FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma, FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma, FIGO Grade 3 Endometrial Endometrioid Adenocarcinoma
Conditions
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.
Interventions
DRUGEntinostat
Given PO
PROCEDUREHysterectomy
Undergo hysterectomy
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMedroxyprogesterone Acetate
Given IM
Sponsors
NRG Oncology
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
The study was open to accrual on 8/17/2017. The first patient was enrolled on October 11, 2017. The study closed to accrual 4 months later on 2/9/2018 after 50 patients were enrolled across 13 unique sites.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA Patients receive medroxyprogesterone acetate IM on day 1 and undergo hysterectomy between days 21-24. | 25 |
| Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat Medroxyprogesterone acetate IM on day 1 and entinostat PO on days 1, 8, and 15. Followed by hysterectomy between days 21-24. | 25 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA | Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat | Total |
|---|---|---|---|
| Age, Customized 30-49 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Customized 50-59 years | 7 Participants | 7 Participants | 14 Participants |
| Age, Customized 60-69 years | 13 Participants | 13 Participants | 26 Participants |
| Age, Customized 70-99 years | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 24 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Participants with Endometrioid Cell Type Cancer | 25 Participants | 25 Participants | 50 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 23 Participants | 22 Participants | 45 Participants |
| Sex: Female, Male Female | 25 Participants | 25 Participants | 50 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 23 |
| other Total, other adverse events | 14 / 23 | 16 / 23 |
| serious Total, serious adverse events | 1 / 23 | 1 / 23 |
Outcome results
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.
Time frame: Specimens were collected at hysterectomy on day 21-24 and analyzed in batch.
Population: Randomized, treated, evaluable specimen. There were 2 participants in each reporting group who withdrew consent prior to treatment; no specimens were submitted for these patients. There were two additional patients with insufficient tumor post-treatment and no slides were submitted; one in each reporting group. There was one additional patient with no specimens submitted in reporting group 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA | Mean Post-treatment Tumor Progesterone Receptor H-score (Histology Score) | 53.6 units on a scale | Standard Deviation 64.8 |
| Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat | Mean Post-treatment Tumor Progesterone Receptor H-score (Histology Score) | 42.7 units on a scale | Standard Deviation 49 |
p-value: 0.87Wilcoxon (Mann-Whitney)
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).
Time frame: Specimens were collected at initial diagnostic biopsy and at hysterectomy on day 21-24 and analyzed in batch.
Population: Randomized, treated, evaluable pre and post treatment specimen available. There were 2 participants in each reporting group who withdrew consent prior to treatment; no specimens were submitted for these patients. There was one participant with an inevaluable pre-treatment slide. There were two additional patients with insufficient tumor post-treatment and no slides were submitted; one in each reporting group. There was one additional patient with no specimens submitted in reporting group 2.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA | Percentage of Participants With a Histologic Response | 16 Participants |
| Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat | Percentage of Participants With a Histologic Response | 14 Participants |
95% CI: [-25, 30]
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.
Time frame: Specimens were collected at initial diagnostic biopsy and at hysterectomy on day 21-24 and analyzed in batch.
Population: Randomized, treated, evaluable pre and post treatment specimens available. There were 2 participants in each reporting group who withdrew consent prior to treatment; no specimens were submitted for these patients. There was one participant with an inevaluable pre-treatment slide. There were two additional patients with insufficient tumor post-treatment and no slides were submitted; one in each reporting group. There was one additional patient with no specimens submitted in reporting group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA | Percent of Participants With a Ki67 Response | 15 Participants |
| Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat | Percent of Participants With a Ki67 Response | 18 Participants |
95% CI: [-16.7, 45.3]
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.
Time frame: Up to 45 days after surgery
Population: Eligible and Treated Patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA | The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) | Grade 3 AE | 2 participants |
| Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA | The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) | Grade 2 AE | 4 participants |
| Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA | The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) | Grade 4 AE | 0 participants |
| Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA | The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) | Grade 5 AE | 0 participants |
| Arm I (Medroxyprogesterone Acetate, Hysterectomy) MPA | The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) | Grade 1 AE | 11 participants |
| Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat | The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) | Grade 5 AE | 0 participants |
| Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat | The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) | Grade 1 AE | 9 participants |
| Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat | The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) | Grade 2 AE | 6 participants |
| Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat | The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) | Grade 3 AE | 2 participants |
| Arm II (Medroxyprogesterone Acetate, Entinostat, Hysterectomy) MPA and Entinostat | The Frequency and Severity of CTCAE Version 4.0 Graded Adverse Events (AE) | Grade 4 AE | 0 participants |
Other Pre-specified
Co-expression of PR, Ki67, and p21
Will be compared between the arms.
Time frame: Up to 3 years
Other Pre-specified
Mean Post-treatment Tumor Estrogen Receptor Score
Time frame: Up to 3 years