administration. Patients were premedicated with gram and chest X-ray were also recorded. On discontinuation of the antiemetics, according to the standard protocols of the investigating study, patients were followed for at least 30 d or until the resolution institution, and with an oral H1(diphenhydramine) and oral H2 of toxicity. blocker (ranitidine or cimetidine) 1h before treatment. Ixabepilone Plasma sampling and analysis. Samples of whole blood (5 mL) were for injection (lyophilized cake in 10- or 20-mg vials), supplied by collected during cycle 1for pharmacokinetic analysis predose, 0.25, 0.5, Bristol-Myers Squibb, was diluted in an ethanol/Cremophor EL mixture 0.75, 1(end of ixabepilone infusion), 1.5,2, 3, 4, 6, 8, 24, 48, and

(1:1, v/v) to achieve a final concentration of 2 mg/mL. This solution 72 h after the start of the ixabepilone infusion into K3EDTA tubes. was further diluted in Ringer’s lactate solution to a final ixabepilone Within 30 min of collection, the plasma was separated by centrifuga- concentration of 0.1to 0.5 mg/mL. Ixabepilone was infused over 1h via tion at 2,000 g for 5 min at 0jCto5jC. Plasma samples were stored an infusion pump on both schedules A and B. Carboplatin was at -20jC for further analysis. It has previously been shown that systemic supplied as sterile aqueous solution for injection (10 mg/mL in 450-mg exposure in humans to the two degradation products of ixabepilone vials) and was further diluted in 250 mL of saline for infusion over (the oxine BMS-249798 and diol BMS-326412) is negligible (14) and, 30 min. The dose of carboplatin was determined by the modified therefore, only ixabepilone (BMS-247550) was analyzed in this study Calvert formula (19) to a target AUC of 5 to 6. Infusion of carboplatin using the published and validated method (14). was started 30 min after completion of the ixabepilone infusion on At 24 h after carboplatin dosing, an additional blood sample was day 1. collected from patients enrolled on schedule B of the study only for Treatment was planned for a minimum of two courses unless clinical analysis of carboplatin pharmacokinetics. The sample was analyzed tumor progression or unacceptable toxicity was observed. Response was according to a published method allowing single-sample estimation of assessed every two cycles using Response Evaluation Criteria in Solid AUC (20). Tumors criteria, and patients could continue on the study for as long as Pharmacokinetic and statistical analyses. Plasma concentration they benefited from treatment. Toxicity was graded according to the versus time data were analyzed using standard noncompartmental National Cancer Institute CTC version 2.0. Re-treatment was scheduled methods. Carboplatin pharmacokinetics were analyzed as described every 3 wk provided hepatic and renal eligibility criteria were still met, above. All other results are summarized using descriptive statistics. all observed drug-related toxicity had resolved to baseline or CTC grade 1, and hematologic indices of absolute neutrophil count z1,500 cells/ mm3 and platelet count z100,000 cells/mm3 had been achieved. Results 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 A total of 55 patients with various solid malignancies were first three patients. DLT was defined as the occurrence of any of the enrolled: 27 on schedule A and 28 on schedule B. Three of the following during cycle 1: absolute neutrophil count <500 cells/mm3 for recruited patients were not treated due to unforeseen events

Table 2. Dose cohorts and DLTs in phase I (dose escalation) (Cont’d)

No. patients requiring No. courses delayed No. courses omitted No. DLT/no. DLT dose reduction ixabepilone (courses given) on day 8 (no. patients) treated 0 1 (14) N/A 0/3 1 4 (19) N/A 1/6 Grade 3 motor neuropathy 3 12 (54) N/A 1/14 Grade 4 febrile neutropenia 1 1 (7) N/A 2/2 Grade 3 febrile neutropenia; grade 3 diarrhea 3 8 (30) 4 (4) 2/9 Grade 3 febrile neutropenia; grade 3 stomatitis 2 17 (49) 5 (5) 3/15 Grade 3 thrombocytopenia; grade 3 infection with neutropenia; delayed hematologic recovery 1 1 (7) 0 3/3 Grade 3 dehydration; grade 3 diarrhea; grade 3 mucositis

