Phase II Study of Oral Vinorelbine in First-Line Advanced Breast Cancer Chemotherapy

By G. Freyer, T. Delozier, M. Lichinister, D. Gedouin, P. Bougnoux, P. His, K. Imadalou, and V. Trillet-Lenoir

Purpose: A phase II trial was performed to evaluate the efcacy, tolerance, and pharmacokinetic proles of oral vinorelbine (Navelbine). Oral Navelbine (NVB; Pierre Fabre Me dicament, Boulogne, France) was given as rst-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 rst 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 signicant 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. J Clin Oncol 21:35-40. 2003 by American Society of Clinical Oncology.

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HEMOTHERAPY 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 prole.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 rmly 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 efcacy is maintained. The development of the oral formulation of Navelbine (NVB Pierre Fabre Me dicament, Boulogne, France) was started in 1987. Initially, powder-lled capsules were produced, followed by a rst 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-nding 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 crossover 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 inuence 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 signicant hematologic toxicity during the rst three cycles,16 and the clinical schedule has therefore been modied in further studies, including our study.
PATIENTS AND METHODS

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 Comite Consultatif de Protection des Personnes se pre tant a ` la Recherche Biome dicale (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 conrmed 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

From the Hospices Civils de Lyon, Department of Medical Oncology and EA 643, Universite Claude Bernard Lyon I, France; Centre Franc ois Baclesse, Caen, France; Cancer Research Center MAS of Russia, Moscow, Russia; Centre Euge ` ne Marquis, Rennes, France; Ho pital Bretonneau, Tours, France; and Institut de Recherche Pierre Fabre, Castres, France. Submitted September 10, 2001; accepted September 3, 2002. Address reprint requests to Ve ronique Trillet-Lenoir, PhD, MD, Centre Hospital er Lyon-Sud, 69495 Pierre Be nite Cedex, France; email: veronique .trillet-lenoir@chu-lyon.fr. 2003 by American Society of Clinical Oncology. 0732-183X/03/2101-35/$20.00

Journal of Clinical Oncology, Vol 21, No 1 (January 1), 2003: pp 35-40 DOI: 10.1200/jco.2003.09.057

35

36
measurable lesion ( 2.0 2.0 cm), aged between 18 and 75 years, World Health Organization (WHO) performance status (PS) 2, initial blood parameters of hemoglobin 10 g/dL, granulocytes 2.0 109/l, platelets 100 109/l, bilirubin less than 1.5 upper limit of normal (ULN), transaminases 2.5 ULN, creatinine 1.5 ULN, more than 2 weeks following any surgery except for biopsy, and more than 6 weeks postirradiation if the measurable or evaluable disease was completely outside the treatment eld and if the radiation volume concerned less than 10% of bone marrow reserve. Patients were ineligible for the study on the basis of the following characteristics: inammatory 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), conrmed metastatic central nervous system disease, uncontrolled hypercalcemia, preexisting signicant peripheral neuropathy; uncontrolled infection, pregnancy or lactation, uncontrolled coronary disease, medically unstable conditions, malabsorption, or prior bowel resection.
Table 1. Patient Demographics
n

FREYER ET AL

Disease-free interval (years) 2 2 Previous adjuvant (or neoadjuvant) chemotherapy Previous hormonotherapy Locally advanced Metastatic Number of involved organs 1 2 3 Visceral involvement Nonvisceral involvement

21 43 20 45 12 52 17 25 22 39 25

32.8 67.2 31.3 70.3 18.7 81.3 26.6 39.0 34.4 60.9 39.1

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Treatment Methods
Oral NVB was administered on a weekly basis for a total of 8 weeks (once per week) unless progression or toxicity occurred. It was given at an initial dose of 60 mg/m2/wk for the rst three administrations and was increased to 80 mg/m2/wk if no grade 4 neutropenia or no more than one episode of grade 3 neutropenia had occurred. Patients who achieved a complete response (CR), partial response (PR), or no change (NC) continued to receive weekly treatment as tolerated, unless reevaluation every 4 weeks revealed progressive disease. The study protocol did not recommend treatment discontinuation for patients with stable disease. Oral NVB was supplied as 30- and 40-mg soft gel capsules. Individual doses were the product of the patients body-surface area (BSA) times the dosage (60 mg/m2 or 80 mg/m2) rounded to the closest multiple of 10 mg. At the beginning of the study, as there was no information on food interaction, all administrations were taken with a glass of water either 2 hours before or 2 hours after a meal, without chewing or sucking the capsules. Dose modications or delays occurred as follows: During the rst three administrations (at 60 mg/m2), neutropenia grade 2 resulted in delay until recovery (patient was withdrawn if there was no recovery within 3 weeks), grade 4 neutropenia or more than one episode of grade 3 neutropenia prevented dose escalation to 80 mg/m2 at cycle 4. During subsequent administrations at 80 mg/m2, grade 2 or 3 neutropenia resulted in delay, and any grade 4 neutropenia, or two episodes of grade 3 neutropenia, resulted in both delay and dose reduction to 60 mg/m2. Re-escalation to 80 mg/m2 was further permitted if no severe hematologic toxicity was documented at 60 mg/m2. Patients experiencing neurotoxicity grade 2 were delayed and nally withdrawn after 3 weeks in case of persistence. Evidence of grade 3 hepatotoxicity resulted in delay of up to 3 weeks, and grade 4 patients were withdrawn.

conrmed 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 prole based on a limited number of samples.20 Four blood samples were taken on the rst four successive cycles and then once more between cycles 9 and 13. Concentrations of VRL were determined by highperformance liquid chromatography with ultraviolet detection assay with a limit of quantitation of 2.5 ng/mL.

