Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in ...

original article

Annals of Oncology 21: 2075–2080, 2010 doi:10.1093/annonc/mdq080 Published online 31 March 2010

Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary à E. Chuang1*, N. Wiener1, P. Christos2, R. Kessler1, M. Cobham1, D. Donovan1, G. L. Goldberg3, T. Caputo4, A. Doyle5, L. Vahdat1 & J. A. Sparano6 1

Department of Medicine and 2Division of Biostatistics and Epidemiology, Department of Public Health, Weill Cornell Medical College, New York, NY; 3Department of Obstetrics and Gynecology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; 4Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY; 5Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; 6Department of Medicine and Gynecology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

Background: Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer. Methods: Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients. Results: Thirty patients received a total of 142 treatment cycles of the PLD–ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m2 on days 1, 8, and 15 plus PLD 30 mg/m2 given on day 1, repeated every 4 weeks. Hand–foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer. Conclusion: Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings. Key words: breast cancer, ixabepilone, liposomal doxorubicin, ovarian cancer

introduction The epothilones are microtubule-stabilizing agents that were originally isolated from the myxobacterium Sorangium cellulosum [1]. Epothilones A and B showed potent cytotoxic activity in paclitaxel-sensitive and paclitaxel-resistant cells expressing P-glycoprotein or mutant tubulin, but are inactivated via esterase cleavage [2]. Ixabepilone is a semisynthetic lactam analogue of epothilone B that is metabolically stable but retains its tubulin polymerization effects and activity against paclitaxel-resistant lines [3]. Two phase III trials including over 1900 patients with *Correspondence to: Dr E. Chuang, Department of Medicine, Weill Cornell Medical College, 425 E. 61st Street, New York, NY 10065, USA. Tel: +1 212-821-0654; Fax: +1 212-821-0796; E-mail: [email protected] This study was led by the New York Cancer Consortium (www.newyorkcancerconsortium.org) and was supported by a contract from the National Institute of Health, National Cancer Institute (N01-CM-62204 [PI: JAS]). à Presented in part at the American Society of Clinical Oncology meeting, 1–5 June 2007, Chicago, IL.

anthracycline- and taxane-pretreated metastatic breast cancer have shown significantly improved objective response and progression-free survival (PFS) for the combination of ixabepilone (40 mg/m2 every 3 weeks) plus oral capecitabine compared with oral capecitabine alone, although survival was not improved [4, 5]. In addition, ixabepilone produces a response rate of 12% when used as a single agent (40 mg/m2 every 3 weeks) in patients with anthracycline-, taxane-, and capecitabine-resistant cancer [6]. Based on the efficacy demonstrated in these trials, ixabepilone was approved by the United States Food and Drug Administration (FDA) in 2007 for treatment of anthracycline- and taxane-resistant metastatic breast cancer [7]. Neutropenia and neuropathy are the most common toxic effects [8]. Other schedules that have been shown to be feasible and potentially associated with less neutropenia and neuropathy include weekly for 3 of 4 weeks [9], or daily for 3 days [10] or 5 days every 3 weeks [11, 12]. To date, no phase II trials of ixabepilone have been reported in patients with ovarian cancer, but responses have been observed in phase I trials in patients with paclitaxel-resistant disease [13].

ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

original article

Received 23 December 2009; revised 15 February 2010; accepted 18 February 2010

original article Although the combination of ixabepilone and capecitabine is approved for metastatic breast cancer, capecitabine is most commonly used as monotherapy in the first-line setting in patients wishing to avoid parenteral therapy or alopecia, or after prior anthracycline and taxane therapy [14]. The development of other ixabepilone-containing combinations that may serve as an alternative to ixabepilone–capecitabine may be desirable for some patients who require combination cytotoxic therapy because of advanced, symptomatic disease [15]. Pegylated liposomal doxorubicin (PLD) is one such agent that is attractive to combine with ixabepilone for several reasons. First, doxorubicin is known to be an active agent in several cancers, including breast and ovarian cancer. Secondly, PLD is associated with a more favorable toxicity profile compared with conventional doxorubicin, with less nausea, alopecia, stomatitis, and cardiotoxicity. In patients with metastatic breast cancer, single-agent treatment with PLD is associated with response rates of 15%–30% [16]. PLD 50 mg/m2 i.v. given every 4 weeks is approved by the FDA for the treatment of patients with platinum refractory ovarian cancer on the basis of response rates of 15%–18% in this population [17, 18]. We report the results of a phase I trial of ixabepilone used in combination with PLD for platinum- and taxane-treated ovarian cancer and for taxane-pretreated breast cancer.

methods patient selection Eligibility criteria included histologically or cytologically confirmed, unresectable adenocarcinoma of the breast, ovary, peritoneum, or fallopian tube with metastatic disease measurable by RECIST (version 1.0) [19]. Patients with nonmeasurable disease were eligible if there was an elevated CA-125 level (for gynecologic cancer) or CA27-29 (for breast cancer) above 50 IU/l on two occasions at least 1 week apart. Patients with a gynecologic cancer were required to have received a platinum and a taxane. Patients with breast cancer were required to have prior taxane therapy. All patients were required to have an Eastern Cooperative Oncology Group performance status score of 0, 1, or 2, be 18 years of age or older, and be able to provide written informed consent. Other requirements included adequate bone marrow function (leukocyte count of at least 3500/ll, neutrophil count of at least 1500/ll, platelets of at least 150 000/ll), kidney function (normal serum creatinine within 1.5-fold above the institutional upper limits of normal), and normal hepatic function (normal bilirubin and aspartate aminotransferase and alanine aminotransferase £2.5 times the upper limit of normal). Patients were excluded if they had grade 2 or greater neuropathy, known hypersensitivity to Cremophor, brain metastases, chemotherapy, or radiation within 3 weeks of registration (6 weeks for nitrosoureas or mitomycin C), an uncontrolled intercurrent illness (e.g. infection, congestive heart failure, unstable angina, cardiac arrhythmia, congenital or acquired immune deficiency, or psychiatric illness that could potentially impact on compliance), or if they were pregnant or breast-feeding.

Annals of Oncology

schedule in combination regimens that included docetaxel [20] or cyclophosphamide [21]. Ixabepilone (Ixempra; Bristol-Myers Squibb, Princeton, NJ) was given every 3 weeks at escalating doses of 24 and 32 mg/ m2 in cohorts 1 and 2, and at a dose of 40 mg/m2 every 4 weeks in cohort 3. In cohorts 4 and 5, ixabepilone 13 mg/m2 (cohort 4) or 16 mg/m2 (cohort 5) was given on days 1, 8, and 15 of a 28-day cycle. The doses in cohorts 1–3 were chosen based upon the FDA approved dose of ixabepilone 40 mg i.v. every 3 weeks, and the weekly doses were chosen taking into consideration results from a phase II study in which single-agent ixabepilone 20 mg weekly for 3 of 4 weeks was associated with a high incidence of neurotoxicity [22]. Ixabepilone was given as a 3-h i.v. infusion (in an appropriate volume of lactated Ringer’s solution) in cohorts 1–3 and as a 1-h infusion in cohorts 4 and 5. PLD was given as a 60-min infusion (in 250 ml 5% dextrose) during the first cycle, and 30 min during subsequent infusions if well tolerated. PLD was given after ixabepilone, and given via a separate i.v. line. All patients received an H1 blocker (e.g. diphenhydramine 50 mg i.v. or equivalent) and an H2 blocker (e.g. ranitidine 50 mg i.v. or equivalent) 30 min before the ixabepilone infusion. Treatment was continued until progression of disease, unacceptable toxicity, intercurrent condition with a declining performance status preventing further treatment, or patient withdrawal.

