Evaluation of Metformin, Targeting Cancer Stem Cells for Prevention of Relapse in Gynecologic Patients

A Phase II Evaluation of Metformin, Targeting Cancer Stem Cells for the Prevention of Relapse in Patients With Stage IIC/III/IV Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

The primary objective of this study is to determine if metformin administered in combination with chemotherapy to women with advanced ovarian, primary peritoneal or fallopian tube cancer will improve recurrence-free survival at 18 months compared to controls.

Despite 70% remission rates with surgery and chemotherapy, the majority of patients with stage III/IV ovarian cancer will relapse and die of their disease. This is consistent with a cancer stem cell (CSC) model in which a few residual treatment resistant stem cells persist and initiate disease recurrence. Laboratory studies indicate therapies targeting CSC will greatly improve cancer outcomes. We have recently characterized a population of CSC in ovarian cancer. Importantly, similar to that observed in breast cancer, we have found that the diabetes drug metformin can restrict ovarian CSC growth and proliferation. In addition metformin increases tumor cell sensitivity to chemotherapy. Consistent with this, epidemiologic studies demonstrate that diabetic patients with ovarian cancer taking metformin have better outcomes than those not taking metformin. However, metformin has not been tested as an anti-cancer stem cell agent in ovarian cancer. Thus we propose to perform a phase II clinical trial using metformin as an anti-cancer stem cell agent in ovarian cancer patients. Patients who plan to receive primary surgical debulking will initiate metformin therapy prior to surgery and then continue after surgery along with chemotherapy. Patients who will be treated neoadjuvantly will initiate metformin with chemotherapy prior to surgery and then continue both metformin and chemotherapy after surgery. Tumor specimens will be acquired for all patients at the time of primary surgery. The primary objective of this study will be to determine if metformin improves the recurrence-free survival (RFS) of patients relative to historical controls. Secondary objectives of this study will be: (a) to compare the amount of CSC in primary tumor specimens in metformin treated patients versus matched controls from our tumor bank, (b) to determine if metformin improves overall survival relative to historical controls, (c) to confirm the safety of metformin in non-diabetic ovarian cancer patients, and (d) as laboratory studies indicate that metformin is most active in p53 mutant cells and p53 is mutated in ~50% of ovarian cancers, we will assess whether response rates correlate with p53 mutation status. If successful, this well tolerated FDA approved drug could be immediately translated into phase III trials and impact patient outcomes.

Inclusion Criteria:

1. Patients with potential diagnosis of ovarian, fallopian, or primary peritoneal cancer.

2. Care plan including surgical debulking and traditional adjuvant or neo-adjuvant chemotherapy (6-9 cycles of platinum and taxane based therapy).

3. Eastern Cooperative Oncology Group performance status 0-2.

4. Age > 18 years or < 80 years.

5. Adequate renal function (serum creatinine <1.4mg/dL).

6. Adequate liver function (bilirubin < 1.5 times ULN).

   • Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) < 5 times the upper limit of normal in case of liver metastases.
   • ALT or AST < 2.5 times the ULN in absence of liver metastases.

7. Ability to understand and complete written informed consent.

8. Mentally, physically, and geographically able to undergo treatment and follow up.

Exclusion Criteria:

1. Patients diabetes mellitus. (Patients with only a history of gestational diabetes will be allowed to be included in the study.)
2. Metformin use in the last 6 months.
3. A known hypersensitivity to metformin.
4. A history of metabolic acidosis, including ketoacidosis or increased risk of lactic acidosis.
5. Pregnancy or Lactation.
6. Patients who have any severe and/or uncontrolled medical conditions.
7. Patients with a history of renal disease.
8. Patients with other known active malignancy (excluding adequately treated basal cell / squamous cell skin cancer, in situ cancer, or other cancer for which the patient has been disease free for 2 years).
9. Patients receiving any other investigational agents.