Vinflunine Research Articles

Stiffening of DU145 prostate cancer cells driven by actin filaments - microtubule crosstalk conferring resistance to microtubule-targeting drugs.

The crucial role of microtubules in the mitotic-related segregation of chromosomes makes them an excellent target for anticancer microtubule targeting drugs (MTDs) such as vinflunine (VFL), colchicine (COL), and docetaxel (DTX). MTDs affect mitosis by directly perturbing the structural organisation of microtubules. By a direct assessment of the biomechanical properties of prostate cancer DU145 cells exposed to different MTDs using atomic force microscopy, we show that cell stiffening is a response to the application of all the studied MTDs (VFL, COL, DTX). Changes in cellular rigidity are typically attributed to remodelling of the actin filaments in the cytoskeleton. Here, we demonstrate that cell stiffening can be driven by crosstalk between actin filaments and microtubules in MTD-treated cells. Our findings improve the interpretation of biomechanical data obtained for living cells in studies of various physiological and pathological processes.

P132 - Vinflunine (VFL) treatment following induction chemotherapy with platinum combinations in patients with metastatic-advanced urothelial cancer. A single institution experience

P132 - Vinflunine (VFL) treatment following induction chemotherapy with platinum combinations in patients with metastatic-advanced urothelial cancer. A single institution experience

Vinflunine in the treatment of relapsed metastatic urothelial cancer: A systematic review and meta-analysis of real-world series.

Vinflunine (VFL) is approved in Europe as second-line treatment of metastatic urothelial cancer after failure of platinum-containing therapy. We performed a systematic review and meta-analysis of real-world data (RWD) to assess utilization, efficacy and safety of VFL. We performed a MEDLINE search for the period of 1/1/2000-31/8/2017. Full-length articles providing post-marketing RWD on VFL in patients failing previous chemotherapy were eligible. Interventional clinical trials were excluded. Ten studies with 797 patients were identified. According to pooled REs analysis, overall response rate was 19%, most frequent, all-grade toxicities were fatigue (41%), constipation (39%), nausea/vomiting (25%), and most prevalent Grade 3-4 toxicities were neutropenia (13%), anaemia (9%), fatigue (8%). Median OS was comparable to results reported in recent randomized studies. Our findings confirm the efficacy and safety of VFL in an unselected population and support the use of VFL in the changing treatment paradigm of relapsed mUC.

Vinflunine for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract: an evidence-based review of safety, efficacy, and place in therapy.

BackgroundA systematic review and meta-analysis of the use of systemic vinflunine (VIN) in the treatment of urothelial carcinoma (UC) was performed to evaluate its efficacy based on current available clinical data.MethodsThis review was prospectively registered at the International Prospective Register of Systematic Reviews, PROSPERO (registration CRD42016049294). Electronic databases including MEDLINE®, Embase®, Cochrane Central Register of Controlled Trials, and Web of Science were searched through December 2016. We performed a meta-analysis of the published data. Primary end points were progression-free survival (PFS) and overall survival (OS). Numerous secondary clinical outcomes were analyzed including response and toxicity data.ResultsWe identified 382 publications, of which 35 met inclusion criteria for this review representing 29 unique studies. A total of 2,255 patients received VIN for the treatment of UC in the included studies. OS and PFS were analyzed in a pooled Kaplan–Meier analysis. Response data were available for 1,416 VIN-treated patients with random effects proportion of complete response in 1%, partial response in 18%, and overall response rate of 21%. Toxicity analysis revealed fatigue (40.1%), nausea (33.9%), constipation (34.1%), and alopecia (26.0%) as the most prevalent overall non-hematologic adverse events (AEs). Most prevalent grade 3–4 AEs were fatigue (10.2%), abdominal pain (8.2%), myalgias (2.5%), and nausea (2.3%). Most common hematologic AEs of all grades were anemia (56.6%), neutropenia (46.0%), thrombocytopenia (25.5%), and febrile neutropenia (6.6%). Grade 3–4 hematologic AEs had the following pooled rates: neutropenia, 24.6%; anemia, 10.2%; febrile neutropenia, 5.4%; and thrombocytopenia, 3.0%.ConclusionVIN has been explored as a combination first-line treatment as well as a single-agent second-line, third-line, and maintenance therapy for advanced and metastatic UC. In first-line treatment of UC, either as a maintenance agent after cisplatin or as a primary combination therapy, VIN may be a promising alternative to current treatments. Further studies are needed to compare first-line combination VIN regimens to the current standard of care in order to assess long-term survival outcomes. Second- and third-line VIN monotherapy does provide a proven, although limited, survival benefit in platinum-refractory patients.

