vinflunine and Neoplasm-Metastasis

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.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Constipation; Europe; Fatigue; Female; Humans; Male; Middle Aged; Nausea; Neoplasm Metastasis; Platinum Compounds; Recurrence; Treatment Outcome; Urologic Neoplasms; Vinblastine; Vomiting

This review summarises the treatment strategies of the last five decades for metastatic urothelial cancer. The introduction of combination chemotherapy in the mid-1980s led to clinically significant response rates and prolonged survival. Two years ago, the results of a phase-3 clinical trial with the PD1 inhibitor pembrolizumab for second-line treatment of metastatic urothelial carcinoma were published. These data were the first to show an overall survival benefit in comparison with a conventional chemotherapy with vinflunine, docetaxel or paclitaxel. Currently, PD1/PD-L1 inhibitors are also tested within randomized phase-3-trials for first-line treatment using different approaches either as a monotherapy or a combination with conventional chemotherapy or CTLA-4 inhibitors. Whereas data from single-arm phase-2 clinical trials have already been published, first phase-3 data are expected in 2019.. Dieser Übersichtsartikel stellt die Ergebnisse verschiedener Behandlungskonzepte für das metastasierte Urothelkarzinom in den letzten fünf Jahrzehnten zusammen. Mit der Einführung von verschiedenen Kombinations-Chemotherapien wurde ab Mitte der 80er Jahre eine signifikante Überlebensverlängerung und potenzielle Heilbarkeit auch fortgeschrittener Erkrankungsstadien in dieser Tumorentität postuliert. Vor zwei Jahren wurden Studiendaten zur Zweitlinientherapie des metastasierten Urothelkarzinoms mit dem PD1-Antikörper Pembrolizumab publiziert, die erstmals einen Vorteil im Gesamtüberleben gegenüber einer konventionellen Chemotherapie mit Paclitaxel, Docetaxel oder Vinflunin zeigen. Aktuell wird in randomisierten Phase-3-Studien der Einsatz von PD-1/PD-L1 gerichteten Substanzen auch in der Erstlinientherapie des metastasierten Urothelkarzinoms untersucht. Dabei werden verschiedene Therapiestrategien verfolgt: Monotherapien mit PD-1/PD-L1-Inhibitoren sowie deren Kombinationen mit CTLA-4-Inhibitoren oder konventioneller Chemotherapie. Es liegen bereits Daten aus einarmigen Phase-2-Studien zur Monotherapie vor. Erste Daten aus randomisierten Studien werden im Laufe des Jahres 2019 erwartet.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Transitional Cell; Clinical Trials as Topic; CTLA-4 Antigen; Docetaxel; Humans; Immunotherapy; Neoplasm Metastasis; Programmed Cell Death 1 Receptor; Randomized Controlled Trials as Topic; Survival Rate; Urinary Bladder Neoplasms; Vinblastine

Microtubules and tubulin are major dynamic and structural cellular components that play a key role in several cell functions, including division, signalling and intracellular trafficking. Normal epithelial cells have a highly structured, rigid cytoskeletal network that is compatible with cell motility. Thus, tubulin and microtubules are compelling cellular targets for chemotherapy. In fact, among anticancer agents, those that target microtubules constitute one of the most effective classes of chemotherapeutics in cancer. The list of compounds that target either tubulin or microtubules is extensive and consists of chemically unique compounds that bind to the tubulin dimers and destabilize microtubules (Vinca alkaloids) and those that bind to the microtubule polymer and stabilize microtubules (taxanes). Tumour-induced angiogenesis, the formation of new capillaries from existing blood vessels, and epithelial-mesenchymal transition are two steps that are critical for both tumour growth and metastatic spread. Three possible mechanisms of action are described with vinflunine, the new-generation Vinca alkaloid to arrive in clinical practice are as follows: it acts against tubulin and microtubules, disrupts newly formed blood vessels and seems to be able to reduce the metastatic process as shown in preclinical studies. These findings support the hypothesis that vinflunine, by blocking microtubule functions that contribute to cell shape, polarization, migration and other processes, might be responsible not only for tumour-cytostatic but also for specific antiangiogenic or antiepithelial-mesenchymal transition effects.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Cell Polarity; Epithelial-Mesenchymal Transition; Humans; Microtubules; Neoplasm Metastasis; Tubulin; Vinblastine; Vinca Alkaloids

