Clinical trial NCT02379390: Cabazitaxel Versus the Switch to Alternative AR Targeted Therapy Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Primary Resistant Patients to Abiraterone or Enzalutamide
Official title: Phase II, Randomized, Open-label, Multicenter Study in Chemotherapy-naïve Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Who Have PRIMary Resistance to Abiraterone Acetate or Enzalutamide Treatment Comparing the Anti-tumor Effect of CABazitaxel to Alternative Androgen Receptors (AR) Targeted Therapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Prostate Cancer Metastatic
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2015-03-04
Enrollment: 8
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objective:

To demonstrate the superiority in term of radiographic Progression-Free Survival (rPFS) of cabazitaxel at at 25 milligram per meter square (mg/m\^2) plus prednisone (Arm A) versus either enzalutamide at 160 milligram (mg) once daily or abiraterone acetate at 1000 mg once daily plus prednisone (Arm B) in chemotherapy-naïve participants with metastatic Castration-Resistant Prostate Cancer (mCRPC) who have disease progression while receiving androgen receptor (AR) targeted therapy (abiraterone plus prednisone or enzalutamide) within 12 months of treatment initiation (≤12 months).

Secondary Objective:

* To compare efficacy for:
* Prostate-specific antigen (PSA) response rate and Time to PSA progression (TTPP).
* Progression Free Survival (PFS).
* Overall Survival (OS).
* Tumor response rate in participants with measurable disease (RECIST 1.1)
* Pain response and time to pain progression.
* Symptomatic skeletal events (SSE) rate and time to occurrence of any SSE.
* To analyze messenger ribonucleic acids (mRNAs) including androgen-receptor splice variant 7 messenger RNA (AR-V7) as a biomarker in Circulating Tumor Cells (CTCs).
* To evaluate safety in the 2 treatment arms.

Detailed description: The duration of the study per participant was approximately 2 years. Each participant was treated until radiographic disease progression, unacceptable toxicity, or participants refusal of further study treatment, and each participant was followed after completion of study treatment until death, study cutoff date, or withdrawal of participant consent.

Eligibility criteria: Inclusion criteria:

* Diagnosis of histologically or cytologically confirmed prostate adenocarcinoma.
* Metastatic disease.
* Progressive disease (PD) while receiving AR targeted therapy with abiraterone acetate or enzalutamide within 12 months of treatment initiation (≤12 months) by at least one of the following:
* Progression in measurable disease Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
* Appearance of 2 or more new bone lesions according to Prostate Cancer Working Group 2 (PCWG2).
* Rising PSA defined (PCWG2) as at least two consecutive rises in PSA to be documented over a reference value (measure 1) taken at least one week apart.
* A PSA value of at least 2 nanogram/milliliter (ng/mL) is required at study entry.
* Effective castration (serum testosterone levels ≤0.5 ng/mL).
* Prior AR targeted therapy (abiraterone acetate or enzalutamide) must be stopped at least 2 weeks before study treatment.
* Signed written informed consent.

Exclusion criteria:

* Prior chemotherapy for prostate cancer, except estramustine and except adjuvant/neoadjuvant treatment completed \>3 years ago. No further anti-cancer therapy after the previous AR targeted therapy and before inclusion. Prior docetaxel in hormone sensitive setting is allowed if completed \>1 year before randomization. Prior immunotherapy is allowed.
* Less than 28 days elapsed from prior treatment with immunotherapy, radiotherapy, or surgery to the time of randomization.
* 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 for Adverse Events \[NCI CTCAE\] v4.0) at the time of randomization.
* Eastern Cooperative Oncology Group (ECOG) performance status \>1.
* History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.
* Prior malignancy. Adequately treated basal cell or squamous cell skin or superficial (pTis, pTa, and pT1) bladder cancer are allowed, as well as any other cancer for which treatment has been completed ≥5 years ago and from which the patient has been disease-free for ≥5 years.
* Participation in another clinical trial and any concurrent treatment with any investigational drug within 30 days prior to randomization.
* Acquired immunodeficiency syndrome (AIDS)-related illnesses or known Human immunodeficiency virus (HIV) disease requiring antiretroviral treatment.
* Any severe acute or chronic medical condition including uncontrolled diabetes mellitus, severe renal impairment, history of cardiovascular disease (uncontrolled hypertension, arterial thrombotic events in the past 6 months, congestive heart failure, severe or unstable angina pectoris, recent myocardial infraction within last 6 months or uncontrolled cardiac arrhythmia), which could impair the ability of the patient to participate to the study or interfere with interpretation of study results, or patient unable to comply with the study procedures.
* Participants with reproductive potential who do not agree to use accepted and effective method of contraception during the study treatment period and up to 6 months after the last administered dose. The definition of "effective method of contraception" will be based on the Investigator's judgment.
* Known allergies, hypersensitivity or intolerance to prednisone or excipients of abiraterone acetate or enzalutamide. History of hypersensitivity to docetaxel or polysorbate 80.
* Known history of mineralocorticoid excess or deficiency (not applicable to participants who have already been treated with abiraterone acetate in first line before inclusion).
* History of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold (not applicable to participants who have already been treated with enzalutamide in first line before inclusion).
* Unable to swallow a whole tablet or capsule.
* Inadequate organ and bone marrow function as evidenced by:
* Hemoglobin \<10.0 g/dL.
* Absolute neutrophil count \<1.5 x 10\^9/L.
* Platelet count \<100 x 10\^9/L.
* Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) \>1.5 x Upper limit of normal (ULN).
* Total bilirubin \>1.0 x ULN.
* Potassium \<3.5 mmol/L.
* Serum albumin \<3.0 g/dL.
* Child-Pugh Class B and C.
* Contraindications to the use of corticosteroid treatment.
* Symptomatic peripheral neuropathy grade ≥2 NCI CTCAE v4.0.
* Concomitant vaccination with yellow fever vaccine.

