Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer

A. Welt1, G. von Minckwitz2, C. Oberhoff3, D. Borquez1, R. Schleucher1, S. Loibl2, A. Harstrick1, M. Kaufmann2, S. Seeber1 and U. Vanhoefer1,*

1 Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Duisburg-Essen Medical School, Essen; 2 Department of Gynecology and Obstetrics, University of Frankfurt, Frankfurt; 3 Department of Gynecology and Obstetrics, University of Duisburg-Essen Medical School, Essen, Germany

* Correspondence to: Dr U. Vanhoefer, Department of Internal Medicine (Medical Oncology), Marienkrankenhaus, Alfredstrasse 9, 22087 Hamburg, Germany. Tel: +49-40-2546-2501; Fax: +49-40-2546-2500; Email: vanhoefer.innere{at}marienkrankenhaus.org


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose: To define the maximum-tolerated dose (MTD) and to evaluate the dose-limiting toxicities (DLT) of the combination of capecitabine and vinorelbine in patients with metastatic breast cancer who relapse after adjuvant and/or first-line treatment. In addition, we aimed to obtain data on efficacy and safety at the recommended dose.

Patients and methods: Patients with measurable metastatic breast cancer after failure of prior chemotherapy (including anthracyclines and/or taxanes) were eligible. Capecitabine was administered with a fixed dose of 1000 mg/m2 orally twice daily for 2 weeks followed by 1 week rest. One treatment cycle consisted of 6 weeks of treatment containing two treatment periods of capecitabine. Vinorelbine was given intravenously at escalated doses of 25 mg/m2 (dose level 1) and 30 mg/m2 (dose level 2) on days 1 and 8, and 22 and 29.

Results: Thirty-three patients received a total of 91 cycles of capecitabine and vinorelbine. The median number of administered cycles per patient was three (range one to six). Thirty-one patients were evaluable for toxicity. At dose level 2 four out of seven patients experienced DLTs (nausea/vomiting, febrile neutropenia, grade 4 neutropenia, infection and diarrhea); thus, the MTD was defined. In order to confirm the safety and efficacy, dose level 1 was extended to 24 patients. Two patients [8.3%; 95% confidence interval (CI) 1% to 27%] showed DLTs (hospitalization due to febrile neutropenia and prolonged neutropenia). The main toxicity was neutropenia, which was observed at National Cancer Institute Common Toxicity Criteria grade 3 and 4 in 39% of patients. The overall response rate for capecitabine and vinorelbine was 55% (95% CI 36% to 72.7%), including three patients with a complete remission. The median time to disease progression was 8 months (95% CI 4.3–11.7) with an overall survival of 19.2 months (95% CI 11.3–27.1) based on intention-to-treat analysis.

Conclusions: The combination of capecitabine and vinorelbine can be administered with manageable toxicity and showed significant efficacy for patients with metastatic breast cancer even after failure of a anthracycline- and/or taxane-based therapy.

Key words: breast cancer, capecitabine, phase I/II study, vinorelbine


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Breast cancer is the most common malignancy in women in Western countries and is the most frequent cause of cancer mortality in this population. Furthermore, older women have a higher risk of developing breast cancer, and the majority of patients with breast cancer are older than 65 years.

Systemic chemotherapy remains the treatment of choice for women with advanced disease that is hormone receptor-negative or resistant to hormonal therapy, or for patients with rapidly progressive visceral disease.

In chemotherapy-naive patients anthracycline- and/or taxane-based regimens {e.g. FAC [5-fluorouracil (5-FU), adriamycin, cyclophosphamide] and AT (adriamycin, docetaxel)} have significant efficacy. It is important to note that the widespread use of anthracyclines and taxanes in the adjuvant setting has led to an increasing number of patients presenting with advanced disease that is resistant to both drugs. In this population, treatment options remain controversial because no standard chemotherapy has been defined.

