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.

Study Type: Interventional

Study Design: Prevention, Randomized, Active Control

Study Primary Completion Date: June 2008

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
• Drug: medroxyprogesterone
  • Given by injection
• Drug: norgestrel
  • Given orally

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 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.
• Experimental: 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.

Primary Measures

• Frequency of endometrial abnormalities by histology at baseline
  • Safety Issue?: No

Secondary Measures

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

DISEASE CHARACTERISTICS:

• Meets criteria for 1 of the following:
• Known hereditary non-polyposis colon cancer (HNPCC)-associated mutation of MLH1, MSH2, MSH3, MSH6, PMS1, or PMS2 identified by gene sequencing
• Fulfills Amsterdam criteria with 1 or more HNPCC-associated cancers
• No known or suspected malignancy of the breast or endometrium
• Must have had a screening mammogram within the past 12 months if age 40 or over

PATIENT CHARACTERISTICS:

Age:

• 25 to 50

Sex:

• Female

Menopausal status:

• No postmenopausal patients with amenorrhea for more than 1 year

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• No liver dysfunction or disease (e.g., hepatic adenomas or carcinoma)
• Liver function tests normal

Renal:

• Not specified

Cardiovascular:

• No active thrombophlebitis
• No prior or concurrent thromboembolic disorders or cerebrovascular disease
• No concurrent hypertension that is not well controlled
• No coronary artery disease

Other:

• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during the first month of study therapy
• No undiagnosed vaginal bleeding
• No gallbladder disease
• No hypersensitivity to medroxyprogesterone contraceptive injection
• No concurrent uncontrolled depression
• No prior or concurrent epilepsy
• No prior or concurrent diabetes
• No tobacco smoking for patients age 35 to 50
• No alcohol dependence or illicit drug use
• No other significant medical history or psychiatric problems that would preclude study participation
• Fasting triglycerides no greater than 400 mg/dL
• Cholesterol no greater than 240 mg/dL
• Low-density lipoprotein (LDL) no greater than 160 mg/dL
• High-density lipoprotein (HDL) at least 35 mg/dL

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• At least 2 years since prior chemotherapy

Endocrine therapy:

• At least 4 months since prior oral contraceptives, medroxyprogesterone, or other hormonal exposure (e.g., hormonal intrauterine device, tamoxifen, raloxifene, or other selective estrogen receptor modulators)
• At least 4 months since prior systemic steroids (e.g., prednisone)
• No concurrent systemic steroids (e.g., prednisone)

Radiotherapy:

• No prior pelvic irradiation

Surgery:

• At least 3 months since prior endometrial biopsy, hysteroscopy, dilation and curettage, or placement of an intrauterine device
• No prior hysterectomy (patients may be scheduled for a prophylactic hysterectomy)
• No prior bilateral oophorectomy

Other:

• No other concurrent participation in a protocol with pharmacological intervention

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 Sponsor: M.D. Anderson Cancer Center

Overall Clinical Trial Officials and Contacts

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

Information obtained from ClinicalTrials.gov on August 29, 2008

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

Study ID Number: CDR0000069277

ClinicalTrials.gov Identifier: NCT00033358

Health Authority: United States: Federal Government

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