High Throughput Drug Sensitivity Assay and Genomics- Guided Treatment of Patients With Relapsed or Refractory Acute Leukemia

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT02551718
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 34
• Location: 1
• Arm: 1
• Actual Duration (Months): 68
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This pilot clinical trial studies the feasibility of choosing treatment based on a high throughput ex vivo drug sensitivity assay in combination with mutation analysis for patients with acute leukemia that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). A high throughput screening assay tests many different drugs individually or in combination that kill leukemia cells in tiny chambers at the same time. High throughput drug sensitivity assay and mutation analysis may help guide the choice most effective for an individual's acute leukemia.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Acute Leukemia of Ambiguous Lineage; Recurrent Acute Lymphoblastic Leukemia; Recurrent Acute Myeloid Leukemia; Refractory Acute Lymphoblastic Leukemia; Refractory Acute Myeloid Leukemia; Refractory Acute Leukemia of Ambiguous Lineage	Other: Chemosensitivity Assay; Other: Cytology Specimen Collection Procedure; Genetic: Gene Expression Analysis; Genetic: Genetic Variation Analysis; Drug: In Vitro Sensitivity-Directed Chemotherapy	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. To test patient cells in a high throughput assay against individual drugs and drug combinations within 21 days to enable optimal choice of drug combinations for therapy.

2. To test gene expression that reveals activation of druggable pathways or mutations in genes that confer susceptibility to specific agents may also be considered in choice of treatment.

SECONDARY OBJECTIVE:

1. To evaluate the response to the chosen therapy.

OUTLINE:

Leukemia cells obtained from blood or bone marrow are analyzed for sensitivity to both individual drugs and drug combinations via high throughput chemotherapy sensitivity assay and next generation sequencing assays. Doctors will then recommend chemotherapy regimens based on the results.

After completion of the chemotherapy regimen, patients are followed up at 2-4 weeks for response, and then every 3 months for 2 years for duration of response and survival.

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: Individualized Treatment for Relapsed/Refractory Acute Leukemia Based on Chemosensitivity and Genomics/Gene Expression Data
• Actual Study Start Date: Sep 11, 2015
• Actual Primary Completion Date: Jun 19, 2020
• Actual Study Completion Date: May 13, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemosensitivity testing, chemotherapy) Leukemia cells purified from blood or bone marrow samples are analyzed for sensitivity to individual drugs and drug combination and by next generation sequencing.

Other: Chemosensitivity Assay; Lab test in which leukemia cells obtained from blood or bone marrow are tested for sensitivity to 115 drugs individually and in certain combinations; Other Names: Chemosensitivity Testing ; Other: Cytology Specimen Collection Procedure; Undergo blood or bone marrow collection; Other Names: Cytologic Sampling ; Genetic: Gene Expression Analysis; Analysis of leukemia cell genes to identify possible drug targets; Genetic: Genetic Variation Analysis; Analysis of leukemia cell genes to identify possible drug targets; Other Names: Genetic Variation GENVAR mutation analysis ; Drug: In Vitro Sensitivity-Directed Chemotherapy; Receive personalized chemotherapy with one or more of the following drugs: Afatinib Arsenic trioxide Axitinib Azacitidine Bexarotene Bortezomib Bosutinib Busulfan Cabazitaxel Cabozantinib Carfilzomib Ceritinib Cladribine Clofarabine Crizotinib Cytarabine HCl Dabrafenib Dasatinib Daunorubicin HCl Decitabine Erlotinib Etoposide Everolimus Fludarabine Gefitinib Gemcitabine HCl Hydroxyurea Imatinib Irinotecan Lapatinib Lomustine Melphalan Mercaptopurine Methotrexate Mitoxantrone Nelarabine Nilotinib Paclitaxel Pazopanib Pentostatin Ponatinib Pralatrexate Rapamycin Regorafenib Romidepsin Ruxolitinib Sorafenib Sunitinib Temsirolimus Thioguanine Topotecan HCl Trametinib Tretinoin

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients we Are Able to Test and Initiate Treatment Within a 21 Day Period [Up to 21 days]

   The study will be considered successful (feasibility demonstrated) if it is possible to choose and initiate a combination drug regimen within 21 days in 9 out of 15 patients. With that outcome, there would be 90% confidence that the true feasibility rate is at least 40%.

