Tamoxifen Citrate or Letrozole With or Without Bevacizumab in Treating Women With Stage IIIB or Stage IV Breast Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00601900
• Collaborator: (none)
• Enrollment: 394
• Locations: 526
• Arms: 2
• Patients Per Site: 0.7

Study Details

Study Description

Brief Summary

This randomized phase III trial studies tamoxifen citrate or letrozole together with bevacizumab to see how well it works compared with tamoxifen citrate or letrozole alone in treating women with stage IIIB or stage IV breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate or letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Immunotherapy with monoclonal antibodies, such as bevacizumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving hormone therapy is more effective with or without bevacizumab in treating advanced breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Invasive Breast Carcinoma; Recurrent Breast Carcinoma; Stage III Breast Cancer AJCC v6; Stage IV Breast Cancer AJCC v6 and v7	Biological: Bevacizumab; Other: Laboratory Biomarker Analysis; Drug: Letrozole; Other: Questionnaire Administration; Drug: Tamoxifen Citrate	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. To compare the progression-free survival of letrozole therapy alone with the combination of letrozole therapy plus bevacizumab as first-line treatment in women with estrogen- and/or progesterone-receptor-positive advanced breast cancer.

SECONDARY OBJECTIVES:

1. To compare the proportion of patients receiving letrozole alone, who remain progression-free at 6 and 12 months, to those receiving letrozole plus bevacizumab.

2. To compare the incidence of objective response (complete response [CR] + partial response [PR]) in patients receiving letrozole with and without bevacizumab, as determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, excluding patients with non-measurable disease.

3. To compare the incidence of clinical benefit (CR + PR + stable disease >= 6 months) in patients receiving letrozole with and without bevacizumab.

4. To compare the duration of objective response in patients receiving letrozole with and without bevacizumab.

5. To compare the time to treatment failure in patients receiving letrozole with and without bevacizumab.

6. To compare the overall survival of patients receiving letrozole with and without bevacizumab, including the probability of survival until 36 months.

7. To compare toxicity levels between the bevacizumab arm and the arm without bevacizumab in both the letrozole-treated patients and in the tamoxifen-treated patients.

8. To compare progression-free survival and overall survival of all patients receiving endocrine therapy with and without bevacizumab (by combining both letrozole and tamoxifen* patient subgroups).

CORRELATIVE OBJECTIVES:

1. To compare baseline and changes in serial levels of circulating endothelial cells and circulating tumor cells in patients treated with endocrine therapy alone or endocrine therapy plus bevacizumab, and to explore the relationship of these markers with progression free survival.

2. To conduct proteomic analysis of longitudinal samples from patients with advanced-stage disease undergoing hormonal therapy to define new serum-based biomarkers related to disease activity.

3. To identify biologic correlates that will predict progression-free survival (PFS) and response to therapy.

4. To conduct pharmacogenomic assessment of candidate variants in the VEGF, CYP2D6, and CYP19 genes and evaluate their association with PFS and other study outcomes.

5. To identify single nucleotide polymorphisms (SNPs) associated with progression free survival in the genome-wide approach (GWAS).

6. To identify factors other than chronological age that predict the risk of grade 3, 4 or 5 toxicity with bevacizumab and endocrine therapy by means of functional age assessment measures.

7. To perform an exploratory analysis of the ability of the other factors included in the functional age assessment (either individual or in combination), to predict the risk of grade 3, 4 or 5 toxicity.

8. To evaluate longitudinal changes in the parameters of the factors described in objective VI while on therapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

NOTE: The placebo-controlled portion of the study was canceled on 5-15-10.

ARM I: Patients receive endocrine therapy* (tamoxifen citrate or letrozole) orally (PO) once daily (QD) on days 1-21 and bevacizumab intravenously (IV) over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive endocrine therapy* (tamoxifen citrate or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 6 months for the first 2 years and then annually for up to 3 years.

• NOTE: As of 5/15/2011, patients only receive letrozole.

Study Design

• Study Type: Interventional
• Actual Enrollment: 394 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Endocrine Therapy With or Without Anti-VEGF Therapy: A Randomized, Phase III Trial of Endocrine Therapy Alone or Endocrine Therapy Plus Bevacizumab (NSC 704865) for Women With Hormone Receptor-Positive Advanced Breast Cancer
• Actual Study Start Date: May 15, 2008
• Actual Primary Completion Date: Jun 30, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (endocrine therapy with monoclonal antibody) Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Letrozole; Given PO; Other Names: CGS 20267 Femara ; Other: Questionnaire Administration; Ancillary studies; Drug: Tamoxifen Citrate; Given PO; Other Names: Apo-Tamox Clonoxifen Dignotamoxi Ebefen Emblon Estroxyn Fentamox Gen-Tamoxifen Genox ICI 46,474 ICI-46474 Jenoxifen Kessar Ledertam Lesporene Nolgen Noltam Nolvadex Nolvadex-D Nourytam Novo-Tamoxifen Novofen Noxitem Oestrifen Oncotam PMS-Tamoxifen Soltamox TAM Tamax Tamaxin Tamifen Tamizam Tamofen Tamoxasta Tamoxifeni Citras Zemide
Active Comparator: Arm II (endocrine therapy) Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Letrozole; Given PO; Other Names: CGS 20267 Femara ; Other: Questionnaire Administration; Ancillary studies; Drug: Tamoxifen Citrate; Given PO; Other Names: Apo-Tamox Clonoxifen Dignotamoxi Ebefen Emblon Estroxyn Fentamox Gen-Tamoxifen Genox ICI 46,474 ICI-46474 Jenoxifen Kessar Ledertam Lesporene Nolgen Noltam Nolvadex Nolvadex-D Nourytam Novo-Tamoxifen Novofen Noxitem Oestrifen Oncotam PMS-Tamoxifen Soltamox TAM Tamax Tamaxin Tamifen Tamizam Tamofen Tamoxasta Tamoxifeni Citras Zemide

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [From randomization until disease progression or death whichever occurs first, assessed up to 5 years]

   The Primary Endpoint for this study was to compare the progression-free survival of letrozole therapy alone with the combination of letrozole therapy plus bevacizumab as first-line treatment in women with estrogen- and/or progesterone-receptor-positive advanced breast cancer. Progression-free survival (PFS) was defined as the time from randomization until disease progression or death, whichever occurs first. The median PFS was estimated using the Kaplan-Meier method. Progression was assessed per RECIST criteria, and defined as at least a 20% increase in the sum of the longest diameters of target lesions from baseline or the appearance of new lesions.

Secondary Outcome Measures

1. 12 Month Progression Free Survival Rate [At 12 months]

   The 12 month progression-free survival rate was defined as the proportion of patients who were alive progression-free 12 months after registration into the study.

2. 6 Month Progression-Free Survival Rate [At 6 months]

   The 6 month progression-free survival rate was defined as the proportion of patients who were alive progression-free 6 months after registration into the study.

3. Objective Response Rate [Assessed up to 5 years]

   Response was defined using RECIST criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions.

4. Overall Survival (OS) [Assessed up to 5 years]

   OS is defined as the time from study entry to death from any cause. The median OS was estimated using the Kaplan-Meier method.

5. Duration of Tumor Response [From the time measurement criteria are met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 years]

   Defined by RECIST criteria.

6. Probability of Surviving Until 36 Months [At 36 months]

7. Site of Progression [Up to 5 years]

8. Time-to-treatment Failure [Up to 5 years]

   From randomization until first disease progression, early termination of protocol therapy due to toxicity or withdrawn consent, or going onto non-protocol therapy. Defined by RECIST criteria. The proportional hazards model will be used to compare the arms on time-to-treatment-failure

9. Treatment Related Toxicity [Up to 5 years]

   Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Tabulated by type, grade, and arm.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologic confirmation of invasive cancer of the female breast in either the primary or metastatic setting

• Stage IV disease or stage IIIB disease (using American Joint Committee on Cancer [AJCC] criteria, 6th edition) not amenable to local therapy

• Patients may not have a "currently active" second malignancy other than non-melanoma skin cancers; patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse

• Tumors (from either primary or metastatic sites) must express estrogen receptor (ER) and/or progesterone receptor (PgR) in >= 1% of cells will be considered positive

• Postmenopausal women are eligible for this trial; before study registration, menopausal status must be defined according to the criteria below:

• Age >= 55 years and one year or more of amenorrhea

• Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/ml

• For women age < 55 with prior hysterectomy but intact ovaries, with an estradiol assay < 20 pg/ml

• Surgical menopause with bilateral oophorectomy (at least 28 days must elapse from surgery to time of study registration)

• Ovarian suppression on a luteinizing hormone-releasing hormone (LH-RH) agonist

• Premenopausal women who do not meet the postmenopausal criteria above are also eligible, but are required to undergo ovarian suppression; this can be initiated any time prior to or on day 1 of protocol therapy, regardless of chosen endocrine therapy, and will continue for the duration of protocol therapy

• Patients must have measurable or non-measurable disease by RECIST criteria, with radiologic scans within 28 days of study registration

• Measurable disease: lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 2.0 cm with conventional techniques or as >= 1.0 cm with spiral computed tomography (CT) scan

• Non-measurable disease: all other lesions, including small lesions (longest diameter < 2.0 cm with conventional techniques or < 1.0 cm with spiral CT scan) and truly non-measurable lesions

• Lesions that are considered non-measurable include the following:

