Endometrial Adenocarcinoma, Endometrial Clear Cell Adenocarcinoma, Endometrial Serous Adenocarcinoma, Endometrial Undifferentiated Carcinoma, Recurrent Uterine Corpus Carcinoma, Stage IIIA Uterine Corpus Cancer AJCC v7, Stage IIIB Uterine Corpus Cancer AJCC v7, Stage IIIC Uterine Corpus Cancer AJCC v7, Stage III Uterine Corpus Cancer AJCC v7, Stage IVA Uterine Corpus Cancer AJCC v7, Stage IVB Uterine Corpus Cancer AJCC v7, Stage IV Uterine Corpus Cancer AJCC v7
Conditions
Brief summary
This randomized phase II/III trial studies how well paclitaxel, carboplatin, and metformin hydrochloride works and compares it to paclitaxel, carboplatin, and placebo in treating patients with endometrial cancer that is stage III, IV, or has come back. Drugs used in chemotherapy, such as paclitaxel and carboplatin, 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 paclitaxel and carboplatin work better by making cancer cells more sensitive to the drugs. It is not yet known whether paclitaxel and carboplatin is more effective with or without metformin hydrochloride in treating endometrial cancer.
Detailed description
PRIMARY OBJECTIVES: I. To determine if the addition of metformin (metformin hydrochloride) to the standard regimen of carboplatin and paclitaxel prolongs progression-free survival (PFS) in women with advanced or recurrent endometrial cancer. (Phase II) II. To determine if the addition of metformin to the standard regimen of carboplatin and paclitaxel prolongs overall survival (OS) in the same population if a phase III study is conducted. Both clinical trials (Phase II and III) will utilize OS as a primary endpoint if a phase III trial is opened. SECONDARY OBJECTIVES: I. To estimate the proportion of patients with objective response (response rate \[RR\]) in the population of patients with measurable disease by treatment. II. To estimate the duration of response in the population of patients with measurable disease who respond by treatment. III. To estimate overall survival (OS) and relative hazards of death for each treatment arm if the study stops after the phase II trial is completed. If the study continues with a phase III clinical trial, then PFS will be a secondary endpoint. IV. To determine the nature, frequency and degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) for each treatment arm. V. To estimate possible differences in RR, PFS, OS, and toxicity rates for the treatment regimens by the patients' level of obesity. TERTIARY OBJECTIVES: I. To test whether PIK3CA mutations/amplifications, PTEN mutations or PIK3R1/PIK3R2 mutations have a lower hazard of progression or death (PFS endpoint) among patients who are treated with metformin. II. To test whether higher expression of MATE 2 is associated with a lower hazard of progression or death (PFS endpoint) among patients who are treated with metformin. III. To explore the association of metabolic factors (i.e. body mass index \[BMI\], hip-to-waist ratio, diabetes status, hemoglobin A1c \[HgbA1C\], fasting insulin and glucose levels, homeostatic model assessment \[HOMA\] scores) with treatment response to metformin/paclitaxel/carboplatin, PFS, and OS. IV. To test whether genomic profiles (i.e. PIK3CA mutations/amplifications, PTEN mutations or PIK3R1/PIK3R2 mutations) differ between the tumors of obese and non-obese endometrial cancer (EC) patients. V. To correlate expression of key targets of the insulin/IGF-1/mTOR signaling pathway (p-IGF1R, p-S6 and p-4EBP-1) with treatment response to metformin/paclitaxel/carboplatin, PFS, OS and obesity status. VI. To determine if the genetic variants of the metformin transporters correspond with treatment response to metformin/paclitaxel/carboplatin, PFS and OS. VII. To estimate differences in physical functioning, physical activity, and fatigue between treatment arms. VIII. To explore the association between metabolic factors (i.e., BMI, hip-to-waist ratio, diabetes status, HgbA1C, fasting insulin and glucose levels, HOMA scores) and physical functioning, physical activity, and fatigue. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours on day 1, carboplatin IV over 30 minutes on day 1, and metformin hydrochloride orally (PO) twice daily (BID) (approximately 10-12 hours apart) on days 1-21 (once daily \[QD\] in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising metformin hydrochloride PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive paclitaxel IV and carboplatin IV as in Arm I. Patients also receive placebo PO BID (approximately 10-12 hours apart) on days 1-21 (QD in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising placebo PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. In both arms, patients who achieve stable disease (SD) or partial response (PR) and still have measurable disease at the completion of course 6 may continue to receive paclitaxel IV and carboplatin IV (with metformin hydrochloride or placebo) for an additional 4 courses at the discretion of the treating investigator. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Interventions
DRUGCarboplatin
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMetformin Hydrochloride
Given PO
DRUGPaclitaxel
Given IV
OTHERPlacebo Administration
