Study to Evaluate Safety and Effectiveness of Lenalidomide in Combination With Docetaxel and Prednisone for Patients With Castrate-Resistant Prostate Cancer

Study Overview
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Brief Summary
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The purpose of the study is to determine whether lenalidomide is safe and effective for use in combination with docetaxel and prednisone for the treatment of subjects with metastatic Castrate-Resistant Prostate Cancer. The addition of lenalidomide to docetaxel and prednisone is proposed to increase the life expectancy of these subjects.

Detailed Description
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In November 2011, the Data Monitoring Committee concluded it was unlikely that the study would meet its primary endpoint of overall survival (OS) and recommended that the study be stopped. The study was terminated in accordance with this recommendation. All sites were instructed to immediately discontinue all patients from experimental lenalidomide/placebo treatment administered either in combination with chemotherapy or as a single agent following chemotherapy discontinuation. Subsequently, Protocol Amendment 3 was issued to provide for the following: To continue to collect information on Second Primary Malignancies (SPMs) and additional treatments for Prostate Cancer in all randomized subjects during survival follow-up. To continue to provide docetaxel and prednisone for up to 10 cycles to subjects randomized at non-US sites who were ongoing in the CC-5013-PC-002 protocol when the decision was made to discontinue lenalidomide/placebo and who were experiencing benefit as per investigator discretion. For subjects who had exceeded 10 cycles of docetaxel and prednisone at the time of Protocol Amendment 3 approval, an additional two cycles were provided. All references to dosing and study procedures pertaining to the safety, efficacy, and exploratory endpoints of lenalidomide/placebo were discontinued as part of Protocol Amendment 3.

Official Title
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A Phase 3 Study to Evaluate the Efficacy and Safety of Docetaxel and Prednisone With or Without Lenalidomide in Subjects With Castrate-Resistant Prostate Cancer (CRPC)

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Docetaxel
* Drug: Prednisone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must sign an Informed Consent Form (ICF) Males ≥ 18 years of age Able to adhere to the study visit schedule and requirements of the protocol Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 Life expectancy of ≥ 12 weeks Willingness to participate in Patient-Reported Outcomes assessments Serum testosterone levels < 50 ng/dL Confirmed metastatic adenocarcinoma of the prostate that is unresponsive or refractory to hormonal therapy Have documented disease progression while receiving or following hormonal therapy as determined by increasing Serum Prostate Specific Antigen (PSA) level, Radiological Progression, or ≥2 new bone lesions Subjects must agree to receive counseling related to pregnancy precautions, teratogenic and other risks of lenalidomide Refrain from donating blood or semen as defined by protocol Exclusion Criteria: A history of clinically significant disease that places subject at an unacceptable risk for study entry Prior Therapy with thalidomide, lenalidomide or pomalidomide Prior chemotherapy for prostate cancer Use of any other experimental drug or therapy within 28 days prior to randomization Prior radiation to ≥ 30% of bone marrow or any radiation therapy within 28 days prior to randomization Prior use of Strontium-89 at any time or Samarium-153 within 56 days prior to randomization Surgery within 28 days prior to randomization Concurrent anti-androgen therapy Abnormal serum chemistry or hematology laboratory values Significant active cardiac disease within the previous 6 months: Thrombotic or thromboembolic events within the past 6 months: History of peripheral neuropathy of ≥grade 2 History of severe hypersensitivity reaction to drugs formulated with polysorbate 80 Paraplegia History of Central nervous system (CNS) or brain metastases History of malignancies other than prostate cancer within the past 5 years, with the exception of treated basal cell/squamous cell carcinoma of the skin Concurrent use of alternative cancer therapies

