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

Phase 1

Completed

Conditions: Prostate Cancer

Interventions: Drug: Cabazitaxel XRP6258
Drug: Abiraterone acetate
Drug: Prednisone 5 mg

Registration Number: NCT01511536

Lead Sponsor: Sanofi

Brief Summary: 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

Detailed Description: 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

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 38

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg	Cabazitaxel XRP6258	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.
Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg	Prednisone 5 mg	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.
Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg	Abiraterone acetate	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.
Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg	Prednisone 5 mg	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.
Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg	Cabazitaxel XRP6258	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.
Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg	Prednisone 5 mg	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.
Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg	Cabazitaxel XRP6258	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.
Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg	Abiraterone acetate	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.
Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg	Abiraterone acetate	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.

Primary Outcome Measures

Name	Time	Method
Phase 1: Maximally Tolerated Dose (MTD) of Cabazitaxel in Combination With Abiraterone Acetate	Up to Cycle 2 of Phase 1 (up to 42 days)	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.
Phase 2: Percentage of Participants With Prostate Specific Antigen (PSA) Response	Baseline, every 3 weeks up to PSA progression (maximum duration: 603 days)	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.

Secondary Outcome Measures

Name	Time	Method
Phase 2: PSA Progression Free Survival	Baseline, every 3 weeks up to PSA progression (maximum duration: 603 days)	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.
Phase 2: Objective Progression Free Survival (PFS)	From baseline until radiological tumor or disease progression or death due to any cause, assessed up to Month 5	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.
Phase 2: Pharmacokinetic of Cabazitaxel : Maximum Plasma Concentration Observed (Cmax)	5 minutes before cabazitaxel infusion; at end of cabazitaxel infusion; 0.25 hours post-cabazitaxel infusion; any time between 1 to 4 hours, between 6 to 24 hours, between 48 to 96 hours post cabazitaxel infusion on Day 1-Cycle 1
Phase 2: Pharmacokinetic of Cabazitaxel : Terminal Half-life (t 1/2z)	5 minutes before cabazitaxel infusion; at end of cabazitaxel infusion; 0.25 hours post-cabazitaxel infusion; any time between 1 to 4 hours, between 6 to 24 hours, between 48 to 96 hours post cabazitaxel infusion on Day 1-Cycle 1
Phase 2: Pharmacokinetic of Abiraterone : Concentration Observed Just Before Treatment Administration During Repeated Dosing at Steady State (Ctrough ss)	Pre abiraterone dose on Day 1 of Cycle 1
Phase 2: Percentage of Participants With Objective Response	Baseline, every 12 weeks there after until disease progression (maximum duration: 603 days)	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).
Phase 2: Overall Survival	From baseline up to death or study cut-off (maximum duration: 603 days)	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.
Phase 2: Pharmacokinetic of Cabazitaxel : Total Plasma Clearance (CL)	5 minutes before cabazitaxel infusion; at end of cabazitaxel infusion; 0.25 hours post-cabazitaxel infusion; any time between 1 to 4 hours, between 6 to 24 hours, between 48 to 96 hours post cabazitaxel infusion on Day 1-Cycle 1
Phase 2: Pharmacokinetic of Cabazitaxel : Area Under the Plasma Concentration Versus Time Curve (AUC)	5 minutes before cabazitaxel infusion; at end of cabazitaxel infusion; 0.25 hours post-cabazitaxel infusion; any time between 1 to 4 hours, between 6 to 24 hours, between 48 to 96 hours post cabazitaxel infusion on Day 1-Cycle 1	Area under the concentration-time curve calculated using the following equation: AUC = Plasma clearance (CL)/dose
Phase 2: Pharmacokinetic of Cabazitaxel : Volume of Distribution at Steady State (Vss)	5 minutes before cabazitaxel infusion; at end of cabazitaxel infusion; 0.25 hours post-cabazitaxel infusion; any time between 1 to 4 hours, between 6 to 24 hours, between 48 to 96 hours post cabazitaxel infusion on Day 1-Cycle 1
Phase 2: Pharmacokinetic of Abiraterone : Maximum Plasma Concentration Observed (Cmax)	0 hour (before abiraterone administration); 1, 2, 4, 6, 8, 12, 24 hours post abiraterone administration on Day 1-Cycle 1
Phase 2: Pharmacokinetic of Abiraterone : First Time to Reach Cmax (Tmax)	0 hour (before abiraterone administration); 1, 2, 4, 6, 8, 12, 24 hours post abiraterone administration on Day 1-Cycle 1
Phase 2: Pharmacokinetic of Abiraterone : Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC 0-24)	0 hour (before abiraterone administration); 1, 2, 4, 6, 8, 12, 24 hours post abiraterone administration on Day 1-Cycle 1	Area under the plasma concentration-time curve calculated using the trapezoidal method from time zero to 24 hours corresponding to abiraterone acetate dosing interval.

Trial Locations

Locations (4): Investigational Site Number 826001
🇬🇧
Sutton, United Kingdom
Investigational Site Number 840002
🇺🇸
New Haven, Connecticut, United States
Investigational Site Number 840001
🇺🇸
San Francisco, California, United States
Investigational Site Number 250001
🇫🇷
Villejuif, France