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© 2003 American Society for Clinical Oncology Phase II Study of Oral Vinorelbine in First-Line Advanced Breast Cancer ChemotherapyFrom the Hospices Civils de Lyon, Department of Medical Oncology and EA 643, Université Claude Bernard Lyon I, France; Centre François Baclesse, Caen, France; Cancer Research Center MAS of Russia, Moscow, Russia; Centre Eugène Marquis, Rennes, France; Hôpital Bretonneau, Tours, France; and Institut de Recherche Pierre Fabre, Castres, France. Address reprint requests to Véronique Trillet-Lenoir, PhD, MD, Centre Hospitalíer Lyon-Sud, 69495 Pierre Bénite Cedex, France; email: veronique.trillet-lenoir{at}chu-lyon.fr.
Purpose: A phase II trial was performed to evaluate the efficacy, tolerance, and pharmacokinetic profiles of oral vinorelbine (Navelbine). Oral Navelbine (NVB; Pierre Fabre Médicament, Boulogne, France) was given as first-line chemotherapy for locally advanced or metastatic breast carcinoma (ABC). Patients and Methods: Sixty-four patients were entered to receive oral NVB on a weekly basis for a total of 8 weeks unless progression or toxicity occurred. Oral NVB was given at 60 mg/m2 weekly for the first three administrations and was increased to 80 mg/m2 for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Patients with objective response or stable disease continued treatment up to a total of 12 weeks or more. Results: Fifty-eight evaluable patients were included in our study. Four patients (6.9%) had complete responses, and 14 (24.1%) had partial responses, for an overall response rate of 31% (95% CI, 19% to 43%). Median progression-free survival was 17.4 weeks. Median overall survival is not yet reached. There were no treatment-related deaths. The main toxicity was neutropenia: grade 4 in 17.2% of the patients, and 1.8% of administrations and associated clinical serious events in 4 patients (6.2%). Grade 3 and 4 nausea and/or vomiting were noted in 3.1% and 4.6% of the patients, respectively. Only one patient developed grade 3 neuroconstipation. An analysis of Quality of Life Questionnaire C30 forms revealed no significant alteration between baseline and weeks 8 and 16 in global quality of life. Conclusion: Oral NVB at this schedule is an effective and well-tolerated agent in the treatment of ABC and offers a promising alternative to the intravenous route. Combination studies are ongoing.
CHEMOTHERAPY MAY OFFER effective palliation in the management of advanced breast cancer (ABC). Vinorelbine (VRL) administered intravenously has been documented to generate a consistent level of activity, with overall response rates ranging from 35% to 50%1–8 and a highly acceptable toxicity profile.1–8 Maintaining the quality of life for these patients is an important objective. In fact, the greater acceptability of oral versus intravenous (IV) agents in this clinical setting has been firmly established.9 The potential advantages of oral chemotherapy agents, which include ease of administration and reduced need for hospitalization, are likely to provide a useful contribution to improvement of care, as long as an equivalent level of efficacy is maintained. The development of the oral formulation of Navelbine (NVB Pierre Fabre Médicament, Boulogne, France) was started in 1987. Initially, powder-filled capsules were produced, followed by a first generation of soft gel capsules. Because of stability problems, both of these initial formulations were discarded after early clinical development.10–12 The soft gel capsules, which are currently in clinical development and have been used in this study, are the third oral formulation. This new soft gel formulation of NVB was introduced into clinical studies in 1994, when a dose-finding phase I study evaluated levels of 60, 80, and 100 mg/m2 administered weekly in a total of 27 patients.13 The maximum-tolerated dose was established at 100 mg/m2, with dose-limiting toxicities being neutropenia, nausea/vomiting, and neuroconstipation. Antitumor activity was observed at both 80 and 100 mg/m2, and the recommended dose for further trials was 80 mg/m2. A bioavailability study has also been performed with intrapatient cross-over dosing of 80 mg/m2 orally and 25 mg/m2 intravenously. The bioavailability of VRL was about 40%,14 which indicated that the dose equivalence was more likely to be as follows: 80 mg/m2 orally corresponding to 30 mg/m2 intravenously and 60 mg/m2 orally corresponding to 25 mg/m2 intravenously. Food has no influence on VRL pharmacokinetics, but the gastrointestinal tolerability seemed to improve in fasting patients.15 Early phase II studies that investigated oral NVB 80 mg/m2 in 82 patients were associated with significant hematologic toxicity during the first three cycles,16 and the clinical schedule has therefore been modified in further studies, including our study.
Study Design and Patient Selection This trial was conducted between November 1997 and July 2000 in 13 centers, 10 in France and three in Russia. The study protocol was reviewed and approved by the French Comité Consultatif de Protection des Personnes se prêtant à la Recherche Biomédicale (CCPPRB) and by the Russian Ethics Committee. The study was designed according to the current revision of the Declaration of Helsinki and was conducted in accordance with good clinical practice. Written informed consent was obtained from each participating patient before entry into the study. The cutoff date for analysis of the study was August 15, 2000.
