Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer

A Randomized Phase II Trial of Tamoxifen Versus Z-Endoxifen HCL in Postmenopausal Women With Metastatic Estrogen Receptor Positive, HER2 Negative Breast Cancer

This randomized phase II trial studies how well tamoxifen citrate works compared with z-endoxifen hydrochloride in treating patients with breast cancer that has spread to nearby tissue or lymph nodes or other parts of the body and has estrogen receptors but not human epidermal growth factor receptor 2 (HER2) receptors on the surface of its cells. Estrogen can cause the growth of tumor cells. Hormone therapy using tamoxifen citrate or z-endoxifen hydrochloride may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether tamoxifen citrate or z-endoxifen hydrochloride is more effective in treating patients with breast cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Recurrent Breast Carcinoma; Stage IV Breast Cancer AJCC v6 and v7; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Tamoxifen Citrate; Drug: Endoxifen Hydrochloride

Detailed Description

PRIMARY OBJECTIVES:

I. To assess whether progression-free survival with z-endoxifen hydrochloride (HCl) relative to that with tamoxifen (tamoxifen citrate) is prolonged in postmenopausal women with local advanced or metastatic estrogen receptor (ER) positive/Her2 negative breast cancer.

SECONDARY OBJECTIVES:

I. To assess the safety profile of each of these agents in this patient population.

II. To assess whether the tumor response rate (as determined using the Response Evaluation Criteria in Solid Tumors [RECIST] criteria) among those randomized to z-endoxifen HCl differs from that among those randomized to tamoxifen.

III. To estimate the median progression-free survival time for those who receive z-endoxifen HCl after disease progression with tamoxifen.

CORRELATIVE SCIENCE OBJECTIVES:

I. To examine whether ER alpha alterations (defined as either ER activating mutations or ER amplification) are associated with longer progression-free survival (PFS) or higher response rates in the z-endoxifen HCl arm compared to the tamoxifen arm.

II. To determine changes in lipid profiles comparing tamoxifen and z-endoxifen HCl.

III. For each treatment, to evaluate changes in markers of bone formation and absorption after 12 weeks (4 cycles) of treatment.

IV. For all patients and by treatment arm, to determine whether progression-free survival differs with respect to the sensitive to endocrine therapy (SET) index.

V. To examine whether deoxyribonucleic acid (DNA) alterations as measured by Foundation medicine in all coding exons of 287 cancer-related genes as well as 78 polymorphisms in 34 absorption, distribution, metabolism, and excretion (ADME)-related genes are associated with longer PFS or higher response rates in the z-endoxifen HCl arm compared to the tamoxifen arm.

VI. To assess whether the molecular characteristics identified in the tumor biopsies are detectable in the circulating tumor cells (CTCs) and/or cell-free DNA (cfDNA).

VII. For each treatment arm: to examine changes in ER expression on CTCs, changes in estrogen receptor (ESR) mutations or amplification in CTCs or CfDNA and explore the impact of these changes on PFS and response rates.

PHARMACOKINETICS AND PHARMACOGENOMICS OBJECTIVES:

I. To further characterize pharmacokinetics, pharmacogenetics and metabolism of z-endoxifen HCl and tamoxifen.

II. To determine the impact of the concentrations of tamoxifen and its metabolites on PFS in the tamoxifen arm.

III. To determine the impact of the concentrations of z-endoxifen HCl and its metabolites on PFS in the endoxifen arm.

V. To determine the impact of genetic variation in the enzymes responsible for tamoxifen and z-endoxifen HCl metabolism.

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

ARM I: Patients receive z-endoxifen hydrochloride orally (PO) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive tamoxifen citrate PO once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression.

After completion of study treatment, patients are followed up yearly for up to 5 years.