In patients with metastatic breast cancer the oral fluoropyrimidine precursor capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) has significant efficacy both as a single agent and in combination with tubulin-interactive agents (e.g. docetaxel, paclitaxel) [1Go–3Go]. Capecitabine as single agent produced an overall response rate of 29% in the salvage setting and a median time to disease progression of 4.6 months in women with advanced disease refractory to two or three previous regimes, one of which contained a taxane [2Go]. The combination of capecitabine and docetaxel was significantly superior compared with docetaxel alone in terms of response rate (42% versus 30%), time to disease progression (6.1 versus 4.2 months) and overall survival (14.5 versus 11.5 months) in anthracycline-pretreated patients [3Go]. The most common severe non-hematological toxicities for the combination of capecitabine with docetaxel were gastrointestinal side-effects and hand–foot syndrome [3Go].

The semisynthetic vinca alkaloid vinorelbine remains an effective treatment option in patients with metastatic breast cancer. In the first-line setting vinorelbine as single agent achieved a response rate of 41% [4Go]. Neutropenia is the main toxicity, but is usually rapidly reversible and does not necessitate hospitalization. In anthracycline- and taxane-pretreated patients, vinorelbine induced objective remissions in 25% of patients, and remissions were seen even in patients who were refractory to taxanes. These data suggest a lack of clinical cross-resistance between vinorelbine and taxanes [5Go]. Furthermore, vinorelbine has been shown to be well tolerated in elderly patients, with no differences in hematological and non-hematological toxicities between patients either younger or older than 60 years [6Go]. Based on its toxic profile and promising efficacy, vinorelbine has also been used in combination with other cytotoxic agents (e.g. adriamycin, 5-FU, trastuzumab). In several studies the combination of vinorelbine with a protracted infusion 5-FU showed significant antitumor activity in heavily pretreated patients, with neutropenia being the main toxicity [7Go, 8Go].

Considering the efficacy of the combination of 5-FU and vinorelbine, the substitution of 5-FU (with or without leucovorin) by the oral administration of capecitabine may provide a convenient alternative in the treatment of advanced breast cancer. Here, we describe the results of a phase I/II trial of capecitabine and vinorelbine in patients with metastatic breast cancer who had failed prior chemotherapy (including anthracyclines and/or taxanes).


    Patients and methods
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 Abstract
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 Patients and methods
 Results
 Discussion
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Eligibility
The eligibility criteria were as follows: age ≥18 and ≤70 years; histological or cytological confirmed breast cancer, with at least one bidimensionally measurable marker lesion; relapse after adjuvant chemotherapy (which may contain an anthracycline and/or taxanes) and/or a maximum of one prior chemotherapy regimen for metastatic disease; predicted life expectancy ≥3 months; Karnofsky performance status ≥60%; no second malignancy; adequate baseline organ functions; normal cardiac function; no chronic diarrhea or unresolved bowel obstruction; no severe uncontrolled co-morbidities or medical conditions (e.g. myocardial infarction within the last 12 months); no symptomatic peripherial neuropathy grade ≥2 according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC); no concurrent treatment with other experimental antineoplastic drugs; signed informed consent. The trial was initiated after institutional review board approval. The study followed the Declaration of Helsinki and Good Clinical Practice guidelines.

Pretreatment evaluation and follow-up
Pretreatment evaluation consisted of a complete history and physical examination, complete blood cell count (CBC), serum chemistry including electrolytes, hepatic and renal function tests, ECG, chest X-ray, and computed tomography (CT) scans of the abdomen/pelvis and chest (if indicated). All sites of measurable disease were initially documented by CT scan. If indicated, bone scans and X-rays were performed. During the study treatment, patient monitoring included the assessment of clinical toxicities, CBC, serum chemistry and physical examinations before each administration of the intravenous chemotherapy. ECG, chest X-ray and measurement of the target lesion(s) by CT scan were additionally performed before each cycle and at the end of treatment. During the follow-up period patients were evaluated every 3 months after the end of study treatment, including physical examination, CBC, serum chemistry, ECG, CT scan of the measurable lesion(s) in case of tumor response or stable disease, until documented disease progression.

