Medroxyprogesterone Acetate With or Without Entinostat Before Surgery in Treating Patients With Endometrioid Endometrial Cancer

FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma Clinical Trial

Official title:

A Randomized Surgical Window Pilot Investigation of the Relationship of Short Term Medroxyprogesterone Acetate (NSC #26386) Compared to Medroxyprogesterone Acetate Plus Entinostat (NSC #706995) on the Morphologic, Biochemical, and Molecular Changes in Primary Endometrioid Adenocarcinoma of the Uterine Corpus

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03018249
• Other study ID #: NCI-2017-00058
• Secondary ID: NCI-2017-00058NR
• Status: Completed
• Phase: Early Phase 1
• Start date: October 11, 2017
• Est. completion date: March 12, 2021

Study information

• Verified date: November 2021
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized surgical window trial evaluates the effect of adding entinostat to medroxyprogesterone acetate before surgery works on progesterone receptors on endometrioid endometrial tumors. Medroxyprogesterone acetate is a progesterone, a hormone produced by body normally. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving medroxyprogesterone acetate with or without entinostat may effect tumors from endometrioid endometrial cancer.

Description:

PRIMARY OBJECTIVES:

I. To determine whether the addition of the histone deacetylase inhibitor, entinostat, in combination with medroxyprogesterone acetate in the pre-operative setting results in up-regulation of activated progesterone receptors (PR) compared to medroxyprogesterone acetate alone.

SECONDARY OBJECTIVES:

I. To assess the response rate (as measured by cellular morphology and proliferation) and change in activated receptor levels with the addition of entinostat at the time of hysterectomy.

OUTLINE: Two arms were randomly allocated to eligible patients with equal probability.

ARM I: Patients receive medroxyprogesterone acetate intramuscularly (IM) on day 1 and undergo hysterectomy between days 21-24.

ARM II: Patients receive medroxyprogesterone acetate IM on day 1 and entinostat orally (PO) on days 1, 8, and 15. Patients undergo hysterectomy between days 21-24.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: March 12, 2021
• Est. primary completion date: April 18, 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have a histologically proven diagnosis of endometrioid endometrial adenocarcinoma by endometrial curettage or biopsy within 8 weeks prior to registration; central pathology review will be required as part of the study but not for registration purposes

• History/physical examination within 42 +/- 5 days of planned surgical procedure (18-21 days from day 1); further protocol-specific assessments

• The trial is open only to women with primary endometrioid adenocarcinoma of the uterine corpus (all histologic grades and stages) who are planned and appropriate for primary surgical treatment to include removal of the uterine corpus via any surgical modality; the patient must be considered a suitable surgical candidate

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3 within 28 days prior to registration

• Formalin-fixed, paraffin-embedded tumor tissue from the biopsy or curettage must be submitted along with the corresponding pathology report

• Platelets >= 100,000/ul

• Granulocytes (ANC) >= 1,500/ul

• Creatinine =< 1.6 mg/dl

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limits of normal

• Bilirubin within institutional normal limits

• The patient must provide study-specific informed consent and authorization permitting release of personal health information prior to study entry

• Any patients of childbearing potential must have a negative pregnancy test

Exclusion Criteria:

• Patients with any non-endometrioid histology (such as serous, clear cell, or carcinosarcoma)

• Patients who have received prior progestin or anti-estrogen therapy during the 3 months before the diagnosis of endometrioid adenocarcinoma of the uterine corpus is established; estrogen therapy alone is allowed

• Patients with ECOG performance grade of 4

• Patients with history of thrombophlebitis within the past 2 years or ongoing thromboembolic disorders

• Patients who have previously received systemic, radiation or other treatment for uterine cancer

• Patients for whom formalin-fixed, paraffin-embedded tumor tissue from the biopsy or curettage is unavailable

• Patients must not have previously received a non Food and Drug Administration (FDA) approved histone deacetylase (HDAC) inhibitor in a clinical trial setting (entinostat, belinostat)

