1 Centre René Gauducheau, Nantes-Saint-Herblain; 2 Institut Gustave Roussy, Villejuif; 3 Institut de Recherche Pierre Fabre, Boulogne-Billancourt, France
Received 28 October 2002; revised 18 November 2002; accepted 3 December 2002
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Abstract |
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Vinflunine is a novel vinca alkaloid obtained by semi-synthesis using super-acidic chemistry to selectively introduce two fluorine atoms at the 20' position of vinorelbine. In human tumour xenografts, vinflunine showed definite antitumour activity in seven out of 11 tumours tested compared with three out of 11 for vinorelbine.
Patients and methods:
In this phase I study, vinflunine was administered to 31 patients with advanced malignancies as a 10-min i.v. infusion every 3 weeks according to an escalating schedule of doses between 30 and 400 mg/m2.
Results:
Pharmacokinetic parameters and toxicities were assessed and, at 400 mg/m2, three out of five patients experienced dose-limiting toxicity. At the maximum tolerated dose (MTD), i.e. 400 mg/m2, the toxicity profile of vinflunine consisted mainly of mucositis, constipation and neutropenia of short duration. Vinflunine area under the curve increased as a proportion of the administered dose whereas no saturation of elimination was observed.
Conclusion:
The MTD of vinflunine was achieved at 400 mg/m2 every 3 weeks. According to protocol rules, the recommended dose was established at 350 mg/m2. A preliminary assessment of first patients included in early phase II trials led to reduction of the recommended dose to 320 mg/m2 every 3 weeks for further development of vinflunine. Three partial responses (two in breast carcinoma, one in renal cell carcinoma) suggest that activity is likely to be seen in less heavily pretreated patient populations.
Key words: dose-proportionality, pharmacokinetics, phase I study, safety, vinflunine
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Introduction |
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Evidence from the preclinical studies was encouraging enough to warrant a phase I study in patients with refractory solid tumours; the primary objective of the study was to establish the maximum tolerated dose (MTD) of vinflunine administered as a 10-min i.v. infusion every 3 weeks. Secondary objectives were to determine the qualitative and quantitative toxicities of vinflunine, describe the pharmacokinetic characteristics and assess preliminary evidence of antitumour activity.
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Patients and methods |
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Treatment plan
Vinflunine was supplied by Institut de Recherche Pierre Fabre (Boulogne-Billancourt, France) at a concentration of 30 mg/ml solution in water for injection in sterile neutral glass vials of 3 ml. For administration, the appropriate dose of vinflunine was diluted in normal saline 50 ml and infused over 10 min via a central venous line.
The starting dose of 30 mg/m2 was based on preclinical toxicity models representing one-sixth of the LD10 for mice and one-sixth of the MTD for dogs and monkeys. It was planned to enroll a single patient at 30 and 60 mg/m2 in order to minimise the number of patients treated at non-therapeutic levels, then treat a maximum of three evaluable patients at subsequent doses. At each level a dose adaptation calculated on the basis of the haematological toxicity was used to determine progress to the next level or escalation within the level being evaluated. Leucopenia and neutropenia are frequently the major dose-limiting toxicities (DLTs) for vinca alkaloids, and particularly for vinorelbine. During phase I trials with i.v. vinorelbine, a dose-proportional increase of blood exposure (area under the curve, AUC) was demonstrated in the range 2040 mg/m2 [10] as well as a significant pharmacokinetic/pharmacodynamic (PK/PD) relationship between blood cell count (per cent decrease at nadir) and AUC [11]. These results suggested that doses inducing a 50% decrease in WBCs were well tolerated and that DLTs were generally observed when the decrease was close to 80%. Pharmacokinetic modelling of preclinical data through a scaling-up approach, combined with a wide experience on the vinorelbine PK/PD relationship, allowed us to predict that the MTD should be reached at a dose level >300 mg/m2. Therefore, an accelerated dose escalation was designed for the initial levels, followed by a more conventional Fibonnacis scheme for further levels when WBC count decreased by 50%. Therefore, if the required number of evaluable patients did not experience haematological toxicity (WBC count
50% of baseline value, neutrophil nadir
1.5 x 109/l), the next dose level was twice the previous level; if haematological toxicity was seen by these criteria, the dose had to be only increased by one-third, then one-quarter for three steps (Figure 3). Dose escalations using these rules were to be continued until at least one out of three patients experienced during cycle 1 DLT defined as: (i) haematological toxicity consisting of nadir neutrophils <0.5 x 109/l for at least 7 days or <0.1 x 109/l for at least 3 days, thrombocytopenia <25 x 109/l or thrombocytopenia with bleeding or requiring platelet transfusion; (ii) febrile neutropenia defined as absolute neutrophil count <0.5 x 109/l and fever (three measured temperatures >38°C in 24 h or one >38.5°C); and/or (iii) any grade 3/4 major organ toxicity except alopecia or unpremedicated nausea/vomiting. If only one out of three patients experienced a DLT, a further three patients were entered at the same dose level; if, however, no further DLT was experienced by the additional patients dose escalation was continued. Conversely, if two out of the first three patients or three out of the six patients experienced DLT an additional three patients were treated on the preceding lower dose. The MTD was defined as the dose at which either two out of three or three out of six patients experienced DLT after the first administration of vinflunine.
