Research ArticleClinical Studies

Phase I Study of Oral Vinorelbine and Capecitabine in Patients with Metastatic Breast Cancer

ANTONIO ANTON, ANA LLUCH, ANTONIO CASADO, MARIANO PROVENCIO, MONTSERRAT MUÑOZ, JUAN LAO, BEGOÑA BERMEJO, ANA B. PAULES, JAVIER GAYO and MIGUEL MARTIN
Anticancer Research June 2010, 30 (6) 2255-2261;

Abstract

Background: To determine the recommended doses of oral vinorelbine (VN) and capecitabine (C) in metastatic breast cancer. Patients and Methods: Eighteen patients with metastatic breast cancer received oral VN (on days 1 and 8) and C (on days 1 to 14) every three weeks at one of four dose levels: I) 60 mg/m2 and 1650 mg/m2/day; II) 70 mg/m2 and 1650 mg/m2/day; III) 70 mg/m2 and 2000 mg/m2/day; IV) 80 mg/m2 and 2000 mg/m2/day, respectively. The primary endpoint was to determine the recommended doses for the combination of oral VN and C in metastatic breast cancer. Secondary endpoints include evaluating response rate, safety profile and whether or not VN dosage escalation was required. Results: Severe neutropenia occurred in 28% of patients; and severe anaemia and leucopenia were observed in one patient each (6%). One patient developed febrile neutropenia. Non-hematological toxicities were rare. The response rate was 28% (95% CI: 10-54) in the intention-to-treat population. Conclusion: The recommended dose is 80 mg/m2 of oral VN on days 1 and 8, and 2000 mg/m2/day of C from days 1 to 14 in three weekly cycles. A phase II study with this schedule is currently under way.

With the exception of skin cancer, breast cancer is the most common type of malignancy occurring in women, accounting for almost one third (32%) of cases. The management of metastatic breast cancer (MBC) in particular is a major challenge for medical oncologists. Unlike early-stage disease, for which surgery, adjuvant chemotherapy, radiotherapy and/or other modalities are often curative, MBC is rarely curable (1). Therefore, the treatment goals in MBC are optimal palliation of symptoms, improvement in quality of life, and prolongation of life when possible. Combination chemotherapy is one of the best options for first-line treatment in patients with MBC (2). Anthracycline/taxane-based therapies are now being used increasingly in the (neo)adjuvant setting (3), so newer effective first-line cytotoxic agents with good safety profiles are needed for pretreated patients with MBC.

Vinorelbine (VN) is a semisynthetic vinca alkaloid. It differs structurally from the other vinca alkaloids in that it has modifications on the catharanthine ring rather than on the vindoline ring. VN exerts its cytotoxic effect by inhibiting the polymerization of tubulin into functional microtubules (4). VN is active against a wide range of tumours, including breast cancer. VN produces response rates of 35% to 59% as first-line single agent treatment of MBC (5, 6). Response rates in second-line treatment are also encouraging, ranging between 46% and 75% when VN is used in combination with anthracyclines, taxanes and/or 5-fluorouracil (5-FU) (5-8). The toxicities of i.v. administered VN have generally been predictable and manageable, and include neutropenia, moderate nausea and vomiting, constipation, neurotoxicity and relatively mild hair loss (9). Oral formulations of VN have been developed to overcome the discomfort and stress caused to patients by i.v. lines. Patient preference (10) and cost savings are significant advantages of oral chemotherapy, as well as avoidance of the local adverse reactions associated with the i.v. route of administration. Moreover, the oral route has been shown to have favourable pharmacokinetics and bioavailability. Bioavailability studies of VN have demonstrated equivalence between 60 mg/m2 oral and 25 mg/m2 i.v. doses, and between 80 mg/m2 oral and 30 mg/m2 i.v. doses (11-13).

Capecitabine (C) is an orally administered fluoropyrimidine prodrug that is transformed into 5-FU by an enzyme in the liver, and preferentially in tumour tissue (14). Prolonged administration of C reproduces the pharmacokinetics of a continuous infusion of 5-FU, with the advantages of oral dosing (15). C is indicated in the treatment of MBC, both as monotherapy (16) and as part of combination therapy (17), and has a good tolerability profile. The major adverse events associated with C are hand-foot syndrome and diarrhoea, both of which can usually be overcome by dose interruption or dose reduction (18).