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Table 3. Grade 3/4 hematologic adverse events by dose cohort

Schedule (21-d cycle) Dosing

(A) Ixa on day 1 + CBDCA on day 1 Ixa 30 mg/m2 + CBDCA AUC 5; n =3 Ixa 30 mg/m2 + CBDCA AUC 6; n =6 Ixa 40 mg/m2 + CBDCA AUC 5; n =14 Ixa 40 mg/m2 + CBDCA AUC 6; n =2 (B) Ixa on days 1 and 8 + CBDCA on day 1 Ixa 20 mg/m2 + CBDCA AUC 5; n =9 Ixa 20 mg/m2 + CBDCA AUC 6; n =15 Ixa 25 mg/m2 + CBDCA AUC 6; n =3

(two patients on schedule A, one patient on schedule B). tolerability (schedule B). Twenty-seven (96%) patients com- Patient characteristics are summarized in Table 1. The majority pleted a median of 3 treatment cycles (range, 1-6; total, 86), of patients had performance status 1and had surgery as with five patients receiving 6 cycles. Six (22%) patients had primary therapy for their disease. Forty-eight percent of patients ixabepilone and/or carboplatin doses reduced. Twelve patients treated in schedule A and 37% treated in schedule B had not had a total of 26 course dose delays. The majority of course received chemotherapy before their entry into the study. No delays were due to delayed recovery from toxicities (21of 26). patients had received prior carboplatin. One patient on each No hypersensitivity reactions due to ixabepilone were observed. schedule had prior treatment with , and one on Hematologic toxicity. The most common DLT of ixabepilone schedule B had received paclitaxel. plus carboplatin combination is myelosuppression (Table 3). Dose levels tested, number of patients requiring dose All patients (100%) treated with ixabepilone 40 mg/m2 plus reductions, and DLTs for both schedules are summarized in carboplatin AUC 6 on schedule A developed grade 4 Table 2. The tolerability of schedule A was explored first, with neutropenia. One patient at the prior dose level (ixabepilone patients receiving a median of 4 courses (range, 1-8; total, 94). 40 mg/m2 plus carboplatin AUC 5) developed a DLT (febrile Nine patients received six or more cycles. Doses were reduced neutropenia) and the dose level was expanded to 14 patients. according to protocol; there was a reduction of one dose level Grade 3/4 neutropenia was observed in 10 (71%) patients, with for both drugs for grade 4 neutropenia z5 days, febrile 2 (14%) cases of febrile neutropenia across any cycle. Dosing neutropenia, grade 3 neuropathy, diarrhea, uncontrollable with ixabepilone 30 mg/m2 plus carboplatin AUC 6 was nausea and vomiting, or grade 3 thrombocytopenia with associated with reduced hematologic toxicity with no reports of bleeding. A platelet nadir of V25,000 mm3 triggered a reduction febrile neutropenia. by AUC 1of carboplatin alone, with further dose reduction of Hematologic toxicities, primarily neutropenia, were also both drugs if thrombocytopenia occurred again. On schedule A, observed with schedule B and resolved quickly. There was 5 (20%) patients had ixabepilone reduced and 6 (24%) had one drug-related toxic death; the patient died of complications carboplatin reduced due to hematologic toxicity. Thirteen from febrile neutropenia at the highest dose level explored, patients had a total of 18 course delays: 5 each due to delayed ixabepilone days 1and 8, 25 mg/m 2 plus carboplatin AUC 6. recovery from hematologic and nonhematologic toxicities and The neutropenia seemed to be dose dependent with both 8 for non–drug-related logistical reasons. schedules. After the maximum tolerated dose of schedule A was Nonhematologic toxicity. The major symptomatic nonhema- established, split dosing of ixabepilone on days 1and 8 of tologic toxicities were cumulative peripheral neuropathy, each 21-day cycle was explored to investigate the effect on myalgia, and arthralgia (Table 4). Four (29%) patients treated

