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Megestrol Acetate With or Without Pterostilbene in Treating Patients With Endometrial Cancer Undergoing Hysterectomy

Primary Purpose

Atypical Endometrial Hyperplasia, Endometrial Carcinoma

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Megestrol Acetate
Pterostilbene
Sponsored by
City of Hope Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Atypical Endometrial Hyperplasia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Documented informed consent of the participant and/or legally authorized representative
  • Willing to undergo an intraoperative biopsy/or standard of care tissue collection during surgery, following completion of treatment with MA +/- PTE
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Histologically confirmed EC or complex atypical hyperplasia of the endometrium
  • Candidate for a total hysterectomy with or without bilateral salpingo-oophorectomy
  • About to initiate preoperative window period, with planned hysterectomy scheduled

  • Platelets >= 100,000/mm^3

    • NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
  • Total bilirubin =< 1.5 X upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) =< 1.5 x ULN
  • Alanine aminotransferase (ALT) =< 1.5 x ULN
  • Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula
  • Women of childbearing potential: negative urine or serum pregnancy test in premenopausal women. Postmenopausal women do not need to undergo a pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

Exclusion Criteria:

  • Pterostilbene supplements within 30 days prior to day 1 of protocol therapy
  • Any of the following phytochemical-based supplements within 30 days prior to day 1 of protocol therapy: resveratrol, genistein, and quercetin
  • Chemotherapy for EC
  • Allergic reaction/hypersensitivity to similar agents, excipients

  • Unstable cardiac disease as defined by one of the following:

    • Cardiac events such as myocardial infarction (MI) within the past 6 months
    • NYHA (New York Heart Association) heart failure class III-IV
    • Uncontrolled atrial fibrillation or hypertensive emergency/urgency (defined as systolic blood pressure >= 180 mmHg and/or diastolic blood pressure >= 120 mmHg)
  • Active or history of recent thromboembolism or stroke, within the past 6 months
  • Cushing's syndrome
  • Acute infection requiring systemic (intravenous) treatment
  • Known history of human immunodeficiency virus (HIV) infection
  • Known active hepatitis B or C infection
  • Inability to swallow tablets/capsules
  • Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc
  • Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Sites / Locations

  • City of Hope Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I (pterostilbene, megestrol acetate)

Arm II (megestrol acetate)

Arm Description

Patients receive pterostilbene PO BID and megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity.

Patients receive megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity.

Outcomes

Primary Outcome Measures

Tumor Ki-67 proliferation index
Ki-67 represents a specific nuclear marker for cell proliferation that is measured by staining with specific antibodies by immunohistochemical (IHC) staining. The Ki-67 proliferation index is defined as percent tumor cells staining positive, and measured on a continuous scale of 0-100%, with higher values indicating higher proliferation. We will compare treatment-associated change in Ki-67 proliferation index between the 2 study arms, using a 1-sided test with significance at p < 0.05. Ki-67 values will be assessed at two time-points during this study, prior to treatment with megace +/- pterostilbene (pre-treatment), and following completion of treatment (post-treatment). Using a generalized estimating equation to take into account the repeated assessment of subjects (pre and post treatment), analysis will use a generalized linear regression model of Ki-67 index. Adjustment for potential confounding factors will be made as appropriate.

Secondary Outcome Measures

Histologic response of gland cellularity
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). Gland cellularity will be assessed by counting the number of cells in one quarter of a high-power field (HPF) (average of 3 fields). This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Histologic response of mitotic index
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The mitotic index will be calculated as the number of mitoses per HPF (average of 3 fields). This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Histologic response of metaplasia
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The percentages of tumor that display squamous or mucinous metaplasia will be estimated as percentages, with < 10% considered negative and >= 10% as positive. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Histologic response of eosinophilic cytoplasm
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The percentages of tumor that display cytoplasmic eosinophilia will be estimated as percentages, with < 10% considered negative and >= 10% as positive. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Immunohistochemical expression of Bcl-2 to assess tumor growth and apoptosis
Immunohistochemistry stains with antibodies directed against Bcl-2 will be performed on pre- and post-treatment endometrial samples. Samples will be scored on a continuous scale (0-100%) using the product of the intensity of cytoplasmic staining, and the proportion of cells staining based on the distribution of staining. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Immunohistochemical expression of Casp3 to assess tumor growth and apoptosis
Immunohistochemistry stains with antibodies directed against Casp3 to assess apoptosis will be performed on pre- and post-treatment endometrial samples. Samples will be scored by counting the number of positive staining nuclei per HPF. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.

