Cabazitaxel Versus Docetaxel Both With Prednisone in Patients With Metastatic Castration Resistant Prostate Cancer

Study Overview
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Brief Summary
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Primary Objective: To demonstrate the superiority of cabazitaxel plus prednisone at 25 mg/m^2 (Arm A) or 20 mg/m^2 (Arm B) versus docetaxel plus prednisone (Arm C) in term of overall survival (OS) in participants with metastatic castration resistant prostate cancer (mCRPC) and not previously treated with chemotherapy. Secondary Objectives: To evaluate safety in the 3 treatment arms. To compare efficacy of cabazitaxel at 20 mg/m^2 and 25 mg/m^2 to docetaxel for: Progression Free Survival (PFS) (RECIST 1.1) Tumor progression free survival (RECIST 1.1) Tumor response in participants with measurable disease (RECIST 1.1), PSA response PSA-Progression free survival (PSA-PFS). Pain response in participants with stable pain at baseline Pain progression free survival Time to occurrence of any skeletal related events (SRE) To compare Health-Related Quality of Life (HRQL). To assess the pharmacokinetics and pharmacogenomics of cabazitaxel.

Detailed Description
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Participants were treated until progressive disease, unacceptable toxicity, or participant's refusal of further study treatment. All participants were followed when on study treatment and after completion of study treatment during follow up period until death or the study cutoff date, whichever comes first.

Official Title
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Randomized, Open Label, Multi-Center Study Comparing Cabazitaxel at 25 mg/m^2 and at 20 mg/m^2 in Combination With Prednisone Every 3 Weeks to Docetaxel in Combination With Prednisone in Patients With Metastatic Castration Resistant Prostate Cancer Not Pretreated With Chemotherapy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Cabazitaxel (XRP6258)
* Drug: Docetaxel (XRP6976)
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : I 01. Histologically- or cytologically-confirmed prostate adenocarcinoma. I 02. Metastatic disease. I 03. Progressive disease while receiving hormonal therapy or after surgical castration. I 04. Effective castration (serum testosterone levels ≤0.50 ng/mL) by orchiectomy and/or luteinizing hormone-releasing hormone (LHRH) agonists or antagonist with or without anti-androgens. Exclusion criteria: E 01. Prior chemotherapy for prostate cancer, E 02. Less than 28 days elapsed from prior treatment with estramustine, radiotherapy or surgery to the time of randomization. Participants on biphosphonates prior to study entry. E 03. Prior isotope therapy, whole pelvic radiotherapy, or radiotherapy to >30% of bone marrow. E 04. Adverse events (excluding alopecia and those listed in the specific exclusion criteria) from any prior anticancer therapy of grade >1(National Cancer Institute Common Terminology Criteria [NCI CTCAE] v4.03) at the time of randomization. E 05. Less than 18 years (or country's legal age of majority if the legal age is >18 years). E 06. Eastern Cooperative Oncology Group (ECOG) performance status >2. E 07. History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease. E 08. Prior malignancy. E 09. Participation in another clinical trial and any concurrent treatment with any investigational drug within 30 days prior to randomization. E 10. Any of the following within 6 months prior to study enrollment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure, stroke or transient ischemic attack. E 11. Any of the following within 3 months prior to randomization: treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event. E 12. Acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV disease requiring antiretroviral treatment. E 13. Any severe acute or chronic medical condition which could impair the ability of the participant to participate to the study or interfere with interpretation of study results, or participants unable to comply with the study procedures. E 14. Absence of signed and dated Institutional Review Board (IRB)-approved participant informed consent form prior to enrollment into the study. E 15. Participants with reproductive potential who did not agree to use accepted and effective method of contraception during the study treatment period. E 16. History of hypersensitivity to docetaxel, or polysorbate 80. E 17. Inadequate organ and bone marrow function E 18. Contraindications to the use of corticosteroid treatment. E 19. Symptomatic peripheral neuropathy grade >2 (National Cancer Institute Common Terminology Criteria [NCI CTCAE] v.4.03). The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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 25 mg/m^2<br>Cabazitaxel 25 mg/m^2 intravenous (IV) infusion on Day 1 of each 21-day cycle in combination with Prednisone 10 mg orally, once daily until disease progression (DP), unacceptable toxicity or participant's refusal. | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form: Solution for injection; Route of administration: Intravenous<br>Drug: Prednisone<br>* Pharmaceutical form: Tablet; Route of administration: Oral<br>|
| Experimental: Cabazitaxel 20 mg/m^2<br>Cabazitaxel 20 mg/m^2 IV infusion on Day 1 of each 21 -day cycle in combination with Prednisone 10 mg orally, once daily until DP, unacceptable toxicity or participant's refusal. | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form: Solution for injection; Route of administration: Intravenous<br>Drug: Prednisone<br>* Pharmaceutical form: Tablet; Route of administration: Oral<br>|
| Active Comparator: Docetaxel 75 mg/m^2<br>Docetaxel (TXT) 75 mg/m^2 IV infusion on Day 1 of each 21-day cycle in combination with Prednisone 10 mg orally, once daily until DP, unacceptable toxicity or participant's refusal. | Drug: Docetaxel (XRP6976)<br>* Pharmaceutical form: Solution for injection'; Route of administration: Intravenous<br>Drug: Prednisone<br>* Pharmaceutical form: Tablet; Route of administration: Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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. | Baseline up to death or study cut-off date, whichever was earlier (maximum duration: 51 months ) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS: time interval between date of randomization to date of first occurrence of any of following events: tumor progression according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; Prostate Specific Antigen (PSA) progression; pain progression or death due to any cause. Analysis was performed by Kaplan-Meier method. | Baseline up to tumor progression, PSA progression, pain progression or death (maximum duration: 51 months) | 
| Time to Tumor Progression Free Survival | Time to tumor progression free survival was defined as the time interval between randomization and the date of first occurrence of tumor progression (assessed using RECIST version 1.1) or death, whichever was earlier. Analysis was performed by Kaplan-Meier method. | Baseline up to tumor progression or death due to any cause or study cut-off date, whichever was earlier (maximum duration: 51 months) | 
| Percentage of Participants With Overall Objective Tumor Response | Overall objective tumor response was defined as having a partial response (PR) or complete response (CR) according to the RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Baseline up to DP or death due to any cause or study cut-off date, whichever was earlier (maximum duration: 51 months) | 
| Time to Prostate Serum Antigen Progression Free Survival (PSA-PFS) | Time to PSA-PFS: time interval between date of randomization & first occurrence of PSA progression/ death, whichever was earlier. PSA progression:1) In PSA responders(≥50% decline from baseline PSA of ≥10 ng/mL):increase of ≥25%(at least 2 ng/mL)over nadir value, confirmed by second PSA value at least 3 weeks later;2)In PSA non-responders(not achieved ≥50% decline from baseline PSA ≥10 ng/mL):increase of ≥25% (at least 2 ng/mL) over baseline value, confirmed by second PSA value at least 3 weeks later;3)In participants not eligible for PSA response(baseline PSA <10 ng/mL):(a)in participants with baseline PSA>0 ng/mL&<10 ng/mL: increase in PSA by 25% (at least 2 ng/mL) above baseline level, confirmed by second PSA value at least 3weeks apart;(b)in participants with baseline value=0ng/mL: a post baseline PSA value ≥2ng/mL.Early rise in PSA only indicated progression if it was associated with another sign of DP or if it continued beyond 12 weeks. Analysis performed by Kaplan-Meier method. | Baseline up to PSA progression or death due to any cause or study cut-off date, whichever was earlier (maximum duration: 51 months) | 
| Percentage of Participants With PSA Response | PSA response was defined as ≥50% decrease from baseline in serum PSA levels, confirmed by a second PSA value at least 3 weeks later in participants with baseline PSA value ≥10 ng/mL. | Baseline up to PSA progression or death due to any cause or study cut-off date, whichever was earlier (maximum duration: 51 months) | 