Table 4. Grade 3/4 nonhematologic adverse events by dose cohort

Schedule Dosing Neuropathy, Myalgia, Arthralgia, (21-d cycle) no. patients (%) no. patients (%) no. patients (%) Grade 3 Grade 4 Grade 2 Grade 3 Grade 2 Grade 3 (A) Ixa on day 1 + Ixa 30 mg/m2 + 000000 CBDCA on day 1 CBDCA AUC 5; n =3 Ixa 30 mg/m2 + 0 0 3 (50) 0 2 (33) 0 CBDCA AUC 6; n =6 Ixa 40 mg/m2 + 4 (29) 0 4 (29) 0 5 (36) 1 (7) CBDCA AUC 5; n =14 Ixa 40 mg/m2 + 0 0 2 (100) 0 1 (50) 0 CBDCA AUC 6; n =2 (B) Ixa on days 1 and Ixa 20 mg/m2 + 3 (33) 0 3 (33) 0 3 (33) 0 8 + CBDCA on day 1 CBDCA AUC 5; n =9 Ixa 20 mg/m2 + 0 0 1 (17) 0 0 0 CBDCA AUC 6; n =15 Ixa 25 mg/m2 + 1 (33) 0 0 0 0 0 CBDCA AUC 6; n =3

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Table 3. Grade 3/4 hematologic adverse events by dose cohort (Cont’d)

Neutropenia, no. patients (%) Thrombocytopenia, no. patients (%) Anemia, no. patients (%) Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 1 (33) 1 (33) 0 0 1 (3) 0 1 (17) 5 (83) 1 (17) 0 0 0 1 (7) 9 (64) 2 (14) 0 2 (14) 0 0 2 (100) 1 (50) 0 1 (50) 0 2 (22) 3 (33) 1 (11) 0 0 1 (11) 2 (13) 6 (40) 3 (20) 0 2 (13) 1 (7) 0 2 (67) 0 0 0 0 with ixabepilone 40 mg/m2 plus carboplatin AUC 5 on 15 (29%) patients received treatment for six cycles, indicating a schedule A developed grade 3 neuropathy. Lower incidence clinical benefit with duration of at least 6 months in this poor and severity of neuropathy were observed after reductions in prognosis and/or treatment-resistant patient population. ixabepilone and/or carboplatin. Eleven patients discontinued Pharmacologic analyses. Samples for pharmacokinetic anal- treatment because of neurotoxicity (sensory in eight patients, ysis were collected from the majority of patients during cycle 1. motor in two patients, and unspecified in one patient). All Samples from 43 of 52 (83%) treated patients were suitable for patients developing sensory neuropathy sufficient to be pharmacokinetic analysis. Ixabepilone pharmacokinetics withdrawn from the study had received three or more courses showed that Cmax increased with dose; the plasma half-life of treatment. Sensory neuropathy was typical, with ‘‘glove and was 24 to 40 hours at all doses studied; and there was a large stocking’’ distribution. Motor neuropathy was observed after volume of distribution. Table 6 summarizes pharmacokinetic one course in one patient and after three courses in a second parameters measured for ixabepilone for schedules A and B. patient. Motor neuropathy resolved on cessation of treatment. Carboplatin pharmacokinetics were analyzed for patients Although myalgia is a common symptom in patients with treated on schedule B only. There was no evidence of an advanced cancer, 21of the 52 (40%) patients in this study alteration in carboplatin pharmacokinetics due to coadminis- experienced myalgia, which was the assigned study drug tration of ixabepilone. Mean AUC values for those patients with causality by the investigator. Myalgia tended to start 3 to 5 a target of 5 mg/mL min was 5.4 F 1.0 mg/mL min, and that days after ixabepilone infusion and affected primarily large for a target of 6 mg/mL min was 6.8 F 2.1mg/mL min. weight-bearing muscle groups. Prophylactic treatment with simple analgesics (paracetamol or nonsteroidal anti-inflamma- Discussion tory drugs) allowed continuation of treatment in the majority of patients. The aim of this phase I study was to assess the feasibility and Response evaluation. Antitumor activity was observed for tolerability of combination ixabepilone plus carboplatin in the ixabepilone plus carboplatin combination. Partial response patients with a variety of solid tumors and to establish a was observed in a total of 6 (12%) patients, consisting of 2 recommended phase II dose and schedule. Ixabepilone has , 1neuroendocrine tumor, 1mesothelioma, and previously been evaluated as a single agent in multiple phase I 2 adenocarcinomas of unknown origin. The clinical character- (14–17, 21–23) and phase II trials (24–31). It has been istics of the six patients who responded to therapy are studied in combination with in summarized in Table 5. Two of the patients had been heavily prostate cancer (32). Ixabepilone has also been studied in pretreated; one of the patients with breast cancer had received combination with in phase II and III trials where it prior therapy with paclitaxel, with a partial response. A total of has shown significant improvement in progression-free survival