The novel third-generation bifluorinated semisynthetic vinca alkaloid, vinflunine, is a microtubule inhibitor that shows superior antitumor activity and a favorable safety profile compared with other vinca alkaloids. The main antineoplastic effects of vinflunine arise from its interaction with tubulin, the major component of microtubules in mitotic spindles. Vinflunine is known to have low affinity for tubulin, high intracellular accumulation, and important effects on microtubule dynamics. It has been shown to have activity against transitional cell carcinoma of the urothelial tract. Vinflunine was investigated in a randomized phase III clinical trial comparing vinflunine and best supportive care versus best supportive care alone in patients with advanced transitional cell carcinoma of the urothelial tract, who were progressive after first-line platinum-containing therapy. At an acceptable safety profile without cumulative toxicity, second-line treatment with vinflunine has shown a survival advantage and has therefore been approved in 2009 for this indication. This review gives a brief outline on vinflunine as a second-line treatment for platin-resistant advanced urothelial carcinoma; it describes pharmacology, efficacy studies, tolerance, and side effects and briefly discusses future clinical perspectives.

Topics: Animals; Antineoplastic Agents; Carcinoma, Transitional Cell; Drug Resistance, Neoplasm; Humans; Neoplasm Metastasis; Organoplatinum Compounds; Urologic Neoplasms; Vinblastine

There is currently no curative treatment for advanced-stage or metastatic transitional cell carcinoma of the uretholial tract. Chemotherapy generally only prolongs survival by a few months. Cisplatin is often used, but there is no consensus protocol. Vinflunine, a fluorinated vinblastine derivative, has been tested in many types of cancer since the 1990s. It was finally authorised in the EU in 2009, but only for second-line treatment of urothelial carcinoma of the bladder. Clinical evaluation of vinflunine in this setting is based on a single unblinded trial in 370 patients with treatment failure. It compared vinflunine plus individually tailored palliative care versus palliative care alone. Vinflunine increased the median overall survival time by 2 months (from 4.6 months to 6.9 months), a difference that was not statistically significant in the protocol-specified primary analysis. Other analyses showed a significant difference, but the gain in survival was still only about 2 months, which is no better than with other cytotoxic drugs. Vinflunine has the same profile of adverse effects as other vinca alkaloids, including frequent, often serious and sometimes fatal haematological disorders, severe constipation, and ileus. Other adverse effects include QT prolongation and cardiac ischaemia. * In practice, vinflunine has an unfavourable risk-benefit balance in patients with bladder cancer. It is better to continue to use better-assessed treatments.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Transitional Cell; Humans; Neoplasm Metastasis; Neoplasm Staging; Survival Rate; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Despite the recent trend toward treatment of early stage breast cancer aggressively with anthracyclines and taxanes, nearly half of those women will have metastatic recurrence. Moreover, because of the increasing prior exposure to these drugs, far more women facing first-line therapy for recurrent disease will now have developed anthracycline- and taxane-refractory metastatic breast cancer (ATRMBC), presenting a major therapeutic challenge. A number of established drugs are showing promise in this setting: capecitabine alone or combined with lapatinib; gemcitabine; vinorelbine; and oxaliplatin. At the same time, a variety of new drugs are emerging for potential use in ATRMBC. Among the drugs in clinical development that have shown promising activity include novel classes of compounds (camptothecins and epothilones), newer members of established classes (pemetrexed and vinflunine), and agents with novel mechanisms of action (the mitosis inhibitor E7389 and the ascidian-derived anticancer compound trabectedin). Several molecularly targeted agents are also being evaluated in ATRMBC, including interleukin-2 receptor-binding denileukin diftitox, and 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), which inhibits the protein chaperone heat shock protein 90.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Camptothecin; Clinical Trials as Topic; Deoxycytidine; Dioxoles; Diphtheria Toxin; Drug Resistance, Neoplasm; Drugs, Investigational; Epothilones; Female; Furans; Gemcitabine; Glutamates; Guanine; Humans; Interleukin-2; Ketones; Lapatinib; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pemetrexed; Quinazolines; Recombinant Fusion Proteins; Tetrahydroisoquinolines; Trabectedin; Vinblastine; Vinorelbine

