The Impact of Obesity and Obesity Treatments on Breast Cancer

Condition(s) targeted: Breast Cancer

Intervention: Exemestane (Drug); Avandamet (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Francisco J. Esteva, MD, PhD, Study Chair, Affiliation: UT MD Anderson Cancer Center

Overall contact:
Francisco J. Esteva, MD, PhD, Phone: 713-792-2817

Primary Objectives:

- To identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the

exemestane plus metformin/rosiglitazone combination (phase I).

Secondary Objectives:

- To determine the pharmacokinetics of exemestane in combination with metformin and

rosiglitazone (Avandamet).

- To determine the nature and degree of toxicity of this triple-drug combination.

Official title: The Impact of Obesity and Obesity Treatments on Breast Cancer: A Phase I Trial of Exemestane With Metformin and Rosiglitazone for Postmenopausal Obese Women With ER+ Metastatic Breast Cancer

Study design: Treatment, Randomized, Open Label, Single Group Assignment, Safety/Efficacy Study

Primary outcome: Dose-limiting toxicity (DLT)

Detailed description: The Study Drugs:

Exemestane decreases the ability of estrogen to help cancer cells grow. This could cause the cancer cells to die.

Avandamet contains two drugs commonly used to control blood sugar levels in patients with diabetes (metformin and rosiglitazone).

Screening Tests:

Before you can start treatment on this study, you will have "screening tests" to help the doctor decide if you are eligible to take part in this study. The following tests and procedures will be performed:

- Your complete medical history will be recorded.

- You will be asked about any drugs you may have taken or may be taking.

- You will have a physical exam, including measurement of your vital signs (temperature,

breathing rate, heart rate, and blood pressure), height, and weight.

- You will be asked how well you are able to perform the normal activities of daily

living (performance status evaluation).

- Blood (about 3-4 teaspoons) will be drawn for routine tests.

- Blood (about 1-2 teaspoons) will be drawn for blood sugar tests. If you have a history

of diabetes, for 8 hours before these blood sugar tests, you will need to "fast" (have nothing to eat or drink except water).

- You will have an electrocardiogram (ECG--test that measures the electrical activity of

the heart).

- You will have magnetic resonance imaging (MRI) scans, positron emission tomography

(PET) scans, computed tomography (CT) scans, and/or x-rays to check the status of the disease.

- You will have a bone scan to check your bones for cancer. If the bone scan shows that

there is cancer in the bone, you will have an x-ray, CT, or MRI to confirm that the cancer has spread to the bone.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups. You will have an equal chance of being assigned to either group. If you are in Group 1, you will take exemestane alone. Exemestane alone is the standard-of-care treatment for the disease. If you are in Group 2, you will take exemestane plus Avandamet.

If you are in Group 2, the dose of Avandamet you receive will depend on when you joined this study. The first group of participants will receive the lowest dose level of Avandamet. Each new group will receive a higher dose of Avandamet than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of Avandamet is found.

All participants will receive the same dose level of exemestane.

Study Drug Administration:

The study drug(s) will be given in 28-day "cycles."

If you are in Group 1, you will take an exemestane tablet by mouth every day.

If you are in Group 2, you will take an exemestane tablet by mouth every day. You will also take tablets of Avandamet by mouth 1 or 2 times a day depending on the dose level to which you are assigned. You should take Avandamet at meals.

Study Visits:

On Day 1 of each cycle, the following tests and procedures will be performed:

- You will have a physical exam, including a measurement of you weight and height.

- Your medical history will be recorded.

- You will be asked about any side effects you may be having.

- You will be asked about any drugs you may have taken or may be taking.

- You will have a performance status evaluation.

- Blood (about 1-2 teaspoons) will be drawn for routine tests. This blood draw can be

done up to 3 days before each cycle.

- Blood (about 1 teaspoons) will be drawn for blood sugar tests. If you have a history of

diabetes, you will need to fast for 8 hours before these blood sugar tests.

Every 2 cycles, you will have scans to check the status of the disease. The scan performed will depend on where the disease is located in the body.

Additional Blood Tests:

- Blood (about 3 teaspoons each time) will be drawn to measure proteins and tumor cells

in the blood at the following time points:

- Before you take the study drug on Day 1 of Cycles 1, 2, and 5.

- Day 1 of every fourth cycle from then on (Cycles 9, 13, and so on).

- At the time you are taken off study.

Blood (about 1 teaspoon each time) will also be drawn for pharmacokinetic (PK) testing. PK testing measures the amount of study drug(s) in the body at different time points. Blood will be drawn for PK testing before you take the study drug(s) and 1, 3, 6, 12, and 23 hours after you take the study drug(s) on Days 1, 8, and 15 of Cycle 1.

