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Urinary Tract, Sexual Organs, and Pregnancy Conditions

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Prostatic Neoplasms

Genital Neoplasms, Male

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Genital Diseases, Male

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Prostatic Diseases

Male Urogenital Diseases

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Anti-Inflammatory Agents

Docetaxel

Abiraterone Acetate

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Cytochrome P-450 Enzyme Inhibitors

Cabazitaxel 20 mg/m\^2 intravenous (IV) infusion on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg orally once daily and prednisone 5 mg orally twice daily until disease progression, unacceptable toxicity or consent withdrawal.

Cabazitaxel 25 mg/m\^2 IV infusion on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg orally once daily and prednisone 5 mg orally twice daily until disease progression, unacceptable toxicity or consent withdrawal.

Cabazitaxel at maximum tolerated dose (MTD) as determined in phase 1 part (25 mg/m\^2) IV infusion on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg orally once daily and prednisone 5 mg orally twice daily until disease progression, unacceptable toxicity or consent withdrawal.

Pharmaceutical form:solution Route of administration: injection

Cabazitaxel XRP6258

Pharmaceutical form:tablets Route of administration: oral

Abiraterone acetate

Prednisone 5 mg

Clinical Sciences & Operations

Primary Objectives:

* To determine the maximum tolerated dose, and dose limiting toxicities of cabazitaxel administered as a 1-hour infusion every 3 weeks in combination with oral daily abiraterone acetate and prednisone in participants with metastatic Castrate-resistant prostate cancer (CRPC)
* To estimate the anti-tumor activity of cabazitaxel in combination with abiraterone acetate and prednisone in terms of prostate-specific antigen (PSA) response rate.

Secondary Objectives:

* To characterize the safety profile of the combination
* To evaluate the pharmacokinetic profile of cabazitaxel and abiraterone in the proposed combination and dosing schedule
* To assess preliminary antitumor activity of the combination in terms of progression-free survival, PSA progression free survival and objective response rate, and overall survival

The study duration was to include a period for inclusion of up to 3 weeks and a 3-week treatment cycle(s). The participants might continue treatment until disease progression, unacceptable toxicity or willingness to stop followed by a minimum of 30-day follow-up

Cabazitaxel and Abiraterone Acetate in Patients With Metastatic Castrate-Resistant Prostate Cancer

A Phase I/II Study of Cabazitaxel Combined With Abiraterone Acetate and Prednisone in Patients With Metastatic Castrate-Resistant Prostate Cancer (CRPC) Whose Disease Has Progressed After Docetaxel Chemotherapy

MTD was defined as highest dose level of cabazitaxel in combination with abiraterone acetate at which no more than 1 participant experienced dose limiting toxicities (DLT). DLT was defined as any of the following events related to study treatment: 1) Grade 3 or 4 non-hematological related adverse event with exception of Grade 3 fever without documented infection; Grade 3 nausea, vomiting, or diarrhea in the absence of effective maximal therapy; and Grade 3 hypersensitivity reaction in the absence of required premedication. 2) Hematological toxicity: Febrile neutropenia (fever of unknown origin ≥38.5°C with neutropenia Grade 3 or 4); Neutropenia Grade 4 lasting \>7 days; Thrombocytopenia Grade 4 or Grade 3 complicated by hemorrhage. 3) Re-treatment delay of more than 2 weeks due to delayed recovery from a toxicity related to study treatment to baseline or ≤ Grade 1 (except for alopecia). Grades were based on National Cancer Institute CommonTerminology Criteria for Adverse Events v4.03.

Prostate specific antigen (PSA) response was defined as ≥50% decrease from baseline in serum PSA levels, confirmed at least 3 weeks later. Increases of any magnitude during the first 12 weeks were ignored in determining PSA response. PSA was to be measured at baseline, every 3 weeks, throughout study period, until progression. PSA progression was defined as: -An increase of 25% above the nadir (at least 2 ng/mL), confirmed by a second PSA value at least 3 weeks apart, in participants who have achieved a ≥50% decline of PSA. -An increase in PSA by 25 % above the baseline level (at least 2 ng/mL), confirmed by a second PSA value at least 3 weeks apart, in participants who have not achieved a ≥50% decline of PSA.

Objective PFS was defined as the time interval between the date of enrollment and the first occurrence of any of the events:

1) Radiological tumor progression (assessed using Response Evaluation Criteria in Solid Tumors \[RECIST\] version 1.1) was defined as at least a 20 percent increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions. in case of progressive disease (PD) diagnosed only on non target bone lesions on bone scan, PD was to be considered only in case of appearance of at least 2 new lesions on bone scan confirmed 6 weeks later by another bone scan, and at least the appearance of 2 new additional lesions. 2) Death due to any cause.

Analysis was performed by Kaplan-Meier method.