Secondary Outcome Measures

1. Rate of Complete Remission [Up to 2 years]

   The secondary objective is to evaluate the response to the chosen therapy. Response will be evaluated using European LeukemiaNet Response Evaluation Criteria in AML (2010 version)

2. Survival [Up to 2 years]

   Disease free and overall survival data will be assessed by contacting the referring MD or the patient every three months for the first two years.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of acute leukemia by World Health Organization (WHO) criteria (e.g.-acute myeloid leukemia, acute lymphoblastic leukemia, acute leukemia of ambiguous origin)

• Either:

• Relapsed after or refractory to prior treatment with at least two regimens or lines of treatment

• Prior failure of at least one regimen or line of treatment, with poor cytogenetic or other risk factors, and ineligible for other clinical trials

• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 3

• Expectation that we can obtain about 10 million blasts from blood and/or marrow (e.g., circulating blast count of 5,000 or greater or cellular marrow with greater than or equal to 20% blasts)

• Bilirubin =< 1.5 x upper limit of normal (ULN) unless elevation is thought to be due to Gilbert's syndrome, hemolysis, or hepatic infiltration by the hematologic malignancy

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SPGT) (alanine aminotransferase [ALT]) =< 2.5 x ULN, unless elevation is thought to be due to hepatic infiltration by the hematologic malignancy

• Alkaline phosphatase =< 2.5 x ULN, unless elevation is thought to be due to hepatic infiltration by the hematologic malignancy

• Serum creatinine =< 2.0 mg/dL

• Informed consent

• Willing to use contraception when appropriate

• Expected survival is greater than 100 days

Exclusion Criteria:

• No other active cancer that requires systemic chemotherapy or radiation

• Active systemic fungal, bacterial, viral or other infection, unless disease is under treatment with antimicrobials and considered controlled in the opinion of the investigator

• Significant organ compromise that will increase risk of toxicity or mortality

• Pregnancy or lactation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mary-Elizabeth Percival, Fred Hutch/University of Washington Cancer Consortium

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 21, 2020

More Information

Publications

None provided.

• Responsible Party: Mary-Beth Percival, Assistant Professor, Division of Hematology, University of Washington
• ClinicalTrials.gov Identifier: NCT02551718
• Other Study ID Numbers: 9226; NCI-2015-01299; 9226; P30CA015704; RG1015012
• First Posted: Sep 16, 2015
• Last Update Posted: Jun 30, 2022
• Last Verified: Jun 1, 2022