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Southern Cancer Center PC-Providence
  • Alaska
    • Anchorage, Alaska, United States, 98508
      • Anchorage Associates in Radiation Medicine
    • Anchorage, Alaska, United States, 99508
      • Alaska Breast Care and Surgery LLC
    • Anchorage, Alaska, United States, 99508
      • Alaska Oncology and Hematology LLC
    • Anchorage, Alaska, United States, 99508
      • Alaska Women's Cancer Care
    • Anchorage, Alaska, United States, 99508
      • Anchorage Oncology Centre
    • Anchorage, Alaska, United States, 99508
      • Katmai Oncology Group
    • Anchorage, Alaska, United States, 99508
      • Providence Alaska Medical Center
    • Anchorage, Alaska, United States, 99504
      • Anchorage Radiation Therapy Center
    • Anchorage, Alaska, United States, 99508
      • Alaska Regional Hospital
    • Fairbanks, Alaska, United States, 99701
      • Fairbanks Memorial Hospital
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital in Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • Arkansas
    • Hot Springs, Arkansas, United States, 71913
      • CHI Saint Vincent Cancer Center Hot Springs
    • Jonesboro, Arkansas, United States, 72401
      • NEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro
  • California
    • Anaheim, California, United States, 92806
      • Kaiser Permanente-Anaheim
    • Arroyo Grande, California, United States, 93420
      • PCR Oncology
    • Auburn, California, United States, 95602
      • Sutter Auburn Faith Hospital
    • Auburn, California, United States, 95603
      • Sutter Cancer Centers Radiation Oncology Services-Auburn
    • Bakersfield, California, United States, 93301
      • AIS Cancer Center at San Joaquin Community Hospital
    • Baldwin Park, California, United States, 91706
      • Kaiser Permanente-Baldwin Park
    • Bellflower, California, United States, 90706
      • Kaiser Permanente-Bellflower
    • Berkeley, California, United States, 94704
      • Alta Bates Summit Medical Center-Herrick Campus
    • Burbank, California, United States, 91505
      • Providence Saint Joseph Medical Center/Disney Family Cancer Center
    • Burlingame, California, United States, 94010
      • Mills-Peninsula Medical Center
    • Cameron Park, California, United States, 95682
      • Sutter Cancer Centers Radiation Oncology Services-Cameron Park
    • Castro Valley, California, United States, 94546
      • Eden Hospital Medical Center
    • Davis, California, United States, 95616
      • Sutter Davis Hospital
    • Dublin, California, United States, 94568
      • Epic Care-Dublin
    • Emeryville, California, United States, 94608
      • Bay Area Breast Surgeons Inc
    • Emeryville, California, United States, 94608
      • Epic Care Partners in Cancer Care
    • Fontana, California, United States, 92335
      • Kaiser Permanente-Fontana
    • Harbor City, California, United States, 90710
      • Kaiser Permanente - Harbor City
    • Irvine, California, United States, 92618
      • Kaiser Permanente-Irvine
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles Medical Center
    • Los Angeles, California, United States, 90034
      • Kaiser Permanente West Los Angeles
    • Martinez, California, United States, 94553-3156
      • Contra Costa Regional Medical Center
    • Marysville, California, United States, 95901
      • Fremont - Rideout Cancer Center
    • Merced, California, United States, 95340
      • Mercy UC Davis Cancer Center
    • Modesto, California, United States, 95355
      • Memorial Medical Center
    • Mountain View, California, United States, 94040
      • Palo Alto Medical Foundation-Camino Division
    • Mountain View, California, United States, 94040
      • Palo Alto Medical Foundation-Gynecologic Oncology
    • Novato, California, United States, 94945
      • Sutter Cancer Research Consortium
    • Oakland, California, United States, 94609
      • Alta Bates Summit Medical Center - Summit Campus
    • Oakland, California, United States, 94609
      • Hematology and Oncology Associates-Oakland
    • Oakland, California, United States, 94609
      • Bay Area Tumor Institute
    • Palo Alto, California, United States, 94301
      • Palo Alto Medical Foundation Health Care
    • Panorama City, California, United States, 91402
      • Kaiser Permanente - Panorama City
    • Riverside, California, United States, 92505
      • Kaiser Permanente-Riverside
    • Roseville, California, United States, 95661
      • Sutter Cancer Centers Radiation Oncology Services-Roseville
    • Roseville, California, United States, 95661
      • Sutter Roseville Medical Center
    • Sacramento, California, United States, 95816
      • Sutter Medical Center Sacramento
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • San Diego, California, United States, 92120
      • Kaiser Permanente-San Diego Zion
    • San Diego, California, United States, 92108
      • Kaiser Permanente-San Diego Mission
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center-Pacific Campus
    • San Marcos, California, United States, 92078
      • Kaiser Permanente-San Marcos
    • Santa Cruz, California, United States, 95065
      • Palo Alto Medical Foundation-Santa Cruz
    • Santa Rosa, California, United States, 95403
      • Sutter Pacific Medical Foundation
    • Sunnyvale, California, United States, 94086
      • Palo Alto Medical Foundation-Sunnyvale
    • Truckee, California, United States, 96161
      • Gene Upshaw Memorial Tahoe Forest Cancer Center
    • Vacaville, California, United States, 95687
      • Sutter Cancer Centers Radiation Oncology Services-Vacaville
    • Vallejo, California, United States, 94589
      • Sutter Solano Medical Center/Cancer Center
    • Woodland Hills, California, United States, 91367
      • Kaiser Permanente-Woodland Hills
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Penrose-Saint Francis Healthcare
    • Colorado Springs, Colorado, United States, 80907
      • Rocky Mountain Cancer Centers-Penrose
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
    • Durango, Colorado, United States, 81301
      • Mercy Medical Center
    • Durango, Colorado, United States, 81301
      • Southwest Oncology PC
    • Golden, Colorado, United States, 80401
      • Mountain Blue Cancer Care Center
    • Lakewood, Colorado, United States, 80228
      • Saint Anthony Hospital
    • Lakewood, Colorado, United States, 80228
      • Rocky Mountain Cancer Centers-Lakewood
    • Littleton, Colorado, United States, 80122
      • Littleton Adventist Hospital
    • Longmont, Colorado, United States, 80501
      • Longmont United Hospital
    • Longmont, Colorado, United States, 80501
      • Rocky Mountain Cancer Centers-Longmont
    • Parker, Colorado, United States, 80138
      • Parker Adventist Hospital
    • Parker, Colorado, United States, 80138
      • Rocky Mountain Cancer Centers-Parker
    • Pueblo, Colorado, United States, 81004
      • Saint Mary Corwin Medical Center
    • Pueblo, Colorado, United States, 81008
      • Rocky Mountain Cancer Centers - Pueblo
    • Thornton, Colorado, United States, 80260
      • Rocky Mountain Cancer Centers-Thornton
  • Connecticut
    • Hartford, Connecticut, United States, 06105
      • Smilow Cancer Hospital Care Center at Saint Francis
    • Middletown, Connecticut, United States, 06457
      • Middlesex Hospital
  • Florida
    • Daytona Beach, Florida, United States, 32114
      • Halifax Health Medical Center-Centers for Oncology
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida
  • Georgia
    • Athens, Georgia, United States, 30607
      • University Cancer and Blood Center LLC
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital
    • Augusta, Georgia, United States, 30912
      • Augusta University Medical Center
    • Cumming, Georgia, United States, 30041
      • Northside Hospital-Forsyth
    • Decatur, Georgia, United States, 30033
      • Dekalb Medical Center
  • Hawaii
    • 'Aiea, Hawaii, United States, 96701
      • Pali Momi Medical Center
    • 'Aiea, Hawaii, United States, 96701
      • Queen's Cancer Center - Pearlridge
    • 'Aiea, Hawaii, United States, 96701
      • The Cancer Center of Hawaii-Pali Momi
    • Honolulu, Hawaii, United States, 96813
