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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00089609
• Collaborator: (none)
• Enrollment: 73
• Location: 1
• Arms: 2
• Actual Duration (Months): 152.7
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	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

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 73 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Docetaxel, Thalidomide, Prednisone and Bevacizumab in Patients With Androgen-Independent Prostate Cancer
• Actual Study Start Date: Apr 19, 2005
• Actual Primary Completion Date: Dec 31, 2011
• Actual Study Completion Date: Jan 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Taxotere ; Drug: Thalidomide; Thalidomide 200 mg by mouth daily throughout the cycle.; Other Names: Thalomid ; Drug: Prednisone; Prednisone 10 mg by mouth daily throughout the cycle.; Other Names: Deltasone ; Biological: bevacizumab; Bevacizumab 15 mg/kg intravenously on cycle 1 day 1 every 21 days.; Other Names: 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 Names: Taxotere ; Drug: Thalidomide; Thalidomide 200 mg by mouth daily throughout the cycle.; Other Names: Thalomid ; Drug: Prednisone; Prednisone 10 mg by mouth daily throughout the cycle.; Other Names: Deltasone ; Biological: bevacizumab; Bevacizumab 15 mg/kg intravenously on cycle 1 day 1 every 21 days.; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

• 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

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ravi Madan, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Mar 7, 2017

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Berchem GJ, Bosseler M, Sugars LY, Voeller HJ, Zeitlin S, Gelmann EP. Androgens induce resistance to bcl-2-mediated apoptosis in LNCaP prostate cancer cells. Cancer Res. 1995 Feb 15;55(4):735-8.
• Horwitz SB. Taxol (paclitaxel): mechanisms of action. Ann Oncol. 1994;5 Suppl 6:S3-6. Review.
• McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM, Campbell ML. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res. 1992 Dec 15;52(24):6940-4.

• Responsible Party: Ravi A. Madan, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00089609
• Other Study ID Numbers: 040257; 04-C-0257; NCT00091364
• First Posted: Aug 9, 2004
• Last Update Posted: Apr 20, 2018
• Last Verified: Mar 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Ravi A. Madan, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC): Hormones; Angiogenesis; Markers; Tumor; Prostate Cancer
• Additional relevant MeSH terms: Prostatic Neoplasms; Thalidomide; Prednisone; Bevacizumab; Docetaxel

Study Results

Participant Flow

Arm/Group Title	Main Cohort - Prostate Cancer	Expansion Cohort - Prostate Cancer
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	60	13
COMPLETED	57	12
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	Main Cohort - Prostate Cancer	Expansion Cohort - Prostate Cancer	Total
Arm/Group Description	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.	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	Total of all reporting groups
Overall Participants	60	13	73
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	29 48.3%	8 61.5%	37 50.7%
>=65 years	31 51.7%	5 38.5%	36 49.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.35 (7.81)	63.31 (8.74)	64.98 (7.96)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	60 100%	13 100%	73 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 5%	1 7.7%	4 5.5%
Not Hispanic or Latino	56 93.3%	12 92.3%	68 93.2%
Unknown or Not Reported	1 1.7%	0 0%	1 1.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	9 15%	2 15.4%	11 15.1%
White	51 85%	11 84.6%	62 84.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	60 100%	13 100%	73 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Had a Prostate-specific Antigen (PSA) Response
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Main Cohort - Prostate Cancer
Arm/Group Description	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.
Measure Participants	60
Count of Participants [Participants]	52 86.7%

2. Primary Outcome

Title	Immune Response
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Expansion Cohort - Prostate Cancer
Arm/Group Description	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
Measure Participants	0

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Main Cohort - Prostate Cancer	Expansion Cohort - Prostate Cancer
Arm/Group Description	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.	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.
Measure Participants	60	13
Count of Participants [Participants]	60 100%	13 100%

4. Secondary Outcome

Title	Time to Progression Using Bubley Criteria
Description	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

Outcome Measure Data

Analysis Population Description

Per protocol, time to progression using Bubley Criteria was not assessed for the expansion cohort.