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Gynecologic Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have measurable stage III, measurable stage IVA, stage IVB (with or without measurable disease) or recurrent (with or without measurable disease) endometrial carcinoma * Histologic confirmation of the original primary tumor is required; patients with the following histologic epithelial cell types are eligible: * Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.) * Measurable disease is defined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1); measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be \>= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or \>= 20 mm when measured by chest x-ray; lymph nodes must be \>= 15 mm in short axis when measured by CT or MRI * Patients must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2 * Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl * Platelets greater than or equal to 100,000/mcl * Creatinine less than 1.4 mg/dl * Bilirubin less than or equal to 1.5 x institutional/laboratory upper limit of normal (ULN) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN * Alkaline phosphatase less than or equal to 2.5 x ULN * Patients must NOT have received prior chemotherapy or targeted therapy, including chemotherapy used for radiation sensitization for treatment of endometrial carcinoma * Patients may have received prior radiation therapy for treatment of endometrial carcinoma; prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy; all radiation therapy must be completed at least 4 weeks prior to the first date of study therapy * Patients may have received prior hormonal therapy for treatment of endometrial carcinoma; all hormonal therapy must be discontinued at least one week prior to the first date of study therapy * Patients must be able to swallow and retain orally-administered medication * Patients must have signed an approved informed consent and authorization permitting release of personal health information; individuals with impaired decision-making capacity are not eligible to participate on the study
Exclusion criteria
* Patients must NOT be taking metformin or have been on metformin in the past 6 months * Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer are excluded if there is any evidence of other malignancy being present within the last three years * 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 * Patients who are pregnant or nursing; if patients are of reproductive age and have not undergone hysterectomy, they must use an effective contraceptive method for the duration of this study * Any condition associated with increased risk of metformin-associated lactic acidosis; (e.g. congestive heart failure defined as New York Heart Association \[NYHA\] class III or IV functional status, history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) (Phase II) | From date of study entry to time of progression or death, whichever occurs first, assessed up to 5 years | Time until disease progression, death, or date of last contact. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined. |
| Overall Survival (OS) (Phase II and III) | From date of study entry to time of death or the date of last contact, assessed up to 5 years | The observed length of life from randomization into the study to death or the date of last contact. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) (Phase II) | From date of study entry to time of death or the date of last contact, assessed up to 5 years. | The observed length of life from randomization into the study to death or the date of last contact. For response, only those patients who had measurable disease were included in an analysis of response. Non-measurable patients are included in the ITT analysis. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined. |
| Duration of Response by Treatment | From the date of response to disease progression, death, or date last seen assessed up to 5 years | Duration of response until disease progression, death, or date last seen among patients who responded. |
| Progression Free Survival (PFS) (Phase III) | From date of study entry to time of progression or death, whichever occurs first, assessed up to 5 years | Time until disease progression, death, or date of last contact. For response, only those patients who had measurable disease were included in an analysis of response. Non-measurable patients are included in the ITT analysis. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined. |
| Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Up to 5 years | Toxicities will be assessed by organ or organ system. For each category of toxicity, each patient will be evaluated by the worst grade experienced during the course of therapy. Data will be summarized by frequency and severity according to the regimen administered. The number of patients with a grade three or greater adverse event will be reported (by system organ class). |
| Level of Obesity | Up to 5 years | Obesity will be quantitative assessed by body mass index (BMI) and will be assessed for its predictive and prognostic significance. The interaction between BMI and metformin treatment will be examined with an interaction term in a Cox proportional hazards model. |
| Proportion of Patients Responding to Therapy | During study treatment, up to 5 years. | The proportion of patients who had a response (complete or partial) by RECIST 1.1. Measurable disease is defined by RECIST (version 1.1). Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be ≥ 10 mm when measured by CT, MRI or caliper measurement by clinical exam; or ≥ 20 mm when measured by chest x-ray. Lymph nodes must be \> 15 mm in short axis when measured by CT or MRI. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Levels of Key Targets of the Metformin/mTOR Signaling Pathway | Up to 5 years | Levels before and after treatment will be assessed for their predictive and prognostic significance. |
| Incidence of PIK3 Mutations/Amplifications | Up to 5 years | PIK3CA mutations/amplifications and PIK3R1/PIK3R2 mutations will be examined for prognostic and predictive significance. |
