cabazitaxel and Urinary-Bladder-Neoplasms

Neoadjuvant cisplatin-based combination chemotherapy improves survival in muscle-invasive bladder cancer. However, response rates and survival remain suboptimal. We evaluated the efficacy, safety, and tolerability of cisplatin plus cabazitaxel.. Objective response was seen in 15 of 26 evaluable patients (57.7%) and more than one- third of patients achieved a pathologic complete response (9/26; 34.6%). Seventy-eight percent of the patients (21/27) completed all cycles of treatment, with only 6.7% of the reported adverse events being graded 3 or 4. There were 6 treatment-related serious adverse event reported, but no suspected unexpected serious adverse reactions. In the patients who achieved an objective response, the median progression-free survival and overall survival were not reached (median follow-up of 41.5 months). In contrast, the median progression-free survival (7.2 months) and overall survival (16.9 months) were significantly worse (P = .001, log-rank) in patients who did not achieve an objective response.. Cabazitaxel plus cisplatin for neoadjuvant treatment of muscle-invasive bladder cancer can be considered a well-tolerated and effective regimen before definitive therapy with higher rates (57.7%) of objective response, comparing favorably to that with of cisplatin/gemcitabine (23%-26%). These results warrant further evaluation in a phase III study.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Cisplatin; Cystectomy; Disease-Free Survival; Humans; Muscles; Neoadjuvant Therapy; Taxoids; Treatment Outcome; Urinary Bladder; Urinary Bladder Neoplasms

For patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer, multi-agent intravesical trials have been limited. In this study we investigate the safety of intravesical cabazitaxel, gemcitabine and cisplatin in the salvage setting.. This was a dose escalation, drug escalation trial for patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer who declined or were ineligible for radical cystectomy. All patients underwent a 6-week induction regimen of sequentially administered cabazitaxel, gemcitabine and cisplatin. Complete response was defined as no cancer on post-induction transurethral bladder tumor resection and negative urine cytology, while partial response allowed for positive cytology. Responders continued with maintenance cabazitaxel and gemcitabine monthly for the first year and bimonthly for the second year.. A total of 18 patients were enrolled. Mean age was 71 years, median followup was 27.8 months (range 16.3 to 46.9) and mean number of previous rounds of intravesical therapies before trial enrollment was 3.7. Nine patients (50%) had received intravesical chemotherapy after bacillus Calmette-Guérin and 7 (39%) were previously treated in a phase I clinical trial setting. At enrollment 6 (33%) subjects had T1 disease and 13 (72%) had carcinoma in situ. There were no dose limiting toxicities. Initial partial and complete response rates were 94% and 89%, respectively. At 1 year recurrence-free survival was 0.83 (range 0.57 to 0.94) and at 2 years estimated recurrence-free survival was 0.64 (0.32 to 0.84).. In this high risk and highly pretreated cohort of bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer cases combination intravesical cabazitaxel, gemcitabine and cisplatin was a well tolerated and potentially effective regimen.

Topics: Administration, Intravesical; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; BCG Vaccine; Carcinoma, Transitional Cell; Cisplatin; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Taxoids; Urinary Bladder Neoplasms

Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine.. This is a multicenter, randomized, open-label, phase II/III study, following a Simon's optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III.. Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7-32.4) and six patients (30%) in the vinflunine arm (95% CI 11.9-54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3- to 4-related adverse events were seen in 41% patients with no difference between the two arms.. This phase II/III second line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously.. NCT01830231.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Transitional Cell; Disease Progression; Disease-Free Survival; Europe; Female; Humans; Liver Neoplasms; Male; Middle Aged; Survival Analysis; Taxoids; Time Factors; Treatment Outcome; Urinary Bladder Neoplasms; Urothelium; Vinblastine

We aimed to identify SNPs associated with cabazitaxel toxicity and response within a Phase II clinical trial using this compound in advanced transitional cell carcinoma after progression to a platinum-based regimen.. Eleven SNPs in CYP3A4, CYP3A5, CYP2C8, ABCB1 and TUBB1 were genotyped in 45 patients.. CYP3A5 rs776746 A allele was associated with protection against gastrointestinal toxicity (odds ratio: 0.06, 95% CI: 0.007-0.63, p = 0.018) and with reduced progression-free survival (hazard ratio: 5.1, 95% CI: 1.7-15.1, p = 0.0038, multivariable analysis). ABCB1 SNPs were associated with total number of grade 3-4 toxicity events (p-values of 0.009, 0.041 and 0.043, respectively).. Polymorphisms in CYP3A5 and ABCB1 may define a subset of patients with different cabazitaxel toxicity and efficacy and therefore could be used as markers for treatment optimization.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Carcinoma, Transitional Cell; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Polymorphism, Single Nucleotide; Taxoids; Tubulin; Urinary Bladder Neoplasms; Urothelium