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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Docetaxel, Prednisone, Lenalidomide (DPL)<br>25 mg lenalidomide orally once each day on Days 1-14; 75 mg/m2 docetaxel intravenously on Day 1; 5 mg prednisone orally twice daily on each day of the treatment cycle | Drug: Lenalidomide<br>* 25 mg lenalidomide orally once each day on Days 1-14<br>* Other names: Revlimid;Drug: Docetaxel<br>* 75 mg/m2 intravenous docetaxel on Day 1<br>* Other names: Taxotere;Drug: Prednisone<br>* 5 mg prednisone orally twice daily on each day of the treatment cycle<br>* Other names: There are multiple brand names for prednisone.;|
| Experimental: Docetaxel and Prednisone (DP)<br>Oral placebo once each day on Days 1-14 of the treatment cycle; 75 mg/m2 docetaxel intravenously on Day 1; 5 mg prednisone orally twice each day on each day of the treatment cycle | Drug: Docetaxel<br>* 75 mg/m2 intravenous docetaxel on Day 1<br>* Other names: Taxotere;Drug: Prednisone<br>* 5 mg prednisone orally twice daily on each day of the treatment cycle<br>* Other names: There are multiple brand names for prednisone.;Drug: Placebo<br>* Oral placebo once each day on Days 1-14 of the treatment cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) was the time from the date of randomization to the date of death from any cause. If no death was reported for a participant before the cut-off date for OS analysis, OS was censored at the last date at which the participant was alive. The median OS was calculated based on Kaplan-Meier estimates and corresponding 95% confidence interval (CI) was calculated using the method provided by Brookmeyer and Crowley. | From randomization until death from any cause up to the cut-off date of 13 January 2012; up to approximately 26 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS was the time from randomization to disease progression, or death, whatever occurred first. Progression criteria was met by analysis of target and non-target lesions as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria. Progressive Disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters while on study or the appearance of one or more new lesions; an increase of at least 5mm as a total sum. Lymph nodes identified as target lesions (≥ 15 mm diameter in short axis) will be followed and reported by changes in diameter of short axis; or the unequivocal progression of a non-target lesion defined as an increase in the overall disease burden based on the change in non-measurable disease that is comparable in scope to the increase required to declare PD for measurable disease; Two or more new bone lesions as detected by bone scan | From randomization until disease progression or death from any cause; up to the cut-off date of 13 Jan 2012; maximum time on study was approximately 26 months | 
| Percentage of Participants With an Objective Response According to Response Evaluation Criteria in Solid Tumors - RECIST Version 1.1 Criteria | Objective response (OR) is defined as having complete response (CR) or partial response (PR) as best overall response based on RECIST Criteria 1.1 and defines a CR = Disappearance of all target lesions except lymph nodes (LN); LN must have a decrease in the short axis to <10mm; PR = 30% decrease in sum of diameters of target lesions taking as reference the baseline sum diameters; Progressed Disease (PD) = 20% increase in sum of diameters of target lesions taking as a reference the smallest sum of diameters and an absolute increase of ≥5 mm; the appearance of ≥1 new lesions; Stable Disease (SD)= Neither shrinkage to qualify for PR nor increase to qualify for PD taking the smallest sum diameters on study as reference. For non-target lesions a CR = Disappearance of all non-target lesions and all LN must be non-pathological in size <10 mm; Non-CR/Non PD: persistence of one or more non-target lesions; PD = unequivocal progression of existing non-target lesions or appearance of new ones | From day 1 to data cut-off 13 January 2012; maximum time on study was approximately 26 months | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) | A TEAE is defined as any AE occurring or worsening on or after the first dose of study drug and within 28 days after the last dose of study drug. A TESAE is defined as any serious adverse event (SAE) occurring or worsening on or after the first dose of study drug and within 28 days after the last dose of study drug. Safety and severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0; Severity of AEs were graded (including second primary malignancies) as Grade 1- Mild; Grade 2- Moderate; Grade 3- Severe; Grade 4- Life-threatening; Grade 5-Fatal; | From the time from of first dose of study drug administration to 28 days after the last dose of study drug and up to the data cut off date of 13 January 2012; the maximum duration of study drug was 93 weeks for DP and 90.6 weeks for DPL | 
| Percentage of Participants Who Received Post-Study Therapies | Percentage of Participants Who Received Post-Study Therapies for advanced Prostate Cancer. | The date when the first consent form was signed to the last date of AE data collection;up to 5 years; up to the date of the final data analysis date of 20 April 2017 | 
| Percentage of Participants With Secondary Primary Malignancies During the Course of the Trial | Second primary malignancies were monitored as events of interest and reported as serious adverse events throughout the course of the trial. | The date when the first consent form was signed to the last date of AE data collection; up to the date of the final data analysis date of 30 November 2016; 7 years and 19 days | 
| Time to Onset of Secondary Primary Malignancies | Time of Onset of Secondary Primary Malignancies was considered an event of interest | The date when the first consent form was signed to the last date of AE data collection; up to the date of the final data analysis date of 30 November 2016; 7 years and 19 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Castrate-Resistant Prostate Cancer, Revlimid, Lenalidomide