Treating Patients With Prostate Cancer That Did Not Respond to Hormone Therapy

• Sponsor: Case Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00460031
• Collaborator: (none)
• Enrollment: 34
• Locations: 6
• Arm: 1
• Actual Duration (Months): 48
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Androgens can cause the growth of prostate cancer cells. Drugs, such as ketoconazole, may stop the adrenal glands from making androgens. Lenalidomide may stop the growth of prostate cancer by blocking blood flow to the tumor. Giving ketoconazole and hydrocortisone together with lenalidomide may be an effective treatment for prostate cancer.

PURPOSE: This phase II trial is studying how well giving ketoconazole and hydrocortisone together with lenalidomide works in treating patients with prostate cancer that did not respond to hormone therapy.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: ketoconazole; Drug: lenalidomide; Drug: therapeutic hydrocortisone	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the objective response frequency in patients with hormone-refractory progressive prostate cancer treated with ketoconazole, hydrocortisone, and lenalidomide.

Secondary

• Determine the effect of this regimen on time to clinical progression in these patients.

• Determine the safety of this regimen in these patients.

• Determine the effects of this regimen on serum cytokines, including tumor necrosis factor-alpha, basic fibroblast growth factor, plasma soluble interleukin (IL)-2 receptor, IL-8, and IL-12, as well as serum vascular endothelial growth factor levels in these patients.

• Determine the co-stimulatory effects of this regimen on dendritic cells and CD4-positive, CD25-positive, T-regulatory cells in these patients.

OUTLINE: This is a nonrandomized, open-label study.

Patients receive oral ketoconazole 3 times daily and oral hydrocortisone twice daily on days 1-28 and oral lenalidomide once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection periodically during study for evaluation of prostate cancer-specific immune response. Blood samples are assessed by serum analysis, flow cytometry, real-time PCR, and enzyme-linked immunosorbent assay techniques to detect and quantify different cytokines, antiangiogenic markers, dendritic cells, and specific T-regulatory cells.

After completion of study therapy, patients are followed at 30 days.

PROJECTED ACCRUAL: A total of 34 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial to Assess the Activity of Ketoconazole Plus Lenalidomide in Patients With Prostate Cancer Progressive After Androgen Deprivation
• Actual Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Aug 31, 2010
• Actual Study Completion Date: Aug 31, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketoconazole Plus Lenalidomide	Drug: ketoconazole; 400 tid; Other Names: held for toxicity, missed days of therapy are not made up. ; Drug: lenalidomide; Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.; Drug: therapeutic hydrocortisone; 20mg qam 10mg qhs

Outcome Measures

Primary Outcome Measures

1. Number of Patients With a Partial Response, Progressive Disease, or Stable Disease Based on Prostate-Specific Antigen (PSA) or Measurable Disease [28 days]

   Patients will be evaluated for clinical benefit monthly with PSA values.Patients who are benefiting from treatment are eligible for additional cycles of treatment. Thereafter, therapy will continue until criteria for progressive disease are met. Response is based on the RECIST criteria from the National Cancer institute. Complete Response (CR) disappearance of all target lesions; Partial Response (PR) >= 30% decrease in the sum of the longest diameter of target lesions from baseline; Progressive Disease (PD) >= increase in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD) neither sufficient for partial response nor sufficient increase for progressive disease.

Secondary Outcome Measures

1. Time to Progression [One year (12 months) after start of treatment]

   Patients will be evaluated for clinical benefit monthly with PSA values.Patients who are benefiting from treatment are eligible for additional cycles of treatment. Thereafter, therapy will continue until criteria for progressive disease are met. Response is based on the RECIST criteria from the National Cancer institute. Complete Response (CR) disappearance of all target lesions; Partial Response (PR) >= 30% decrease in the sum of the longest diameter of target lesions from baseline; Progressive Disease (PD) >= increase in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD) neither sufficient for partial response nor sufficient increase for progressive disease.

2. Number of Patients With Grade 3 and 4 Toxicity as Assessed by NCI CTCAE v3.0 [Up to 30 days after discontinuation of treatment]

   Patients will be evaluated for toxicity every 2 weeks during the first cycle. Thereafter, evaluations will be done every 28 days or more frequently if clinically indicated.

