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Dose-Finding Study of Capecitabine in Combination with Weekly Paclitaxel

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Dose-Finding Study of Capecitabine in Combination with Weekly Paclitaxel Journal of BUON 12: 189-196, 2007 © 2007 Zerbinis Medical Publications. Printed in Greece ORIGINAL ARTICLE Dose-fi nding study of capecitabine in combination with weekly paclitaxel for patients with anthracycline-pretreated metastatic breast cancer S. Susnjar1, S. Bosnjak1, S. Radulovic2, J. Stevanovic3, M. Gajic-Dobrosavljevic3, M. Kreacic1 1Department of Medical Oncology, 2Department of Experimental Oncology, 3Department of Radiology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia Summary luable for toxicity and response. Two patients receiving paclitaxel 75 mg/m2 experienced grade 3 nail toxicity, with Purpose: Capecitabine and paclitaxel show high grade 3 hand-foot syndrome (HFS) in one patient and grade effi cacy, non-overlapping toxicity profi les and preclinical 2 dermatitis in the other. Although not life-threatening, synergism, providing the rationale for their combination in these were considered unacceptable and the preceding dose metastatic breast cancer (MBC). This dose-escalation study level was selected. Eight of 11 patients achieved objective aimed at determining the maximum tolerated dose (MTD) responses. of capecitabine plus paclitaxel in anthracycline-pretreated Conclusion: The recommended regimen is capecitabi- 2 MBC patients. ne 1,000 mg/m twice daily, days 1-14, plus paclitaxel 60 2 Patients and methods: Patients with MBC received mg/m /week. Escalation of the paclitaxel dose above 60 2 fl at-dose of oral capecitabine (1,000 mg/m2 twice daily, days mg/m /week is not feasible due to severe skin toxicity. 1-14) plus weekly paclitaxel 60, 75, or 90 mg/m2, i.v., days 1, 8 and 15, every 3 weeks. Key words: capecitabine, metastatic breast cancer, pa- Results: All 11 patients enrolled onto study were eva- clitaxel Introduction active treatment option after disease progression with anthracyclines [3,4]. First- and second-line monoche- The goal of chemotherapy in MBC is to reduce motherapy with paclitaxel 175 mg/m2 given as a 3- tumor burden, resulting in improvement of tumor-re- hour infusion every 3 weeks is highly effective in lated symptoms and delay of disease progression. In MBC [5-7]. Recently reported results of the Cancer anthracycline-naïve patients, anthracycline-containing and Leukemia Group B (CALGB) 9840 study [8] regimens are often used as fi rst-line chemotherapy for confi rmed the superiority of weekly paclitaxel over a MBC, giving an objective response rate (ORR) of 3-weekly regimen in terms of response rate and time more than 50% and overall survival of approximately to progression (TTP), although this was accompanied 2 years [1,2]. The introduction of taxanes provided an by a signifi cantly higher incidence of severe sensory and motor neuropathy. Capecitabine (Xeloda; F. Hoffmann-La Roche, Basel, Switzerland), an oral fl uoropyrimidine carba- Received 02-04-2007; Accepted 24-04-2007 mate, is activated preferentially in tumor tissue through Author and address for correspondence: exploitation of the signifi cantly higher activity of thy- Snezana Susnjar, MD midine phosphorylase (TP) in tumor cells compared Department of Medical Oncology with normal tissue. The standard capecitabine dose of Institute for Oncology and Radiology of Serbia 2 Pasterova 14 1,250 mg/m twice daily, days 1-14, followed by a 7- 11000 Belgrade day rest period, has demonstrated high activity in an- Serbia thracycline and taxane-pretreated MBC [9-13] and as Tel: +381 11 2067113 Fax: +381 11 2685300 first-line therapy [14]. The most common adverse E-mail: [email protected] events are diarrhea, stomatitis and HFS, which are ge- 190 nerally manageable with appropriate dose modifi ca- aminotransferase [ALT] < 2.5×UNL), renal (serum tion. Severe hematologic toxicity is rare and alopecia creatinine < 1.5×UNL; if serum creatinine concentra- is absent. tion was > 1.25×UNL, creatinine clearance had to be The rationale for combining capecitabine and ≥ 60 ml/min) and cardiac function (ejection fraction paclitaxel in breast cancer is based on the high single- ≥ 50% measured by MUGA scan or ultrasound). agent effi cacy of both drugs, non-overlapping toxicity profi les and preclinical data showing synergistic anti- Study design tumor activity of paclitaxel and capecitabine via up- regulation of TP [15]. In addition, capecitabine plus This was a prospective, open-label, single-center, docetaxel has demonstrated high effi cacy in a large dose-fi nding study. The study was designed during the randomized phase III trial, extending survival com- Workshop on Methods in Clinical Cancer Research, pared with docetaxel alone [16]. Two phase II studies held in Flims (Switzerland), 2000, and was approved of capecitabine and 3-weekly paclitaxel in MBC dem- by the Institutional Ethics Committee. All patients onstrated ORRs of 51-52% and median TTP of 10.6 signed informed consent