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

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Cabazitaxel XRP6258
* Drug: Abiraterone acetate
* Drug: Prednisone 5 mg


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Diagnosis of prostate adenocarcinoma proven histologically or cytologically, resistant to hormone therapy and previously treated with a docetaxel-containing regimen. In Phase 2 part, participants should have been treated with abiraterone acetate for at least 3 months and should continue treatment with abiraterone acetate before study entry Presence of metastatic prostate cancer. Participant must had progressive disease documented by rising PSA defined as 2 sequential increases above a previous lowest reference value (each PSA value must be obtained at least 1 week apart. A PSA value of at least 6 ng/mL was required at study entry). In Phase 1 part, in addition to rising PSA, progressive disease must be documented by: Increase in non-measureable or measurable disease, and/or Appearance of new lesions, including those on bone scan (≥2 new lesions on 2 consecutive bone scans if progressive disease diagnosed on bone scan only) consistent with progressive prostate cancer Effective castration (serum testosterone levels ≤0.50 ng/mL) by orchiectomy and/or luteinizing hormone-releasing hormone agonists /antagonist. If the participant had been treated with luteinizing hormone-releasing hormone agonists/antagonist (i.e., without orchiectomy), then this therapy had been initiated at least 4 weeks prior to cycle 1 day 1 and should be continued throughout the study. Prior anti-androgen therapy should be stopped before enrollment Eastern Cooperative Oncology Group performance status: 0 - 1. Exclusion criteria: Previous treatment with mitoxantrone or cabazitaxel. Prior bone-seeking radio-isotope therapy (participants treated with Radium223 were not excluded from the study). Radiotherapy to ≥30% of bone marrow. Adverse events from any prior anticancer therapy of grade >1 at the time of enrollment. Prior surgery, radiation, chemotherapy, or other anti-cancer therapy within 4 weeks prior to enrollment in the study (except luteinizing hormone-releasing hormone agonist /antagonist and abiraterone acetate in the Phase 2 part of the study); small field single fraction palliative radiation within 1 week. Prior malignancy. Curatively treated basal cell or squamous cell skin or superficial (pTis, pTa, and pT1) bladder cancer were allowed, as well as any other cancer for which chemotherapy had been completed ≥ 3 years ago and from which the participant had been disease-free for ≥ 3 years. Participation in another clinical trial and any concurrent treatment with any investigational drug within 30 days prior to enrollment. Known brain or leptomeningeal metastases. Any severe acute or chronic medical condition which could impair the ability of the participant to participate to the study or to comply with the study procedures or interfere with interpretation of study results. Other concurrent serious illness or medical conditions Absence of signed and dated participant informed consent form prior to enrollment into the study. History of hypersensitivity to docetaxel, polysorbate 80 Known allergies, hypersensitivity or intolerance to prednisone or excipients of abiraterone acetate Known history of mineralocorticoid excess or deficiency Inadequate organ and bone marrow function Contraindications to the use of corticosteroid treatment. Symptomatic peripheral neuropathy grade > 1 Concurrent treatment with strong inducers or strong inhibitors of cytochrome P450 (CYP450) 3A4 Concurrent treatment with medications metabolized by cytochrome P2D6 (CYP2D6), particularly for those with a small therapeutic window History of cardiac arrhythmias requiring medical therapy such as atrial fibrillation requiring anticoagulation or digoxin/digitalis; uncontrolled angina pectoris. History of congestive heart failure or myocardial infarction within last 6 months was also not allowed. Uncontrolled hypertension (systolic BP ≥160 mmHg or diastolic BP ≥ 95 mmHg). Participants with a history of hypertension were allowed, provided that blood pressure was controlled to within these limits by anti-hypertensive treatment Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 12 months, severe or unstable angina, or New York Heart Association Class III or IV heart disease or cardiac left ventricular ejection fraction measurement of <50% at baseline Participants with reproductive potential who did not agree to use accepted and effective method of contraception in conjunction with their partner(s) during the study treatment period. The above information is 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg<br>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. | Drug: Cabazitaxel XRP6258<br>* Pharmaceutical form:solution Route of administration: injection<br>Drug: Abiraterone acetate<br>* Pharmaceutical form:tablets Route of administration: oral<br>Drug: Prednisone 5 mg<br>* Route of administration: oral<br>|
| Experimental: Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg<br>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. | Drug: Cabazitaxel XRP6258<br>* Pharmaceutical form:solution Route of administration: injection<br>Drug: Abiraterone acetate<br>* Pharmaceutical form:tablets Route of administration: oral<br>Drug: Prednisone 5 mg<br>* Route of administration: oral<br>|
| Experimental: Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg<br>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. | Drug: Cabazitaxel XRP6258<br>* Pharmaceutical form:solution Route of administration: injection<br>Drug: Abiraterone acetate<br>* Pharmaceutical form:tablets Route of administration: oral<br>Drug: Prednisone 5 mg<br>* Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Objective Progression Free Survival (PFS) | 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. | From baseline until radiological tumor or disease progression or death due to any cause, assessed up to Month 5 | 
| Phase 2: PSA Progression Free Survival | 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. | Baseline, every 3 weeks up to PSA progression (maximum duration: 603 days) | 
| Phase 2: Percentage of Participants With Objective Response | 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). | Baseline, every 12 weeks there after until disease progression (maximum duration: 603 days) | 
| Phase 2: Overall Survival | 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. | From baseline up to death or study cut-off (maximum duration: 603 days) | 
| 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 : Area Under the Plasma Concentration Versus Time Curve (AUC) | Area under the concentration-time curve calculated using the following equation: AUC = Plasma clearance (CL)/dose | 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 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 : 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) | Area under the plasma concentration-time curve calculated using the trapezoidal method from time zero to 24 hours corresponding to abiraterone acetate dosing interval. | 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 : Concentration Observed Just Before Treatment Administration During Repeated Dosing at Steady State (Ctrough ss) |  | Pre abiraterone dose on Day 1 of Cycle 1 |