Treatment of Locally Advanced or Metastatic Transitional Cell Carcinoma With Cabazitaxel

Study Overview
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Brief Summary
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A study for patients with confirmed locally advanced or metastatic Transitional Cell Carcinoma of the bladder or upper urinary tracts who have developed progressive disease within 12 months of their platinum based chemotherapy. The study aims to compare the overall response rate of cabazitaxel treatment versus best supportive care including single agent chemotherapy.

Detailed Description
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Bladder cancer was the 9th most common cause of cancer worldwide in 2002. About 70% of patients have superficial tumour and 30% have invasive tumour at diagnosis. Patients with superficial tumour are treated by surgery, which is the only curative treatment. However, about 50% of these patients will relapse, and cannot be cured by local treatment in the majority of cases. The survival of untreated metastatic patients does not exceed 3 to 6 months, and systemic chemotherapy increases overall survival of patients with unresectable disease. However, the overall survival of patients with advanced disease treated with chemotherapy remains short (14 months), which reflects a substantial unmet medical need for more effective therapy in this very poor prognosis disease. Cabazitaxel is a new taxane, taxanes have demonstrated activity in advanced bladder cancer, and are among the most active new cytotoxic agents to be assessed in transitional cell carcinoma. Cabazitaxel has demonstrated activity in cell lines with acquired resistance to doxorubicin, vincristine, vinblastine, paclitaxel, and docetaxel. This is a randomised, open-label, parallel-group phase 2 study of cabazitaxel versus best supportive care (including chemotherapy). The study is divided into three phases: screening, treatment, and follow-up. The treatment phase comprises a maximum of six three-weekly cycles of therapy, with a post treatment discontinuation visit taking place 3 weeks after last dose of treatment before the follow-up phase begins. This phase 2 study will initially recruit 25 patients and after interim analysis will to increase to recruit 96 patients randomised between the two treatment options and the study is expected to last about 2 years.

Official Title
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Cabazitaxel in Platinum Pre-treated Patients With Locally Advanced or Metastatic Transitional Cell Carcinoma Who Developed Disease Progression Within 12 Months of Platinum Based Chemotherapy.

Conditions
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Transitional Cell Carcinoma

Intervention / Treatment
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* Drug: Cabazitaxel
* Other: Best Supportive Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age ≥ 18 Life expectancy ≥ 12 weeks Patients with histology/cytology confirmed Transitional Cell Carcinoma (TCC) including mixed pathology with predominantly TCC, with locally advanced (T4b) or metastatic (lymph node or visceral) TCC arising from bladder or upper urinary tracts. Treated patients with incidental prostate cancer (pT2, Gleason ≤ 6) and PSA (Prostate Specific Antigen) ≤ 0.5 ng/mL are eligible Measurable disease as per RECIST Criteria 1.1 ECOG Performance Status 0-1. Previously received first line platinum based treatment. Recurrence within 12 months (by RECIST criteria version 1.1) from last cycle of chemotherapy. Exclusion Criteria: Previous therapy with a taxane. Pure non TCC histologies Grade II or more peripheral neuropathy Prior surgery, radiation, chemotherapy, or other anti-cancer therapy within 4 weeks prior to enrolment in the study. Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus) Inadequate organ and bone marrow function as evidenced by: Hemoglobin < 9.0 g/dL Absolute neutrophil count < 1.5 x 109/L, Platelet count < 100 x 109/L, AST/SGOT and/or ALT/SGPT > 2.5 x ULN; Total bilirubin > 1.0 x ULN, Serum creatinine > 1.5 x ULN. If creatinine 1.0 - 1.5 x ULN, creatinine clearance will be calculated according to CKD-EPI formula and patients with creatinine clearance ≤ 30 mL/min should be excluded (see Appendix 6 for formula) Symptomatic brain metastases or leptomeningeal disease (CT or MRI scan of the brain required only in case of clinical suspicion of central nervous system involvement). History of another neoplasm except non-metastatic melanoma skin cancers, carcinoma in situ of the cervix, or cancer cured by surgery, small field radiation or chemotherapy < 5 years prior to randomization. History of inflammatory bowel disease, significant bowel obstruction. History of hypersensitivity to platinum, gemcitabine, taxanes, Polysorbate-80, or to compounds with similar chemical structures. Any of the following events within 6 months prior to randomization: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft surgery, clinically symptomatic and uncontrolled cardiovascular disease, or clinically significant arrhythmias (grade 3-4). Concurrent treatment with strong inhibitors of cytochrome P450 3A4 or patients planning to receive these treatments. For patients who were receiving treatment with such agents, a one-week washout period is required prior to randomization. Women who are breastfeeding and women of child bearing potential (not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus)) unless in agreement to use an adequate method of contraception during the treatment period and for 6 months after the last dose of the study drug. Men unless in agreement that they will use effective contraception (and condom to protect against exposure to seminal liquid) whilst participating in the trial and for 6 months after the last dose of study medication.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cabazitaxel<br>6 cycles (3 weekly) of 25 mg/m^2 IV infusion | Drug: Cabazitaxel<br>* 25 mg/m2, IV (in the vein) on day 1 of each 21 day cycle. Number of Cycles: maximum 6<br>* Other names: Jevtana, XRP6258, RPR116258A;|
| Other: Best Supportive Care<br>Best supportive care including single agent chemotherapy as determined by the patient's study doctor | Other: Best Supportive Care<br>* Best Supportive Care including single agent chemotherapy as determined by the patient's study physician<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | To compare the overall response rate of patients administered cabazitaxel vs best supportive care (including single agent chemotherapy) in patients with transitional cell carcinoma who have previously progressed on a platinum-based regimen. | Change from baseline at Week 9 and Week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Defined as the time interval from the date of randomization to the date of death due to any cause. In absence of confirmation of death, survival time will be censored at the earlier of the last date the patient is known to be alive and the study cut-off date. | From date of randomisation to the date of tumour progression or death (from any cause) (or survival at study cut-off date), whichever came first up to 12months after the final patient has completed study treatment | 
| Quality of Life | QOL will be assessed by using a validated instrument; the EuroQOL (EQ-5D). | Change from baseline at Week 6, Week 12, Week 18, Week 21 | 
| Safety and tolerability | Dose delays and dose reductions, adverse events, laboratory safety data | From date of randomisation up to 30 days after final dose of study medication | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Transitional cell carcinoma, Bladder cancer, Oncology, Cabazitaxel