Metformin and Chemotherapy in Treating Patients With Stage III-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

PRIMARY OBJECTIVES:

I. To determine if the addition of metformin to standard adjuvant or neoadjuvant chemotherapy
plus extended metformin (metformin hydrochloride) beyond standard chemotherapy increases
progression free survival when compared to 6 cycles of standard chemotherapy alone in
non-diabetic subjects with stage III (with any gross residual disease) or stage IV ovarian,
primary peritoneal, or fallopian tube carcinoma.

SECONDARY OBJECTIVES:

I. To determine whether the addition of metformin to standard chemotherapy plus extended
metformin beyond standard chemotherapy increases the time to biochemical progression when
compared to chemotherapy alone.

II. To compare biochemical (cancer antigen [CA]-125) response rates in the two arms.

III. To describe and compare toxicities in the two arms. IV. To compare overall survival in
both arms.

TERTIARY OBJECTIVES:

I. To elucidate metformin's molecular mechanism of action in ovarian, fallopian tube or
primary peritoneal cancer by: determining whether metformin's anti-cancer effects are
mediated by systemic metabolic changes, a direct effect on tumor cells, or both, and testing
the metabolic and proteomic alterations induced in biospecimens from non-diabetic patients
prospectively treated with standard chemotherapy in conjunction with metformin compared to
placebo.

OUTLINE:

Patients receive a standard chemotherapy regimen at the discretion of the treating physician.
Regimens include either paclitaxel intravenously (IV) over 2-3 hours and carboplatin IV over
30-60 minutes on day 1; docetaxel IV over 1 hour on and carboplatin IV over 30-60 minutes on
day 1; or paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30-60
minutes on day 1. Treatment repeats every 21 days for up to 6 courses. Patients are
randomized to 1 of 2 treatment arms.

ARM I: Patients receive metformin hydrochloride orally (PO) twice daily (BID) and standard
chemotherapy regimen as above for 6 courses. Treatment for metformin hydrochloride continues
for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO BID and standard chemotherapy regimen as above for 6
courses. Treatment for placebo continues for up to 2 years in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2 years.

Inclusion Criteria:

ELIGIBILITY CRITERIA FOR PRE-REGISTRATION

- A reasonable suspicion of ovarian cancer by the treating oncologist is required,
evidenced by abdominal carcinomatosis, omental caking, pleural effusions or ascites
AND an elevated CA125 > 250 OR CA125:carcinoembryonic antigen (CEA) ratio > 25 OR
CA125 =< 250 with no evidence of gastrointestinal (GI) cancer

- Aged 18 years or older

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< upper normal institutional limits (except for patients with
Gilbert's disease who are eligible despite elevated serum bilirubin level)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.0 × institutional upper limit of normal

- Creatinine =< institutional upper limit of normal (ULN) OR creatinine clearance >= 60
mL/min/1.73 m^2

- Blood glucose =< 126 mg/dL fasting or =< 140 mg/dL nonfasting

- Signed written pre-registration informed consent document

ELIGIBILITY CRITERIA FOR REGISTRATION:

- Histologically confirmed carcinoma consistent with ovarian, fallopian tube, or primary
peritoneal carcinoma

- Subjects undergoing primary debulking surgery must have stage III or IV disease and
have undergone surgery to include, at a minimum, removal of the uterus, ovaries and
fallopian tubes; these patients may be optimally debulked (less than 1 cm residual
disease) but must have grossly visible macroscopic residual disease OR be suboptimally
debulked

- Subjects for whom neoadjuvant chemotherapy followed by interval cytoreductive surgery
is planned must have fine needle aspirate (FNA) or other cytology showing
adenocarcinoma OR core biopsies OR surgically directed biopsies showing adenocarcinoma
AND CA125 over 250 OR CA125:CEA ratio > 25 OR CA =< 250 with no evidence of GI cancer;
they should have presumed stage III or IV disease, generally based on abdominal
carcinomatosis, omental caking, pleural effusions or ascites