3. Change in Immune Response From Baseline [Week 8]

   The pattern of immune response by assessing T cell and dendritic cell markers, specifically by measuring the levels of CD4+ FoxP3+ Regulatory T cells

4. Ratio of Change in Immune Response From Baseline [Week 8]

   The pattern of immune response by assessing T cell and dendritic cell markers, specifically by measuring the ratio of BDCA-2 to BDCA-1 cells

Eligibility Criteria

Criteria

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

PATIENTS WITH PROSTATE CANCER PROGRESSIVE AFTER ANDROGEN DEPRIVATION Inclusion Criteria Understand and voluntarily sign an informed consent form. Age 18 years at the time of signing the informed consent form. Histologically confirmed adenocarcinoma of the prostate. Testosterone less than 50 ng/dL. Patients must continue primary androgen deprivation with an LHRH analogue if they have not undergone orchiectomy. All previous cancer therapy, including radiation, and surgery, must have been discontinued at least 4 weeks prior to receive first dose of study drug.

Progressive disease after androgen deprivation.

Exclusion Criteria Prior systemic chemotherapy for hormone refractory prostate cancer. Prior neoadjuvant and adjuvant chemotherapy are allowed when completed at least 12 months prior to enrollment.

Prior ketoconazole, aminoglutethimide or corticosteroids for the treatment of progressive prostate cancer.

Prior immunotherapy including, but not limited to, vaccines, Thalidomide, and or Lenalidomide like agents.

Supplements or complementary medicines/botanicals are not permitted while on protocol therapy, except for any combination of the following:

conventional multivitamin supplements selenium lycopene soy supplements Patients should review the label with their doctor prior to enrollment, and discontinue disallowed agents prior to study enrollment Serious intercurrent infections or non-malignant medical illnesses including autoimmune disorders that are uncontrolled.

Psychiatric illnesses/social situations that would limit compliance with protocol requirements.

Evidence of CNS (brain or Leptomeningeal) metastases or large pleural/pericardial effusions.

Known contraindication to receive Ketoconazole or Lenalidomide Concurrent use of ketoconazole with statin compounds is absolutely contraindicated. Thus, patients receiving Statin drugs (fluvastatin, atorvastatin, and simvastatin) should discontinue them for at least 7 days before starting ketoconazole.

Patients taking astemizole, terfenadine, or cisapride, rifampin or isoniazid are not eligible, unless they agreed to completely discontinue those agents. In that case, any of these agents should be discontinued at least 7 days prior to start therapy with Ketoconazole.

Use of any other experimental drug or therapy within 28 days of baseline. Known hypersensitivity to thalidomide or its analogues. Any prior use of Lenalidomide. Known positive for HIV or infectious hepatitis, type A, B or C. Disease free of prior malignancies for 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the breast.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lake/University Seidman Cancer Center	Cleveland	Ohio	United States	44060
2	University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
3	University Suburban Health Center	Cleveland	Ohio	United States	44121
4	UHHS Chagrin Highlands Medical Center	Cleveland	Ohio	United States	44122
5	UHHS Westlake Medical Center	Cleveland	Ohio	United States	44145
6	Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• Case Comprehensive Cancer Center

Investigators

• Principal Investigator: Jorge Garcia, MD, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
• Principal Investigator: Matthew M. Cooney, MD, University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT00460031
• Other Study ID Numbers: CASE12805
• First Posted: Apr 13, 2007
• Last Update Posted: Jul 24, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Case Comprehensive Cancer Center: adenocarcinoma of the prostate; stage III prostate cancer; stage IV prostate cancer; recurrent prostate cancer
• Additional relevant MeSH terms: Prostatic Neoplasms; Ketoconazole; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Lenalidomide

Study Results

Participant Flow

Recruitment Details	Thirty seven (37) patients were screened from Cleveland Clinic and University Hospitals in the Cleveland area from February 2007 to April 2009.Three patients were not eligible.