Inhibition of survivin expression after using oxaliplatin and vinflunine to induce cytogenetic damage in vitro in lymphocytes from colon cancer patients and healthy individuals.

Chemotherapy drugs usually inflict a lethal dose to tumour cells with the consequence that these cells are being killed by cell death. However, each round of chemotherapy also causes damage to normal somatic cells. The DNA cross-linking agent oxaliplatin (OXP), which causes DNA double-strand breaks, and vinflunine (VFN), which disrupts the mitotic spindle, are two of these chemotherapy drugs which were evaluated in vitro using peripheral lymphocytes from colorectal cancer patients and healthy individuals to determine any differential response. Endpoints examined included micronucleus (MN) induction using the cytokinesis-blocked micronucleus (CBMN) assay and pancentromeric fluorescence in situ hybridisation. Also, survivin expression was monitored since it regulates the mitotic spindle checkpoint and inhibits apoptosis. OXP produced cytogenetic damage (micronuclei in binucleated cells) via its clastogenic but also previously unknown aneugenic action, possibly through interfering with topoisomerase II, whilst VFN produced micronuclei in mononucleated cells because of incomplete karyokinesis. Survivin expression was found to be significantly reduced in a concentration-dependent manner by not only OXP but surprisingly also VFN. This resulted in large numbers of multinucleated cells found with the CBMN assay. As survivin is upregulated in cancers, eliminating apoptosis inhibition might provide a more targeted chemotherapy approach; particularly, when considering VFN, which only affects cycling cells by inhibiting their mitotic spindle, and alongside possibly other pro-apoptotic compounds. Hence, these newly found properties of VFN -the inhibition of survivin expression-might demonstrate a promising chemotherapeutic approach as VFN induces less DNA damage in normal somatic cells compared to other chemotherapeutic compounds.

Vinflunine and bladder cancer: present and future indications

Urothelial cancer (UC) frequently affects male sex over the sixth decade of life, and in about 30% of the cases, it is diagnosed as muscle-invasive disease. For patients with metastatic disease, the prognosis is grim and the typical treatment is polychemotherapy involving cisplatin. Secondline chemotherapy is often employed, but a standard scheme does not exist. Vinflunine (VFL) is a new generation vinca alkaloid able to reversibly link the subunits of tubulin, causing the arrest of mitotic spindle polymerization. In critical trials, VFL has shown good activity and manageable toxicity; in a phase III randomized trial, it significantly improved survival compared with the best supportive care (BSC). VFL has received European Medicines Agency (EMA) approval for use as second-line treatment in UC patients who progressed after a first-line cisplatin-containing chemotherapy. Due to its low toxicity and promising efficacy, VFL is under clinical experimentations aimed to assess its role in other disease settings.

Metastatic Bladder Cancer: Second-Line Treatment and Recommendations of the Genitourinary Tumor Division of the Galician Oncologic Society (SOG-GU).

Once metastatic bladder cancer has progressed to first-line treatment, the number of therapeutic options is scarce. Among chemotherapeutic agents showing activity in phase II trials, including taxanes, vinflunine (VFL) is the only one shown to increase overall survival in a phase III trial. In addition to its efficacy, VFL is safe in special population groups. Despite this, the prognosis for these patients remains poor, and more effective therapies need to be developed. Agents acting on new therapeutic targets as well as biomarkers to aid matching patients to specific treatments are currently under evaluation. In this regard, immunotherapy is showing promising results. In this article, a critical review of current treatments and future prospects is made, and therapy recommendations are made based on existing scientific evidence.

850TiP - JaNEO – A phase Ib/II study assessing the neo-adjuvant combination therapy of vinflunine (VFL) with cisplatin (CDDP) followed by radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC)

850TiP - JaNEO – A phase Ib/II study assessing the neo-adjuvant combination therapy of vinflunine (VFL) with cisplatin (CDDP) followed by radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC)

C25 - Vinflunine (VFL) maintenance therapy in metastatic urothelial carcinoma (UC) after response to 1st line platinum-based chemotherapy (CT): an observational prospective study

C25 - Vinflunine (VFL) maintenance therapy in metastatic urothelial carcinoma (UC) after response to 1st line platinum-based chemotherapy (CT): an observational prospective study

C14 - Retrospective observational study of Vinflunine (VFL) in patients (pts) with transitional cell carcinoma of the urothelial tract (TCCU): final results of a real world population study (MOVIE-GOIRC01/2014 trial)

C14 - Retrospective observational study of Vinflunine (VFL) in patients (pts) with transitional cell carcinoma of the urothelial tract (TCCU): final results of a real world population study (MOVIE-GOIRC01/2014 trial)

Randomized, placebo-controlled phase II trial (MAJA): Efficacy results of maintenance vinflunine after cisplatin chemotherapy (CT) in patients with advanced urothelial carcinoma (UC)—SOGUG 2011-02.