• Bone lesions

• Leptomeningeal disease

• Ascites

• Pleural/pericardial effusion

• Inflammatory breast disease

• Abdominal masses that are not confirmed and followed by imaging techniques

• Cystic lesions

• Prior endocrine therapy is not required

• Prior endocrine therapy in the metastatic setting is not permitted (unless tamoxifen or an aromatase inhibitor was initiated within 4 weeks prior to registration to facilitate enrollment of patients who recently started first-line endocrine therapy for metastatic breast cancer); if prior letrozole therapy was initiated within the past 4 weeks, the patients should remain on letrozole as the study therapy; patients who began therapy with tamoxifen, anastrozole or exemestane must switch to letrozole to be eligible to participate in this study

• Prior endocrine therapy in the adjuvant setting is permitted; there is no time restriction for how long the patient must be on the adjuvant endocrine therapy, nor is there a time restriction for how long the patient needs to be off prior adjuvant endocrine therapy before beginning protocol therapy on 40503

• Prior treatment with ovarian suppression is allowed in either the adjuvant or metastatic setting; if medical ovarian suppression is being administered it can be initiated any time prior to or at the start of protocol therapy, and continued throughout the duration of the trial; surgical castration with bilateral oophorectomy must be performed at least 28 days prior to study registration (due to concerns of poor wound healing on bevacizumab)

• Patients may not have received any prior anti-VEGF or VEGFR tyrosine kinase inhibitor therapy

• Prior radiotherapy must have been completed and all toxicities resolved at least two weeks prior to registration

• Chemotherapy in the adjuvant or neoadjuvant setting is permitted; at least twelve months prior to registration must have elapsed since the completion of adjuvant or neoadjuvant chemotherapy and all toxicities must have resolved; taxane-related neurotoxicity must have resolved to sensory grade < 2 and no motor neuropathy of any grade is allowed

• Patients may have received one prior chemotherapy regimen for metastatic disease; the final dose of prior chemotherapy must have been administered at least 3 weeks prior to study registration

• Treatment with bisphosphonates is allowed and recommended as per American Society of Clinical Oncology (ASCO) guidelines

• Patients must not have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study registration, and must have fully recovered from any such procedure

• Patients must not have anticipation of need for major surgical procedure during the course of the study

• Patients must not have had a core biopsy or other minor surgical procedure, within 7 days prior to study registration; placement of a vascular access device is allowed within 7 days of registration

• Patients must not have a history of abdominal fistula, or intra-abdominal abscess within 6 months prior to study registration

• Patients with a history of gastrointestinal (GI) perforation within 12 months prior to registration are not eligible

• Patients with a history of significant bleeding episodes (e.g., hemoptysis, upper or lower GI bleeding) within 6 months prior to registration are not eligible

• Patients must not have clinically significant cardiovascular disease that includes the following:

• Uncontrolled hypertension defined as systolic blood pressure > 150 and/or diastolic blood pressure > 90 mmHg on antihypertensive medications or any prior history of hypertensive crisis or hypertensive encephalopathy

• History of myocardial infarction or unstable angina within past 6 months

• New York Heart Association (NYHA) grade 2 or greater congestive heart failure

• Symptomatic peripheral vascular disease

• Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or arterial thrombotic events

• Full dose anticoagulation therapy is allowed for the treatment of prior conditions such as venous thrombosis or atrial fibrillation, but not for the treatment of prior arterial thrombotic events; patients on full dose anticoagulants must be on a stable dose of warfarin and have an in-range international normalized ratio (INR) (usually between 2 and 3) or be on a stable dose of low-molecular weight (LMW) heparin; patients receiving antiplatelet agents are eligible, as are patients on daily prophylactic aspirin or anticoagulation for atrial fibrillation

• Patients may not have a history of stroke or transient ischemic attack within 6 months prior to study registration

• Patients with a history of seizures must be well controlled with standard medication

• Patients must not have known central nervous system (CNS) metastases or leptomeningeal disease (screening with brain imaging is not required for asymptomatic patients)

• In aromatase inhibitor (AI)-treated patients: no known allergies to imidazole drugs, (e.g. clotrimazole, ketoconazole, miconazole, econazole, sulconazole, tioconazole, or terconazole) or compounds structurally similar to bevacizumab

• In tamoxifen treated patients: no known allergies to selective estrogen receptor modulators (e.g. tamoxifen, raloxifene or toremifene) or compounds structurally similar to bevacizumab; for patients enrolled after Update #5, endocrine therapy will consist of letrozole only and this criterion will no longer apply

• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status =< 1

• No serious, non-healing wound, ulcer, or bone fracture

• Life expectancy of >= 12 weeks

• All patients who are premenopausal (if not already receiving ovarian suppression therapy/surgical oophorectomy) must have a negative beta-human chorionic gonadotropin (beta-Hcg) prior to starting on study treatment; patients may not be pregnant or nursing at any time during the study; ovarian suppression is required in women of childbearing potential by the start of protocol therapy, and will continue for the duration of protocol therapy

• Granulocytes >= 1,000/ul

• Platelet count >= 100,000/ul

• Creatinine =< 2.0 mg/dL

• Bilirubin =< 1.5 times upper limit of normal (ULN) unless due to Gilbert's syndrome

• Transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) =< 2.5 times ULN

• International normalized ratio (INR) =< 1.6, unless on full dose warfarin

• Beta-Hcg negative in premenopausal women

• Urine protein =< 1+ or urine to plasma creatinine (UPC) < 1

• Patients discovered to have >= 2+ proteinuria at baseline must undergo a 24-hour urine collection that must demonstrate < 1 g of protein/24 hr, or UPC ratio < 1 to allow participation in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Providence Hospital	Mobile	Alabama	United States	36608
2	Sparks Regional Medical Center	Fort Smith	Arkansas	United States	72901
3	East Bay Medical Oncology Hematology Medical Associates-Antioch	Antioch	California	United States	94531
4	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California	United States	94704
5	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California	United States	91505
6	Mills-Peninsula Medical Center	Burlingame	California	United States	94010
7	East Bay Radiation Oncology Center	Castro Valley	California	United States	94546
8	Eden Hospital Medical Center	Castro Valley	California	United States	94546
9	Valley Medical Oncology Consultants-Castro Valley	Castro Valley	California	United States	94546
10	Adventist Health Cancer Care Center Chico	Chico	California	United States	95973
11	Community Cancer Institute	Clovis	California	United States	93611
12	Bay Area Breast Surgeons Inc	Emeryville	California	United States	94608
13	Valley Medical Oncology Consultants-Fremont	Fremont	California	United States	94538
14	Marin General Hospital	Greenbrae	California	United States	94904
15	Los Angeles County-USC Medical Center	Los Angeles	California	United States	90033
16	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
17	Contra Costa Regional Medical Center	Martinez	California	United States	94553-3156
18	Fremont - Rideout Cancer Center	Marysville	California	United States	95901
19	Memorial Medical Center	Modesto	California	United States	95355
20	El Camino Hospital	Mountain View	California	United States	94040
21	Sutter Cancer Research Consortium	Novato	California	United States	94945
22	Highland General Hospital	Oakland	California	United States	94602
23	Alta Bates Summit Medical Center - Summit Campus	Oakland	California	United States	94609
24	Bay Area Tumor Institute	Oakland	California	United States	94609
25	Hematology and Oncology Associates-Oakland	Oakland	California	United States	94609
26	Tom K Lee Inc	Oakland	California	United States	94609
27	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
28	East Bay Medical Oncology Hematology Medical Associates Inc-Pleasant Hill	Pleasant Hill	California	United States	94523
29	John Muir Health Cancer Medical Group	Pleasant Hill	California	United States	94523
30	Valley Care Health System - Pleasanton	Pleasanton	California	United States	94588
31	Valley Medical Oncology Consultants	Pleasanton	California	United States	94588
32	Pomona Valley Hospital Medical Center	Pomona	California	United States	91767
33	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
34	Saint Helena Hospital	Saint Helena	California	United States	94574
35	Zuckerberg San Francisco General Hospital	San Francisco	California	United States	94110
36	California Pacific Medical Center-Pacific Campus	San Francisco	California	United States	94115
37	UCSF Medical Center-Mount Zion	San Francisco	California	United States	94115
38	East Bay Medical Oncology Hematology Associates Inc	San Leandro	California	United States	94578
39	Doctors Medical Center- JC Robinson Regional Cancer Center	San Pablo	California	United States	94806
40	Gene Upshaw Memorial Tahoe Forest Cancer Center	Truckee	California	United States	96161
41	Northbay Cancer Center	Vacaville	California	United States	95687
42	Sutter Solano Medical Center/Cancer Center	Vallejo	California	United States	94589
43	The Medical Center of Aurora	Aurora	Colorado	United States	80012
44	Boulder Community Hospital	Boulder	Colorado	United States	80301
45	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado	United States	80907
46	Porter Adventist Hospital	Denver	Colorado	United States	80210
47	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado	United States	80218
48	SCL Health Saint Joseph Hospital	Denver	Colorado	United States	80218
49	Rose Medical Center	Denver	Colorado	United States	80220
50	Western States Cancer Research NCORP	Denver	Colorado	United States	80222
51	Swedish Medical Center	Englewood	Colorado	United States	80113
52	Poudre Valley Hospital	Fort Collins	Colorado	United States	80524
53	Saint Mary's Hospital and Regional Medical Center	Grand Junction	Colorado	United States	81501
54	North Colorado Medical Center	Greeley	Colorado	United States	80631
55	Saint Anthony Hospital	Lakewood	Colorado	United States	80228
56	Littleton Adventist Hospital	Littleton	Colorado	United States	80122
57	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
58	Longmont United Hospital	Longmont	Colorado	United States	80501
59	McKee Medical Center	Loveland	Colorado	United States	80539
60	Saint Mary Corwin Medical Center	Pueblo	Colorado	United States	81004
61	North Suburban Medical Center	Thornton	Colorado	United States	80229
62	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
63	Hartford Hospital	Hartford	Connecticut	United States	06102
64	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
65	Middlesex Hospital	Middletown	Connecticut	United States	06457
66	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
67	Yale University	New Haven	Connecticut	United States	06520
68	Stamford Hospital/Bennett Cancer Center	Stamford	Connecticut	United States	06904
69	Beebe Medical Center	Lewes	Delaware	United States	19958
70	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
71	Sibley Memorial Hospital	Washington	District of Columbia	United States	20016
72	Boca Raton Regional Hospital	Boca Raton	Florida	United States	33486
73	Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
74	Florida Cancer Specialists-Gainesville Cancer Center	Gainesville	Florida	United States	32605
75	Jupiter Medical Center	Jupiter	Florida	United States	33458
76	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
77	University Cancer and Blood Center LLC	Athens	Georgia	United States	30607
78	Piedmont Hospital	Atlanta	Georgia	United States	30309
79	Atlanta Regional CCOP	Atlanta	Georgia	United States	30342
80	Emory Saint Joseph's Hospital	Atlanta	Georgia	United States	30342
81	Northside Hospital	Atlanta	Georgia	United States	30342
82	Augusta University Medical Center	Augusta	Georgia	United States	30912
83	WellStar Cobb Hospital	Austell	Georgia	United States	30106
84	John B Amos Cancer Center	Columbus	Georgia	United States	31904
85	Dekalb Medical Center	Decatur	Georgia	United States	30033
86	Dublin Hematology Oncology Care PC	Dublin	Georgia	United States	31021
87	Piedmont Fayette Hospital	Fayetteville	Georgia	United States	30214
88	Eisenhower Army Medical Center	Fort Gordon	Georgia	United States	30905-5650
89	Northeast Georgia Medical Center-Gainesville	Gainesville	Georgia	United States	30501
90	Northside Hospital - Gwinnett	Lawrenceville	Georgia	United States	30046
91	Medical Center of Central Georgia	Macon	Georgia	United States	31201
92	Wellstar Kennestone Hospital	Marietta	Georgia	United States	30060
93	Southern Regional Medical Center	Riverdale	Georgia	United States	30274
94	Harbin Clinic Medical Oncology and Clinical Research	Rome	Georgia	United States	30165
95	Pali Momi Medical Center	'Aiea	Hawaii	United States	96701
96	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii	United States	96813
97	Queen's Medical Center	Honolulu	Hawaii	United States	96813
98	Straub Clinic and Hospital	Honolulu	Hawaii	United States	96813
99	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
100	Queen's Cancer Center - Kuakini	Honolulu	Hawaii	United States	96817
101	The Cancer Center of Hawaii-Liliha	Honolulu	Hawaii	United States	96817
102	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
103	Maui Memorial Medical Center	Wailuku	Hawaii	United States	96793
104	Pacific Cancer Institute of Maui	Wailuku	Hawaii	United States	96793
105	Saint Anthony's Health	Alton	Illinois	United States	62002
106	Rush - Copley Medical Center	Aurora	Illinois	United States	60504
107	Saint Joseph Medical Center	Bloomington	Illinois	United States	61701
108	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61704
109	Graham Hospital Association	Canton	Illinois	United States	61520
110	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
111	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
112	Memorial Hospital	Carthage	Illinois	United States	62321
113	Mount Sinai Hospital Medical Center	Chicago	Illinois	United States	60608
114	John H Stroger Jr Hospital of Cook County	Chicago	Illinois	United States	60612
115	Mercy Hospital and Medical Center	Chicago	Illinois	United States	60616
116	Presence Resurrection Medical Center	Chicago	Illinois	United States	60631
117	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
118	Advocate Illinois Masonic Medical Center	Chicago	Illinois	United States	60657
119	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
120	Heartland Cancer Research NCORP	Decatur	Illinois	United States	62526
121	Advocate Good Samaritan Hospital	Downers Grove	Illinois	United States	60515
122	AMITA Health Alexian Brothers Medical Center	Elk Grove Village	Illinois	United States	60007
123	Elmhurst Memorial Hospital	Elmhurst	Illinois	United States	60126
124	Eureka Hospital	Eureka	Illinois	United States	61530
125	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
126	Freeport Memorial Hospital/Leonard C Ferguson Cancer Center	Freeport	Illinois	United States	61032
127	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
128	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
129	Illinois CancerCare-Havana	Havana	Illinois	United States	62644
130	Mason District Hospital	Havana	Illinois	United States	62644
131	Duly Health and Care Joliet	Joliet	Illinois	United States	60435
132	Presence Saint Mary's Hospital	Kankakee	Illinois	United States	60901
133	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
134	AMITA Health Adventist Medical Center	La Grange	Illinois	United States	60525
135	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
136	Mcdonough District Hospital	Macomb	Illinois	United States	61455
137	Garneau, Stewart C MD (UIA Investigator)	Moline	Illinois	United States	61265
138	Porubcin, Michael MD (UIA Investigator)	Moline	Illinois	United States	61265
139	Sharis, Christine M MD (UIA Investigator)	Moline	Illinois	United States	61265
140	Spector, David MD (UIA Investigator)	Moline	Illinois	United States	61265
141	Stoffel, Thomas J MD (UIA Investigator)	Moline	Illinois	United States	61265
142	Trinity Medical Center	Moline	Illinois	United States	61265
143	Holy Family Medical Center	Monmouth	Illinois	United States	61462
144	Illinois CancerCare-Monmouth	Monmouth	Illinois	United States	61462
145	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
146	Bromenn Regional Medical Center	Normal	Illinois	United States	61761
147	Carle Cancer Institute Normal	Normal	Illinois	United States	61761
148	Illinois CancerCare-Community Cancer Center	Normal	Illinois	United States	61761
149	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
150	Ottawa Regional Hospital and Healthcare Center	Ottawa	Illinois	United States	61350
151	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
152	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois	United States	61554
153	Proctor Hospital	Peoria	Illinois	United States	61614
154	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
155	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
156	OSF Saint Francis Medical Center	Peoria	Illinois	United States	61637
157	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
158	Illinois Valley Hospital	Peru	Illinois	United States	61354
159	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
160	Perry Memorial Hospital	Princeton	Illinois	United States	61356
161	Illinois CancerCare-Spring Valley	Spring Valley	Illinois	United States	61362
162	Memorial Medical Center	Springfield	Illinois	United States	62781
163	Carle Cancer Center	Urbana	Illinois	United States	61801
164	Franciscan Saint Francis Health-Beech Grove	Beech Grove	Indiana	United States	46107
165	Elkhart Clinic	Elkhart	Indiana	United States	46514-2098
166	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana	United States	46514
167	Elkhart General Hospital	Elkhart	Indiana	United States	46515
168	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana	United States	46845
169	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
170	Community Howard Regional Health	Kokomo	Indiana	United States	46904
171	IU Health La Porte Hospital	La Porte	Indiana	United States	46350