| Expression of MATE 2 | Up to 5 years | Expression will be examined by immunohistochemistry with intensity of staining and the percentage of cells staining positive. From these statistics, an H-score will be calculated. Expression will be further dichotomized as high expression and low expression at the median to maximize the power of the study. |
| Metabolic Factor Levels | Up to 5 years | Hip-to-waist ratio, diabetes status, hemoglobin A1c, fasting insulin glucose levels, and homeostatic model assessment scores will be assessed for their predictive and prognostic significance. Variables will be analyzed as continuous covariates (or as appropriate with transformations such as the logarithm) with Cox models or logistic regression. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) Patients receive 175 mg/m2 paclitaxel IV over 3 hours on day 1, carboplatin AUC 5 IV over 30 minutes on day 1, and 850 mg metformin hydrochloride PO BID (approximately every 10-12 hours apart) on days 1-21 (QD in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising metformin hydrochloride PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | 234 |
| Arm II (Paclitaxel, Carboplatin, Placebo) Patients receive 175 mg/m2 paclitaxel IV and carboplatin AUC 5 IV as in Arm I. Patients also receive placebo PO BID (approximately every 10-12 hours apart) on days 1-21 (QD in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising placebo PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | 235 |
| Total | 469 |
Baseline characteristics
| Characteristic | Arm II (Paclitaxel, Carboplatin, Placebo) | Total | Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) |
|---|---|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 9 | 65 years STANDARD_DEVIATION 9 | 65 years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 21 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 223 Participants | 437 Participants | 214 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 11 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 13 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 61 Participants | 39 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 17 Participants | 10 Participants |
| Race (NIH/OMB) White | 201 Participants | 372 Participants | 171 Participants |
| Sex: Female, Male Female | 235 Participants | 469 Participants | 234 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 95 / 234 | 95 / 235 |
| other Total, other adverse events | 222 / 234 | 222 / 235 |
| serious Total, serious adverse events | 46 / 234 | 53 / 235 |
Outcome results
Primary
Overall Survival (OS) (Phase II and III)
The observed length of life from randomization into the study to death or the date of last contact. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
Time frame: From date of study entry to time of death or the date of last contact, assessed up to 5 years
Population: All patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Overall Survival (OS) (Phase II and III) | 34.6 Months |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Overall Survival (OS) (Phase II and III) | 30.4 Months |
Primary
Progression-free Survival (PFS) (Phase II)
Time until disease progression, death, or date of last contact. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
Time frame: From date of study entry to time of progression or death, whichever occurs first, assessed up to 5 years
Population: All patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Progression-free Survival (PFS) (Phase II) | 9.0 Months |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Progression-free Survival (PFS) (Phase II) | 8.5 Months |
Secondary
Duration of Response by Treatment
Duration of response until disease progression, death, or date last seen among patients who responded.
Time frame: From the date of response to disease progression, death, or date last seen assessed up to 5 years
Population: Patients who responded
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Duration of Response by Treatment | 8.0 Months |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Duration of Response by Treatment | 8.0 Months |
Secondary
Level of Obesity
Obesity will be quantitative assessed by body mass index (BMI) and will be assessed for its predictive and prognostic significance. The interaction between BMI and metformin treatment will be examined with an interaction term in a Cox proportional hazards model.
Time frame: Up to 5 years
Population: All patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Level of Obesity | 0.4957 proportion of participants obese |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Level of Obesity | 0.4979 proportion of participants obese |
Comparison: The interaction between BMI and metformin treatment will be examined with an interaction term in a Cox proportional hazards model. Historical data indicate that approximately 50% of people are obese (BMI\>=30). For the purposes of examining the relationship, we will classify patients into two levels (high versus low) at the median BMI, which will increase the likelihood of detecting an interaction between metformin treatment and obesity.p-value: 0.9482Regression, Cox
Secondary
Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4
Toxicities will be assessed by organ or organ system. For each category of toxicity, each patient will be evaluated by the worst grade experienced during the course of therapy. Data will be summarized by frequency and severity according to the regimen administered. The number of patients with a grade three or greater adverse event will be reported (by system organ class).
