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Originally published as JCO Early Release 10.1200/JCO.2006.08.7304 on January 29 2007 © 2007 American Society of Clinical Oncology. Phase I Study of the Novel Epothilone Analog Ixabepilone (BMS-247550) in Patients With Advanced Solid Tumors and Lymphomas
From the Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, New York, NY; Sarah Cannon Cancer Center, Nashville, TN; Bristol-Myers Squibb, Princeton, NJ; and Bristol-Myers Squibb Oncology, Wallingford, CT Address reprint requests to Carol Aghajanian, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: aghajanc{at}mskcc.org
Purpose: To establish the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or relapsed/refractory non-Hodgkin's lymphoma. Dosing schedules of 40 mg/m2 and 50 mg/m2 over 3 hours were also evaluated. Patients and Methods: Sixty-one patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase, with doses of ixabepilone ranging from 7.4 to 65 mg/m2. The pharmacokinetics of ixabepilone and two of its chemical degradation products were evaluated. Plasma pharmacodynamics were evaluated for both 1- and 3-hour infusions using an assay that measures the amount of endogenous tubulin in peripheral-blood mononuclear cells that exists in the polymerized versus the unpolymerized state. Response evaluation was performed every 6 weeks. Results: The most common DLTs were neutropenia, stomatitis/pharyngitis, myalgia, and arthralgia. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase less than proportionally to dose. Durable objective responses were seen in eight patients, including two complete responses. Five of the responders had experienced treatment failure with a taxane. Conclusion: The recommended dose of ixabepilone for the initiation of phase II studies on the basis of these results is 50 mg/m2 over 1 hour every 3 weeks. The promising efficacy and tolerability results demonstrated by ixabepilone in this study warrant its continued development.
The epothilones are a new class of antimicrotubule agent derived from the myxobacterium Sorangium cellulosum.1 The antineoplastic activities of the epothilones have been linked to stabilization of microtubules, which results in mitotic arrest at the G2/M transition.1 Ixabepilone (BMS-247550) is a semisynthetic analog of epothilone B designed to optimize the characteristics of its natural precursor. It is distinct from other antineoplastic agents because it has low susceptibility to common mechanisms of tumor resistance, including those mediated by P-glycoprotein and multidrug resistance protein.2-4 It also has good metabolic stability and low protein binding. Preclinically, ixabepilone has demonstrated high activity against a broad range of tumors, including taxane-resistant human tumor xenografts,5 which prompted the initiation of phase I studies. The primary objectives of this trial were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and safety of ixabepilone administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors unresponsive to currently available therapies or with no known effective therapy; the aim was to define the recommended phase II dose. Assessments of safety and efficacy in patients with pretreated non-Hodgkin's lymphoma (NHL) or mantle-cell lymphoma were also performed. Secondary objectives were to evaluate the pharmacokinetics and pharmacodynamics of ixabepilone and to assess antitumor activity.
Patient Selection Patients had to have a histologically or cytologically confirmed diagnosis of nonhematologic cancer unresponsive to currently available therapies or for which there is no known effective therapy or a diagnosis of relapsed or refractory aggressive B-cell lymphoma. Patients with a diagnosis of aggressive lymphoma were required to have experienced treatment failure with an anthracycline-based treatment program. Patients with indolent forms of NHL were excluded. Patients had to have measurable (by Response Evaluation Criteria in Solid Tumors [RECIST])6 or nonmeasurable disease,be age 18 years or older, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (or 0 to 1 for patients who had received more than two prior chemotherapy regimens in the metastatic setting and for all lymphoma patients), a life expectancy of at least 3 months, and adequate bone marrow, hepatic, and renal function. Lymphoma patients could have received three or fewer prior chemotherapy regimens and must have been ineligible for, and not have received previously, peripheral-blood progenitor cell transplantation. Patients with solid tumors could have received four or fewer prior chemotherapy regimens in the metastatic setting (or two or fewer of such regimens for patients enrolled after the MTD had been established). At least 4 weeks had to have elapsed between the start of protocol treatment and last chemotherapy (6 weeks for nitrosoureas, mitomycin, and liposomal doxorubicin), immunotherapy, and radiotherapy. Patients had to have peripheral neuropathy grade 1 or lower according to Common Toxicity Criteria (CTC), no prior hypersensitivity reaction (HSR) to therapies containing Cremophor EL, and no active brain metastases. The study protocol was approved by the institutional review boards of the participating institutions and all patients gave written informed consent. The study was conducted according to the Declaration of Helsinki.
