II Pharmacokinetic Study of Pemetrexed and Epirubicin in Patients with Locally Advanced or Metastatic Breast Cancer

original

contribution

Phase I/II Pharmacokinetic Study of Pemetrexed and Epirubicin in Patients with Locally Advanced or Metastatic Breast Cancer Robert Paridaens,1 Luc Dirix,2 Herlinde Dumez,1 Annemie Prové,2 Hans Wildiers,1 Ana Alvarez,3 Celia Tosello Oliveira,4 Jane Latz,5 Lorinda Simms,5 Allen Melemed5 Abstract Background: Pemetrexed and epirubicin are each active in patients with advanced/metastatic breast cancer (MBC). This phase I/II study evaluated these drugs as a combination regimen. Patients and Methods: Women with locally advanced or MBC were enrolled. Pemetrexed 400-600 mg/m2 and epirubicin 60-90 mg/m2 were administered on day 1 every 21 days. The recommended phase II dose was evaluated in a 2-stage design. Results: Phase I enrolled 34 patients and evaluated 5 dose levels. Dose-limiting toxicities were neutropenia and febrile neutropenia. Patients received a median of 7.5 cycles (range, 1-8 cycles), and promising efficacy (partial response [PR], 32%; stable disease [SD], 50%) was observed. Pharmacokinetics of pemetrexed was unchanged when combined with epirubicin. Selected phase II regimen (pemetrexed 600 mg/m2 and epirubicin 75 mg/m2) was administered to 22 patients (median, 4.5 cycles; range 1-13 cycles). Five patients experienced a PR (23%), and 10 experienced SD (46%). This response was below the predefined efficacy requirements for subsequent enrollment, and accrual was stopped. Median time to progression was 5.3 months (95% CI, 3.1-8.9 months), and median time to treatment failure was 3.5 months (95% CI, 2.65.9 months). Conclusion: The regimen is safe but cannot be recommended as first-line chemotherapy in advanced breast cancer because of the low response rate.

Clinical Breast Cancer, Vol. 7, No. 11, 861-866, 2007 Key words: Dose reduction, Left ventricular ejection fraction, Neutropenia, Pharmacokinetics

Introduction Breast cancer is the most common cancer among women worldwide.1 Although early stages of breast cancer can be cured by multimodality therapy, advanced or metastatic breast cancer (MBC) is, in general, incurable. In the latter situation, adequate palliation can be achieved with systemic therapy, and chemotherapy remains an 1Universitair Ziekenhuis Gasthuisberg, Katholieke Universiteit Leuven, Belgium 2Algemeen Ziekenhuis St. Augustinus-Oncologisch Centrum, Antwerp, Belgium 3Instituto Angel Roffo, Buenos Aires, Argentina 4Instituto Brasileiro De Controle Do Cancer, Sao Paulo, Brazil 5Eli Lilly and Company, Indianapolis, IN

Submitted: Apr 20, 2007; Revised: Sep 19, 2007; Accepted: Oct 3, 2007 Address for correspondence: Robert J. Paridaens, MD, PhD, Katholieke Universiteit Leuven, Leuven, Belgium Fax: 32-0-16346901; e-mail: [email protected]

important treatment modality for hormone-independent or hormone-refractory disease. Anthracyclines like doxorubicin form the backbone of many combination chemotherapy regimens in the adjuvant and MBC settings2; however, because doxorubicin is associated with cumulative cardiac toxicity, other less toxic anthracyclines—like epirubicin3,4—need to be investigated in combination chemotherapy regimens. In MBC, epirubicin is as effective as doxorubicin and has a superior cardiac safety profile. Single-agent epirubicin has been administered in a variety of doses and schedules, with response rates (RRs) ranging from 30% to 40%.2,5-8 Pemetrexed is a folate antimetabolite that inhibits ≥ 3 enzymes in the folate pathway and has shown tumor response in a variety of cancers.9,10 Pemetrexed 500 mg/m2 and 600 mg/m2 has shown promising single-agent activity and a favorable toxicity profile in patients with locally advanced or MBC.11,12 Response rates of 8%-31% have been

