Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer

• Sponsor: Gynecologic Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02065687
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 469
• Locations: 431
• Arms: 2
• Anticipated Duration (Months): 113.9
• Patients Per Site: 1.1
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma; Stage III Uterine Corpus Cancer AJCC v7; Stage IIIA Uterine Corpus Cancer AJCC v7; Stage IIIB Uterine Corpus Cancer AJCC v7; Stage IIIC Uterine Corpus Cancer AJCC v7; Stage IV Uterine Corpus Cancer AJCC v7; Stage IVA Uterine Corpus Cancer AJCC v7; Stage IVB Uterine Corpus Cancer AJCC v7	Drug: Carboplatin; Other: Laboratory Biomarker Analysis; Drug: Metformin Hydrochloride; Drug: Paclitaxel; Other: Placebo Administration; Other: Quality-of-Life Assessment; Other: Questionnaire Administration	Phase 2/Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. To estimate the proportion of patients with objective response (response rate [RR]) in the population of patients with measurable disease by treatment.

2. To estimate the duration of response in the population of patients with measurable disease who respond by treatment.

3. 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.

4. To determine the nature, frequency and degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) for each treatment arm.

5. To estimate possible differences in RR, PFS, OS, and toxicity rates for the treatment regimens by the patients' level of obesity.

TERTIARY OBJECTIVES:

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. To determine if the genetic variants of the metformin transporters correspond with treatment response to metformin/paclitaxel/carboplatin, PFS and OS.

7. To estimate differences in physical functioning, physical activity, and fatigue between treatment arms.

8. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 469 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II/III Study of Paclitaxel/Carboplatin/Metformin (NSC#91485) Versus Paclitaxel/Carboplatin/Placebo as Initial Therapy for Measurable Stage III or IVA, Stage IVB, or Recurrent Endometrial Cancer
• Actual Study Start Date: Mar 17, 2014
• Actual Primary Completion Date: Apr 17, 2019
• Anticipated Study Completion Date: Sep 13, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (paclitaxel, carboplatin, metformin hydrochloride) Patients receive paclitaxel IV over 3 hours on day 1, carboplatin IV over 30 minutes on day 1, and 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. In both arms, patients who achieve SD or 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.	Drug: Carboplatin; Given IV; Other Names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Metformin Hydrochloride; Given PO; Other Names: APO-Metformin Cidophage Dimefor Glifage Glucoformin Glucophage Glucophage ER Metformin HCl Riomet Siofor ; Drug: Paclitaxel; Given IV; Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat ; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Other: Questionnaire Administration; Ancillary studies
Active Comparator: Arm II (paclitaxel, carboplatin, placebo) Patients receive paclitaxel IV and carboplatin 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. In both arms, patients who achieve SD or 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.	Drug: Carboplatin; Given IV; Other Names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carboplatinum Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Paclitaxel; Given IV; Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat ; Other: Placebo Administration; Given PO; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Other: Questionnaire Administration; Ancillary studies

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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).

6. 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.

Other Outcome Measures

1. 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.

