Randomized Study Comparing Docetaxel Plus Dasatinib to Docetaxel Plus Placebo in Castration-resistant Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether survival can be prolonged in patients with castration-resistant prostate cancer who receive dasatinib with docetaxel and prednisone.

Official Title
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A Randomized Double-Blind Phase 3 Trial Comparing Docetaxel Combined With Dasatinib to Docetaxel Combined With Placebo in Castration-Resistant Prostate Cancer

Conditions
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Prostatic Neoplasms

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of histologically diagnosed prostate cancer Evidence of metastatic disease by any 1 of the following: computed tomography scan, magnetic resonance imaging, bone scan, or skeletal survey Evidence of progression, as defined by 1 of the following: rising prostate specific antigen levels at least 1 week apart with the final value being >=2 ng/mL; progression of measurable nodal or visceral disease, with nodal lesions >=20 mm and visceral lesions measurable per response evaluation criteria for solid tumors (Response Evaluation in Solid Tumors, version 1); 2 or more lesions appearing on bone scan compared with previous scan; or local recurrence in the prostate or prostate bed Maintaining castrate status: Participants who have not undergone surgical orchiectomy should have received and continue on medical therapies, such as gonadotropin releasing hormone analogs, to maintain castrate levels of serum testosterone <=50 ng/dL Eastern Cooperative Oncology Group Performance Status of 0 to 2 At least 4 weeks since an investigational agent prior to starting study therapy At least 8 weeks since radioisotope therapy prior to starting study therapy Recovery from any local therapy including surgery or radiation/radiotherapy for a minimum of 7 days prior to starting study therapy Required initial laboratory values: white blood cell count >=3,000/mm^3; absolute neutrophil count >=1,500/mm^3; platelet count >=100,000/mm^3; creatinine level <=1.5*upper limit of normal (ULN); bilirubin <=ULN; aspartate aminotransferase <=2.5*ULN; alanine aminotransferase <=2.5*ULN. Exclusion Criteria: Symptomatic brain metastases or leptomeningeal metastases Clinically significant cardiovascular disease, including myocardial infarction; ventricular tachyarrhythmia within 6 months; prolonged QTc >450 msec; ejection fraction <40%; or major conduction abnormality, unless a cardiac pacemaker is present Pleural or pericardial effusion of any Common Terminology Criteria (CTC) grade Peripheral neuropathy CTC Grade >=2 Currently active second malignancy other than nonmelanoma skin cancers. Participants are not considered to have a currently active malignancy if they have completed therapy and are now considered (by their physician) to be at less than 30% risk for relapse Uncontrolled intercurrent illness including ongoing or active infection, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements HIV infection-positive patients receiving combination antiretroviral therapy History of allergic reactions attributed to compounds of similar chemical or biologic composition to the investigational agents Receipt of any other investigational agents for the treatment of prostate cancer Prior cytotoxic chemotherapy in the metastatic setting, with the exception of estramustine Patients may continue on a daily multivitamin but must discontinue all other herbal, alternative, and food supplements before enrollment Ketoconazole must be discontinued 4 weeks prior to starting study therapy Antiandrogens must be discontinued prior to starting study therapy. Patients with a history of response to an antiandrogen and subsequent progression while on that antiandrogen should be assessed for antiandrogen withdrawal response for 4 weeks. Observation for antiandrogen withdrawal response is not necessary for those who have never responded to antiandrogens Bisphosphonates must not be initiated within 28 days prior to starting study therapy QT prolonging agents strongly associated with torsade de pointes.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo, given orally once daily, plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily | Drug: Placebo<br> <br> Drug: Docetaxel<br> <br> Drug: Prednisone<br> <br> |