Prostate-specific antigen progression-free survival was defined as the time interval between the date of treatment start and the date of either first documented PSA progression or death due to any cause, whichever was earlier. PSA was to be measured at baseline, every 3 weeks, throughout study period, until progression. PSA progression was defined as: -An increase of 25% above the nadir (at least 2 ng/mL), confirmed by a second PSA value at least 3 weeks apart, in participants who have achieved a ≥50% decline of PSA. -An increase in PSA by 25 % above the baseline level (at least 2 ng/mL), confirmed by a second PSA value at least 3 weeks apart, in participants who have not achieved a ≥50% decline of PSA.

Analysis was performed by Kaplan Meire method.

Objective response was defined as having complete response (CR) or Partial Response (PR) assessed by RECIST 1.1. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level and all lymph nodes size was \<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).

Overall survival was defined as the time interval from the date of treatment start to the date of death due to any cause. In absence of confirmation of death, survival time was censored at the earlier of the last date the participant was known to be alive and the study cut-off date. Analysis was performed by Kaplan-Meier method.

Area under the concentration-time curve calculated using the following equation: AUC = Plasma clearance (CL)/dose

Area under the plasma concentration-time curve calculated using the trapezoidal method from time zero to 24 hours corresponding to abiraterone acetate dosing interval.

Sanofi

Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during 'on treatment period' (time from first dose of study drug \[cabazitaxel or abiraterone, whichever came first\] to last dose of study drug \[cabazitaxel or abiraterone, whichever came last\] + 30 days). Analysis was performed on safety population.

Cabazitaxel 20 mg/m\^2 IV infusion on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg orally once daily and prednisone 5 mg orally twice daily until disease progression, unacceptable toxicity or consent withdrawal.

Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg

Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg

Cabazitaxel at MTD as determined in phase 1 part (25 mg/m\^2) IV infusion on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg orally once daily and prednisone 5 mg orally twice daily until disease progression, unacceptable toxicity or consent withdrawal.

Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg

Total

Age, Continuous

Sex: Female, Male

All treated/safety population defined as all registered participants exposed to both investigational medicinal product (IMP) components, regardless of the amount of treatment administered.

Trial Transparency Team

Cabazitaxel 20 or 25 mg/m\^2 IV infusion on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg orally once daily and prednisone 5 mg orally twice daily until disease progression, unacceptable toxicity or consent withdrawal.

Phase 1: Overall Population

Analysis was performed on DLT evaluable population defined as all participants who received the first 2 cycles, unless they discontinued the study drug during the first 2 cycles for a DLT.

Phase 1: Maximally Tolerated Dose (MTD) of Cabazitaxel in Combination With Abiraterone Acetate

Analysis was performed on efficacy/activity population included all participants who had received at least 2 cycles of the study drug in Phase 2, and had a baseline and at least one post-baseline assessment for the efficacy variable of interest.

Phase 2: Percentage of Participants With Prostate Specific Antigen (PSA) Response

Analysis was performed on efficacy/activity population.

Phase 2: Objective Progression Free Survival (PFS)

Phase 2: PSA Progression Free Survival

Efficacy/activity population. Number of participants analyzed=participants with measurable disease at baseline.

Phase 2: Percentage of Participants With Objective Response

Phase 2: Overall Survival

Analysis was performed on pharmacokinetic (PK) population which included all participants who received at least 1 treatment. Pre-dose samples from 3 participants of Phase 2, were above lower limit of quantification (LLOQ) (1.00 ng/mL). Hence, those participants were excluded from analysis.

Phase 2: Pharmacokinetic of Cabazitaxel : Maximum Plasma Concentration Observed (Cmax)

Phase 2: Cabazitaxel 25 mg/ m^2 + Abiraterone 1000 mg

Phase 2: Pharmacokinetic of Cabazitaxel : Area Under the Plasma Concentration Versus Time Curve (AUC)

Phase 2: Pharmacokinetic of Cabazitaxel : Terminal Half-life (t 1/2z)

Phase 2: Pharmacokinetic of Cabazitaxel : Total Plasma Clearance (CL)

Phase 2: Pharmacokinetic of Cabazitaxel : Volume of Distribution at Steady State (Vss)

Analysis was performed on PK population. One participant was excluded from analysis due to aberrant data.

Phase 2: Pharmacokinetic of Abiraterone : Maximum Plasma Concentration Observed (Cmax)

Phase 2: Pharmacokinetic of Abiraterone : First Time to Reach Cmax (Tmax)

Phase 2: Pharmacokinetic of Abiraterone : Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC 0-24)

Phase 2: Pharmacokinetic of Abiraterone : Concentration Observed Just Before Treatment Administration During Repeated Dosing at Steady State (Ctrough ss)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Cabazitaxel and Abiraterone Acetate in Patients With Metastatic Castrate-Resistant Prostate Cancer	NCT01511536	Prostate Cancer	Cabazitaxel XRP... Abiraterone ace... Prednisone 5 mg	18 Years -	Sanofi
Cabazitaxel and Abiraterone Acetate in Patients With Metastatic Castrate-Resistant Prostate Cancer	NCT01511536	Prostate Cancer	Cabazitaxel XRP... Abiraterone ace... Prednisone 5 mg	18 Years -	Sanofi

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