Arm/Group Title	Ketoconazole Plus Lenalidomide
Arm/Group Description	Ketoconazole will be administered daily on days 1-28 of the cycle at a dose of 400mg po tid with hydrocortisone 20mg po every morning and 10mg po at bedtime. Hydrocortisone will be given on a continuous basis. Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.
Period Title: Overall Study
STARTED	34
COMPLETED	23
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Ketoconazole Plus Lenalidomide
Arm/Group Description	Ketoconazole will be administered daily on days 1-28 of the cycle at a dose of 400mg po tid with hydrocortisone 20mg po every morning and 10mg po at bedtime. Hydrocortisone will be given on a continuous basis. Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.
Overall Participants	34
Age, Customized (participants) [Number]
40-49 years	2 5.9%
50-59 years	5 14.7%
60-69 years	10 29.4%
70-79 years	11 32.4%
80-89 years	6 17.6%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	34 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	33 97.1%
Unknown or Not Reported	1 2.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 8.8%
White	30 88.2%
More than one race	0 0%
Unknown or Not Reported	1 2.9%
Region of Enrollment (participants) [Number]
United States	34 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With a Partial Response, Progressive Disease, or Stable Disease Based on Prostate-Specific Antigen (PSA) or Measurable Disease
Description	Patients will be evaluated for clinical benefit monthly with PSA values.Patients who are benefiting from treatment are eligible for additional cycles of treatment. Thereafter, therapy will continue until criteria for progressive disease are met. Response is based on the RECIST criteria from the National Cancer institute. Complete Response (CR) disappearance of all target lesions; Partial Response (PR) >= 30% decrease in the sum of the longest diameter of target lesions from baseline; Progressive Disease (PD) >= increase in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD) neither sufficient for partial response nor sufficient increase for progressive disease.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

All patients who completed the study

Arm/Group Title	Ketoconazole Plus Lenalidomide
Arm/Group Description	Ketoconazole will be administered daily on days 1-28 of the cycle at a dose of 400mg po tid with hydrocortisone 20mg po every morning and 10mg po at bedtime. Hydrocortisone will be given on a continuous basis. Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.
Measure Participants	23
Partial Response	7 20.6%
Progressive Disease	7 20.6%
Stable Disease	9 26.5%

2. Secondary Outcome

Title	Time to Progression
Description	Patients will be evaluated for clinical benefit monthly with PSA values.Patients who are benefiting from treatment are eligible for additional cycles of treatment. Thereafter, therapy will continue until criteria for progressive disease are met. Response is based on the RECIST criteria from the National Cancer institute. Complete Response (CR) disappearance of all target lesions; Partial Response (PR) >= 30% decrease in the sum of the longest diameter of target lesions from baseline; Progressive Disease (PD) >= increase in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD) neither sufficient for partial response nor sufficient increase for progressive disease.
Time Frame	One year (12 months) after start of treatment

Outcome Measure Data

Analysis Population Description

Patients with disease progression

Arm/Group Title	Ketoconazole Plus Lenalidomide
Arm/Group Description	Ketoconazole will be administered daily on days 1-28 of the cycle at a dose of 400mg po tid with hydrocortisone 20mg po every morning and 10mg po at bedtime. Hydrocortisone will be given on a continuous basis. Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.
Measure Participants	7
Median (95% Confidence Interval) [Months]	3

3. Secondary Outcome

Title	Number of Patients With Grade 3 and 4 Toxicity as Assessed by NCI CTCAE v3.0
Description	Patients will be evaluated for toxicity every 2 weeks during the first cycle. Thereafter, evaluations will be done every 28 days or more frequently if clinically indicated.
Time Frame	Up to 30 days after discontinuation of treatment

Outcome Measure Data

Analysis Population Description

All patients who received at least one treatment in the study

Arm/Group Title	Ketoconazole Plus Lenalidomide
Arm/Group Description	Ketoconazole will be administered daily on days 1-28 of the cycle at a dose of 400mg po tid with hydrocortisone 20mg po every morning and 10mg po at bedtime. Hydrocortisone will be given on a continuous basis. Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.
Measure Participants	34
Number [participants]	19 55.9%

4. Secondary Outcome

Title	Change in Immune Response From Baseline
Description	The pattern of immune response by assessing T cell and dendritic cell markers, specifically by measuring the levels of CD4+ FoxP3+ Regulatory T cells
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

All patients who completed the study

Arm/Group Title	Ketoconazole Plus Lenalidomide
Arm/Group Description	Ketoconazole will be administered daily on days 1-28 of the cycle at a dose of 400mg po tid with hydrocortisone 20mg po every morning and 10mg po at bedtime. Hydrocortisone will be given on a continuous basis. Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.
Measure Participants	23
Mean (Standard Deviation) [cells/ul]	0.18 (0.31)