definition of dose limiting toxicity and criteria for dose escalation Patients at each of the five dose levels were treated in cohorts of three to six patients using a standard phase I design, with escalation to the next dose level if none of three or one of six patients had a dose-limiting toxicity (DLT). DLT was defined as grade 3–4 nonhematologic toxicity (except fatigue) or grade 4 hematologic toxicity for >7 days in cycle 1, or grade 3–4 hand–foot syndrome (HFS) occurring during cycle 1 or 2. The recommended phase II dose was the highest dose level at which none of three or one of six patients had a DLT.

criteria for treatment and dose modifications Treatment was given if the neutrophil count was at least 1500/ll, platelets at least 100 000/ll, and all toxicity had recovered to grade 1 or less (or fatigue to grade 2 or less). A delay of more than 2 weeks due to toxicity required discontinuation of protocol therapy. Toxicity which required a 1 dose level reduction in ixabepilone and PLD included grade 4 neutropenia, grade 3–4 febrile neutropenia, grade 4 thrombocytopenia, grade 3–4 thrombocytopenia with bleeding, grade 3–4 diarrhea, and grade 3–4 stomatitis. Grade 3–4 HFS or grade 2 HFS, which had not resolved to grade 1 or less by the next planned PLD dose. Toxicity which required a one dose level reduction in ixabepilone alone included grade 3–4 neuropathy or grade 2 neuropathy lasting 7 days or longer. If the PLD dose was reduced, the lower dose levels were 22 mg/m2, then 16 mg/m2. If ixabepilone required dose reduction at dose level 2, 3, or 5, it was reduced to the previous dose level. If ixabepilone dose required dose reduction at dose level 1, it was reduced from 24 to 16 mg/m2 every 3 weeks, and at dose level 4 it was reduced from 13 to 10 mg/m2 (weekly on days 1, 8, and 15 every 4 weeks). Patients requiring more than 2 dose reductions were removed from study at dose levels 1–4, and more than 1 dose level reduction were removed from study at dose level 5.

treatment regimen and dose escalation schema

response, progression-free survival, overall survival, and overall toxicity

All patients received PLD (Doxil; Ortho Biotech Products, LP, Horsham, PA; Caelyx; Schering-Plough, Kenilworth, NJ) at a dose of 30 mg/m2 on day 1 of each cycle. For cohorts 1 and 2, PLD was administered every 3 weeks and for cohorts 3–5 PLD was administered every 4 weeks. PLD has previously been shown to be well tolerated when given on a 3-week

Computed tomography or magnetic resonance imaging scans of measurable lesions were obtained at baseline and at every 8 weeks. Responses were classified according to RECIST criteria (version 1.0) [19]. National Cancer Institute Common Adverse Events Criteria version 3.0 was used to grade toxicity; 95% confidence intervals (CI) for objective response were

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estimated via binomial proportions. PFS and overall survival (OS) were also estimated using the Kaplan–Meier method, and 95% CIs were constructed for median PFS and OS. PFS was defined as the time between registration and either progression of disease or death from any cause. All P-values are two-sided with statistical significance evaluated at the 0.05 alpha level. All analyses were carried out in SAS version 9.2 (SAS Institute, Inc., Cary, NC) and Stata version 10.0 (StataCorp., College Station, TX). All patients had progressive disease or discontinued therapy at the time of the analysis.

informed consent and regulatory approval The study was reviewed and approved by the Cancer Therapy Evaluation Program of the National Cancer Institute (P7229, ClinicalTrials.gov identifier NCT00182767), and by the institutional review board at each participating institution in the New York Cancer Consortium, including Montefiore Medical Center, and New York Presbyterian Hospital/Weill Cornell Medical College. All patients provided written informed consent, which was reviewed and approved by the local institutional review board.

results patient characteristics Thirty patients were enrolled and treated between January 2006 and July 2009, and their characteristics are shown in Table 1. The median age was 58 years (range 34–75). Seventeen patients Table 1. Patient characteristics Characteristic Number Age (years) Median (range) Gender, n (%) Female Race, n (%) White Asian Black Other/Unknown Ethnicity, n (%) Non-Hispanic Hispanic ECOG PS, n (%) 0 1 2 Primary site, n (%) Breast Ovarian No prior chemo regimens, median (range) Breast Ovarian Ovarian cancer patients, n (%) Platinum sensitive Platinum resistant Breast cancer patients, n (%) Prior anthracycline Prior taxane ECOG, Eastern Cooperative Oncology Group.