2. Incidence of PIK3 Mutations/Amplifications [Up to 5 years]

   PIK3CA mutations/amplifications and PIK3R1/PIK3R2 mutations will be examined for prognostic and predictive significance.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	Tennessee Valley Gynecologic Oncology	Huntsville	Alabama	United States	35805
3	Cancer Center at Saint Joseph's	Phoenix	Arizona	United States	85004
4	Saint Joseph's Hospital and Medical Center	Phoenix	Arizona	United States	85013
5	Arizona Oncology Associates-Biltmore Cancer Center	Phoenix	Arizona	United States	85016
6	Arizona Oncology Associates-West Orange Grove	Tucson	Arizona	United States	85704
7	Arizona Oncology Associates-Wilmot	Tucson	Arizona	United States	85710
8	Banner University Medical Center - Tucson	Tucson	Arizona	United States	85719
9	University of Arizona Cancer Center-North Campus	Tucson	Arizona	United States	85719
10	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
11	John Muir Medical Center-Concord Campus	Concord	California	United States	94520
12	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093
13	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California	United States	90027
14	Los Angeles County-USC Medical Center	Los Angeles	California	United States	90033
15	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
16	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
17	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California	United States	90095
18	Palo Alto Medical Foundation-Gynecologic Oncology	Mountain View	California	United States	94040
19	Kaiser Permanente-Oakland	Oakland	California	United States	94611
20	Saint Joseph Hospital - Orange	Orange	California	United States	92868
21	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
22	Palo Alto Medical Foundation Health Care	Palo Alto	California	United States	94301
23	Stanford Cancer Institute Palo Alto	Palo Alto	California	United States	94304
24	Keck Medical Center of USC Pasadena	Pasadena	California	United States	91105
25	Kaiser Permanente-Roseville	Roseville	California	United States	95661
26	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
27	Kaiser Permanente - Sacramento	Sacramento	California	United States	95825
28	Zuckerberg San Francisco General Hospital	San Francisco	California	United States	94110
29	California Pacific Medical Center-Pacific Campus	San Francisco	California	United States	94115
30	Kaiser Permanente-San Francisco	San Francisco	California	United States	94115
31	UCSF Medical Center-Mount Zion	San Francisco	California	United States	94115
32	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
33	Kaiser Permanente-Santa Teresa-San Jose	San Jose	California	United States	95119
34	Kaiser Permanente San Leandro	San Leandro	California	United States	94577
35	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California	United States	95051
36	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California	United States	95065
37	Kaiser Permanente-South San Francisco	South San Francisco	California	United States	94080
38	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California	United States	94086
39	Olive View-University of California Los Angeles Medical Center	Sylmar	California	United States	91342
40	Kaiser Permanente-Vallejo	Vallejo	California	United States	94589
41	Kaiser Permanente-Walnut Creek	Walnut Creek	California	United States	94596
42	John Muir Medical Center-Walnut Creek	Walnut Creek	California	United States	94598
43	University of Colorado Hospital	Aurora	Colorado	United States	80045
44	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado	United States	80907
45	Poudre Valley Hospital	Fort Collins	Colorado	United States	80524
46	Smilow Cancer Hospital-Derby Care Center	Derby	Connecticut	United States	06418
47	Smilow Cancer Hospital Care Center-Fairfield	Fairfield	Connecticut	United States	06824
48	Smilow Cancer Hospital Care Center - Guiford	Guilford	Connecticut	United States	06437
49	Hartford Hospital	Hartford	Connecticut	United States	06102
50	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
51	Midstate Medical Center	Meriden	Connecticut	United States	06451
52	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
53	Yale University	New Haven	Connecticut	United States	06520
54	Yale-New Haven Hospital North Haven Medical Center	North Haven	Connecticut	United States	06473
55	Smilow Cancer Hospital-Orange Care Center	Orange	Connecticut	United States	06477
56	Smilow Cancer Hospital-Torrington Care Center	Torrington	Connecticut	United States	06790
57	Smilow Cancer Hospital Care Center-Trumbull	Trumbull	Connecticut	United States	06611
58	Smilow Cancer Hospital-Waterbury Care Center	Waterbury	Connecticut	United States	06708
59	Christiana Gynecologic Oncology LLC	Newark	Delaware	United States	19713
60	Helen F Graham Cancer Center	Newark	Delaware	United States	19713
61	Medical Oncology Hematology Consultants PA	Newark	Delaware	United States	19713
62	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
63	Beebe Health Campus	Rehoboth Beach	Delaware	United States	19971
64	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware	United States	19801
65	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
66	AdventHealth Orlando	Orlando	Florida	United States	32803
67	Women's Cancer Associates	Saint Petersburg	Florida	United States	33713
68	Sarasota Memorial Hospital	Sarasota	Florida	United States	34239
69	Emory University Hospital Midtown	Atlanta	Georgia	United States	30308
70	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
71	Northside Hospital	Atlanta	Georgia	United States	30342
72	Augusta University Medical Center	Augusta	Georgia	United States	30912
73	Dekalb Medical Center	Decatur	Georgia	United States	30033
74	Northeast Georgia Medical Center-Gainesville	Gainesville	Georgia	United States	30501
75	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia	United States	31405
76	Pali Momi Medical Center	'Aiea	Hawaii	United States	96701
77	Queen's Cancer Center - Pearlridge	'Aiea	Hawaii	United States	96701
78	The Cancer Center of Hawaii-Pali Momi	'Aiea	Hawaii	United States	96701
79	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii	United States	96813
80	Queen's Medical Center	Honolulu	Hawaii	United States	96813
81	Straub Clinic and Hospital	Honolulu	Hawaii	United States	96813
82	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
83	Hawaii Cancer Care Inc-Liliha	Honolulu	Hawaii	United States	96817
84	Kuakini Medical Center	Honolulu	Hawaii	United States	96817
85	Queen's Cancer Center - Kuakini	Honolulu	Hawaii	United States	96817
86	The Cancer Center of Hawaii-Liliha	Honolulu	Hawaii	United States	96817
87	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
88	Wilcox Memorial Hospital and Kauai Medical Clinic	Lihue	Hawaii	United States	96766
89	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
90	Northwest Community Hospital	Arlington Heights	Illinois	United States	60005
91	Rush - Copley Medical Center	Aurora	Illinois	United States	60504
92	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61704
93	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
94	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
95	Northwestern University	Chicago	Illinois	United States	60611
96	Rush University Medical Center	Chicago	Illinois	United States	60612
97	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
98	Carle on Vermilion	Danville	Illinois	United States	61832
99	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois	United States	62526
100	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
101	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
102	Crossroads Cancer Center	Effingham	Illinois	United States	62401
103	AMITA Health Alexian Brothers Medical Center	Elk Grove Village	Illinois	United States	60007
104	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
105	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
106	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
107	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois	United States	60134
108	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois	United States	60026
109	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois	United States	60035
110	Sudarshan K Sharma MD Limited-Gynecologic Oncology	Hinsdale	Illinois	United States	60521
111	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
112	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
113	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
114	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois	United States	60451
115	Cancer Care Center of O'Fallon	O'Fallon	Illinois	United States	62269
116	University of Chicago Medicine-Orland Park	Orland Park	Illinois	United States	60462
117	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
118	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
119	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
120	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
121	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
122	North Shore Medical Center	Skokie	Illinois	United States	60076
123	Central Illinois Hematology Oncology Center	Springfield	Illinois	United States	62702
124	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
125	Springfield Clinic	Springfield	Illinois	United States	62702
126	Memorial Medical Center	Springfield	Illinois	United States	62781
127	Carle Cancer Center	Urbana	Illinois	United States	61801
128	The Carle Foundation Hospital	Urbana	Illinois	United States	61801
129	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois	United States	60555
130	Rush-Copley Healthcare Center	Yorkville	Illinois	United States	60560
131	Michiana Hematology Oncology PC-Crown Point	Crown Point	Indiana	United States	46307
132	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana	United States	46514
133	Elkhart General Hospital	Elkhart	Indiana	United States	46515
134	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
135	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
136	IU Health La Porte Hospital	La Porte	Indiana	United States	46350
137	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana	United States	46360
138	Woodland Cancer Care Center	Michigan City	Indiana	United States	46360
139	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana	United States	46545
140	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana	United States	46545
141	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana	United States	46601
142	Michiana Hematology Oncology PC-Westville	Westville	Indiana	United States	46391
143	Mary Greeley Medical Center	Ames	Iowa	United States	50010
144	McFarland Clinic PC - Ames	Ames	Iowa	United States	50010
145	McFarland Clinic PC-Boone	Boone	Iowa	United States	50036
146	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa	United States	50325
147	Mercy Cancer Center-West Lakes	Clive	Iowa	United States	50325
148	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa	United States	50314
149	Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
150	McFarland Clinic PC-Trinity Cancer Center	Fort Dodge	Iowa	United States	50501
151	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
152	McFarland Clinic PC-Jefferson	Jefferson	Iowa	United States	50129
153	McFarland Clinic PC-Marshalltown	Marshalltown	Iowa	United States	50158
154	Mercy Medical Center - North Iowa	Mason City	Iowa	United States	50401
155	Saint Elizabeth Medical Center South	Edgewood	Kentucky	United States	41017
156	Saint Elizabeth Fort Thomas	Fort Thomas	Kentucky	United States	41075
157	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
158	Woman's Hospital	Baton Rouge	Louisiana	United States	70817
159	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
160	Maine Medical Center- Scarborough Campus	Scarborough	Maine	United States	04074
161	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
162	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
163	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
164	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
165	Tufts Medical Center	Boston	Massachusetts	United States	02111
166	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
167	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
168	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
169	Lowell General Hospital	Lowell	Massachusetts	United States	01854
170	Baystate Medical Center	Springfield	Massachusetts	United States	01199
171	UMass Memorial Medical Center - Memorial Division	Worcester	Massachusetts	United States	01605
172	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan	United States	48106
173	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
174	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
175	Bronson Battle Creek	Battle Creek	Michigan	United States	49017
176	Beaumont Hospital - Dearborn	Dearborn	Michigan	United States	48124
177	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
178	Green Bay Oncology - Escanaba	Escanaba	Michigan	United States	49829
179	Weisberg Cancer Treatment Center	Farmington Hills	Michigan	United States	48334
180	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
181	Hurley Medical Center	Flint	Michigan	United States	48503
182	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
183	Mercy Health Saint Mary's	Grand Rapids	Michigan	United States	49503
184	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
185	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan	United States	49801
186	Allegiance Health	Jackson	Michigan	United States	49201
187	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
188	Sparrow Hospital	Lansing	Michigan	United States	48912
189	Saint Mary Mercy Hospital	Livonia	Michigan	United States	48154
190	Monroe Cancer Center	Monroe	Michigan	United States	48162
191	Mercy Health Mercy Campus	Muskegon	Michigan	United States	49444
192	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
193	Lake Huron Medical Center	Port Huron	Michigan	United States	48060
194	Spectrum Health Reed City Hospital	Reed City	Michigan	United States	49677
195	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan	United States	48073
196	Ascension Saint Mary's Hospital	Saginaw	Michigan	United States	48601
197	Munson Medical Center	Traverse City	Michigan	United States	49684
198	William Beaumont Hospital - Troy	Troy	Michigan	United States	48085
199	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
200	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota	United States	56601
201	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
202	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
203	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
204	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
205	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
206	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
207	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
208	United Hospital	Saint Paul	Minnesota	United States	55102
209	Lakeview Hospital	Stillwater	Minnesota	United States	55082
210	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota	United States	55125
211	Saint Dominic-Jackson Memorial Hospital	Jackson	Mississippi	United States	39216
212	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
213	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
214	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri	United States	65401
215	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri	United States	65401
216	Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
217	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
218	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
219	Cancer Research for the Ozarks NCORP	Springfield	Missouri	United States	65804