Statistical Methods
The one-sample multiple testing procedure for phase II clinical trials, described by Fleming,21 was used to test the hypothesis that antitumor activity would be between a minimum response rate P0 30%, below which further investigation was not required, and a response rate PA 50%, implying efcacy at an acceptable level. Sensitivity levels would be 5%, 10%, and 2. The total required sample of evaluable patients was 50, and the rst test was to be conducted after inclusion of the rst 25 evaluable patients. The duration of response and survival analysis were conducted using the Kaplan-Meier method. 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.

Evaluation Methods
Clinical staging was performed for all patients and included complete history and physical examination with tumor measurement. Complete blood cell counts were performed within a 2-week period before study entry and weekly throughout treatment. Biochemical prole was performed pretreatment and then at 4 weekly intervals. An electrocardiogram was also required before starting treatment. The extent of the disease was documented at entry, and assessment of response relied on clinical examination, chest x-ray, bone scintigraphy, liver ultrasound (conrmed by computed tomography [CT] if abnormal), and CT of the brain if necessary. All enrolled patients were included in the efcacy 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 modications suggested by the European Organization for Research and Treatment of Cancer (EORTC).18 CR was dened 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 dened 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 insufcient to qualify for PR or progressive disease. To be considered evaluable for efcacy, a patient had to receive at least four administrations within 8 weeks. All tumor responses had to be

RESULTS

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

ORAL VINORELBINE FOR ADVANCED BREAST CANCER

Table 2. Response Rates According to Patient Characteristics
No. Responders/ No. Evaluable Patients Response rate (%)

37
Table 3. Toxicity by Patient and by Administration
By Patient All Grades (%) Grade 3/4 (%) By Administration All Grades (%) Grade 3/4 (%)

Metastatic sites Visceral Nonvisceral Numbers of organs involved 1-2 3 Prior therapy Adjuvant hormonotherapy Neoadjuvant chemotherapy No prior adjuvant therapy Overall

10/36 8/22 14/37 4/21 7/13 5/16 6/29 18/58

27.8 36.4 37.8 19.0 69.2 31.2 20.7 31

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%), investigators 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. Efcacy One patient was ineligible because of the absence of measurable disease, as she presented with skin lymphangitis as the sole lesion. Five additional patients were not evaluable for efcacy. For three of them, the reasons were early discontinuation as a result of treatment refusal after one dose, occurrence of pancreatitis secondary to cholecystitis after one dose, and myocardial infarction after three administrations. The two remaining patients were considered not evaluable after the panel review: one had liver lesions documented by CT at baseline then by ultrasound only during treatment, and the other had bone lesions documented by CT scan at baseline but not during treatment. 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
Table 4.

Neutropenia Leucopenia Anemia Thrombocytopenia Infection Gastrointestinal Nausea Vomiting Diarrhea Stomatitis Alopecia Neurologic Neuroconstipation Neuromotor/sensory Asthenia

70.3 75.0 64.1 17.2 10.9 78.1 50.0 53.1 9.3 23.4 15.6 25.0 40.6

39.1 28.1 6.3 0 4.7 3.1 4.7 4.7 3.1 1.6 1.6 3.1

20.4 27.2 40.9 2.7 1.3 28.6 15.3 16.5 2.1 2.4 5.9 12.2

4.9 2.5 0.5 0 0.4 0.3 0.4 1.9 0.3 0.1 0.2 0.3

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(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. The response rates tended to be higher in patients who did not present visceral involvement, had less than three organs involved, and/or had received prior adjuvant hormonotherapy. In the intent-to-treat population of 64 patients, the response rate was 30% (95% CI, 18% to 41%). Median progression-free survival was 17.4 weeks. Follow-up was too short to report an overall survival analysis. 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 rst 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, dened 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

Neutropenia Related to Dose of VRL

By Patient By Administration Grade 3/4 (%) N All Grades (%) Grade 3/4 (%)

All Grades (%)

First 3 administrations: 60 mg/m2 Beyond the rst 3 administrations: 80 mg/m2 60 mg/m2

64 58 12

29.7 73.2 58.3

7.9 49.3 41.7

187 489 99

13.4 23.5 18.2

2.7 4.8 0.9

38

FREYER ET AL

Fig 1.

Quality of life: functional scales.

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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: rst 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, rst, and second evaluations. There were no signicant 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 signicant 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 rst 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 fth administration, which might be related to her high exposure after the fourth administration (AUCobs,0-24 hours 899 h/ng/mL).
DISCUSSION

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

Fig 2.

Quality of life: symptom scales.

ORAL VINORELBINE FOR ADVANCED BREAST CANCER

39

Fig 3. Vinorelbine AUCobs,0-24 h observed during administrations 1 to 13 (mean SEM).

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agents have been developed. With the new generation of drugs, including oral uoropyrimidines22,25 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 ( three organs involved) was higher (34.4% v 23%), and the percentage of patients with visceral metastases was greater (60.9% v 34%). These factors may account for the slightly lower response rates in our study. However, response duration and progression-free survival are comparable to those of all published NVB IV studies in which the median duration of responses ranged from 18 to 60 weeks and median time to progression ranged from 13 to 25 weeks.1-8 Oral NVB given in this schedule and NVB IV given in the standard regimen have similar toxicity proles. The main ad-

verse 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 benets of treatment-related efcacy 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 ndings on VRL pharmacokinetics, given that AUCobs,0-24 hours was stable during the rst 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 conrmed previous NVB characteristics established during phase I studies.13 In conclusion, the efcacy and toxicity proles 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 efcacy of oral NVB are ongoing.

40
ACKNOWLEDGMENT

FREYER ET AL

The acknowledgment is available online at www.jco.org.

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