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Recurrence; Acute Disease

Study Results

Participant Flow

Arm/Group Title	Chemosensitivity Testing
Arm/Group Description	Leukemia cells purified from blood or bone marrow samples are analyzed for sensitivity to individual drugs and drug combination and by next generation sequencing. Chemosensitivity Assay: Lab test in which leukemia cells obtained from blood or bone marrow are tested for sensitivity to 115 drugs individually and in certain combinations Cytology Specimen Collection Procedure: Undergo blood or bone marrow collection Gene Expression Analysis: Analysis of leukemia cell genes to identify possible drug targets Genetic Variation Analysis: Analysis of leukemia cell genes to identify possible drug targets In Vitro Sensitivity-Directed Chemotherapy: Receive personalized chemotherapy with one or more of the following drugs: Afatinib Arsenic trioxide Axitinib Azacitidine Bexarotene Bortezomib Bosutinib Busulfan Cabazitaxel Cabozantinib Carfilzomib Ceritinib Cladribine Clofarabine Crizotinib Cytarabine HCl Dabrafenib Dasatinib Daunorubicin HCl Decitabine Erlotinib Etoposide Everolimus Fludarabine Gefitinib Gemcitabine HCl Hydroxyurea Imatinib Irinotecan Lapatinib Lomustine Melphalan Mercaptopurine Methotrexate Mitoxantrone Nelarabine Nilotinib Paclitaxel Pazopanib Pentostatin Ponatinib Pralatrexate Rapamycin Regorafenib Romidepsin Ruxolitinib Sorafenib Sunitinib Temsirolimus Thioguanine Topotecan HCl Trametinib Tretinoin
Period Title: Overall Study
STARTED	34
COMPLETED	34
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Chemosensitivity Testing
Arm/Group Description	Leukemia cells purified from blood or bone marrow samples are analyzed for sensitivity to individual drugs and drug combination and by next generation sequencing. Chemosensitivity Assay: Lab test in which leukemia cells obtained from blood or bone marrow are tested for sensitivity to 115 drugs individually and in certain combinations Cytology Specimen Collection Procedure: Undergo blood or bone marrow collection Gene Expression Analysis: Analysis of leukemia cell genes to identify possible drug targets Genetic Variation Analysis: Analysis of leukemia cell genes to identify possible drug targets In Vitro Sensitivity-Directed Chemotherapy: Receive personalized chemotherapy with one or more of the following drugs: Afatinib Arsenic trioxide Axitinib Azacitidine Bexarotene Bortezomib Bosutinib Busulfan Cabazitaxel Cabozantinib Carfilzomib Ceritinib Cladribine Clofarabine Crizotinib Cytarabine HCl Dabrafenib Dasatinib Daunorubicin HCl Decitabine Erlotinib Etoposide Everolimus Fludarabine Gefitinib Gemcitabine HCl Hydroxyurea Imatinib Irinotecan Lapatinib Lomustine Melphalan Mercaptopurine Methotrexate Mitoxantrone Nelarabine Nilotinib Paclitaxel Pazopanib Pentostatin Ponatinib Pralatrexate Rapamycin Regorafenib Romidepsin Ruxolitinib Sorafenib Sunitinib Temsirolimus Thioguanine Topotecan HCl Trametinib Tretinoin
Overall Participants	34
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	23 67.6%
>=65 years	11 32.4%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	54
Sex: Female, Male (Count of Participants)
Female	17 50%
Male	17 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.9%
Not Hispanic or Latino	33 97.1%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 11.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 2.9%
White	29 85.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	34 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients we Are Able to Test and Initiate Treatment Within a 21 Day Period
Description	The study will be considered successful (feasibility demonstrated) if it is possible to choose and initiate a combination drug regimen within 21 days in 9 out of 15 patients. With that outcome, there would be 90% confidence that the true feasibility rate is at least 40%.
Time Frame	Up to 21 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chemosensitivity Testing and Treatment Initiation Within 21 Days
Arm/Group Description	Leukemia cells purified from blood or bone marrow samples are analyzed for sensitivity to individual drugs and drug combination and by next generation sequencing. Chemosensitivity Assay: Lab test in which leukemia cells obtained from blood or bone marrow are tested for sensitivity to 115 drugs individually and in certain combinations Cytology Specimen Collection Procedure: Undergo blood or bone marrow collection Gene Expression Analysis: Analysis of leukemia cell genes to identify possible drug targets Genetic Variation Analysis: Analysis of leukemia cell genes to identify possible drug targets In Vitro Sensitivity-Directed Chemotherapy: Receive personalized chemotherapy with one or more of the following drugs: Afatinib Arsenic trioxide Axitinib Azacitidine Bexarotene Bortezomib Bosutinib Busulfan Cabazitaxel Cabozantinib Carfilzomib Ceritinib Cladribine Clofarabine Crizotinib Cytarabine HCl Dabrafenib Dasatinib Daunorubicin HCl Decitabine Erlotinib Etoposide Everolimus Fludarabine Gefitinib Gemcitabine HCl Hydroxyurea Imatinib Irinotecan Lapatinib Lomustine Melphalan Mercaptopurine Methotrexate Mitoxantrone Nelarabine Nilotinib Paclitaxel Pazopanib Pentostatin Ponatinib Pralatrexate Rapamycin Regorafenib Romidepsin Ruxolitinib Sorafenib Sunitinib Temsirolimus Thioguanine Topotecan HCl Trametinib Tretinoin
Measure Participants	34
Count of Participants [Participants]	21 61.8%

2. Secondary Outcome

Title	Rate of Complete Remission
Description	The secondary objective is to evaluate the response to the chosen therapy. Response will be evaluated using European LeukemiaNet Response Evaluation Criteria in AML (2010 version)
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Number of complete remissions + complete remissions with incomplete blood counts

Arm/Group Title	Treatment (Chemosensitivity Testing, Chemotherapy)
Arm/Group Description	Leukemia cells purified from blood or bone marrow samples are analyzed for sensitivity to individual drugs and drug combination and by next generation sequencing. Chemosensitivity Assay: Lab test in which leukemia cells obtained from blood or bone marrow are tested for sensitivity to 115 drugs individually and in certain combinations Cytology Specimen Collection Procedure: Undergo blood or bone marrow collection Gene Expression Analysis: Analysis of leukemia cell genes to identify possible drug targets Genetic Variation Analysis: Analysis of leukemia cell genes to identify possible drug targets In Vitro Sensitivity-Directed Chemotherapy: Receive personalized chemotherapy with one or more of the following drugs: Afatinib Arsenic trioxide Axitinib Azacitidine Bexarotene Bortezomib Bosutinib Busulfan Cabazitaxel Cabozantinib Carfilzomib Ceritinib Cladribine Clofarabine Crizotinib Cytarabine HCl Dabrafenib Dasatinib Daunorubicin HCl Decitabine Erlotinib Etoposide Everolimus Fludarabine Gefitinib Gemcitabine HCl Hydroxyurea Imatinib Irinotecan Lapatinib Lomustine Melphalan Mercaptopurine Methotrexate Mitoxantrone Nelarabine Nilotinib Paclitaxel Pazopanib Pentostatin Ponatinib Pralatrexate Rapamycin Regorafenib Romidepsin Ruxolitinib Sorafenib Sunitinib Temsirolimus Thioguanine Topotecan HCl Trametinib Tretinoin
Measure Participants	34
Count of Participants [Participants]	5 14.7%

