Phase I and pharmacokinetic study of IV vinflunine in cancer patients with liver dysfunction.

Vinflunine is a novel tubulin-targeted agent that is currently indicated as a monotherapy in bladder cancer patients. The recommended dose of 320 mg/m(2) is given as an intravenous infusion once every 3 weeks. Vinflunine is metabolized through CYP3A4 and mainly eliminated via the feces. A phase I trial was designed to explore the tolerability and pharmacokinetics of vinflunine in cancer patients with ranging degrees of liver dysfunction (LD). A sequential design was used for patient accrual, with the objective of determining the maximum tolerated dose (MTD) and the recommended dose (RD) of vinflunine in 3 groups of increasing LD levels. Vinflunine and its only active metabolite 4-O-deacetylvinflunine were quantified in serial whole blood samples. PK parameters were derived and compared between LD groups and with a reference PK database. Vinflunine and 4-O-deacetylvinflunine PK parameters were not affected in any of the explored LD levels. Geometric mean values for vinflunine total clearance were 47.8, 37.5 and 45.4 L/h in the 3 groups of increasing degrees of LD, as compared to 42.5 L/h in reference patients with no LD. No relationship was found between vinflunine clearance and the presence or absence of cirrhosis, nor was it found with the presence or absence of liver metastasis or with liver-related biochemical parameters. Based on the observed tolerability profile, the recommended doses of i.v. vinflunine are 320 mg/m(2), 250 mg/m(2) or 200 mg/m(2) for patients with increasing degrees of liver dysfunction.

A phase 1 study of vinflunine in combination with trastuzumab for the treatment for HER2-positive metastatic breast cancer.

OBJECTIVE: To determine the recommended dose (RD) of vinflunine in combination with trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and to investigate potential pharmacokinetic (PK) interactions. PATIENTS AND METHODS: In the first part of the study, two dose levels of vinflunine given every 3 weeks were explored (280 and 320 mg/m(2)) combined with trastuzumab (4 mg/kg loading dose and 2 mg/kg weekly). For each level of dose, six patients were enrolled to determine the RD for phase 2 studies (RP2S). In the second part of the study, 18 additional patients at RP2S have been evaluated to confirm safety and investigate preliminary antitumor activity. RESULTS: The RD was 320 mg/m(2) according to the dose escalation plan. Eleven of 15 additional patients who received this dose experienced dose-limiting toxicities, leading to a reduction in the RD to 280 mg/m(2). When compared to prior trials when vinflunine was used as a single agent, neither vinflunine total blood clearance nor trastuzumab serum concentrations were modified when the drugs were combined. All patients were evaluable, and the overall response rate was 73.3 % (95 % CI 54.1-87.7). The median progression-free survival was 11.3 months (95 % CI 9.4-21.0). At the dose of 280 mg/m(2), grade 3-4 neutropenia were seen in 4 patients (44.4 %) without febrile neutropenia. Non-hematologic grade 4 toxicities were not reported while grade 3 peripheral sensory neuropathy concerned 2 patients (22.2 %). CONCLUSION: The RD of vinflunine in combination with the standard regimen of trastuzumab is 280 mg/m(2) every 3 weeks. No mutual PK drug-drug interaction was seen. This regimen appears to be active with a favorable safety profile. Its role in HER2-positive MBC treatment needs to be defined in prospective comparative clinical trials.

Phase II study of IV vinflunine in patients with chemotherapy naive metastatic malignant melanoma.

This phase II study evaluated vinflunine in chemotherapy naive patients with metastatic melanoma. Vinflunine was administered at 350 mg/m(2) every 3 weeks, but after 9 patients this was reduced to 320 mg/m(2) based on interim analyses of all phase II trials. A partial response was observed in 1 of the first 9 patients (11.1%) treated at 350 mg/m(2), which gives a 3.0% [95% confidence interval (CI): 0.08-15.8] response rate in 33 patients. No change was the best response in 13 patients (39.4%) with progressive disease in 16 (48.5%) and 3 were not evaluable for response. The time to response was 1.4 months and duration was 6 months. At 350 mg/m(2) grade 4 neutropaenia occurred in 3 patients (33.3%) and grade 3 in 2 patients (22.2%) while at 320 mg/m(2) grade 4 neutropaenia occurred in 6 patients (25%) and grade 3 in 3 patients (12.5%) with 2 episodes of grade 3 febrile neutropaenia. Two patients (8.3%) had grade 3 anaemia. These results do not show activity at this dose and schedule for vinflunine in patients with chemotherapy naive metastatic melanoma.