      • Queen's Medical Center
    • Honolulu, Hawaii, United States, 96817
      • The Cancer Center of Hawaii-Liliha
    • Honolulu, Hawaii, United States, 96813
      • Hawaii Cancer Care Inc - Waterfront Plaza
    • Honolulu, Hawaii, United States, 96813
      • Queen's Cancer Cenrer - POB I
    • Honolulu, Hawaii, United States, 96813
      • Straub Clinic and Hospital
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii Cancer Center
    • Honolulu, Hawaii, United States, 96817
      • Hawaii Cancer Care Inc-Liliha
    • Honolulu, Hawaii, United States, 96817
      • Kuakini Medical Center
    • Honolulu, Hawaii, United States, 96817
      • Queen's Cancer Center - Kuakini
    • Honolulu, Hawaii, United States, 96826
      • Kapiolani Medical Center for Women and Children
    • Honolulu, Hawaii, United States, 96813
      • Island Urology
    • Lihue, Hawaii, United States, 96766
      • Wilcox Memorial Hospital and Kauai Medical Clinic
  • Idaho
    • Boise, Idaho, United States, 83706
      • Saint Alphonsus Cancer Care Center-Boise
    • Boise, Idaho, United States, 83712
      • Saint Luke's Cancer Institute - Boise
    • Caldwell, Idaho, United States, 83605
      • Saint Alphonsus Cancer Care Center-Caldwell
    • Coeur d'Alene, Idaho, United States, 83814
      • Kootenai Health - Coeur d'Alene
    • Emmett, Idaho, United States, 83617
      • Walter Knox Memorial Hospital
    • Fruitland, Idaho, United States, 83619
      • Saint Luke's Cancer Institute - Fruitland
    • Meridian, Idaho, United States, 83642
      • Idaho Urologic Institute-Meridian
    • Meridian, Idaho, United States, 83642
      • Saint Luke's Cancer Institute - Meridian
    • Nampa, Idaho, United States, 83686
      • Saint Luke's Cancer Institute - Nampa
    • Nampa, Idaho, United States, 83687
      • Saint Alphonsus Cancer Care Center-Nampa
    • Post Falls, Idaho, United States, 83854
      • Kootenai Clinic Cancer Services - Post Falls
    • Sandpoint, Idaho, United States, 83864
      • Kootenai Cancer Clinic
    • Twin Falls, Idaho, United States, 83301
      • Saint Luke's Cancer Institute - Twin Falls
  • Illinois
    • Aurora, Illinois, United States, 60504
      • Rush - Copley Medical Center
    • Bloomington, Illinois, United States, 61704
      • Illinois CancerCare-Bloomington
    • Bloomington, Illinois, United States, 61701
      • Saint Joseph Medical Center
    • Canton, Illinois, United States, 61520
      • Illinois CancerCare-Canton
    • Carbondale, Illinois, United States, 62902
      • Memorial Hospital of Carbondale
    • Carterville, Illinois, United States, 62918
      • SIH Cancer Institute
    • Carthage, Illinois, United States, 62321
      • Illinois CancerCare-Carthage
    • Centralia, Illinois, United States, 62801
      • Centralia Oncology Clinic
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Chicago, Illinois, United States, 60612
      • John H Stroger Jr Hospital of Cook County
    • Chicago, Illinois, United States, 60657
      • UChicago Medicine Comprehensive Cancer Center - Saint Joseph Hospital
    • Danville, Illinois, United States, 61832
      • Carle at The Riverfront
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Decatur, Illinois, United States, 62526
      • Cancer Care Specialists of Illinois - Decatur
    • Effingham, Illinois, United States, 62401
      • Crossroads Cancer Center
    • Effingham, Illinois, United States, 62401
      • Carle Physician Group-Effingham
    • Elk Grove Village, Illinois, United States, 60007
      • Ascension Alexian Brothers - Elk Grove Village
    • Eureka, Illinois, United States, 61530
      • Illinois CancerCare-Eureka
    • Galesburg, Illinois, United States, 61401
      • Western Illinois Cancer Treatment Center
    • Galesburg, Illinois, United States, 61401
      • Illinois CancerCare-Galesburg
    • Kewanee, Illinois, United States, 61443
      • Illinois CancerCare-Kewanee Clinic
    • Macomb, Illinois, United States, 61455
      • Illinois CancerCare-Macomb
    • Mattoon, Illinois, United States, 61938
      • Carle Physician Group-Mattoon/Charleston