Patients with histologically confirmed ABC were eligible if they met the following requirements: no previous chemotherapy for locally advanced disease or metastatic breast cancer, adjuvant chemotherapy allowed if completed at least 12 months before study entry, adjuvant hormonal treatment allowed, clear evidence of progression after one or more hormonal treatments for advanced disease, presence of at least one bidimensionally measurable lesion ( Patients were ineligible for the study on the basis of the following characteristics: inflammatory breast cancer, male sex, prior chemotherapy for ABC, prior treatment with vinca alkaloids, concurrent treatment with experimental agents, previous or current malignancies (except adequately treated in situ carcinoma of the cervix or basal or squamous cell carcinoma of skin), confirmed metastatic central nervous system disease, uncontrolled hypercalcemia, preexisting significant peripheral neuropathy; uncontrolled infection, pregnancy or lactation, uncontrolled coronary disease, medically unstable conditions, malabsorption, or prior bowel resection.
Treatment Methods
Dose modifications or delays occurred as follows: During the first three administrations (at 60 mg/m2), neutropenia
Evaluation Methods All enrolled patients were included in the efficacy analysis on an intent-to-treat basis. Because the study was initiated before the publication of the Recist criteria, response assessment relied on the previous WHO criteria,17 with the modifications suggested by the European Organization for Research and Treatment of Cancer (EORTC).18 CR was defined as complete disappearance of disease for at least 4 weeks, without appearance of a new lesion. PR consisted of 50% or greater reduction in the sum of the size of all measurable lesions for at least 4 weeks, without appearance of a new lesion or progression of any lesion. Progressive disease (PD) was defined as the appearance of a new lesion or an increase of 25% or greater in the sum of the size of any measurable lesion. NC was a change insufficient to qualify for PR or progressive disease. To be considered evaluable for efficacy, a patient had to receive at least four administrations within 8 weeks. All tumor responses had to be confirmed by redocumentation with the same investigations after 4 weeks and validated by an independent review panel. Adverse events were graded according to National Cancer Institute common toxicity criteria. Quality of life was measured with the Quality of Life Questionnaire C30 (QLQ-C30)19 at study entry and every 8 weeks thereafter. Pharmacokinetic assessments were performed in a subset of patients using a limited sampling strategy, based on a population approach, which allowed us to obtain maximal information on patients’ pharmacokinetic profile based on a limited number of samples.20 Four blood samples were taken on the first four successive cycles and then once more between cycles 9 and 13. Concentrations of VRL were determined by high-performance liquid chromatography with ultraviolet detection assay with a limit of quantitation of 2.5 ng/mL.
Statistical Methods For pharmacokinetic parameters, descriptive statistics were calculated for each administration on blood concentration and an area under the curve (AUC), which was estimated with Kinetica (Innaphase, France) software.
Patient Characteristics Sixty-four patients were included. The median age of the population was 63 years (range, 35 to 79 years), and 87.5% of the patients were postmenopausal. The WHO PS was 0 in 31 patients (48.4%) and 1 or 2 in 33 patients (51.6%). Patient demographics are shown in Table 1  . The median time from diagnosis of the primary tumor to study entry was 34 months (range, 3 days to 25 years). Approximately one third of the patients (30%) had stage IV disease at the time of diagnosis. Seventy-three (73%) of the patients had two or more organs involved, the most frequent disease sites being lymph nodes (56%), liver, lung, and bone (34% each). Approximately one third of the patients had received previous adjuvant and/or neoadjuvant chemotherapy, of whom 60% had been treated with anthracycline-containing regimens.
Chemotherapy Administration A total of 794 administrations were given to the 64 patients, with a median number of doses of nine (range, 1 to 56) and a median treatment length of 10.4 weeks (range, 1 to 77). Of the 60 patients who received the intended three administrations at 60 mg/m2, only two were not escalated to 80 mg/m2; one as a result of grade 4 neutropenia and the other because of protocol violation. During the period of the initial three administrations, delays of more than 3 days were reported in eight patients (12.5%), concerning 10 administrations in total (5.4%). At the 80 mg/m2 level, dose delays of more than 3 days were reported for 29 patients (50%), concerning 53 administrations in total (11.9%). Dose reduction from 80 to 60 mg/m2 as a result of hematologic toxicity was needed in 10 patients (17.2%), but re-escalation after a further three administrations without toxicity was possible for three patients (5.2%). The mean value of NVB dose intensity was 62.9 ± 10.7 mg/m2/wk, and the median relative dose intensity was 91.2% (range, 46 to 112). Reasons for premature study discontinuation were disease progression in 30 patients out of 64 (46.9%), adverse events in seven patients (10.9%), patient refusal in four patients (6.3%), investigator’s decision in seven patients (10.9%), and intercurrent disease in three patients (4.7%). Thirteen patients (20.3%) were still ongoing when this article was written.