Arm/Group Title	Main Cohort - Prostate Cancer
Arm/Group Description	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.
Measure Participants	60
Median (95% Confidence Interval) [Months]	18.3

5. Secondary Outcome

Title	Disease Progression by Clinical and Radiographic Criteria Without the Use of Prostate-Specific Antigen (PSA)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Main Cohort - Prostate Cancer
Arm/Group Description	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.
Measure Participants	33
Complete Response (CR)	2 3.3%
Partial Response (PR)	19 31.7%
Stable Disease (SD)	11 18.3%
Progressive Disease (PD)	1 1.7%

6. Secondary Outcome

Title	Number of Participants Who Died After a Follow Up of 34 Months Following Treatment
Description	From on study date to date of death at 34 months.
Time Frame	34 months

Outcome Measure Data

Analysis Population Description

Per protocol, this outcome was not assessed for the expansion cohort.

Arm/Group Title	Main Cohort - Prostate Cancer
Arm/Group Description	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.
Measure Participants	60
Count of Participants [Participants]	38 63.3%

7. Secondary Outcome

Title	Plasma Concentrations of Docetaxel and Thalidomide and Clinical Activity or Toxicity
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Main Cohort - Prostate Cancer
Arm/Group Description	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.
Measure Participants	0

8. Secondary Outcome

Title	Number of Participants With a Significant Increase in Circulating Apoptotic Endothelial Cell (CAEC) Level
Description	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)

Outcome Measure Data

Analysis Population Description

Only 17/60 participants were evaluable for this outcome. Per protocol CAECs were not assessed in the expansion cohort.

Arm/Group Title	Main Cohort - Particpants With ≥75% PSA Decline	Main Cohort - Particpants With <75% PSA Decline
Arm/Group Description	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.	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.
Measure Participants	14	3
Count of Participants [Participants]	14 23.3%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Main Cohort - Prostate Cancer, Expansion Cohort - Prostate Cancer
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.02
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Analyze the Patients Genotype With Regard to Cytochrome P450 2C19 Polymorphism and Correlate That With Pharmacokinetics and Efficacy
Description	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

Outcome Measure Data

Analysis Population Description

The outcome was not assessed as the clinical significance of cytochrome P450 2C19 polymorphism in angiogenesis is undetermined. This analysis will not be pursued.

Arm/Group Title	Main Cohort - Prostate Cancer
Arm/Group Description	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.
Measure Participants	0

10. Secondary Outcome

Title	Usefulness of Dynamic Magnetic Resonance Imaging (MRI) to Monitor the Progression of Bony and Soft Tissue Disease in Metastatic Prostate Cancer
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Main Cohort - Prostate Cancer
Arm/Group Description	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.
Measure Participants	0

11. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Main Cohort - Prostate Cancer
Arm/Group Description	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.
Measure Participants	0

