Clinical trial NCT01511536: Cabazitaxel and Abiraterone Acetate in Patients With Metastatic Castrate-Resistant Prostate Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Prostate Cancer
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2012-01-18
Enrollment: 38
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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:

  1. Increase in non-measureable or measurable disease, and/or
  2. 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.

  1. 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.
  2. 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.

Primary outcomes:
measure: Phase 1: Maximally Tolerated Dose (MTD) of Cabazitaxel in Combination With Abiraterone Acetate
timeFrame: Up to Cycle 2 of Phase 1 (up to 42 days)
measure: Phase 2: Percentage of Participants With Prostate Specific Antigen (PSA) Response
timeFrame: Baseline, every 3 weeks up to PSA progression (maximum duration: 603 days)
Secondary outcomes:
measure: Phase 2: Objective Progression Free Survival (PFS)
timeFrame: From baseline until radiological tumor or disease progression or death due to any cause, assessed up to Month 5
measure: Phase 2: PSA Progression Free Survival
timeFrame: Baseline, every 3 weeks up to PSA progression (maximum duration: 603 days)
measure: Phase 2: Percentage of Participants With Objective Response
timeFrame: Baseline, every 12 weeks there after until disease progression (maximum duration: 603 days)
measure: Phase 2: Overall Survival
timeFrame: From baseline up to death or study cut-off (maximum duration: 603 days)
measure: Phase 2: Pharmacokinetic of Cabazitaxel : Maximum Plasma Concentration Observed (Cmax)
timeFrame: 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
measure: Phase 2: Pharmacokinetic of Cabazitaxel : Area Under the Plasma Concentration Versus Time Curve (AUC)
timeFrame: 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
measure: Phase 2: Pharmacokinetic of Cabazitaxel : Terminal Half-life (t 1/2z)
timeFrame: 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
measure: Phase 2: Pharmacokinetic of Cabazitaxel : Total Plasma Clearance (CL)
timeFrame: 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
measure: Phase 2: Pharmacokinetic of Cabazitaxel : Volume of Distribution at Steady State (Vss)
timeFrame: 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
measure: Phase 2: Pharmacokinetic of Abiraterone : Maximum Plasma Concentration Observed (Cmax)
timeFrame: 0 hour (before abiraterone administration); 1, 2, 4, 6, 8, 12, 24 hours post abiraterone administration on Day 1-Cycle 1
measure: Phase 2: Pharmacokinetic of Abiraterone : First Time to Reach Cmax (Tmax)
timeFrame: 0 hour (before abiraterone administration); 1, 2, 4, 6, 8, 12, 24 hours post abiraterone administration on Day 1-Cycle 1
measure: Phase 2: Pharmacokinetic of Abiraterone : Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC 0-24)
timeFrame: 0 hour (before abiraterone administration); 1, 2, 4, 6, 8, 12, 24 hours post abiraterone administration on Day 1-Cycle 1
measure: Phase 2: Pharmacokinetic of Abiraterone : Concentration Observed Just Before Treatment Administration During Repeated Dosing at Steady State (Ctrough ss)
timeFrame: Pre abiraterone dose on Day 1 of Cycle 1
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Investigational Site Number 840001
state: California
city: New Haven
country: United States
facility: Investigational Site Number 840002
state: Connecticut
city: Villejuif
country: France
facility: Investigational Site Number 250001
city: Sutton
country: United Kingdom
facility: Investigational Site Number 826001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Massard C, Mateo J, Loriot Y, Pezaro C, Albiges L, Mehra N, Varga A, Bianchini D, Ryan CJ, Petrylak DP, Attard G, Shen L, Fizazi K, de Bono J. Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone. Ann Oncol. 2017 Jan 1;28(1):90-95. doi: 10.1093/annonc/mdw441.
citation: Huang X, Chau CH, Figg WD. Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures. J Hematol Oncol. 2012 Jul 2;5:35. doi: 10.1186/1756-8722-5-35.