4529Background: Vinflunine (VFL) is a microtubule inhibitor approved by EMA as treatment after platinum progression in metastatic UC. We evaluated whether maintenance VFL delays progression after r...

Vinflunine (VFL) in patients (pts) with metastatic transitional cell carcinoma of the urothelial tract (mTCCU): Clinical outcome and prognostic factors in a nationwide, real-life setting (MOVIE trial).

e16031Background: To assess the clinical impact of VFL in pts with mTCCU and verify the prognostic factors in a large, unselected population treated according to routine clinical practice (CP). Met...

Maintenance vinflunine post cisplatin chemotherapy (CT) in patients with advanced urothelial carcinoma (UC): Preliminary analysis of a randomized placebo controlled phase II trial (MAJA trial)—SOGUG 2011-02.

4529 Background: Vinflunine (VFL) is a microtubule inhibitor approved by EMA as treatment after platinum progression, in metastatic bladder cancer. We evaluated whether maintenance VFL delays progression after response to CT. Methods: Patients (pts) with measurable disease, locally recurrent/metastatic UC and adequate organ function with radiological response or stabilization after 4-6 cy of a cisplatin/gemcitabine chemotherapy (carboplatin allowed after cy 4) were randomized 1:1 to receive VFL 320 mg/m2 or 280mg/m2(in case of PS 1, age ≥ 75 years, prior pelvic radiotherapy or CrCl < 60ml/min) every 21 days vs best supportive care (BSC), until disease progression. The primary endpoint was progression free survival (PFS). With a median PFS considered unacceptable for the experimental arm 4 months (p0) and a very acceptable 6.5 (p1). 39 eligible pts per treatment arm were required to select better therapy with a type I error of 0.05 (α, one-tailed test), and a type II 0.1 (β) error. Results: 88 patients fro...

Role of the microtubule-targeting drug vinflunine on cell-cell adhesions in bladder epithelial tumour cells.

BackgroundVinflunine (VFL) is a microtubule-targeting drug that suppresses microtubule dynamics, showing anti-metastatic properties both in vitro and in living cancer cells. An increasing body of evidence underlines the influence of the microtubules dynamics on the cadherin-dependent cell-cell adhesions. E-cadherin is a marker of epithelial-to-mesenchymal transition (EMT) and a tumour suppressor; its reduced levels in carcinoma are associated with poor prognosis. In this report, we investigate the role of VFL on cell-cell adhesions in bladder epithelial tumour cells.MethodsHuman bladder epithelial tumour cell lines HT1376, 5637, SW780, T24 and UMUC3 were used to analyse cadherin-dependent cell-cell adhesions under VFL treatment. VFL effect on growth inhibition was measured by using a MTT colorimetric cell viability assay. Western blot, immunofluorescence and transmission electron microscopy analyses were performed to assess the roles of VFL effect on cell-cell adhesions, epithelial-to-mesenchymal markers and apoptosis. The role of the proteasome in controlling cell-cell adhesion was studied using the proteasome inhibitor MG132.ResultsWe show that VFL induces cell death in bladder cancer cells and activates epithelial differentiation of the remaining living cells, leading to an increase of E-cadherin-dependent cell-cell adhesion and a reduction of mesenchymal markers, such as N-cadherin or vimentin. Moreover, while E-cadherin is increased, the levels of Hakai, an E3 ubiquitin-ligase for E-cadherin, were significantly reduced in presence of VFL. In 5637, this reduction on Hakai expression was blocked by MG132 proteasome inhibitor, indicating that the proteasome pathway could be one of the molecular mechanisms involved in its degradation.ConclusionsOur findings underscore a critical function for VFL in cell-cell adhesions of epithelial bladder tumour cells, suggesting a novel molecular mechanism by which VFL may impact upon EMT and metastasis.

Vinflunine plus capecitabine for advanced breast cancer previously treated with or resistant to anthracycline and resistant to taxane: A phase III study versus capecitabine.