Length of Study:

You may take the study drug(s) for as long as the disease is stable and/or responding. You may be taken off study if the disease gets worse or intolerable side effects occur.

This is an investigational study. Exemestane and Avandamet are FDA approved and commercially available. Exemestane is approved for the treatment of metastatic breast cancer. Avandamet is approved for the treatment of diabetes. The use of this drug combination is investigational.

Up to 24 patients will take part in this study. All will be enrolled at M. D. Anderson.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

Inclusion Criteria:

1. Postmenopausal obese women with a history of biopsy-proven ER+, HER2-negative breast cancer and clinical evidence of metastatic disease. Obesity is defined as BMI greater than 30 kg/m^2. Postmenopausal status is defined by one of the following: a.) no spontaneous menses for over 1 year, in women > 55 years: b.) no spontaneous menses within the past 1 year in women < 55 years with postmenopausal gonadotrophin levels (LH and FSH levels > 40 IU/L) or postmenopausal estradiol levels (< 27 ng/dl); or c) bilateral oophorectomy.

2. Prior antiestrogens and non-steroidal aromatase inhibitors are allowed, either in the adjuvant setting or for metastatic breast cancer. Patients may have received chemotherapy in the adjuvant setting. Only 1 prior chemotherapy is allowed in the metastatic setting.

3. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as >/= 10 mm with conventional techniques. Bone metastases are eligible provided there is a measurable site of bone metastasis >/= 10 mm that can be followed by MRI or CT scan. Pleural or peritoneal effusions will not be accepted as measurable disease.

4. Localized radiotherapy, which does not influence the signal of evaluable lesion, is allowed prior to the initiation of study medications.

5. Performance status 6. Absolute neutrophil count (ANC) >/= 1000/µl, platelets >/= 75,000/µl, hemoglobin >/= 8. 5 gm/dL; serum creatinine < 2. 0 mg/dL; bilirubin < 1. 8 mg/dL; sGPT <3 x normal; alkaline phosphatase < 3 x normal; calcium 7. Patients must be competent to give informed consent and to state that they understand the investigational nature of the proposed treatment.

Exclusion Criteria:

1. Prior treatment with exemestane, metformin or rosiglitazone.

2. Extensive radiotherapy within previous 4 weeks (greater than or equal to 30% of marrow-bearing bone, e. g., whole pelvis or half spine).

3. Uncontrolled diabetes mellitus (hemoglobin A1C > 9 or random plasma glucose > 400 mg/dL).

4. History of acromegaly, Cushing's syndrome, Cushing's disease, Addison's disease (treated or untreated).

5. Patients with unstable angina, uncontrolled ischemic cardiac disease or symptomatic congestive heart failure (e. g. Class III or IV New York Heart Association's Functional Classification).

6. Other concurrent malignant disease with the exception of cone-biopsied in situ carcinoma of the cervix/uterus, or adequate treated basal or squamous cell carcinoma of the skin, or other curable cancer, e. g. Hodgkin's disease or non-Hodgkin's lymphoma, provided 5 years have elapsed from completion of therapy, and there has been no recurrence.

7. Any intercurrent systemic anti-cancer therapy after prior non-steroidal AI therapy.

8. Concurrently receiving and are unwilling to discontinue hormonal (estrogen with or without progesterone) replacement therapy.

9. Other investigational drugs within the past 3 weeks or concurrently.

10. Patients with known chronic liver disease (i. e., chronic active hepatitis, and cirrhosis).

11. Laboratory results sustained at: International normalized ratio (INR) > 1. 6; ALT or AST > 2. 5 x ULN if no demonstrable liver metastases or > 5 x ULN in presence of liver metastasis; No more than 3 retests within screening period

12. Patients with known diagnosis of human immunodeficiency virus (HIV) infection.

13. Patients who received chemotherapy within 4 weeks (6 weeks for nitrosourea or mitomycin-C)

14. Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol e. g., severe renal or hepatic impairment or currently unstable or uncompensated respiratory or cardiac conditions.

15. History of hypersensitivity to active or inactive excipients of the study medications

- exemestane, metformin or rosiglitazone.

16. Presence of life-threatening metastatic visceral disease, defined as extensive hepatic involvement, or any degree of brain or leptomeningeal involvement (past or present), or symptomatic pulmonary lymphangitic spread. Subjects with discrete pulmonary parenchymal metastases are eligible, provided their respiratory function is not compromised as a result of disease.

Francisco J. Esteva, MD, PhD, Phone: 713-792-2817

UT MD Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting
Francisco J. Esteva, MD, PhD, Principal Investigator

UT MD Anderson Cancer Center website

Starting date: July 2009
Last updated: July 6, 2009