- Subject and her physician must agree to six cycles or up to 8 cycles of one of the
standard of care regimens allowed on this protocol; these regimens (starting dosage)
include:

If < 70 years old:

- IV paclitaxel 175 mg/m^2 and carboplatin area under the curve (AUC) 5-6 every 21 days

- IV docetaxel 75 mg/m^2 and carboplatin AUC 5-6 every 21 days

- IV paclitaxel 80 mg/m^2 day 1, 8, and 15 and carboplatin AUC 5-6 day 1 every 21 days

If 70 years or older:

- IV paclitaxel 135 mg/m^2 plus IV carboplatin AUC 5 plus optional G-CSF every 21 days

- IV paclitaxel 60 mg/m^2 day 1, 8, 15 plus IV carboplatin AUC 5 every 21 days (Day 15
paclitaxel optional)

- IV paclitaxel 60 mg/m^2 plus IV carboplatin AUC 2 day 1, 8, and 15 every 21 days

- ECOG performance status =< 2

- Leukocytes >= 3,000/mcL

- absolute neutrophil count >= 1,500/mcL

- platelets >= 100,000/mcL

- total bilirubin =< upper normal institutional limits (except for patients with
Gilbert's disease who are eligible despite elevated serum bilirubin level)

- AST(SGOT)/ALT(SGPT) =< 2.0 × institutional upper limit of normal

- creatinine =< OR institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2

- blood glucose =< 126 mg/dL fasting or =< 140 mg/dL nonfasting

- women of child-bearing potential must agree to use an effective method of birth
control on trial, as the safety of metformin in pregnancy has not been
established; an effective method of birth control includes surgical sterilization
of woman or her partner, abstinence, or two barrier methods (e.g. condom plus
diaphragm); hormonal methods of birth control are not permitted on this study

- ability to understand and the willingness to sign a written informed consent
document

Exclusion Criteria:

EXCLUSION CRITERIA FOR PRE-REGISTRATION

- Subjects with known diabetes and those taking metformin, sulfonylureas,
thiazolidinediones or insulin for any reason

- Patients who are receiving any other investigational agents

- Subjects with comorbidities that would limit their two year survival for reasons other
than ovarian cancer

- Concurrent active invasive malignancy or one previously diagnosed with a greater than
30% chance of recurrence in the next two years

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to metformin

- Subjects must not have conditions associated with increased risk of
metformin-associated lactic acidosis, including New York Heart Association class III
or IV congestive heart failure, history of acidosis of any type, alcoholic liver
disease, or habitual intake of 3 or more alcoholic beverages per day

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
major infection, unstable angina pectoris, or psychiatric illness/social situations
that would limit compliance with study requirements

- Pregnant or nursing women

EXCLUSION CRITERIA FOR REGISTRATION:

- mucinous adenocarcinoma, borderline tumors

- subjects who will undergo intraperitoneal chemotherapy

- subjects receiving neoadjuvant chemotherapy for whom interval debulking surgery
(assuming adequate response to therapy) is not planned

- subjects receiving chemotherapy regimens not specified in the inclusion criteria

- subjects should not be participating in other clinical trials of interventions
designed to reduce risk of ovarian cancer recurrence or plan to receive off -protocol
maintenance therapy (e.g. paclitaxel or bevacizumab)

- subjects with known diabetes, fasting glucose over 126 mg/dL or random glucose over
140 mg/dL and those taking metformin, sulfonylureas, thiazolidenediones or insulin for
any reason

- patients who are receiving any other investigational agents

- subjects with comorbidities which would lead to a clinical expectation that they will
not survive two years for reasons other than ovarian cancer

- concurrent active invasive malignancy or one previously diagnosed with a greater than
30% chance of recurrence in the next two years

- history of allergic reactions attributed to compounds of similar chemical or biologic
composition to metformin

- subjects must not have conditions associated with increased risk of
metformin-associated lactic acidosis, including New York Heart Association class III
or IV congestive heart failure, history of acidosis of any type, alcoholic liver
disease, or habitual intake of 3 or more alcoholic beverages per day

- uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- pregnant or nursing women