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Background: Tasquinimod is a small molecule with immunomodulatory, anti-angiogenic, and anti-metastatic properties that targets the tumor microenvironment. This study aimed to obtain a clinical proof of concept that tasquinimod was active and tolerable in patients with advanced solid tumors., Patients and Methods: This early stopping design, open-label, proof-of-concept clinical trial evaluated the clinical activity of tasquinimod in four independent cohorts of patients with advanced hepatocellular (n = 53), ovarian (n = 55), renal cell (n = 38), and gastric (n = 21) cancers. Tasquinimod was given orally every day (0.5 mg/day for at least 2 weeks, with dose increase to 1 mg/day) until radiological progression according to Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria, intolerable toxicity, or patient withdrawal. The primary efficacy endpoint was progression-free survival (PFS) rate according to RECIST 1.1 by central assessment., Results: Interim futility analyses at 8 weeks (6 weeks for the gastric cancer cohort) found adequate clinical activity of tasquinimod only in the hepatocellular cohort and recruitment to the other three cohorts was stopped. PFS rates were 26.9% at 16 weeks, 7.3% at 24 weeks, 13.2% at 16 weeks, and 9.5% at 12 weeks, respectively, in hepatocellular, ovarian, renal cell, and gastric cancer cohorts. The pre-defined PFS threshold was not reached in the hepatocellular cancer cohort at the second stage of the trial. The most common treatment-related adverse events were fatigue (48.5%), nausea (34.1%), decreased appetite (31.7%), and vomiting (24.6%)., Conclusions: This study failed to demonstrate clinical activity of tasquinimod in heavily pre-treated patients with advanced hepatocellular, ovarian, renal cell, and gastric cancer., Trial Registration: NCT01743469.

Purpose: Tasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit., Patients and Methods: Men with chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point., Results: In all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) between March 2011 and December 2012 at 241 sites in 37 countries. Baseline characteristics were balanced between groups: median age, 71 years; Karnofsky performance status ≥ 90%, 77.3%; and visceral metastases, 21.1%. Estimated median rPFS by central review was 7.0 months (95% CI, 5.8 to 8.2 months) with tasquinimod and 4.4 months (95% CI, 3.5 to 5.5 months) with placebo (HR, 0.64; 95% CI, 0.54 to 0.75; P < .001). Median OS was 21.3 months (95% CI, 19.5 to 23.0 months) with tasquinimod and 24.0 months (95% CI, 21.4 to 26.9 months) with placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). Grade ≥ 3 adverse events were more frequent with tasquinimod (42.8% v 33.6%), the most common being anemia, fatigue, and cancer pain., Conclusion: In chemotherapy-naïve men with mCRPC, tasquinimod significantly improved rPFS compared with placebo. However, no OS benefit was observed., (© 2016 by American Society of Clinical Oncology.)

Purpose: 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., Methods: 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., Results: 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., Conclusions: 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.

Objective: A multicenter, open-label, phase 2 study evaluated the efficacy and safety of intravenous vinflunine as third-line treatment in patients with progressing metastatic breast cancer (MBC) after failure of anthracycline- and taxane-based chemotherapy., Patients and Methods: Fifty-six patients with MBC, relapsing after receiving 2 previous treatments for advanced disease, including both anthracyclines and taxanes, received 320 mg/m(2) of vinflunine once every 3 weeks (median number of 2.5 cycles, range: 1-13)., Results: According to an independent radiologist, the response rate was 12.5% (95% CI: 5.2-24.1) and 14% (95% CI: 5.3-27.9) (6 partial responses) in the treated and evaluable populations, respectively. Disease control was achieved in 42.9% and 51.2% of the patients, respectively. Median progression-free survival was 2.6 months (95% CI: 1.6-4.0 months) with a median overall survival of 11.4 months (95% CI: 7.4-14.2 months). Duration of response was 6.8 months (95% CI: 5.6 months, upper limit not reached). Leukopenia was the most frequent hematologic toxicity, with grade 3/4 severity in 49.1% of the patients. Grade 3 neutropenia in 30.9%, grade 4 in 40.0% of patients, febrile neutropenia (5.4%), and 1 case of neutropenia infection (1.8%) were reported. Other grade 3 toxicities included anemia (5.5%), fatigue (14.3%), and constipation (7.1%), which were noncumulative. The adverse events associated with vinflunine were predictable and manageable., Conclusions: Vinflunine is an active and well-tolerated agent as third-line treatment of patients with MBC after failure of anthracycline- and taxane-based therapy. These results warrant further investigation of vinflunine monotherapy or in combination for the treatment of MBC.