172	IU Health Arnett Cancer Care	Lafayette	Indiana	United States	47904
173	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana	United States	46360
174	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana	United States	46545
175	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana	United States	46545
176	Michiana Hematology Oncology PC-Plymouth	Plymouth	Indiana	United States	46563
177	Reid Health	Richmond	Indiana	United States	47374
178	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
179	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana	United States	46601
180	Northern Indiana Cancer Research Consortium	South Bend	Indiana	United States	46628
181	Michiana Hematology Oncology PC-Westville	Westville	Indiana	United States	46391
182	McFarland Clinic PC - Ames	Ames	Iowa	United States	50010
183	Constantinou, Costas L MD (UIA Investigator)	Bettendorf	Iowa	United States	52722
184	University of Iowa Healthcare Cancer Services Quad Cities	Bettendorf	Iowa	United States	52722
185	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa	United States	50325
186	Mercy Capitol	Des Moines	Iowa	United States	50307
187	Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
188	Iowa-Wide Oncology Research Coalition NCORP	Des Moines	Iowa	United States	50309
189	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa	United States	50309
190	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa	United States	50314
191	Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
192	Iowa Lutheran Hospital	Des Moines	Iowa	United States	50316
193	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
194	Ottumwa Regional Health Center	Ottumwa	Iowa	United States	52501
195	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
196	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51102
197	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
198	HaysMed University of Kansas Health System	Hays	Kansas	United States	67601
199	Hutchinson Regional Medical Center	Hutchinson	Kansas	United States	67502
200	University of Kansas Cancer Center	Kansas City	Kansas	United States	66160
201	Olathe Cancer Center	Olathe	Kansas	United States	66061
202	Ascension Via Christi - Pittsburg	Pittsburg	Kansas	United States	66762
203	Salina Regional Health Center	Salina	Kansas	United States	67401
204	Cotton O'Neil Cancer Center / Stormont Vail Health	Topeka	Kansas	United States	66606
205	University of Kansas Health System Saint Francis Campus	Topeka	Kansas	United States	66606
206	Our Lady Bellefonte Hospital	Ashland	Kentucky	United States	41101
207	Doctors Carrol, Sheth, Raghavan	Louisville	Kentucky	United States	40215
208	Hematology/Oncology Clinic PLLC	Baton Rouge	Louisiana	United States	70809
209	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana	United States	70809
210	Ochsner Health Center-Summa	Baton Rouge	Louisiana	United States	70809
211	Ochsner Health Center-Covington	Covington	Louisiana	United States	70433
212	Louisiana State University Health Science Center	New Orleans	Louisiana	United States	70112
213	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
214	Ochsner Baptist Medical Center	New Orleans	Louisiana	United States	70115
215	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
216	Harold Alfond Center for Cancer Care	Augusta	Maine	United States	04330
217	Eastern Maine Medical Center	Bangor	Maine	United States	04401
218	Maine Center for Cancer Medicine-Scarborough	Scarborough	Maine	United States	04074
219	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
220	Veterans Administration Medical Center-Baltimore	Baltimore	Maryland	United States	21201
221	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
222	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
223	Christiana Care - Union Hospital	Elkton	Maryland	United States	21921
224	Frederick Memorial Hospital	Frederick	Maryland	United States	21701
225	Meritus Medical Center	Hagerstown	Maryland	United States	21742
226	Kaiser Permanente - Largo Medical Center	Largo	Maryland	United States	20774
227	Kaiser Permanente Lutherville - Timonium Medical Center	Lutherville	Maryland	United States	21093
228	Kaiser Permanente - Shady Grove Medical Center	Rockville	Maryland	United States	20850
229	Holy Cross Hospital	Silver Spring	Maryland	United States	20910
230	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
231	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
232	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
233	Addison Gilbert Hospital	Gloucester	Massachusetts	United States	01930
234	Cape Cod Hospital	Hyannis	Massachusetts	United States	02601
235	Lowell General Hospital	Lowell	Massachusetts	United States	01854
236	Holy Family Hospital	Methuen	Massachusetts	United States	01844
237	Dana-Farber/Brigham and Women's Cancer Center at Milford Regional	Milford	Massachusetts	United States	01757
238	Newton-Wellesley Hospital	Newton	Massachusetts	United States	02462
239	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan	United States	48106
240	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
241	Bronson Battle Creek	Battle Creek	Michigan	United States	49017
242	McLaren Cancer Institute-Bay City	Bay City	Michigan	United States	48706
243	Spectrum Health Big Rapids Hospital	Big Rapids	Michigan	United States	49307
244	Beaumont Hospital - Dearborn	Dearborn	Michigan	United States	48124
245	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
246	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
247	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
248	Green Bay Oncology - Escanaba	Escanaba	Michigan	United States	49829
249	Hurley Medical Center	Flint	Michigan	United States	48503
250	Genesys Regional Medical Center-West Flint Campus	Flint	Michigan	United States	48532
251	McLaren Cancer Institute-Flint	Flint	Michigan	United States	48532
252	Cancer Research Consortium of West Michigan NCORP	Grand Rapids	Michigan	United States	49503
253	Mercy Health Saint Mary's	Grand Rapids	Michigan	United States	49503
254	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
255	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan	United States	49801
256	Allegiance Health	Jackson	Michigan	United States	49201
257	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
258	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
259	Borgess Medical Center	Kalamazoo	Michigan	United States	49048
260	Karmanos Cancer Institute at McLaren Greater Lansing	Lansing	Michigan	United States	48910
261	Sparrow Hospital	Lansing	Michigan	United States	48912
262	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan	United States	48154
263	UP Health System Marquette	Marquette	Michigan	United States	49855
264	MyMichigan Medical Center Midland	Midland	Michigan	United States	48670
265	Mercy Health Partners-Hackley Campus	Muskegon	Michigan	United States	49442
266	Mercy Health Mercy Campus	Muskegon	Michigan	United States	49444
267	Lakeland Hospital Niles	Niles	Michigan	United States	49120
268	McLaren Cancer Institute-Northern Michigan	Petoskey	Michigan	United States	49770
269	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
270	Lake Huron Medical Center	Port Huron	Michigan	United States	48060
271	Ascension Saint Mary's Hospital	Saginaw	Michigan	United States	48601
272	Lakeland Medical Center Saint Joseph	Saint Joseph	Michigan	United States	49085
273	Marie Yeager Cancer Center	Saint Joseph	Michigan	United States	49085
274	Ascension Providence Hospitals - Southfield	Southfield	Michigan	United States	48075
275	Munson Medical Center	Traverse City	Michigan	United States	49684
276	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
277	Metro Health Hospital	Wyoming	Michigan	United States	49519
278	Medini, Eitan MD (UIA Investigator)	Alexandria	Minnesota	United States	56308
279	Essentia Health Cancer Center	Duluth	Minnesota	United States	55805
280	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota	United States	55805
281	Miller-Dwan Hospital	Duluth	Minnesota	United States	55805
282	Etzell, Paul S MD (UIA Investigator)	Fergus Falls	Minnesota	United States	56537
283	Swenson, Wade II, MD (UIA Investigator)	Fergus Falls	Minnesota	United States	56537
284	Mayo Clinic Health Systems-Mankato	Mankato	Minnesota	United States	56001
285	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota	United States	56303
286	Saint Cloud Hospital	Saint Cloud	Minnesota	United States	56303
287	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
288	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
289	Singing River Hospital	Pascagoula	Mississippi	United States	39581
290	Central Care Cancer Center - Bolivar	Bolivar	Missouri	United States	65613
291	Cox Cancer Center Branson	Branson	Missouri	United States	65616
292	Southeast Missouri Hospital	Cape Girardeau	Missouri	United States	63701
293	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
294	Southeast Cancer Center	Cape Girardeau	Missouri	United States	63703
295	University of Missouri - Ellis Fischel	Columbia	Missouri	United States	65212
296	Capital Region Southwest Campus	Jefferson City	Missouri	United States	65109
297	Freeman Health System	Joplin	Missouri	United States	64804
298	Truman Medical Centers	Kansas City	Missouri	United States	64108
299	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri	United States	65401
300	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri	United States	63109
301	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
302	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
303	Comprehensive Cancer Care PC	Saint Louis	Missouri	United States	63141
304	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
305	Saint Louis-Cape Girardeau CCOP	Saint Louis	Missouri	United States	63141
306	Cancer Research for the Ozarks NCORP	Springfield	Missouri	United States	65804
307	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
308	CoxHealth South Hospital	Springfield	Missouri	United States	65807
309	Billings Clinic Cancer Center	Billings	Montana	United States	59101
310	Northern Rockies Radiation Oncology Center	Billings	Montana	United States	59101
311	Saint Vincent Healthcare	Billings	Montana	United States	59101
312	Montana Cancer Consortium NCORP	Billings	Montana	United States	59102
313	Saint Vincent Frontier Cancer Center	Billings	Montana	United States	59102
314	Bozeman Deaconess Hospital	Bozeman	Montana	United States	59715
315	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana	United States	59701
316	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana	United States	59405
317	Berdeaux, Donald MD (UIA Investigator)	Great Falls	Montana	United States	59405
318	Great Falls Clinic	Great Falls	Montana	United States	59405
319	Northern Montana Hospital	Havre	Montana	United States	59501
320	Saint Peter's Community Hospital	Helena	Montana	United States	59601
321	Glacier Oncology PLLC	Kalispell	Montana	United States	59901
322	Kalispell Medical Oncology	Kalispell	Montana	United States	59901
323	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
324	Montana Cancer Specialists	Missoula	Montana	United States	59802
325	Saint Patrick Hospital - Community Hospital	Missoula	Montana	United States	59802
326	Community Medical Hospital	Missoula	Montana	United States	59804
327	Guardian Oncology and Center for Wellness	Missoula	Montana	United States	59804
328	CHI Health Saint Francis	Grand Island	Nebraska	United States	68803
329	Nebraska Cancer Research Center	Lincoln	Nebraska	United States	68510
330	Great Plains Health Callahan Cancer Center	North Platte	Nebraska	United States	69101
331	Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
332	Alegent Health Immanuel Medical Center	Omaha	Nebraska	United States	68122
333	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska	United States	68124
334	Creighton University Medical Center	Omaha	Nebraska	United States	68131
335	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
336	Renown Regional Medical Center	Reno	Nevada	United States	89502
337	New Hampshire Oncology Hematology PA-Concord	Concord	New Hampshire	United States	03301
338	Cheshire Medical Center-Dartmouth-Hitchcock Keene	Keene	New Hampshire	United States	03431
339	LRGHealthcare-Lakes Region General Hospital	Laconia	New Hampshire	United States	03246
340	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
341	Solinsky Center for Cancer Care	Manchester	New Hampshire	United States	03103
342	Saint Joseph Hospital	Nashua	New Hampshire	United States	03060
343	Cooper Hospital University Medical Center	Camden	New Jersey	United States	08103
344	CentraState Medical Center	Freehold	New Jersey	United States	07728
345	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
346	Morristown Medical Center	Morristown	New Jersey	United States	07960
347	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
