Phase II study of pemetrexed in breast cancer patients pretreated with anthracyclines

Martín, Miguel; Spielmann, M.; Namer, M.; duBois, Andreas; Unger, Clemens; Dodwell, David; Vodvárka, P; Lind, Michael; Calvert, Hilary; Casado, Antonio; Zelek, Laurent; Lluch, Aña; Carrasco, Eva; Kayitalire, L.; Zielinski, Christoph

doi:10.1093/annonc/mdg339

Cited by 44 publications

(20 citation statements)

References 16 publications

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“…The response rate was comparable to the 21% observed when 600 mg/m 2 of pemetrexed was given to patients with locally advanced or metastatic breast cancer, most of whom had one prior chemotherapy regimen (6). As expected, the vitamin supplementation included in this study greatly improved the pemetrexed safety profile over that observed by Martin et al (6).…”

Section: Discussionsupporting

confidence: 77%

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A Randomized, Double-Blind, Phase II Study of Two Doses of Pemetrexed as First-Line Chemotherapy for Advanced Breast Cancer

Llombart-Cussac

Martín

Harbeck

et al. 2007

Clinical Cancer Research

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Purpose: Pemetrexed has shown varied response rates in advanced breast cancer. This randomized, double-blind, phase II study was conducted to assess the efficacy and safety of two doses of pemetrexed in a homogeneous population. A secondary objective was to identify molecular biomarkers correlating with response and toxicity. Experimental Design: Patients with newly diagnosed metastatic breast cancer or locally recurrent breast cancer received 600 mg/m 2 (P600 arm) or 900 mg/m 2 (P900 arm) of pemetrexed on day 1of a 21-day cycle. All patients received folic acid and vitamin B 12 supplementation. Results: The P600 (47 patients) and P900 (45 patients) arms had response rates of 17.0% (95% confidence interval, 7.7-30.8%) and 15.6% (95% confidence interval, 6.5-29.5%) with f50% stable disease per arm, median progression-free survival of 4.2 and 4.1 months, and median times to tumor progression of 4.2 and 4.6 months, respectively. Both arms exhibited minimal toxicity (grade 3/4 neutropenia <20%, leukopenia <9%, and other toxicities <5%). Tumor samples from 49 patients were assessed for the expression levels of 12 pemetrexed-related genes. Folylpolyglutamate synthetase and thymidine phosphorylase correlated with efficacy. Best response rates and median time to tumor progression for high versus low thymidine phosphorylase expression were 27.6 % versus 6.3 % (P = 0.023) and 5.4 versus 1.9 months (P = 0.076), and for folylpolyglutamate synthetase were 37.5% versus 10.0% (P = 0.115) and 8.6 versus 3.0 months (P = 0.019), respectively. g-Glutamyl hydrolase expression correlated with grade 3/4 toxicities: 78.6% for high versus 27.3% for low g-glutamyl hydrolase (P = 0.024). Conclusion: The two pemetrexed doses yielded similar efficacy and safety profiles. Exploratory biomarker analysis identified efficacy and toxicity correlations and warrants further evaluation.Patients with advanced breast cancer who experience tumor progression after anthracycline-and taxane-based regimens were considered unlikely to benefit from other chemotherapeutics (1). However, the development of novel agents like gemcitabine (2) and capecitabine (3) has yielded palliative improvement and survival gains. Additional development of novel, safe, and effective agents is greatly needed to further improve the palliation and survival of these patients.Several phase II studies have established the single-agent activity of 600 mg/m 2 of pemetrexed, and later, 500 mg/m 2 of pemetrexed, in patients with untreated (4), minimally pretreated (one to two prior chemotherapies; refs. 5, 6), or heavily pretreated (three to five prior chemotherapies; refs. 7, 8) advanced breast cancer. Response rates ranged from 8% to 31%, with higher rates in the 600 mg/m 2 studies with untreated or minimally pretreated patients. Although both doses yielded an acceptable safety profile, toxicities in the later 600 mg/m 2 studies were significantly reduced with folic acid and vitamin B 12 supplementation before and during treatment. In view of the heterogeneous patient popul...

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Section: Discussionsupporting

confidence: 77%

“…For each patient, the P600 arm administered a mean of 6.1 cycles (median, 6; range, , and the P900 arm administered a mean of 6.0 cycles (median, 5; range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Both arms received a high percentage of the planned dose (P600 = 98.2%; P900 = 95.7%).…”

Section: Treatmentmentioning

confidence: 99%

A Randomized, Double-Blind, Phase II Study of Two Doses of Pemetrexed as First-Line Chemotherapy for Advanced Breast Cancer