Drug Administration In the accelerated dose-escalation phase, doses were doubled in successive patient cohorts. Three new patients per cohort were treated and observed for at least 3 weeks before the next dose level was opened for enrollment. At each new dose level, patients were enrolled simultaneously until the first DLT or two CTC grade 2 or higher toxicities were observed. DLT was defined as any of the following events during the first cycle: grade 4 neutropenia for at least 5 consecutive days and/or febrile neutropenia; thrombocytopenia less than 25,000 platelets/mm3 or bleeding episode requiring platelet transfusion; grade 3 or higher nausea and/or vomiting despite maximal medical management; any nonhematologic toxicity grade 3 or higher; and treatment delay of more than 2 weeks resulting from delayed recovery. If one patient experienced DLT, three additional patients were added to the dose level. If two of six patients experienced DLT, the previous dose level was declared the MTD. If only one of six patients experienced DLT, dose escalation could continue. When predefined toxicity was observed (first instance of any grade 2 toxicity in the first course, unless two additional patients were treated at the same dose without CTC grade 2 or higher toxicity; second instance of any CTC grade 2 or higher toxicity in the first course; or first instance of DLT in the first course of treatment), the accelerated phase was terminated and the standard phase began. In the standard phase, dose escalation was altered to a modified Fibonacci scheme. Three patients were entered per dose level. The first patient treated at each new dose level was observed for at least 2 weeks before two more patients were enrolled/treated at that dose level. During both the accelerated and standard phases of the trial, intrapatient dose escalation was allowed after two courses if a patient had no toxicities of grade 2 or greater and another patient had already safely received one cycle at the next dose level. After the maximum administered dose (the dose level at which at least two of six patients experienced DLT during the first course of treatment) was defined, there was no further dose escalation; a dose level below the maximum administered dose was considered the MTD. A maximum of 15 patients were to be treated at the MTD to determine if it was a suitable dose for phase II studies. Colony-stimulating factors were not administered prophylactically. Interventional use of growth factors was allowed in the case of febrile neutropenia.
Evaluation
Pharmacokinetics
Pharmacodynamics
Patient Characteristics and Dosing Sixty-one patients (median age, 58 years; range 18 to 81 years) were enrolled and treated. Forty-six patients (75%) had solid tumors, and 15 (25%) had lymphoma; 53 patients (87%) had measurable tumors. Nearly all patients (98%) had received prior chemotherapy, and 67% of patients had received at least two prior chemotherapy regimens (Table 1). All patients with lymphoma had received at least one prior chemotherapy regimen, including 87% who received a regimen containing cyclophosphamide/doxorubicin/vincristine. Eight different ixabepilone regimens were evaluated: a 1-hour infusion with doses of 7.4, 15, 30, 50, 57, and 65 mg/m2; and a 3-hour infusion with doses of 40 and 50 mg/m2. Patients received a median of two cycles (range, 1 to 12 cycles).
Toxicity No DLT was observed with the 1-hour infusion at doses below 50 mg/m2. Of the 28 patients treated with the 1-hour infusion at 50 mg/m2 and above, eight experienced DLT. The most common DLTs were neutropenia, stomatitis/pharyngitis, myalgia, and arthralgia. The MTD was established at 50 mg/m2 over 1 hour on the basis of the tolerability of this regimen in an expanded cohort of 22 patients. In patients treated with the 3-hour infusion, four of 16 patients treated with 40 mg/m2 and one of eight patients who received 50 mg/m2 experienced DLTs (Table 2).
The most frequent grade 3/4 ixabepilone-related adverse events (AEs) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), and nausea (5%). The most frequent treatment-related AEs are shown in Table 3, according to dose.
Neuropathy Thirty patients (49%) developed sensory neuropathy on treatment (grade 2 or lower, n = 22; grade 3, n = 8). The occurrence of sensory neuropathy seemed dose related; seven of eight patients who developed grade 3 sensory neuropathy were treated at doses of 50 mg/m2 or higher. The severity of neuropathy typically increased with repeated exposures; all dose reductions and discontinuations due to sensory neuropathy occurred after at least three cycles of therapy. Recovery to baseline was reported in four of eight patients experiencing treatment-related grade 3 sensory neuropathy; this occurred in less than 1 month in three of these patients and in less than 2 months in the other. In two additional patients, grade 3 neuropathy improved to grade 1 during follow-up, in less than 4 months in one patient (after improving to grade 2 after < 1 month), and in less than 5 months in the other. In a seventh patient, sensory neuropathy had improved to grade 2 within 3 months, with no drug-related toxicity at the last follow-up, less than 4 months from discontinuation. The final patient had ongoing neuropathy of unspecified grade  5 months after discontinuation, but had no drug-related toxicities at the last follow-up, 1 month later. Four (7%) of 61 patients developed treatment-related motor neuropathy; this was grade 3 in only one patient, with no grade 4 cases (Table 4). Eight patients, seven of whom started at doses of 50 mg/m2 or higher, discontinued due to neuropathy, and one due to dizziness/lightheadedness.