    • Mount Vernon, Illinois, United States, 62864
      • Good Samaritan Regional Health Center
    • New Lenox, Illinois, United States, 60451
      • UC Comprehensive Cancer Center at Silver Cross
    • O'Fallon, Illinois, United States, 62269
      • Cancer Care Center of O'Fallon
    • Ottawa, Illinois, United States, 61350
      • Illinois CancerCare-Ottawa Clinic
    • Ottawa, Illinois, United States, 61350
      • Radiation Oncology of Northern Illinois
    • Pekin, Illinois, United States, 61554
      • Illinois CancerCare-Pekin
    • Pekin, Illinois, United States, 61554
      • OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center
    • Peoria, Illinois, United States, 61636
      • Methodist Medical Center of Illinois
    • Peoria, Illinois, United States, 61637
      • OSF Saint Francis Medical Center
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Peoria, Illinois, United States, 61615
      • OSF Saint Francis Radiation Oncology at Peoria Cancer Center
    • Peru, Illinois, United States, 61354
      • Illinois CancerCare-Peru
    • Peru, Illinois, United States, 61354
      • Valley Radiation Oncology
    • Princeton, Illinois, United States, 61356
      • Illinois CancerCare-Princeton
    • Springfield, Illinois, United States, 62781
      • Memorial Medical Center
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University School of Medicine
    • Springfield, Illinois, United States, 62702
      • Springfield Clinic
    • Springfield, Illinois, United States, 62702
      • Central Illinois Hematology Oncology Center
    • Swansea, Illinois, United States, 62226
      • Southwest Illinois Health Services LLP
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center
    • Urbana, Illinois, United States, 61801
      • The Carle Foundation Hospital
    • Yorkville, Illinois, United States, 60560
      • Rush-Copley Healthcare Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University/Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • Sidney and Lois Eskenazi Hospital
    • Indianapolis, Indiana, United States, 46290
      • Springmill Medical Center
    • Michigan City, Indiana, United States, 46360
      • Franciscan Saint Anthony Health-Michigan City
    • Michigan City, Indiana, United States, 46360
      • Woodland Cancer Care Center
    • Mishawaka, Indiana, United States, 46545
      • Memorial Regional Cancer Center Day Road
    • Richmond, Indiana, United States, 47374
      • Reid Health
    • South Bend, Indiana, United States, 46601
      • Memorial Hospital of South Bend
  • Iowa
    • Ames, Iowa, United States, 50010
      • Mary Greeley Medical Center
    • Ames, Iowa, United States, 50010
      • McFarland Clinic - Ames
    • Boone, Iowa, United States, 50036
      • McFarland Clinic - Boone
    • Clive, Iowa, United States, 50325
      • Mercy Cancer Center-West Lakes
    • Clive, Iowa, United States, 50325
      • Medical Oncology and Hematology Associates-West Des Moines
    • Council Bluffs, Iowa, United States, 51503
      • Alegent Health Mercy Hospital
    • Creston, Iowa, United States, 50801
      • Greater Regional Medical Center
    • Des Moines, Iowa, United States, 50314
      • Mercy Medical Center - Des Moines
    • Des Moines, Iowa, United States, 50314
      • Mission Cancer and Blood - Laurel
    • Fairfield, Iowa, United States, 52556
      • JCHC McCreery Cancer Center
    • Fort Dodge, Iowa, United States, 50501
      • McFarland Clinic - Trinity Cancer Center
    • Jefferson, Iowa, United States, 50129
      • McFarland Clinic - Jefferson
    • Marshalltown, Iowa, United States, 50158
      • McFarland Clinic - Marshalltown
    • Ottumwa, Iowa, United States, 52501
      • Ottumwa Regional Health Center
    • West Des Moines, Iowa, United States, 50266
      • Mercy Medical Center-West Lakes
  • Kansas
    • Chanute, Kansas, United States, 66720
      • Cancer Center of Kansas - Chanute
    • Dodge City, Kansas, United States, 67801
      • Cancer Center of Kansas - Dodge City
    • El Dorado, Kansas, United States, 67042
      • Cancer Center of Kansas - El Dorado
    • Fort Scott, Kansas, United States, 66701