Adverse Events

Time Frame	37 months
Arm/Group Title	Main Cohort - Prostate Cancer		Expansion Cohort - Prostate Cancer
Arm/Group Description	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.		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
All Cause Mortality
	Main Cohort - Prostate Cancer		Expansion Cohort - Prostate Cancer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/60 (58.3%)		1/13 (7.7%)
Serious Adverse Events
	Main Cohort - Prostate Cancer		Expansion Cohort - Prostate Cancer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/60 (80%)		4/13 (30.8%)
Blood and lymphatic system disorders
Leukocytes (total WBC)	1/60 (1.7%)	1	0/13 (0%)	0
Neutrophils/granulocytes (ANC/AG)	4/60 (6.7%)	4	0/13 (0%)	0
Platelets	1/60 (1.7%)	1	0/13 (0%)	0
Hemoglobin	0/60 (0%)	0	1/13 (7.7%)	1
Cardiac disorders
Cardiac arrhythmia - Other, Specify, new onset of A. fib	1/60 (1.7%)	1	0/13 (0%)	0
Cardiac general - Other, Specify, aortic dissection	1/60 (1.7%)	1	0/13 (0%)	0
Hypertension	2/60 (3.3%)	2	1/13 (7.7%)	1
Hypotension	2/60 (3.3%)	2	0/13 (0%)	0
Pain::Cardiac/heart	1/60 (1.7%)	1	1/13 (7.7%)	1
Supraventricular and nodal arrhythmia::Atrial fibrillation	2/60 (3.3%)	3	0/13 (0%)	0
Supraventricular and nodal arrhythmia::Nodal/Junctional	0/60 (0%)	0	1/13 (7.7%)	1
Cardiac ischemia/infarction	1/60 (1.7%)	1	0/13 (0%)	0
Gastrointestinal disorders
Dehydration	1/60 (1.7%)	1	0/13 (0%)	0
Hemorrhage, GI: Abdomen NOS	1/60 (1.7%)	1	0/13 (0%)	0
Hemorrhage, GI: Colon	1/60 (1.7%)	1	0/13 (0%)	0
Hemorrhage, GI::Rectum	1/60 (1.7%)	1	0/13 (0%)	0
Hemorrhage, GI: Upper GI NOS	1/60 (1.7%)	1	0/13 (0%)	0
Ascites (non-malignant)	0/60 (0%)	0	1/13 (7.7%)	1
General disorders
Death not associated with CTCAE term::Death NOS	9/60 (15%)	9	0/13 (0%)	0
Death not associated with CTCAE term: Death Progression NOS	25/60 (41.7%)	25	1/13 (7.7%)	1
Fatigue (asthenia, lethargy, malaise)	1/60 (1.7%)	1	0/13 (0%)	0
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	2/60 (3.3%)	2	0/13 (0%)	0
Death not associated with CTCAE term: Death, Progression NOS	1/60 (1.7%)	1	0/13 (0%)	0
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	0/60 (0%)	0	1/13 (7.7%)	1
Infections and infestations
Febrile neutropenia	1/60 (1.7%)	1	0/13 (0%)	0
Infection	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:Abdomen NOS	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Anal/perianal	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Bladder (urinary)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Bronchus	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Catheter-related	0/60 (0%)	0	1/13 (7.7%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Colon	0/60 (0%)	0	1/13 (7.7%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Lung (pneumonia)	4/60 (6.7%)	4	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Skin (cellulitis)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with unknown ANC: Urinary tract NOS	1/60 (1.7%)	1	0/13 (0%)	0
Infection (documented clinically or microbiologically)	1/60 (1.7%)	1	0/13 (0%)	0
