Hormone Therapy in Preventing Endometrial Cancer in Patients With a Genetic Risk For Hereditary Nonpolyposis Colon Cancer

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00033358

Collaborator

(none)

Enrollment

Location

Arms

Study Details

Study Description

Brief Summary

Randomized phase II trial to compare two different hormone therapy regimens in preventing endometrial cancer in women who have a genetic risk for hereditary nonpolyposis colon cancer. Hormone therapy may prevent the development of endometrial cancer in women with a genetic risk for hereditary nonpolyposis colon cancer. It is not yet known which hormone therapy regimen is more effective in preventing endometrial cancer.

Condition or Disease	Intervention/Treatment	Phase
Endometrial Cancer	Drug: medroxyprogesterone Drug: ethinyl estradiol Drug: norgestrel Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

The primary objective is to evaluate the effect of progesterone therapy versus combination estrogen and progesterone therapy on potential surrogate endpoint biomarkers (SEBs) relevant to endometrial carcinogenesis.
To evaluate changes in histology and ultrasound appearance of the endometrium in women with HNPCC after 3 months of progesterone therapy versus combination estrogen and progesterone therapy compared with baseline.
To establish a point estimate of the baseline frequency of endometrial abnormalities looking at histological and molecular markers in a cohort of females carrying an HNPCC gene mutation.

OUTLINE: Patients are randomized to 1 of 2 arms.

All patients undergo a baseline transvaginal ultrasound and endometrial biopsy.

Arm I: Patients receive medroxyprogesterone intramuscularly once on day 1. Approximately 90 days after the injection, patients undergo a repeat transvaginal ultrasound and endometrial biopsy.

Arm II: Patients receive oral contraceptive pills (OCP) comprising ethinyl estradiol and norgestrel once daily on days 1-21. Treatment repeats every 28 days for 3-4 courses (3-4 packs of OCP) in the absence of unacceptable toxicity. Approximately 1 week after starting the fourth pack of OCP, patients undergo a repeat transvaginal ultrasound and endometrial biopsy.

Patients are followed at 6 weeks and are encouraged to return in 6 months to participate in continued endometrial screening.

Study Design

Study Type:

Interventional

Actual Enrollment :

52 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Modulation Of Putative Surrogate Endpoint Biomarkers In Endometrial Biopsies From Women With HNPCC

Study Start Date :

Feb 1, 2002

Actual Primary Completion Date :

Oct 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (medroxyprogesterone) Patients receive medroxyprogesterone intramuscularly once on day 1. Approximately 90 days after the injection, patients undergo a repeat transvaginal ultrasound and endometrial biopsy.	Drug: medroxyprogesterone Given intramuscularly Other Names: Depo-Provera medroxyprogesterone acetate MPA Provera Provera Dosepak Other: laboratory biomarker analysis Correlative studies
Experimental: Arm II (ethinyl estradiol, norgestrel) Patients receive OCP comprising ethinyl estradiol and norgestrel once daily on days 1-21. Treatment repeats every 28 days for 3-4 courses (3-4 packs of OCP) in the absence of unacceptable toxicity. Approximately 1 week after starting the fourth pack of OCP, patients undergo a repeat transvaginal ultrasound and endometrial biopsy.	Drug: ethinyl estradiol Given orally Other Names: Diogyn E EE Estinyl Ethinoral Eticylol Drug: norgestrel Given orally Other Names: Microlut NORGES Ovrette Wy-3707 Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Arm I (medroxyprogesterone)

Patients receive medroxyprogesterone intramuscularly once on day 1. Approximately 90 days after the injection, patients undergo a repeat transvaginal ultrasound and endometrial biopsy.

Drug: medroxyprogesterone

Given intramuscularly

Other Names:

Depo-Provera

medroxyprogesterone acetate

MPA

Provera

Provera Dosepak

Other: laboratory biomarker analysis

Correlative studies

Experimental: Arm II (ethinyl estradiol, norgestrel)

Patients receive OCP comprising ethinyl estradiol and norgestrel once daily on days 1-21. Treatment repeats every 28 days for 3-4 courses (3-4 packs of OCP) in the absence of unacceptable toxicity. Approximately 1 week after starting the fourth pack of OCP, patients undergo a repeat transvaginal ultrasound and endometrial biopsy.

Drug: ethinyl estradiol

Given orally

Other Names:

Diogyn E

Estinyl

Ethinoral

Eticylol

Drug: norgestrel

Given orally

Other Names:

Microlut

NORGES

Ovrette

Wy-3707

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

Change in potential SEBs relevant to endometrial carcinogenesis. [From baseline to completion of hormone therapy]

Secondary Outcome Measures

Changes in histology and ultrasound appearance of the endometrium in women with HNPCC [From baseline to 3 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

25 Years to 50 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Women with known mutation of an HNPCC-associated gene (hMLH-1, hMSH-2, or hMSH-6) or fulfill Amsterdam Criteria and have had one or more HNPCC-associated cancers
No prior hysterectomy; (participants may be scheduled for prophylactic hysterectomy following the study)
Voluntary consent documented by a signed and witnessed informed consent
Negative serum pregnancy test at baseline evaluation
No history of pelvic irradiation for whatever cause
No chemotherapy for two years
Women >= 40 must have had a screening mammogram within the last 12 months prior to participation in this study
Women who are at 50% risk of having a mutation and willing to have genetic testing

Exclusion Criteria:

Use of oral contraceptives or depoMPA or hormonal exposure, such as hormonal IUD, tamoxifen, raloxifene, or other selective estrogen receptor modulators (SERMs) within four months of initiating study; women will be asked to be off oral contraceptives or other hormonal exposure for 4 months prior to initiating study
Medical contraindication to use of oral contraceptives or depoMPA including:
Known or suspected pregnancy
Undiagnosed vaginal bleeding
Known or suspected malignancy of breast or endometrium
Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease
Gall bladder disease or liver dysfunction or disease, including hepatic adenomas or carcinoma, or abnormal liver function tests
Known hypersensitivity to depoMPA contraceptive injection (medroxyprogesterone acetate or any of its other ingredients)
Depression that is currently not under control, in the judgement of the Principal Investigator
History of epilepsy
History of diabetes
Coronary artery disease
Age >=35 and a current tobacco smoker
Known inability to participate in the scheduled follow-up tests (i.e., alcohol dependence or illicit drug use)
Significant medical history or psychiatric problems which would make the participant a poor protocol candidate, in the opinion of the principal investigator
Post surgical removal of both ovaries
Postmenopausal women with amenorrhea greater than 12 months
Previous history of endometrial biopsy, hysteroscopy, dilatation and curettage, or IUD in place within the past 3 months
Known participation in a concurrent protocol with a pharmacological intervention
Recent or concurrent use of systemic steroids (i.e. prednisone) within the past four months of initiating study
Positive serum pregnancy test at baseline evaluation
Fasting triglycerides level >= 400 mg/dl
Cholesterol level >= 240 mg/dl
LDL level >= 160 mg/dl
HDL level =< 35 mg/dl
Hypertension that is currently not under good control, in the judgement of the principal investigator