348	Overlook Hospital	Summit	New Jersey	United States	07902
349	Inspira Medical Center Vineland	Vineland	New Jersey	United States	08360
350	Montefiore Medical Center-Weiler Hospital	Bronx	New York	United States	10461
351	Montefiore Medical Center-Wakefield Campus	Bronx	New York	United States	10466
352	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
353	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York	United States	13057
354	Elmhurst Hospital Center	Elmhurst	New York	United States	11373
355	Arnot Ogden Medical Center/Falck Cancer Center	Elmira	New York	United States	14905
356	Adirondack Cancer Center	Glens Falls	New York	United States	12801
357	Queens Hospital Center	Jamaica	New York	United States	11432
358	Mount Sinai Union Square	New York	New York	United States	10003
359	Mount Sinai West	New York	New York	United States	10019
360	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
361	Ralph Lauren Center for Cancer Care and Prevention	New York	New York	United States	10035
362	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
363	NYP/Weill Cornell Medical Center	New York	New York	United States	10065
364	Highland Hospital	Rochester	New York	United States	14620
365	Interlakes Foundation Inc-Rochester	Rochester	New York	United States	14623
366	University of Rochester	Rochester	New York	United States	14642
367	Staten Island University Hospital	Staten Island	New York	United States	10305
368	Faxton-Saint Luke's Healthcare	Utica	New York	United States	13502
369	Randolph Hospital	Asheboro	North Carolina	United States	27203
370	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
371	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
372	Wayne Memorial Hospital	Goldsboro	North Carolina	United States	27534
373	Cone Health Cancer Center	Greensboro	North Carolina	United States	27403
374	Vidant Oncology-Kinston	Kinston	North Carolina	United States	28501
375	Annie Penn Memorial Hospital	Reidsville	North Carolina	United States	27320
376	Rutherford Hospital	Rutherfordton	North Carolina	United States	28139
377	Southeast Clinical Oncology Research Consortium NCORP	Winston-Salem	North Carolina	United States	27104
378	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
379	Mid Dakota Clinic	Bismarck	North Dakota	United States	58501
380	Saint Alexius Medical Center	Bismarck	North Dakota	United States	58501
381	Sanford Bismarck Medical Center	Bismarck	North Dakota	United States	58501
382	Altru Cancer Center	Grand Forks	North Dakota	United States	58201
383	Trinity Cancer Care Center	Minot	North Dakota	United States	58701
384	Mary Rutan Hospital	Bellefontaine	Ohio	United States	43311
385	Aultman Health Foundation	Canton	Ohio	United States	44710
386	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
387	MetroHealth Medical Center	Cleveland	Ohio	United States	44109
388	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
389	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
390	Columbus NCI Community Oncology Research Program	Columbus	Ohio	United States	43215
391	Grant Medical Center	Columbus	Ohio	United States	43215
392	Mount Carmel Health Center West	Columbus	Ohio	United States	43222
393	Doctors Hospital	Columbus	Ohio	United States	43228
394	Grandview Hospital	Dayton	Ohio	United States	45405
395	Good Samaritan Hospital - Dayton	Dayton	Ohio	United States	45406
396	Miami Valley Hospital	Dayton	Ohio	United States	45409
397	Miami Valley Hospital North	Dayton	Ohio	United States	45415
398	Dayton Veterans Affairs Medical Center	Dayton	Ohio	United States	45428
399	Grady Memorial Hospital	Delaware	Ohio	United States	43015
400	Blanchard Valley Hospital	Findlay	Ohio	United States	45840
401	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
402	Wayne Hospital	Greenville	Ohio	United States	45331
403	Kettering Medical Center	Kettering	Ohio	United States	45429
404	Fairfield Medical Center	Lancaster	Ohio	United States	43130
405	Saint Rita's Medical Center	Lima	Ohio	United States	45801
406	Marietta Memorial Hospital	Marietta	Ohio	United States	45750
407	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
408	Licking Memorial Hospital	Newark	Ohio	United States	43055
409	Southern Ohio Medical Center	Portsmouth	Ohio	United States	45662
410	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
411	Upper Valley Medical Center	Troy	Ohio	United States	45373
412	Saint Ann's Hospital	Westerville	Ohio	United States	43081
413	Clinton Memorial Hospital	Wilmington	Ohio	United States	45177
414	Greene Memorial Hospital	Xenia	Ohio	United States	45385
415	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio	United States	43701
416	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
417	Saint Charles Health System	Bend	Oregon	United States	97701
418	Clackamas Radiation Oncology Center	Clackamas	Oregon	United States	97015
419	Legacy Mount Hood Medical Center	Gresham	Oregon	United States	97030
420	Providence Milwaukie Hospital	Milwaukie	Oregon	United States	97222
421	Providence Newberg Medical Center	Newberg	Oregon	United States	97132
422	Providence Willamette Falls Medical Center	Oregon City	Oregon	United States	97045
423	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon	United States	97210
424	Providence Portland Medical Center	Portland	Oregon	United States	97213
425	Adventist Medical Center	Portland	Oregon	United States	97216
426	Providence Saint Vincent Medical Center	Portland	Oregon	United States	97225
427	Kaiser Permanente Northwest	Portland	Oregon	United States	97227
428	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
429	Legacy Meridian Park Hospital	Tualatin	Oregon	United States	97062
430	Jefferson Abington Hospital	Abington	Pennsylvania	United States	19001
431	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania	United States	18103
432	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
433	Doylestown Hospital	Doylestown	Pennsylvania	United States	18901
434	Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301
435	West Penn Hospital	Pittsburgh	Pennsylvania	United States	15224
436	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania	United States	15232
437	Guthrie Medical Group PC-Robert Packer Hospital	Sayre	Pennsylvania	United States	18840
438	Mercy Hospital	Scranton	Pennsylvania	United States	18501
439	Scranton Hematology Oncology	Scranton	Pennsylvania	United States	18510
440	Grand View Hospital	Sellersville	Pennsylvania	United States	18960
441	Chester County Hospital	West Chester	Pennsylvania	United States	19380
442	Reading Hospital	West Reading	Pennsylvania	United States	19611
443	UPMC Susquehanna	Williamsport	Pennsylvania	United States	17701
444	Lankenau Medical Center	Wynnewood	Pennsylvania	United States	19096
445	Hematology and Oncology Associates of Rhode Island Inc	Cranston	Rhode Island	United States	02920
446	Memorial Hospital of Rhode Island	Pawtucket	Rhode Island	United States	02860
447	Kent Hospital	Warwick	Rhode Island	United States	02886
448	AnMed Health Cancer Center	Anderson	South Carolina	United States	29621
449	AnMed Health Hospital	Anderson	South Carolina	United States	29621
450	McLeod Regional Medical Center	Florence	South Carolina	United States	29506
451	Saint Francis Hospital	Greenville	South Carolina	United States	29601
452	Spartanburg Medical Center	Spartanburg	South Carolina	United States	29303
453	Avera Cancer Institute-Aberdeen	Aberdeen	South Dakota	United States	57401
454	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
455	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota	United States	57104
456	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
457	Medical X-Ray Center	Sioux Falls	South Dakota	United States	57105
458	Avera McKennan Hospital and University Health Center	Sioux Falls	South Dakota	United States	57117-5045
459	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
460	Erlanger Medical Center	Chattanooga	Tennessee	United States	37403
461	Doctor's Hospital of Laredo	Laredo	Texas	United States	78041
462	Sentara Martha Jefferson Hospital	Charlottesville	Virginia	United States	22901
463	Danville Regional Medical Center	Danville	Virginia	United States	24541
464	Kaiser Permanente - Fair Oaks Medical Center	Fairfax	Virginia	United States	22033
465	Providence Regional Cancer System-Centralia	Centralia	Washington	United States	98531
466	Saint Francis Hospital	Federal Way	Washington	United States	98003
467	Saint Clare Hospital	Lakewood	Washington	United States	98499
468	Providence - Saint Peter Hospital	Olympia	Washington	United States	98506-5166
469	MultiCare Good Samaritan Hospital	Puyallup	Washington	United States	98372
470	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
471	Providence Holy Family Hospital	Spokane	Washington	United States	99208
472	Rockwood Clinic	Spokane	Washington	United States	99220
473	MultiCare Allenmore Hospital	Tacoma	Washington	United States	98405
474	Saint Joseph Medical Center	Tacoma	Washington	United States	98405
475	PeaceHealth Southwest Medical Center	Vancouver	Washington	United States	98664
476	West Virginia University Charleston Division	Charleston	West Virginia	United States	25304
477	Wheeling Hospital/Schiffler Cancer Center	Wheeling	West Virginia	United States	26003
478	Langlade Hospital and Cancer Center	Antigo	Wisconsin	United States	54409
479	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin	United States	53105
480	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin	United States	54729
481	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin	United States	54701
482	Aurora Cancer Care-Franklin	Franklin	Wisconsin	United States	53132
483	Aurora Health Care Germantown Health Center	Germantown	Wisconsin	United States	53022
484	Aurora Cancer Care-Glendale	Glendale	Wisconsin	United States	53212
485	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301-3526
486	Bellin Memorial Hospital	Green Bay	Wisconsin	United States	54301
487	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
488	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
489	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin	United States	54303
490	Aurora BayCare Medical Center	Green Bay	Wisconsin	United States	54311
491	Mercyhealth Hospital and Cancer Center - Janesville	Janesville	Wisconsin	United States	53548
492	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin	United States	53142
493	Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
494	Dean Hematology and Oncology Clinic	Madison	Wisconsin	United States	53717
495	Holy Family Memorial Hospital	Manitowoc	Wisconsin	United States	54221
496	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin	United States	54143
497	Bay Area Medical Center	Marinette	Wisconsin	United States	54143
498	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin	United States	54449
499	Marshfield Medical Center	Marshfield	Wisconsin	United States	54449
500	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
501	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
502	Aurora Sinai Medical Center	Milwaukee	Wisconsin	United States	53233
503	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin	United States	54548
504	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin	United States	53066
505	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin	United States	54154
506	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin	United States	54904
507	Aurora Cancer Care-Racine	Racine	Wisconsin	United States	53406
508	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
509	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin	United States	54868
510	HSHS Saint Nicholas Hospital	Sheboygan	Wisconsin	United States	53081
511	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin	United States	53081
512	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin	United States	54481
513	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
514	Aurora Medical Center in Summit	Summit	Wisconsin	United States	53066
515	Vince Lombardi Cancer Clinic-Two Rivers	Two Rivers	Wisconsin	United States	54241
516	Aurora Cancer Care-Waukesha	Waukesha	Wisconsin	United States	53188
517	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin	United States	53188
518	Aspirus Regional Cancer Center	Wausau	Wisconsin	United States	54401
519	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin	United States	53226
520	Aurora West Allis Medical Center	West Allis	Wisconsin	United States	53227
521	Marshfield Medical Center - Weston	Weston	Wisconsin	United States	54476
522	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin	United States	54494
523	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494
524	Rocky Mountain Oncology	Casper	Wyoming	United States	82609
525	Welch Cancer Center	Sheridan	Wyoming	United States	82801
526	San Juan City Hospital	San Juan		Puerto Rico	00936

