A Randomized Placebo Controlled Phase II Trial of Metformin in Conjunction With Chemotherapy Followed by Metformin Maintenance Therapy in Advanced Stage Ovarian, Fallopian Tube and Primary Peritoneal Cancer
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 110
- 试验地点
- 10
- 主要终点
- Progression free survival (PFS) evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and Gynecological Cancer Intergroup (GCIG) criteria
研究概览
简要总结
This randomized phase II trial studies how well metformin hydrochloride and combination chemotherapy works in treating patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer. Drugs used in chemotherapy, such as carboplatin, paclitaxel and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Metformin hydrochloride may help carboplatin, paclitaxel and docetaxel work better by making tumor cells more sensitive to the drugs. Studying samples of blood and tissue in the laboratory from patients receiving metformin hydrochloride may help doctors learn more about the effects of metformin hydrochloride on cells. It may also help doctors understand how well patients respond to treatment. Giving metformin hydrochloride together with combination chemotherapy may kill more tumor cells.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Metformin plus chemotherapy
Patients receive metformin hydrochloride PO BID and standard chemotherapy for 6 -8 cycles. Treatment with metformin hydrochloride continues for up to 2 years in the absence of disease progression or unacceptable toxicity.
干预措施: metformin hydrochloride (Drug)
Metformin plus chemotherapy
Patients receive metformin hydrochloride PO BID and standard chemotherapy for 6 -8 cycles. Treatment with metformin hydrochloride continues for up to 2 years in the absence of disease progression or unacceptable toxicity.
干预措施: Chemotherapy (Drug)
Placebo plus chemotherapy
Patients receive placebo PO BID and standard chemotherapy for 6 -8 cycles. Treatment with placebo continues for up to 2 years in the absence of disease progression or unacceptable toxicity.
干预措施: placebo (Drug)
Placebo plus chemotherapy
Patients receive placebo PO BID and standard chemotherapy for 6 -8 cycles. Treatment with placebo continues for up to 2 years in the absence of disease progression or unacceptable toxicity.
干预措施: Chemotherapy (Drug)
结局指标
主要结局
Progression free survival (PFS) evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and Gynecological Cancer Intergroup (GCIG) criteria
时间窗: Time from randomization until disease progression or death from any cause, assessed up to 2 years
Kaplan-Meier curves will be generated and the metformin and placebo groups compared using a logrank test stratified by initial treatment (primary debulking surgery or neoadjuvant therapy). A one-sided alpha level of 0.15 will be used to determine statistical significance. Median PFS and associated 90% confidence interval will be estimated using the method described in Brookmeyer and Crowley. A Cox regression model will also be fit to assess and adjust for the effects of the stratification factor and other baseline covariates (for example, age, ECOG performance status).
次要结局
- Time to biochemical (CA-125) progression using GCIG criteria(Up to 2 years)
- Overall survival(Up to 2 years)
- Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0(Up to 2 years)