Vinflunine Research Articles

Phase II study of IV Vinflunine (VFL) as second line treatment of patients (pts) with advanced non-small-cell lung cancer (NSCLC) previously treated with a platinum based regimen. Final results

7139 Background: Pts with NSCLC who progress on or after 1st line therapy but continue to have a good performance status (PS) may be offered 2nd line chemotherapy. VFL (Javlor) is a novel fluorinated vinca-alkaloid derivative synthesised using superacidic chemistry which has shown high activity in experimental tumour models. Methods: The aim of this trial was to determine the response rate and safety of VFL (320 mg/m2 q 3 weeks) as a single agent in pts with advanced NSCLC, who failed to a previous platinum-based regimen. Results: Sixty-three pts have been treated, 47 males, 16 females, median (m) age 60 years; Karnofsky PS 100 %: 14 pts, 90 %: 21 pts and 80 %: 28 pts. Prior platinum combinations included taxanes (31 % pts), vincas (31 % pts) and other (38 % pts). The total number of cycles administered was 221 (m: 5 [1 - 9]). Of the 62 evaluable pts, 38 (61 %, [95 % CI: 49–73 %]) achieved disease control: 5 pts (8 %, [95 % CI: 1–15 %]) partial response (independent radiological review) lasting 5.8 months (mo) [95 % CI: 4.6–7.9] and 33 pts (53 %, [95 % CI: 41–66 %]) stabilisation. Progression free survival (PFS) was established at 2.6 mo [95 % CI: 1.4–3.8]. In terms of tolerance, grade (G) 3/4 neutropenia was observed in 15.8 % of cycles (25.4 % of pts) and 10.4 % cycles (23.8 % of pts) respectively; G3 anaemia and thrombocytopenia were rare. Two pts suffered from febrile neutropenia and 2 other from neutropenic infection. G ≥3 non-haematological toxicities observed were: myalgia 5 % cycles (15.9 % of pts), fatigue 1.9 % cycles (6.4 % of pts), stomatitis 1.4 % cycles (4.8 % of pts); constipation was present in 2.3 % cycles (7.9 % of pts), abdominal pain and arthralgia were observed in 1.4 % cycles (4.8 % of pts). Neither grade G3/4 peripheral neuropathy nor phlebitis was observed. Conclusions: In NSCLC patients previously treated with platinum containing regimens VFL achieved encouraging efficacy in terms of disease control and PFS. Toxicity was manageable and reversible. Based on these results a phase III is currently ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Institut de Recherche Pierre Fabre (IRPF), France

Phase II study of IV Vinflunine (VFL) as second line treatment of patients (pts) with advanced non-small-cell lung cancer (NSCLC) previously treated with a platinum based regimen. Final results

7139 Background: Pts with NSCLC who progress on or after 1st line therapy but continue to have a good performance status (PS) may be offered 2nd line chemotherapy. VFL (Javlor) is a novel fluorinated vinca-alkaloid derivative synthesised using superacidic chemistry which has shown high activity in experimental tumour models. Methods: The aim of this trial was to determine the response rate and safety of VFL (320 mg/m2 q 3 weeks) as a single agent in pts with advanced NSCLC, who failed to a previous platinum-based regimen. Results: Sixty-three pts have been treated, 47 males, 16 females, median (m) age 60 years; Karnofsky PS 100 %: 14 pts, 90 %: 21 pts and 80 %: 28 pts. Prior platinum combinations included taxanes (31 % pts), vincas (31 % pts) and other (38 % pts). The total number of cycles administered was 221 (m: 5 [1 - 9]). Of the 62 evaluable pts, 38 (61 %, [95 % CI: 49–73 %]) achieved disease control: 5 pts (8 %, [95 % CI: 1–15 %]) partial response (independent radiological review) lasting 5.8 months (mo) [95 % CI: 4.6–7.9] and 33 pts (53 %, [95 % CI: 41–66 %]) stabilisation. Progression free survival (PFS) was established at 2.6 mo [95 % CI: 1.4–3.8]. In terms of tolerance, grade (G) 3/4 neutropenia was observed in 15.8 % of cycles (25.4 % of pts) and 10.4 % cycles (23.8 % of pts) respectively; G3 anaemia and thrombocytopenia were rare. Two pts suffered from febrile neutropenia and 2 other from neutropenic infection. G ≥3 non-haematological toxicities observed were: myalgia 5 % cycles (15.9 % of pts), fatigue 1.9 % cycles (6.4 % of pts), stomatitis 1.4 % cycles (4.8 % of pts); constipation was present in 2.3 % cycles (7.9 % of pts), abdominal pain and arthralgia were observed in 1.4 % cycles (4.8 % of pts). Neither grade G3/4 peripheral neuropathy nor phlebitis was observed. Conclusions: In NSCLC patients previously treated with platinum containing regimens VFL achieved encouraging efficacy in terms of disease control and PFS. Toxicity was manageable and reversible. Based on these results a phase III is currently ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Institut de Recherche Pierre Fabre (IRPF), France