Infection (documented clinically or microbiologically) with Grade 3 or 4	0/60 (0%)	0	1/13 (7.7%)	1
Infection with unknown ANC: Wound	0/60 (0%)	0	1/13 (7.7%)	1
Infection - Other (sepsis)	1/60 (1.7%)	1	0/13 (0%)	0
Injury, poisoning and procedural complications
Fracture	1/60 (1.7%)	1	1/13 (7.7%)	1
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	1/60 (1.7%)	1	0/13 (0%)	0
AST, SGOT(serum glutamic oxaloacetic transaminase)	1/60 (1.7%)	1	0/13 (0%)	0
CPK (creatine phosphokinase)	1/60 (1.7%)	1	0/13 (0%)	0
Hemoglobin	3/60 (5%)	3	0/13 (0%)	0
Potassium, serum-high (hyperkalemia)	1/60 (1.7%)	1	1/13 (7.7%)	2
Proteinuria	1/60 (1.7%)	1	0/13 (0%)	0
Sodium, serum-low (hyponatremia)	0/60 (0%)	0	1/13 (7.7%)	1
Creatinine	0/60 (0%)	0	1/13 (7.7%)	2
Glucose, serum-high (hyperglycemia)	0/60 (0%)	0	1/13 (7.7%)	1
Uric acid, serum-high (hyperuricemia)	0/60 (0%)	0	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy)::Whole body/generalized	1/60 (1.7%)	1	0/13 (0%)	0
Pain: Back	1/60 (1.7%)	1	0/13 (0%)	0
Nervous system disorders
CNS cerebrovascular ischemia	2/60 (3.3%)	3	0/13 (0%)	0
Neurology-Other (somnolence	1/60 (1.7%)	1	0/13 (0%)	0
Syncope (fainting)	2/60 (3.3%)	2	0/13 (0%)	0
Renal and urinary disorders
Renal failure	1/60 (1.7%)	1	0/13 (0%)	0
Renal/Genitourinary - Other (acute kidney injury; chronic kidney disease)	0/60 (0%)	0	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	1/60 (1.7%)	1	0/13 (0%)	0
Hemorrhage, pulmonary/upper respiratory::Nose	1/60 (1.7%)	1	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Wound complication, non-infectious	1/60 (1.7%)	1	0/13 (0%)	0
Vascular disorders
Thrombosis/thrombus/embolism	3/60 (5%)	3	0/13 (0%)	0
Vessel injury-artery: Aorta	1/60 (1.7%)	1	0/13 (0%)	0
Other (Not Including Serious) Adverse Events
	Main Cohort - Prostate Cancer		Expansion Cohort - Prostate Cancer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/60 (100%)		13/13 (100%)
Blood and lymphatic system disorders
Blood/Bone marrow - Other (Specify)	1/60 (1.7%)	1	1/13 (7.7%)	1
Coagulation - Other (Specify)	1/60 (1.7%)	1	0/13 (0%)	0
DIC (disseminated intravascular coagulation)	0/60 (0%)	0	1/13 (7.7%)	1
Dermal change lymphedema, phlebolymphedema	3/60 (5%)	3	0/13 (0%)	0
Edema: limb	13/60 (21.7%)	17	5/13 (38.5%)	6
Hemolysis (e.g., immune hemolytic anemia, drug related hemolysis)	1/60 (1.7%)	1	0/13 (0%)	0
Leukocytes (total WBC)	36/60 (60%)	74	11/13 (84.6%)	27
Lymphatics - Other (Specify)	1/60 (1.7%)	1	0/13 (0%)	0
Lymphopenia	37/60 (61.7%)	160	9/13 (69.2%)	35
Neutrophils/granulocytes (ANC/AGC)	35/60 (58.3%)	71	11/13 (84.6%)	29
PTT (Partial Thromboplastin Time)	12/60 (20%)	24	1/13 (7.7%)	3
Platelets	13/60 (21.7%)	21	2/13 (15.4%)	5
Hemorrhage/Bleeding - other (Specify)	6/60 (10%)	8	0/13 (0%)	0
Cardiac disorders
Cardiac arrhythmia - Other, Specify,	3/60 (5%)	3	1/13 (7.7%)	1
Cardiac general - Other, Specify,	3/60 (5%)	3	2/13 (15.4%)	2
Hypertension	17/60 (28.3%)	20	4/13 (30.8%)	5
Hypotension	7/60 (11.7%)	7	1/13 (7.7%)	1
Pain::Cardiac/heart	1/60 (1.7%)	2	0/13 (0%)	0
Pain::Chest wall	2/60 (3.3%)	2	1/13 (7.7%)	1
Pain::Chest/thorax NOS	2/60 (3.3%)	2	0/13 (0%)	0