Purpose: Combination of intravenous (i.v.) vinorelbine and docetaxel was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated in first-line treatment a regimen alternating i.v. and oral vinorelbine in combination with docetaxel., Patients and Methods: Forty-nine patients (median age, 53 years) with MBC received a maximum of 6 cycles consisting of i.v. vinorelbine 20 mg/m(2) plus docetaxel 60 mg/m(2) given on day 1, and oral vinorelbine 60 mg/m(2) on day 15 every 3 weeks in an open-label, multicentre phase II study (recommended dose established in phase I study [1])., Results: Sixty-three percent of the patient had received prior adjuvant chemotherapy and 78% presented visceral involvement. Twenty-four responses were documented and validated by an independent panel review, yielding response rates of 49% (95% CI: 34-64) in the 49 enrolled patients and 55.8% (95% CI: 40-71) in the 43 evaluable patients. Median duration of response was 9.4 months. Median progression-free survival and median overall survival were 5.5 and 33.2 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, four patients having experienced febrile neutropenia and one having developed neutropenic infection. Other frequently reported adverse events included alopecia, fatigue, stomatitis, constipation, diarrhoea and nausea, which were rarely severe., Conclusions: This regimen alternating oral and i.v. vinorelbine in combination with docetaxel is effective and manageable. Vinorelbine i.v. per oral day 1 per day 15-docetaxel day 1 every 3 weeks represents a convenient option to combine docetaxel and vinorelbine for the palliative treatment of MBC.

Introduction: Cisplatin in combination with vinorelbine has reported an optimal activity/tolerance ratio when used in combination with radiotherapy in locally advanced unresectable non-small cell lung cancer. The currently available oral formulation of vinorelbine should be easier to use assuming a similar activity profile. An international phase II trial with vinorelbine oral and cisplatin as induction followed by oral vinorelbine and cisplatin with concomitant radiotherapy was implemented to evaluate the efficacy in terms of objective response (OR) following this combination as primary end point and duration or response, progression-free survival, overall survival, and safety as secondary endpoints., Material and Methods: The study included patients between 18 and 75 years, with histologically proven untreated locally advanced inoperable stage IIIA/IIIB (supraclavicular lymph nodes and pleural effusion excluded) non-small cell lung cancer, adequate bone marrow, hepatic and renal function, Karnofsky performance status >/=80%. Patients were treated with oral vinorelbine 60 mg/m day 1,8 cycle 1 and 80 mg/m day 1,8 cycle 2 (if no grade 3-4 toxicity) and cisplatin 80 mg/m day 1 every 3 weeks for 2 cycles as induction. Patients without progression received oral vinorelbine 40 mg/m day 1, 8 and cisplatin 80 mg/m day 1 every 3 weeks for 2 more cycles with radiotherapy 66 Gy in 6.5 weeks., Results: Patient and disease characteristics (n = 54) included: median age 57 years; female sex 24%; stage IIIA 48% and IIIB 52%; Squamous carcinoma 59%, Karnofsky performance status 100% (range, 80-100%) 50%, patients >/=5% weight loss at baseline 7%. Relative dose intensities of oral vinorelbine/cisplatin were 86%/93% and 97%/98% at induction and in combination with radiotherapy, respectively. Forty-one patients (76%) increased oral vinorelbine from 60 to 80 mg/m day during induction (reasons for nonescalation: hematological 7 patients, nonhematological 2 patients, error 4 patients). After two cycles of chemotherapy induction, the OR intent-to-treat in the 54 patients was 37%. Toxicities during induction were as follows: Neutropenia G3-4 (28%), Febrile Neutropenia (7%), nausea G3 (11%), vomiting G3-4 (9%), anorexia G3 (4%), diarrhea G4 (2%), constipation G3 (2%). Forty-seven out of 54 (87%) patients received concomitant chemo-radiotherapy.Median radiotherapy delivered dose was 66 Gy. Tolerance: 9% G3 Neutropenia; 4% G3 dysphagia/radiation; 2% G3 radiation dermatitis. Late pulmonary fibrosis was reported in one patient (1.8%). One month after completion of chemo-radiotherapy, the overall OR intent-to-treat in the 54 patients was 54% (95% CI: 40-67%). With a median follow-up of 37 months (95% CI: 34-41) the median progression-free survival and overall survival were: 12.5 (95% CI: 9.6-16.4) and 23.4 (95% CI: 17.6-29.8) months, respectively., Conclusion: Oral vinorelbine in combination with cisplatin is an effective combination in stage IIIA/IIIB patients. The excellent tolerance profile allowed to complete concomitant chemo-radiotherapy in 87% of patients. Oral vinorelbine in combination with cisplatin is a new and promising option that facilitates the administration of concomitant chemo-radiotherapy with high rates of treatment completion.

