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

Early Phase 1

Completed

Conditions: FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma
FIGO Grade 3 Endometrial Endometrioid Adenocarcinoma
FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma

Interventions: Drug: Entinostat
Procedure: Hysterectomy
Other: Laboratory Biomarker Analysis
Drug: Medroxyprogesterone Acetate

Registration Number: NCT03018249

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Detailed 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 & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 50

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (medroxyprogesterone acetate, entinostat, hysterectomy)	Hysterectomy	Patients receive medroxyprogesterone acetate IM on day 1 and entinostat PO on days 1, 8, and 15. Patients undergo hysterectomy between days 21-24.
Arm II (medroxyprogesterone acetate, entinostat, hysterectomy)	Laboratory Biomarker Analysis	Patients receive medroxyprogesterone acetate IM on day 1 and entinostat PO on days 1, 8, and 15. Patients undergo hysterectomy between days 21-24.
Arm I (medroxyprogesterone acetate, hysterectomy)	Hysterectomy	Patients receive medroxyprogesterone acetate IM on day 1 and undergo hysterectomy between days 21-24.
Arm I (medroxyprogesterone acetate, hysterectomy)	Laboratory Biomarker Analysis	Patients receive medroxyprogesterone acetate IM on day 1 and undergo hysterectomy between days 21-24.
Arm I (medroxyprogesterone acetate, hysterectomy)	Medroxyprogesterone Acetate	Patients receive medroxyprogesterone acetate IM on day 1 and undergo hysterectomy between days 21-24.
Arm II (medroxyprogesterone acetate, entinostat, hysterectomy)	Entinostat	Patients receive medroxyprogesterone acetate IM on day 1 and entinostat PO on days 1, 8, and 15. Patients undergo hysterectomy between days 21-24.
Arm II (medroxyprogesterone acetate, entinostat, hysterectomy)	Medroxyprogesterone Acetate	Patients receive medroxyprogesterone acetate IM on day 1 and entinostat PO on days 1, 8, and 15. Patients undergo hysterectomy between days 21-24.

Primary Outcome Measures

Name	Time	Method
Mean Post-treatment Tumor Progesterone Receptor H-score (Histology Score)	Specimens were collected at hysterectomy on day 21-24 and analyzed in batch.	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.

Secondary Outcome Measures

Name	Time	Method
Percent of Participants With a Ki67 Response	Specimens were collected at initial diagnostic biopsy and at hysterectomy on day 21-24 and analyzed in batch.	A response was defined as a decrease in Ki-67 protein expression in tumor from pre- to post-treatment.
Percentage of Participants With a Histologic Response	Specimens were collected at initial diagnostic biopsy and at hysterectomy on day 21-24 and analyzed in batch.	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).
The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE)	Up to 45 days after surgery	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.

Trial Locations

Locations (234): CHI Saint Vincent Cancer Center Hot Springs
🇺🇸
Hot Springs, Arkansas, United States
John Muir Medical Center-Concord Campus
🇺🇸
Concord, California, United States
John Muir Medical Center-Walnut Creek
🇺🇸
Walnut Creek, California, United States
Rocky Mountain Cancer Centers-Aurora
🇺🇸
Aurora, Colorado, United States
University of Colorado Hospital
🇺🇸
Aurora, Colorado, United States
Boulder Community Hospital
🇺🇸
Boulder, Colorado, United States
Rocky Mountain Cancer Centers-Boulder
🇺🇸
Boulder, Colorado, United States
Penrose-Saint Francis Healthcare
🇺🇸
Colorado Springs, Colorado, United States
Rocky Mountain Cancer Centers-Penrose
🇺🇸
Colorado Springs, Colorado, United States
Denver Health Medical Center
🇺🇸
Denver, Colorado, United States
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CHI Saint Vincent Cancer Center Hot Springs
🇺🇸Hot Springs, Arkansas, United States