The above information was not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Primary outcomes:
measure: Radiographic Progression-Free Survival (rPFS)
timeFrame: Baseline until tumor progression or bone lesion progression or death due to any cause (maximum duration: 1059 days)
Secondary outcomes:
measure: Number of Participants With Prostate Specific Antigen (PSA) Response
timeFrame: Baseline up to PSA progression or death due to any cause (maximum duration: 1059 days)
measure: Progression-free Survival (PFS)
timeFrame: Baseline upto progression or death due to any cause (maximum duration: 1059 days)
measure: Overall Survival
timeFrame: Baseline until death or study cut-off date, whichever was earlier (maximum duration: 1059 days)
measure: Time to PSA Progression
timeFrame: Baseline up to PSA progression or death due to any cause (maximum duration: 1059 days)
measure: Number of Participants Achieving Tumor Response
timeFrame: Baseline up to disease progression or death due to any cause (maximum duration: 1059 days)
measure: Duration of Tumor Response
timeFrame: Baseline up to disease progression or death due to any cause (maximum duration: 1059 days)
measure: Pain Response Using Brief Pain Inventory-Short Form (BPI-SF) for Pain Intensity Score
timeFrame: Baseline until the end of study (maximum duration: 1059 days)
measure: Time to Pain Progression
timeFrame: Baseline until disease progression, start of another anticancer therapy or study cut off, whichever came first (maximum duration: 1059 days)
measure: Percentage of Participants With Symptomatic Skeletal Event (SSE)
timeFrame: Baseline until the end of study (maximum duration: 1059 days)
measure: Time to Occurrence of Any Symptomatic Skeletal Events (SSE)
timeFrame: Baseline up to occurrence of the first event defining a SSE (maximum duration: 1059 days)
Other outcomes:
Locations:
city: Muscle Shoals
country: United States
facility: Investigational Site Number 840030
state: Alabama
city: Anchorage
country: United States
facility: Investigational Site Number 840024
state: Alaska
city: Anaheim
country: United States
facility: Investigational Site Number 840028
state: California
city: Sacramento
country: United States
facility: Investigational Site Number 840004
state: California
city: Boca Raton
country: United States
facility: Investigational Site Number 840002
state: Florida
city: Lakeland
country: United States
facility: Investigational Site Number 840027
state: Florida
city: Port Saint Lucie
country: United States
facility: Investigational Site Number 840006
state: Florida
city: Ottawa
country: United States
facility: Investigational Site Number 840015
state: Illinois
city: Covington
country: United States
facility: Investigational Site Number 840001
state: Louisiana
city: Metairie
country: United States
facility: Investigational Site Number 840017
state: Louisiana
city: Rockville
country: United States
facility: Investigational Site Number 840012
state: Maryland
city: Omaha
country: United States
facility: Investigational Site Number 840026
state: Nebraska
city: Canton
country: United States
facility: Investigational Site Number 840022
state: Ohio
city: Myrtle Beach
country: United States
facility: Investigational Site Number 840016
state: South Carolina
city: Edmonton
country: Canada
facility: Investigational Site Number 124003
city: Greenfield Park
country: Canada
facility: Investigational Site Number 124010
city: Hamilton
country: Canada
facility: Investigational Site Number 124005
city: London
country: Canada
facility: Investigational Site Number 124004
city: Montreal
country: Canada
facility: Investigational Site Number 124002
city: Montreal
country: Canada
facility: Investigational Site Number 124006
city: Ottawa
country: Canada
facility: Investigational Site Number 124007
city: Quebec
country: Canada
facility: Investigational Site Number 124009
city: Saskatoon
country: Canada
facility: Investigational Site Number 124008
city: Vancouver
country: Canada
facility: Investigational Site Number 124001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: