A phase II study of vinflunine in bladder cancer patients progressing after first-line platinum-containing regimen

Abstract

A multicentre phase II trial to determine the efficacy of vinflunine as second-line therapy in patients with advanced transitional cell carcinoma (TCC) of the bladder; secondary objectives were to assess duration of response, progression-free survival (PFS) and overall survival (OS), and to evaluate the toxicity associated with this treatment. Patients had tumours that failed or progressed after first-line platinum-containing regimens for advanced or metastatic disease, or had progressive disease after platinum-containing chemotherapy given with adjuvant or neoadjuvant intent. Response and adverse events were assessed according to WHO criteria and NCI-CTC (version 2), respectively. Out of 51 patients treated with 320 mg m À2 of vinflunine, nine patients responded to the therapy yielding an overall response rate of 18% (95% CI: 8.4 -30.9%), and 67% (95%CI: 52.1 -79.3%) achieved disease control (PR þ SD). Of note, responses were seen in patients with relatively poor prognostic factors such as a short (o12 months) interval from prior platinum therapy (19%, including an 11% response rate in those progressing o3 months after platinum treatment), prior treatment for metastatic disease (24%), prior treatment with vinca alkaloids (14%) and visceral involvement (20%). The median duration of response was 9.1 months (95% CI: 4.2 -15.0) and the median PFS was 3.0 months (95% CI: 2.4 -3.8). The median OS was 6.6 months (95% CI: 4.8 -7.6). The main haematological toxicity was grade 3 -4 neutropenia, observed in 67% of patients (42% of cycles). Febrile neutropenia was observed in five patients (10%) and among them two were fatal. Constipation was frequently observed (but was manageable and noncumulative) and was grade 3 -4 in only 8% of patients. The incidence of grade 3 nausea and vomiting was very low (4 and 6% of patients, respectively). Neither grade 3 -4 sensory neuropathy nor severe venous irritation was observed. Moreover, and of importance in this particular study population, no grade 3 -4 renal function impairment was observed. Vinflunine is an active agent for the treatment of platinum-pretreated bladder cancer, and these results warrant further investigation in phase III trials, either as monotherapy or in combination with other agents as treatment of advanced/metastatic TCC of the bladder.

Vinflunine in platinum‐pretreated patients with locally advanced or metastatic urothelial carcinoma

“…The RR defined by the IRRC was similar to the estimate identified at study design, and confirmed the RR previously obtained with singleagent vinflunine in this patient population. 12 Responses were observed in all subsets of patients, including those with poor prognostic factors (visceral disease and decreased KPS) or with unfavorable characteristics (renal impairment, advanced age, and refractory disease defined as disease recurring <3 months after last prior therapy).…”

“…The primary objective of this trial was to confirm the activity of vinflunine demonstrated in the smaller phase 2 trial, 12 and to define the objective RR with more precision. The primary hypothesis of the trial was that vinflunine would result in a RR of approximately 15%.…”

“…11 The clinical activity of vinflunine was recently assessed in 51 bladder cancer patients from Europe who had received prior platinum treatment. 12 The response rate (RR) was 18% (95% confidence interval [95% CI], 8%-31%), with a median progression-free survival (PFS) of 3.0 months and a median overall survival (OS) of 6.6 months. Given these promising results, and the unmet need for second-line treatment, 2 trials were initiated evaluating the efficacy of vinflunine in this setting.…”

Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

“…Vinflunine-related adverse events were not cumulative and included mostly grade 3-4 neutropenia, fatigue, and constipation (69,71).…”

“…Recently completed clinical trials showed the activity of vinflunine in patients with advanced transitional cell carcinoma of the urothelium (TCCU; refs. 69,70), breast (71), NSCLC (72), and malignant pleural mesothelioma (73). In a recently reported phase 3 trial, the efficacy of vinflunine was equivalent to docetaxel in pretreated patients with NSCLC (74).…”