Hypersensitivity A mild HSR, characterized by grade 1 facial flushing during 30 mg/m2 1-hour ixabepilone infusion, was observed in one patient early in the study. All subsequent patients enrolled received premedication with oral H1 and H2 blockers. Two patients experienced an HSR to 1-hour ixabepilone infusion (30 and 65 mg/m2) despite premedication, but both reactions were mild (grade 1). There were no severe HSRs or treatment discontinuations because of HSRs.
Myelosuppression
Deaths There were six deaths during the study. Four were judged to result from progressive disease, one from an infection with neutropenia in a 79-year-old man with NHL who had received extensive prior treatment, and one from pneumonia/sepsis without neutropenia in a 71-year-old man with esophageal cancer who had received extensive prior treatment.
Pharmacokinetics
Pharmacodynamics
Response
This trial was conducted to determine the MTD, DLT, and safety of ixabepilone administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors unresponsive to currently available therapies or for which there is no known effective therapy, with the aim of defining the recommended phase II dose. Lymphoma patients were later enrolled in the study. Because of neuropathy observed with the 1-hour infusion schedule in other ongoing ixabepilone studies, 18 months into the study, the infusion time was increased to 3 hours. A dose of 40 mg/m2 over 3 hours was subsequently explored because of GI toxicities in four of eight patients on the 50 mg/m2 over 3-hour schedule. No DLT was observed at doses less than 50 mg/m2. Five of the six patients enrolled at the two highest dose levels as 1-hour infusions experienced DLTs: two of three at 65 mg/m2 and all three at 57 mg/m2. The MTD was, therefore, established as 50 mg/m2 over 1 hour. Overall, ixabepilone demonstrated an acceptable safety profile; myelosuppression was dose-dependent and typically resulted from neutropenia or leukopenia, not thrombocytopenia or anemia. Sensory neuropathy was the most frequent ixabepilone-related AE leading to dose reductions or discontinuations, but it was generally mild to moderate in severity, and dose reductions or discontinuations generally occurred at doses of 50 mg/m2 or higher. Neuropathy was reversible to baseline or grade 1 or lower in some patients after dose reduction or discontinuation from the study, and typically increased with repeated exposures. Analysis of data from this and other ixabepilone trials should allow neurotoxicity to be minimized in the future, perhaps by identifying patients most likely to develop this AE and allowing prospective dose planning and management. Discontinuations due to study drug–related AEs occurred in a minority of patients (15%). Because ixabepilone is formulated in Cremophor EL, there is a potential for HSRs, but these occurred rarely and were mild. On the basis of the results of this study, it was recommended that phase II studies should be initiated using a dose of 50 mg/m2, administered over 1 hour. While this schedule was used as the starting dose in phase II trials, the dose was amended to 40 mg/m2 over 3 hours on the basis of early safety results.8,9 This is also consistent with the recommended phase II dose from other phase I studies.7,10 Consistent with the safety demonstrated in several phase II studies of ixabepilone in breast cancer and other tumors,8,9,11,12 the 16 patients treated with 40 mg/m2 over 3 hours in this study tolerated their treatment well.