We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit.. Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming-A'Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m. Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression.. Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease.. NCT02057913.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Patient Safety; Penile Neoplasms; Survival Rate; Treatment Outcome; Tubulin Modulators; Vinblastine

There is no standard treatment after progression on second-line chemotherapy for metastatic breast cancer (MBC). We compared vinflunine with physician's choice of alkylating agent (AA) for patients with heavily pretreated MBC.. In this open-label phase III trial, patients with MBC were included if they had received at least two prior chemotherapy regimens for MBC and had received anthracycline, taxane, antimetabolite and vinca alkaloid therapy. Patients were no longer candidates for these chemotherapies because of resistance and/or intolerance. Patients were randomised to either vinflunine 280 mg/m2 intravenously every 3 weeks (q3w) or AA monotherapy q3w. Stratification factors were performance status, number of prior chemotherapy lines for MBC, disease measurability and study site. The primary end point was overall survival (OS).. A total of 594 patients were randomised (298 to vinflunine, 296 to AA). There was no difference between treatment arms in OS (hazard ratio 1.04, P = 0.67; median 9.1 months for vinflunine versus 9.3 months for AA), progression-free survival (hazard ratio 0.94, P = 0.49; median 2.5 versus 1.9 months, respectively) or overall response rate (6% versus 4%, respectively). However, the disease control rate was significantly higher with vinflunine than AA (44% versus 35%, respectively; P = 0.04). The most common adverse events (any grade) were haematological and gastrointestinal disorders and asthenia in both arms. The most common grade 3/4 adverse events were neutropenia (19% versus 11% with vinflunine versus AA, respectively) and asthenia (10% versus 4%).. Vinflunine 280 mg/m2 q3w did not improve OS compared with the physician's choice of AA as third- or later-line therapy for MBC. Vinflunine demonstrated an acceptable safety profile, suggesting that vinflunine 320 mg/m2 merits evaluation.. NCT01091168.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Quality of Life; Survival Analysis; Treatment Outcome; Vinblastine

Vinflunine is recommended in the European guideline for the treatment of advanced or metastatic urothelial cell carcinoma (UCC) after failure of platinum-based therapy.. This prospective, non-interventional study investigated the safety and efficacy of vinflunine in platinum-pretreated UCC patients in routine clinical practice. Data were prospectively collected on patients with advanced or metastatic UCC undergoing vinflunine treatment in 39 German hospitals and medical practices. Dosing of vinflunine, tumor assessments and concomitant medications followed physician's routine clinical practice. Primary endpoints were toxicity and assessment of vinflunine treatment modalities. Secondary aims included overall response rate (ORR), overall survival (OS) time and a prognostic risk-model.. Seventy-seven platinum-pretreated patients were recruited. Vinflunine was predominantly administered as second-line (66%) therapy or in subsequent treatment lines (21%). One third of the patients received at least six cycles of vinflunine and the average number was 4.7 cycles. A vinflunine starting dose of 320 mg/m2 was chosen in 48% of patients and 280 mg/m2 in 39%. Grade 3/4 toxicities were leucopenia 16.9%, anemia 6.5%, elevated liver enzymes 6.5% and constipation 5.2%. ORR was 23.4% and OS was 7.7 (CI 4.1 to 10.4) months. Patients with zero, one, two or ≥three risk factors displayed a median OS of 18.2, 9.5, 4.1 and 2.8 months, respectively (p=0.0005; HR=1.82).. Vinflunine delivers a meaningful benefit to an unselected population of advanced platinum-pretreated UCC patients managed in routine clinical practice.