3. Secondary Outcome

Title	Survival
Description	Disease free and overall survival data will be assessed by contacting the referring MD or the patient every three months for the first two years.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Overall survival in months from date of study consent

Arm/Group Title	Treatment (Chemosensitivity Testing, Chemotherapy)
Arm/Group Description	Leukemia cells purified from blood or bone marrow samples are analyzed for sensitivity to individual drugs and drug combination and by next generation sequencing. Chemosensitivity Assay: Lab test in which leukemia cells obtained from blood or bone marrow are tested for sensitivity to 115 drugs individually and in certain combinations Cytology Specimen Collection Procedure: Undergo blood or bone marrow collection Gene Expression Analysis: Analysis of leukemia cell genes to identify possible drug targets Genetic Variation Analysis: Analysis of leukemia cell genes to identify possible drug targets In Vitro Sensitivity-Directed Chemotherapy: Receive personalized chemotherapy with one or more of the following drugs: Afatinib Arsenic trioxide Axitinib Azacitidine Bexarotene Bortezomib Bosutinib Busulfan Cabazitaxel Cabozantinib Carfilzomib Ceritinib Cladribine Clofarabine Crizotinib Cytarabine HCl Dabrafenib Dasatinib Daunorubicin HCl Decitabine Erlotinib Etoposide Everolimus Fludarabine Gefitinib Gemcitabine HCl Hydroxyurea Imatinib Irinotecan Lapatinib Lomustine Melphalan Mercaptopurine Methotrexate Mitoxantrone Nelarabine Nilotinib Paclitaxel Pazopanib Pentostatin Ponatinib Pralatrexate Rapamycin Regorafenib Romidepsin Ruxolitinib Sorafenib Sunitinib Temsirolimus Thioguanine Topotecan HCl Trametinib Tretinoin
Measure Participants	34
Mean (Standard Deviation) [months]	6.91 (7.64)