Full Information

First Posted
July 27, 2018
Last Updated
March 14, 2023
Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03671811
Brief Title
Megestrol Acetate With or Without Pterostilbene in Treating Patients With Endometrial Cancer Undergoing Hysterectomy
Official Title
Open-Label Randomized Phase II Trial of Megestrol Acetate With or Without Pterostilbene in Patients With Endometrial Cancer Scheduled for Hysterectomy
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 21, 2019 (Actual)
Primary Completion Date
December 7, 2023 (Anticipated)
Study Completion Date
December 7, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial studies how well megestrol acetate with or without pterostilbene works in treating patients with endometrial cancer undergoing hysterectomy. Drugs used in chemotherapy, such as megestrol acetate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pterostilbene is an antioxidant found in blueberries or grapes, and it has been shown to be effective in killing tumor cells and reducing cancer burden. It is not yet known whether giving megestrol acetate with or without pterostilbene may work better in treating patients with endometrial cancer.
Detailed Description
PRIMARY OBJECTIVE: I. Determine the effect of megestrol acetate (MA) plus pterostilbene (PTE) versus MA alone on tumor proliferation (Ki-67) during the preoperative window in patients with endometrial cancer (EC) who are scheduled for hysterectomy. EXPLORATORY OBJECTIVES: I. Determine the effect of MA plus PTE versus MA alone on histologic response during the preoperative window in patients with EC or endometrial complex atypical hyperplasia who are scheduled for hysterectomy. II. Explore biological characteristics of tumors to determine potential biomarkers which could select for treatment eligibility in future studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive pterostilbene orally (PO) twice daily (BID) and megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity. ARM II: Patients receive megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity. After completion of study treatment, patients are followed up at 6 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Atypical Endometrial Hyperplasia, Endometrial Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
44 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (pterostilbene, megestrol acetate)
Arm Type
Experimental
Arm Description
Patients receive pterostilbene PO BID and megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity.
Arm Title
Arm II (megestrol acetate)
Arm Type
Experimental
Arm Description
Patients receive megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity.
Intervention Type
Drug
Intervention Name(s)
Megestrol Acetate
Other Intervention Name(s)
17-Hydroxy-6-methylpregna-4,6-diene-3,20-dione acetate, 17.alpha.-Acetoxy-6-methylpregna-4,6-diene-3,20-dione, 6-Dehydro-6-methyl-17.alpha.-acetoxyprogesterone, 6-Methyl-6-dehydro-17.alpha.-acetoxyprogesterone, BDH 1298, BDH-1298, Maygace, Megace, Megestat, Megestil, Niagestin, Ovaban, Pallace, SC-10363
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
Pterostilbene
Other Intervention Name(s)
3'',5''-Dimethoxy-4-stilbenol, 3,5-Dimethoxy-4''-hydroxystilbene, Trans-3,5-dimethoxy-4-hydroxystilbene
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Tumor Ki-67 proliferation index
Description
Ki-67 represents a specific nuclear marker for cell proliferation that is measured by staining with specific antibodies by immunohistochemical (IHC) staining. The Ki-67 proliferation index is defined as percent tumor cells staining positive, and measured on a continuous scale of 0-100%, with higher values indicating higher proliferation. We will compare treatment-associated change in Ki-67 proliferation index between the 2 study arms, using a 1-sided test with significance at p < 0.05. Ki-67 values will be assessed at two time-points during this study, prior to treatment with megace +/- pterostilbene (pre-treatment), and following completion of treatment (post-treatment). Using a generalized estimating equation to take into account the repeated assessment of subjects (pre and post treatment), analysis will use a generalized linear regression model of Ki-67 index. Adjustment for potential confounding factors will be made as appropriate.
Time Frame
Pre- and post-treatment up to 6 weeks
Secondary Outcome Measure Information:
Title
Histologic response of gland cellularity
Description
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). Gland cellularity will be assessed by counting the number of cells in one quarter of a high-power field (HPF) (average of 3 fields). This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Time Frame
Up to 6 weeks
Title
Histologic response of mitotic index
Description
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The mitotic index will be calculated as the number of mitoses per HPF (average of 3 fields). This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Time Frame
Up to 6 weeks
Title
Histologic response of metaplasia
Description
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The percentages of tumor that display squamous or mucinous metaplasia will be estimated as percentages, with < 10% considered negative and >= 10% as positive. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Time Frame
Up to 6 weeks
Title
Histologic response of eosinophilic cytoplasm
Description
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The percentages of tumor that display cytoplasmic eosinophilia will be estimated as percentages, with < 10% considered negative and >= 10% as positive. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Time Frame
Up to 6 weeks
Title
Immunohistochemical expression of Bcl-2 to assess tumor growth and apoptosis
Description
Immunohistochemistry stains with antibodies directed against Bcl-2 will be performed on pre- and post-treatment endometrial samples. Samples will be scored on a continuous scale (0-100%) using the product of the intensity of cytoplasmic staining, and the proportion of cells staining based on the distribution of staining. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Time Frame
Pre- and post-treatment up to 6 weeks
Title
Immunohistochemical expression of Casp3 to assess tumor growth and apoptosis
Description
Immunohistochemistry stains with antibodies directed against Casp3 to assess apoptosis will be performed on pre- and post-treatment endometrial samples. Samples will be scored by counting the number of positive staining nuclei per HPF. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms.
Time Frame
Pre- and post-treatment up to 6 weeks