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If the above changes had not resolved by 2 weeks after the scheduled date of the next treatment, therapy was stopped. On an individual patient basis, dose reduction (dose level n to dose level n 1) was applied in case of occurrence during the previous cycle of neutropenia <0.5 x 109/l, lasting at least 7 days, or <0.1 x 109/l, lasting at least 3 days, and/or major organ toxicity or grade 3 (except for nausea and vomiting despite adequate premedication).
Pretreatment and follow-up examinations
At entry to the study, patients were evaluated with a complete medical history and physical examination including measurement of vital signs (temperature, pulse rate and blood pressure), electrocardiogram (ECG), complete blood count (CBC), serum electrolytes, hepatic and renal function, chest X-ray and CT or magnetic resonance imaging (MRI) scans to define the extent of tumour involvement. During the treatment period patients were monitored with CBC and biochemical tests twice weekly for the first two cycles then subsequently on day 1 of each planned cycle. ECGs were scheduled at 30 min, 3 and 6 h after the end of the vinflunine infusion on cycle 1 and before each subsequent infusion. Toxicity assessments using the NCI-CTC scale [8] were made at baseline to record residual toxicity from previous therapy and before each cycle. Tumour response was assessed according to the WHO criteria [12, 13].
Pharmacokinetics
Blood and urine samples were collected following vinflunine administration on the first cycle of treatment. During the first cycle, blood samples were collected over a 96-h period. Elimination in urine was followed over a 48-h period. This shorter period of collection was considered as a compromise between getting enough scientific data and assuring complete and accurate urine collection without inconveniencing patients over a protracted period. Vinflunine blood and urinary concentrations were quantified by a fully validated high-performance liquid chromatography method. Vinflunine was extracted from the biological fluid by diethyl ether in alkaline conditions followed by a back-extraction in acidic conditions. Vinflunine was separated from other compounds on a reverse phase column and quantified by ultraviolet detection. The limits of quantification were 2 ng/ml and 20 ng/ml in blood and urine, respectively. Precision and accuracy of the method were >93% and 98%, respectively.
The pharmacokinetic analysis was carried out by a conventional model-independent approach. The main pharmacokinetic parameters [area under the curve extrapolated to infinity (AUC), terminal half-life (T Z), terminal volume of distribution (Vd)and total body clearance (Cltot)] were calculated.
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Results |
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A total of 96 cycles were delivered with a median of two per patient (range 18); six patients received six cycles of therapy (Table 2). All patients were evaluable for toxicity, and 25 were evaluable for response with the following exclusions: four patients received only one dose of vinflunine (one patient because of PS deterioration, one patient died of septic shock and two patients withdrew as a result of toxicity); one patient died due to disease progression after the second dose of vinflunine and one patient was still on treatment at the study cut-off date but too early for tumour response assessment.
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No patient experienced DLT by haematological criteria alone (as defined by neutropenia <0.5 x 109/l for 7 days or <0.1 x 109/l for 3 days).
Pharmacokinetics
Mean blood pharmacokinetic profiles are illustrated in Figure 4 for the 30400 mg/m2 dose range explored. Blood concentrations increased up to the end of vinflunine infusion and then a tri-exponential decay was observed with a sharp decrease during the first phase. Concentrations are easily quantified at the last sampling time (96 h) for the highest dose levels. Volume of distribution is large (1517 ± 503 l), indicating an important degree of tissue distribution. Total clearance is substantial (41.4 ± 12.9 l/h). The resulting mean half-life value was assessed at 25.5 ± 3.9 h based on a 96-h sampling period. A dose-proportional increase of blood exposure concentration was demonstrated on both AUC and Cmax. The interindividual variability is moderate, ranging from 10% to 40%.