220	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
221	CoxHealth South Hospital	Springfield	Missouri	United States	65807
222	Billings Clinic Cancer Center	Billings	Montana	United States	59101
223	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana	United States	59405
224	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
225	CHI Health Saint Francis	Grand Island	Nebraska	United States	68803
226	CHI Health Good Samaritan	Kearney	Nebraska	United States	68847
227	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
228	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
229	Women's Cancer Center of Nevada	Las Vegas	Nevada	United States	89169
230	Center of Hope at Renown Medical Center	Reno	Nevada	United States	89502
231	Renown Regional Medical Center	Reno	Nevada	United States	89502
232	Wentworth-Douglass Hospital	Dover	New Hampshire	United States	03820
233	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
234	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey	United States	07920
235	Cooper Hospital University Medical Center	Camden	New Jersey	United States	08103
236	Memorial Sloan Kettering Monmouth	Middletown	New Jersey	United States	07748
237	Morristown Medical Center	Morristown	New Jersey	United States	07960
238	Virtua Memorial	Mount Holly	New Jersey	United States	08060
239	Overlook Hospital	Summit	New Jersey	United States	07902
240	MD Anderson Cancer Center at Cooper-Voorhees	Voorhees	New Jersey	United States	08043
241	Virtua Voorhees	Voorhees	New Jersey	United States	08043
242	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
243	Southwest Gynecologic Oncology Associates Inc	Albuquerque	New Mexico	United States	87106
244	Women's Cancer Care Associates LLC	Albany	New York	United States	12208
245	Montefiore Medical Center-Einstein Campus	Bronx	New York	United States	10461
246	Montefiore Medical Center-Weiler Hospital	Bronx	New York	United States	10461
247	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
248	State University of New York Downstate Medical Center	Brooklyn	New York	United States	11203
249	New York-Presbyterian/Brooklyn Methodist Hospital	Brooklyn	New York	United States	11215
250	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
251	Memorial Sloan Kettering Commack	Commack	New York	United States	11725
252	Glens Falls Hospital	Glens Falls	New York	United States	12801
253	Memorial Sloan Kettering Westchester	Harrison	New York	United States	10604
254	NYU Winthrop Hospital	Mineola	New York	United States	11501
255	Mount Sinai Union Square	New York	New York	United States	10003
256	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
257	Mount Sinai Hospital	New York	New York	United States	10029
258	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
259	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
260	Memorial Sloan Kettering Sleepy Hollow	Sleepy Hollow	New York	United States	10591
261	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
262	Memorial Sloan Kettering Nassau	Uniondale	New York	United States	11553
263	Westchester Medical Center	Valhalla	New York	United States	10595
264	Dickstein Cancer Treatment Center	White Plains	New York	United States	10601
265	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
266	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
267	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
268	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina	United States	28328
269	Atrium Health Cabarrus/LCI-Concord	Concord	North Carolina	United States	28025
270	Duke University Medical Center	Durham	North Carolina	United States	27710
271	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina	United States	27534
272	Wayne Memorial Hospital	Goldsboro	North Carolina	United States	27534
273	AdventHealth Hendersonville	Hendersonville	North Carolina	United States	28792
274	Onslow Memorial Hospital	Jacksonville	North Carolina	United States	28546
275	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina	United States	28546
276	Novant Health Cancer Institute - Kernersville	Kernersville	North Carolina	United States	27284
277	Novant Health Cancer Institute - Mount Airy	Mount Airy	North Carolina	United States	27030
278	FirstHealth of the Carolinas-Moore Regional Hospital	Pinehurst	North Carolina	United States	28374
279	Duke Raleigh Hospital	Raleigh	North Carolina	United States	27609
280	Novant Health Cancer Institute - Statesville	Statesville	North Carolina	United States	28625
281	Novant Health Cancer Institute - Thomasville	Thomasville	North Carolina	United States	27360
282	Novant Health Cancer Institute - Wilkesboro	Wilkesboro	North Carolina	United States	28659
283	New Hanover Regional Medical Center/Zimmer Cancer Center	Wilmington	North Carolina	United States	28401
284	Novant Health Oncology Specialists	Winston-Salem	North Carolina	United States	27103
285	Winston-Salem Health Care	Winston-Salem	North Carolina	United States	27103
286	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
287	Sanford Bismarck Medical Center	Bismarck	North Dakota	United States	58501
288	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
289	Sanford Clinic North-Fargo	Fargo	North Dakota	United States	58122
290	Sanford Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
291	Summa Health System - Akron Campus	Akron	Ohio	United States	44304
292	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio	United States	45219
293	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio	United States	45220
294	Bethesda North Hospital	Cincinnati	Ohio	United States	45242
295	Case Western Reserve University	Cleveland	Ohio	United States	44106
296	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio	United States	44111
297	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
298	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
299	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
300	Columbus NCI Community Oncology Research Program	Columbus	Ohio	United States	43215
301	The Mark H Zangmeister Center	Columbus	Ohio	United States	43219
302	Grandview Hospital	Dayton	Ohio	United States	45405
303	Good Samaritan Hospital - Dayton	Dayton	Ohio	United States	45406
304	Miami Valley Hospital	Dayton	Ohio	United States	45409
305	Miami Valley Hospital North	Dayton	Ohio	United States	45415
306	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio	United States	44124
307	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio	United States	44060
308	ProMedica Flower Hospital	Sylvania	Ohio	United States	43560
309	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio	United States	43606
310	Wright-Patterson Medical Center	Wright-Patterson Air Force Base	Ohio	United States	45433
311	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
312	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma	United States	74146
313	Jefferson Abington Hospital	Abington	Pennsylvania	United States	19001
314	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania	United States	18015
315	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
316	Adams Cancer Center	Gettysburg	Pennsylvania	United States	17325
317	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania	United States	15601
318	Cherry Tree Cancer Center	Hanover	Pennsylvania	United States	17331
319	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania	United States	18201
320	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania	United States	17837
321	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
322	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
323	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
324	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
325	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
326	UPMC-Magee Womens Hospital	Pittsburgh	Pennsylvania	United States	15213
327	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania	United States	15232
328	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania	United States	15237
329	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania	United States	17901
330	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania	United States	16346
331	Geisinger Medical Group	State College	Pennsylvania	United States	16801
332	UPMC Uniontown Hospital Radiation Oncology	Uniontown	Pennsylvania	United States	15401
333	Chester County Hospital	West Chester	Pennsylvania	United States	19380
334	Reading Hospital	West Reading	Pennsylvania	United States	19611
335	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania	United States	18711
336	WellSpan Health-York Hospital	York	Pennsylvania	United States	17403
337	Women and Infants Hospital	Providence	Rhode Island	United States	02905
338	AnMed Health Cancer Center	Anderson	South Carolina	United States	29621
339	Medical University of South Carolina	Charleston	South Carolina	United States	29425
340	Saint Francis Hospital	Greenville	South Carolina	United States	29601
341	Gibbs Cancer Center-Pelham	Greer	South Carolina	United States	29651
342	Carolina Blood and Cancer Care Associates PA-Lancaster	Lancaster	South Carolina	United States	29720
343	Carolina Blood and Cancer Care Associates PA	Rock Hill	South Carolina	United States	29732
344	Spartanburg Medical Center	Spartanburg	South Carolina	United States	29303
345	Black Hills Obstetrics and Gynecology	Rapid City	South Dakota	United States	57701
346	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
347	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota	United States	57104
348	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
349	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
350	Chattanooga's Program in Women's Oncology	Chattanooga	Tennessee	United States	37403
351	University of Tennessee - Knoxville	Knoxville	Tennessee	United States	37920
352	Dell Seton Medical Center at The University of Texas	Austin	Texas	United States	78701
353	Texas Oncology-Austin Midtown	Austin	Texas	United States	78705
354	Texas Oncology - Central Austin Cancer Center	Austin	Texas	United States	78731
355	Texas Oncology - South Austin Cancer Center	Austin	Texas	United States	78745
356	Texas Oncology Bedford	Bedford	Texas	United States	76022
357	MD Anderson in The Woodlands	Conroe	Texas	United States	77384
358	Texas Health Presbyterian Hospital Dallas	Dallas	Texas	United States	75231
359	Parkland Memorial Hospital	Dallas	Texas	United States	75235
360	Texas Oncology at Baylor Charles A Sammons Cancer Center	Dallas	Texas	United States	75246
361	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
362	Texas Oncology - Fort Worth Cancer Center	Fort Worth	Texas	United States	76104
363	Lyndon Baines Johnson General Hospital	Houston	Texas	United States	77026-1967
364	Houston Methodist Hospital	Houston	Texas	United States	77030
365	M D Anderson Cancer Center	Houston	Texas	United States	77030
366	Memorial Hermann Texas Medical Center	Houston	Texas	United States	77030
367	Methodist Willowbrook Hospital	Houston	Texas	United States	77070
368	MD Anderson West Houston	Houston	Texas	United States	77079
369	MD Anderson League City	League City	Texas	United States	77573
370	Texas Oncology-Longview Cancer Center	Longview	Texas	United States	75601
371	MD Anderson in Sugar Land	Sugar Land	Texas	United States	77478
372	Houston Methodist Sugar Land Hospital	Sugar Land	Texas	United States	77479
373	Texas Oncology Cancer Center Sugar Land	Sugar Land	Texas	United States	77479
374	Texas Oncology-The Woodlands	The Woodlands	Texas	United States	77380
375	Tyler Cancer Center	Tyler	Texas	United States	75702
376	Deke Slayton Cancer Center	Webster	Texas	United States	77598
377	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah	United States	84003
378	Sandra L Maxwell Cancer Center	Cedar City	Utah	United States	84720
379	Logan Regional Hospital	Logan	Utah	United States	84321
380	Intermountain Medical Center	Murray	Utah	United States	84107
381	McKay-Dee Hospital Center	Ogden	Utah	United States	84403
382	Utah Valley Regional Medical Center	Provo	Utah	United States	84604
383	Dixie Medical Center Regional Cancer Center	Saint George	Utah	United States	84770
384	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah	United States	84106
385	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112
386	LDS Hospital	Salt Lake City	Utah	United States	84143
387	Southwestern Vermont Medical Center	Bennington	Vermont	United States	05201
388	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont	United States	05602
389	University of Vermont Medical Center	Burlington	Vermont	United States	05401
390	University of Vermont and State Agricultural College	Burlington	Vermont	United States	05405
391	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont	United States	05819
392	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
393	Inova Schar Cancer Institute	Fairfax	Virginia	United States	22031
394	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
395	Henrico Doctor's Hospital	Richmond	Virginia	United States	23229
396	Virginia Gynecologic Oncology	Richmond	Virginia	United States	23229
397	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
398	Carilion Clinic Gynecological Oncology	Roanoke	Virginia	United States	24016
399	Highline Medical Center-Main Campus	Burien	Washington	United States	98166
400	MultiCare Gig Harbor Medical Park	Gig Harbor	Washington	United States	98335
401	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
402	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
403	University of Washington Medical Center - Northwest	Seattle	Washington	United States	98133
404	Women's Cancer Center of Seattle	Seattle	Washington	United States	98133
405	University of Washington Medical Center - Montlake	Seattle	Washington	United States	98195
406	MultiCare Tacoma General Hospital	Tacoma	Washington	United States	98405
407	Edwards Comprehensive Cancer Center	Huntington	West Virginia	United States	25701
408	Monongalia Hospital	Morgantown	West Virginia	United States	26505
409	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin	United States	54729
410	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin	United States	54701
411	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301-3526
412	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
413	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
414	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin	United States	54303
415	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
416	Holy Family Memorial Hospital	Manitowoc	Wisconsin	United States	54221
417	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin	United States	54449
418	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
419	ProHealth D N Greenwald Center	Mukwonago	Wisconsin	United States	53149
420	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin	United States	53066
421	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin	United States	54154
422	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin	United States	54868
423	Marshfield Clinic Stevens Point Center	Stevens Point	Wisconsin	United States	54482
424	Saint Vincent Hospital Cancer Center at Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235-1495
425	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
426	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin	United States	53188
427	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin	United States	53188
428	Aspirus Regional Cancer Center	Wausau	Wisconsin	United States	54401
429	Marshfield Clinic-Wausau Center	Wausau	Wisconsin	United States	54401
430	Marshfield Medical Center - Weston	Weston	Wisconsin	United States	54476
431	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494

Sponsors and Collaborators

• Gynecologic Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Victoria L Bae-Jump, NRG Oncology

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 21, 2017

More Information

Publications

None provided.

• Responsible Party: Gynecologic Oncology Group
• ClinicalTrials.gov Identifier: NCT02065687
• Other Study ID Numbers: GOG-0286B; NCI-2013-02284; s14-01068; GOG-0286B; GOG-0286B; GOG-0286B; U10CA180830; U10CA180868; U10CA027469
• First Posted: Feb 19, 2014
• Last Update Posted: Sep 30, 2021
• Last Verified: Sep 1, 2021

• Additional relevant MeSH terms: Carcinoma; Adenocarcinoma; Endometrial Neoplasms; Cystadenocarcinoma, Serous; Adenocarcinoma, Clear Cell; Recurrence; Metformin; Paclitaxel; Carboplatin; Albumin-Bound Paclitaxel

Study Results

Participant Flow

Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)	Arm II (Paclitaxel, Carboplatin, Placebo)
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	234	235
COMPLETED	234	235
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)	Arm II (Paclitaxel, Carboplatin, Placebo)	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	234	235	469
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65 (9)	64 (9)	65 (9)
Sex: Female, Male (Count of Participants)
Female	234 100%	235 100%	469 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 5.1%	9 3.8%	21 4.5%
Not Hispanic or Latino	214 91.5%	223 94.9%	437 93.2%
Unknown or Not Reported	8 3.4%	3 1.3%	11 2.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 1.3%	2 0.9%	5 1.1%
Asian	10 4.3%	3 1.3%	13 2.8%
Native Hawaiian or Other Pacific Islander	1 0.4%	0 0%	1 0.2%
Black or African American	39 16.7%	22 9.4%	61 13%
White	171 73.1%	201 85.5%	372 79.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	10 4.3%	7 3%	17 3.6%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) (Phase II)
Description	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

Outcome Measure Data

Analysis Population Description

All patients

Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)	Arm II (Paclitaxel, Carboplatin, Placebo)
Arm/Group Description	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.	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.
Measure Participants	234	235
Median (95% Confidence Interval) [Months]	9.0	8.5

2. Primary Outcome

Title	Overall Survival (OS) (Phase II and III)
Description	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

Outcome Measure Data

Analysis Population Description

All patients.

Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)	Arm II (Paclitaxel, Carboplatin, Placebo)
Arm/Group Description	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.	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.
Measure Participants	234	235
Median (95% Confidence Interval) [Months]	34.6	30.4

3. Secondary Outcome

Title	Proportion of Patients Responding to Therapy
Description	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.

Outcome Measure Data

Analysis Population Description

Evaluable for response

Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)	Arm II (Paclitaxel, Carboplatin, Placebo)
Arm/Group Description	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.	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.
Measure Participants	164	171
Number (95% Confidence Interval) [percentage of patients]	61.6	60.2

4. Secondary Outcome

Title	Duration of Response by Treatment
Description	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

Outcome Measure Data

Analysis Population Description

Patients who responded

Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)	Arm II (Paclitaxel, Carboplatin, Placebo)
Arm/Group Description	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.	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.
Measure Participants	101	103
Median (95% Confidence Interval) [Months]	8.0	8.0

5. Secondary Outcome

Title	Overall Survival (OS) (Phase II)
Description	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.

Outcome Measure Data

Analysis Population Description

All patients

Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)	Arm II (Paclitaxel, Carboplatin, Placebo)
Arm/Group Description	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.	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.
Measure Participants	234	235
Median (95% Confidence Interval) [Months]	34.6	30.4

6. Secondary Outcome

Title	Progression Free Survival (PFS) (Phase III)
Description	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

Outcome Measure Data

Analysis Population Description

All patients.

Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)	Arm II (Paclitaxel, Carboplatin, Placebo)
Arm/Group Description	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.	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.
Measure Participants	234	235
Median (95% Confidence Interval) [Months]	9.0	8.5

7. Secondary Outcome

Title	Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4
Description	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

Outcome Measure Data

Analysis Population Description

All patients.

Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)	Arm II (Paclitaxel, Carboplatin, Placebo)
Arm/Group Description	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.	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.
Measure Participants	234	235
Blood and lymphatic system disorders	23 9.8%	17 7.2%
Cardiac disorders	2 0.9%	2 0.9%
Ear and labyrinth disorders	1 0.4%	0 0%
Endocrine disorders	0 0%	0 0%
Eye disorders	0 0%	0 0%
Gastrointestinal disorders	17 7.3%	10 4.3%
General disorders administration site conditions	5 2.1%	6 2.6%
Immune system disorders	0 0%	1 0.4%
Infections and infestations	14 6%	10 4.3%
Injury, poisoning and procedural complications	2 0.9%	6 2.6%
Investigations	38 16.2%	28 11.9%
Metabolism and Nutrition Disorders	8 3.4%	18 7.7%
Musculoskeletal and connective tissue disorders	1 0.4%	3 1.3%
Neoplasms benign, malignant and unspecified	1 0.4%	0 0%
Nervous system disorders	8 3.4%	9 3.8%
Psychiatric disorders	0 0%	2 0.9%
Renal and urinary disorders	1 0.4%	5 2.1%
Reproductive system and breast disorders	1 0.4%	0 0%
Respiratory, thoracic and mediastinal disorders	7 3%	4 1.7%
Skin and subcutaneous tissue disorders	2 0.9%	1 0.4%
Vascular disorders	10 4.3%	18 7.7%

8. Secondary Outcome

Title	Level of Obesity
Description	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

Outcome Measure Data

Analysis Population Description

All patients

Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)	Arm II (Paclitaxel, Carboplatin, Placebo)
Arm/Group Description	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.	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.
Measure Participants	234	235
Number [proportion of participants obese]	0.4957 0.2%	0.4979 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride), Arm II (Paclitaxel, Carboplatin, Placebo)
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	The null hypothesis is that there is no relationship between BMI and metformin treatment (i.e. the parameter associated with the interaction term of BMI * treatment is equal to 0).
Statistical Test of Hypothesis	p-Value	0.9482
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	-0.01787
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.27472
	Estimation Comments