Table 5. Details of patients showing response to study treatment

Tumor type Age/sex Prior therapy Extent of disease Schedule and dose Breast 53/F RT, CMF, , , Nodal disease* Schedule A: Ixa 30 mg/m2 + tamoxifen, anastrozole CBDCA AUC 6 Breast 46/F RT, doxorubicin, paclitaxel, Lung and liver metastases Schedule B: Ixa 20 mg/m2 + 5-FU, CBDCA AUC 6 Adenocarcinoma of 69/F None Liver , lung metastasis, Schedule A: Ixa 40 mg/m2 + unknown primary origin and pleural disease CBDCA AUC 5 Neuroendocrine tumor 63/M None Cervical nodes Schedule A: Ixa 40 mg/m2 + CBDCA AUC 5 Adenocarcinoma of 72/M None Liver metastasis, lung metastasis, Schedule B: Ixa 20 mg/m2 + unknown primary origin pleural disease, and nodal disease CBDCA AUC 6 Mesothelioma 71/M None Pleural disease Schedule B: Ixa 20 mg/m2 + CBDCA AUC 6

Abbreviations: RT, radiotherapy; 5-FU, 5-; Ixa, ixabepilone; CMF, --5-fluorouracil. *Soft tissue nodes outside primary area precarinal (3.5 cm), subcarinal (5 cm), and right anterior mediastinum (1.5 cm).

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Table 6. Pharmacokinetic parameters of ixabepilone

Schedule Dose of Dose of nCmax, ng/mL AUC0-1, ng/mL h Mean T 1/2, CLT, V ss, L (SD) (21-d cycle) ixabepilone carboplatin (%CV) (%CV) h (SD) L/h (SD) (mg/m2) (AUC) (A) Ixa on day 1 + 30 5 3 376 (38) 1,209 (27) 40.6 (13.7) 41.9 (15.9) 1,420 (980) CBDCA on day 1 30 6 5 489 (14) 1,604 (56) 28.7 (4.8) 36.0 (12.8) 898 (341) 40 5 13 635 (35) 2,059 (32) 23.5 (8.8) 36.6 (14.7) 658 (149) 40 6 2* 543 (9) 1,641 (16) 25.5 45.1 962 (B) Ixa on days 1 and 20 5 4 391 (49) 1,416 (49) 33.7 (14.9) 28.2 (9.8) 881 (431) 8 + CBDCA on day 1 20 6 13 446 (62) 1,217 (35) 27.0 (8.7) 28.4 (7.9) 673 (273) 25 6 3 758 (74) 2,373 (55) 31.6 (3.7) 23.1 (20.3) 818 (740)