Results of a phase I / II and pharmacokinetic study of vinflunine (VFL) in combination with cisplatin (CDDP) for primary treatment of advanced non-small cell lung cancer (NSCLC)

7110 Background: VFL (Javlor) is a new semi-synthetic vinca alkaloid which has shown synergistic effects in vitro againts A549 human NSCLC line when combined with CDDP. Platinum-based doublets are the standard treatment in advanced NSCLC. Methods: The phase I part of this trial was designed to determine the recommended dose (RD) and to study the possible pharmacokinetic (PK) interaction of the combination VFL and CDDP. The RD was established at of VFL 320 mg/m2 plus CDDP 80 mg/m2 on day 1 every 3 weeks; no PK interaction was observed. We describe the results of the phase II part of the study, which was designed to to determine the response rate (WHO) and safety (NCI-CTC) of the combination. Results: At the RD 53 patients (41 males, 12 females), median age 57, initial stages IIB 2 pts, IIIB 15 pts and IV 36 pts were treated. Karnofsky performance status was: 100 % 11 pts, 90 % 32 pts, 80 % 10 pts. The median number of cycles administered was 6 [1–8] and the median dose intensities of both drugs are > 97 %. Disease control was achieved in 77 % of the 49 evaluable pts: there were 16 confirmed responses (after external radiological review) (33 %) (95 % CI [20–48]) and 22 stabilizations. In terms of tolerance, among 237 cycles analyzed grades 3/4 neutropenia and anemia were reported in 43 % and 7 % of cycles respectively; 5 patients experienced febrile neutropenia and there were 2 neutropenic infections. Grades 3/4 non-hematological toxicities observed were: fatigue 3.8 % cycles (15.1 % pts), abdominal pain 3 % cycles (9.4 % pts), nausea 1.7 % cycles (3.8 % pts), vomiting 1.2 % cycles (3.8 % pts) constipation: 1.3 % cycles (5.7 % pts), diarrhea and dehydration 0.4 % cycles (1.4 % pts). No peripheral neuropathy grades 3/4 has been observed.Conclusions: Very good results were achieved in terms of dose intensities and toxicity profile. In first line treatment of advanced NSCLC patient, the combination of VFL 320 mg/m2 plus CDDP 80 mg/m2 both given once every 3 weeks is an highly active combination in terms of response rate. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Institut de Recherche Pierre Fabre (IRPF), France

Results of a phase I / II and pharmacokinetic study of vinflunine (VFL) in combination with cisplatin (CDDP) for primary treatment of advanced non-small cell lung cancer (NSCLC)

7110 Background: VFL (Javlor) is a new semi-synthetic vinca alkaloid which has shown synergistic effects in vitro againts A549 human NSCLC line when combined with CDDP. Platinum-based doublets are the standard treatment in advanced NSCLC. Methods: The phase I part of this trial was designed to determine the recommended dose (RD) and to study the possible pharmacokinetic (PK) interaction of the combination VFL and CDDP. The RD was established at of VFL 320 mg/m2 plus CDDP 80 mg/m2 on day 1 every 3 weeks; no PK interaction was observed. We describe the results of the phase II part of the study, which was designed to to determine the response rate (WHO) and safety (NCI-CTC) of the combination. Results: At the RD 53 patients (41 males, 12 females), median age 57, initial stages IIB 2 pts, IIIB 15 pts and IV 36 pts were treated. Karnofsky performance status was: 100 % 11 pts, 90 % 32 pts, 80 % 10 pts. The median number of cycles administered was 6 [1–8] and the median dose intensities of both drugs are > 97 %. Disease control was achieved in 77 % of the 49 evaluable pts: there were 16 confirmed responses (after external radiological review) (33 %) (95 % CI [20–48]) and 22 stabilizations. In terms of tolerance, among 237 cycles analyzed grades 3/4 neutropenia and anemia were reported in 43 % and 7 % of cycles respectively; 5 patients experienced febrile neutropenia and there were 2 neutropenic infections. Grades 3/4 non-hematological toxicities observed were: fatigue 3.8 % cycles (15.1 % pts), abdominal pain 3 % cycles (9.4 % pts), nausea 1.7 % cycles (3.8 % pts), vomiting 1.2 % cycles (3.8 % pts) constipation: 1.3 % cycles (5.7 % pts), diarrhea and dehydration 0.4 % cycles (1.4 % pts). No peripheral neuropathy grades 3/4 has been observed.Conclusions: Very good results were achieved in terms of dose intensities and toxicity profile. In first line treatment of advanced NSCLC patient, the combination of VFL 320 mg/m2 plus CDDP 80 mg/m2 both given once every 3 weeks is an highly active combination in terms of response rate. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Institut de Recherche Pierre Fabre (IRPF), France