Vinflunine -- an active chemotherapy for treatment of advanced non-small-cell lung cancer previously treated with a platinum-based regimen: results of a phase II study.

A multicentre, single-arm, phase II trial designed to determine the efficacy of single-agent vinflunine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with a platinum-based regimen. The objectives were to assess efficacy in terms of tumour response rate (primary end point), duration of response, progression-free survival (PFS) and overall survival (OS), and to evaluate the toxicity associated with this treatment. Patients with advanced NSCLC with progressive disease having failed prior platinum-based first-line treatment for advanced disease. Five responses out of the 63 treated patients were documented by WHO criteria and validated by an independent panel review (IRP), yielding a response rate of 7.9% (95% CI: 2.6-17.6) in the intent-to-treat analysis and 8.3% (95% CI: 2.8-18.4) in the evaluable population. Disease control was achieved in 35 out of 60 evaluable patients (58.3%). The median duration of response (complete response+partial response), according to modified WHO criteria was 7.8 months (95% CI: 4.6-NR). Median PFS was 2.6 months (95% CI: 1.4-3.8), and the median survival was 7.0 months (95% CI: 5.8-9.2). Grades 3-4 neutropenia was reported in 50% of patients; febrile neutropenia was observed in two patients (3.2%); grades 3-4 myalgia and grade 3 constipation were experienced by 10 (15.9%) and six (9.5%) of patients, respectively. Constipation was manageable, non-cumulative and could be prevented with laxative prophylaxis. The encouraging results from this phase II study with vinflunine warrant further investigations in phase III trials as second- or first-line treatment of advanced non-small-cell lung carcinoma, as a single agent or in combination with other active drugs.

Phase II study of vinflunine in patients with metastatic renal cell carcinoma.

PURPOSE: An open-label, multicentre, non-comparative phase II trial to determine the response rate of intravenous vinflunine as first line chemotherapy in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with metastatic RCC were treated with vinflunine 350 mg/m2 (n = 11) or 320 mg/m2 (n = 22) administered intravenously every 21 days. RESULTS: Out of 33 patients included in this study, one partial response was observed in the group treated at 350 mg/m2 and none in the group receiving 320 mg/m2 resulting in a response rate in this population of 9.1% (95% CI: 0.2-41.3). Median progression free survival was 5.6 months (95% CI: 2.8-14.4) for patients treated at 350 mg/m2, and 3.3 months (95% CI: 1.6-6.4) for those treated at 320 mg/m2.The median survival time was 10.4 months (95% CI: 6.8-12.4) for the whole study population. The principal toxicities were grade 3/4 neutropaenia -90.9% at 350 mg/m2 and 68.1% at 320 mg/m2, febrile neutropaenia was recorded in 3 patients (27.3%) at 350 mg/m2 and in 5 patients (22.7%) at 320 mg/m2. One episode of thromboembolic event was reported in 1 patient at each dose level. CONCLUSION: Vinflunine given intravenously once every 3 weeks has not shown any clinically relevant activity in the management of patients with metastatic renal cell carcinoma; tolerance of the treatment was better at a dose of 320 mg/m2 than at 350 mg/m2.

Oxaliplatin or paclitaxel in patients with platinum-pretreated advanced ovarian cancer: A randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group.