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Hope S Rugo, Alliance for Clinical Trials in Oncology

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00601900
• Other Study ID Numbers: NCI-2009-00477; NCI-2009-00477; CALGB-40503; CDR0000584091; CALGB 40503/CTSU 40503; CALGB-40503; CALGB-40503; U10CA180821; U10CA031946
• First Posted: Jan 28, 2008
• Last Update Posted: Jul 28, 2022
• Last Verified: May 1, 2022

• Additional relevant MeSH terms: Carcinoma; Breast Neoplasms; Tamoxifen; Bevacizumab; Antineoplastic Agents, Immunological; Letrozole; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G

Study Results

Participant Flow

Arm/Group Title	Arm I (Endocrine Therapy With Monoclonal Antibody)	Arm II (Endocrine Therapy)
Arm/Group Description	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	195	199
COMPLETED	195	196
NOT COMPLETED	0	3

Baseline Characteristics

Arm/Group Title	Arm I (Endocrine Therapy With Monoclonal Antibody)	Arm II (Endocrine Therapy)	Total
Arm/Group Description	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	195	196	391
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55.5	58.9	57.7
Sex: Female, Male (Count of Participants)
Female	195 100%	196 100%	391 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	195 100%	196 100%	391 100%
Endocrine Therapy Elected (participants) [Number]
Letrozole	174 89.2%	174 88.8%	348 89%
Tamoxifen	21 10.8%	22 11.2%	43 11%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	The Primary Endpoint for this study was to compare the progression-free survival of letrozole therapy alone with the combination of letrozole therapy plus bevacizumab as first-line treatment in women with estrogen- and/or progesterone-receptor-positive advanced breast cancer. Progression-free survival (PFS) was defined as the time from randomization until disease progression or death, whichever occurs first. The median PFS was estimated using the Kaplan-Meier method. Progression was assessed per RECIST criteria, and defined as at least a 20% increase in the sum of the longest diameters of target lesions from baseline or the appearance of new lesions.
Time Frame	From randomization until disease progression or death whichever occurs first, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

Per protocol, the analysis of the primary endpoint was restricted to patients that elected letrozole as endocrine therapy. Of the 348 patients electing Letrozole, 5 did not receive treatment (1 on Arm I, and 4 on Arm II). This left 343 patients (173 on the Arm I and 170 on Arm II) evaluable for the primary endpoint.

Arm/Group Title	Arm I (Endocrine Therapy With Monoclonal Antibody)	Arm II (Endocrine Therapy)
Arm/Group Description	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	173	170
Median (95% Confidence Interval) [months]	20.2	15.6

2. Secondary Outcome

Title	12 Month Progression Free Survival Rate
Description	The 12 month progression-free survival rate was defined as the proportion of patients who were alive progression-free 12 months after registration into the study.
Time Frame	At 12 months

Outcome Measure Data

Analysis Population Description

Per protocol, the analysis of the primary endpoint was restricted to patients that elected letrozole as endocrine therapy. Of the 348 patients electing Letrozole, 5 did not receive treatment (1 on Arm I, and 4 on Arm II). This left 343 patients (173 on the Arm I and 170 on Arm II) evaluable for the primary endpoint.

Arm/Group Title	Arm I (Endocrine Therapy With Monoclonal Antibody)	Arm II (Endocrine Therapy)
Arm/Group Description	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	173	170
Number (95% Confidence Interval) [percentage of participants]	73 37.4%	61 31.1%

3. Secondary Outcome

Title	6 Month Progression-Free Survival Rate
Description	The 6 month progression-free survival rate was defined as the proportion of patients who were alive progression-free 6 months after registration into the study.
Time Frame	At 6 months

Outcome Measure Data

Analysis Population Description

Per protocol, the analysis of the primary endpoint was restricted to patients that elected letrozole as endocrine therapy. Of the 348 patients electing Letrozole, 5 did not receive treatment (1 on Arm I, and 4 on Arm II). This left 343 patients (173 on the Arm I and 170 on Arm II) evaluable for the primary endpoint.

Arm/Group Title	Arm I (Endocrine Therapy With Monoclonal Antibody)	Arm II (Endocrine Therapy)
Arm/Group Description	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	173	170
Number (95% Confidence Interval) [percentage of participants]	87 44.6%	77 39.3%

4. Secondary Outcome

Title	Objective Response Rate
Description	Response was defined using RECIST criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions.
Time Frame	Assessed up to 5 years

Outcome Measure Data

Analysis Population Description

Per protocol, the analysis of this endpoint was restricted to patients that elected letrozole as endocrine therapy and began treatment with measureable disease. A total of 213 patients (Arm A:106; Arm B:107) had measureable disease. Of the 213, 197 (Arm A:98, Arm B:99) patients were assessed for response during treatment.

Arm/Group Title	Arm I (Endocrine Therapy With Monoclonal Antibody)	Arm II (Endocrine Therapy)
Arm/Group Description	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	98	99
Complete Response (CR)	4 2.1%	7 3.6%
Partial Response (PR)	65 33.3%	42 21.4%
Stable Disease (SD)	22 11.3%	34 17.3%

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from study entry to death from any cause. The median OS was estimated using the Kaplan-Meier method.
Time Frame	Assessed up to 5 years

Outcome Measure Data

Analysis Population Description

Per protocol, the analysis of the primary endpoint was restricted to patients that elected letrozole as endocrine therapy. Of the 348 patients electing Letrozole, 5 did not receive treatment (1 on Arm I, and 4 on Arm II). This left 343 patients (173 on the Arm I and 170 on Arm II) evaluable for the primary endpoint.

Arm/Group Title	Arm I (Endocrine Therapy With Monoclonal Antibody)	Arm II (Endocrine Therapy)
Arm/Group Description	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	173	170
Median (95% Confidence Interval) [months]	47.2	43.9