Efficacy
In the 58 evaluable patients, the response rates were as follows: CR 4 (6.9%), PR 14 (24.1%), NC 18 (31%), and PD 22 (37.9%), for an overall response rate of 31% (95% CI, 19% to 43%), with a median duration of response of 38.1 weeks. The number of patients in each subset is small, but some factors affecting response rates are listed in Table 2
Tolerability and Toxicity All 64 patients were evaluable for toxicity and received 794 administrations of oral NVB, 789 of which were available at the cutoff point of the study. The most frequent adverse events by patient and by administrations are listed in Table 3 . Throughout the study period, neutropenia was observed in 45 patients (70.3%), with grade 3 and 4 toxicity observed in 14 (21.9%) and 11 (17.2%) patients, respectively. The incidence of neutropenia varied according to the dose of NVB and timing of the administrations. Overall rates of neutropenia and of grade 3 and 4 toxicity were lower during the first three administrations at 60 mg/m2 and higher during subsequent administrations at 80 mg/m2 and at intermediate levels in patients who later received 60 mg/m2 (see Table 4). Febrile neutropenia, defined as grade 4 neutropenia concomitant with grade  2 fever, was observed in three patients (4.7%), and one other patient developed an episode of ocular infection associated with grade 4 neutropenia. The most frequent gastrointestinal symptom was nausea/vomiting, but the incidence of grade 3 and 4 toxicity was low even though primary antiemetic prophylaxis was not given. Diarrhea also was frequently reported, but mild and neuroconstipation at grade 3 was documented in only one patient. Peripheral neuropathy was mild and of low incidence.
Quality of Life Analysis Baseline questionnaires were completed by 56 patients (87.5%), but less than half of the population was still on study at the time of the third and fourth evaluations. The rate of completed questionnaires decreased as follows: first evaluation, 71.7%; second evaluation, 50%; third evaluation, 23.8%; and fourth evaluation, 17.6%. Therefore, the analysis was restricted to the available sets containing the baseline, first, and second evaluations. There were no significant differences between these assessments for the functional scales, and the symptom scales showed increases for nausea/vomiting and diarrhea but decreases for constipation and pain. Global health status showed no significant variation between baseline and second evaluation (Figs 1 and 2).
Pharmacokinetic Results A total of 13 patients, who received a total of 54 administrations, were included in the analysis (from first administration up to 13th administration for some patients). Mean values of the 0 to 24 hours interpolated VRL AUC (AUCobs,0–24 hours), reported in Fig 2  , increased between the third (60 mg/m2) and fourth (80 mg/m2) administrations in proportion to the dose. Of the 13 evaluable patients for pharmacokinetic analysis, 12 did not experience any side effects and had an AUCobs,0–24 hours close to the average value (637 ± 248 h/ng/mL). Only one patient experienced a febrile neutropenia after the fifth administration, which might be related to her high exposure after the fourth administration (AUCobs,0–24 hours = 899 h/ng/mL).
Orally active chemotherapy provides a valuable option for treating ABC because of its advantages, including ease of administration, greater convenience for the patient, and reduced need for hospitalization. During the past years, among all cytotoxic drugs, only alkylating agents such as cyclophosphamide and etoposide were available orally, but important interpatient variations in drug disposition have limited their use. Since then, new oral cytotoxic agents have been developed. With the new generation of drugs, including oral fluoropyrimidines22,25 and oral NVB, reliable blood exposure has been achieved.14,26 Such improved oral strategies should not only improve access to chemotherapy for many more patients but also provide better comfort, allowing more prolonged administration. VRL IV formulation has been studied extensively and has been demonstrated to be active in the treatment of ABC, both as a single agent1–8 and in combination with other compounds.27,28 This study has shown that oral NVB given on an adapted schedule at a starting dose of 60 mg/m2 weekly for three administrations followed by escalation to 80 mg/m2 is an effective and well-tolerated treatment for ABC.