• Patients must not be currently taking or have ever taken vorinostat (Zolinza, Merck), panobinostat (Farydak, Novartis) or romidepsin (Istodax, Gloucester Pharmaceuticals)

Related Conditions & MeSH terms

• Adenocarcinoma
• Carcinoma, Endometrioid
• FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma
• FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma
• FIGO Grade 3 Endometrial Endometrioid Adenocarcinoma

Intervention

Drug:
• Entinostat
Given PO

Procedure:
• Hysterectomy
Undergo hysterectomy

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Medroxyprogesterone Acetate
Given IM

Locations

Country	Name	City	State
United States	Abington Memorial Hospital	Abington	Pennsylvania
United States	Women's Cancer Care Associates LLC	Albany	New York
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Rocky Mountain Cancer Centers-Aurora	Aurora	Colorado
United States	University of Colorado Hospital	Aurora	Colorado
United States	Saint Louis Cancer and Breast Institute-Ballwin	Ballwin	Missouri
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	Flaget Memorial Hospital	Bardstown	Kentucky
United States	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Central Care Cancer Center - Bolivar	Bolivar	Missouri
United States	Boulder Community Hospital	Boulder	Colorado
United States	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Cox Cancer Center Branson	Branson	Missouri
United States	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington
United States	Harrison Medical Center	Bremerton	Washington
United States	State University of New York Downstate Medical Center	Brooklyn	New York
United States	Saint Joseph Regional Cancer Center	Bryan	Texas
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Highline Medical Center-Main Campus	Burien	Washington
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Memorial Hospital	Chattanooga	Tennessee
United States	Cheyenne Regional Medical Center-West	Cheyenne	Wyoming
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Bethesda North Hospital	Cincinnati	Ohio
United States	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio
United States	TriHealth Cancer Institute-Anderson	Cincinnati	Ohio
United States	TriHealth Cancer Institute-Westside	Cincinnati	Ohio
United States	Prisma Health Cancer Institute - Laurens	Clinton	South Carolina
United States	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Billings Clinic-Cody	Cody	Wyoming
United States	Kootenai Medical Center	Coeur d'Alene	Idaho
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Rocky Mountain Cancer Centers-Penrose	Colorado Springs	Colorado
United States	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Mount Carmel East Hospital	Columbus	Ohio
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	The Mark H Zangmeister Center	Columbus	Ohio
United States	John Muir Medical Center-Concord Campus	Concord	California
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Commonwealth Cancer Center-Corbin	Corbin	Kentucky
United States	Alegent Health Mercy Hospital	Council Bluffs	Iowa
United States	Greater Regional Medical Center	Creston	Iowa
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Delaware Health Center-Grady Cancer Center	Delaware	Ohio
United States	Delaware Radiation Oncology	Delaware	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	Denver Health Medical Center	Denver	Colorado
United States	National Jewish Health-Main Campus	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado
United States	Rocky Mountain Cancer Centers-Midtown	Denver	Colorado
United States	Rocky Mountain Cancer Centers-Rose	Denver	Colorado
United States	Rose Medical Center	Denver	Colorado
United States	SCL Health Saint Joseph Hospital	Denver	Colorado
United States	The Women's Imaging Center	Denver	Colorado
United States	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mercy Medical Center	Durango	Colorado
United States	Southwest Oncology PC	Durango	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	Prisma Health Cancer Institute - Easley	Easley	South Carolina
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Mountain Blue Cancer Care Center - Swedish	Englewood	Colorado
United States	Swedish Medical Center	Englewood	Colorado
United States	Saint Elizabeth Hospital	Enumclaw	Washington
United States	Saint Francis Hospital	Federal Way	Washington
United States	Parkview Hospital Randallia	Fort Wayne	Indiana
United States	Vanderbilt-Ingram Cancer Center Cool Springs	Franklin	Tennessee
United States	Unity Hospital	Fridley	Minnesota
United States	Mountain Blue Cancer Care Center	Golden	Colorado
