Prostatic Neoplasms
Conditions
Keywords
Hormones, Angiogenesis, Markers, Tumor, Prostate Cancer
Brief summary
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.
Detailed description
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.
Interventions
DRUGDocetaxel
Docetaxel 75 mg/m\^2 intravenously over 60 minutes on cycle 1 day 1 repeated every 21 days.
DRUGThalidomide
Thalidomide 200 mg by mouth daily throughout the cycle.
DRUGPrednisone
Prednisone 10 mg by mouth daily throughout the cycle.
BIOLOGICALbevacizumab
Bevacizumab 15 mg/kg intravenously on cycle 1 day 1 every 21 days.
GENETICpolymorphism analysis
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.
OTHERimmunoenzyme technique
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.
OTHERlaboratory biomarker analysis
Serum and urine samples will be collected at baseline and monthly to measure VEGF (vascular endothelial growth factor) levels.
OTHERpharmacological study
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.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Androgen-independent metastatic adenocarcinoma of the prostate defined as progressive metastatic disease while on gonadotropin releasing hormone (GnRH) agonists or post surgical castration Histopathological documentation of prostate cancer confirmed in the National Cancer Institute (NCI) Laboratory of Pathology at the National Institutes of Health, the Pathology Department at Walter Reed Medical Center or the Pathology Department at National Naval Medical Center, prior to starting this study. In addition, patients whose slides are lost or unavailable will be eligible for the study if they provide documentation of prostate cancer and if they meet criteria of clinically progressive prostate cancer as outlined in section 3.1.1.3. Clinically progressive prostate cancer documented prior to entry. Progression must be documented by at least one of the following parameters: * Two consecutively rising prostate-specific antigen (PSA) levels. The first rising PSA must be a minimum of one week from a reference value. It is recognized that PSA fluctuations are such that the confirmatory PSA value might be less than the previous one. In these cases, that patient would still be eligible provided the next PSA was greater than the first rising PSA value. Patients must have PSA greater than or equal to 5.0. * At least one new lesion on bone scan. * Progressive measurable disease. Patients must have undergone bilateral surgical castration or must continue on GNRH agonist. Those patients receiving an anti-androgen agent and are entering the trial due to a rise in PSA must demonstrate a continued rise in PSA 4 weeks after stopping flutamide and 6 weeks after stopping bicalutamide or nilutamide. Patients may not have received any chemotherapy for metastatic prostate cancer Age greater than or equal to 18 years Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 Life expectancy of greater than 3 months Patients must have adequate organ and marrow function as defined below: Leukocytes- greater than or equal to 3,000/microliter Absolute neutrophil count- greater than or equal to 1,500/microliter Platelets- greater than or equal to 100,000/microliter Hemoglobin- greater than or equal to 8.0g/L - transfusions acceptable Total bilirubin- less than or equal to 1.5 times the institutional upper limits of normal Aspartate aminotransferase (AST)serum glutamic oxaloacetic transaminase(SGOT) and alanine aminotransferase (ALT)serum glutamic pyruvic transaminase(SGPT) - less than or equal to 2.5 times the institutional upper limits of normal Creatinine or Creatinine clearance- less than or equal to 1.5 times the institutional upper limits of normal or greater than or equal to 40 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal. Recovered from any toxicity from surgery or radiotherapy Must be willing to travel from their home to the National Institutes of Health (NIH) for follow-up visits Able and willing to follow instructions and conform to protocol. Patients may have had no other active malignancy within the past 2 years with the exception of non-melanoma skin cancer and superficial bladder carcinoma No history of myocardial infarction within the past 6 months, uncontrolled congestive heart failure (CHF) or uncontrolled angina pectoris Patients must agree to use adequate contraception (abstinence; hormonal or barrier method of birth control) for the study and at least 2 months after completion. Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
Present clinical signs or symptoms of brain and/or leptomeningeal metastases confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) brain scan. Uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (American Heart Association (AHA) Class II or worse), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Persistent systolic blood pressure greater than or equal to 170 mmHg or diastolic blood pressure greater than or equal to 100 mmHg. Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with docetaxel, bevacizumab, and/or the combination. Proteinuria, as demonstrated by a urine, protein, creatinine (UPC) ratio greater than or equal to 1.0 at screening, required to be assessed if urine dipstick is greater than or equal to 1+. Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio. For UPC ratio \> 0.5, 24-hour urine protein should be obtained and the level should be \< 1000 mg for patient enrollment. Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm. UPC ratio is calculated using one of the following formula: * \[urine protein\]/\[urine creatinine\] - if both protein and creatinine are reported in mg/dL * \[(urine protein) x 0.088\]/\[urine creatinine\] - if urine creatinine is reported in mmol/L Therapeutic anticoagulation with coumadin, heparins, or heparinoids. Greater than Grade 2 peripheral neuropathy at baseline. History of transient ischemic attacks (TIA) or cerebrovascular accident (CVA) within the past 2 years. History of allergic reaction to docetaxel, prednisone, thalidomide and/or bevacizumab or related products. Patients who are on concurrent investigational agent(s) Patients who are unable to ingest oral medication. INCLUSION OF WOMEN AND MINORITIES Men of all races and ethnic groups are eligible for this trial. Every effort will be made to recruit minorities in this study. Women are ineligible for this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had a Prostate-specific Antigen (PSA) Response | 21.6 months | 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. |
| Immune Response | 6 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Progression by Clinical and Radiographic Criteria Without the Use of Prostate-Specific Antigen (PSA) | up to 34 months | 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. |
| Number of Participants Who Died After a Follow Up of 34 Months Following Treatment | 34 months | From on study date to date of death at 34 months. |
| Plasma Concentrations of Docetaxel and Thalidomide and Clinical Activity or Toxicity | 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 | The analysis will be performed using a validated method based on liquid chromatography with mass-spectrometric detection. |