VN and C therefore have different mechanisms of action but acceptable safety profiles, and have demonstrated synergistic antitumour activity in preclinical models (19). The combination of i.v. VN and C has been shown to be effective and well tolerated in the first-line treatment of women with MBC (20-22). Oral combination of these agents has also been investigated, showing similar efficacy and safety results in women with MBC (23). However, although phase I trials have identified feasible oral dosages of 80 mg/m2 on days 1 and 8 for VN, and 2000 mg/m2/day on days 1 to 14 for C on three-weekly cycles, the final recommendation from these trials was to administer 60 mg/m2 and 2000 mg/m2/day, respectively (24, 25). It has been argued that a weekly dose of 80 mg/m2 for VN is associated with an excessive rate of early deaths in non-small cell lung cancer patients as a result of complicated neutropenia, and that the administration of 60 mg/m2/week for the first three cycles with subsequent dose escalation to 80 mg/m2/week in the following cycles could decrease the incidence of severe neutropenia (26). However, it may be inappropriate to extrapolate dose recommendations made on the basis of results from studies of these agents in non-small cell lung cancer using a weekly treatment cycle to the setting of metastatic breast cancer using a three-weekly treatment cycle.

To address ongoing dosing concerns, we carried out a phase I study of an oral combination of VN and C in patients with MBC to identify the doses to be used in a subsequent phase II trial of this combination in MBC. Secondary objectives included evaluation of response rate and safety profile of this oral combination and whether or not VN dosage escalation is required.

Patients and Methods

Study design. This was a multicentre, phase I, dose escalating trial performed in five hospitals in Spain. Patients were recruited between April 2005 and March 2007. The study protocol was approved by the Institutional Review Board of each participating site and the Spanish Medicine Agency (AEMPS; EudraCT Trial Registration No.: 2004-000602-44); and the procedures followed were in accordance with their ethical standards and with the Helsinki Declaration of 1975, as revised in 2000. All patients provided written informed consent. Study data were recorded on specifically designed clinical research forms and all study data were verified against patient medical records.

Selection criteria. Inclusion criteria were a histologically and cytologically confirmed diagnosis of advanced breast carcinoma with at least one measurable lesion; age between 18 and 70 years; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; a life expectancy of at least three months; adequate bone marrow function: neutrophils ≥1.5×109/l, platelets ≥100×109/l and haemoglobin ≥10 g/dl; adequate renal and hepatic function: creatinine clearance >50 ml/min, total bilirubin ≤1.5 × upper normal limit (UNL), normal levels of aspartate, alanine aminotransferase and gamma glutamyl transpeptidase or <5 × UNL in the presence of liver metastasis, and normal levels of alkaline phosphatase or <5 × UNL in the presence of liver metastasis. Previous chemotherapy for advanced disease, including anthracyclines, but not VN or C, was allowed if at least one year had elapsed since its completion. Previous hormonal therapy was also allowed if it was discontinued at the time of entry to the study. The time interval between any previous surgery and radiotherapy and study entry was required to be at least two and four weeks, respectively.

Exclusion criteria included concomitant treatment with any other antineoplastic therapy, antiviral agents such as sorivudine and its analogues, or any other experimental agent; presence of concomitant diseases such as uncontrolled active infections, grade 2 peripheral neuropathy or higher, uncompensated diabetes, uncontrolled arterial hypertension, decompensated heart failure, peptic ulcer, lack of integrity of the digestive tract, active disease of the central nervous system, and cerebral or leptomeningeal metastasis. Patients were also ineligible if they had a history of malignancy (except basal cell carcinoma and/or cervix carcinoma in situ) and/or a history of intensification treatment followed by bone marrow or peripheral precursor cell support. Women of childbearing age were excluded if they were pregnant or lactating and if not on adequate contraception. Any psychological, social, family or geographical circumstance potentially limiting patient comprehension, or implementation and monitoring of treatment was also considered an exclusion criterion.

Treatment plan. Eligible patients received oral VN (Nabelbine Oral®; Pierre Fabre Médicament, Barcelona, Spain) as soft gelatine capsules on days 1 and 8 and oral C (Xeloda®; Roche, Basel, Switzerland) as tablets from days 1 to 14, with treatment cycles repeated every three weeks. The trial medications were administered for at least six cycles unless there was disease progression or unacceptable toxicity, or the patient declined further treatment. Four dose levels were established: I) VN 60 mg/m2 + C 1650 mg/m2/day; II) VN 70 mg/m2 + C 1650 mg/m2/day; III) VN 70 mg/m2 + C 2000 mg/m2/day; and IV) VN 80 mg/m2 + C 2000 mg/m2/day. No higher dose levels were included in the study because of the increased toxicity with higher dosages of VN and C seen in earlier trials. At least three patients needed to be treated at each dose level. If none of the first three patients treated at a particular dose level had a dose-limiting toxicity (DLT), the dose was escalated to the next level. If one of the three patients at a particular dose level had a DLT, three more patients were enrolled at that level. Intrapatient dose escalation was not permitted.