6. Secondary Outcome

Title	Duration of Tumor Response
Description	Defined by RECIST criteria.
Time Frame	From the time measurement criteria are met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Probability of Surviving Until 36 Months
Time Frame	At 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Site of Progression
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Time-to-treatment Failure
Description	From randomization until first disease progression, early termination of protocol therapy due to toxicity or withdrawn consent, or going onto non-protocol therapy. Defined by RECIST criteria. The proportional hazards model will be used to compare the arms on time-to-treatment-failure
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Treatment Related Toxicity
Description	Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Tabulated by type, grade, and arm.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	All patients that received study treatment and were analyzed for adverse events are included in this summary.
Arm/Group Title	Arm I (Endocrine Therapy With Monoclonal Antibody)		Arm II (Endocrine Therapy)
Arm/Group Description	Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.		Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Arm I (Endocrine Therapy With Monoclonal Antibody)		Arm II (Endocrine Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (Endocrine Therapy With Monoclonal Antibody)		Arm II (Endocrine Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/195 (28.7%)		30/196 (15.3%)
Blood and lymphatic system disorders
Hemoglobin decreased	2/195 (1%)	2	0/196 (0%)	0
Cardiac disorders
Cardiac valve disease	0/195 (0%)	0	1/196 (0.5%)	1
Cardiopulmonary arrest	0/195 (0%)	0	1/196 (0.5%)	1
Left ventricular failure	2/195 (1%)	2	0/196 (0%)	0
Myocardial ischemia	1/195 (0.5%)	1	1/196 (0.5%)	1
Pericardial effusion	1/195 (0.5%)	1	0/196 (0%)	0
Gastrointestinal disorders
Abdominal distension	1/195 (0.5%)	1	0/196 (0%)	0
Abdominal pain	3/195 (1.5%)	3	1/196 (0.5%)	1
Colitis	2/195 (1%)	2	0/196 (0%)	0
Constipation	1/195 (0.5%)	1	1/196 (0.5%)	1
Diarrhea	3/195 (1.5%)	3	0/196 (0%)	0
Enteritis	2/195 (1%)	2	0/196 (0%)	0
Gastric hemorrhage	1/195 (0.5%)	1	1/196 (0.5%)	1
Gastritis	2/195 (1%)	2	0/196 (0%)	0
Ileus	2/195 (1%)	2	0/196 (0%)	0
Nausea	8/195 (4.1%)	8	1/196 (0.5%)	1
Pancreatitis	1/195 (0.5%)	1	0/196 (0%)	0
Rectal hemorrhage	1/195 (0.5%)	1	0/196 (0%)	0
Small intestinal obstruction	1/195 (0.5%)	2	0/196 (0%)	0
Upper gastrointestinal hemorrhage	1/195 (0.5%)	1	0/196 (0%)	0
Vomiting	5/195 (2.6%)	5	1/196 (0.5%)	1
General disorders
Chest pain	2/195 (1%)	2	1/196 (0.5%)	1
Death NOS	1/195 (0.5%)	1	0/196 (0%)	0
Disease progression	0/195 (0%)	0	3/196 (1.5%)	3
Edema limbs	2/195 (1%)	2	0/196 (0%)	0
Fatigue	3/195 (1.5%)	3	1/196 (0.5%)	1
Fever	6/195 (3.1%)	6	2/196 (1%)	2
Sudden death	0/195 (0%)	0	1/196 (0.5%)	1
Hepatobiliary disorders
Cholecystitis	1/195 (0.5%)	1	0/196 (0%)	0
Hepatic pain	0/195 (0%)	0	1/196 (0.5%)	1
Hepatobiliary disease	1/195 (0.5%)	1	0/196 (0%)	0
Infections and infestations
Appendicitis	0/195 (0%)	0	1/196 (0.5%)	1
Appendicitis perforated	0/195 (0%)	0	2/196 (1%)	2
Endocarditis infective	0/195 (0%)	0	1/196 (0.5%)	1
Eye infection	0/195 (0%)	0	1/196 (0.5%)	1
Infection	0/195 (0%)	0	1/196 (0.5%)	1
Infection without neutropenia	1/195 (0.5%)	1	0/196 (0%)	0
Pneumonia	1/195 (0.5%)	1	0/196 (0%)	0
Sepsis	0/195 (0%)	0	2/196 (1%)	2
Sinusitis	1/195 (0.5%)	1	0/196 (0%)	0
Skin infection	2/195 (1%)	2	2/196 (1%)	2
Tooth infection	1/195 (0.5%)	1	0/196 (0%)	0
Urinary tract infection	2/195 (1%)	2	0/196 (0%)	0
Wound infection	3/195 (1.5%)	3	0/196 (0%)	0
Injury, poisoning and procedural complications
Fracture	2/195 (1%)	2	0/196 (0%)	0
Intraoperative reproductive tract injury - Uterus	1/195 (0.5%)	1	0/196 (0%)	0
Small intestinal anastomotic leak	1/195 (0.5%)	1	0/196 (0%)	0
Wound dehiscence	1/195 (0.5%)	1	1/196 (0.5%)	1
Investigations
Alanine aminotransferase increased	1/195 (0.5%)	1	1/196 (0.5%)	1
Alkaline phosphatase increased	3/195 (1.5%)	3	0/196 (0%)	0
Aspartate aminotransferase increased	3/195 (1.5%)	3	1/196 (0.5%)	1
Blood bilirubin increased	2/195 (1%)	2	1/196 (0.5%)	1
Cardiac troponin T increased	1/195 (0.5%)	1	0/196 (0%)	0
Creatinine increased	2/195 (1%)	2	0/196 (0%)	0
INR increased	1/195 (0.5%)	1	0/196 (0%)	0
Leukocyte count decreased	0/195 (0%)	0	1/196 (0.5%)	1
Lymphocyte count decreased	1/195 (0.5%)	1	0/196 (0%)	0
Neutrophil count decreased	1/195 (0.5%)	1	0/196 (0%)	0
Platelet count decreased	1/195 (0.5%)	1	1/196 (0.5%)	1
Metabolism and nutrition disorders
Acidosis	1/195 (0.5%)	1	0/196 (0%)	0
Anorexia	4/195 (2.1%)	4	1/196 (0.5%)	1
Blood glucose increased	0/195 (0%)	0	1/196 (0.5%)	2
Dehydration	4/195 (2.1%)	4	1/196 (0.5%)	1
Serum albumin decreased	1/195 (0.5%)	1	0/196 (0%)	0
Serum calcium decreased	1/195 (0.5%)	1	0/196 (0%)	0
Serum phosphate decreased	2/195 (1%)	2	0/196 (0%)	0
Serum potassium decreased	1/195 (0.5%)	1	0/196 (0%)	0
Serum potassium increased	1/195 (0.5%)	1	1/196 (0.5%)	1
Serum sodium decreased	3/195 (1.5%)	3	1/196 (0.5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	24/195 (12.3%)	31	12/196 (6.1%)	18
Muscle weakness	3/195 (1.5%)	3	0/196 (0%)	0
Myalgia	0/195 (0%)	0	1/196 (0.5%)	1
Osteonecrosis	1/195 (0.5%)	1	0/196 (0%)	0
Osteoporosis	1/195 (0.5%)	2	0/196 (0%)	0
Nervous system disorders
Depressed level of consciousness	1/195 (0.5%)	1	0/196 (0%)	0
Headache	13/195 (6.7%)	15	4/196 (2%)	5
Intracranial hemorrhage	1/195 (0.5%)	1	1/196 (0.5%)	1
Ischemia cerebrovascular	2/195 (1%)	2	1/196 (0.5%)	1
Leukoencephalopathy	1/195 (0.5%)	1	0/196 (0%)	0
Memory impairment	1/195 (0.5%)	1	0/196 (0%)	0
Neuralgia	1/195 (0.5%)	1	0/196 (0%)	0
Neurological disorder NOS	1/195 (0.5%)	1	0/196 (0%)	0
Peripheral sensory neuropathy	1/195 (0.5%)	1	0/196 (0%)	0
Seizure	1/195 (0.5%)	1	0/196 (0%)	0
Speech disorder	0/195 (0%)	0	1/196 (0.5%)	1
Syncope	3/195 (1.5%)	3	1/196 (0.5%)	1
Psychiatric disorders
Confusion	1/195 (0.5%)	1	0/196 (0%)	0
Depression	2/195 (1%)	2	1/196 (0.5%)	2
Renal and urinary disorders
Proteinuria	18/195 (9.2%)	21	2/196 (1%)	3
Renal failure	3/195 (1.5%)	3	0/196 (0%)	0
Reproductive system and breast disorders
Vaginal hemorrhage	0/195 (0%)	0	1/196 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Apnea	0/195 (0%)	0	1/196 (0.5%)	1
Atelectasis	0/195 (0%)	0	1/196 (0.5%)	1
Dyspnea	5/195 (2.6%)	5	2/196 (1%)	2
Epistaxis	2/195 (1%)	3	0/196 (0%)	0
Hypoxia	3/195 (1.5%)	3	1/196 (0.5%)	1
Pleural effusion	0/195 (0%)	0	1/196 (0.5%)	1
Pneumonitis	1/195 (0.5%)	1	1/196 (0.5%)	1
Pneumothorax	1/195 (0.5%)	1	0/196 (0%)	0
Respiratory disorder	2/195 (1%)	2	0/196 (0%)	0
Vascular disorders
Hypertension	20/195 (10.3%)	23	6/196 (3.1%)	6
Hypotension	2/195 (1%)	2	1/196 (0.5%)	1
Thrombosis	0/195 (0%)	0	3/196 (1.5%)	3
Other (Not Including Serious) Adverse Events
	Arm I (Endocrine Therapy With Monoclonal Antibody)		Arm II (Endocrine Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	174/195 (89.2%)		145/196 (74%)
Blood and lymphatic system disorders
Blood disorder	0/195 (0%)	0	1/196 (0.5%)	1
Hemoglobin decreased	5/195 (2.6%)	12	2/196 (1%)	2
Hemolysis	2/195 (1%)	2	0/196 (0%)	0
Cardiac disorders
Atrial fibrillation	1/195 (0.5%)	16	0/196 (0%)	0