5. Secondary Outcome

Title	Ratio of Change in Immune Response From Baseline
Description	The pattern of immune response by assessing T cell and dendritic cell markers, specifically by measuring the ratio of BDCA-2 to BDCA-1 cells
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

All patients who completed the study

Arm/Group Title	Ketoconazole Plus Lenalidomide
Arm/Group Description	Ketoconazole will be administered daily on days 1-28 of the cycle at a dose of 400mg po tid with hydrocortisone 20mg po every morning and 10mg po at bedtime. Hydrocortisone will be given on a continuous basis. Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.
Measure Participants	23
Mean (Standard Deviation) [ratio]	-0.39 (1.44)

Adverse Events

Time Frame	30 Days
Arm/Group Title	Ketoconazole Plus Lenalidomide
Arm/Group Description	Ketoconazole will be administered daily on days 1-28 of the cycle at a dose of 400mg po tid with hydrocortisone 20mg po every morning and 10mg po at bedtime. Hydrocortisone will be given on a continuous basis. Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.
All Cause Mortality
	Ketoconazole Plus Lenalidomide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ketoconazole Plus Lenalidomide
	Affected / at Risk (%)	# Events
Total	12/34 (35.3%)
Blood and lymphatic system disorders
Blood/Bone Marrow	1/34 (2.9%)
Hemoglobin	2/34 (5.9%)
Coagulation	1/34 (2.9%)
Infection/Febrile Neutropenia	1/34 (2.9%)
Cardiac disorders
Cardiovascular/Arrhythmia	1/34 (2.9%)
Cardiac-ischemia/infarction	1/34 (2.9%)
Cardiovascular/General	2/34 (5.9%)
Eye disorders
Vision-blurred vision	1/34 (2.9%)
Gastrointestinal disorders
Constipation	1/34 (2.9%)
dehydration	1/34 (2.9%)
Diarrhea patients without colostomy	2/34 (5.9%)
Vomiting	3/34 (8.8%)
Nausea	1/34 (2.9%)
General disorders
Edema	1/34 (2.9%)
Constitutional Symptoms	1/34 (2.9%)
Fatigue (Lethargy, malaise, asthenia)	1/34 (2.9%)
Hepatobiliary disorders
Liver dysfunction	1/34 (2.9%)
SGOT (AST) (serum glutamic oxaloacetic transaminase)	1/34 (2.9%)
Investigations
Bilirubin	1/34 (2.9%)
SGPT (ALT) (serum glutamic pyruvic transaminase)	1/34 (2.9%)
Musculoskeletal and connective tissue disorders
Muscle weakness (not due to neuropathy)	1/34 (2.9%)
Musculoskeletal	1/34 (2.9%)
Nervous system disorders
Dizziness/lightheadedness	2/34 (5.9%)
Neuropathy-sensory	1/34 (2.9%)
Renal and urinary disorders
Renal failure	1/34 (2.9%)
Skin and subcutaneous tissue disorders
Hand-foot skin reaction	1/34 (2.9%)
Rash/desquamation	1/34 (2.9%)
Other (Not Including Serious) Adverse Events
	Ketoconazole Plus Lenalidomide
	Affected / at Risk (%)	# Events
Total	34/34 (100%)
Blood and lymphatic system disorders
Platelets	13/34 (38.2%)	37
Leukocytes (total WBC)	12/34 (35.3%)	47
Blood/Bone Marrow	4/34 (11.8%)	4
Infection/Febrile Neutropenia	6/34 (17.6%)	10
Coagulation	3/34 (8.8%)	4
Cardiac disorders
Chest pain (non-cardiac and non-pleuritic)	3/34 (8.8%)	3
Sinus bradycardia	2/34 (5.9%)	2
Ear and labyrinth disorders
Auditory/Hearing	2/34 (5.9%)	2
Endocrine disorders