PURPOSE: This was a multicentric, open, randomized, phase II study of single-agent paclitaxel and oxaliplatin to evaluate the efficacy of oxaliplatin in a relapsing progressive ovarian cancer patient population and to analyze the safety profile and impact of both agents on quality of life, time to progression, and survival. PATIENTS AND METHODS: Eighty-six patients with platinum-pretreated advanced ovarian cancer were randomly assigned to two arms: 41 received paclitaxel at 175 mg/m(2) over 3 hours every 3 weeks, and 45 received oxaliplatin at 130 mg/m(2) over 2 hours every 3 weeks. For inclusion, patients had to have a performance status of 0 to 2 and to have received at least one and no more than two prior cisplatin- and/or carboplatin-containing chemotherapy regimens within the last 12 months. RESULTS: Seven confirmed responses were observed in each arm, for an overall response rate in the total treated population of 17% (95% confidence interval [CI], 7% to 32%) in the paclitaxel arm and 16% (95% CI, 7% to 29%) in the oxaliplatin arm. Median time to progression was 14 weeks and 12 weeks, and overall survival was 37 weeks and 42 weeks in the paclitaxel and oxaliplatin arms, respectively. Among 63 patients with a 0- to 6-month progression-free, platinum-free interval, there were five objective responses with paclitaxel in 31 patients and two objective responses with oxaliplatin in 32 patients. Nine patients (22%) in the paclitaxel arm had grade 3 or 4 neutropenia (National Cancer Institute of Canada [NCIC] Common Toxicity Criteria). Two patients (4%) experienced grade 3 thrombocytopenia in the oxaliplatin arm. Maximum grade (grade 3) NCIC neurosensory toxicity was experienced by three patients (7%) in the paclitaxel arm and by four patients (9%) in the oxaliplatin arm. CONCLUSION: Single-agent oxaliplatin at 130 mg/m(2) every 3 weeks is active with moderate toxicity in patients with cisplatin-/carboplatin-pretreated advanced ovarian cancer.

Pathological classification and grading of primary ovarian carcinoma: experience of the ARTAC ovarian study group.

One hundred and fifty-seven cases of high stage ovarian carcinomas (FIGO stage III and IV) have been selected for therapeutic protocol under the aegis of ARTAC. One hundred and forty-six cases have been reviewed, of which 15 were peritoneal tumors: eight ovarian tumors were excluded. One hundred and twenty-three primary ovarian carcinomas have been graded and classified. The slides were reviewed independently by three pathologists with a perfect correlation and no significant difference was observed with the initial diagnosis. The World Health Organisation classification of ovarian epithelial tumors was used as a basis for the study (98 serous types, three mucinous tumors, five endometrioid tumors, two clear cell tumors, five mixed epithelial tumors, seven undifferentiated tumors and three unclassified). The adopted grading associates the degree of architecture differentiation and the cytological features using Broder's classification. The architecture grading or degree of differentiation includes well differentiated, moderately differentiated, poorly differentiated and undifferentiated patterns. The nuclear grading is based on pleomorphism of size and form, hyperchromatism, nucleoli, mitotic figures. The proposed grading based on well-known criterions is simple to use and easily reproducible. Grade 1 (6.5%) are well differentiated tumors with no atypia. Grade 2 (17.89%) are moderately well differentiated tumors without nuclear atypia. Grade 3 (32.52%) correspond to moderately well differentiated tumors with nuclear atypia. Grade 4 (43.09%) are poorly differentiated or undifferentiated tumors with nuclear atypia. The authors consider the different correlations between grade, histological type, stage and prognosis. The implications of these findings are discussed and the results are compared to those of the literature.

[Study of vinorelbine (V) combined with hexamethylmelamine (H) (combination V-H) in adenocarcinoma of the ovary: results a phase I-IIA trial, NHO-88, of ARTAC "ovarian" group]. / Etude de la vinorelbine (V) associée à l'hexaméthylmélamine (H) (combinaison V-H) dans les adénocarcinomes de l'ovaire: résultats d'un essai phase I-IIA, NHO-88, du groupe "ovaire" de l'ARTAC.