A secondary objective was to evaluate the pharmacokinetics of ixabepilone. This study showed that, after intravenous administration, systemic exposure to the two degradation products of ixabepilone are negligible, indicating that these are not major circulating products. Summary statistics suggest that geometric mean maximum serum concentration (Cmax) and area under the concentration time curve (AUC0– Ixabepilone demonstrated antitumor activity, with eight patients achieving durable objective responses across a variety of tumor types. Nearly all responders had experienced treatment failure with multiple prior therapies, including five patients who had previously been treated with a taxane. Of particular note, responses were seen in two patients with B-cell DLCL who had relapsed after chemotherapy and were refractory to rituximab; phase II studies are underway to further investigate the use of ixabepilone in lymphoma patients. Preclinical studies with ixabepilone have shown a low susceptibility to common mechanisms of tumor resistance and activity in a broad spectrum of tumor types.2,3,5 The acceptable tolerability and promising efficacy results demonstrated by ixabepilone in this phase I study, which included a broad range of tumor types, are encouraging and suggest that further development of the compound is warranted. The results from current phase II and III studies are eagerly awaited.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Marvin B. Cohen, Bristol-Myers Squibb; Ronald Peck, Bristol-Myers Squibb; Martee L. Hensley, Bristol-Myers Squibb (Spouse employed) Leadership: N/A Consultant: Suzanne Jones, Bristol-Myers Squibb; F. Anthony Greco, Bristol-Myers Squibb Stock: Marvin B. Cohen, Bristol-Myers Squibb; Ronald Peck, Bristol-Myers Squibb Honoraria: Howard A. Burris III, Bristol-Myers Squibb; Owen A. O'Connor, Bristol-Myers Squibb Research Funds: Carol Aghajanian, Bristol-Myers Squibb; F. Anthony Greco, Bristol-Myers Squibb Testimony: N/A Other: N/A
Conception and design: Carol Aghajanian, David R. Spriggs, Owen A. O'Connor Provision of study materials or patients: Carol Aghajanian, Howard A. Burris III, Suzanne Jones, David R. Spriggs, Paul Sabbatini, Martee L. Hensley, F. Anthony Greco, Jakob Dupont, Owen A. O'Connor Collection and assembly of data: Carol Aghajanian, Howard A. Burris III, Suzanne Jones, Owen A. O'Connor Data analysis and interpretation: Carol Aghajanian, Howard A. Burris III, Suzanne Jones, Marvin B. Cohen, Jakob Dupont, Owen A. O'Connor Manuscript writing: Carol Aghajanian, Howard A. Burris III, Marvin B. Cohen, Ronald Peck, F. Anthony Greco, Jakob Dupont, Owen A. O'Connor Final approval of manuscript: Carol Aghajanian, Howard A. Burris III, Suzanne Jones, David R. Spriggs, Ronald Peck, Paul Sabbatini, Martee L. Hensley, F. Anthony Greco, Jakob Dupont
We thank Caroline Barnett, BSc (Hons), Medicus International, for her editorial assistance.
published online ahead of print at www.jco.org on January 29, 2007. Supported by Bristol-Myers Squibb, Princeton, NJ. Presented in part in poster format at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Bollag DM, McQueney PA, Zhu J, et al: Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 55:2325-2333, 1995 2. Wartmann M, Altmann KH: The biology and medicinal chemistry of epothilones. Curr Med Chem Anticancer Agents 2:123-148, 2002 3. Jordan MA, Miller H, Ray A, et al: The Pat-21 breast cancer model derived from a patient with primary Taxol resistance recapitulates the phenotype of its origin, has altered beta-tubulin expression and is sensitive to ixabepilone. Proc Amer Assoc Cancer Res 47, 2006 (abstr LB-280) 4. Kowalski RJ, Giannakakou P, Hamel E: Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J Biol Chem 272:2534-2541, 1997 5. Lee FY, Borzilleri R, Fairchild CR, et al: BMS-247550: A novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7:1429-1437, 2001 6. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 7. Gadgeel SM, Wozniak A, Boinpally RR, et al: Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B design. Clin Cancer Res 11:6233-6239, 2005 8. Roché HH, Cure H, Bunnell C, et al: A phase II study of epothilone analog BMS-247550 in patients (pts) with metastatic breast cancer (MBC) previously treated with an anthracycline. Proc Am Soc Clin Oncol 22:18, 2003 (abstr 69) 9. Thomas E, Tabernero J, Fornier M, et al: A phase II study of the epothilone B analog BMS-247550 in patients (pts) with taxane-resistant metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 22:8, 2003 (abstr 30) 10. Mani S, McDaid H, Hamilton A, et al: Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors. Clin Cancer Res 10:1289-1298, 2004 11. Hussain M, Tangen CM, Lara PN Jr, et al: Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: A Southwest Oncology Group trial S0111. J Clin Oncol 23:8724-8729, 2005 12. Baselga J, Gianni L, Llombart A, et al: Predicting response to ixabepilone: Genomics study in patients receiving single agent ixabepilone as neoadjuvant treatment for breast cancer (BC). Breast Cancer Res Treat 94:S31, 2005 (abstr 305) Submitted August 15, 2006; accepted December 15, 2006. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
; AUC calculated from time zero extrapolated to infinity) seem to increase less than proportionally to dose. The microtubule-stabilizing ability of ixabepilone was demonstrated by the increase in polymerized tubulin, which occurred soon after dosing and was maintained for more than 24 hours postdose. Because of the small sample sizes involved in some instances, however, results of these pharmacokinetic and pharmacodynamic evaluations should be interpreted with caution. 