1013^ Background: Vinflunine (VFL) is a microtubule inhibitor with single-agent activity in advanced breast cancer (ABC) pretreated with anthracycline (A) and resistant to taxane (T). Synergy with capecitabine (CAPE) was demonstrated in this setting. This phase 3 study compared VFL plus CAPE with CAPE alone in A pretreated or resistant and T-resistant ABC. Methods: Open-label, multicenter study, in which 770 ABC patients with up to 3 prior chemotherapy (CT) regimens were randomised to VFL 280 mg/m² on day 1 plus CAPE 1,650 mg/m² (N = 384) or to CAPE alone at 2,500 mg/m² (N = 386) on days 1 to 14 every 3 weeks. Randomization was stratified by resistance to anthracycline, performance status, disease measurability and number of prior lines of CT for ABC. Primary endpoint was PFS assessed by a blinded independent review committee (IRC) in the ITT population. Results: Patients had a median age of 54 years (range: 27 - 81); metastatic disease for 97%; anthracycline resistance for 63%; received study treatment a...

Feasibility and activity of two vinflunine (VFL)-based combinations as first-line chemotherapy (CT) in CDDP-unfit patients (pts) with advanced urothelial carcinoma (UC): VFL-gemcitabine (GEM) or VFL-CBDCA in a randomized international phase II trial (JASINT).

4534 Background: There is no standard 1st line CT for advanced or metastatic UC in patients (pts) unfit for a CDDP-based regimen. CBDCA-GEM doublet or single agents are frequently used. VFL, a nove...

A phase I clinical and pharmacokinetic study evaluating vinflunine in combination with epirubicin as first-line treatment in metastatic breast cancer

Vinflunine (VFL) is a bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with epirubicin (EPR) to establish the recommended dose (RD), to evaluate the safety and efficacy profiles and to investigate potential pharmacokinetic (PK) drug-drug interaction (DDI). Two schedules (day 1 every 3 weeks; days 1 and 8 every 3 weeks) were investigated as first-line chemotherapy of metastatic breast cancer patient. PK DDI was evaluated through population PK approaches. Thirty-nine patients received a total of 197 cycles of the VFL-EPR combination (median 6). The RDs were VFL 250 mg/m(2) + EPR 75 mg/m(2) every 3 weeks for schedule 1 and VFL 170 mg/m(2) + EPR 35 mg/m(2) every 3 weeks for schedule 2. The PK analysis demonstrated no clinically relevant mutual DDI between VFL and EPR. The main dose-limiting toxicity was neutropenia. The most frequent non-haematological adverse events were nausea, fatigue, constipation, vomiting, anorexia and stomatitis. Objective response rate was achieved in 45.9 % of the patients. VFL-EPR combination is feasible with manageable toxicity. The antitumour activity was promising and supports further evaluation.

How to manage intravenous vinflunine in cancer patients with renal impairment: results of a pharmacokinetic and tolerability phase I study

Vinflunine (VFL) ditartrate, a novel tubulin-targeted inhibitor, is registered for the treatment of patients with advanced or metastatic urothelial transitional cell carcinoma. This phase I study assessed the effect of renal impairment on the pharmacokinetics and tolerability of VFL. VFL was infused in patients with advanced/metastatic solid tumours once every 3 weeks with anticipated dose reduction on the first cycle stratified according to the creatinine clearance (CLcr ) values. Pharmacokinetic data were collected on the first two cycles in renally impaired patients (CLcr ≤ 60 ml min(-1) ) and were compared with a control cohort of patients (CLcr > 60 ml min(-1) ). Thirty-three patients (46-86 years) were treated, 13 in group 1 (40 ml min(-1) ≤ CLcr ≤ 60 ml min(-1) ) and 20 in group 2 (20 ml min(-1) ≤ CLcr < 40 ml min(-1) ). The renal dysfunction induced a mean decrease in VFL clearance of 12% in group 1 and 28% in group 2, compared with the control group. The anticipated dose reduction given in renally impaired patients (i.e. 280 mg m(-2) and 250 mg m(-2) in groups 1 and 2, respectively) yielded similar drug exposure to control patients. The tolerance profile of VFL in patients with renal dysfunction was similar to that observed in patients with CLcr > 60 ml min(-1) . In conclusion, the recommended doses of intravenous VFL administered once every 3 weeks in cancer patients with renal impairment are 280 mg m(-2) when CLcr is between 40 and 60 ml min(-1) and 250 mg m(-2) when CLcr is between 20 and <40 ml min(-1) .

Safety and effectiveness of vinflunine in patients with metastatic transitional cell carcinoma of the urothelial tract (TCCU) after failure to one cisplatin-based systemic therapy in clinical practice.