The study protocol allowed for treatment modification if patients developed certain haematological and/or non-haematological toxicities. VN was to be discontinued on day 8 if the number of neutrophils was <1.5×109/l and/or platelets was <75×109/l. C was to be discontinued if a patient developed any grade 2 toxicity that coincided with grade 4 neutropenia or febrile neutropenia. Study treatment was to be suspended until recovery in patients who developed grade 2 mucositis, hand-foot syndrome, diarrhoea, neurological toxicity, bilirubin >1.25 × UNL, serum glutamic oxaloacetic transaminase and/or serum glutamic pyruvic transaminase >2.5 × UNL. Study treatment was to be discontinued in the event of development of a second episode of febrile neutropenia already treated with granulocyte colony-stimulating factors, grade 3-4 neurological toxicity, grade 3 mucositis or hand-foot syndrome, grade 4 diarrhoea, or if the time elapsed between two treatment cycles was longer than five weeks.

The use of prophylactic antiemetic treatment (namely 5-HT3 antagonists) was mandatory. No prophylactic growth factors were allowed. However, growth factors could be used to treat febrile neutropenia, grade 4 neutropenia or neutropenic infection.

Evaluation of safety and response. Baseline evaluation was performed up to four weeks before study entry, and consisted of a medical history and physical examination, assessment of ECOG performance status, measurement of metastases, electrocardiography, chest radiography, computed tomography imaging of thorax and abdomen, bone scintigraphy, pregnancy testing in premenopausal patients, and other examinations as clinically indicated. Biochemical and haematological analyses were performed at baseline, before each VN administration, and upon completion of each treatment cycle.

All patients were evaluated for toxicity during each treatment cycle and on completion of the treatment schedules. Toxicities were recorded and graded according to the Common Toxicity Criteria of the National Cancer Institute (Version 2). Clinical response was assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST) (27) at the end of each three-weekly treatment cycle and upon study completion.

Statistical analysis. The primary aim of this study was to determine the recommended doses for the combination of oral VN and C in MBC. Secondary objectives included evaluation of response rate and safety profile of this oral combination and to identify whether or not VN dosage escalation may be required.

Safety analysis included all patients who received at least one dose of VN or C (safety population). Efficacy analyses were carried out on the intent-to-treat population (efficacy population). Additionally, overall response rate (ORR) was also calculated according to protocol criteria. The maximum tolerated dose (MTD) was defined as that causing DLT in more than 50% of the patients treated (i.e. more than three in a six-patient cohort) during the first two cycles or two weeks after the last dose was given (25). DLT was defined as grade 4 neutropenia lasting ≥7 days; grade 3 thrombocytopenia; grade 3-4 infection concomitant with grade ≥3 neutropenia; febrile neutropenia; or any grade ≥3 non-haematological toxicity, excluding weakness, diarrhoea, nausea and vomiting inadequately treated. The recommended dose (RD) for phase II trials was defined as the dose below the MTD. If none of the first three patients treated at a particular dose level had a DLT, the dose was escalated to the next level. If one of the three patients at a particular dose level had a DLT, three more patients were enrolled at that level. Of note is that six patients were to be tested at the RD for the phase II trial.

View this table:
Table I.

Patient characteristics at baseline (n=18).

Results

Patient characteristics. Clinical characteristics of the 18 patients participating in this trial are summarized in Table I. The median patient age was 61 years. Sixty-one percent of patients had early-stage disease at diagnosis. The majority of patients had received previous treatment for their disease, including chemotherapy (94%), surgery (88%) or hormonal therapy (88%). All patients had an acceptable ECOG performance status.

Treatment administration. A total of 91 treatment cycles were administered, of which 13% were at dose level I, 20% at dose level II, 32% at dose level III and 35% at dose level IV. VN dosing was delayed and/or reduced on day 1 in 24 cycles (26%) mainly because of haematological (15, 63%) and non-haematological (6, 25%) toxicities. VN dosage was delayed and/or reduced on day 8 in six cycles (7%) because of both haematological (3, 50%), non-haematological (2, 33%) toxicities and patient's convenience (1, 17%). C administration was modified in 28 cycles (31%) because of haematological toxicities (13, 46%), non-haematological toxicities (10, 36%) and for reasons not related to the trial medications (5, 18%). Thirteen patients completed treatment according to the study protocol and five discontinued because of disease progression (n=3) and adverse events (n=2).

View this table:
Table II.

Overall response on an intention-to-treat basis (n=18).

