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

• Register: REBEC
• Last refreshed on: 29 April 2013
• Main ID: RBR-36w269
• Date of registration: 13/06/2011
• Primary sponsor: Bristol-Myers Squibb - Brazil
• Public title: A Randomized Double-Blind Phase 3 Trial Comparing Docetaxel Combined with Dasatinib to Docetaxel Combined with Placebo in Castration-Resistant Prostate Cancer
• Scientific title: A Randomized Double-Blind Phase 3 Trial Comparing Docetaxel Combined with Dasatinib to Docetaxel Combined with Placebo in Castration-Resistant Prostate Cancer
• Date of first enrolment: 01/01/2010
• Target sample size: 1380
• Recruitment status: recruitment completed
• URL: http://www.ensaiosclinicos.gov.br/rg/RBR-36w269/
• Study design: Therapeutic , Multicenter, Double-Blind, Randomized, Parallel Arm with 2 and Phase 3; Clinical Trial

Countries of recruitment

Australia, Brazil, Canada, Czech Republic, Finland, France, Germany, Greece, Hungary, India, Italy, Korea, Republic of, Norway, Poland, Romania, Russian Federation, South Africa, Switzerland, United Kingdom, United States

Contacts

• Name: Juliana Castro
• Affiliation: Bristol-Myers Squibb

• Name: Juliana Castro
• Affiliation: Bristol-Myers Squibb

Key inclusion & exclusion criteria

Inclusion criteria: Subjects must have signed an informed consent document stating that they
understand the investigational nature of the proposed treatment.
History of histologically diagnosed prostate cancer.
Evidence of metastatic disease by any 1 of the following modalities: CT scan,
MRI, bone scan, or skeletal survey.
Evidence of progression, as defined by 1 of the following:
Rising PSA values at least 1 week apart with the final value being >= 2 ng/mL,or
Progression of measurable nodal or visceral disease:
Nodal lesions must be >= 20 mm
Visceral lesions must be measurable per RECIST criteria, or
Two or more new lesions appearing on a bone scan compared with a prior
scan, or
Local recurrence in the prostate or prostate bed.
Maintaining castrate status: Subjects who have not undergone surgical
orchiectomy should have received and continue on medical therapies [eg,
gonadotropin releasing hormone analogs (GnRH/LHRH analogs)] to maintain
castrate levels of serum testosterone <= 50 ng/dL (1.7 nmol/L).
ECOG Performance Status 0 - 2.
At least 4 weeks since major surgery, radiotherapy, and an investigational agent.
At least 8 weeks since radioisotope therapy (eg, Strontium-89, Samarium-153 or
similar agents).
Recovery from local primary therapy of surgery or radiation.
Required initial laboratory values:
WBC >= 3,000/mm3.
ANC >= 1,500/mm3.
Platelet count >= 100,000/mm3.
Creatinine <= 1.5 x upper limits of normal.
Bilirubin <= upper limit of normal (does not apply for subjects with Gilbert’s
Disease).
SGOT (AST) <= 2.5 x upper limits of normal.
SGPT (ALT) <= 2.5 x upper limits of normal.
Men only, at least 18 years old.
Exclusion criteria: Women.
Sexually active fertile men not using effective birth control if their partners are WOCBP.
Subjects with active brain metastases or leptomeningeal metastases are excluded
from this clinical trial.
Clinically significant cardiovascular disease, including myocardial infarction or
ventricular tachyarrhythmia within 6 months, prolonged QTc > 450 msec, ejection
fraction (EF) < 40% or major conduction abnormality, unless a cardiac pacemaker
is present.
Pleural or pericardial effusion of any CTC grade.
Peripheral neuropathy CTC Grade >= 2.
Subjects with a “currently active” second malignancy other than non-melanoma
skin cancers are not to be enrolled into the study. Subjects 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, but not limited to, ongoing or active infection, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
HIV-positive subjects receiving combination anti-retroviral therapy.
History of allergic reactions attributed to compounds of similar chemical or
biologic composition to the investigational agents.
Subjects may not be receiving any other investigational agents for the treatment of
prostate cancer.
No prior cytotoxic chemotherapy in the metastatic setting, with the exception of
estramustine.
Subjects may continue on a daily multi-vitamin but all other herbal, alternative
and food supplements (eg, PC-Spes, Saw Palmetto, St John’s Wort) must be
discontinued before enrollment into the study.
Ketoconazole must be discontinued 4 weeks prior to starting study therapy.
Anti-androgens should be discontinued prior to starting study therapy. Subjects
with a history of response to an anti-androgen and subsequent progression while
on that anti-androgen should be assessed for anti-androgen withdrawal response
for 4 weeks. Observation for anti-androgen withdrawal response is not necessary
for subjects who have never responded to anti-androgens.
Bisphosphonates must not be initiated within 28 days prior to starting study
therapy.
QT prolonging agents strongly associated with torsade de pointes.
Prisoners or subjects who are involuntarily incarcerated.
Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness

Age minimum: 18Y
Age maximum: 0
Gender: M

Health Condition(s) or Problem(s) studied

C00-D48

Castration-Resistant Prostate Cancer
C04.588.945.440.770
C61

Intervention(s)

Comparison group: 690 patients receive docetaxel 75 mg/m2 administered IV over 1 hour every 3 weeks for 10 cycles plus prednisone 5 mg 2x / d given continuously + dasatinib 100 mg 1x / d until disease progression, control group: 690 patients receive docetaxel 75 mg/m2 administered IV over 1 hour every 3 weeks for 10 cycles plus prednisone 5 mg 2x / d + placebo given continuously until disease progression

Primary Outcome(s)

Overall Survival will be defined as the time from the date of randomization to the date of death. If the subject did not die, survival will be censored on the last date the subject was known to be alive.

The primary endpoint in this study is Overall Survival and will be based on the Intention To Treat (ITT) population. The primary analysis of Overall Survival will be a comparison between the 2 treatment arms using a two-sided, alpha = 0.0463 (0.0002, 0.012 for the first and second interim analyses respectively) log-rank test, stratified by ECOG - Eastern Cooperative Oncology Group performance status (0 - 1 vs 2), baseline biphosphonates intake (yes or no), and urinary N-telopeptide value (< 60 nmol/mmol creatinine vs >= 60 nmol/mmol creatinine). The alpha level is adjusted for 2 planned interim analyses using the O’Brien-Fleming alpha spending function.
Further analysis of Overall Survival will include the computation of hazard ratios and the estimation of survival functions. The survival hazard ratio of dasatinib in combination with docetaxel and prednisone to placebo in combination with docetaxel and prednisone and an associated two-sided 95.37% (99.98% and 98.8% for the first and second interim analyses respectively) confidence interval, will be computed using unadjusted and adjusted Cox proportional hazards model stratified by ECOG - Eastern Cooperative Oncology Group performance status (0 - 1 vs 2), baseline bisphosphonate intake (yes/no), and urinary N-telopeptide value (< 60 nmol/mmol creatinine vs >= 60 nmol/mmol creatinine). The adjusted Cox proportional hazards model will include treatment and pre-specified prognostic factors including age (< 70, >= 70 years), presence of bone metastases (any bone metastases vs no bone mestastases), baseline alkaline phosphatase, type of progression (PSA (prostatic specific antigen), measurable disease, bone scan progression), number of metastases sites (< 2 vs >= 2), baseline hemoglobin, and baseline PSA (prostatic specific antigen)level.
The proportional hazards assumption will be assessed using time-dependent covariates. The survival function for each treatment will be estimated using the Kaplan-Meier product limit method. In addition, 2-sided 95% confidence intervals for the median survival will be computed by treatment arm.

Secondary Outcome(s)

Secondary efficacy endpoints include rate of uNTx (Urinary N-Telopeptide) change from baseline, time to first skeletal-related event, change in pain intensity, time to PSA (prostatic specific antigen) progression, objective tumor response rate, and rate of stable disease by bone scans. Secondary efficacy endpoints will be tested hierarchically.
Time to first skeletal-related event and time to PSA (prostatic specific antigen) progression in each arm will be estimated using the Kaplan-Meier product limit method. A two-sided 95% confidence interval for median TFSRE (time to free Slekeletal-Related Event) and time to PSA (prostatic specific antigen) progression will be computed using the methods of Brookmeyer and Crowley. TFSRE (time to free Slekeletal-Related Event) and time to PSA (prostatic specific antigen) progression will also be compared between treatment arms with a two-sided, alpha= 05 level, log-rank test, stratified by ECOG - Eastern Cooperative Oncology Group performance status (0 - 1 vs 2), baseline bisphosphonate intake (yes/no), and urinary N-telopeptide value (< 60 nmol/mmol creatinine vs >=60 nmol/mmol creatinine).
The proportion change in pain intensity, the stable disease by bone scans rate and the objective tumor response rate (RR) will be summarized for the 2 treatment arms with a Cochran-Mantel-Haenszel (CMH) test, an associated odds ratio estimate and a 95% confidence interval, stratified by ECOG - Eastern Cooperative Oncology Group performance status (0 - 1 vs 2), baseline bisphosphonate intake (yes/no), and urinary N-telopeptide value (< 60 nmol/mmol creatinine vs >= 60 nmol/mmol creatinine).
Secondary efficacy analyses will be performed at the time final survival analysis is performed.

Secondary ID(s)

400/2009

451/2009

NCT00744497

Source(s) of Monetary Support

Bristol-Myers Squibb - Brazil