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Documented informed consent of the participant and/or legally authorized representative Willing to undergo an intraoperative biopsy/or standard of care tissue collection during surgery, following completion of treatment with MA +/- PTE Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Histologically confirmed EC or complex atypical hyperplasia of the endometrium Candidate for a total hysterectomy with or without bilateral salpingo-oophorectomy About to initiate preoperative window period, with planned hysterectomy scheduled Platelets >= 100,000/mm^3 NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement Total bilirubin =< 1.5 X upper limit of normal (ULN) Aspartate aminotransferase (AST) =< 1.5 x ULN Alanine aminotransferase (ALT) =< 1.5 x ULN Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula Women of childbearing potential: negative urine or serum pregnancy test in premenopausal women. Postmenopausal women do not need to undergo a pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required Exclusion Criteria: Pterostilbene supplements within 30 days prior to day 1 of protocol therapy Any of the following phytochemical-based supplements within 30 days prior to day 1 of protocol therapy: resveratrol, genistein, and quercetin Chemotherapy for EC Allergic reaction/hypersensitivity to similar agents, excipients Unstable cardiac disease as defined by one of the following: Cardiac events such as myocardial infarction (MI) within the past 6 months NYHA (New York Heart Association) heart failure class III-IV Uncontrolled atrial fibrillation or hypertensive emergency/urgency (defined as systolic blood pressure >= 180 mmHg and/or diastolic blood pressure >= 120 mmHg) Active or history of recent thromboembolism or stroke, within the past 6 months Cushing's syndrome Acute infection requiring systemic (intravenous) treatment Known history of human immunodeficiency virus (HIV) infection Known active hepatitis B or C infection Inability to swallow tablets/capsules Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thanh H Dellinger
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States

12. IPD Sharing Statement

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Megestrol Acetate With or Without Pterostilbene in Treating Patients With Endometrial Cancer Undergoing Hysterectomy

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