9. Other Pre-specified Outcome

Title	Metabolic Factor Levels
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Incidence of PIK3 Mutations/Amplifications
Description	PIK3CA mutations/amplifications and PIK3R1/PIK3R2 mutations will be examined for prognostic and predictive significance.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Expression of MATE 2
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Levels of Key Targets of the Metformin/mTOR Signaling Pathway
Description	Levels before and after treatment will be assessed for their predictive and prognostic significance.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Patients are followed for the occurrence of adverse events for five years.
Arm/Group Title	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)		Arm II (Paclitaxel, Carboplatin, Placebo)
Arm/Group Description	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.		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.
All Cause Mortality
	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)		Arm II (Paclitaxel, Carboplatin, Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	95/234 (40.6%)		95/235 (40.4%)
Serious Adverse Events
	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)		Arm II (Paclitaxel, Carboplatin, Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/234 (19.7%)		53/235 (22.6%)
Blood and lymphatic system disorders
Anemia	1/234 (0.4%)		1/235 (0.4%)
Febrile Neutropenia	2/234 (0.9%)		3/235 (1.3%)
Cardiac disorders
Atrial Fibrillation	1/234 (0.4%)		0/235 (0%)
Myocardial Infarction	0/234 (0%)		1/235 (0.4%)
Gastrointestinal disorders
Colonic Perforation	1/234 (0.4%)		0/235 (0%)
Colitis	1/234 (0.4%)		0/235 (0%)
Diarrhea	0/234 (0%)		1/235 (0.4%)
Vomiting	1/234 (0.4%)		2/235 (0.9%)
Abdominal Pain	1/234 (0.4%)		1/235 (0.4%)
Nausea	2/234 (0.9%)		1/235 (0.4%)
Ascites	1/234 (0.4%)		0/235 (0%)
General disorders
Multi-Organ Failure	0/234 (0%)		1/235 (0.4%)
Infusion Site Extravasation	0/234 (0%)		1/235 (0.4%)
Non-Cardiac Chest Pain	0/234 (0%)		1/235 (0.4%)
Fatigue	1/234 (0.4%)		0/235 (0%)
Fever	0/234 (0%)		2/235 (0.9%)
Infusion Related Reaction	2/234 (0.9%)		0/235 (0%)
Immune system disorders
Anaphylaxis	0/234 (0%)		1/235 (0.4%)
Allergic Reaction	0/234 (0%)		1/235 (0.4%)
Infections and infestations
Infections And Infestations - Other	0/234 (0%)		1/235 (0.4%)
Uterine Infection	1/234 (0.4%)		0/235 (0%)
Soft Tissue Infection	1/234 (0.4%)		0/235 (0%)
Skin Infection	2/234 (0.9%)		0/235 (0%)
Sepsis	3/234 (1.3%)		5/235 (2.1%)
Lung Infection	4/234 (1.7%)		1/235 (0.4%)
Device Related Infection	0/234 (0%)		1/235 (0.4%)
Urinary Tract Infection	2/234 (0.9%)		1/235 (0.4%)
Catheter Related Infection	1/234 (0.4%)		1/235 (0.4%)
Bronchial Infection	1/234 (0.4%)		0/235 (0%)
Biliary Tract Infection	0/234 (0%)		1/235 (0.4%)
Appendicitis	1/234 (0.4%)		0/235 (0%)
Abdominal Infection	0/234 (0%)		1/235 (0.4%)
Injury, poisoning and procedural complications
Wound Dehiscence	1/234 (0.4%)		0/235 (0%)
Hip Fracture	1/234 (0.4%)		0/235 (0%)
Fracture	0/234 (0%)		1/235 (0.4%)
Fall	0/234 (0%)		1/235 (0.4%)
Investigations
Weight Loss	2/234 (0.9%)		0/235 (0%)
Creatinine Increased	0/234 (0%)		1/235 (0.4%)
Neutrophil Count Decreased	1/234 (0.4%)		1/235 (0.4%)
Blood Bilirubin Increased	0/234 (0%)		1/235 (0.4%)
Metabolism and nutrition disorders
Hyponatremia	1/234 (0.4%)		0/235 (0%)
Hypokalemia	0/234 (0%)		2/235 (0.9%)
Hypocalcemia	0/234 (0%)		1/235 (0.4%)
Hypercalcemia	0/234 (0%)		2/235 (0.9%)
Dehydration	0/234 (0%)		2/235 (0.9%)
Musculoskeletal and connective tissue disorders
Bone Pain	0/234 (0%)		1/235 (0.4%)
Back Pain	0/234 (0%)		1/235 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms Benign, Malignant And Unspecified (Incl	0/234 (0%)		3/235 (1.3%)
Leukemia Secondary To Oncology Chemotherapy	1/234 (0.4%)		0/235 (0%)
Nervous system disorders
Stroke	0/234 (0%)		1/235 (0.4%)
Peripheral Sensory Neuropathy	0/234 (0%)		1/235 (0.4%)
Peripheral Motor Neuropathy	1/234 (0.4%)		0/235 (0%)
Neuralgia	1/234 (0.4%)		0/235 (0%)
Ischemia Cerebrovascular	1/234 (0.4%)		0/235 (0%)
Intracranial Hemorrhage	0/234 (0%)		1/235 (0.4%)
Headache	0/234 (0%)		2/235 (0.9%)
Syncope	3/234 (1.3%)		0/235 (0%)
Dizziness	2/234 (0.9%)		0/235 (0%)
Psychiatric disorders
Psychosis	1/234 (0.4%)		0/235 (0%)
Renal and urinary disorders
Bladder Perforation	1/234 (0.4%)		0/235 (0%)
Acute Kidney Injury	2/234 (0.9%)		1/235 (0.4%)
Respiratory, thoracic and mediastinal disorders
Respiratory, Thoracic And Mediastinal Disorders -	1/234 (0.4%)		0/235 (0%)
Respiratory Failure	0/234 (0%)		1/235 (0.4%)
Pleural Effusion	1/234 (0.4%)		0/235 (0%)
Dyspnea	0/234 (0%)		3/235 (1.3%)
Adult Respiratory Distress Syndrome	1/234 (0.4%)		0/235 (0%)
Vascular disorders
Thromboembolic Event	4/234 (1.7%)		6/235 (2.6%)
Hypotension	0/234 (0%)		1/235 (0.4%)
Hypertension	0/234 (0%)		2/235 (0.9%)
Hematoma	1/234 (0.4%)		0/235 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride)		Arm II (Paclitaxel, Carboplatin, Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	222/234 (94.9%)		222/235 (94.5%)
Blood and lymphatic system disorders
Thrombotic Thrombocytopenic Purpura	1/234 (0.4%)		0/235 (0%)
Lymph Node Pain	1/234 (0.4%)		1/235 (0.4%)
Leukocytosis	2/234 (0.9%)		1/235 (0.4%)
Anemia	168/234 (71.8%)		154/235 (65.5%)
Febrile Neutropenia	9/234 (3.8%)		5/235 (2.1%)
Cardiac disorders
Atrial Fibrillation	3/234 (1.3%)		2/235 (0.9%)
Ventricular Tachycardia	0/234 (0%)		1/235 (0.4%)
Supraventricular Tachycardia	0/234 (0%)		1/235 (0.4%)
Palpitations	9/234 (3.8%)		13/235 (5.5%)
Myocardial Infarction	0/234 (0%)		1/235 (0.4%)
Heart Failure	1/234 (0.4%)		0/235 (0%)
Restrictive Cardiomyopathy	1/234 (0.4%)		0/235 (0%)
Ventricular Arrhythmia	0/234 (0%)		1/235 (0.4%)
Sinus Tachycardia	7/234 (3%)		7/235 (3%)
Chest Pain - Cardiac	3/234 (1.3%)		1/235 (0.4%)
Ear and labyrinth disorders
Middle Ear Inflammation	0/234 (0%)		1/235 (0.4%)
Vertigo	1/234 (0.4%)		1/235 (0.4%)
Tinnitus	8/234 (3.4%)		16/235 (6.8%)
Hearing Impaired	5/234 (2.1%)		5/235 (2.1%)
Vestibular Disorder	0/234 (0%)		1/235 (0.4%)
Ear Pain	3/234 (1.3%)		3/235 (1.3%)
Endocrine disorders
Hypothyroidism	0/234 (0%)		4/235 (1.7%)
Hyperthyroidism	1/234 (0.4%)		0/235 (0%)