| Number of Participants With Adverse Events | 37 months | Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module. |
| Analyze the Patients Genotype With Regard to Cytochrome P450 2C19 Polymorphism and Correlate That With Pharmacokinetics and Efficacy | Patient entry onto the study | 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. |
| Usefulness of Dynamic Magnetic Resonance Imaging (MRI) to Monitor the Progression of Bony and Soft Tissue Disease in Metastatic Prostate Cancer | Baseline and at 3 month intervals until progression | 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. |
| 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 | Baseline and monthly | — |
| Number of Participants With a Significant Increase in Circulating Apoptotic Endothelial Cell (CAEC) Level | Baseline and at 6 weeks (after two cycles of treatment) | 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 to Progression Using Bubley Criteria | up to 40 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Main Cohort - Prostate Cancer 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. | 60 |
| Expansion Cohort - Prostate Cancer Docetaxel 75 mg/m\^2 intravenously over 60 minutes and Bevacizumab 15 mg/kg intravenously was given for 2 cycles. After two cycles Prednisone 10 mg by mouth daily and Thalidomide 200 mg by mouth daily was added | 13 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Main Cohort - Prostate Cancer | Expansion Cohort - Prostate Cancer | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 31 Participants | 5 Participants | 36 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 8 Participants | 37 Participants |
| Age, Continuous | 65.35 years STANDARD_DEVIATION 7.81 | 63.31 years STANDARD_DEVIATION 8.74 | 64.98 years STANDARD_DEVIATION 7.96 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 56 Participants | 12 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 2 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 51 Participants | 11 Participants | 62 Participants |
| Region of Enrollment United States | 60 Participants | 13 Participants | 73 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 60 Participants | 13 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 35 / 60 | 1 / 13 |
| other Total, other adverse events | 60 / 60 | 13 / 13 |
| serious Total, serious adverse events | 48 / 60 | 4 / 13 |
Outcome results
Primary
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
Population: Cellular immune response and cytokines were not analyzed as the study outcomes were concentrated on the dual-anti-angiogenesis inhibition properties of the regimen and not immunomodulatory changes.
Primary
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
Population: The main cohort was designed to evaluate clinical progression and the expansion cohort was designed to evaluate immune response. Thus the expansion cohort is not included here.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Main Cohort - Prostate Cancer | Number of Participants Who Had a Prostate-specific Antigen (PSA) Response | 52 Participants |
Secondary
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
Population: The outcome was not assessed as the clinical significance of cytochrome P450 2C19 polymorphism in angiogenesis is undetermined. This analysis will not be pursued.
Secondary
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
Population: The outcome was not assessed. In the study, assessment of circulating apoptotic endothelial cells was the main outcome evaluated for assessing the treatment's antiangiogenic activity. Changes in the molecular markers of angiogenesis will not be pursued.
Secondary
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
Population: Only 33/60 participants had measurable disease and were evaluable for this outcome measure.~Per protocol, disease progression by clinical and radiographic criteria without the use of PSA was not assessed for the expansion cohort.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Main Cohort - Prostate Cancer | Disease Progression by Clinical and Radiographic Criteria Without the Use of Prostate-Specific Antigen (PSA) | Partial Response (PR) | 19 Participants |
| Main Cohort - Prostate Cancer | Disease Progression by Clinical and Radiographic Criteria Without the Use of Prostate-Specific Antigen (PSA) | Stable Disease (SD) | 11 Participants |
| Main Cohort - Prostate Cancer | Disease Progression by Clinical and Radiographic Criteria Without the Use of Prostate-Specific Antigen (PSA) | Complete Response (CR) | 2 Participants |
| Main Cohort - Prostate Cancer | Disease Progression by Clinical and Radiographic Criteria Without the Use of Prostate-Specific Antigen (PSA) | Progressive Disease (PD) | 1 Participants |
Secondary
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
Population: Per protocol, this outcome was not assessed for the expansion cohort.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Main Cohort - Prostate Cancer | Number of Participants Who Died After a Follow Up of 34 Months Following Treatment | 38 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Main Cohort - Prostate Cancer | Number of Participants With Adverse Events | 60 Participants |
| Expansion Cohort - Prostate Cancer | Number of Participants With Adverse Events | 13 Participants |
Secondary
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)
Population: Only 17/60 participants were evaluable for this outcome. Per protocol CAECs were not assessed in the expansion cohort.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Main Cohort - Prostate Cancer | Number of Participants With a Significant Increase in Circulating Apoptotic Endothelial Cell (CAEC) Level | 14 Participants |
| Expansion Cohort - Prostate Cancer | Number of Participants With a Significant Increase in Circulating Apoptotic Endothelial Cell (CAEC) Level | 0 Participants |
p-value: 0.02Wilcoxon (Mann-Whitney)
Secondary
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
Population: The outcome was not assessed as the analysis of plasma bevacizumab concentrations was the main pharmacokinetic secondary outcome in the study. The plasma levels of docetaxel and thalidomide (without bevacizumab) had minimal significance in this study. Analysis of plasma concentrations of docetaxel and thalidomide will not be done.
Secondary
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
Population: Per protocol, time to progression using Bubley Criteria was not assessed for the expansion cohort.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Main Cohort - Prostate Cancer | Time to Progression Using Bubley Criteria | 18.3 Months |
Secondary
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
Population: The outcome was not assessed as the functionality of dynamic MRI in prostate cancer was poor at the time of this study. Earlier prostate MRI techniques suffered from poor sensitivity and specificity for monitoring progression.