Adverse Events

Time Frame	5 years
Adverse Event Reporting Description	Non-hematologic toxicities >/= grade 3 were recorded from time of assay-guided therapy administration through 14 days after last administration of study therapy Hospitalizations or prolongation of hospitalizations for protocol-scheduled procedures, blood product transfusions, or for social reasons (i.e. awaiting transport home) were not considered SAEs. And hospitalization or prolongation of hospitalizations for fever and/or infection were considered expected, and not considered SAEs.
Arm/Group Title	Chemosensitivity Testing
Arm/Group Description	Leukemia cells purified from blood or bone marrow samples are analyzed for sensitivity to individual drugs and drug combination and by next generation sequencing. Chemosensitivity Assay: Lab test in which leukemia cells obtained from blood or bone marrow are tested for sensitivity to 115 drugs individually and in certain combinations Cytology Specimen Collection Procedure: Undergo blood or bone marrow collection Gene Expression Analysis: Analysis of leukemia cell genes to identify possible drug targets Genetic Variation Analysis: Analysis of leukemia cell genes to identify possible drug targets In Vitro Sensitivity-Directed Chemotherapy: Receive personalized chemotherapy with one or more of the following drugs: Afatinib Arsenic trioxide Axitinib Azacitidine Bexarotene Bortezomib Bosutinib Busulfan Cabazitaxel Cabozantinib Carfilzomib Ceritinib Cladribine Clofarabine Crizotinib Cytarabine HCl Dabrafenib Dasatinib Daunorubicin HCl Decitabine Erlotinib Etoposide Everolimus Fludarabine Gefitinib Gemcitabine HCl Hydroxyurea Imatinib Irinotecan Lapatinib Lomustine Melphalan Mercaptopurine Methotrexate Mitoxantrone Nelarabine Nilotinib Paclitaxel Pazopanib Pentostatin Ponatinib Pralatrexate Rapamycin Regorafenib Romidepsin Ruxolitinib Sorafenib Sunitinib Temsirolimus Thioguanine Topotecan HCl Trametinib Tretinoin
All Cause Mortality
	Chemosensitivity Testing
	Affected / at Risk (%)	# Events
Total	32/34 (94.1%)
Serious Adverse Events
	Chemosensitivity Testing
	Affected / at Risk (%)	# Events
Total	11/34 (32.4%)
Blood and lymphatic system disorders
Leukocytosis	1/34 (2.9%)	1
Intermittent Thrombocytopenia	1/34 (2.9%)	2
General disorders
Pain	1/34 (2.9%)	1
Immune system disorders
Anaphylaxis	1/34 (2.9%)	1
Infections and infestations
Enterobacter Cloacae Sepsis	1/34 (2.9%)	1
Neutropenic fever with Sepsis Physiology	1/34 (2.9%)	1
Pneumonia	2/34 (5.9%)	2
Rhizopus Pneumonia	1/34 (2.9%)	1
Septic Shock	1/34 (2.9%)	1
Metabolism and nutrition disorders
Tumor Lysis Syndrome	1/34 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/34 (2.9%)	1
Hypoxemic Respiratory Failure	1/34 (2.9%)	1
Pulmonary Edema	1/34 (2.9%)	1
Respiratory Distress	1/34 (2.9%)	1
Vascular disorders
Hypotension	1/34 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Chemosensitivity Testing
	Affected / at Risk (%)	# Events
Total	26/34 (76.5%)
Blood and lymphatic system disorders
Subdural Hematoma	1/34 (2.9%)	1
Cardiac disorders
Atrial Fibrillation with RVR	1/34 (2.9%)	1
Heart Failure	1/34 (2.9%)	1
Gastrointestinal disorders
C. Diff Colitis with Diarrhea	1/34 (2.9%)	2
Diarrhea	2/34 (5.9%)	2
General disorders
Pain	1/34 (2.9%)	1
Infections and infestations
Anorectal Infection	1/34 (2.9%)	1
Bacteremia Infection	1/34 (2.9%)	1
Catheter Related Infection	1/34 (2.9%)	1
Coag Negative Staph Bacteremia	2/34 (5.9%)	2
Distributive Shock	1/34 (2.9%)	1
Enterocolitis	2/34 (5.9%)	2
Eye Infection	1/34 (2.9%)	1
Febrile Neutropenia	10/34 (29.4%)	19
Granulicatella Adiacens Bacteremia	1/34 (2.9%)	1
Invasive Fungal Sinusitis	1/34 (2.9%)	1
Lung Infection	3/34 (8.8%)	3
Oral Mucositis	2/34 (5.9%)	2
Pseudomonas Bacteremia	1/34 (2.9%)	1
Pneumonia	2/34 (5.9%)	2
Rothia Mucilaginosa Bacteremia	1/34 (2.9%)	1
Sepsis	3/34 (8.8%)	4
Staph Epidermidis Bacteremia	2/34 (5.9%)	2
Staphylococcus Infection	1/34 (2.9%)	1
Stenotrophomonas Maltophilia Bacteremia	1/34 (2.9%)	1
Urinary Tract Infection	1/34 (2.9%)	1
Injury, poisoning and procedural complications
Fall	1/34 (2.9%)	1
Investigations
Alanine Aminotransferase Increased	1/34 (2.9%)	2
Aspartate Aminotransferase Increased	1/34 (2.9%)	1
Hyperbilirubinemia	2/34 (5.9%)	4
INR Increased	1/34 (2.9%)	1
Transaminitis	1/34 (2.9%)	1
Metabolism and nutrition disorders
Anorexia	2/34 (5.9%)	2
Hyperglycemia	1/34 (2.9%)	1
Tumor Lysis Syndrome	2/34 (5.9%)	2
Nervous system disorders
Syncope	1/34 (2.9%)	1
Renal and urinary disorders
Acute Kidney Injury	1/34 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	3/34 (8.8%)	4
Pleural Effusion	1/34 (2.9%)	1
Pulmonary Edema	2/34 (5.9%)	2
Skin and subcutaneous tissue disorders
Rash Maculopapular	1/34 (2.9%)	1
Vascular disorders
Central Line Associated DVT	1/34 (2.9%)	1
Hypertension	1/34 (2.9%)	1
Hypotension	1/34 (2.9%)	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.