Topics: Adult; Aged; Carcinoma; Disease-Free Survival; Female; Germany; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Erlotinib, the epidermal growth factor receptor tyrosine kinase inhibitor, and the intra-venous vinflunine vinca alkaloid microtubule inhibitor have been shown to be effective in the setting of non-small-cell lung cancer (NSCLC) palliative patients with acceptable toxicities. This phase I study was conducted to determine the maximal tolerated dose (MTD) and the safety of an all-oral combination. A potential pharmacokinetic drug-drug interaction was also investigated.. Patients with unresectable stage IIIB or stage IV NSCLC who failed one or two previous chemotherapy regimens were treated with flat doses of oral vinflunine from day 1 to day 5 and from day 8 to day 12 every 3 weeks and erlotinib daily on a continuous basis. The dose levels of vinflunine/erlotinib were 95/100, 115/100, 115/150 and 135/100 mg.. Thirty patients were enroled. The recommended dose was 115/150 mg and the MTD 135/100 mg. Dose-limiting toxicities included grade 3 febrile neutropenia (1 patient) and related death (1 patient). Non-haematologic grade 3/4 toxicities included fatigue, condition aggravated, hypokalaemia, tumour pain, acneiform dermatitis, diarrhoea, hyperbilirubinaemia and pulmonary haemorrhage, in one patient each. Of 25 patients evaluable for tumour response, 2 patients had partial response and 20 patients had stable disease.. The recommended doses for oral vinflunine and erlotinib combination were, respectively, 115 mg/day from day 1 to day 5 and from day 8 to day 12 every 3 weeks and 150 mg/day. There was no mutual impact on pharmacokinetics. The combination was safe but evaluation in phase II is needed to further refine the activity and toxicity that can be expected with prolonged administration of this dose schedule.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Drug Interactions; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Quinazolines; Vinblastine

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.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Epirubicin; Female; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Vinblastine; Young Adult

A phase III trial demonstrated an overall survival advantage with the addition of vinflunine to best supportive care (BSC) in platinum-refractory advanced urothelial cancer. We subsequently examined the impact of an additional 2 years of survival follow-up and evaluated the influence of first-line platinum therapy on survival.. The 357 eligible patients from the phase III study were categorised into two cohorts depending on prior cisplatin treatment: cisplatin or non-cisplatin. Survival was calculated using the Kaplan-Meier method.. The majority had received prior cisplatin (70.3%). Survival was higher in the cisplatin group (HR: 0.76; CI 95% 0.58-0.99; P=0.04) irrespective of treatment arm. Multivariate analysis including known prognostic factors (liver involvement, haemoglobin, performance status) and prior platinum administration did not show an independent effect of cisplatin. Vinflunine reduced the risk of death by 24% in the cisplatin-group (HR: 0.76; CI 95% 0.58-0.99; P=0.04) and by 35% in non-cisplatin patients (HR: 0.65; CI 95% 0.41-1.04; P=0.07).. Differences in prognostic factors between patients who can receive prior cisplatin and those who cannot may explain the survival differences in patients who undergo second line therapy. Prior cisplatin administration did not diminish the subsequent benefit of vinflunine over BSC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Cisplatin; Cohort Studies; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Vinflunine ditartrate is a microtubule inhibitor belonging to the vinca alkaloid family. This phase I study was carried out to evaluate the maximal tolerated dose, the safety profile, the pharmacokinetics and the activity of oral vinflunine (VFL) given daily in patients with advanced/metastatic solid tumours and who have failed standard therapy.. Patients were treated with oral VFL administered once daily for 6 weeks followed by a two-week rest. Sequential dose-escalating cohorts of patients were enrolled into 5 dose levels: 20, 40, 60, 75 and 95 mg/day.. In total, 27 patients received 53 cycles. Dose-limiting toxicities (DLT) were observed from 60 mg/day. The dose levels 75 and 95 mg/day were both assessed as maximal tolerated dose. The most frequent dose-limiting toxicities were of haematological origin. The recommended dose was defined as 60 mg/day, dose at which 4 patients experienced long stabilizations (≥4 months) and also received longer treatment duration in comparison with the other dose levels. Blood exposure of VFL and its active metabolite 4-O-deacetyl vinflunine (DVFL) increased proportionally to the dose levels. The concentrations of VFL and DVFL reached a steady state at, respectively, 5 and 20 days and remained stable for the rest of the cycle. Increased incidence of DLT/SAE was consistent with the increase of VFL dose and drug exposure.. These results showed the feasibility of daily oral vinflunine administration on a 6-week treatment duration. This new schedule of administrations enabled sustained and stable blood concentrations of both VFL and DVFL. The recommended dose was defined at 60 mg/day, dose at which 4 patients experienced clinical benefit.

