Cabazitaxel

OS was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the last date participant was known to be alive, or at the cut-off date if the participant's last contact was after the cut-off date. The study cut-off date for the final analysis of OS was the date when the 774th death had been observed. Analysis was performed by Kaplan-Meier method.

Overall survival was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, the survival time was censored at the last date patient was known to be alive or at the cut-off date, whichever had come first.

To evaluate the favorable response rate of cabazitaxel treatment in patients with highly-pretreated nonseminomatous germ-cell tumors (NSGCT)

To explore molecular effects of treatment with Cabazitaxel on the tumor microenvironment of patients with mCRPC in correlation with measures of outcome (ie clinical benefit, Prostate-Specific Androgen (PSA) decline, radiographic response, time to treatment discontinuation), in an effort to identify predictors of response or resistance to therapy.

The primary endpoint compares the cumulative dose of cabazitaxel that is received relative to the planned dose at 18 weeks of therapy. The cumulative dose of cabazitaxel in relation to the expected dose is a reflection of both tolerability and efficacy. Patients stopping treatment due to disease progression prior to week 18 will have lower relative cumulative doses as will patients with poor tolerability due to dose reductions and delays.

The primary endpoint will be progression free survival, assessed at 12 weeks after start of treatment

Pathological stage at diagnosis (T2/T3 - see baseline characteristics) was compared to pathological stage of the surgical specimen at cystectomy. A response is considered as a decrease in T stage from T2/T3 seen at baseline to T1 or less indicating a reduction in tumour size/invasiveness. The T stage describes how far the primary tumour has spread. The higher the stage the further the tumour has grown through the bladder wall and into the surrounding tissues. The stages are Ta - non-invasive papillary carcinoma, Tis - flat non-invasive carcinoma, T1 - grown through the connective tissue but not into the muscle of the bladder wall, T2 - tumour has grown through the connective tissue and into the muscle of the bladder wall, T3 - tumour has grown through the muscle and into the fatty layer surrounding the bladder and T4 - the cancer has spread to surrounding tissues.

MTD is defined as the dose level immediately below the DLT. The study will be conducted until MTD and recommended Phase II dose are established.

DLT is defined as a grade3 toxicity lasting more than 7 days or grade 4 or 5 toxicity, with the exception of febrile neutropenia which will be considered as ½ DLT per full dose per episode. The DLT will be the basis for determining the MTD. Treatment cohorts will be dosed in escalating order only after the safety of the previous dose level is established, or until an MTD has been determined.

The investigator is measuring safety by looking at the number of events that occur during the study

The investigator is measuring efficacy by the number of complete responders to the treatment

MTD was highest dose level of cabazitaxel at which no more than 1 of 6 evaluable participants experienced dose limiting toxicities (DLT). DLT defined as an AE or abnormal laboratory values related to study treatment: hematologic DLTs: any Grade(G)4 hematologic toxicity except neutropenia G4 lasting≤7 days,G3 or 4 febrile neutropenia except G3 or 4 febrile neutropenia in absence of granulocyte-colony stimulating factor prophylaxis, G4 thrombocytopenia; non-hematologic DLTs:any G≥3 non-hematologic toxicity except G3 nausea or G3 or4 vomiting, G3 or4 diarrhea,G3 or4 dehydration,G3 fatigue lasting≤7 days, inadequately treated hypersensitivity reactions, elevated transaminases\<10\* upper limit of normal of ≤7 days, re-treatment delay of\>2 weeks due to delayed recovery from toxicity related to study treatment to baseline G or≤ G1(except for alopecia) and platelet transfusion during Cycle1. Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

OR in participants was defined as the participants with a Complete Response (CR) or Partial Response (PR) after 3 cycles of cabazitaxel treatment and maintained for at least 4 weeks. CR and PR were based on modified response assessment in neuro-oncology (RANO) criteria for participants with CNS tumors. CR was defined as disappearance of all target lesions. PR was defined as ≥50% decrease in the sum of the products of the two perpendicular diameters of target lesions, compared to the baseline measurement.

DOR defined as time (in days) from date of first response until date of first documented progressive disease (PD) or death (from any cause), whichever came first. If progression or death was not observed, participant was censored at the date of participant's last progression-free tumor assessment prior to study cut-off date. PD as per RANO criteria was defined as ≥ 25% increase in the product of perpendicular diameters of any target lesion, taking as reference the smallest product observed since the start of treatment or the appearance of one or more new lesions, or worsening neurologic status not explained by causes unrelated to tumor progression (example, anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc.) plus any increase in tumor cross-sectional area (or tumor volume).

A clinical adverse event or a laboratory abnormality is defined as DLT when it is drug-related as assessed by the investigator and agreed upon by the study committee.