to participate in the study. months and 8.1 months, with acceptable safety profi le The primary objective was to determine the MTD [17,18]. Most recently, a randomized phase III trial of weekly paclitaxel when combined with capecitabine demonstrated a 52% response rate, median progres- 1,000 mg/m2 twice daily, days 1-14. MTD was defi ned sion-free survival of 12.0 months, and median overall as one dose level below the one causing a dose-limiting survival of 25.6 months in patients receiving fi rst-line toxicity (DLT) in 2 or more patients. capecitabine plus 3-weekly paclitaxel [19]. The com- The National Cancer Institute of Canada Com- bination of capecitabine and weekly paclitaxel was mon Toxicity Criteria (NCIC CTC), version 3.0, were expected to be more effi cacious and better tolerated. used to grade toxicity. The following acute and cumu- In a phase I study in patients with advanced solid tu- lative adverse events were considered as DLTs: grade mors reported by Elza-Brown et al., capecitabine 4 neutropenia lasting > 7 days, febrile neutropenia, 1,000 mg/m2 twice daily, days 1-14, and weekly pa- grade 4 thrombocytopenia, hemorrhagic syndrome clitaxel 60 mg/m2 showed promising results [20]. due to thrombocytopenia, grade 4 diarrhea, grade 4 The aim of the current study was to determine the nausea, grade 4 vomiting, grade 4 neurotoxicity, grade maximum tolerated dose (MTD), tolerability, and 4 constipation, or grade 3 stomatitis. preliminary antitumor activity of capecitabine plus Three patients were to be treated at dose level 1. escalating doses of weekly paclitaxel therapy in pa- If 1 of these patients experienced a DLT, 3 further pa- tients with MBC previously treated with anthracy- tients were to be treated at the same dose level. If no cline-based regimens. DLT occurred at dose level 1, or a DLT occurred in only one of 6 patients, 3 patients were to be treated at the next dose level. If a DLT occurred in more than 1 Patients and methods patient receiving dose level 1, the study was to be closed. The fi rst 2 patients included in the fi rst or sec- ond dose level had to complete the fi rst 2 cycles of Eligibility criteria therapy (6 weeks) without DLT before enrolment to Eligible patients were females ≥ 18 years old the next dose level was allowed. If a DLT occurred with histologically proven MBC who had previously during any cycle at any dose level, any patients already received adjuvant or fi rst-line anthracycline-contain- being treated at a higher dose level were to be moved ing therapy, had received no more than one prior line down to one level below the one that caused the DLT. of chemotherapy, and had received the last dose of chemotherapy at least 12 weeks prior to enrollment. Treatment Previous capecitabine or taxane therapy was not per- mitted, but endocrine therapy for metastatic disease Oral capecitabine (1,000 mg/m2 twice daily, days was allowed. Other eligibility criteria were: Eastern 1-14) was combined with escalating doses of weekly Cooperative Oncology Group (ECOG) performance paclitaxel administered as a 1-hour i.v. infusion on status ≤ 2, presence of at least one measurable lesion, days 1, 8, and 15 (level 1: 60 mg/m2/week; level 2: 75 and normal hematologic (absolute neutrophil count mg/m2/week; level 3: 90 mg/m2/week). Day 21 was [ANC] ≥ 2.0×109/L and platelets ≥ 100×109/L), he- the fi rst day of the next cycle. The following premedi- patic (total bilirubin < 1.5×upper normal limit [UNL] cation was administered 30 min prior to each pacli- and/or aspartate aminotransferase [AST] and alanine taxel dose: dexamethasone 8 mg i.v. during the fi rst 191 cycle, with de-escalation as appropriate (in the absence lower limit of 50%, or > 20% decrease in LVEF be- of hypersensitivity reaction, 4 mg dexamethasone dur- tween two successive measurements. ing the second cycle and no further dexamethasone during subsequent paclitaxel doses); chlorpyramine 20 mg i.v.; ranitidine 50 mg i.v., and ondansetron 8 mg Results p.o. Patients achieving a complete response (CR) re- ceived 2 further cycles after first recording of CR Patient characteristics (minimum of 6 cycles). Patients with a partial response (PR) were treated until progression or unacceptable Between February 2003 and April 2004 11 pa- toxicity. Treatment was stopped if patients achieved tients were enrolled, all of whom were assessable for stable disease (SD) for 18 weeks. Post-study therapy toxicity and response. Median age was 48 years (range was at the physician’s discretion. 35-60). Baseline characteristics are shown in Table 1. Ten patients received the combination as first-line therapy and one as second-line therapy. HER2 status Study assessments was unknown in all patients; none had received prior Complete medical history and physical examina- trastuzumab. Previous anthracycline-based chemo- tion, laboratory tests (complete blood count [CBC], therapy consisted of doxorubicin, cyclophosphamide, serum biochemistry), and tumor measurement (chest and fl uorouracil in all patients.
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