Drug administration
Capecitabine was supplied by Hoffmann-La Roche (Grenzach, Germany) as 150 and 500 mg film-coated tablets and vinorelbine was supplied by Pierre Fabre Pharma (Freiburg, Germany) in vials containing 10 mg drug in 1 ml of water for injection. Capecitabine was administered twice daily (approximately every 12 h) on days 1–14 and 22–35. The daily doses were rounded up to the nearest calculated dose and adjustments were done if indicated. Vinorelbine was administered on days 1, 8, 22 and 29 as an intravenous infusion of 5 min. One treatment cycle consisted of 42 days (Figure 1).



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Figure 1. Regimen administration.

 
Administration of capecitabine and vinorelbine was interrupted if diarrhea or mucositis grade >2 occurred (symptomatic treatment, e.g. loperamide was recommended). Vinorelbine was re-administered if neutophil count was >1500/µl and platelet count was >100 000/µl, and non-hematological toxicities had recovered to grade ≤1 or to the individual baseline level. Treatment could be delayed up to 2 weeks pending full recovery. Each cycle of chemotherapy consisted of 6 weeks of treatment. Treatment was routinely given on an outpatient basis. Patients with documented objective response or stable disease continued study treatment for at least one further cycle.

Dose escalation plan
The starting dose (dose level 1) was 2x 1000 mg/m2 of capecitabine daily on days 1–14 and 22–35 in combination with 25 mg/m2 of vinorelbine given on days 1, 8, 22 and 29. One treatment cycle consisted of two treatment periods of capecitabine (Figure 1).

At dose level 2, the dose of vinorelbine was escalated to 30 mg/m2. No intrapatient dose escalation was performed. If any dose-limiting toxicity (DLT) was observed in one out of the first three patients, an additional three patients were enrolled at the same dose level. If two or more patients at the same dose level experienced any DLT, the maximum tolerated dose (MTD) had been reached and the dose level below the MTD was considered to be the recommended dose for further extension.

Evaluation of toxicities and response
Toxicities were evaluated on days 1 and 8, and 22 and 29 of each treatment period and graded according to the NCI-CTC criteria. DLTs were defined as neutropenia NCI-CTC grade 4 or 3 associated with complications (e.g. neutropenic fever), thrombocytopenia grade 4, failure of neutrophils and platelets to recover by day 50 to grade 1, any grade ≥3 or persisting (until day 50) grade 2 non-hematological toxicity (except alopecia, inadequately treated nausea/vomiting, asthenia and serum bilirubin) during the first cycle. In addition, a toxicity-related discontinuation of capecitabine treatment for >1 week and/or a delay in the administration of two doses of vinorelbine due to toxicity were also defined as DLT.

Tumor response was defined according to the standardized response definitions of the WHO. CT scans of the target lesion(s) were performed at base-line and before each new cycle of chemotherapy (every 6 weeks) and at the end of treatment. Tumor responses were confirmed by a second evaluation at least 4 weeks apart.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
From November 1999 to January 2002, 33 patients with measurable metastatic breast cancer were enrolled into this trial (Table 1). Twenty-three patients (70%) had prior (neo-) adjuvant chemotherapy and 23 patients (70%) had received chemotherapy for metastatic disease. Almost all patients (94%) were pretreated with anthracyclines and 12 patients (36%) had prior treatment with taxanes. The detailed patients characteristics are listed in Table 2.


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Table 1. Dose-escalation scheme and incidence of DLTs

 

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Table 2. Patient characteristics (n=33)

 
A total of 91 cycles (one cycle consisted of 6 weeks of treatment) were administered, and the median number of cycles per patient was three (range one to six). Thirty-one patients received at least one administration of chemotherapy and were assessable for toxicity. Two patients were withdrawn due to major protocol violation (one patient with severe multiple sclerosis, one patient lost early to follow-up). These two patients were not included in the intention-to-treat analysis.

In the first part of the study (dose finding) 14 patients were treated at dose levels 1 and 2. At dose level 1, only one out of six patients experienced DLT. With the dose escalation of vinorelbine to 30 mg/m2 (dose level 2) the MTD was reached, with DLTs occurring in four out of seven evaluable patients [57.3%; 95% CI 18.4% to 90.1%]. DLTs were NCI-CTC grade 3 nausea/vomiting, febrile neutropenia and grade 4 neutropenia, infection and diarrhea.

Based on these data, dose level 1 with capecitabine 1000 mg/m2 twice daily and vinorelbine 25 mg/m2 was defined as the recommended dose. To evaluate more precisely the safety and efficacy at the recommended dose, an additional 19 patients were entered at this dose level. In total, two out of 24 evaluable patients showed DLTs during the first cycle (hospitalization due to febrile neutropenia and neutrophils <1500/µl until end of cycle 1 for one patient each) at this dose level. No treatment-related death occurred during this study.

Neutropenia was the main toxicity, with an incidence of grade 3 or 4 in 26% (95% CI 11.9% to 44.6%) and 13% (95% CI 3.6% to 29.8%) of patients, respectively (Table 3). Neutropenia was not cumulative after multiple cycles and severe infections were rare (two cases of grade 3 or 4 infections). Other hematological toxicities were mild, and no severe thrombocytopenia or anemia was observed. Severe hand–foot syndrome (HFS) occurred only in one patient, with NCI-CTC grade 3 at the recommended dose. Other non-hematological toxicities were mild (mainly grade 1) and consisted of diarrhea, paresthesia and constipation. Alopecia grade 3 was only observed in two patients (6%). The safety profile of capecitabine and vinorelbine in terms of liver toxicity was assessed routinely for all patients (91 cycles) and revealed no increase of serum bilirubin or elevation of transaminases exceeding NCI-CTC grade 1.


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Table 3. Worst toxicities for the first and after multiple cycles

 
The median relative dose density of capecitabine and vinorelbine at the recommended dose was 8587 mg/m2/week and 15.7 mg/m2/week, respectively, demonstrating that 90% of the initially intended doses for both drugs were administered (Table 4).


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Table 4. Median dose density of capecitabine and vinorelbine per dose level

 
Twenty-nine (93.5%) out of 31 patients received at least one complete cycle of chemotherapy and were assessed for efficacy. Two patients decided to stop study treatment during the first cycle because of nausea/vomiting (grade 2 and 3, respectively). Seventeen patients achieved a confirmed objective response, including three complete remissions, resulting in an overall response rate of 59% (95% CI 38.9% to 76.5%) (intention-to-treat analysis, n=31: 55%; 95% CI 36% to 72.7%). Remissions were achieved at both dose levels. Based on an intention-to-treat analysis the median time to disease progression and overall survival were 8 months (95% CI 4.3–11.7) and 19.2 months (95% CI 11.3–27.1) (Figures 2 and 3), respectively.



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Figure 2. Time to progression (TTP) (Kaplan–Meier, intention-to-treat analysis). Median TTP is 8 months (95% CI 4.3–11.7).

 


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Figure 3. Overall survival (Kaplan–Meier, intention-to-treat analysis). Median survival is 19.2 months (95% CI 11.3–27.1). One- and 2-year survival rates are 74% and 45%, respectively.

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
There is an increasing number of patients with metastatic breast cancer who were pretreated with anthracylines and/or taxanes in the (neo-)adjuvant situation. Therefore, it is a challenge to define effective and well tolerated drug combinations for the treatment of metastatic breast cancer. Vinorelbine has shown significant activity as single agent in advanced breast cancer with a response rate of 41% [4Go]. Severe neutropenia is the main toxicity of vinorelbine, but in general is rapidly reversible and does not necessitate hospitalization. Other toxicities (e.g. constipation, neurotoxicity) are usually mild to moderate and occur infrequently. The combination of vinorelbine with infusional 5-FU has been well established in anthracycline- and/or taxane-pretreated patients with advanced breast cancer [7Go, 8Go].

Capecitabine is an oral precursor of 5-FU with significant antitumor activity in breast cancer. The recent results of a randomized trial in anthracycline-pretreated patients showed superiority of the combination of capecitabine and docetaxel over docetaxel alone in terms of response rate, time to disease progression and overall survival [3Go]. However, patients receiving the combination regimen experienced a higher incidence of adverse events, especially HFS and gastrointestinal toxicities (e.g. diarrhea, stomatitis, nausea/vomiting). Dose reduction of capecitabine alone or of both drugs was required for adverse events in 65% and 51% of all patients, respectively [3Go].