332 Background: Vinflunine (VFL) is the first agent to show a survival improvement for platinum-refractory patients (pts) with metastatic TCCU in a phase III clinical trial. After EMA approval in September 2009, ESMO (Bellmunt, 2011) and SOGUG (Castellano, 2012) guidelines recommend VFL as second-line therapy. Methods: This is a multicenter and retrospective study to describe the experience with VFL in Spain. Pts with histologically confirmed metastatic TCCU were treated with VFL (280-320mg/m2 every 3 weeks) until progression or unacceptable toxicity. Pts were evaluated according to institutional local follow-up program. Results: From April 2010 to June 2013, we registered 102 pts in fifteen Spanish centers. All patients are evaluable for safety and 98 for efficacy. Median age: 67years (range 45-83), ECOG 0/1/2 previous to VFL (pts%): 31/61/8. Bladder carcinoma was the primary disease site in 84 pts and 46 % of them received cisplatinum-based chemotherapy. Metastatic involvement was: lymph nodes 67.7%, lung 36.4%, bone 28.1%, and liver 21.6%. The median number of cycles of VFL was 4 (1-18). The objective response rate was 25.5% (CR in 2 pts and PR in 23 pts), stable disease in 42.9% and progressive disease in 31.6%. The median follow-up was 6.6 months (0.4 to 43): median progression-free survival 3.9 months (95% CI, 2.3 to 5.5), median time to progression 4.3 months (95% CI, 2.6 to 5.9) and median overall survival 10 months (95% CI, 7.3 to 12.8). At the time of the analysis, 79.4%pts had progressive disease after VFL and 64.7% died. Grade 3/4 adverse events included: nausea/vomiting 13.8% of pts, neutropenia 12.8%, constipation 5.9%, and abdominal pain 4.9%. No toxic death were reported. Conclusions: This retrospective analysis confirms the benefit of VFL in patients with TCCU after failure in a platinum-containing chemotherapy regimen. Results of the randomized trial are reproducible in Spanish Oncology Centers on a daily clinical practice and its toxicity profile results are acceptable and manageable.

Vinflunine maintenance therapy versus best supportive care after platinum combination in advanced bladder cancer: A phase II, randomized, open label, study (MAJA study, SOGUG 2011-02)—Interim analysis on safety.

359 Background: Vinflunine (VFL) is a novel microtubule inhibitor currently approved by EMA as treatment after platinum progression, in metastasic bladder cancer. We evaluated whether maintenance vinflunine delays progression after response to CT. Methods: Multicenter, randomized, open label, proof-of-concept study that is being performed in 21 institutions members of the Spanish Oncology Genitourinary Group (SOGUG). Subjects are randomized to receive (arm A) VFL 320 mg/m2 (280mg/m2 for patients with PS=1, age ≥ 75 years, prior pelvic radiotherapy or creatinine clearance Cr &lt;60ml/min) every 21 days plus best supportive care (BSC) vs. (arm B) BSC alone until disease progression. Main inclusion criteria: Subjects ≥18 and&lt; 80 years of age with histological diagnosis of transitional cell carcinoma of the urothelial tract and measurable disease whith radiological response or stabilization after 4 to 6 cy of a cisplatin-containing doublet for metastasic/advanced disease (carboplatin allowed on cy 5-6). Primary objective: progression free survival (PFS). A sample size of 86 patients allocated in a 1:1 ratio is planned. Recruitment started on April 2012. A pharmacogenomic translational study will be conducted. Results: To September 2013, 46 pts have been enrolled, 20 in the VFL+BSC group, 26 in the BSC group. We present the results of the interim analysis including data from first 25 patients who have completed at least 2 cycles. Median age 65.6 years (range 54-77); PS 0/1, 44%/56%; CrCl &lt;60 ml/min 16%; liver metastasis 16%; prior pelvic RT 8%. Primary tumour location: bladder 76%, upper urinary tract 20%, urethra 4%. Pure transitional cells 84%. Metastatic/locoregional disease, 72% / 28%. We analyzed 63 cy in the chemotherapy arm. Most common G3/4 (% cycles) AEs on vinflunine were constipation (12.7%), neutropenia (7.9%), fatigue (4.8%), myalgia (3.2%). One death was reported due to dyspnea, not related to the treatment. No febrile neutropenia was reported at the time of the analysis. Conclusions: Maintenance with vinflunine presented an acceptable security profile leading to trial continuation. Clinical trial information: 2011-001271-39.