Long-term prognosis of inducible ventricular flutter: not an innocent finding

Vinflunine (Javlor) has shown significant antitumour activity in advanced non-small cell lung cancer (NSCLC). We propose to define the recommended dose of vinflunine in combination with gemcitabine for treatment of advanced NSCLC in chemonaive patients.A phase I and pharmacokinetic study was conducted to determine the maximum tolerated dose and to establish the recommended dose of vinflunine (VFL) administered on day 1 every 21 days combined with gemcitabine given on days 1 and 8 every 3 weeks.Nineteen patients were included in this study. Three patients experienced a dose limiting toxicity, with constipation in one patient, hypertension in one patient, and constipation and febrile neutropenia in one patient. The combination of VFL 320 mg/m2 and gemcitabine 1250 mg/m2 was defined as the maximum tolerated dose. The recommended dose was established at the dose of VFL 320 mg/m2 combined with gemcitabine 1000 mg/m2. Neither VFL nor gemcitabine seemed to be influencing the pharmacokinetics of each other. All patients were evaluable for tumor response. Seven presented a partial response and eight experienced a stable disease.The combination of VFL 320 mg/m2 administered on day 1 combined with gemcitabine 1000 mg/m2 given on days 1 and 8 every 3 weeks is established as the RD and was shown to be active in these chemonaive NSCLC patients.

843 Role of surgery in patients with liver metastases from nonseminomatous germ cell tumors

Vinflunine (VFL) is a novel microtubule inhibitor indicated in the treatment of advanced or metastatic urothelial transitional cell cancer after failure of a prior platinum-containing regimen at the recommended dose of 320 mg/m² q3 weeks. This trial was designed to assess the pharmacokinetic (PK) behavior and tolerance of VFL in elderly patients (pts), and to propose dose-adjustments if necessary.Three groups of cancer pts over 70 years old (y) were open to recruitment: 70–75 y, 75–80 y and ≥ 80 y. Each group of pts received intravenous VFL, respectively at 320, 280 and 250 mg/m² on cycle 1. Pharmacokinetics and safety data were collected at cycle 1 and were compared to reference values from younger pts < 70 y.46 pts were treated. For pts 70–75 y and 75–80 y, there was no statistically age-related change for VFL PK. For pts ≥ 80 y, VFL blood total clearance (Cltot) was significantly decreased by 18%. The most common adverse events observed in this elderly population were not different from those seen in younger pts. No toxic death was recorded. Main toxicities were neutropenia (Grade 3/4: 73% of pts), constipation (all grade: 63%) and asthenia (all grade: 56%), without any relationship between the observed incidence and the ageing of pts.Based on PK and safety data, a dose reduction at 280 mg/m² and 250 mg/m² is recommended in pts 75–80 y and ≥ 80 y respectively.

844 A phase II study testing intravenous (iv) vinflunine (VFL) as second line therapy in patients with advanced transitional cell cancer (TCC) of the bladder

844 A phase II study testing intravenous (iv) vinflunine (VFL) as second line therapy in patients with advanced transitional cell cancer (TCC) of the bladder

803 Phase I/II and pharmacokinetic study of vinflunine (VFL) in combination with clsplatin (CDCP) for treatment of advanced non-small cell lung cancer (NSCLC) in chemonaive patients: Preliminary results

803 Phase I/II and pharmacokinetic study of vinflunine (VFL) in combination with clsplatin (CDCP) for treatment of advanced non-small cell lung cancer (NSCLC) in chemonaive patients: Preliminary results

Higher antitumor activity of vinflunine than vinorelbine against an orthotopic murine model of transitional cell carcinoma of the bladder

