Study of TAK-228 (MLN0128) in Soft Tissue Sarcomas

• Sponsor: Fox Chase Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02987959
• Collaborator: (none)
• Enrollment: 6
• Location: 1
• Arm: 1
• Actual Duration (Months): 23.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is an open-label phase II study of TAK-228 for patients ≥ 18 years of age with complex genomic sarcomas exhibiting Phosphoinositide-3 Kinase (PI3K) pathway dysregulation. Patients must have surgically unresectable or metastatic disease that is refractory to at least one prior line of therapy (not including neoadjuvant or adjuvant therapy in a curative setting). Patients disease must also have evidence of progression prior to enrollment. The purpose of this study is to determine the antitumor activity in this group of patients. Patients must meet all eligibility criteria as detailed in section 10. A total of up to 33 patients will be included in the study. Patients will undergo screening evaluations to determine eligibility within 28 days of the first dose. All patients will be required to submit baseline tumor samples for analysis. Patients who have had their tumors tested commercially for PI3K/ AKT/mechanistic Target of Rapamycin (mTOR) alterations will be assessed on a case by case basis for eligibility and for determination as to whether additional tissue is required.

TAK-228 will be administered orally at 3 mg daily for a 21 day cycle. Clinical and laboratory assessments will be made on day 1 of each cycle. Disease will be assessed by comparing unidimensional tumor measurements on pre and peritreatment imaging (CT or MRI) after weeks 6, 12, 18 and every 12 weeks thereafter. Response will be assessed according to RECIST 1.1. Therapy will continue until disease progression or unacceptable toxicity or withdrawal of consent.

Condition or Disease	Intervention/Treatment	Phase
Soft-tissue Sarcoma	Drug: TAK-228	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of TAK-228 (MLN0128) in Soft Tissue Sarcomas With Dysregulation of the mTOR Pathway
• Actual Study Start Date: Feb 21, 2017
• Actual Primary Completion Date: Jan 30, 2019
• Actual Study Completion Date: Jan 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TAK-228 treatment Patients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228	Drug: TAK-228; TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).; Other Names: MLN0128

Outcome Measures

Primary Outcome Measures

1. The Progression Free Survival Rate With TAK-228 in Sarcoma Patients With PI3K/AKT/mTOR Pathway Dysregulation [12 weeks post-treatment]

   Progression free rate will be determined by determining the number of patients with complete response, partial response and stable disease

Secondary Outcome Measures

1. The Rate of Toxicity of TAK-228 in This Patient Population as Per Common Terminology Criteria for Adverse Events (CTCAE)v4.03 Criteria. [1 year]

   Toxicity will be assessed by calculating number of participants experiencing adverse events as per CTCAEv4.03 criteria

2. The Objective Response Rate (ORR) of TAK-228 in This Patient Population. [upto 4 years]

   Objective response rate will be defined as patients with complete response and partial response. As per RECIST v1.1 guidelines, complete response is defined as the disappearance of all measurable lesions, and partial response is defined as >=30% decrease in sum of diameters of target lesions compared to the baseline sum of diameters.

3. Progression Free Survival in This Patient Population. [upto 4 years]

   Progression Free Survival, defined as the time from initiation of treatment until disease progression will be calculated.

4. Overall Survival Rate in This Patient Population [upto 4 years]

   Overall Survival, defined as the time from initiation of treatment until death from any cause will be calculated.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• This trial has two step inclusion criteria.

Step 1 Inclusion Criteria

1. Male or female patients 18 years or older.

2. Patients must have a diagnosis of a locally advanced or metastatic sarcoma that is progressing. The following subtypes (considered genomically complex) will be eligible: leiomyosarcoma (well differentiated or poorly differentiated), undifferentiated pleomorphic sarcoma, myxofibrosarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, malignant peripheral nerve sheath tumor, angiosarcoma or extraskeletal osteosarcoma. Other potentially genomically complex Soft Tissue Sarcomas (STS) subtypes may be included on a case-by-case basis after discussion with the principal investigator.

3. Measurable disease by RECIST 1.1 criteria (at least one target lesion outside of previous radiation fields or progressed within a previous radiation field), described in detail in section 15.

4. Progression of disease by radiographic imaging (10% increase in size by RECIST v1.1 within 6 months of registration) or presence of new lesions.

5. Must have received at least 1 prior systemic therapy for advanced disease (does not include adjuvant/neoadjuvant therapy in a curative setting).

6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

7. Adequate contraception as follows:

For women:

Postmenopausal for at least 1 year before the screening visit, OR Surgically sterile, OR If they are of childbearing potential, agree to practice 1 effective method of contraception, and 1 additional (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling [eg. United Surgical Partners Internationals (USPI), Summary of Product Characteristics (SmPC), etc;]) after the last dose of study drug OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (Periodic abstinence [e.g, calendar, ovulation, symptothermal, postovulation methods] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

Highly effective methods:

Intra-uterine devices (IUD) Hormonal (birth control pills/oral contraceptives, injectable contraceptives, contraceptive patches, or contraceptive implants)

Other effective Methods:

Latex Condoms Diaphragm with spermicide; Cervical cap;Sponge

For men, even if surgically sterilized (ie, status post-vasectomy), they must:

Agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (Periodic abstinence [e.g, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

Agree not to donate sperm during the course of this study or 120 days after receiving their last dose of study drug

1. Screening clinical laboratory values as specified below:

1. Bone marrow reserve consistent with: i. absolute neutrophil count (ANC) ≥ 1.5 x 10(9)/L; ii. platelet count ≥ 100 x 10(9)/L; iii. hemoglobin ≥ 9 g/dL without transfusion within 1 week preceding study drug administration b) Hepatic: i. total bilirubin ≤ 1.5 x upper limit of normal (ULN), ii. transaminases (Aspartate aminotransferase/Serum Glutamic Oxaloacetic Transaminase (AST/SGOT) and Alanine aminotransferase/Serum Glutamic Pyruvic Transaminase (ALT/SGPT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present); c) Renal: creatinine clearance ≥ 50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour); d) Metabolic: i. Glycosylated hemoglobin (HbA1c) ≤ 7.0%, ii. fasting serum glucose ≤ 130 mg/dL iii. fasting triglycerides ≤ 300 mg/dL

1. Ability to swallow oral medications.

2. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

3. Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:

4. Brain metastases which have been treated

5. No evidence of disease progression for ≥ 3 months or hemorrhage after treatment

6. Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228

7. No ongoing requirement for dexamethasone or anti-epileptic drugs

Step 2 Inclusion Criteria: Must be met after meeting step1inclusion and exclusion criteria.

1. Tumor must have dysregulation of the PI3K/AKT/mTOR pathway. For the purposes of this study, patients must have either PTEN protein or genomic loss, or phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA)/ Phosphatase and tensin homolog (PTEN) mutation. Patients must be willing to provide sufficient archival tissue. If this is not available fresh tumor for biopsy is required. In the event that a patient has had tumor analyzed for PTEN/PIK3CA status through commercial means, their eligibility and need for additional tissue will be determined on a case by case basis by the principle investigator.

Exclusion Criteria:

• Step 1 Exclusion Criteria

1. Any clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient's participation in the study.

2. Known human immunodeficiency virus infection.

3. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.

4. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

5. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

6. Breast feeding or pregnant.

7. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK-228. In addition, patients with enteric stomata are also excluded.

8. Treatment with any investigational products, radiation therapy, surgery, tumor embolization, chemotherapy or immunotherapy within 21 days before the first dose of the study drug. For biologic or hormonal therapy treatment within 14 days or five half-lives of a drug (whichever is longer) before the first dose of study drug.