The lack of decisive progress in ovarian cancer chemotherapy in recent years led the ARTAC "Ovary" group to initiate a study based on the hypothesis of collateral sensitivities. In this phase I-II trial, NHO-88, the V-H combination (associating vinorelbine (VNB) and hexamethylmelamine (HMM) was studied in patients with advanced ovarian adenocarcinomas, most of which had become resistant to previous chemotherapy. The aim of the study was to find an active combination without complete cross resistance with first-line platinum salt based combinations, such as CAP, FAP or CACb-300. A pilot feasibility study was first carried out to determine the maximum tolerated weekly dose (MTWD) of VNB (20 mg/m2/week), HMM being administered per os on days 1-14 of every 28-day cycle at a standard dose of 250 mg/m2/day. An open phase II-A study was further carried out according to a 2-step sequential analysis method for phase II clinical trials. We observed: 1), a good tolerance of the V-H combination apart from frequent neutropenia; 2), a response rate of 35% (95% confidence interval: 23-47%); 3), a median response duration of 4 months (range: 1-7 months); 4), in some cases, the absence of a complete cross-resistance between the V-H regimen and the previously administered platinum-based combinations. These results, which are currently being validated (phase II-B ongoing), constitute the first step in the search for active systems of sequential or alternate chemotherapeutic regimens for the treatment of advanced carcinomas.

Phase I/pharmacokinetic study of intraperitoneal teniposide (VM 26).

A phase I/pharmacokinetic study of the i.p. administration of teniposide (VM 26) was undertaken. Eighteen patients with various malignancies and refractory malignant ascites consented to enter this trial. The dose escalation was made according to the modified Fibonacci scheme. Twenty-four courses were evaluable for toxicity, response and pharmacokinetics. The maximum tolerated dose was reached at 450 mg/m2 and the limiting toxicity was myelosuppression, principally leukopenia. Abdominal pain occurred in one half of the courses but was not limiting. No partial remission, but two 'no change' were achieved for more than 2 months. A reduction or disappearance of ascites was seen in two patients. Pharmacokinetic studies, carried out in all courses, showed that the total exposure for peritoneal cavity averaged 10-fold greater than that of plasma. Based on the outcome of this phase I study, we could recommend phase II studies at a dose of 390 mg/m2 i.p. repeated every 4 weeks with a 4 h dwell-time.

Clinical and pharmacokinetic study of 96-h infusions of doxorubicin in advanced cancer patients.

A phase I and a pharmacokinetic study of 96-h infusions of doxorubicin were performed in order to evaluate the maximum tolerated dose with this schedule of administration. Seventeen patients suffering from a digestive carcinoma were included in the study and a total of 71 courses of treatment were performed. The starting dose was 15 mg/m2/day and was increased in 2.5 mg/m2/day increments. The main toxicities observed were neutropenia and mucositis, which became limiting from 22.5 mg/m2/day (90 mg/m2 over a 96-h period); this dose was therefore defined as the maximal tolerated dose. No objective response to treatment was observed. For further studies, the recommended dose should not exceed 20 mg/m2/day. A plasma plateau concentration of doxorubicin was reached within 24 h. Despite a constant infusion rate, the plasma concentration of doxorubicin showed transient variations in several patients. However, an average plasma concentration could be evaluated for 33 courses of treatment, and this was linearly related to the dose. Doxorubicinol was the only detected metabolite of doxorubicin and its plasma concentration progressively increased throughout infusion. A detailed pharmacokinetic study was performed in 13 courses of treatment. The mean plasma clearance of doxorubicin was 25.2 l/h/m2 and the mean terminal half-lives of doxorubicin and doxorubicinol were respectively 43.6 and 66.2 h. Urinary excretion of doxorubicin plus metabolite was regular from the 24th to the 96th hour of infusion; however, the proportion of doxorubicinol progressively increased in urine. The protracted half-life of this metabolite probably explains its accumulation during infusion.

300 mg/m2 carboplatin (Cb), adriamycin (A) cyclophosphamide (C) (CACb-300) combination in advanced ovarian carcinoma: a feasibility study.

Carboplatin (Cb) is an active drug in ovarian carcinoma that has fewer visceral side effects than cisplatin (CDDP) but higher myelotoxicity, which makes it difficult to combine at efficient doses with other myelotoxic drugs. In a preliminary study in advanced ovarian carcinoma, Rosso et al. showed the maximum tolerated dose of Cb given in combination with cyclophosphamide (C) and adriamycin (A) to be 200 mg/m2. Since the efficacy of Cb may be dose-dependent, as is that of CDDP, we started a feasibility study of a CACb-300 regimen, that is, using Cb at 300 mg/m2 with lower C and A doses. Our data shows that the CACb-300 combination can safely be given in previously untreated patients for at least six 28-day cycles.