30 58 (34–75) 30 (100) 22 1 4 3

(73) (3) (13) (10)

26 (87) 4 (13) 15 (50) 12 (40) 3 (10) 13 (43) 17 (57) 5 (1–11) 3 (1–6) 4 (24) 13 (76) 11 (85) 13 (100)

(57%) had ovarian cancer and 13 patients (43%) had breast cancer. The median number of prior regimens for recurrent disease was 3 (range 1–6) for ovarian cancer patients and 5 (range 1–11) for breast cancer patients.

results of dose escalation The results of dose escalation are shown in Table 2. A total of 142 treatment cycles were administered. The dose of PLD was 30 mg/m2 for all five ixabepilone dose levels evaluated. At the first two dose levels, PLD was given every 3 weeks. At dose level 1 of ixabepilone (24 mg/m2), one of three patients experienced grade 3 mucositis; no additional DLTs were observed after three additional patients were accrued at this dose level. At dose level 2 of ixabepilone (32 mg/m2), one of three patients experienced grade 3 HFS; no additional DLTs were observed after three additional patients were accrued at this dose level. Although prohibitive toxicity was not observed during the first two treatment cycles at dose levels 1 and 2 such that escalation to the next dose level would be halted, cumulative toxicity was observed with additional treatment cycles. Five of 12 patients (42%) treated at the first two dose levels experienced grades 2–3 HFS, and five patients (42%) experienced grades 2–3 mucositis. Therefore, an amendment was made to the protocol to lengthen the interval of PLD treatment from 3 weeks to 4 weeks in order to decrease the incidence of mucocutaneous toxicity [23]. The every 4-week PLD schedule was evaluated in dose levels 3–5. At dose level 3 of ixabepilone (40 mg/m2) using the every 4-week schedule, however, two of six patients experienced DLT, including one patient who had grade 3 HFS and another patient with grade 3 rash. Due to prohibitive toxicity, the ixabepilone schedule for dose level 3 was modified from the standard 40 mg/m2 dose given every 4 weeks used for breast cancer [4, 6] to a weekly schedule given on days 1, 8, and 15 every 28 days in combination with PLD. At dose level 4 of ixabepilone (13 mg/m2, days 1, 8, and 15), none of three patients had a DLT. At dose level 5 of ixabepilone (16 mg/m2, days 1, 8, and 15), none of three patients had a DLT. In order to better assess the safety and tolerability of the weekly ixabepilone schedule, dose level 5 was expanded to include an additional six patients; no patients experienced DLT. The recommended phase 2 dose was ixabepilone 16 mg/m2 on days 1, 8, and 15 plus PLD 30 mg/m2 on day 1 every 4 weeks. adverse events The incidence of grades 2–4 adverse events in the every 3- to 4-week schedule (levels 1–3) and the weekly schedule (levels 4–5) is shown in Table 3. The most common grade 3 toxic effects at dose levels 1–3 included mucositis (21%) and rash/ desquamation (16%). At dose levels 4–5, the most common toxic effects included neutropenia (36% grade 3 and 9% grade 4). Neutropenia was not associated with fever or infection in these patients. The incidence of grade 3 HFS was higher using the every 3-week compared with the weekly schedules (10% in dose levels 1–3 and 0% in dose levels 4–5), as was the incidence

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Table 2. Results of dose escalation Dose level

Ixabepilone

PLD, 30 mg/m2

n

No. DLT

DLT

Total no. treatment cycles

Median no. cycles (range)

