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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

Phase 2
19 Years
79 Years
Open (Enrolling)
Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

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Trial Information

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

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 therpay prior to surgery and then continue after surgrey along with chemotherapy.
Patients who will be treated neoadjuvantly will initiate metformin with chemtherapy prior to
sugrery and then continue both metformin and chemotherpy 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

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

3. ECOG 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).

- ALT or AST < 5X ULN in case of liver metastases.

- ALT or AST < 2.5X 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

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.

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Improved Recurrence-Free Survival

Outcome Description:

Determine if metformin administered in combination with chemotherapy to women with advanced ovarian, primary peritoneal or fallopian tube cancer will improve recurrence-free survival (RFS) at 18 months compared to historical controls.

Outcome Time Frame:

5 years

Safety Issue:


Principal Investigator

Ronald J. Buckanovich, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Michigan


United States: Institutional Review Board

Study ID:

UMCC 2011.037



Start Date:

October 2011

Completion Date:

October 2016

Related Keywords:

  • Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
  • Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
  • Peritoneal Neoplasms



University of MichiganAnn Arbor, Michigan  48109-0624