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.

Background: Intravenous vinorelbine plus cisplatin is widely prescribed for the treatment of NSCLC. The objective of this phase II study was to define the efficacy of an oral form of vinorelbine combined with cisplatin for first line treatment of advanced/metastatic NSCLC., Patients and Methods: From September 2002 to December 2003, 46 chemotherapy-naive patients received 80 mg/m(2) of cisplatin on day 1 and oral vinorelbine at 60 mg/m(2) on days 1 and 8, every 3 weeks., Results: After an independent panel review, the response rate was 37.5 % [95% confidence interval (CI): 22.7-54.2%] in the evaluable population and 32.6% [95% CI: 19.5-48] in the intent-to-treat population. Median progression-free survival was 5.6 months and overall survival was 11.2 months. Grades 3 and 4 neutropenia was observed in 58.7% of patients, with febrile neutropenia and neutropenic infection in 4.3 and 8.7% of patients, respectively. The main non-haematological toxicities were hypotension, fatigue (8.7% for each) and gastrointestinal disorders with rare grades 3 and 4., Conclusions: These results suggest that the combination of cisplatin at 80 mg/m(2) on day 1 with oral vinorelbine at 60 mg/m(2) on days 1 and 8, every 3 weeks, is an active regimen, associated with acceptable toxicity. Oral vinorelbine is therefore a good alternative to the i.v. formulation.

Purpose: The objective of this trial was to compare two vinorelbine-based doublets with carboplatin (CBDCA-VC) or with gemcitabine (VG) in patients with stage IIIB-IV non-small cell lung cancer (NSCLC)., Patients and Methods: A total of 316 patients with advanced NSCLC previously untreated were randomized to either vinorelbine 30 mg/m(2) D1,8 with carboplatin AUC 5 D1 (VC) or vinorelbine 25mg/m(2) with gemcitabine (VG) 1000 mg/m(2) both given D1,8 every 3 weeks. The primary endpoint was response rate with secondary parameters being survival (OS), progression-free survival (PFS), tolerance and clinical benefit., Results: The median number of cycles was four in each arm with a total of 1268 cycles. The objective response (OR) on intent-to-treat was 20.8% in VC and 28% in VG (p=0.15). Median PFS was 3.9 months in VC and 4.4 months (mo) in VG (p=0.18). Median survival was significantly longer (p=0.01) for VG with 11.5 mo compared to 8.6 mo in VC with 1 year survival at 48.9 and 34.4%, respectively. Tolerance was better in the VG arm as compared to the VC patients. Four toxic deaths were recorded in the VC group. Clinical benefit response rate was 32.4% compared to 40.9% in 111 and 110 evaluable patients in VC and VG, respectively., Conclusion: VG compared to VC resulted in a similar overall response rate, favourable median survival and a better toxicity profile. For non-cisplatin-based chemotherapy, VG is a useful alternative.