1 2 3 4

24 32 40 13

mg/m2, every 3 weeks mg/m2, every 3 weeks mg/m2, every 4 weeks mg/m2, days 1, 8, and 15, every 4 weeks 16 mg/m2, day 1, 8, and 15, every 4 weeks

Every Every Every Every

weeks weeks weeks weeks

6 6 6 3

1 1 2 0

Grade 3 mucositis Grade 3 HFS Grade 3 HFS, grade 3 rash None

25 18 37 21

3.5 3 5.5 8

Every 4 weeks

9

0

None

41

5

3 3 4 4

(2–8) (2–4) (3–12) (5–8)

3 (1–12)

HFS, hand–foot syndrome.

Table 3. Grades 2–4 treatment-related toxic effects

Levels 1–3 (n = 18) Bilirubin (hyperbilirubinemia) CNS cerebrovascular ischemia Constipation Creatinine Diarrhea Edema: limb Fatigue (asthenia, lethargy, malaise) Fever in the absence of neutropenia Heartburn/dyspepsia Hemoglobin Hemorrhage, pulmonary/ upper respiratory Hyperpigmentation Infection with grade 3 or 4 neutrophils Infection with £grade 2 neutrophils Leukocytes (total WBC) Mucositis/stomatitis Muscle weakness Nail changes Nausea Neuropathy: sensory Neutrophils/granulocytes (ANC/AGC) Pain Phlebitis (including superficial thrombosis) Platelets Rash/desquamation Rash: hand–foot skin reaction Vomiting Levels 4–5 (n = 12) Anorexia Constipation


Table 3. (Continued)

Grade 2, n (%)

Grade 3, n (%)

Grade 4, n (%)

0

1 (5)

0

0

1 (5)

0

1 (5) 0 0 0 2 (10)

0 0 0 0 0

1 (5)

0

0

1 (5) 1 (5) 0

0 1 (5) 0

0 0 1 (5)

1 (5) 0

0 1 (5)

0 0

4 (20)

1 (5)

0

6 6 1 1 1 4 3

(32) (32) (5) (5) (5) (21) (16)

2 4 0 0 0 1 2

1 (5) 0 0 0 0 0 1 (5)

7 (36) 1 (5)

0 0

0 0

2 (10) 3 (16) 7 (36)

0 3 (16) 2 (10)

0 0 0

0

1 (5)

0

3 (27) 1 (9)

0 0

0 0

0 1 2 1 2

(5) (10) (5) (10)

(10) (21)

(5) (10)

Diarrhea Dyspnea (shortness of breath) Fatigue Hemoglobin Leukocytes (total WBC) Magnesium, serum-low Mood alteration: depression Mucositis/stomatitis Nausea Neutrophils/granulocytes (ANC/AGC) Platelets Rash/desquamation Rash: hand–foot skin reaction Vomiting

Grade 2, n (%)

Grade 3, n (%)

Grade 4, n (%)

1 (9) 0

0 1 (9)

0 0

2 5 2 1 1

(18) (45) (18) (9) (9)

1 (9) 1 (9) 2 (18) 0 0

1 (9) 0 0 0 0

2 (18) 2 (18) 2 (18)

1 (9) 0 4 (36)

0

1 (9) 1 (9) 1 (9)

0 1 (9) 0

0 0 0

1 (9)

0

0

1 (9)

CNS, central nervous system; WBC, white blood cell; ANC/AGC, absolute neutrophil count/absolute granulocyte count.

of grade 2 HFS (39% in dose levels 1–3 versus 9% in dose levels 4–5). Grade 3 mucositis also occurred more commonly using the every 3-week schedule (21% in dose levels 1–3 versus 9% in dose levels 4–5). Grade 3 neuropathy was uncommon, occurring in 5% of patients in dose levels 1–3 and 0% of patients in levels 4–5.