Llombart-Cussac

Martín

Harbeck

et al. 2007

Clinical Cancer Research

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“…Llombart-Cussac and colleagues observed response rates of 17 and 19% when pemetrexed was given at 600 and 900 mg/m 2 to MBC patients in the first-line setting on Day 1 of a 21-day cycle [25]. Earlier 21-day trials have shown response rates in anthracyclinerefractory groups (ORR 17%), anthracycline-failure groups (ORR 24%), anthracycline-and taxane-pretreated groups (ORR 26% and ORR 28%, respectively), and heavily pretreated groups who had received prior anthracycline, a taxane, and capecitabine (ORR 8%) [15,17,26]. In combination trials, pemetrexed with gemcitabine and pemetrexed with epirubicin produced response rates not dramatically different from those in trials using single-agent pemetrexed [27,28].…”

Section: Discussionmentioning

confidence: 99%

Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer

Robert

Conkling

O’Rourke

et al. 2010

Breast Cancer Res Treat

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Palliation is the primary goal in metastatic breast cancer (MBC), and safe, efficacious, new single-agent options are needed. Pemetrexed, an antifolate, inhibits several folate-dependent enzymes involved in purine biosynthesis. The primary goal of this study was to determine the objective response rate in patients with advanced or MBC given pemetrexed as a first-line, dose-dense, every 2-week chemotherapy. Women with HER2-negative advanced or MBC, without prior cytotoxic treatment for this stage of disease, were treated with intravenous pemetrexed 600 mg/m² on Day 1 of each 14-day cycle. Standard dexamethasone, folic acid, and vitamin B(12) premedications were given. 37 patients enrolled; 36 received ≥ 1 dose of pemetrexed and 35 were evaluable for response. Median age of patients was 61.4 years, 76% were hormone receptor positive (ER+ and/or PR+). Prior treatment included adjuvant chemotherapy (57%) and/or endocrine (65%). Patients received a median of 6 cycles of pemetrexed (range, 1-21). Based on 35 evaluable patients, the overall response rate (ORR) was 26% (1 CR and 8 PR), and the clinical benefit rate (CR+ PR+ stable disease [SD] ≥ 6 months) was 40%. Median progression-free survival (PFS) was 4.1 months (range, <1-22.4). Median overall survival (OS) was 18.9 months (range, <1-27.7). Grades 3-4 treatment-related toxicities included: neutropenia (36%), leukopenia (17%), fatigue (14%), and anemia (14%). Grade 1/2 alopecia was seen in 8% of patients. This phase II study of dose-dense, single-agent pemetrexed showed moderate activity in the first-line setting with acceptable toxicity and no significant alopecia.

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“…The drug has been recently approved for the treatment of inoperable malignant mesothelioma [3]; moreover, pemetrexed has been registered for the second-line treatment of locally advanced or metastatic non-small cell lung cancer, since it has shown comparable efficacy but a better toxicity profile compared to docetaxel [4]. In addition, pemetrexed has shown significant activity against a broad spectrum of solid tumors [5,6,7,8,9,10,11,12,13]. Pemetrexed has a favorable toxicity profile although its use is associated with myelosuppression, gastrointestinal toxicity, skin rash and mucositis [14, 15].…”

Section: Introductionmentioning

confidence: 99%

A Dose Escalation Study of Gemcitabine plus Pemetrexed Administered Biweekly in Patients with Solid Tumors

Kalykaki

Vamvakas²,

Agelaki³

et al. 2006

Oncology

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Purpose: The study aimed to determine the maximum tolerated doses (MTDs) and identify the dose-limiting toxicities of the biweekly administration of pemetrexed plus gemcitabine in patients with solid tumors. Patients and Methods: Patients with advanced malignancies were treated with escalated doses of gemcitabine and pemetrexed (starting doses 1,250 and 300 mg/m², respectively) both given on days 1 and 15 in cycles of 4 weeks. Results: Forty-one patients were treated at 7 dose levels. The MTD was reached at the dose of 1,750 mg/m² for gemcitabine and 450 mg/m² for pemetrexed. Dose-limiting events were grade IV neutropenia, febrile neutropenia and treatment delay due to grade III hematological toxicities. One partial response in a pretreated patient with ovarian cancer was observed, while 4 other patients experienced stable disease. Conclusions: The biweekly administration of gemcitabine plus pemetrexed at the recommended MTDs is safe, well tolerated and demonstrates antitumor activity which merits further evaluation in phase II studies.

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Phase II study of pemetrexed in breast cancer patients pretreated with anthracyclines

Abstract: Our trial demonstrates pemetrexed to be active in breast cancer, with manageable toxicity. Activity of pemetrexed did not appear to be adversely affected by prior taxane, 5-fluorouracil or endocrine treatments.

Cited by 44 publications

References 16 publications

A Randomized, Double-Blind, Phase II Study of Two Doses of Pemetrexed as First-Line Chemotherapy for Advanced Breast Cancer

A Randomized, Double-Blind, Phase II Study of Two Doses of Pemetrexed as First-Line Chemotherapy for Advanced Breast Cancer

Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer

A Dose Escalation Study of Gemcitabine plus Pemetrexed Administered Biweekly in Patients with Solid Tumors

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