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Phase I/II Study of Pemetrexed and Epirubicin in MBC observed in treated and untreated patients with breast cancer who have undergone single- or multiple-line regimens. Studies with human breast cancer xenografts have demonstrated additive efficacy for the combination pemetrexed/ doxorubicin.13 An in vitro study with a human breast carcinoma cell line suggested that pemetrexed administration preceding the anthracycline was more effective.14 With differing mechanisms of action, possible additivity, and a favorable toxicity profile of the 2 agents, pemetrexed/ epirubicin might offer several advantages. We conducted a phase I/II study to investigate this combination in patients with locally advanced or MBC. In the phase I portion, the objectives were to determine the maximum tolerated dose (MTD), assess safety, determine the recommended phase II dose, and assess the pharmacokinetic relationship between systemic exposure and toxicity. For the phase II portion, the primary objective was to determine the tumor RR.

Patients and Methods Eligibility Criteria Women aged ≥ 18 years with histologically or cytologically diagnosed breast cancer that was locally advanced or metastatic and not amenable to surgery or radiation therapy were enrolled. Previous anthracycline treatment was allowed if the cumulative dose did not exceed 300 mg/m2 for epirubicin or 200 mg/m2 for doxorubicin and if given > 6 months before enrollment. Patients had a World Health Organization (WHO) performance status (PS) of 0-2. Adequate organ function was required, including normal bone marrow reserve and adequate hepatic and renal function. In the phase II portion, neoadjuvant and/or adjuvant chemotherapy was allowed, but previous chemotherapy for advanced disease was not. Patients were also required to have ≥ 1 bidimensionally measurable lesion. Patients were excluded if they were treated in the past 30 days with a drug that had not yet received regulatory approval. Other exclusion criteria included serious concomitant systemic disorders, second primary malignancy, symptomatic central nervous system metastases, or significant cardiovascular disease, including a left ventricular ejection fraction (LVEF) < 45%. Patients provided written informed consent before study entry. The ethics committee of each participating institution approved the study, which was in compliance with the Good Clinical Practice guidelines and the Declaration of Helsinki.

Treatment Plan Patients received pemetrexed followed by epirubicin; both drugs were given as a 10-minute infusion on day 1 of a 21-day cycle. Patients received folic acid 350-1000 μg orally daily and vitamin B12 injections 1000 μg once every 9 weeks. To prevent rash, prophylactic dexamethasone 4 mg or equivalent was administered twice daily for 3 days around each pemetrexed dose. Patients remained on study until disease progression, unacceptable toxicity, failure to recover from treatment-related toxicities for 42 days, or at

862 • Clinical Breast Cancer December 2007

the discretion of the patient or the physician/investigator. Discontinuation occurred if a lifetime cumulative dose of epirubicin ≥ 1000 mg/m2 or the doxorubicin equivalent was reached. Hematologic dose adjustments were based on absolute neutrophil count (ANC) and platelet count from the preceding cycle. Minimum requirements to start a cycle were ANC ≥ 1.5 × 109/L and platelet count ≥ 100 × 109/L. Treatment could be delayed to allow for toxicity-related recoveries. Upon recovery, patients with an ANC < 0.5 × 109/L for ≥ 5 days and platelet count ≥ 50 × 109/L had both drugs reduced by 25% (without granulocyte colony-stimulating factor [G-CSF] support) or started G-CSF support. Patients with an ANC < 0.5 × 109/L for ≥ 5 days even with G-CSF support and platelet count ≥ 50 × 109/L had both drugs reduced by 25% and continued G-CSF support. Those with platelet counts < 50 × 109/L regardless of ANC had both drugs reduced by 50%. If grade 3/4 neutropenia or thrombocytopenia recurred through 2 dose reductions, discontinuation occurred. Dose adjustments were also dependent on nonhematologic toxicities. For grade 3/4 mucositis, pemetrexed was reduced by 50%; if it recurred, epirubicin was also reduced by 50%. If grade 3/4 mucositis recurred through 2 dose reductions, discontinuation occurred. For other grade 3/4 nonhematologic toxicities (excluding alanine aminotransferase [ALT]/aspartate aminotransferase [AST] elevations, nausea with or without vomiting, and alopecia), both drugs were delayed until patient returned to baseline levels or lower. When treatment resumed, both drugs were reduced by 25%. For diarrhea, only pemetrexed was reduced by 25% when treatment resumed; grade 3 ALT/AST increase lasting ≥ 3 weeks or any occurrence of grade 4 ALT/AST increase required a 25% dose reduction of both drugs. Discontinuation occurred for cardiac toxicity, such as congestive heart failure (CHF), an LVEF decrease of ≥ 10% from baseline,15 or a repeated LVEF decrease below the institution’s lower limit of normal.