The aim of this report was to investigate the feasibility of systemic treatment of transitional cell carcinoma of the bladder with vinflunine (VFL), and to compare its activity in respect to vinorelbine (VRL). Exposure of MB49 murine bladder cancer cells to both drugs showed a higher chemosensitivity of the cells to VRL than to VFL (IC 50 values of 60 nM and 400 nM, respectively). Pretreatment of MB49 cells with non-cytotoxic drug concentrations revealed an inhibition of control in vitro invasiveness of 40 to 70% (1–25 nM VRL) and 22 to 80% (1–100 nM VFL) ( P<0.0001, ANOVA). The intraperitoneal administration of the drugs twice a week for 4 weeks in C57Bl/6 female mice revealed that VFL was very well tolerated, with a 8-fold increase in the maximum tolerated dose in respect to VRL (40 mg/kg and 4.8 mg/kg, respectively). The administration schedule was evaluated in C57Bl/6 female mice inoculated transurethraly with 5×10 4 MB49 cells. Intravesical tumor incidence on day 21 was 0% and 17% in mice treated intraperitoneally with 20 and 10 mg/kg VFL respectively ( P=0.0017 and P=0.0001, Fischer's Exact Test), contrasting with 75–83% obtained in all VRL-treated groups and Controls. All mice treated with 20 mg/kg VFL were still alive 60 days after intravesical MB49 tumor implantation, as well as 50% of those treated with 10 mg/kg VFL, while most of the remaining mice (Control and VRL-treated) died before day 32. These studies clearly demonstrate the activity of VFL against a murine bladder cancer model, with a favorable toxicity profile.

Markedly diminished drug resistance-inducing properties of vinflunine (20′,20′-difluoro-3′,4′-dihydrovinorelbine) relative to vinorelbine, identified in murine and human tumour cells in vivo and in vitro

Vinflunine (VFL) is a novel Vinca alkaloid with markedly superior experimental in vivo antitumour activity to its parent molecule, vinorelbine (Navelbine, NVB), against a panel of murine and human tumours. The aim of this study was to establish whether there are differences in the rate and extent of development of resistance, both in vivo and in vitro, to these two newer Vinca alkaloids under identical selection conditions. Using P388 leukaemia cells in vivo, it was evident that VFL induced drug resistance far less readily than NVB, as shown by the number of passages required to select for total resistance. Under in vitro conditions, using A549 human lung carcinoma cells, it was also clearly shown by drug sensitivity determinations that VFL was a less-potent inducer of drug resistance than NVB. Resistance resulting from either in vivo or in vitro selection was associated with a classic multidrug resistance profile. Further characterization of the drug-resistance phenotype of the most highly resistant A549 sublines showed that the level of total beta-tubulin expression appeared to be modified exclusively in the NVB-resistant cells. The clear demonstration that resistance to VFL developed far less readily than resistance to NVB both in vivo and in vitro may have potential clinical implications.

Vinflunine (20',20'-difluoro-3',4'-dihydrovinorelbine), a novel Vinca alkaloid, which participates in P-glycoprotein (Pgp)-mediated multidrug resistance in vivo and in vitro.

Vinflunine (VFL) is a novel derivative of vinorelbine (NVB, Navelbine), which has shown markedly superior antitumor activity to NVB, in various experimental animal models. To establish whether this new Vinca alkaloid participates in P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), VFL-resistant murine P388 cells (P388/VFL) were established in vivo and used in conjunction with the well established MDR P388/ADR subline, to define the in vivo resistance profile for VFL. P388/VFL cells proved cross-resistant to drugs implicated in MDR (other Vinca alkaloids, doxorubicin, etoposide), but not to campothecin or cisplatin and showed an increased expression of Pgp, without any detectable alterations in topoisomerase II or in glutathione metabolism. The P388/ADR cells proved cross-resistant to VFL both in vivo and in vitro, and this VFL resistance was efficiently modulated by verapamil in vitro. Cellular transport experiments with tritiated-VFL revealed differential uptake by P388 sensitive and P388/ADR resistant cells, comparable with data obtained using tritiated-NVB. In various in vitro models of human MDR tumor cells, whilst full sensitivity was retained in cells expressing alternative non-Pgp-mediated MDR mechanisms, cross resistance was identified in Pgp-overexpressing cells. Differences were, however, noted in terms of the drug resistance profiles relative to the other Vinca, with tumor cell lines proving generally least cross-resistant to VFL. Overall, these results suggest that VFL, like other Vinca alkaloids, participates in Pgp-mediated MDR, with tumor cells selected for resistance to VFL overexpressing Pgp, yet MDR tumor cell lines proved generally less cross resistant to VFL relative to the other Vinca alkaloids.