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Phase I Study of Oral Vinorelbine and Capecitabine in Patients with Metastatic Breast Cancer
ANTONIO ANTON1, ANA LLUCH2, ANTONIO CASADO3, MARIANO PROVENCIO4, MONTSERRAT MUOZ5, JUAN LAO1, BEGOA BERMEJO2, ANA B. PAULES6, JAVIER GAYO6 and MIGUEL MARTIN3
Hospital Miguel Servet, Zaragoza, Spain; University Hospital, Valencia, Spain; 3Clinical University Hospital San Carlos, Center affiliated with the Red Temtica de Investigacin Cooperativa (RD06/0020/0021), Carlos III Health Institute (ISCIII), Spanish Ministry of Science and Innovation, Madrid, Spain; 4University Hospital Puerta de Hierro, Madrid, Spain; 5University Hospital Clinic i Provincial, Barcelona, Spain; 6Pierre Fabre Ibrica, Barcelona, Spain
2Clinical
1University
Correspondence to: Dr. Antonio Anton, MD, Medical Oncology Service, University Hospital Miguel Servet, Avda. Isabel La Catlica 1-3, 50009 Zaragoza, Spain. Tel: +34 976765644, Fax: +34 976359268, e-mail: aantont@salud.aragon.es Key Words: Vinorelbine, capecitabine, metastatic breast cancer, oral chemotherapy.
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/taxanebased 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 5fluorouracil (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
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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 <1.5109/l and/or platelets was <75109/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 handfoot 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 nonhaematological 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
Table I. Patient characteristics at baseline (n=18). Characteristic Median age, years (range) 61 (44-80) Gender Female Male ECOG performance status 0 1 Disease stage at diagnosis I/II III/IV Hormonal receptor status OR+ (n=17) PR+ (n=16) Previous treatment (n=16) Surgery Hormonal therapy Chemotherapy Adjuvant only Advanced disease only Adjuvant + advanced disease No. of patients
17 1 13 5 11 7 14 9 14 14 15 10 4 1
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.
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 patients 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
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Haematological Anaemia Febrile neutropenia Leucopenia Neutropenia Non-haematological Asthenia Constipation Hand-foot syndrome Diarrhoea Pain Phlebitis
1 1 1 5 1 1 1 1 2 1
1 1 1 12 1 1 1 1 2 2
according to the study protocol and five discontinued because of disease progression (n=3) and adverse events (n=2). 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 nonhaematological 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
Table IV. Grade 3/4 treatment-related toxicity per dose level (n=18). I (n=3) n Pain Neutropenia Anaemia Phlebitis Diarrhoea Asthenia Hand-foot syndrome Febrile neutropenia Constipation Leucopenia 1 1 2 1 1 1 II (n=3) n III (n=6) n IV (n=6) n 1 2
1 1 1 1 1
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.
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
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(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 dosefinding 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 KellokumpuLehtinen 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
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Acknowledgements
The Authors thank Francisco Javier Prez (Barcelona, Spain) for carrying out the statistical analysis of the study, HealthCo (Madrid, Spain) for providing medical writing services, and Pierre Fabre Ibrica for the financial funding of the project.
Competing Interests
This study has received financial support from Pierre Fabre Ibrica. 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.
References
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Received October 6, 2009 Revised April 14, 2010 Accepted April 20, 2010
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