Time frame: Up to 5 years
Population: All patients.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Musculoskeletal and connective tissue disorders | 1 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Renal and urinary disorders | 1 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Reproductive system and breast disorders | 1 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Respiratory, thoracic and mediastinal disorders | 7 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Skin and subcutaneous tissue disorders | 2 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Vascular disorders | 10 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Ear and labyrinth disorders | 1 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Metabolism and Nutrition Disorders | 8 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Neoplasms benign, malignant and unspecified | 1 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Nervous system disorders | 8 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Psychiatric disorders | 0 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Blood and lymphatic system disorders | 23 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Cardiac disorders | 2 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Endocrine disorders | 0 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Eye disorders | 0 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Gastrointestinal disorders | 17 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | General disorders administration site conditions | 5 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Infections and infestations | 14 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Immune system disorders | 0 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Injury, poisoning and procedural complications | 2 Participants |
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Investigations | 38 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Eye disorders | 0 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Nervous system disorders | 9 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Renal and urinary disorders | 5 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Injury, poisoning and procedural complications | 6 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Reproductive system and breast disorders | 0 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Gastrointestinal disorders | 10 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Respiratory, thoracic and mediastinal disorders | 4 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Blood and lymphatic system disorders | 17 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Skin and subcutaneous tissue disorders | 1 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Immune system disorders | 1 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Vascular disorders | 18 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Cardiac disorders | 2 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Psychiatric disorders | 2 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Ear and labyrinth disorders | 0 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | General disorders administration site conditions | 6 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Investigations | 28 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Endocrine disorders | 0 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Metabolism and Nutrition Disorders | 18 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Musculoskeletal and connective tissue disorders | 3 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Infections and infestations | 10 Participants |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 | Neoplasms benign, malignant and unspecified | 0 Participants |
Secondary
Overall Survival (OS) (Phase II)
The observed length of life from randomization into the study to death or the date of last contact. For response, only those patients who had measurable disease were included in an analysis of response. Non-measurable patients are included in the ITT analysis. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
Time frame: From date of study entry to time of death or the date of last contact, assessed up to 5 years.
Population: All patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Overall Survival (OS) (Phase II) | 34.6 Months |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Overall Survival (OS) (Phase II) | 30.4 Months |
Secondary
Progression Free Survival (PFS) (Phase III)
Time until disease progression, death, or date of last contact. For response, only those patients who had measurable disease were included in an analysis of response. Non-measurable patients are included in the ITT analysis. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
Time frame: From date of study entry to time of progression or death, whichever occurs first, assessed up to 5 years
Population: All patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Progression Free Survival (PFS) (Phase III) | 9.0 Months |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Progression Free Survival (PFS) (Phase III) | 8.5 Months |
Secondary
Proportion of Patients Responding to Therapy
The proportion of patients who had a response (complete or partial) by RECIST 1.1. Measurable disease is defined by RECIST (version 1.1). Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be ≥ 10 mm when measured by CT, MRI or caliper measurement by clinical exam; or ≥ 20 mm when measured by chest x-ray. Lymph nodes must be \> 15 mm in short axis when measured by CT or MRI.
Time frame: During study treatment, up to 5 years.
Population: Evaluable for response
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) | Proportion of Patients Responding to Therapy | 61.6 percentage of patients |
| Arm II (Paclitaxel, Carboplatin, Placebo) | Proportion of Patients Responding to Therapy | 60.2 percentage of patients |
Other Pre-specified
Expression of MATE 2
Expression will be examined by immunohistochemistry with intensity of staining and the percentage of cells staining positive. From these statistics, an H-score will be calculated. Expression will be further dichotomized as high expression and low expression at the median to maximize the power of the study.
Time frame: Up to 5 years
Other Pre-specified
Incidence of PIK3 Mutations/Amplifications
PIK3CA mutations/amplifications and PIK3R1/PIK3R2 mutations will be examined for prognostic and predictive significance.
Time frame: Up to 5 years
Other Pre-specified
Levels of Key Targets of the Metformin/mTOR Signaling Pathway
Levels before and after treatment will be assessed for their predictive and prognostic significance.
Time frame: Up to 5 years
Other Pre-specified
Metabolic Factor Levels
Hip-to-waist ratio, diabetes status, hemoglobin A1c, fasting insulin glucose levels, and homeostatic model assessment scores will be assessed for their predictive and prognostic significance. Variables will be analyzed as continuous covariates (or as appropriate with transformations such as the logarithm) with Cox models or logistic regression.
Time frame: Up to 5 years