Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Conditions
Keywords
Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Brief summary
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.
Detailed description
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.
Interventions
DRUGMetformin
Patients receiving primary surgical debulking followed by adjuvant chemotherapy will initiate metformin prior to primary surgery. Following surgery patients will be initiated on metformin prior to the initiation of chemotherapy. Patients treated with neoadjuvant chemotherapy will be initiated on metformin prior to the initiation of chemotherapy. Following surgery patients will be initiated on metformin prior to the re-initiation of chemotherapy.
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
19 Years to 79 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-Free Survival | 18 months | Determine the percentage of patients alive without recurrence at 18 months. Investigators will also determine recurrence free survival when patients with persistent disease are excluded. Definition of progression or recurrence and survival will be defined as increasing clinical, radiological or histological evidence of disease since study entry or two serum values of CA-125 greater than or equal to two times the upper limits of normal (ULN) performed at least one week apart, regardless of CT scan results. Recurrence-Free Interval will be defined as date from start of chemotherapy to the date of first clinical, biochemical, or radiological evidence of progression or death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 3 Years | Determine the median overall survival time for all patients who complete treatment as well as for patients presenting with stage IIc/ III and stage IV ovarian cancer. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin Metformin: Patients receiving primary surgical debulking followed by adjuvant chemotherapy will initiate metformin prior to primary surgery. Following surgery patients will be initiated on metformin prior to the initiation of chemotherapy.
Patients treated with neoadjuvant chemotherapy will be initiated on metformin prior to the initiation of chemotherapy. Following surgery patients will be initiated on metformin prior to the re-initiation of chemotherapy. | 90 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible after treatment start | 40 |
| Overall Study | Noncompliance | 3 |
| Overall Study | Patient choice | 3 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Metformin |
|---|---|
| Age, Continuous | 58 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 69 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 19 Participants |
| Sex: Female, Male Female | 90 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 90 |
| other Total, other adverse events | 40 / 90 |
| serious Total, serious adverse events | 26 / 90 |
Outcome results
Primary
Recurrence-Free Survival
Determine the percentage of patients alive without recurrence at 18 months. Investigators will also determine recurrence free survival when patients with persistent disease are excluded. Definition of progression or recurrence and survival will be defined as increasing clinical, radiological or histological evidence of disease since study entry or two serum values of CA-125 greater than or equal to two times the upper limits of normal (ULN) performed at least one week apart, regardless of CT scan results. Recurrence-Free Interval will be defined as date from start of chemotherapy to the date of first clinical, biochemical, or radiological evidence of progression or death due to any cause.
Time frame: 18 months
Population: 90 patients were enrolled, only 38 completed treatment and were analyzed. Patients found to have persistent disease were censored at the time they were found to have progressive disease. 11 patients had persistent disease.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin - All Patients Analyzed | Recurrence-Free Survival | 58.1 percentage of patients |
| Metformin - Patients With Persistent Disease Excluded | Recurrence-Free Survival | 55.6 percentage of patients |
Secondary
Overall Survival
Determine the median overall survival time for all patients who complete treatment as well as for patients presenting with stage IIc/ III and stage IV ovarian cancer.
Time frame: Up to 3 Years
Population: 90 patients were enrolled and only 38 patients completed treatment. 25 of the 38 patients had stage IIc/III ovarian cancer. 13 of the 38 patients had stage IV ovarian cancer.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metformin - All Patients Analyzed | Overall Survival | 43 months |
| Metformin - Patients With Persistent Disease Excluded | Overall Survival | 52 months |
| Metformin - Patients With Stage IV Ovarian Cancer | Overall Survival | 36 months |