response, PFS, and OS Objective response occurred in 3 of 13 patients (23%, 95% CI = 5% to 54%) with breast cancer; median PFS was 2.7 months (95% CI = 1.9–3.9 months) and OS was 7.5 months (95% CI = 2.7–20.7 months). Objective response occurred in 5 of 17 patients (29%, 95% CI = 10% to 56%) with ovarian cancer (including one patient who had a complete response); median PFS was 4.1 months (95% CI = 2.7–8.2 months) and median OS was 28.4 months (95% CI = 7.6 months, upper limit not reached). Included in the responses were two cases for which response was not confirmed and therefore did not meet RECIST criteria for response.


original article

Annals of Oncology

discussion We carried out a phase I trial of the epothilone B analogue ixabepilone plus PLD in patients with advanced breast and ovarian cancer. All patients with breast cancer were required to have prior taxane therapy, and all ovarian patients were also required to have prior treatment with a platinum and a taxane. All patients received PLD at a dose of 30 mg/m2 every 3 or 4 weeks. Although treatment could be administered for 1–2 cycles without prohibitive toxicity when both agents were given every 3 or 4 weeks, mucocutaneous toxicity was cumulative and treatment limiting after two cycles. When PLD was given on day 1 every 4 weeks plus ixabepilone given weekly on days 1, 8, and 15 of each 4-week cycle, the regimen was much better tolerated. It is noteworthy that the dose-limiting toxic effects of HFS and rash are typically associated with PLD, not ixabepilone, and were observed at a relatively low dose level of PLD (30 mg/m2) at which these complications occur infrequently after two cycles of therapy. This suggests that ixabepilone may enhance cutaneous toxicity associated with PLD, possibly due to a pharmacokinetic interaction between polyethoxylated castor oil (Cremophor EL; BASF Corp., Ludwigshafen, Germany) used to solubilize ixabepilone and doxorubicin [24, 25]. This combination may be suitable for further evaluation in patients with advanced ovarian and breast cancer. PLD is approved as monotherapy for patients with platinum-pretreated ovarian cancer. The pivotal trial included 474 patients who were randomized to receive PLD (50 mg/m2 every 4 weeks) or topotecan, which showed improved OS and less hematologic toxicity for the PLD arm [17, 18]. Another trial demonstrated a marginal survival benefit for PLD compared with gemcitabine [26]. PLD has also been shown to have comparable activity and less cardiotoxicity than conventional doxorubicin for metastatic breast cancer [27]. In addition, the PLD–docetaxel combination has been shown to be more effective than docetaxel monotherapy without cardiac toxicity in patients with advanced breast cancer who recurred after prior adjuvant doxorubicin, a group that previously would not be considered for anthracycline therapy [20]. As taxanes become increasingly used in the adjuvant setting, the PLD–ixabepilone combination may be particularly suitable for patients with anthracyclineand taxane-pretreated breast cancer who have advanced, symptomatic disease and require combination therapy. In conclusion, our phase I trial demonstrated that ixabepilone and PLD could be safely combined when ixabepilone was administered using a weekly schedule (16 mg/m2 days 1, 8, and 15) and PLD (30 mg/m2) was given every 28 days. Mucocutaneous toxicity was prohibitive when both agents were given every 3 or 4 weeks. The combination demonstrated activity in patients with advanced taxanepretreated breast cancer and platinum- and taxane-pretreated ovarian cancer, and merits further evaluation. We are therefore continuing to evaluate this combination in an ongoing phase II extension of this trial.

acknowledgements The authors acknowledge the late Dr Scott Wadler, our colleague and friend. As founder of the New York Cancer


Consortium, he supported the design and conduct of this trial during his leadership. He will be remembered for his skills as clinician, scholar, and mentor. The authors would also like to thank Dr Carolyn Runowicz for helpful discussions.

disclosure LV has received research funding and has served on advisory boards for Bristol Myers Squibb. JAS has served as a consultant for Bristol Myers Squibb and for Johnson and Johnson and has received honoraria from Bristol Myers Squibb. The other authors have no conflicts of interests.

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