Hot flashes/flushes	4/34 (11.8%)	4
Eye disorders
Dry eye	4/34 (11.8%)	6
Vision-blurred vision	4/34 (11.8%)	6
Ocular/Visual	2/34 (5.9%)	2
Vision-flashing lights/floaters	2/34 (5.9%)	2
Gastrointestinal disorders
Nausea	14/34 (41.2%)	18
Anorexia	10/34 (29.4%)	12
Constipation	10/34 (29.4%)	12
Taste disturbance (dysgeusia)	8/34 (23.5%)	9
Vomiting	7/34 (20.6%)	9
Diarrhea patients without colostomy	5/34 (14.7%)	7
Dyspepsia/heartburn	3/34 (8.8%)	3
Flatulence	3/34 (8.8%)	3
Dehydration	2/34 (5.9%)	2
Gastrointestinal	2/34 (5.9%)	2
Mouth dryness	2/34 (5.9%)	2
General disorders
"Fatigue (lethargy, malaise, asthenia)"	27/34 (79.4%)	50
General Disorders	5/34 (14.7%)	7
"Fever (in the absence of neutropenia, where neutropenia is defined as AGC<1.0 x 10e9/L)"	3/34 (8.8%)	3
Weight loss	3/34 (8.8%)	10
"Rigors, chills"	2/34 (5.9%)	2
Sweating (diaphoresis)	2/34 (5.9%)	3
Edema	13/34 (38.2%)	18
Pain	11/34 (32.4%)	23
Immune system disorders
Allergy	2/34 (5.9%)	2
Infections and infestations
Infection without neutropenia	5/34 (14.7%)	6
Injury, poisoning and procedural complications
Bruising (in absence of grade 3 or 4 thrombocytopenia)	3/34 (8.8%)	4
Investigations
Hemoglobin	18/34 (52.9%)	38
Lymphopenia	17/34 (50%)	61
Neutrophils/granulocytes (ANC/AGC)	10/34 (29.4%)	30
Alkaline phosphatase	13/34 (38.2%)	19
SGPT (ALT) (serum glutamic pyruvic transaminase)	13/34 (38.2%)	19
SGOT (AST) (serum glutamic oxaloacetic transaminase)	11/34 (32.4%)	17
Bilirubin	2/34 (5.9%)	4
Creatinine	10/34 (29.4%)	20
Metabolism and nutrition disorders
Hypocalcemia	14/34 (41.2%)	34
Hyperglycemia	8/34 (23.5%)	14
Metabolic/Laboratory	8/34 (23.5%)	18
Hyperkalemia	6/34 (17.6%)	8
Hyperuricemia	5/34 (14.7%)	7
Hypokalemia	4/34 (11.8%)	4
Hyponatremia	4/34 (11.8%)	4
Bicarbonate	3/34 (8.8%)	3
Hypophosphatemia	3/34 (8.8%)	3
Hypoglycemia	2/34 (5.9%)	2
Hypoalbuminemia	10/34 (29.4%)	21
Musculoskeletal and connective tissue disorders
Arthralgia (joint pain)	2/34 (5.9%)	2
Musculoskeletal	8/34 (23.5%)	15
Muscle weakness (not due to neuropathy)	6/34 (17.6%)	6
Nervous system disorders
Dizziness/lightheadedness	9/34 (26.5%)	12
Neuropathy-sensory	4/34 (11.8%)	5
Mood alteration-depression	3/34 (8.8%)	3
Neurology-Other	3/34 (8.8%)	3
Psychiatric disorders
Insomnia	5/34 (14.7%)	5
Renal and urinary disorders
Urinary frequency/urgency	2/34 (5.9%)	2
Urinary discoloration	2/34 (5.9%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	12/34 (35.3%)	17
Cough	6/34 (17.6%)	7
Pulmonary	2/34 (5.9%)	2
Voice Alteration	2/34 (5.9%)	2
Epistaxis	4/34 (11.8%)	5
"Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)"	4/34 (11.8%)	4
Skin and subcutaneous tissue disorders
Rash/desquamation	16/34 (47.1%)	28
Dry skin	10/34 (29.4%)	14
Dermatology/Skin	7/34 (20.6%)	8
Pruritus	7/34 (20.6%)	8
Alopecia	2/34 (5.9%)	2
Nail changes	2/34 (5.9%)	2
Vascular disorders
Hypertension	4/34 (11.8%)	5
Hypotension	3/34 (8.8%)	3
Thrombosis/embolism	3/34 (8.8%)	4
Cardiovascular/General	2/34 (5.9%)	2
Hemorrhage	4/34 (11.8%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.