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Efficacy
Twenty-five out of the 31 patients were assessable for response, with three patients achieving a partial response. Two women with breast carcinoma previously treated with one adjuvant and two lines of chemotherapy for metastatic disease showed evidence of objective response (one in liver metastases and the other in lymph nodes). One patient had previously received adjuvant chemotherapy with a combination of 5-fluorouracil (5-FU), cyclophosphamide and epirubicin plus docetaxel, followed by capecitabine for metastatic disease. Partial response was confirmed after the study cut-off date. Progression was observed after the ninth cycle. The second patient had previously received adjuvant chemotherapy with a combination of 5-FU, cyclosphosphamide and epirubicin, and second lines of chemotherapy, including docetaxel, 5-FU and vinorelbine for metastatic disease. At study withdrawal and after six cycles of vinflunine, the partial response was confirmed. A chemonaive patient with metastatic renal carcinoma showed an objective response in lung metastases. Partial response on evaluable lung metastases was seen after two cycles and progression was identified after the fifth cycle. The breast cancer patients were treated at 400 and 350 mg/m2 and the renal carcinoma patient received vinflunine 350 mg/m2. Four patients had stable disease and 18 patients had disease progression after two cycles.
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Discussion |
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In this phase I study, the schedule of vinflunine evaluated consisted of 10-min i.v. infusions every 3 weeks. The experimental findings suggest that the DLT of this mode of administration are febrile neutropenia, constipation and mucosal toxicity. The PK/PD relationship demonstrated a high correlation between body exposure to vinflunine and maximum neutrophil count decrease from baseline. Given that AUC increases with the administered dose, occurrence of severe neutropenia was more frequent at doses ranging from 320 to 400 mg/m2, corresponding to the highest body exposures. Grade 4 neutropenia occurred in 11 cycles (11%) and was observed at doses from 320 to 400 mg/m2. However, the duration of neutrophil suppression was relatively brief, not exceeding 5 days, even at the highest dose level. Neutropenia was only responsible for treatment delay (of at least 4 days beyond the date the next dose was due) in three patients, and resulted in dose reduction in one patient. One infection complicating a period of neutropenia after a dose of 350 mg/m2 resulted in death due to septic shock. This was the only drug-related death to occur in the study. Stomatitis or oesophagitis were recorded as the DLT in two patients treated at 320 mg/m2 and abdominal pain or constipation, presumed to be related to autonomic neuropathy, was recorded as the DLT in three patients (one treated at 320 mg/m2 and two treated at 400 mg/m2).
In one patient, grade 3 cardiac failure was diagnosed within 90 min of completing the infusion of vinflunine at 400 mg/m2; this patient (locally advanced non-small-cell lung cancer previously irradiated on the mediastinum) was withdrawn from the study and recovered without clinical consequences. The absence in preclinical data of cardiac toxicity events did not lead to a requirement for intensive clinical cardiac patient monitoring. All the ECGs recorded during the study were reviewed centrally, and no abnormality was seen, except for this particular patient.
A second patient developed grade 3 dyspnoea with moderate hypertension 5 days after the first injection of vinflunine 350 mg/m2 and recovered; a further injection of vinflunine was administered without any side-effect. The role of vinflunine in these manifestations is unclear but it does not appear to result in cumulative or irreversible toxicity.
None of the patients treated at the lower dose levels of vinflunine in this study experienced DLT of any sort (30250 mg/m2); at the higher dose levels two out of six patients treated at 320 mg/m2 (one stomatitis, one stomatitis/oesophagitis and constipation) and three out of five patients treated at 400 mg/m2 (one abdominal pain, one constipation, one heart failure) experienced DLT. The final dose level explored was lower than the MTD of 400 mg/m2, but higher than the previously tested dose of 320 mg/m2. Two out of six patients treated at 350 mg/m2 experienced DLT (one dyspnoea/hypertension and one fatal neutropenic fever/septic shock). According to protocol rules and definitions the recommended dose was established at 350 mg/m2. Nevertheless, data from early phase II trials have shown that due to toxicity the vinflunine single-agent suitable dose is 320 mg/m2 once every 3 weeks.
In this phase I study, which was conducted in patients with refractory malignancies, no accurate estimate of antitumour efficacy can be made. However, the achievement of objective responses in three out of 31 patients is sufficiently promising to warrant exploration of this schedule in phase II trials [14, 15].
The results of this study indicate that vinflunine is a generally well tolerated agent, with neutropenia, mucositis and constipation as its major DLT; cardiac effects are less well-defined and will need careful follow-up in subsequent trials, even though their relationship to the administration of vinflunine is currently unclear. Furthermore, due to the study design (i.e. determination of MTD after one administration), and the limited experience with long-term treatment, this will also require subsequent clinical data.
Vinflunine pharmacokinetics was linear in the investigated dose range (30400 mg/m2). Vinflunine given as a 10-min i.v. infusion every 3 weeks is suitable for wider evaluation in phase II trials at a recommended dose of 350 mg/m2 and is likely to be associated with clinical activity in less heavily pretreated populations [16].
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Acknowledgements |
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Footnotes |
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References |
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