Eye disorders
Uveitis	0/234 (0%)		1/235 (0.4%)
Watering Eyes	1/234 (0.4%)		2/235 (0.9%)
Flashing Lights	2/234 (0.9%)		0/235 (0%)
Cataract	2/234 (0.9%)		2/235 (0.9%)
Photophobia	1/234 (0.4%)		0/235 (0%)
Conjunctivitis	1/234 (0.4%)		0/235 (0%)
Retinopathy	0/234 (0%)		1/235 (0.4%)
Blurred Vision	23/234 (9.8%)		21/235 (8.9%)
Dry Eye	2/234 (0.9%)		3/235 (1.3%)
Floaters	3/234 (1.3%)		1/235 (0.4%)
Gastrointestinal disorders
Dysphagia	8/234 (3.4%)		5/235 (2.1%)
Dyspepsia	18/234 (7.7%)		18/235 (7.7%)
Dry Mouth	6/234 (2.6%)		4/235 (1.7%)
Colonic Perforation	1/234 (0.4%)		0/235 (0%)
Colonic Fistula	0/234 (0%)		1/235 (0.4%)
Colitis	2/234 (0.9%)		1/235 (0.4%)
Constipation	100/234 (42.7%)		111/235 (47.2%)
Diarrhea	133/234 (56.8%)		79/235 (33.6%)
Cheilitis	1/234 (0.4%)		1/235 (0.4%)
Vomiting	75/234 (32.1%)		62/235 (26.4%)
Bloating	9/234 (3.8%)		11/235 (4.7%)
Small Intestinal Perforation	0/234 (0%)		1/235 (0.4%)
Stomach Pain	5/234 (2.1%)		2/235 (0.9%)
Small Intestinal Obstruction	1/234 (0.4%)		2/235 (0.9%)
Anal Hemorrhage	2/234 (0.9%)		1/235 (0.4%)
Rectal Fistula	1/234 (0.4%)		0/235 (0%)
Abdominal Pain	57/234 (24.4%)		58/235 (24.7%)
Rectal Hemorrhage	4/234 (1.7%)		5/235 (2.1%)
Oral Dysesthesia	0/234 (0%)		2/235 (0.9%)
Mucositis Oral	21/234 (9%)		27/235 (11.5%)
Lower Gastrointestinal Hemorrhage	1/234 (0.4%)		0/235 (0%)
Ileal Obstruction	1/234 (0.4%)		0/235 (0%)
Intra-Abdominal Hemorrhage	0/234 (0%)		1/235 (0.4%)
Gastrointestinal Pain	1/234 (0.4%)		0/235 (0%)
Oral Pain	1/234 (0.4%)		4/235 (1.7%)
Abdominal Distension	5/234 (2.1%)		7/235 (3%)
Nausea	126/234 (53.8%)		125/235 (53.2%)
Gastroesophageal Reflux Disease	16/234 (6.8%)		11/235 (4.7%)
Rectal Pain	2/234 (0.9%)		0/235 (0%)
Esophageal Ulcer	0/234 (0%)		1/235 (0.4%)
Fecal Incontinence	1/234 (0.4%)		3/235 (1.3%)
Hemorrhoidal Hemorrhage	0/234 (0%)		1/235 (0.4%)
Hemorrhoids	7/234 (3%)		2/235 (0.9%)
Ascites	6/234 (2.6%)		4/235 (1.7%)
Toothache	3/234 (1.3%)		3/235 (1.3%)
Dental Caries	1/234 (0.4%)		0/235 (0%)
Flatulence	5/234 (2.1%)		5/235 (2.1%)
Gastritis	0/234 (0%)		2/235 (0.9%)
General disorders
General Disorders And Administration Site Conditio	0/234 (0%)		1/235 (0.4%)
Pain	33/234 (14.1%)		27/235 (11.5%)
Malaise	4/234 (1.7%)		4/235 (1.7%)
Localized Edema	3/234 (1.3%)		5/235 (2.1%)
Injection Site Reaction	2/234 (0.9%)		0/235 (0%)
Infusion Site Extravasation	3/234 (1.3%)		2/235 (0.9%)
Flu Like Symptoms	8/234 (3.4%)		3/235 (1.3%)
Edema Trunk	1/234 (0.4%)		4/235 (1.7%)
Non-Cardiac Chest Pain	9/234 (3.8%)		12/235 (5.1%)
Edema Limbs	45/234 (19.2%)		37/235 (15.7%)
Edema Face	1/234 (0.4%)		2/235 (0.9%)
Fatigue	174/234 (74.4%)		151/235 (64.3%)
Fever	14/234 (6%)		15/235 (6.4%)
Gait Disturbance	6/234 (2.6%)		3/235 (1.3%)
Chills	6/234 (2.6%)		14/235 (6%)
Infusion Related Reaction	17/234 (7.3%)		16/235 (6.8%)
Immune system disorders
Anaphylaxis	0/234 (0%)		1/235 (0.4%)
Allergic Reaction	14/234 (6%)		12/235 (5.1%)
Autoimmune Disorder	0/234 (0%)		1/235 (0.4%)
Infections and infestations
Infections And Infestations - Other	1/234 (0.4%)		0/235 (0%)
Wound Infection	2/234 (0.9%)		1/235 (0.4%)
Upper Respiratory Infection	9/234 (3.8%)		9/235 (3.8%)
Tooth Infection	3/234 (1.3%)		2/235 (0.9%)
Vulval Infection	0/234 (0%)		1/235 (0.4%)
Soft Tissue Infection	2/234 (0.9%)		0/235 (0%)
Skin Infection	7/234 (3%)		5/235 (2.1%)
Sinusitis	3/234 (1.3%)		5/235 (2.1%)
Sepsis	7/234 (3%)		5/235 (2.1%)
Rhinitis Infective	0/234 (0%)		1/235 (0.4%)
Rash Pustular	1/234 (0.4%)		0/235 (0%)
Otitis Media	1/234 (0.4%)		1/235 (0.4%)
Papulopustular Rash	2/234 (0.9%)		2/235 (0.9%)
Otitis Externa	1/234 (0.4%)		0/235 (0%)
Nail Infection	0/234 (0%)		1/235 (0.4%)
Mucosal Infection	0/234 (0%)		1/235 (0.4%)
Lung Infection	3/234 (1.3%)		4/235 (1.7%)
Kidney Infection	0/234 (0%)		1/235 (0.4%)
Eye Infection	0/234 (0%)		1/235 (0.4%)
Conjunctivitis Infective	1/234 (0.4%)		1/235 (0.4%)
Vaginal Infection	4/234 (1.7%)		2/235 (0.9%)
Urinary Tract Infection	28/234 (12%)		21/235 (8.9%)
Catheter Related Infection	1/234 (0.4%)		1/235 (0.4%)
Bronchial Infection	2/234 (0.9%)		1/235 (0.4%)
Enterocolitis Infectious	0/234 (0%)		1/235 (0.4%)
Biliary Tract Infection	0/234 (0%)		1/235 (0.4%)
Appendicitis	1/234 (0.4%)		0/235 (0%)
Abdominal Infection	0/234 (0%)		1/235 (0.4%)
Injury, poisoning and procedural complications
Wound Dehiscence	4/234 (1.7%)		1/235 (0.4%)
Vascular Access Complication	0/234 (0%)		1/235 (0.4%)
Spinal Fracture	0/234 (0%)		2/235 (0.9%)
Hip Fracture	1/234 (0.4%)		0/235 (0%)
Fracture	3/234 (1.3%)		1/235 (0.4%)
Fall	11/234 (4.7%)		7/235 (3%)
Wound Complication	2/234 (0.9%)		3/235 (1.3%)
Dermatitis Radiation	0/234 (0%)		1/235 (0.4%)
Bruising	10/234 (4.3%)		16/235 (6.8%)
Ankle Fracture	1/234 (0.4%)		2/235 (0.9%)
Investigations
Weight Loss	27/234 (11.5%)		22/235 (9.4%)
Weight Gain	3/234 (1.3%)		9/235 (3.8%)
Platelet Count Decreased	90/234 (38.5%)		85/235 (36.2%)
Lymphocyte Count Increased	1/234 (0.4%)		1/235 (0.4%)
Lymphocyte Count Decreased	19/234 (8.1%)		19/235 (8.1%)
Inr Increased	0/234 (0%)		1/235 (0.4%)
Hemoglobin Increased	0/234 (0%)		1/235 (0.4%)
Ggt Increased	1/234 (0.4%)		0/235 (0%)
Creatinine Increased	25/234 (10.7%)		25/235 (10.6%)
Cholesterol High	2/234 (0.9%)		1/235 (0.4%)
Neutrophil Count Decreased	117/234 (50%)		119/235 (50.6%)
Blood Bilirubin Increased	5/234 (2.1%)		4/235 (1.7%)
White Blood Cell Decreased	134/234 (57.3%)		133/235 (56.6%)
Aspartate Aminotransferase Increased	19/234 (8.1%)		25/235 (10.6%)
Alkaline Phosphatase Increased	27/234 (11.5%)		24/235 (10.2%)
Alanine Aminotransferase Increased	27/234 (11.5%)		24/235 (10.2%)
Activated Partial Thromboplastin Time Prolonged	1/234 (0.4%)		0/235 (0%)
Metabolism and nutrition disorders
Obesity	0/234 (0%)		1/235 (0.4%)
Hypophosphatemia	3/234 (1.3%)		6/235 (2.6%)
Hyponatremia	29/234 (12.4%)		32/235 (13.6%)
Hypomagnesemia	49/234 (20.9%)		32/235 (13.6%)
Hypokalemia	34/234 (14.5%)		35/235 (14.9%)
Hypoglycemia	4/234 (1.7%)		4/235 (1.7%)
Hypocalcemia	17/234 (7.3%)		14/235 (6%)
Hypoalbuminemia	28/234 (12%)		39/235 (16.6%)
Hyperuricemia	0/234 (0%)		1/235 (0.4%)
Hypertriglyceridemia	1/234 (0.4%)		0/235 (0%)
Hypernatremia	7/234 (3%)		4/235 (1.7%)
Hypermagnesemia	1/234 (0.4%)		0/235 (0%)
Hyperkalemia	2/234 (0.9%)		6/235 (2.6%)