Palpitations	2/60 (3.3%)	2	1/13 (7.7%)	1
Pericardial effusion (non-malignant)	2/60 (3.3%)	2	1/13 (7.7%)	1
Supraventricular and nodal arrhythmia::Atrial fibrillation	3/60 (5%)	3	0/13 (0%)	0
Supraventricular and nodal arrhythmia::Sinus bradycardia	1/60 (1.7%)	1	1/13 (7.7%)	2
Vasovagal episode	2/60 (3.3%)	2	0/13 (0%)	0
Ear and labyrinth disorders
Hearing: patients with/without baseline auidgram and not enrolled in a monitoring program)	2/60 (3.3%)	2	1/13 (7.7%)	1
Tinnitus	3/60 (5%)	4	1/13 (7.7%)	1
Endocrine disorders
Hot flashes/flushes	6/60 (10%)	7	1/13 (7.7%)	1
Thyroid function, low (hypothyroidism)	1/60 (1.7%)	1	0/13 (0%)	0
Eye disorders
Dry eye syndrome	6/60 (10%)	7	1/13 (7.7%)	1
Keratitis (corneal inflammatory/corneal ulceration)	1/60 (1.7%)	1	0/13 (0%)	0
Ocular/Visual-Other (Specify,___)	3/60 (5%)	3	2/13 (15.4%)	3
Ophthalmoplegia/diplopia (double vision)	0/60 (0%)	0	1/13 (7.7%)	1
Scleral necrosis/meli	1/60 (1.7%)	1	0/13 (0%)	0
Vision-blurred vision	9/60 (15%)	10	0/13 (0%)	0
Vision-flashing lights/floaters	1/60 (1.7%)	1	0/13 (0%)	0
Watery eye (epiphora, tearing)	26/60 (43.3%)	32	7/13 (53.8%)	8
Gastrointestinal disorders
Anorexia	7/60 (11.7%)	8	3/13 (23.1%)	4
Chelitis	0/60 (0%)	0	1/13 (7.7%)	1
Dehydration	3/60 (5%)	7	1/13 (7.7%)	1
Dental: periodontal disease	2/60 (3.3%)	2	0/13 (0%)	0
Dental: teeth	4/60 (6.7%)	4	1/13 (7.7%)	1
Diarrhea	21/60 (35%)	24	6/13 (46.2%)	9
Dry mouth/salivary gland (xerostomia)	22/60 (36.7%)	22	0/13 (0%)	0
Dysphagia (difficulty swallowing)	3/60 (5%)	3	2/13 (15.4%)	2
Gastritis (including bile reflux gastritis)	1/60 (1.7%)	1	0/13 (0%)	0
Gastrointestinal-Other (Specify)	3/60 (5%)	3	5/13 (38.5%)	7
Heartburn/dyspepsia	4/60 (6.7%)	4	0/13 (0%)	0
Hemorrhage, GI: Abdomen NOS	1/60 (1.7%)	1	0/13 (0%)	0
Hemorrhage, GI::Rectum	5/60 (8.3%)	5	0/13 (0%)	0
Hemorrhoids	2/60 (3.3%)	2	0/13 (0%)	0
Incontinence, anal	5/60 (8.3%)	5	0/13 (0%)	0
Mucositis/stomatitis (clinical exam)::Oral cavity	6/60 (10%)	7	1/13 (7.7%)	1
Mucositis/stomatitis (functional/symptomatic)::Espophagus	3/60 (5%)	3	0/13 (0%)	0
Mucositis/stomatitis (functional/symptomatic)::Oral cavity	3/60 (5%)	4	0/13 (0%)	0
Nausea	9/60 (15%)	10	4/13 (30.8%)	9
Pain: Abdomen NOS	2/60 (3.3%)	2	2/13 (15.4%)	2
Pain::Oral cavity	4/60 (6.7%)	4	1/13 (7.7%)	1
Pain::Oral gums	1/60 (1.7%)	1	0/13 (0%)	0
Pain::Rectum	1/60 (1.7%)	1	0/13 (0%)	0
Perforation, GI::Colon	1/60 (1.7%)	1	0/13 (0%)	0
Salivary gland changes/saliva	1/60 (1.7%)	1	0/13 (0%)	0
Taste alteration (dysgeusia)	33/60 (55%)	38	8/13 (61.5%)	9
Ulcer, GI: Rectum	1/60 (1.7%)	1	0/13 (0%)	0
Vomiting	6/60 (10%)	7	4/13 (30.8%)	4
Constipation	46/60 (76.7%)	64	8/13 (61.5%)	10
General disorders
Constitutional Symptoms-Other (Specify,_____)	3/60 (5%)	4	0/13 (0%)	0
Fatigue (asthenia, lethargy, malaise)	52/60 (86.7%)	76	11/13 (84.6%)	23
Fever	6/60 (10%)	9	2/13 (15.4%)	2
Pain-Other (Specify,R leg pain; shoulder pain; tooth pain; jaw)	13/60 (21.7%)	18	2/13 (15.4%)	2
Pain::Pain NOS	1/60 (1.7%)	1	0/13 (0%)	0
Weight gain	3/60 (5%)	3	2/13 (15.4%)	3
Weight loss	10/60 (16.7%)	15	1/13 (7.7%)	2