9. History of any of the following within the last 6 months before administration of the first dose of the drug:

10. Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures

11. Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures

12. Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia)

13. Placement of a pacemaker for control of rhythm

14. New York Heart Association (NYHA) Class III or IV heart failure

15. Pulmonary embolism

16. Significant active cardiovascular or pulmonary disease including:

17. Uncontrolled hypertension (i.e., systolic blood pressure >180 mm Hg, diastolic blood pressure >95 mm Hg). Use of anti-hypertensive agents to control hypertension before Cycle1 Day 1 is allowed.

18. Pulmonary hypertension

19. Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis or pulse oximetry on room air

20. Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement

21. Medically significant (symptomatic) bradycardia

22. History of arrhythmia requiring an implantable cardiac defibrillator

23. Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval >480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes)

24. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c)

7% ; patients with a history of transient glucose intolerance due to corticosteroid administration or gestational diabetes may be enrolled in this study if all other inclusion/exclusion criteria are met.

1. Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, CYP2C19 or CYP2C9 within 1 week preceding the first dose of study drug.

2. Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug.

3. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111

Sponsors and Collaborators

• Fox Chase Cancer Center

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 12, 2018
• Informed Consent Form - Nov 1, 2018

More Information

Publications

None provided.

• Responsible Party: Fox Chase Cancer Center
• ClinicalTrials.gov Identifier: NCT02987959
• Other Study ID Numbers: SAR-081
• First Posted: Dec 9, 2016
• Last Update Posted: Apr 28, 2022
• Last Verified: Apr 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Fox Chase Cancer Center: TAK-228; MLN0128; mTOR
• Additional relevant MeSH terms: Sarcoma

Study Results

Participant Flow

Arm/Group Title	TAK-228 Treatment
Arm/Group Description	Patients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228 TAK-228: TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
Period Title: Overall Study
STARTED	6
COMPLETED	0
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	TAK-228 Treatment
Arm/Group Description	Patients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228 TAK-228: TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	4 66.7%
>=65 years	2 33.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53
Sex: Female, Male (Count of Participants)
Female	4 66.7%
Male	2 33.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	6 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	1 16.7%
Black or African American	0 0%
White	5 83.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%
Tumor type (Count of Participants)
Leiomyosarcoma	4 66.7%
Extraskeletal osteosarcoma	1 16.7%
Soft tissue sarcoma	1 16.7%

Outcome Measures

1. Primary Outcome

Title	The Progression Free Survival Rate With TAK-228 in Sarcoma Patients With PI3K/AKT/mTOR Pathway Dysregulation
Description	Progression free rate will be determined by determining the number of patients with complete response, partial response and stable disease
Time Frame	12 weeks post-treatment

Outcome Measure Data

Analysis Population Description

Insufficient number of patients accrued for a meaningful analysis. No data collected from any participant.

Arm/Group Title	TAK-228 Treatment
Arm/Group Description	Patients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228 TAK-228: TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
Measure Participants	0

2. Secondary Outcome

Title	The Rate of Toxicity of TAK-228 in This Patient Population as Per Common Terminology Criteria for Adverse Events (CTCAE)v4.03 Criteria.
Description	Toxicity will be assessed by calculating number of participants experiencing adverse events as per CTCAEv4.03 criteria
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TAK-228 Treatment
Arm/Group Description	Patients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228 TAK-228: TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
Measure Participants	6
Count of Participants [Participants]	6 100%

3. Secondary Outcome

Title	The Objective Response Rate (ORR) of TAK-228 in This Patient Population.
Description	Objective response rate will be defined as patients with complete response and partial response. As per RECIST v1.1 guidelines, complete response is defined as the disappearance of all measurable lesions, and partial response is defined as >=30% decrease in sum of diameters of target lesions compared to the baseline sum of diameters.
Time Frame	upto 4 years

Outcome Measure Data

Analysis Population Description

Insufficient number of patients accrued for a meaningful analysis. No data collected from any participant.