Topics: Adult; Aged; Anemia; Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Area Under Curve; Asthenia; Biotransformation; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Neutropenia; Prospective Studies; Treatment Outcome; Vinblastine

A phase I study was performed to determine the maximal tolerated dose (MTD), recommended dose (RD), safety and efficacy of vinflunine when combined with capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes, with pharmacokinetic blood sampling to test potential drug-drug interactions.. Sixteen patients with MBC who had received anthracyclines and taxanes in the neo/adjuvant setting, if progression occurred during or within 12 months of chemotherapy completion, and/or as first-line chemotherapy of MBC were enrolled. Vinflunine (VFL) was given on day 1 with capecitabine (CAPE) twice daily from days 1 to 14, every 3 weeks. Three dose levels (DL) were investigated (DL1: VFL 280 mg/m² and CAPE 1,650 mg/m²/day, DL2: VFL 320 mg/m² and CAPE 1,650 mg/m²/day and DL3: VFL 280 mg/m² and CAPE 2,000 mg/m²/day).. The RD was established as vinflunine 280 mg/m² on day 1 plus capecitabine 1,650 mg/m²/day on days 1 to 14 given every 3 weeks. Dose-limiting toxicities were grade 4 neutropenia lasting at least 7 days for 2 patients, anorexia with fatigue for 1 patient and diarrhoea with fatigue, anorexia and febrile neutropenia for 1 patient. Neutropenia was the main toxicity of the combination, it was reported in 15 patients (93.8%) with grade 3 in 7 patients (43.8%) and 22.6% of cycles and grade 4 in 7 patients (43.8%) and 19.8% of cycles. Complications were rare with only one patient experiencing febrile neutropenia at DL exceeding the RD. The most frequent non-haematological toxicities were fatigue and gastrointestinal disorders; however, no grade 3 or 4 episode was observed at the RD. Hand-foot syndrome was reported in 5 patients (31.3%) and 22.6% of cycles, no episode of grade 3 was seen. Concerning pharmacokinetics, no modifications were detected for VFL, while slight accumulation between days 1 and 14 was observed for 5-FU formed from CAPE. The risk of clinical significant drug-drug interaction was considered weak. Objective partial responses were reported in 7 patients, yielding a response rate of 43.8% in the all-treated population according to the investigator assessment.. The combination of vinflunine and capecitabine is safe and showed promising antitumour activity in MBC patients who have failed prior anthracyclines and taxanes. Further clinical development of this combination is warranted.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Female; Fluorouracil; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome; Vinblastine

Vinflunine (VFL) has been approved in the European Union for second-line treatment of advanced transitional cell carcinoma of the urothelial tract (TCCU) in patients who progress after a platinum based regimen. However, very few patients achieve response by response evaluation criteria in solid tumours (RECIST). Therefore, another 'response' threshold may be more useful than RECIST 1.0 in this setting.. One hundred and seventy nine patients with advanced TCCU treated with second-line VFL therapy had chest Computed Tomography (CT) and abdominal/pelvic CT or MRI performed at baseline and at first follow-up (6 weeks ± 3 days) after therapy initiation. Tumour measurements and response by RECIST 1.0 were correlated with overall survival (OS). Kaplan-Meier and receiver operating characteristic (ROC) analysis were then used to determine the optimal size threshold to define 'responders'. Impact of adverse prognostic factors including Eastern Cooperative Oncology Group Performance Status (ECOG PS) >0, Hb <10 g/dL, and liver metastases was analysed.. Tumour response included 13 partial responses (PR) by RECIST 1.0 and 52 patients with ≥ 10% decrease in the sum of longest diameters. Responders by RECIST 1.0 did not have a statistically significant improvement in OS, while patients with sum long axis diameter (SLD) reduction of ≥ 10% had a longer OS than those with SLD reduction of <10%: 11.3 versus 6.9 months (log rank p=0.0224). ROC analysis yielded ≥ 10% decrease in SLD as the optimal size change correlating with OS. These results persisted on multivariate analysis.. In the study population, a ≥ 10% reduction in SLD at first follow-up imaging is a better early predictor of outcome than RECIST.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Transitional Cell; Diagnostic Imaging; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Image Processing, Computer-Assisted; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Metastasis; Prognosis; ROC Curve; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Vinflunine is a new microtubule inhibitor of the vinca-alkaloid family. It is marketed in transitional cell carcinoma of urothelial tract as a 20 min infusion given every 3 weeks in Europe.. In this phase I study, vinflunine was administered to patients with advanced malignancies as hard capsules given twice a day on days 1-2 every week, with 3 weeks cycles. Serial blood samples were collected during the first cycle for pharmacokinetic investigations.. Thirty-six patients (pts) were treated at 6 dose levels 150 (3 pts), 190 (3 pts), 230 (8 pts), 300 mg/day (6 pts) and then 250 (3 pts) and 270 mg/day (13 pts). The Maximal Tolerated Dose (MTD) was reached at 300 mg/day where 2 patients out of 6 experienced a dose limiting toxicity (febrile neutropenia with diarrhea). The lower dose level of 270 mg/day was the recommended dose (RD), the toxicity profile being mainly anaemia, neutropenia, fatigue and constipation. The pharmacokinetic analysis demonstrated the adequacy of the flat-fixed dosing regimen, as no correlation between clearance of vinflunine and body surface area was evidenced. Blood concentrations and exposure increased with dose, and a pharmacokinetic accumulation was observed, which is consistent with the terminal half-life of the compounds. The inter-individual exposure variability at the RD was 35%.. Repeated weekly administration of oral vinflunine is feasible and exhibits a moderate inter-individual PK variability. The MTD was achieved at 300 mg/day given for 2 consecutive days. According to the protocol rules, the RD was established at 270 mg/day.