Hepatobiliary disorders
Liver dysfunction/failure (clinical)	1/60 (1.7%)	1	0/13 (0%)	0
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	4/60 (6.7%)	4	1/13 (7.7%)	1
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	7/60 (11.7%)	7	2/13 (15.4%)	2
Cytokine release syndrome/acute infusion reaction	3/60 (5%)	3	0/13 (0%)	0
Flu-like symptoms	1/60 (1.7%)	1	0/13 (0%)	0
Infections and infestations
Febrile Neutropenia	13/60 (21.7%)	15	0/13 (0%)	0
Infection	1/60 (1.7%)	1	1/13 (7.7%)	1
Infection - Other, Specify	3/60 (5%)	4	2/13 (15.4%)	3
Infection with normal ANC or Grade 1 or 2 neutrophils: Anal/perianal	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils: Blood	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils: Conjuctiva	2/60 (3.3%)	2	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:Larynx	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:Lung (pneumonia)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:Middle ear (otitis media)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:Muscle (infection myositis)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:Nerve-peripheral	1/60 (1.7%)	2	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:Nose	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:Oral cavity-gums (gingivitis)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:paranasal	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:Sinus	5/60 (8.3%)	5	1/13 (7.7%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils:Skin (cellulitis)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils:Ungual (nails)	0/60 (0%)	0	1/13 (7.7%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils:Upper airway NOS	2/60 (3.3%)	2	1/13 (7.7%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils:Urinary tract NOS	3/60 (5%)	3	0/13 (0%)	0
Infection with unknown ANC::Middle ear (otitis media)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with unknown ANC::Oral cavity-gums (gingivitis)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with unknown ANC:Sinus	2/60 (3.3%)	2	1/13 (7.7%)	1
Infection with unknown ANC::Skin (cellulitis)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with unknown ANC::Soft tissue NOS	1/60 (1.7%)	1	0/13 (0%)	0
Infection with unknown ANC::Ungual (nails)	1/60 (1.7%)	1	0/13 (0%)	0
Infection with unknown ANC::Upper airway NOS	1/60 (1.7%)	1	2/13 (15.4%)	2
Infection with unknown ANC::Urinary tract NOS	2/60 (3.3%)	2	2/13 (15.4%)	2
Opportunistic infection associated with >=Grade 2 Lymphopenia	2/60 (3.3%)	2	0/13 (0%)	0
Infection (documented clinically or microbiologically): dental tooth	1/60 (1.7%)	1	0/13 (0%)	0
Infection (documented clinically or microbiologically): upper airway NOS	2/60 (3.3%)	2	0/13 (0%)	0
Infection (documented clinically or microbiologically): urinary tract NOS	1/60 (1.7%)	1	0/13 (0%)	0
Infection (documented clinically or microbiologically): cellulitis	1/60 (1.7%)	1	0/13 (0%)	0
Injury, poisoning and procedural complications
Burn	1/60 (1.7%)	1	1/13 (7.7%)	1
Fracture	1/60 (1.7%)	2	1/13 (7.7%)	1
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	14/60 (23.3%)	20	2/13 (15.4%)	8
