Hormone Therapy in Preventing Endometrial Carcinogenesis (Cancer) in Women With a Genetic Risk For Hereditary Nonpolyposis Colon Cancer

Official Title: “Modulation Of Putative Surrogate Endpoint Biomarkers In Endometrial Biopsies From Women With HNPCC”

RATIONALE: Hormone therapy may prevent the development of endometrial carcinogenesis (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.

PURPOSE: 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.

OBJECTIVES: - Compare the effect of medroxyprogesterone vs ethinyl estradiol and norgestrel on potential surrogate endpoint biomarkers relevant to endometrial carcinogenesis in women with a known hereditary non-polyposis colon cancer (HNPCC)-associated gene mutation or HNPCC-associated cancer(s). - Compare the 3-month changes in histology and ultrasound appearance of the endometrium in patients treated with these preventive regimens.

OUTLINE: This is a randomized, multicenter study. 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.

PROJECTED ACCRUAL: A total of 44 patients (22 per arm) will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: Ethinyl estradiol
  • Given orally once daily as part of oral contraceptive pills (OCP) on days 1-21
• Drug: Medroxyprogesterone
  • Intramuscularly injection once on day 1.
• Drug: Norgestrel
  • Given orally once daily as part of oral contraceptive pills (OCP) on days 1-21; repeats every 28 days for 3-4 courses (3-4 packs of OCP) in the absence of unacceptable toxicity.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Arm I
  • Medroxyprogesterone intramuscularly once on Day 1.
• Experimental: Arm II
  • Oral contraceptive pills (OCP) comprising ethinyl estradiol and norgestrel once daily on days 1-21.

Primary Measures

• Frequency of endometrial abnormalities by histology at baseline
  • Time Frame: At Baseline (Day 1)
    Safety Issue?: No

Secondary Measures

• Changes in histology and ultrasound appearance at 3 months
  • Time Frame: 3 Months
    Safety Issue?: No
• Changes in surrogate endpoint biomarkers at 3 months
  • Time Frame: 3 Months
    Safety Issue?: No

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.
• Age >/= 25 and </= 50.
• 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.

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 25 Years

Maximum Age for this Clinical Trial: 50 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: M.D. Anderson Cancer Center Other

Overall Clinical Trial Officials and Contacts

Karen H. Lu, MD Study Chair M.D. Anderson Cancer Center  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00033358

Study ID Number: ID01-340

ClinicalTrials.gov Identifier: NCT00033358

Health Authority: United States: Food and Drug Administration

Clinical trial summary from the National Cancer Institute's PDQ® database

UT MD Anderson Cancer Center Website