| Active Comparator: Dasatinib<br>Participants received dasatinib, 100 mg, orally once daily plus docetaxel, 75 mg/m^2, given intravenously every 3 weeks as a 1-hour infusion, plus prednisone, 5 mg, given orally twice daily | Drug: Dasatinib<br> <br> * Other names: BMS-354825;Drug: Docetaxel<br> <br> Drug: Prednisone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival: Time From Randomization to Date of Death | Overall survival is defined as time in months from the randomization date to the date of death due to any cause (in the randomized population). If the patient did not die, survival was censored on the last date he or she was known to be alive. | From randomization to death or date of last contact (maximum reached: 45 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Objective Tumor Response by Modified Response Evaluation Criteria in Solid Tumors (RECIST) | Objective tumor response rate=the percentage of randomized participants with a best tumor response of partial (PR) or complete response (CR), within 42 days of end of dosing, divided by total number of patients who were evaluable (with at least 1 target lesion at baseline). By RECIST: CR=disappearance of clinical and radiologic evidence of target and nontarget lesions confirmed by another evaluation at least 6 weeks later. PR=a >30% or greater decrease in the sum of longest diameter (LD) of target lesions in reference to the baseline sum LD confirmed by another evaluation at least 6 weeks later. Stable disease=neither sufficient increase to qualify for PD nor shrinkage to qualify for PR, and at least 8 weeks since start of study therapy. Progressive disease=a 20% or greater increase in sum of LD of all target lesions, taking as reference the smallest sum of LD at or following baseline, or unequivocal progression on existing nontarget lesions, or new lesions are present. | At baseline and every 12 weeks thereafter to end of treatment, at end of treatment, and at follow-up (within 42 days of end of dosing) | 
| Time to First Skeletal-related Event (SRE) | Time to first SRE is defined as the time in months from the date of randomization to the date of first SRE (unless SRE occurred while the patient was undergoing subsequent cancer therapy). Participants with a first SRE while on subsequent cancer therapy, those who died without a reported SRE, and those who did not have an SRE were censored on the date of their last SRE assessment prior to start of subsequent cancer therapy, if any. Participants who had no SRE assessments were censored on the day they were randomized. | From day of randomization to date of first SRE or to last SRE assessment, if subsequent cancer therapy begun or no SRE (maximum reached: 42 months) | 
| Percentage of Participants With A Reduction in Urinary N-telopeptide (uNTx) Level From Baseline | The percentage of participants who had an on-study uNTx value confirmed (at least 3 weeks later) within normal limits (or ≥3 and <60 nmol/mmol creatinine, if normal limits were missing) or an on-study uNTx level reduction from baseline of ≥35%, even when on-study uNTx value remained abnormal. | At baseline, prior to each docetaxel infusion (every 3 weeks) to end of treatment, at end of treatment, and at follow-up (within 14 days of end of dosing) | 
| Progression-free Survival (PFS) | PFS is defined as the time from the randomization date until the date of earliest evidence of disease progression or death, for participants who progressed or died before subsequent cancer therapy. Those who progressed or died while on subsequent cancer therapy and those who did not die or progress were censored at their last radiologic bone scan/imaging, skeletal related-event, or tumor assessment or at measurement of prostate specific antigen levels, whichever occurred last prior to start of subsequent cancer therapy ,if any. Participants with no assessments were censored on the day of randomization. | From day of randomization to disease progression or death (or to last clinical assessment, if subsequent cancer therapy started or no progression or death) (maximum reached: approximately 43 months) | 
| Time to Prostate Specific Antigen (PSA) Progression | PSA progression is defined as the time from randomization to the date of the first PSA level measurement that led to confirmed PSA progression, for participants who had not started subsequent cancer therapy. For participants who did not progress or who progressed on cancer therapy, PSA progression is defined as the time from randomization to the date of the last PSA level measurement before the start of cancer therapy, if any. Participants who had no on-study PSA level measurements were censored on the day they were randomized. | From randomization to date of first PSA measurement leading to confirmed PSA progression (or to last bone scan assessment, if no progression or if cancer therapy started) (maximum reached: 30 months) | 
| Percentage of Participants With a Reduction in Pain Intensity From Baseline | The percentage of participants with a reduction in pain intensity from baseline was defined as the number of participants who achieved a 30% or more decrease in pain intensity from baseline for at least 2 consecutive pain assessments (at least 14 days apart) within 14 days of end of dosing divided by the number of randomized participants who had a baseline pain intensity of at least 2. Pain intensity was assessed based on question 3 of the brief pain inventory questionnaire. | At baseline, prior to each docetaxel infusion (every 3 weeks), at end of treatment, and at follow-up (within 14 days of end of dosing) |