AST, SGOT(serum glutamic oxaloacetic transaminase)	14/60 (23.3%)	28	2/13 (15.4%)	6
Albumin, serum-low (hypoalbuminemia)	41/60 (68.3%)	97	5/13 (38.5%)	7
Alkaline phosphatase	12/60 (20%)	19	2/13 (15.4%)	8
Bilirubin (hyperbilirubinemia)	4/60 (6.7%)	6	1/13 (7.7%)	4
CPK (creatine phosphokinase)	2/60 (3.3%)	2	0/13 (0%)	0
Calcium, serum-high (hypercalcemia)	7/60 (11.7%)	9	1/13 (7.7%)	2
Calcium, serum-low (hypocalcemia)	22/60 (36.7%)	36	3/13 (23.1%)	4
Creatinine	1/60 (1.7%)	1	1/13 (7.7%)	1
GGT (gamma-Glutamyl transpeptidase)	1/60 (1.7%)	1	0/13 (0%)	0
Glucose, serum-high (hyperglycemia)	3/60 (5%)	8	1/13 (7.7%)	5
Glucose, serum-low (hypoglycemia)	3/60 (5%)	3	0/13 (0%)	0
Hemoglobinuria	0/60 (0%)	0	1/13 (7.7%)	1
Lipase	1/60 (1.7%)	1	0/13 (0%)	0
Magnesium, serum-high (hypermagnesemia)	7/60 (11.7%)	8	2/13 (15.4%)	2
Magnesium, serum-low (hypomagnesemia)	2/60 (3.3%)	2	0/13 (0%)	0
Metabolic/Laboratory - Other (Specify)	0/60 (0%)	0	1/13 (7.7%)	1
Phosphate, serum-low (hypophosphatemia)	24/60 (40%)	54	5/13 (38.5%)	19
Potassium, serum-high (hyperkalemia)	15/60 (25%)	20	4/13 (30.8%)	8
Potassium, serum-low (hypokalemia)	5/60 (8.3%)	7	0/13 (0%)	0
Proteinuria	10/60 (16.7%)	17	2/13 (15.4%)	2
Sodium, serum-low (hyponatremia)	9/60 (15%)	14	2/13 (15.4%)	5
Uric acid, serum-high (hyperuricemia)	0/60 (0%)	0	1/13 (7.7%)	5
Hemoglobin	35/60 (58.3%)	153	8/13 (61.5%)	23
Sodium, serum-high (hypernatremia)	1/60 (1.7%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy)::Extremity-lower	6/60 (10%)	8	2/13 (15.4%)	2
Muscle weakness, generalized or specific area (not due to neuropathy)::Left-sided	1/60 (1.7%)	1	0/13 (0%)	0
Muscle weakness, generalized or specific area (not due to neuropathy)::trunk	2/60 (3.3%)	2	0/13 (0%)	0
Muscle weakness, generalized or specific area (not due to neuropathy)::Whole body/generalized	8/60 (13.3%)	8	0/13 (0%)	0
Musculoskeletal/Soft tissue - Other (Specify,)	1/60 (1.7%)	1	2/13 (15.4%)	2
Myositis (inflammation/damage of muscle)	0/60 (0%)	0	1/13 (7.7%)	1
Osteonecrosis (avascular necrosis)	11/60 (18.3%)	12	1/13 (7.7%)	1
Pain: Back	11/60 (18.3%)	12	6/13 (46.2%)	6
Pain::Extremity-limb	6/60 (10%)	6	0/13 (0%)	0
Pain::Joint	5/60 (8.3%)	6	2/13 (15.4%)	2
Pain::Muscle	7/60 (11.7%)	9	1/13 (7.7%)	1
Muscle weakness, generalized or specific area (not due to neuropathy)::Extremity-upper	1/60 (1.7%)	1	0/13 (0%)	0
Pain::Bone	3/60 (5%)	3	0/13 (0%)	0
Extremity-lower (gait/walking)	1/60 (1.7%)	1	0/13 (0%)	0
Nervous system disorders
Ataxia (incoordination)	6/60 (10%)	10	0/13 (0%)	0
Cognitive disturbance	3/60 (5%)	3	1/13 (7.7%)	1
Dizziness	17/60 (28.3%)	22	3/13 (23.1%)	3
Memory impairment	3/60 (5%)	3	0/13 (0%)	0
Mood alteration-agitation	2/60 (3.3%)	2	0/13 (0%)	0
Mood alteration::Anxiety	1/60 (1.7%)	1	2/13 (15.4%)	2
Mood alteration::Depression	6/60 (10%)	9	1/13 (7.7%)	2
Neurology-Other (Specify,______)	10/60 (16.7%)	14	0/13 (0%)	0
Neuropathy - cranial::CN IX Motor-pharynx; sensory-ear, pharynx tongue	2/60 (3.3%)	2	0/13 (0%)	0
Neuropathy - cranial::CN V Motor-jaw muscles; sensory-facial	2/60 (3.3%)	2	0/13 (0%)	0