The favorable toxicity profile of capecitabine compared with 5-FU, the convenience of oral drug administration, especially compared with infusional 5-FU/leucovorin, together with the synergic efficacy of capecitabine and vinorelbine against human breast tumor xenografts [9Go], led to the clinical evaluation of this combination in patients with metastatic breast cancer.

In the present study the MTD of capecitabine and vinorelbine was defined with capecitabine 1000 mg/m2 twice daily (days 1–14 and 22–35) and vinorelbine 30 mg/m2 (days 1 and 8, and 22 and 29); thus, the preceding dose level was considered as the recommended dose for further clinical evaluation. The DLTs consisted of diarrhea, neutropenia, febrile neutropenia and nausea/vomiting.

In order to define more precisely the treatment-related toxicity before embarking on further clinical trials, additional patients were treated at the recommended dose. The extension of this dose level to 24 evaluable patients showed an incidence of 8.3% (95% CI 1% to 27%] of DLTs. Based on these data, the recommended dose has been defined with capecitabine 1000 mg/m2 twice daily and vinorelbine 25 mg/m2. The recommended dose was further supported by the safety analysis of multiple cycles, demonstrating an incidence of neutropenia NCI-CTC grade 3 or 4 in 39% (95% CI 18.8% to 59%) of patients, with no evidence of cumulative myelosuppression.

HFS is a common side-effect of capecitabine, which was observed at NCI-CTC grade 3 in 17% of patients treated with capecitabine alone. In the present study, HFS was mild and did not result in treatment withdrawal. Of importance is that the combination of capecitabine and vinorelbine at the doses used rarely led to alopecia. Other non-hematological toxicities like paresthesia, diarrhea and constipation were moderate (Table 3) and manageable. No severe mucositis occurred. Furthermore, calculation of the median dose density of capecitabine and vinorelbine revealed almost full administration of the initial intended doses of both drugs (Table 4). These results confirm the results of another phase I study, defining similar recommended doses and DLTs [10Go].

Although antitumor activity was not considered a primary objective of this study, the overall response rate of 55% suggests considerable antitumor activity, even after pretreatment with anthracyclines or taxanes in 94% and 36% of all patients, respectively. The promising antitumor activity was supported by the median time to disease progression of 8 months and the overall survival of 19.2 months based on an intention-to-treat analysis. Stuart et al. [11Go] administered capecitabine at a dose of 1000 mg/m2 twice daily for 2 weeks in combination with vinorelbine at a dose of 25 mg/m2 on days 1 and 8. The overall response rate was 43%, and the main toxicity was neutropenia. The median dose intensities for capecitabine and vinorelbine was 1560 mg/day and 14 mg/week (78% and 82% of the intended dose), respectively. The overall response rate of 40% in anthracycline-pretreated patients was similar to that reported herein. Ahn et al. [12Go] reported a response rate of 50% for a higher dose of capecitabine (1250 mg/m2 twice daily for 2 weeks) in combination with 25 mg/m2 of vinorelbine.

Recently, oral vinorelbine has been investigated in the first-line treatment of patients with advanced or metastatic breast cancer. Oral vinorelbine was given at a dose of 60 mg/m2 weekly for the first three administrations and then increased to 80 mg/m2 for the subsequent treatment if no neutropenia NCI-CTC grade 3 (multiple episodes) or grade 4 occurred. Objective responses were achieved in 18 out of 58 (31%; 95% CI 19% to 43%) patients and NCI-CTC grade 4 neutropenia was the main toxicity [13Go]. Based on these data, the combination of capecitabine and oral vinorelbine is currently under clinical development [14Go]. Taken together, the data reported herein suggest that the combination of capecitabine and vinorelbine is feasible and has significant antitumor activity in women with advanced breast cancer, even after prior treatment with anthracyclines and/or taxanes.


    Acknowledgements
 
This study was supported in part by Hoffmann-La Roche, Grenzach, Germany. Presented in part at the 27th Congress of the European Society for Medical Oncology, Nice, France, 18–22 October 2002, and at the 25th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, December 2002.

Received for publication April 22, 2004. Revision received July 25, 2004. Accepted for publication September 2, 2004.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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