United States	National Jewish Health-Western Hematology Oncology	Golden	Colorado
United States	CHI Health Saint Francis	Grand Island	Nebraska
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Great Falls Clinic	Great Falls	Montana
United States	North Colorado Medical Center	Greeley	Colorado
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Prisma Health Greenville Memorial Hospital	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania
United States	Saint Peter's Community Hospital	Helena	Montana
United States	Pulmonary Medicine Center of Chattanooga-Hixson	Hixson	Tennessee
United States	CHI Saint Vincent Cancer Center Hot Springs	Hot Springs	Arkansas
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	UPMC-Johnstown/John P. Murtha Regional Cancer Center	Johnstown	Pennsylvania
United States	Freeman Health System	Joplin	Missouri
United States	Mercy Hospital Joplin	Joplin	Missouri
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	CHI Health Good Samaritan	Kearney	Nebraska
United States	Heartland Hematology and Oncology	Kearney	Nebraska
United States	Northwestern Medicine Lake Forest Hospital	Lake Forest	Illinois
United States	Rocky Mountain Cancer Centers-Lakewood	Lakewood	Colorado
United States	Saint Anthony Hospital	Lakewood	Colorado
United States	Saint Clare Hospital	Lakewood	Washington
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Women's Cancer Center of Nevada	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Beebe Medical Center	Lewes	Delaware
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Lewistown Hospital	Lewistown	Pennsylvania
United States	Saint Joseph Hospital East	Lexington	Kentucky
United States	Saint Joseph Radiation Oncology Resource Center	Lexington	Kentucky
United States	Saint Elizabeth Regional Medical Center	Lincoln	Nebraska
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Rocky Mountain Cancer Centers-Littleton	Littleton	Colorado
United States	Saint Joseph London	London	Kentucky
United States	Rocky Mountain Cancer Centers-Sky Ridge	Lone Tree	Colorado
United States	Longmont United Hospital	Longmont	Colorado
United States	Rocky Mountain Cancer Centers-Longmont	Longmont	Colorado
United States	Jewish Hospital	Louisville	Kentucky
United States	Jewish Hospital Medical Center Northeast	Louisville	Kentucky
United States	Saints Mary and Elizabeth Hospital	Louisville	Kentucky
United States	McKee Medical Center	Loveland	Colorado
United States	OhioHealth Mansfield Hospital	Mansfield	Ohio
United States	Fairview Clinics and Surgery Center Maple Grove	Maple Grove	Minnesota
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	OhioHealth Marion General Hospital	Marion	Ohio
United States	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Health Partners Inc	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Community Medical Hospital	Missoula	Montana
United States	UPMC-Coraopolis/Heritage Valley Radiation Oncology	Moon	Pennsylvania
United States	Good Samaritan Regional Health Center	Mount Vernon	Illinois
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Louisiana State University Health Science Center	New Orleans	Louisiana
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	New Ulm Medical Center	New Ulm	Minnesota
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Licking Memorial Hospital	Newark	Ohio
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Newark Radiation Oncology	Newark	Ohio
United States	Mercy Hospital Oklahoma City	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Alegent Health Lakeside Hospital	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Hematology and Oncology Consultants PC	Omaha	Nebraska
United States	Memorial GYN Plus	Ooltewah	Tennessee
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Midlands Community Hospital	Papillion	Nebraska
United States	Parker Adventist Hospital	Parker	Colorado
United States	Rocky Mountain Cancer Centers-Parker	Parker	Colorado
United States	Sacred Heart Hospital	Pensacola	Florida
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Magee Womens Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Presbyterian Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Saint Clair Hospital Cancer Center	Pittsburgh	Pennsylvania
United States	UPMC-Saint Margaret	Pittsburgh	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Kootenai Cancer Center	Post Falls	Idaho
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Harrison HealthPartners Hematology and Oncology-Poulsbo	Poulsbo	Washington
United States	Women and Infants Hospital	Providence	Rhode Island