Neuropathy - cranial::CN VIII Hearing and balance	2/60 (3.3%)	2	0/13 (0%)	0
Neuropathy: motor	9/60 (15%)	11	1/13 (7.7%)	1
Neuropathy: sensory	45/60 (75%)	65	6/13 (46.2%)	9
Pain::Head/headache	7/60 (11.7%)	9	3/13 (23.1%)	5
Speech impairment (e.g., dysphasia or aphasia)	1/60 (1.7%)	1	0/13 (0%)	0
Syncope (fainting)	8/60 (13.3%)	15	1/13 (7.7%)	2
Tremor	8/60 (13.3%)	8	0/13 (0%)	0
Psychiatric disorders
Insomnia	2/60 (3.3%)	2	1/13 (7.7%)	1
Renal and urinary disorders
Bladder spasms	1/60 (1.7%)	1	0/13 (0%)	0
Hemorrhage, GU: Bladder	0/60 (0%)	0	1/13 (7.7%)	1
Hemorrhage, GU: Urethra	2/60 (3.3%)	2	0/13 (0%)	0
Hemorrhage, GU: Urinary NOS	1/60 (1.7%)	1	0/13 (0%)	0
Incontinence, urinary	2/60 (3.3%)	2	0/13 (0%)	0
Renal/Genitourinary-Other (Specify)	3/60 (5%)	3	0/13 (0%)	0
Urinary frequency/urgency	7/60 (11.7%)	7	0/13 (0%)	0
Urinary retention (including neurogenic bladder)	2/60 (3.3%)	3	0/13 (0%)	0
Obstruction, GU: Ureter	0/60 (0%)	0	1/13 (7.7%)	1
Obstruction, GU: Urethra	0/60 (0%)	0	1/13 (7.7%)	1
Reproductive system and breast disorders
Gynecomastia	1/60 (1.7%)	1	0/13 (0%)	0
Pain::Pelvis	0/60 (0%)	0	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	10/60 (16.7%)	16	2/13 (15.4%)	2
Dyspnea (shortness of breath)	26/60 (43.3%)	37	3/13 (23.1%)	3
Hemorrhage, pulmonary/upper respiratory: Nose	19/60 (31.7%)	32	5/13 (38.5%)	7
Hemorrhage, pulmonary/upper respiratory: Respiratory tract NOS	1/60 (1.7%)	1	0/13 (0%)	0
Nasal cavity/paranasal sinus reactions	25/60 (41.7%)	27	3/13 (23.1%)	3
Pain::Throat/pharynx/larynx	3/60 (5%)	3	0/13 (0%)	0
Pleural effusion (non-malignant)	14/60 (23.3%)	17	2/13 (15.4%)	2
Pulmonary/Upper Respiratory - Other (Specify, )	2/60 (3.3%)	2	0/13 (0%)	0
Voice changes/dysarthria (e.g., hoarseness, loss or alteration in voice, laryngitis)	13/60 (21.7%)	14	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	8/60 (13.3%)	8	0/13 (0%)	0
Dry skin	12/60 (20%)	12	1/13 (7.7%)	1
Flushing	2/60 (3.3%)	2	0/13 (0%)	0
Hair loss/alopecia (scalp or body)	31/60 (51.7%)	33	5/13 (38.5%)	5
Hyperpigmentation	1/60 (1.7%)	1	0/13 (0%)	0
Hypopigmentation	1/60 (1.7%)	1	0/13 (0%)	0
Injection site reaction/extravasation changes	3/60 (5%)	3	0/13 (0%)	0
Nail changes	29/60 (48.3%)	31	7/13 (53.8%)	9
Pain: Face	1/60 (1.7%)	1	0/13 (0%)	0
Pruritus/itching	1/60 (1.7%)	1	0/13 (0%)	0
Rash/desquamation	13/60 (21.7%)	14	7/13 (53.8%)	8
Rash: acne/acneiform	1/60 (1.7%)	1	0/13 (0%)	0
Rash: hand-foot skin reaction	11/60 (18.3%)	14	0/13 (0%)	0
Skin breakdown/decubitus ulcer	3/60 (5%)	4	0/13 (0%)	0
Sweating (diaphoresis)	2/60 (3.3%)	2	2/13 (15.4%)	2
Ulceration	3/60 (5%)	4	1/13 (7.7%)	1
Wound complication, non-infectious	2/60 (3.3%)	2	1/13 (7.7%)	1
Dermatology/Skin-Other (Specify,_____)	9/60 (15%)	14	0/13 (0%)	0
Vascular disorders
Phlebitis (including superficial thrombosis)	1/60 (1.7%)	1	0/13 (0%)	0
Thrombosis/thrombus/embolism	3/60 (5%)	3	0/13 (0%)	0
Vessel injury-vein: Extremity-lower	1/60 (1.7%)	1	0/13 (0%)	0
Vessel injury-vein: Other NOS	1/60 (1.7%)	1	1/13 (7.7%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.