Hyperglycemia	56/234 (23.9%)		46/235 (19.6%)
Hypercalcemia	12/234 (5.1%)		14/235 (6%)
Glucose Intolerance	1/234 (0.4%)		2/235 (0.9%)
Dehydration	14/234 (6%)		18/235 (7.7%)
Anorexia	71/234 (30.3%)		65/235 (27.7%)
Musculoskeletal and connective tissue disorders
Pain In Extremity	36/234 (15.4%)		42/235 (17.9%)
Osteoporosis	0/234 (0%)		1/235 (0.4%)
Neck Pain	4/234 (1.7%)		3/235 (1.3%)
Myalgia	45/234 (19.2%)		48/235 (20.4%)
Muscle Weakness Upper Limb	1/234 (0.4%)		3/235 (1.3%)
Muscle Weakness Lower Limb	4/234 (1.7%)		9/235 (3.8%)
Muscle Weakness Left-Sided	1/234 (0.4%)		0/235 (0%)
Joint Range Of Motion Decreased Lumbar Spine	0/234 (0%)		1/235 (0.4%)
Joint Range Of Motion Decreased	0/234 (0%)		1/235 (0.4%)
Generalized Muscle Weakness	24/234 (10.3%)		24/235 (10.2%)
Flank Pain	2/234 (0.9%)		3/235 (1.3%)
Chest Wall Pain	0/234 (0%)		2/235 (0.9%)
Buttock Pain	1/234 (0.4%)		3/235 (1.3%)
Bone Pain	24/234 (10.3%)		24/235 (10.2%)
Back Pain	30/234 (12.8%)		36/235 (15.3%)
Arthritis	3/234 (1.3%)		7/235 (3%)
Arthralgia	43/234 (18.4%)		55/235 (23.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor Pain	3/234 (1.3%)		1/235 (0.4%)
Leukemia Secondary To Oncology Chemotherapy	1/234 (0.4%)		0/235 (0%)
Nervous system disorders
Tremor	4/234 (1.7%)		2/235 (0.9%)
Transient Ischemic Attacks	0/234 (0%)		1/235 (0.4%)
Stroke	0/234 (0%)		1/235 (0.4%)
Seizure	2/234 (0.9%)		0/235 (0%)
Presyncope	1/234 (0.4%)		3/235 (1.3%)
Peripheral Sensory Neuropathy	145/234 (62%)		157/235 (66.8%)
Peripheral Motor Neuropathy	14/234 (6%)		16/235 (6.8%)
Paresthesia	20/234 (8.5%)		9/235 (3.8%)
Neuralgia	1/234 (0.4%)		1/235 (0.4%)
Memory Impairment	9/234 (3.8%)		10/235 (4.3%)
Lethargy	3/234 (1.3%)		1/235 (0.4%)
Ischemia Cerebrovascular	1/234 (0.4%)		0/235 (0%)
Movements Involuntary	1/234 (0.4%)		1/235 (0.4%)
Intracranial Hemorrhage	1/234 (0.4%)		1/235 (0.4%)
Headache	44/234 (18.8%)		33/235 (14%)
Facial Muscle Weakness	1/234 (0.4%)		0/235 (0%)
Encephalopathy	0/234 (0%)		1/235 (0.4%)
Dysphasia	1/234 (0.4%)		0/235 (0%)
Dysgeusia	27/234 (11.5%)		25/235 (10.6%)
Dysesthesia	0/234 (0%)		2/235 (0.9%)
Dysarthria	1/234 (0.4%)		2/235 (0.9%)
Syncope	6/234 (2.6%)		0/235 (0%)
Dizziness	33/234 (14.1%)		37/235 (15.7%)
Depressed Level Of Consciousness	0/234 (0%)		1/235 (0.4%)
Concentration Impairment	1/234 (0.4%)		1/235 (0.4%)
Cognitive Disturbance	4/234 (1.7%)		1/235 (0.4%)
Ataxia	1/234 (0.4%)		0/235 (0%)
Akathisia	1/234 (0.4%)		3/235 (1.3%)
Psychiatric disorders
Psychosis	1/234 (0.4%)		0/235 (0%)
Personality Change	1/234 (0.4%)		3/235 (1.3%)
Restlessness	0/234 (0%)		2/235 (0.9%)
Insomnia	36/234 (15.4%)		42/235 (17.9%)
Hallucinations	1/234 (0.4%)		1/235 (0.4%)
Depression	30/234 (12.8%)		30/235 (12.8%)
Delirium	0/234 (0%)		2/235 (0.9%)
Confusion	3/234 (1.3%)		8/235 (3.4%)
Anxiety	24/234 (10.3%)		38/235 (16.2%)
Agitation	3/234 (1.3%)		6/235 (2.6%)
Renal and urinary disorders
Renal And Urinary Disorders - Other	0/234 (0%)		1/235 (0.4%)
Urinary Urgency	7/234 (3%)		5/235 (2.1%)
Urinary Tract Obstruction	0/234 (0%)		2/235 (0.9%)
Urinary Retention	1/234 (0.4%)		2/235 (0.9%)
Urinary Incontinence	12/234 (5.1%)		19/235 (8.1%)
Urinary Tract Pain	14/234 (6%)		15/235 (6.4%)
Urinary Frequency	19/234 (8.1%)		14/235 (6%)
Urinary Fistula	1/234 (0.4%)		0/235 (0%)
Renal Calculi	0/234 (0%)		2/235 (0.9%)
Proteinuria	5/234 (2.1%)		3/235 (1.3%)
Hematuria	7/234 (3%)		14/235 (6%)
Cystitis Noninfective	1/234 (0.4%)		2/235 (0.9%)
Chronic Kidney Disease	1/234 (0.4%)		2/235 (0.9%)
Bladder Spasm	1/234 (0.4%)		1/235 (0.4%)
Bladder Perforation	1/234 (0.4%)		0/235 (0%)
Acute Kidney Injury	2/234 (0.9%)		1/235 (0.4%)
Reproductive system and breast disorders
Vaginal Perforation	1/234 (0.4%)		0/235 (0%)
Vaginal Pain	3/234 (1.3%)		2/235 (0.9%)
Vaginal Hemorrhage	11/234 (4.7%)		19/235 (8.1%)
Vaginal Dryness	3/234 (1.3%)		2/235 (0.9%)
Uterine Hemorrhage	1/234 (0.4%)		0/235 (0%)
Perineal Pain	1/234 (0.4%)		0/235 (0%)
Pelvic Pain	8/234 (3.4%)		12/235 (5.1%)
Menorrhagia	1/234 (0.4%)		0/235 (0%)
Vaginal Discharge	11/234 (4.7%)		11/235 (4.7%)
Vaginal Inflammation	2/234 (0.9%)		0/235 (0%)
Breast Pain	1/234 (0.4%)		1/235 (0.4%)
Respiratory, thoracic and mediastinal disorders
Voice Alteration	2/234 (0.9%)		1/235 (0.4%)
Sore Throat	8/234 (3.4%)		6/235 (2.6%)
Sneezing	0/234 (0%)		1/235 (0.4%)
Respiratory Failure	0/234 (0%)		2/235 (0.9%)
Postnasal Drip	4/234 (1.7%)		2/235 (0.9%)
Pneumothorax	1/234 (0.4%)		1/235 (0.4%)
Pneumonitis	0/234 (0%)		1/235 (0.4%)
Pleural Effusion	2/234 (0.9%)		2/235 (0.9%)
Nasal Congestion	10/234 (4.3%)		4/235 (1.7%)
Pleuritic Pain	1/234 (0.4%)		0/235 (0%)
Productive Cough	5/234 (2.1%)		4/235 (1.7%)
Hypoxia	2/234 (0.9%)		1/235 (0.4%)
Hoarseness	3/234 (1.3%)		2/235 (0.9%)
Sleep Apnea	2/234 (0.9%)		0/235 (0%)
Hiccups	0/234 (0%)		1/235 (0.4%)
Epistaxis	5/234 (2.1%)		4/235 (1.7%)
Dyspnea	63/234 (26.9%)		51/235 (21.7%)
Cough	27/234 (11.5%)		38/235 (16.2%)
Wheezing	2/234 (0.9%)		1/235 (0.4%)
Atelectasis	0/234 (0%)		2/235 (0.9%)
Allergic Rhinitis	12/234 (5.1%)		5/235 (2.1%)
Skin and subcutaneous tissue disorders
Urticaria	2/234 (0.9%)		0/235 (0%)
Skin Ulceration	1/234 (0.4%)		1/235 (0.4%)
Skin Induration	1/234 (0.4%)		0/235 (0%)
Skin Hyperpigmentation	4/234 (1.7%)		1/235 (0.4%)
Scalp Pain	3/234 (1.3%)		4/235 (1.7%)
Rash Acneiform	11/234 (4.7%)		18/235 (7.7%)
Purpura	1/234 (0.4%)		1/235 (0.4%)
Pruritus	16/234 (6.8%)		11/235 (4.7%)
Pain Of Skin	2/234 (0.9%)		1/235 (0.4%)
Rash Maculo-Papular	27/234 (11.5%)		24/235 (10.2%)
Nail Ridging	0/234 (0%)		1/235 (0.4%)
Nail Discoloration	3/234 (1.3%)		4/235 (1.7%)
Telangiectasia	0/234 (0%)		1/235 (0.4%)
Hyperhidrosis	3/234 (1.3%)		1/235 (0.4%)
Dry Skin	12/234 (5.1%)		11/235 (4.7%)
Bullous Dermatitis	1/234 (0.4%)		0/235 (0%)
Alopecia	146/234 (62.4%)		131/235 (55.7%)
Vascular disorders
Thromboembolic Event	20/234 (8.5%)		28/235 (11.9%)
Superficial Thrombophlebitis	0/234 (0%)		1/235 (0.4%)
Phlebitis	3/234 (1.3%)		1/235 (0.4%)
Lymphedema	3/234 (1.3%)		2/235 (0.9%)
Hypotension	5/234 (2.1%)		8/235 (3.4%)
Hypertension	40/234 (17.1%)		47/235 (20%)
Hot Flashes	24/234 (10.3%)		28/235 (11.9%)
Hematoma	2/234 (0.9%)		0/235 (0%)
Flushing	7/234 (3%)		3/235 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.