At dose level III, the median absolute and relative dose intensities were 39.1 mg/m2/week (84%) and 7893 mg/m2/week (85%) for VN and C, respectively. However, at dose level IV, the median absolute and relative dose intensities were 49.9 mg/m2/week (89%) and 8292 mg/m2/week (94%) for VN and C, respectively.

Efficacy. Table II shows the ORR on an intention-to-treat basis. One patient at dose level II showed a complete response (CR) and five patients at dose levels III and IV showed a partial response (PR) for an ORR of 33% (95% confidence interval: 13-59). Stable disease was achieved in eight patients (44%) and disease progression occurred in three patients (17%). Clinical response could not be evaluated in one patient (6%).

Safety. Severe haematological and non-haematological toxicities per patient and per cycle are shown in Table III. The most common severe haematological toxicity was neutropenia (occurring in 5/18 patients and 13% of cycles). Leucopenia, anaemia and febrile neutropenia were observed in one patient and one cycle (1%) each. With regard to severe non-haematological toxicities, pain was observed in two patients, one cycle each (2%). Other severe non-haematological toxicities observed were asthenia, constipation, hand-foot syndrome, diarrhoea and phlebitis. Two patients were withdrawn from the study because of toxicity. One patient being treated with dose level III was withdrawn because of grade 2 hyperbilirubinaemia. Another patient developed a severe intestinal occlusion at dose level IV.

Table IV shows the incidence of severe toxicity per patient and per dose level during treatment. At dose level I, three patients were included and one suffered grade 3 pain. Another three patients received VN and C at dose level II, one of whom developed grade 3 neutropenia. At dose level III, six patients were included and only grade 3 toxicities were observed. No grade 4 toxicities were observed at this dose level. Six patients received the treatment schedule at dose level IV, in whom toxicities were grade 3/4. The only grade 4 toxicity observed at this dose level was grade 4 constipation and grade 4 neutropenia in one patient each. No DLTs were observed during the first two cycles or two weeks after the last administration of trial medication at any dose level.

View this table:
Table III.

Grade 3/4 treatment-related toxicity (n=18).

View this table:
Table IV.

Grade 3/4 treatment-related toxicity per dose level (n=18).

Discussion

This dose-escalating study assessed four dose levels of oral VN (on days 1 and 8) and C (on days 1 to 14) every three weeks in MBC patients. The dose levels tested were I) VN 60 mg/m2 + C 1650 mg/m2/day; II) VN 70 mg/m2 + C 1650 mg/m2/day; III) VN 70 mg/m2 + C 2000 mg/m2/day; and IV) VN 80 mg/m2 + C 2000 mg/m2/day. The dose levels were chosen according to previous phase I and II studies of VN and C (20-25) and on the basis of the established bioequivalence between the i.v. and oral formulations of VN (28). Dose level IV (VN 80 mg/m2 + C 2000 mg/m2/day) was selected for subsequent phase II investigation.

Our results showed that the combination of oral VN and C was generally well tolerated. Neutropenia was the most frequent severe toxicity, observed in 5/18 patients and 13% of cycles. Other severe toxicities were rarely observed. Furthermore, no DLTs were observed at any dose level during administration of the first two treatment cycles or at two weeks after the last administration as defined in the study protocol. With regard to treatment administration, the median relative dose intensity was 84% and 85% for VN and C at dose level III, respectively. At dose level IV, the median relative dose intensity administered was 89% and 94% for VN and C, respectively.

One of the first published reports of oral VN was a dose-finding phase I trial in which doses of 60, 80 and 100 mg/m2/week were tested as single-agent treatment in patients with MBC (11). The authors concluded that the safety profile of oral VN appeared to be comparable with that found when this agent is administered by the i.v. route. The MTD was identified as 100 mg/m2/week because of dose-limiting neutropenia, nausea, vomiting and constipation in five out of six patients. Therefore, 80 mg/m2/week of oral VN as a single agent was established as the RD for subsequent phase II trials in MBC. Toxicities at this dose level were manageable, with grade 3-4 neutropenia being the most significant, so regular monitoring of neutrophil counts was advised.

Oral VN has also been tested in combination with C in patients with MBC in several previous studies. One of the first and largest phase I studies evaluated oral VN at a dose of 60 or 80 mg/m2 on days 1, 8 and 15, with escalating doses of C from 1650 to 2500 mg /m2/day from days 1 to 14 every three or four weeks in 44 patients (25). When oral VN was administered at 80 mg/m2 on days 1 and 8 every three weeks, the MTD was reached at the first dose level of C (i.e. 1650 mg/m2/day) as a result of four out of five patients experiencing a DLT. Thereafter, further dose levels of C were tested every four weeks, escalating from 1650 mg/m2/day to 2000 mg/m2/day. None of the patients treated with these C doses in combination with VN at 80 mg/m2 every four weeks experienced any DLT, except for one patient who developed transient febrile neutropenia.

