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

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.

• Entinostat (Drug), also known as HDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275: Given PO
• Hysterectomy (Procedure), also known as Hysterectomy NOS: Undergo hysterectomy
• Laboratory Biomarker Analysis (Other): Correlative studies
• Medroxyprogesterone Acetate (Drug), also known as Amen, Aragest, Ciclotal, Clinofem, Clinovir, Cycrin, Depo-Clinovir, Depo-Provera, Depot-Medroxyprogestereone Acetate, Farlutal, G-Farlutal, Gestapuran, Hysron, Lutoral, Medroxyprogesterone 17-Acetate, Medroxyprogesteroni Acetas, Methylacetoxyprogesterone, Metipregnone, MPA, Nadigest, Nadigest (vet), Nidaxin, Nidaxin (vet), Oragest, Perlutex, Prodasone, Provera, Sodelut G, Veramix: Given IM

Primary outcomes

• 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 outcomes

• 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).
• 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.
• 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.

Other outcomes

• Mean Post-treatment Tumor Estrogen Receptor Score [Up to 3 years]
• Co-expression of PR, Ki67, and p21 [Up to 3 years]: Will be compared between the arms.

Sex: Female, ages: 18 Years to any

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)

Participant flow

Outcome results

• Mean Post-treatment Tumor Progesterone Receptor H-score (Histology Score) (Primary), Mean, units on a scale: Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA 53.6 +/- 64.8; Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat 42.7 +/- 49.0 (p 0.87)
• Percentage of Participants With a Histologic Response (Secondary), Count of participants, Participants: Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA 16; Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat 14
• Percent of Participants With a Ki67 Response (Secondary), Count of participants, Participants: Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA 15; Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat 18
• The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) (Secondary), Number, participants: Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA 11; Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat 9
• Mean Post-treatment Tumor Estrogen Receptor Score (Other pre specified)
• Co-expression of PR, Ki67, and p21 (Other pre specified)

Adverse events

Time frame: From initiation of treatment up to 45 days post-surgery

Serious adverse events by term

Other adverse events by term

134 more sites not listed.

• Study Protocol and Statistical Analysis Plan (PDF, 2018-11-20)

• Linda R Duska, Principal investigator, NRG Oncology

NIH grants: U10CA180868