United States	Rocky Mountain Cancer Centers - Pueblo	Pueblo	Colorado
United States	Saint Mary Corwin Medical Center	Pueblo	Colorado
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	University of Rochester	Rochester	New York
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Kootenai Cancer Clinic	Sandpoint	Idaho
United States	Community Medical Center	Scranton	Pennsylvania
United States	TidalHealth Nanticoke / Allen Cancer Center	Seaford	Delaware
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	Geisinger Medical Oncology-Selinsgrove	Selinsgrove	Pennsylvania
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Jewish Hospital Medical Center South	Shepherdsville	Kentucky
United States	Welch Cancer Center	Sheridan	Wyoming
United States	Willis-Knighton Medical and Cancer Center	Shreveport	Louisiana
United States	Prisma Health Cancer Institute - Spartanburg	Spartanburg	South Carolina
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Geisinger Medical Group	State College	Pennsylvania
United States	Lakeview Hospital	Stillwater	Minnesota
United States	Franciscan Research Center-Northwest Medical Plaza	Tacoma	Washington
United States	Northwest Medical Specialties PLLC	Tacoma	Washington
United States	National Jewish Health-Northern Hematology Oncology	Thornton	Colorado
United States	Rocky Mountain Cancer Centers-Thornton	Thornton	Colorado
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	UPMC Uniontown Hospital Radiation Oncology	Uniontown	Pennsylvania
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	John Muir Medical Center-Walnut Creek	Walnut Creek	California
United States	Mercy Hospital Washington	Washington	Missouri
United States	UPMC Washington Hospital Radiation Oncology	Washington	Pennsylvania
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Saint Ann's Hospital	Westerville	Ohio
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Fairview Lakes Medical Center	Wyoming	Minnesota
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Mean Post-treatment Tumor Estrogen Receptor Score		Up to 3 years
Other	Co-expression of PR, Ki67, and p21	Will be compared between the arms.	Up to 3 years
Primary	Mean Post-treatment Tumor Progesterone Receptor H-score (Histology Score)	The H-score is defined as the percent cells staining positive (0-100) multiplied by the staining intensity (0, 1, 2 or 3) measured in the tumor by immunohistochemistry and averaged over 3 reviewers. This score can range from 0 to 300. In general, PRs are expected to decrease in response to medroxyprogesterone acetate. It was hypothesized that entinostat would mitigate the decrease in PR relative to the medroxyprogesterone acetate only arm post treatment. Higher PR H-scores post treatment in the arm with entinostat relative to the medroxyprogesterone alone arm would be consistent with this hypothesis. Arm II was thought to result in higher scores which was expected to have a more favorable outcome when treated with MPA therapy.	Specimens were collected at hysterectomy on day 21-24 and analyzed in batch.
Secondary	Percentage of Participants With a Histologic Response	Pre- and post-treatment slides for each patient were evaluated in pairs for complete or partial histologic response by one reviewer. Pre- and post-treatment slides for each patient were evaluated in pairs for complete or partial histologic response by one reviewer. A histologic response was defined as either the absence of identifiable adenocarcinoma in the hysterectomy specimen section (complete) or, subjectively, as the presence of a complex proliferation of glands that retain the architectural characteristics of adenocarcinoma, but with features of secretion, decreased nuclear stratification, or the presence of eosinophilic, squamous or mucinous metaplasia, when this was absent in the initial sample (partial).	Specimens were collected at initial diagnostic biopsy and at hysterectomy on day 21-24 and analyzed in batch.
Secondary	Percent of Participants With a Ki67 Response	A response was defined as a decrease in Ki-67 protein expression in tumor from pre- to post-treatment.	Specimens were collected at initial diagnostic biopsy and at hysterectomy on day 21-24 and analyzed in batch.
Secondary	The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE)	Maximum grade of physician assessed adverse events reported during treatment and up to 45 days after surgery. Grades start with 1 which is considered mild through grade 5 which is death. Participants on this study had adverse event grades up to grade 3 which is considered moderately severe.	Up to 45 days after surgery