In another phase I study, 21 patients with MBC received C at a fixed dose of 2000 mg/m2/day on days 2 to 7 and days 9 to 14 and escalating doses of oral VN in 10 mg/m2 increments from 40 to 80 mg/m2 on days 1 and 8 every three weeks (24). The MTD could not be defined because no DLTs were observed in any cohort of patients. Although intrapatient dose escalation was permitted, VN dose escalation >60 mg/m2 was rarely achieved. For this reason, the RDs for subsequent studies of the oral combination defined by the authors was C 2000 mg/m2/day and VN at 60 mg/m2 every three weeks.

Another phase I study, for which only preliminary results are thus far available, tested different doses of C (from 1600 to 2500 mg/m2/day on days 1 to 14) and oral VN (from 40 to 80 mg/m2 on days 1 and 8) (29). The investigators concluded that the combination of both agents was safe and feasible and that the RDs for future studies should be 1250 mg/m2/day of C and 60 mg/m2 of VN every three weeks. However, it was not explained why the highest level doses (1250 mg/m2/day of C and 80 mg/m2 of oral VN) were ruled out.

With regard to the efficacy profile of this oral combination, our data seem to be in the range of the results previously reported. In the present study, one patient achieved a CR and four patients (two at dose level III and two at dose level IV) showed a PR. The ORR was 28% for the intention-to-treat population (and 45% for the evaluable population), and the clinical benefit rate was 45% on the intention-to-treat population (and 73% on evaluable population). These response rates seem similar than those of Nole et al. (25) and Delcambre et al. (29) who reported ORRs of 41% and 51% on evaluable populations, respectively, and much better than those reported by Kellokumpu-Lehtinen et al. (24) with an ORR on evaluable patients of 11% and a clinical benefit rate of 37%. The differences observed between these studies may be attributable to the characteristics of the different patient populations studied. In the studies performed by Nole et al. (25) and Delcambre et al. (29), the trial combination was administered as first-line therapy in most cases (80% and 66%, respectively), whereas in the study by Kellokumpu-Lehtinen et al. (24), 57% of patients had received one prior chemotherapy schedule for MBC and 43% of patients had received two or more prior chemotherapies. It should be borne in mind that phase I studies are not appropriate for assessing the efficacy profile of a chemotherapeutic combination because of the very specific research conditions under which they are undertaken.

A recent phase II study, in which oral VN was administered at 80 mg/m2 on days 1 and 8 (60 mg/m2 in the first cycle) and C was administered at 2000 mg/m2/day on days 1 to 14, also showed good results regarding efficacy and tolerability, with an ORR of 52% and a clinical benefit of 63%, both for evaluable patients only (30). Similar results were observed with oral VN (60 mg/m2 on days 1, 8 and 15) and C (2000 mg/m2/day on days 1 to 14) with an ORR of 55% in evaluable patients (31).

In conclusion, an oral combination of VN and C seems to be a good alternative to i.v. VN and C in patients with MBC because it can be administered safely and appears to be active against this disease. In view of its tolerability profile and the dose intensities administered for both agents, we have defined an RD for subsequent phase II oral studies of VN 80 mg/m2 on days 1 and 8 and C 2000 mg/m2/day from days 1 to 14 in three-weekly cycles. Additionally, oral VN dose escalation does not seem to be required. Based on these results, a multicentre phase II trial of this promising oral combination in patients with MBC is now underway.

Acknowledgements

The Authors thank Francisco Javier Pérez (Barcelona, Spain) for carrying out the statistical analysis of the study, HealthCo (Madrid, Spain) for providing medical writing services, and Pierre Fabre Ibérica for the financial funding of the project.

Footnotes

  • Competing Interests

    This study has received financial support from Pierre Fabre Ibérica. All the investigators had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses.

  • Received October 6, 2009.
  • Revision received April 14, 2010.
  • Accepted April 20, 2010.

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Phase I Study of Oral Vinorelbine and Capecitabine in Patients with Metastatic Breast Cancer
ANTONIO ANTON, ANA LLUCH, ANTONIO CASADO, MARIANO PROVENCIO, MONTSERRAT MUÑOZ, JUAN LAO, BEGOÑA BERMEJO, ANA B. PAULES, JAVIER GAYO, MIGUEL MARTIN
Anticancer Research Jun 2010, 30 (6) 2255-2261;
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