Topics: Adult; Aged; Capsules; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Tubulin Modulators; Vinblastine

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.. 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.. 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 %).. 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.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Interactions; Female; Humans; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Trastuzumab; Vinblastine

Patients with metastatic prostate cancer resistant to hormones and docetaxel were treated with vinflunine (320 mg/m(2) every 21 days), a new vinca alkaloid with improved preclinical activity. Only 1 of 36 patients (3%) had partial response; the median progression-free survival (PFS) was 2.1 months. Treatment was well tolerated, with myelosuppression as the only frequent toxicity. Vinflunine has a low level of activity in the treatment of refractory metastatic prostate cancer, and should not be further developed for this indication.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Humans; Male; Middle Aged; Neoplasm Metastasis; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Salvage Therapy; Vinblastine

We investigated the microtubulin inhibitor vinflunine—with trastuzumab in human epidermal growth factor receptor-2 (HER2)-positive patients—as first-line metastatic breast cancer therapy. HER2-negative patients received vinflunine on day 1; HER2-positive patients received vinflunine/trastuzumab every 21 days. Forty-eight patients in each treatment group were planned; the sponsor terminated the study early. Thirty-two evaluable patients (vinflunine, 11; vinflunine/trastuzumab, 21) were enrolled. In HER2-positive patients, vinflunine/trastuzumab produced an objective response rate (33%), clinical benefit rate (71%), and progression-free survival (6.2 months). Grade-3/4 neutropenia occurred in 14 (44%) patients; gastrointestinal toxicities were common and six patients were hospitalized for treatment-related toxicity. The vinflunine/trastuzumab combination was active and well tolerated, but our results do not suggest advantages over taxane/trastuzumab or vinorelbine/trastuzumab.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Middle Aged; Neoplasm Metastasis; Neutropenia; Pain; Receptor, ErbB-2; Trastuzumab; Treatment Outcome; Vinblastine

The activity and safety of vinflunine was evaluated in patients with locally advanced or metastatic urothelial carcinoma (UC) who developed disease progression within 12 months of platinum-containing chemotherapy.. Patients with UC were eligible if they received a prior platinum-based regimen in the neoadjuvant/adjuvant setting or as first-line treatment for advanced/metastatic disease and had developed disease progression within 12 months. Vinflunine was administered intravenously every 3 weeks. Patients with Karnofsky performance status of 80 or 90, impaired renal function, prior pelvic irradiation, or age>or=75 years received an initial dose of 280 mg/m2, which was escalated to 320 mg/m2 in Cycle 2 if well tolerated. All other patients received an initial dose of 320 mg/m2. The primary endpoint was response rate defined by an independent response review committee (IRRC).. Per the IRRC, 22 patients achieved a partial response, with a response rate of 15% (95% confidence interval, 9%-21%) with a median duration of response of 6.0 months. Sixty-four (42%) patients had stable disease. The median progression-free survival was 2.8 months, and the median overall survival was 8.2 months. Myelosuppression was the most frequent adverse event, with grade 3 of 4 (adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria [version 2.0] guidelines) neutropenia reported in 58% of the patients. Grade 3 of 4 febrile neutropenia occurred in 10 (7%) patients. Nonhematologic treatment-related events (grade 3 of 4) were generally manageable and included constipation (17%), asthenia/fatigue (13%), ileus (5%), and abdominal pain (5%). No cumulative toxicity was observed.. Vinflunine demonstrates moderate activity in patients with platinum-pretreated UC. Toxicity is manageable and noncumulative.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Transitional Cell; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Platinum Compounds; Retreatment; Urinary Bladder Neoplasms; Vinblastine