Dose-Escalation Scheme In the phase I portion, the starting dose was pemetrexed 400 mg/m2 and epirubicin 60 mg/m2. Each dose level enrolled ≥ 3 patients. Dose escalation was based on cycle 1 doselimiting toxicities (DLTs). A DLT was defined as grade 4 neutropenia lasting ≥ 5 days, febrile neutropenia, grade 4 thrombocytopenia, or grade 3 thrombocytopenia requiring platelet transfusion. A DLT was also any grade 3/4 nonhematologic toxicity, excluding alopecia, nausea, and vomiting manageable with antiemetic therapy, or isolated grade 3 increased ALT/AST levels that returned to grade 1 or baseline values within 3 weeks. If 1 of these 3 patients had a DLT, 3 additional patients were enrolled at the same dose level. If the same DLT occurred in ≥ 2 patients at the same dose level, this was the MTD. If DLTs appeared at any dose level, an alternative dose level could be explored in which the other drug was escalated instead of the one that was most recently escalated. This ensured that the recommended dose for phase II had the highest possible dosage of both drugs.

Robert Paridaens et al Baseline and Treatment Assessment

Results

Baseline assessment included a complete medical history and physical examination; PS evaluation; tumor measurement of palpable or visible lesions; hematologic, blood chemistry, creatinine clearance assessment; and LVEF determination by multigated acquisition (MUGA) scan. Throughout the study, hematology, blood chemistry, and creatinine clearance were assessed within 4 days before each cycle; hematology and blood chemistry were also monitored weekly. A MUGA scan was repeated every other cycle for patients who received a cumulative dose of epirubicin 400 mg/m2 (or the doxorubicin equivalent). All patients who received ≥ 1 dose of either drug were evaluable for safety. Toxicity was assessed before each cycle according to National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0. Antitumor activity was documented using Southwest Oncology Group criteria.16 Patients were evaluable for tumor response if they had measurable disease and had received ≥ 1 cycle. Secondary objectives in the phase II portion included time to event analyses. Time to treatment failure (TTF) was the time from study entry to the first observation of disease progression, early discontinuation of treatment, start of another anticancer therapy, or death from any cause, with censoring at last contact date. Time to progression (TTP) was the time from study entry to the first observation of disease progression, start of another anticancer therapy, or disease-related death, with censoring at last progression-free assessment.

Patient Characteristics

Pharmacokinetic Analyses All patients enrolled in the phase I portion were eligible for pharmacokinetic analysis. An assessment of pemetrexed systemic exposure was performed using pemetrexed concentrations from limited blood sampling (2 samples from each patient: end of infusion and 6-8–hour time point) of patients during the phase I portion. Dose-normalized pemetrexed concentration versus time data from the current study (pemetrexed administered in combination with epirubicin) were compared with reference data from 10 phase II studies in which single-agent pemetrexed was administered17; a population pharmacokinetic analysis incorporating the current data and the reference data was also conducted. Dose-normalized epirubicin concentration versus dose by time point was evaluated to identify any overt nonlinearity in epirubicin pharmacokinetics across the range of doses administered in this study.

Statistical Considerations Up to 57 patients were to be enrolled for the phase II portion in a 2-stage sequential design.18 If ≥ 9 of the first 20 patients had responses, an additional 37 patients were to be enrolled. This procedure gives a 6% chance of terminating enrollment early at the end of the first stage if the true RR is ≥ 60% and a 76% chance of stopping early if the true RR is 35%.