Abbreviations: %CV, percent coefficient of variation; CLT, total clearance. *SDs are not presented; N V 2.

for patients with metastatic breast cancer (33, 34). Overall, Pharmacokinetic analysis of ixabepilone was done on the myelosuppression has been dose limiting on all schedules first cycle for most patients. The results were comparable to investigated, and cumulative sensory neuropathy has been those already reported in single-agent pharmacokinetic studies reported to varying degrees in all studies. (14, 17); consequently, there was no evidence that coadminis- In the phase I trial reported here, two dosing schedules were tration of carboplatin affects the pharmacokinetics of this agent. investigated. On schedule A, the maximum tolerated dose was Conversely, there was no evidence of alterations in carboplatin ixabepilone 40 mg/m2 plus carboplatin AUC 5. The most pharmacokinetics when coadministered with ixabepilone. frequent grade 3/4 adverse events with this schedule and dose This study showed that it is possible to deliver the phase II were neutropenia in 10 (71%) patients and thrombocytopenia recommended dose of ixabepilone in combination with and anemia in 2 (14%) patients each. In addition, cumulative carboplatin. The combination therapy was well tolerated in grade 3/4 neuropathy occurred in 4 (29%) patients. At the next the majority of patients. The major toxicities, although dose- lower dose level of 30 mg/m2 plus carboplatin AUC 6, no limiting in some cases, were primarily sensory neuropathy and patients developed grade 3/4 neuropathy. Based on the neutropenia, both of which were reversible. It is possible that improved safety profile of this dose level, 30 mg/m2 plus extending the infusion of ixabepilone in the every 21-day carboplatin AUC 6 is chosen as the recommended dose. schedule to 3 hours, consistent with the recommended schedule Previous single-agent studies suggested that the incidence of in breast cancer, could help reduce the risk of neuropathy neuropathy may be linked to peak concentration of ixabepilone; associated with this combination; however, confirmation is a consecutive 5-day schedule every 21days had a lower rate of needed in future studies. There were no new toxicities observed neuropathy (17). Correlation of neuropathy with peak dose has with the combination of ixabepilone plus carboplatin. been observed with other microtubule inhibitors such as The data from the present study show the feasibility and paclitaxel; it is known that weekly dosing of this drug allows a tolerability of ixabepilone, administered both as a single and as higher dose delivery with fewer toxicities (35, 36). Therefore, it a split dose, in combination with carboplatin every 3 weeks. was decided to investigate a split-dosing schedule for ixabepilone Based on the observed DLTs, the recommended dose for (schedule B) in combination with carboplatin as a strategy for schedule A is ixabepilone 30 mg/m2 (administered on day 1of maintaining dose delivery and reducing potential neurotoxicity. a 21-day cycle) plus carboplatin AUC 6. The recommended Schedule B allowed delivery of the selected phase II dose of dose for schedule B is ixabepilone 20 mg/m2 (administered on ixabepilone in combination with a therapeutic dose of days 1and 8 of a 21-daycycle) plus carboplatin AUC 6. carboplatin. The most frequent grade 3/4 adverse events on Based on feasibility of combined administration, ixabepilone schedule B were gastrointestinal or hematologic. Ixabepilone plus carboplatin is suitable for further investigation in a variety doses were reduced on schedule B due to neuropathy and of solid tumors including non–small-cell lung cancer, for diarrhea, but few were due to hematologic toxicities. All which ixabepilone has proven activity as monotherapy (26). carboplatin dose reductions on schedule B were due to nonhematologic toxicities. All toxicities occurred at doses of Disclosure of Potential Conflicts of Interest ixabepilone that were at or close to the maximum tolerated dose for schedule B 20 mg/m2 plus carboplatin AUC 6. F. Namouni, M. Cohen, P. Hewitt, employees, .

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