| Time to Pain Progression Free Survival (Pain PFS) | Time to pain PFS was defined as the time interval between date of randomization and the date of the first occurrence of pain progression or death, whichever was earlier. Pain progression was defined as an increase of ≥1 point in the median present pain intensity (PPI) score from the nadir confirmed by a second assessment at least 3 weeks later or ≥25 % increase in the mean analgesic score from baseline, due to cancer related pain confirmed by a second assessment at least 3 weeks later or requirement for local palliative radiotherapy. PPI was rated by participant in a diary using a scale of 0=no pain, 1=mild, 2=discomforting, 3=distressing, 4=horrible 5=excruciating. Analgesic use was recorded by the participant in a diary. Analgesic score was calculated from the analgesic use data based on a table of analgesic medications, with non-narcotic medications assigned a value of 1 point and narcotic medications assigned a value of 4 points. Analysis was performed by Kaplan-Meier method. | Baseline until disease progression, death or study cut-off date (maximum duration: 51 months) | 
| Percentage of Participants With Pain Response | Pain response was defined as either a ≥2-point decrease from baseline median PPI score without increase in analgesic score, or a ≥50% decrease in analgesic use from baseline mean analgesic score (only in participants with baseline mean analgesic score≥10) without increase in the pain. Either criterion was maintained for 2 consecutive evaluations at least 3 weeks apart. PPI was rated by participant in a diary using a scale of 0=no pain, 1=mild, 2=discomforting, 3=distressing, 4=horrible 5=excruciating. Analgesic use was recorded by the participant in a diary. Analgesic score was calculated from the analgesic use data based on a table of analgesic medications, with non-narcotic medications assigned a value of 1 point and narcotic medications assigned a value of 4 points. | Baseline until pain progression, death or study cut-off date (maximum duration: 51 months) | 
| Skeletal Related Events (SRE) Free Survival | SRE free survival was defined as the time interval between the date of randomization and the date of the occurrence of the first event defining a SRE or death due to any cause, whichever was earlier. SRE were assessed by clinical evaluation. Occurrence of SRE was defined as: pathological fracture(s) and/or spinal cord compression; need for bone irradiation, including radioisotopes or bone surgery; and change of antineoplastic therapy (including introduction of bisphosphonates or denosumab in the setting of increased pain) to treat bone pain. Analysis was performed by Kaplan-Meier method. | Baseline until occurrence of first SRE or death (maximum duration: 51 months) | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) Total Score as a Measure of Health Related Quality of Life (HRQoL) | FACT-P was a 39-item participant rated questionnaire that measures the concerns of participants with prostate cancer. It consisted of 5 sub-scales assessing physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), functional well-being (7 items), and prostate-specific concerns (12 items). FACT-P total score was the sum of all 5 subscale scores. It ranged from 0 to156 with higher score indicated better quality of life with fewer symptoms. | Baseline, Day 1 of each cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 (each cycle 21-day); post-treatment follow up 1, 2, 3, 4, 5, 6 (each up to 12 weeks) | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P):Trial Outcome Index (TOI) as a Measure of HRQoL | FACT-P was a 39-item participant rated questionnaire that measures the concerns of participants with prostate cancer. It consisted of 5 sub-scales assessing physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), functional well-being (7 items), and prostate-specific concerns (12 items). Physical well being, functional well being, and prostate-specific concerns sub-scales of the FACT-P questionnaire were combined to calculate TOI. Total TOI score ranges from 0 to 104, with higher scores representing a better quality of life with fewer symptoms. | Baseline, Day 1 of each cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 (each cycle 21-day); post-treatment follow up 1, 2, 3, 4, 5, 6 (each up to 12 weeks) |