Docetaxel, Thalidomide, Prednisone, and Bevacizumab to Treat Metastatic Prostate Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
William Dahut Jr., M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00089609
First received: August 6, 2004
Last updated: April 19, 2016
Last verified: April 2016
  Purpose
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.

Condition Intervention Phase
Prostatic Neoplasms
Drug: Docetaxel
Drug: Thalidomide
Drug: Prednisone
Biological: bevacizumab
Genetic: polymorphism analysis
Other: immunoenzyme technique
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Docetaxel, Thalidomide, Prednisone and Bevacizumab in Patients With Androgen-Independent Prostate Cancer

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Number of Participants Who Had a Prostate-specific Antigen (PSA) Response [ Time Frame: 21.6 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Number of Participants With Adverse Events [ Time Frame: 79 months ] [ Designated as safety issue: Yes ]
    Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

  • Time to Progression Using Bubley Criteria [ Time Frame: up to 40 months ] [ Designated as safety issue: No ]
    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.

  • Disease Progression by Clinical and Radiographic Criteria Without the Use of Prostate-Specific Antigen (PSA) [ Time Frame: up to 34 months ] [ Designated as safety issue: No ]
    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 20% increase 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 [ Time Frame: 34 months ] [ Designated as safety issue: No ]
    From on study date to date of death at 34 months.

  • Plasma Concentrations of Docetaxel and Thalidomide and Clinical Activity or Toxicity [ 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 ] [ Designated as safety issue: No ]
    The analysis will be performed using a validated method based on liquid chromatography with mass-spectrometric detection.

  • Number of Participants With a Significant Increase in Circulating Apoptotic Endothelial Cell (CAEC) Level [ Time Frame: Baseline and at 6 weeks (after two cycles of treatment) ] [ Designated as safety issue: No ]
    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.

  • Analyze the Patients Genotype With Regard to Cytochrome P450 2C19 Polymorphism and Correlate That With Pharmacokinetics and Efficacy [ Time Frame: Patient entry onto the study ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and at 3 month intervals until progression ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and monthly ] [ Designated as safety issue: No ]

Enrollment: 73
Study Start Date: August 2004
Estimated Study Completion Date: January 2018
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: Docetaxel
Docetaxel 75 mg/m^2 intravenously over 60 minutes on cycle 1 day 1 repeated every 21 days.
Other Name: Taxotere
Drug: Thalidomide
Thalidomide 200 mg by mouth daily throughout the cycle.
Other Name: Thalomid
Drug: Prednisone
Prednisone 10 mg by mouth daily throughout the cycle.
Other Name: Deltasone
Biological: bevacizumab
Bevacizumab 15 mg/kg intravenously on cycle 1 day 1 every 21 days.
Other Name: Avastin
Genetic: polymorphism 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.
Other: immunoenzyme 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.
Other: laboratory biomarker analysis
Serum and urine samples will be collected at baseline and monthly to measure VEGF (vascular endothelial growth factor) levels.
Other: pharmacological 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.
Experimental: 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.
Drug: Docetaxel
Docetaxel 75 mg/m^2 intravenously over 60 minutes on cycle 1 day 1 repeated every 21 days.
Other Name: Taxotere
Drug: Thalidomide
Thalidomide 200 mg by mouth daily throughout the cycle.
Other Name: Thalomid
Drug: Prednisone
Prednisone 10 mg by mouth daily throughout the cycle.
Other Name: Deltasone
Biological: bevacizumab
Bevacizumab 15 mg/kg intravenously on cycle 1 day 1 every 21 days.
Other Name: Avastin

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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00089609

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: William L Dahut, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: William Dahut Jr., M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00089609     History of Changes
Obsolete Identifiers: NCT00091364
Other Study ID Numbers: 040257  04-C-0257 
Study First Received: August 6, 2004
Results First Received: October 12, 2012
Last Updated: April 19, 2016
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Hormones
Angiogenesis
Markers
Tumor
Prostate Cancer

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Bevacizumab
Thalidomide
Docetaxel
Prednisone
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Immunosuppressive Agents
Immunologic Factors
Leprostatic Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on August 25, 2016