Thirty-four patients were enrolled in the phase I portion, and 22 in the phase II portion (Table 1).

Phase I: Determination of Maximum Tolerated Dose and Recommended Phase II Dose Observed DLTs included grade 3 febrile neutropenia and grade 4 neutropenia lasting > 5 days. Dose-limiting toxicities occurred in 3 of 12 patients at dose level 3 (pemetrexed 500 mg/m2 and epirubicin 80 mg/m2) and in 2 of 6 patients at dose level 5 (pemetrexed 600 mg/m2 and epirubicin 90 mg/m2). The initial MTD occurred at dose level 3, but an alternative dose was explored per protocol. At dose level 5, the final MTD was reached. Thus, dose level 4 (pemetrexed 600 mg/m2 and epirubicin 75 mg/m2), which had only 1 DLT among 6 patients, was the recommended phase II dose.

Dose Administration In the phase I study, a median of 7.5 cycles (range, 1-8 cycles) was administered. Among the 215 cycles administered in the phase I portion, 13 (6%) were reduced because of neutropenia (10 cycles), granulocytopenia (2 cycles), and febrile neutropenia (1 cycle). Twenty-two cycles (10.2%) were delayed because of scheduling conflicts (15 delays), transient elevation of transaminases (4 cycles), abnormal hepatic function (2 cycles), and febrile neutropenia (1 cycle). No doses were omitted; however, 6 patients discontinued treatment because of adverse events consisting of decreased ejection fraction (n = 2), granulocytopenia (n = 1), constipation (n = 1), palpitations (n = 1), and monoparesis (n = 1). In the phase II portion, 109 cycles were administered, and 5 cycles (4.6%) had reductions because of neutropenia (4 cycles) and cellulitis (1 cycle). Twenty-three delays (21.1%) occurred because of neutropenia (7 delays), scheduling conflict (8 delays), and the presence of bilirubin, cellulitis, constipation, decreased creatinine clearance, fatigue, hypertension, skin infection, and other unspecified reasons (1 delay each). No doses were omitted; however, 2 patients discontinued treatment because of adverse events (diverticulitis and CHF, respectively). A median of 4.5 cycles (range, 1-13 cycles) were administered, with a relative dose intensity of 90.2% for pemetrexed and 89.6% for epirubicin.

Efficacy Although efficacy was not a phase I objective, a partial response (PR) was observed in 11 patients (32.4%), stable disease (SD) in 17 patients (50%), and progressive disease (PD) in 5 patients (14.7%). All 22 patients from the phase II portion were evaluable for the efficacy analysis. Five patients (22.7%) had PRs, 10 patients (45.5%) had SD, 4 patients (18.2%) had PD, and 3 patients (13.6%) were unknown/not done. The overall RR (ORR) was 22.7% (95% CI, 5.2%-40.2%). Enrollment stopped early because ≤ 9 of the first 20 patients responded. The median TTP was 5.3 months (95% CI, 3.1-8.9 months); 7 patients (31.8%) were

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Phase I/II Study of Pemetrexed and Epirubicin in MBC Table 2 Phase I/II: Maximum Grade 3/4 Toxicities*

Table 1 Phase I/II: Patient Characteristics Parameter Median Age, Years (Range)

Phase I (N = 34)

Phase II (N = 22)

55.5 (35-73)

56 (35-78)

32 (94.1)

22 (100)

2 (5.9)

0

WHO Performance Status, n (%) 0/1 2

34 (100)

15 (68.2)

Hispanic

0

5 (22.7)

Other

0

2 (9.1)

ER/PgR Status, n (%) +/+

19 (55.9)

9 (40.9)

+/–

8 (23.5)

1 (4.5)

–/+

0

2 (9.1)

–/–

5 (14.7)

7 (31.8)

Unknown

2 (5.9)

3 (13.6)

Number of Metastatic Sites, n (%) 1

2 (5.9)

2 (9.1)

2

16 (47.1)