Cardiac valve disease	0/195 (0%)	0	1/196 (0.5%)	2
Left ventricular failure	4/195 (2.1%)	4	0/196 (0%)	0
Myocardial ischemia	1/195 (0.5%)	1	2/196 (1%)	4
Palpitations	0/195 (0%)	0	1/196 (0.5%)	1
Eye disorders
Cataract	0/195 (0%)	0	2/196 (1%)	4
Dry eye syndrome	1/195 (0.5%)	17	0/196 (0%)	0
Vision blurred	1/195 (0.5%)	1	0/196 (0%)	0
Gastrointestinal disorders
Abdominal pain	3/195 (1.5%)	6	0/196 (0%)	0
Anal hemorrhage	2/195 (1%)	5	0/196 (0%)	0
Anal pain	0/195 (0%)	0	1/196 (0.5%)	1
Colitis	1/195 (0.5%)	1	0/196 (0%)	0
Colonic hemorrhage	1/195 (0.5%)	1	0/196 (0%)	0
Constipation	2/195 (1%)	3	2/196 (1%)	2
Diarrhea	4/195 (2.1%)	29	0/196 (0%)	0
Dyspepsia	1/195 (0.5%)	1	0/196 (0%)	0
Esophageal pain	1/195 (0.5%)	1	0/196 (0%)	0
Esophagitis	1/195 (0.5%)	1	0/196 (0%)	0
Gastric ulcer	1/195 (0.5%)	1	0/196 (0%)	0
Gastritis	1/195 (0.5%)	20	0/196 (0%)	0
Gastrointestinal disorder	1/195 (0.5%)	1	0/196 (0%)	0
Hemorrhoidal hemorrhage	1/195 (0.5%)	1	0/196 (0%)	0
Hemorrhoids	0/195 (0%)	0	1/196 (0.5%)	2
Mouth necrosis	1/195 (0.5%)	3	0/196 (0%)	0
Nausea	5/195 (2.6%)	19	1/196 (0.5%)	1
Oral hemorrhage	2/195 (1%)	5	1/196 (0.5%)	1
Rectal hemorrhage	2/195 (1%)	2	2/196 (1%)	2
Toothache	1/195 (0.5%)	1	0/196 (0%)	0
Upper gastrointestinal hemorrhage	1/195 (0.5%)	1	0/196 (0%)	0
Vomiting	1/195 (0.5%)	1	0/196 (0%)	0
General disorders
Chest pain	2/195 (1%)	3	1/196 (0.5%)	1
Chills	1/195 (0.5%)	1	0/196 (0%)	0
Edema limbs	3/195 (1.5%)	5	0/196 (0%)	0
Fatigue	19/195 (9.7%)	69	12/196 (6.1%)	21
Fever	24/195 (12.3%)	32	15/196 (7.7%)	18
Flu-like symptoms	1/195 (0.5%)	1	0/196 (0%)	0
Localized edema	1/195 (0.5%)	1	0/196 (0%)	0
Pain	4/195 (2.1%)	15	1/196 (0.5%)	1
Hepatobiliary disorders
Cholecystitis	1/195 (0.5%)	1	0/196 (0%)	0
Hepatic pain	1/195 (0.5%)	1	0/196 (0%)	0
Immune system disorders
Hypersensitivity	13/195 (6.7%)	27	2/196 (1%)	2
Infections and infestations
Appendicitis	1/195 (0.5%)	1	0/196 (0%)	0
Bladder infection	0/195 (0%)	0	2/196 (1%)	2
Bronchitis	2/195 (1%)	2	2/196 (1%)	3
Catheter related infection	0/195 (0%)	0	1/196 (0.5%)	1
Conjunctivitis infective	0/195 (0%)	0	1/196 (0.5%)	1
Endocarditis infective	0/195 (0%)	0	1/196 (0.5%)	2
Eye infection	0/195 (0%)	0	1/196 (0.5%)	1
Gingival infection	1/195 (0.5%)	2	1/196 (0.5%)	1
Infection	3/195 (1.5%)	3	1/196 (0.5%)	1
Infectious colitis	0/195 (0%)	0	1/196 (0.5%)	1
Lip infection	0/195 (0%)	0	1/196 (0.5%)	1
Otitis externa	1/195 (0.5%)	1	0/196 (0%)	0
Pharyngitis	1/195 (0.5%)	4	0/196 (0%)	0
Pneumonia	0/195 (0%)	0	3/196 (1.5%)	3
Sinusitis	7/195 (3.6%)	25	3/196 (1.5%)	4
Skin infection	2/195 (1%)	3	1/196 (0.5%)	1
Tooth infection	4/195 (2.1%)	6	0/196 (0%)	0
Upper aerodigestive tract infection	1/195 (0.5%)	1	0/196 (0%)	0
Upper respiratory infection	10/195 (5.1%)	14	5/196 (2.6%)	11
Ureteritis	0/195 (0%)	0	1/196 (0.5%)	1
Urinary tract infection	10/195 (5.1%)	16	4/196 (2%)	5
Vaginal infection	1/195 (0.5%)	1	2/196 (1%)	4
Vulvitis	1/195 (0.5%)	1	0/196 (0%)	0
Wound infection	1/195 (0.5%)	6	0/196 (0%)	0
Injury, poisoning and procedural complications
Fracture	0/195 (0%)	0	2/196 (1%)	2
Wound dehiscence	6/195 (3.1%)	8	1/196 (0.5%)	2
Investigations
Alanine aminotransferase increased	4/195 (2.1%)	8	2/196 (1%)	6
Alkaline phosphatase increased	4/195 (2.1%)	9	1/196 (0.5%)	1
Aspartate aminotransferase increased	7/195 (3.6%)	14	3/196 (1.5%)	5
Blood bilirubin increased	2/195 (1%)	2	0/196 (0%)	0
Creatinine increased	3/195 (1.5%)	7	1/196 (0.5%)	2
Gamma-glutamyltransferase increased	2/195 (1%)	3	0/196 (0%)	0
INR increased	2/195 (1%)	10	0/196 (0%)	0
Leukocyte count decreased	1/195 (0.5%)	12	1/196 (0.5%)	1
Lymphocyte count decreased	2/195 (1%)	3	0/196 (0%)	0
Neutrophil count decreased	2/195 (1%)	14	1/196 (0.5%)	1
Platelet count decreased	3/195 (1.5%)	28	0/196 (0%)	0
Weight loss	5/195 (2.6%)	39	1/196 (0.5%)	2
Metabolism and nutrition disorders
Anorexia	2/195 (1%)	22	0/196 (0%)	0
Blood glucose increased	4/195 (2.1%)	26	4/196 (2%)	8
Dehydration	1/195 (0.5%)	1	0/196 (0%)	0
Glucose intolerance	1/195 (0.5%)	4	0/196 (0%)	0
Obesity	0/195 (0%)	0	1/196 (0.5%)	4
Serum calcium decreased	4/195 (2.1%)	5	0/196 (0%)	0
Serum calcium increased	0/195 (0%)	0	1/196 (0.5%)	1
Serum glucose decreased	1/195 (0.5%)	1	0/196 (0%)	0
Serum magnesium decreased	1/195 (0.5%)	2	0/196 (0%)	0
Serum phosphate decreased	1/195 (0.5%)	3	0/196 (0%)	0
Serum potassium decreased	2/195 (1%)	3	2/196 (1%)	2
Serum potassium increased	3/195 (1.5%)	3	0/196 (0%)	0
Serum sodium decreased	4/195 (2.1%)	8	2/196 (1%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	137/195 (70.3%)	1597	115/196 (58.7%)	1120
Back pain	13/195 (6.7%)	37	7/196 (3.6%)	23
Bone pain	10/195 (5.1%)	16	2/196 (1%)	3
Chest wall pain	0/195 (0%)	0	2/196 (1%)	2
Muscle weakness	0/195 (0%)	0	2/196 (1%)	2
Muscle weakness lower limb	1/195 (0.5%)	1	0/196 (0%)	0
Myalgia	7/195 (3.6%)	14	6/196 (3.1%)	19
Neck pain	1/195 (0.5%)	3	3/196 (1.5%)	6
Osteonecrosis	2/195 (1%)	5	0/196 (0%)	0
Osteoporosis	1/195 (0.5%)	1	0/196 (0%)	0
Pain in extremity	6/195 (3.1%)	12	2/196 (1%)	15
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	0/195 (0%)	0	2/196 (1%)	2
Nervous system disorders
Acoustic nerve disorder NOS	0/195 (0%)	0	1/196 (0.5%)	1
Dizziness	4/195 (2.1%)	5	2/196 (1%)	2
Headache	85/195 (43.6%)	409	58/196 (29.6%)	245
Ischemia cerebrovascular	1/195 (0.5%)	1	0/196 (0%)	0
Memory impairment	0/195 (0%)	0	1/196 (0.5%)	1
Neuralgia	3/195 (1.5%)	7	0/196 (0%)	0
Neurological disorder NOS	0/195 (0%)	0	1/196 (0.5%)	1
Peripheral sensory neuropathy	4/195 (2.1%)	4	2/196 (1%)	5
Syncope	1/195 (0.5%)	1	0/196 (0%)	0
Tremor	1/195 (0.5%)	1	0/196 (0%)	0
Psychiatric disorders
Anxiety	4/195 (2.1%)	6	3/196 (1.5%)	4
Confusion	1/195 (0.5%)	1	1/196 (0.5%)	1
Depression	5/195 (2.6%)	24	2/196 (1%)	3
Insomnia	3/195 (1.5%)	3	3/196 (1.5%)	3
Personality change	0/195 (0%)	0	1/196 (0.5%)	1
Renal and urinary disorders
Proteinuria	93/195 (47.7%)	818	13/196 (6.6%)	42
Renal failure	1/195 (0.5%)	1	0/196 (0%)	0
Urinary frequency	0/195 (0%)	0	1/196 (0.5%)	1
Reproductive system and breast disorders
Breast pain	0/195 (0%)	0	1/196 (0.5%)	1
Irregular menstruation	0/195 (0%)	0	1/196 (0.5%)	2
Pelvic pain	1/195 (0.5%)	1	0/196 (0%)	0
Vaginal dryness	1/195 (0.5%)	1	1/196 (0.5%)	6
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	3/195 (1.5%)	16	2/196 (1%)	2
Bronchopulmonary hemorrhage	2/195 (1%)	2	0/196 (0%)	0
Cough	3/195 (1.5%)	3	1/196 (0.5%)	1
Dyspnea	3/195 (1.5%)	3	5/196 (2.6%)	5
Epistaxis	24/195 (12.3%)	160	2/196 (1%)	5
Hypoxia	0/195 (0%)	0	1/196 (0.5%)	1
Pleural effusion	1/195 (0.5%)	4	1/196 (0.5%)	1
Pneumothorax	1/195 (0.5%)	1	0/196 (0%)	0
Respiratory disorder	2/195 (1%)	2	0/196 (0%)	0
Voice alteration	2/195 (1%)	2	0/196 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	1/195 (0.5%)	1	1/196 (0.5%)	1
Pruritus	0/195 (0%)	0	1/196 (0.5%)	1
Rash desquamating	1/195 (0.5%)	2	0/196 (0%)	0
Skin disorder	1/195 (0.5%)	1	0/196 (0%)	0
Skin ulceration	1/195 (0.5%)	7	0/196 (0%)	0
Vascular disorders
Hemorrhage	3/195 (1.5%)	4	0/196 (0%)	0
Hot flashes	12/195 (6.2%)	46	8/196 (4.1%)	34
Hypertension	115/195 (59%)	1029	61/196 (31.1%)	528
Hypotension	0/195 (0%)	0	1/196 (0.5%)	1
Thrombosis	6/195 (3.1%)	7	2/196 (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.