Vinflunine is a microtubule inhibitor of the vinca alkaloid class approved for the treatment of urothelial bladder carcinoma after a platinum-containing regimen.. To evaluate the effectiveness of vinflunine, we enrolled 80 subjects with a histologically confirmed diagnosis of metastatic urothelial bladder carcinoma that had previously undergone chemotherapy with a platinum-containing regimen and had measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST). The patients (n = 80) received vinflunine (Javlor®) every 3 weeks at 320 mg/m2 via 20-min intravenous infusion. The endpoints were progression-free survival (PFS), objective response rate, overall survival (OS), and tolerability. The cumulative survival of the patients was analyzed using the Kaplan-Meier method.. In this retrospective study, vinflunine treatment was well tolerated and resulted in a good level of disease control (complete response + partial response + stable disease >50%), with a manageable toxicity profile. The median PFS and OS were 3.2 and 6.8 months, respectively. A significant correlation between pain and PFS was also noted. The major hematologic adverse event was neutropenia, observed in 47% of the patients. The most common nonhematologic adverse events were constipation in 48% of the patients and fatigue in 26%.. In this real-word non-randomized clinical trial setting, the data showed that vinflunine is an efficacious and safe therapeutic option for second-line treatment of patients with metastatic urothelial carcinoma of the bladder after a platinum-containing regimen.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Urinary Bladder Neoplasms; Vinblastine

Urothelial carcinoma of the bladder are rare but aggressive tumors with a high metastatic potential. The prognosis of these tumors has not drastically changed over the past 30 years, with an overall survival of less than two years in advanced or metastatic situations. Even though immune checkpoints inhibitors have changed this picture, it is beneficial for less than 30% of patients and there is no reliable biomarkers to identify this specific population of responders. Vinflunine is a vinca-alkaloid that was specifically developed as second line treatment post-platinum. As of today, it is the sole anticancer agent for which clinical trials have been pushed to phase III and that was approved for patients in good conditions. Unfortunately, it has been withdrawn from the list of reimbursed drugs, which impairs its prescription. Based on the results of phase III clinical trials with immunotherapies, this review provides the reader with argumentations in favor of patients' and clinicians' request to reimburse vinflunine for the treatment of advanced or metastatic urothelial carcinoma of the bladder.

Topics: Humans; Neoplasm Metastasis; Neoplasm Staging; Urinary Bladder Neoplasms; Vinblastine

Despite an expected prognostic disadvantage for upper tract versus lower tract metastatic urothelial carcinomas (UTUC/LTUC), only few studies have been conducted to elucidate potential differences in chemotherapy treatment.. A post-hoc subgroup analysis of a non-interventional study investigating vinflunine after failure of a platinum-based chemotherapy in metastatic/locally advanced UC patients was performed.. A total of 18 and 59 out of 77 patients had UTUC and LTUC, respectively. The effectiveness of vinflunine treatment was comparable with an overall response rate of 22.2% and 23.7% respectively and a median progression-free survival of 2.76 months in both groups. Median overall survival was 5.0 months in UTUC compared to 8.2 months in the LTUC group (p=0.478). The safety profile was in accordance with previous vinflunine experiences, with a comparable frequency of adverse events in both groups.. Vinflunine can be applied in the 2nd line for UC regardless of the primary tumor localization.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Carcinoma, Transitional Cell; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Prospective Studies; Survival Analysis; Treatment Outcome; Urologic Neoplasms; Vinblastine