8 (36.4)

q3

16 (47.1)

12 (54.5)

Leukopenia

Phase II (N = 22)

Grade 4 Grade 3

Grade 4

0

0

2 (9.1)

2 (9.1)

2 (5.9)

2 (5.9)

3 (13.6)

1 (4.5)

Lymphopenia

0

0

1 (4.5)

0

Neutropenia

1 (2.9)

20 (58.8)

5 (22.7)

7 (31.8)

Thrombocytopenia

2 (5.9)

0

0

0

Anorexia

1 (2.9)

0

0

0

ALT increase

2 (5.9)

0

1 (4.5)

0

AST increase

0

0

1 (4.5)

0

Cardiac (LVEF)

0

0

1 (4.5)

0

Edema

0

0

1 (4.5)

0

Fatigue

1 (2.9)

0

2 (9.1)

0

Febrile neutropenia

Nonhematologic

2 (5.9)

1 (2.9)

1 (4.5)

0

Hypocalcemia

0

0

0

1 (4.5)

Hyponatremia

0

0

1 (4.5)

0

Infection with grade 3/4 neutropenia

0

0

2 (9.1)

0

1 (2.9)

0

0

0

Palpitations

Sites of Metastases, n (%)

Phase I (N = 34) Grade 3

Hematologic Anemia

Ethnicity, n (%) White

Parameter, n (%)

Liver

20 (58.8)

8 (36.4)

Pruritus

0

0

1 (4.5)

0

Bone

13 (38.2)

8 (36.4)

Vaginal bleeding

0

0

1 (4.5)

0

Lung

12 (35.3)

8 (36.4)

Previous Surgery, n (%)

26 (76.5)

16 (72.7)

Previous Radiation Therapy, n (%)

25 (73.5)

12 (54.5)

Previous Hormonal Therapy, n (%)

25 (73.5)

8 (36.4)

Previous Chemotherapy, n (%)

9 (26.5)

9 (40.9)

Adjuvant setting

7 (20.6)

8 (36.4)

Neoadjuvant setting

1 (2.9)

2 (9.1)

Metastatic setting

1 (2.9)

0

Alopecia (grade 1/2) was observed in 31 patients (91.2%) in phase I and in 18 patients (81.8%) in phase II. *Toxicities were graded according to NCI-CTC, version 2.0.

censored. The median TTF was 3.5 months (95% CI, 2.65.9 months); 1 patient (4.5%) was censored. With only 5 responders, duration of response was not computed.

data consisted of 1596 pemetrexed concentration results from 287 patients.17 Dose-normalized concentrations of pemetrexed in plasma were consistent with the reference data (Figure 1), suggesting that there were no overt alterations in the pharmacokinetics of pemetrexed in the current population. Pemetrexed clearance was not different in the current study relative to single-agent administration, but volume of distribution was 30% lower. Dose-normalized plasma epirubicin concentrations did not show a trend by dose, thereby indicating that epirubicin pharmacokinetics were linear over the range of epirubicin doses administered in this study (data not shown).

Safety

Discussion

All 56 patients were evaluable for safety. Table 2 details the observed grade 3/4 toxicities. The most commonly reported grade 3/4 hematologic toxicity was neutropenia, whereas the nonhematologic toxicities were minimal. No deaths occurred for any patient while on study.

The present trial was conducted to determine a safe combination of pemetrexed with epirubicin and to test the efficacy of the selected regimen as a novel first-line chemotherapy for MBC. The selected regimen (pemetrexed 600 mg/m2 and epirubicin 75 mg/m2) had both drugs at levels that would be considered active, and overall, the combination had an RR of 32% in phase I.19 However, only 5 patients (22%) in the phase II portion responded, and no complete remissions occurred. As a result, the study was stopped early.

