This is a Phase II study of docetaxel, bevacizumab, prednisone and thalidomide in patients with androgen independent metastatic prostate cancer who are previously untreated with chemotherapy. The primary objective of this study is to determine if the combination of docetaxel, thalidomide and bevacizumab is able to be associated with a sufficiently high proportion of patients with a prostate-specific antigen (PSA) response to be worthy of further investigation in metastatic prostate cancer. We will also be looking at multiple secondary endpoints. These will include possible pharmacokinetic interactions among the study agents, potential correlation between patient genotype and efficacy of treatment. We will also be looking for circulating tumor cells in blood before and after treatment. Additionally we will be monitoring the tolerability of the regimen and survival duration as endpoints as well. We hope to use this trial to build on the promising results seen in our thalidomide/docetaxel protocol where there was a significant PSA decline and a trend toward survival benefit.
This is a Phase II study of docetaxel, bevacizumab, prednisone and thalidomide in patients with androgen independent metastatic prostate cancer who are previously untreated with chemotherapy. The primary objective of this study is to determine if the combination of docetaxel, thalidomide and bevacizumab is able to be associated with a sufficiently high proportion of patients with a PSA response to be worthy of further investigation in metastatic prostate cancer. We will also be looking at multiple secondary endpoints. These will include possible pharmacokinetic interactions among the study agents, potential correlation between patient genotype and efficacy of treatment. We will also be looking for circulating endothelial cells in blood before and after treatment. Additionally we will be monitoring the tolerability of the regimen, time to disease progression, and survival duration as endpoints as well. We hope to use this trial to build on the promising results seen in our thalidomide/docetaxel protocol where there was a significant PSA decline and a trend toward survival benefit.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
73
Docetaxel 75 mg/m\^2 intravenously over 60 minutes on cycle 1 day 1 repeated every 21 days.
Thalidomide 200 mg by mouth daily throughout the cycle.
Prednisone 10 mg by mouth daily throughout the cycle.
Bevacizumab 15 mg/kg intravenously on cycle 1 day 1 every 21 days.
Two buffy coat tubes (two 7mL blue tiger top tubes) will be obtained and wrapped in foil when the patient enters onto the study. DNA (deoxyribonucleic acid) will be isolated only for the purpose of genotype analysis of enzymes with putative relevance for docetaxel or thalidomide disposition.
The PBMC (peripheral blood mononuclear cells) of patients will be analyzed pre-treatment and post cycle 2 for any changes in the function of regulatory T cells. The following analysis will be performed: flow cytometry analysis, CD4 CD25 T cell enrichment, and immunosuppression assay.
Serum and urine samples will be collected at baseline and monthly to measure VEGF (vascular endothelial growth factor) levels.
Plasma concentrations of docetaxel and thalidomide will be determined to assess interactions between docetaxel (and thalidomide) and the concomitant therapy.The analysis will be performed using a validated method based on liquid chromotography with mass-spectrometric detection.
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
Number of Participants Who Had a Prostate-specific Antigen (PSA) Response
PSA response was assessed by the PSA Consensus Criteria. PSA decline is defined as a decline in PSA of at least 50% with no other evidence of disease progression.
Time frame: 21.6 months
Immune Response
Cellular immune response and cytokines were evaluated after two cycles of therapy in the expansion cohort. Those cycles included treatment with bevacizumab and docetaxel as a pre-medication.
Time frame: 6 weeks
Number of Participants With Adverse Events
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
Time frame: 37 months
Time to Progression Using Bubley Criteria
Time to disease progression was based on the Prostate-Specific Antigen (PSA) Working Group 1 Criteria (Bubley Criteria) and standard Response Evaluation Criteria in Solid Tumors (RECIST) for measurable disease. Per the criteria, investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period.
Time frame: up to 40 months
Disease Progression by Clinical and Radiographic Criteria Without the Use of Prostate-Specific Antigen (PSA)
Clinical and radiographic response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions. taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking s reference the smallest sum LD since the treatment started. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded or the appearance of one or more new lesions.
Time frame: up to 34 months
Number of Participants Who Died After a Follow Up of 34 Months Following Treatment
From on study date to date of death at 34 months.
Time frame: 34 months
Plasma Concentrations of Docetaxel and Thalidomide and Clinical Activity or Toxicity
The analysis will be performed using a validated method based on liquid chromatography with mass-spectrometric detection.
Time frame: Pre-dose on C1D1, 5 minutes before the end of infusion, and 15, and 30 minutes, and 1, 2,4,8, and 24 hours after the end of infusion
Number of Participants With a Significant Increase in Circulating Apoptotic Endothelial Cell (CAEC) Level
The assay utilized has no standard curve. Categorizing patients with ≥ 75% PSA decline in one group and \< PSA decline in another group, every patient is their own control with comparison of CAEC at baseline vs. 6 weeks (after two cycles of treatment). Blood is drawn from the patient and a million viable mononuclear cells are counted and then it is determined how many CAECs are in the specimen. The cell count is then compared from baseline to post 2 cycles of treatment. Thus, "significant increase" is dependent upon this comparison and varies between patients.
Time frame: Baseline and at 6 weeks (after two cycles of treatment)
Analyze the Patients Genotype With Regard to Cytochrome P450 2C19 Polymorphism and Correlate That With Pharmacokinetics and Efficacy
Single nucleotide polymorphisms in genes that play an important role in eliminations pathways for docetaxel (in the CYP3A4 and CYP3A5 genes) and thalidomide (CYP2C19) will be evaluated.
Time frame: Patient entry onto the study
Usefulness of Dynamic Magnetic Resonance Imaging (MRI) to Monitor the Progression of Bony and Soft Tissue Disease in Metastatic Prostate Cancer
Target lesions in the bone or soft tissues will be identified from the participant computed tomography (CT) scan. Dynamic MRI will be performed after the intravenous administration of 0.1 mmol/kg of Gadolinium chelate. Progression is defined by the RECIST criteria and is at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment starts or the appearance of new lesions.
Time frame: Baseline and at 3 month intervals until progression
Changes in the Molecular Markers of Angiogenesis (Including, But Not Limited to Serum and Urine Vascular Endothelial Growth Factor (VEGF)) Before and After Administration of Docetaxel, Prednisone, Thalidomide and Bevacizumab
Time frame: Baseline and monthly
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