To retrospectively assess the efficacy and safety of Vinflunine (VFL) under routine conditions and identify overall survival (OS) prognostic factors.. Twenty centres participated in the retrospective study (minimum 4 patients undergoing VFL treatment for advanced/metastatic UC after platinum-based regimen progression. Primary endpoint was OS. Secondary endpoints: progression-free survival (PFS), radiological response rate (RR) RECIST criteria and toxicity (CTC NCI v3).. These centres enrolled 134 patients. Prior chemotherapy (CT) lines (≥ 1 palliative): 1 and ≥ 2 in 69% and 26% of patients, respectively. Performance status (PS): 0, 1, 2 in 25%, 46% and 23% of patients. Median OS = 8.2 months [6.5-9.4], PFS = 4.2 months and RR 22%, median number of 5 cycles. In risk groups based on 0-3 presence of adverse prognostic factors (PS ≥ 1, haemoglobin ≤ 10 g/dl and liver metastasis), median OS: 13.2, 9.9, 3.6, and 2.4 months (P < .0001), respectively; 3.3 months (1.9-5.6) in PS ≥ 2 subgroup.. This study reflects routine UC management and confirmed VFL patient efficacy. The drug is safe with gastro-intestinal and haematological prophylaxis. Analysis of prognostic factors for OS is consistent with pivotal trials.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Platinum; Retrospective Studies; Urologic Neoplasms; Urothelium; Vinblastine

The objective of this retrospective study was to investigate the efficacy and safety of vinflunine monotherapy and the utility of second-line prognostic factors in patients with advanced or metastatic urothelial cancer relapsing/progressing during or after a prior platinum-containing regimen under daily routine clinical conditions in Germany.. The selection was based on the marketing authorization indication and recommendations as well as on the evaluation of second-line prognostic factors issued from prior pivotal trials.. Eight centers across Germany provided a total of 21 patient records. Demographic and clinical characteristics were similar to the data previously reported in pivotal trials. Complete and partial response to vinflunine treatment was observed in 1 (4.8%) and 3 (14.3%) patients, respectively, resulting in an overall response rate of 19.1%. The disease control rate reached 47.7%. The median progression-free survival amounted to 4.4 months (95% CI 2.6-6.6), with a median overall survival of 6.2 months (95% CI 3.9-10.7). The observed toxicity profile was manageable and consistent with prior clinical trials: leukopenia (33.3%), neutropenia (9.5%), anemia (9.5%) and hyperglycemia (4.8%). The reported satisfaction rate with the treatment was 90.5 and 61.9% among patients and physicians, respectively.. This retrospective study confirms that the clinical outcomes obtained from routine medical practice in Germany with vinflunine in the treatment of advanced/metastatic urothelial cancer are in line with the data observed in prior clinical trials.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Disease-Free Survival; Female; Germany; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Platinum; Prognosis; Recurrence; Retrospective Studies; Risk; Treatment Outcome; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Patients with transitional cell carcinoma of the urothelial tract (TCCU) who fail initial platinum-based chemotherapy for advanced disease represent a challenge in daily clinical practice. Vinflunine is approved by the European Medicine Agency (EMA) but, up to now, limited experience has been reported outside clinical trials.. We assessed the efficacy and safety of vinflunine in an unselected group of 102 consecutive patients with metastatic TCCU.. The median age was 67 years (range 45-83). Among the most common comorbidities that patients presented at baseline were hypertension (50.5%) and diabetes (20.7%).Distant metastases were present in retroperitoneal nodes (58%), lung (29.3%), and bone (20.2%). The ECOG 0, 1 and 2 performance status at the start of vinflunine were 31.3%, 60.6% and 8.1%, respectively. The most commonly reported adverse events of any grade were constipation 70.6% (5.9% grade 3-4), vomiting 49.1% (2% grade 3-4), neutropenia 48.1% (12.8% grade 3-4) and abdominal pain 34.3% (4.9% grade 3-4). A median of 4 cycles of vinflunine was administered per patient (range 1-18). Median progression free and overall survival for all patients (N = 102) were 3.9 months (2.3-5.5) and 10 months (7.3-12.8), respectively. Time to tumor progression was 4.3 months (2.6-5.9). Two patients (2%) achieved CR, 23 (22.5%) patients had PR, and 42 (41.2%) presented SD as best response. The clinical benefit rate with vinflunine was 65.7%.. Our results show that the behavior of vinflunine in routine clinical practice resembles that of the pivotal phase III randomized study.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Retreatment; Survival Analysis; Treatment Failure; Treatment Outcome; Urinary Bladder Neoplasms; Vinblastine