Abbreviations: ER = estrogen receptor; PgR = progesterone receptor

Pharmacokinetics In total, 67 pemetrexed concentration results were available from the 34 phase I patients. Single-agent reference

864 • Clinical Breast Cancer December 2007

Robert Paridaens et al

Conclusion In conclusion, this phase II study of pemetrexed and epirubicin in patients with locally advanced or MBC was stopped

Figure 1 Pemetrexed Concentration in Plasma Versus Time

Pemetrexed Concentration Plasma (μg/mL)

In various pemetrexed-based combinations for MBC, RRs were 24%-50% when used with carboplatin,20 gemcitabine,21 and cyclophosphamide.22 Therefore, it is surprising that our study with pemetrexed and epirubicin did not elicit a higher RR. In the phase II portion, the majority of patients were chemotherapy naive, and only 41% had adjuvant/neoadjuvant chemotherapy. Thus, one cannot argue that patients with an unfavorable previous treatment profile were selected. In fact, our RR is similar to that of other patient populations treated with single-agent epirubicin, doxorubicin, taxanes, pemetrexed, or gemcitabine.2,22-24 A recent randomized phase II study of pemetrexed as first-line therapy for patients with advanced breast cancer evaluated 2 different doses of pemetrexed (600 mg/m2 and 900 mg/m2) and showed a modest ORR of 15.6%-17%.25 This suggests that, as used in this regimen, perhaps pemetrexed and epirubicin are not synergistic, in contrast with the results from an in vitro study in human breast carcinoma cells showing synergism with pemetrexed and doxorubicin.14 There are several possible reasons for the lower phase II RR compared with the phase I response, including statistical variance. The phase I portion used 5 different dose levels, compared with 1 dose level in phase II. The patient populations for both portions were also different; eg, 100% of phase I patients were white compared with 68% of phase II patients. The hormone receptor status for the 2 patient populations had some differences; eg, the estrogen receptor–negative/progesterone receptor–negative statuses were 32% in patients in phase II versus 15% in patients in phase I. Moreover, the phase I study was carried out in 1 country (Belgium, at 2 different centers), whereas the phase II was a multinational study. In summary, the ORR among the patients in the phase II portion of this study (and even the combined phase I patients population) did not reach the predefined minimal threshold of 45%, which would have justified the continuation of this trial. Interestingly, a lower median of 4.5 cycles (range, 1-13 cycles) was administered in phase II compared with a median of 7.5 cycles (range, 1-8 cycles) in phase I, although the toxicity profiles of the 2 phases were similar. In general, the observed toxicities, mostly hematologic, were manageable. In both phases of the study, neutropenia was the major grade 3/4 toxicity, occurring in approximately 55%-62% of patients. The nonhematologic toxicities were mild, and none were observed in > 10% of the patients. These findings are in agreement with the good safety profiles of the 2 individual drugs. Population pharmacokinetic analysis indicated that pemetrexed clearance was not different in the current study relative to single-agent administration. The lack of alteration in pemetrexed pharmacokinetics when co-administered with epirubicin eliminates pemetrexed pharmacokinetics as a potential explanation for the poor synergism between the 2 compounds in this study.

Time from Dose (Hours)

Normalized to 875 mg (500 mg/m2 ×1.75 m2).

early because of its unexpectedly low RR. The regimen of pemetrexed 600 mg/m2 and epirubicin 75 mg/m2 once every 21 days is safe but cannot be recommended for use as firstline chemotherapy in advanced breast cancer. It remains to be seen whether a similar ongoing study of pemetrexed and doxorubicin conducted in patients with MBC will show a better response. We observed an apparent lack of pharmacokinetic inferences between epirubicin and pemetrexed. If this is also seen in an ongoing study of pemetrexed and doxorubicin in MBC,26 this information might help build combinations of pemetrexed and anthracyclines potentially helpful for treating other neoplastic diseases.

Acknowledgements The authors acknowledge the assistance in data management from Nicole Mellaerts (Universitair Ziekenhuis Gasthuisberg, Katholieke Universiteit, Leuven, Belgium). The authors thank Ghulam Kalimi and Peter Fairfield for supporting the manuscript preparation, Yiyong Fu and Sindee Sutherland for their assistance with statistical analyses, Pat Guiney for her data management support, and Debbie Pardue for project management support. This study was sponsored by Eli Lilly and Company.

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