The response rate for this study is 31% in a population of 58 evaluable patients. It is worth noting that the majority of enrolled patients had lung or liver metastases and multiple organ involvement. The study population seems to be associated with poorer prognostic factors than those treated in the largest phase II study conducted with single-agent NVB IV by Fumoleau et al.1 When comparing our study of oral NVB with the Fumoleau et al1 NVB IV study, the proportion of patients with primary diagnosed stage IV disease was higher (29.7% v 12%), the median interval between diagnosis and study entry was shorter (34 months v 53.5 months), the number of patients with extensive disease ( Oral NVB given in this schedule and NVB IV given in the standard regimen have similar toxicity profiles. The main adverse events associated with oral NVB were neutropenia and gastrointestinal disorders. Neutropenia was documented in 70.3% of the patients and in 20.4% of the administrations. Grade 4 was seen in 17.2% of the patients and in 1.8% of the administrations and was rarely associated with complications. Nausea and vomiting were frequent (78% and 58% of the patients, respectively). However, the incidence of grade 3 and 4 was less than 5%, although no primary antiemetic therapy was recommended in the study. The use of primary antiemetic prophylaxis should be standard in future trials with oral NVB. These data correspond with the previous clinical experience of NVB IV in ABC1–8 and with the recently performed randomized comparison between oral and IV NVB in non–small-cell lung cancer.29 Serial measurement of quality of life using the EORTC QLQ-C30 provides excellent support for the acceptability of oral NVB as palliation of ABC. The benefits of treatment-related efficacy were not affected by symptoms caused by the toxic effects, and the global health status of patients was maintained throughout treatment. This study met previous findings on VRL pharmacokinetics, given that AUCobs,0–24 hours was stable during the first three administrations at 60 mg/m2 and then increased as a proportion of the dose from the third to fourth administration. Linear pharmacokinetics and reproducible blood exposure over administrations were demonstrated during this phase II trial and confirmed previous NVB characteristics established during phase I studies.13 In conclusion, the efficacy and toxicity profiles of oral NVB compare favorably with those of NVB IV, and this new formulation seems to be a potentially useful alternative to the IV form. Combination chemotherapy regimens studies testing the safety and efficacy of oral NVB are ongoing.
We thank the following investigators for their participation in this study: P. Kerbrat (Centre Eugéne Marquis, Rennes, France), H. Orfeuvre (Hôpital Fleyriat, Bourg en Bresse, France), L. Mauriac (Institut Bergonié, Bordeaux, France), Y. Merrouche (Centre Jean Minjoz, Besancon, France), S. Culine (Centre Val d’Aurelle, Montpellier, France), P. Fargeot (Centre Georges-François Leclerc, Dijon, France), P. Fumoleau (Centre René Gauducheau, Nantes, France), V.A. Gorbunova, and A.M. Garin (Cancer Research Center MAS of Russia, Moscow, Russia).
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2. Garcia Conde J, Lluch A, Martin M, et al: Phase II trial of weekly IV vinorelbine in first-line advanced breast cancer chemotherapy. Ann Oncol 5:854–857, 1994 3. Romero A, Rabinovitch MG, Vallejo CT, et al: Vinorelbine as first-line chemotherapy for metastatic breast carcinoma. J Clin Oncol 12:336–341, 1994[Abstract] 4. Weber BL, Vogel C, Jones S, et al: Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. J Clin Oncol 13:2722–2730, 1995[Abstract]
5. Vogel C, Rourke M, Winer, E, et al: Vinorelbine as first-line chemotherapy for advanced breast cancer in women 60 years old. Ann Oncol 10:397–402, 1999 6. Bruno S, Puerto VL, Mickiewicz, E, et al: Phase II trial of weekly IV vinorelbine as single agent in first-line advanced breast cancer chemotherapy: The Latin-American experience. Am J Clin Oncol 18:392–396, 1995[Medline] 7. Twelves SC, Dobbs NA, Curnow A, et al: A phase II, multicenter UK study of vinorelbine in advanced breast cancer. Br J Cancer 70:990–993, 1994[Medline] 8. Terenziani M, Demicheli R, Brambilla C, et al: Vinorelbine: An active, non-cross-resistant drug in advanced breast cancer: Results from a phase II study. Breast Cancer Res Treat 39:285–291, 1996[CrossRef][Medline]
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14. Marty M, Fumoleau P, Adenis A, et al: Oral vinorelbine phase I parmacokinetics and absolute bioavailability study in patients with solid tumors. Ann Oncol 12:1643–1649, 2001 15. Bugat R, Variol P, Roche H, et al: The effects of food on the pharmacokinetic profile of oral vinorelbine. Cancer Chemother Pharmacol 50:285–290, 2002[CrossRef][Medline]
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29. Jassem J, Ramlau E, Karnicka-Modkowska H, et al: A multicenter randomized phase II study of oral versus intravenous vinorelbine in advanced non-small-cell lung patients. Ann Oncol 12:1375–1381, 2001 Submitted September 10, 2001; accepted September 3, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2, initial blood parameters of hemoglobin 
= 5%, ß = 10%, and 
= 2. The total required sample of evaluable patients was 50, and the first test was to be conducted after inclusion of the first 25 evaluable patients. The duration of response and survival analysis were conducted using the Kaplan-Meier method. 