Arm/Group Title	TAK-228 Treatment
Arm/Group Description	Patients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228 TAK-228: TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
Measure Participants	0

4. Secondary Outcome

Title	Progression Free Survival in This Patient Population.
Description	Progression Free Survival, defined as the time from initiation of treatment until disease progression will be calculated.
Time Frame	upto 4 years

Outcome Measure Data

Analysis Population Description

Insufficient number of patients accrued for a meaningful analysis. No data collected from any participant.

Arm/Group Title	TAK-228 Treatment
Arm/Group Description	Patients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228 TAK-228: TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
Measure Participants	0

5. Secondary Outcome

Title	Overall Survival Rate in This Patient Population
Description	Overall Survival, defined as the time from initiation of treatment until death from any cause will be calculated.
Time Frame	upto 4 years

Outcome Measure Data

Analysis Population Description

Insufficient number of patients accrued for a meaningful analysis. No data collected from any participant.

Arm/Group Title	TAK-228 Treatment
Arm/Group Description	Patients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228 TAK-228: TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
Measure Participants	0

Adverse Events

Time Frame	1 year
Arm/Group Title	TAK-228 Treatment
Arm/Group Description	Patients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228 TAK-228: TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
All Cause Mortality
	TAK-228 Treatment
	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)
Serious Adverse Events
	TAK-228 Treatment
	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)
Gastrointestinal disorders
Intractable nausea and vomiting	1/6 (16.7%)	1
Musculoskeletal and connective tissue disorders
Septic arthritis	1/6 (16.7%)	1
Renal and urinary disorders
Acute kidney injury	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	TAK-228 Treatment
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
Anemia	1/6 (16.7%)	1
Cardiac disorders
Cardiac disorders - Other, specify	1/6 (16.7%)	1
Palpitations	1/6 (16.7%)	1
Eye disorders
Eye disorders - Other, specify	1/6 (16.7%)	1
Gastrointestinal disorders
Mucositis oral	3/6 (50%)	3
Nausea	3/6 (50%)	3
Diarrhea	2/6 (33.3%)	2
Abdominal pain	1/6 (16.7%)	1
Constipation	1/6 (16.7%)	1
Taste alteration	1/6 (16.7%)	1
Vomiting	1/6 (16.7%)	1
General disorders
Fatigue	4/6 (66.7%)	4
Pain	2/6 (33.3%)	2
Edema	1/6 (16.7%)	1
Fever	1/6 (16.7%)	1
Infections and infestations
Infections and infestations - Other, specify	2/6 (33.3%)	2
Injury, poisoning and procedural complications
Wound complication	1/6 (16.7%)	1
Investigations
Investigations - Other, specify	2/6 (33.3%)	2
Activated partial thromboplastin time prolonged	1/6 (16.7%)	1
Alanine aminotransferase increased	1/6 (16.7%)	1
Weight loss	1/6 (16.7%)	1
White blood cell decreased	1/6 (16.7%)	1
Metabolism and nutrition disorders
Anorexia	1/6 (16.7%)	1
Hyperglycemia	1/6 (16.7%)	1
Musculoskeletal and connective tissue disorders
Myalgia	2/6 (33.3%)	2
Back pain	1/6 (16.7%)	1
Generalized muscle weakness	1/6 (16.7%)	1
Right hip cramps	1/6 (16.7%)	1
Nervous system disorders
Dizziness	2/6 (33.3%)	2
Headache	1/6 (16.7%)	1
Syncope	1/6 (16.7%)	1
Tremor	1/6 (16.7%)	1
Psychiatric disorders
Depression	1/6 (16.7%)	1
Renal and urinary disorders
Proteinuria	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/6 (33.3%)	2
Cough	1/6 (16.7%)	1
Epistaxis	1/6 (16.7%)	1
Nasal congestion	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders - Other, specify	1/6 (16.7%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	3/6 (50%)	3
Skin and subcutaneous tissue disorders - Other, specify	2/6 (33.3%)	2
Dry skin	1/6 (16.7%)	1
Pruritus	1/6 (16.7%)	1

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.