      • Cancer Center of Kansas - Fort Scott
    • Independence, Kansas, United States, 67301
      • Cancer Center of Kansas-Independence
    • Kingman, Kansas, United States, 67068
      • Cancer Center of Kansas-Kingman
    • Lawrence, Kansas, United States, 66044
      • Lawrence Memorial Hospital
    • Liberal, Kansas, United States, 67905
      • Cancer Center of Kansas-Liberal
    • Manhattan, Kansas, United States, 66502
      • Cancer Center of Kansas-Manhattan
    • McPherson, Kansas, United States, 67460
      • Cancer Center of Kansas - McPherson
    • Newton, Kansas, United States, 67114
      • Cancer Center of Kansas - Newton
    • Parsons, Kansas, United States, 67357
      • Cancer Center of Kansas - Parsons
    • Pratt, Kansas, United States, 67124
      • Cancer Center of Kansas - Pratt
    • Salina, Kansas, United States, 67401
      • Cancer Center of Kansas - Salina
    • Wellington, Kansas, United States, 67152
      • Cancer Center of Kansas - Wellington
    • Wichita, Kansas, United States, 67214
      • Ascension Via Christi Hospitals Wichita
    • Wichita, Kansas, United States, 67208
      • Cancer Center of Kansas-Wichita Medical Arts Tower
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas - Wichita
    • Wichita, Kansas, United States, 67208
      • Associates In Womens Health
    • Wichita, Kansas, United States, 67214
      • Wichita NCI Community Oncology Research Program
    • Winfield, Kansas, United States, 67156
      • Cancer Center of Kansas - Winfield
  • Kentucky
    • Bardstown, Kentucky, United States, 40004
      • Flaget Memorial Hospital
    • Corbin, Kentucky, United States, 40701
      • Baptist Health Corbin
    • Corbin, Kentucky, United States, 40701
      • Commonwealth Cancer Center-Corbin
    • Crestview Hills, Kentucky, United States, 41017
      • Oncology Hematology Care Inc-Crestview
    • Elizabethtown, Kentucky, United States, 42701
      • Baptist Health Hardin
    • Lexington, Kentucky, United States, 40504
      • Saint Joseph Radiation Oncology Resource Center
    • Lexington, Kentucky, United States, 40509
      • Saint Joseph Hospital East
    • Lexington, Kentucky, United States, 40503
      • Baptist Health Lexington
    • Louisville, Kentucky, United States, 40202
      • Jewish Hospital
    • Louisville, Kentucky, United States, 40245
      • UofL Health Medical Center Northeast
    • Louisville, Kentucky, United States, 40207
      • Baptist Health Louisville
    • Louisville, Kentucky, United States, 40215
      • Saints Mary and Elizabeth Hospital
    • Madisonville, Kentucky, United States, 42431
      • Baptist Health Madisonville/Merle Mahr Cancer Center
    • Paducah, Kentucky, United States, 42003
      • Baptist Health Paducah
    • Shepherdsville, Kentucky, United States, 40165
      • Jewish Hospital Medical Center South
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Ochsner Health Center-Summa
    • Kenner, Louisiana, United States, 70065
      • Ochsner Medical Center Kenner
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center Jefferson
  • Maine
    • Augusta, Maine, United States, 04330
      • Harold Alfond Center for Cancer Care
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
    • Brewer, Maine, United States, 04412
      • Lafayette Family Cancer Center-EMMC
  • Maryland
    • Elkton, Maryland, United States, 21921
      • Christiana Care - Union Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Saint Joseph Mercy Hospital
    • Battle Creek, Michigan, United States, 49017
      • Bronson Battle Creek
    • Brighton, Michigan, United States, 48114
      • Saint Joseph Mercy Brighton
    • Brighton, Michigan, United States, 48114
      • Trinity Health IHA Medical Group Hematology Oncology - Brighton
    • Canton, Michigan, United States, 48188
      • Saint Joseph Mercy Canton
    • Canton, Michigan, United States, 48188
      • Trinity Health IHA Medical Group Hematology Oncology - Canton
    • Caro, Michigan, United States, 48723
      • Caro Cancer Center
    • Chelsea, Michigan, United States, 48118
      • Saint Joseph Mercy Chelsea
    • Chelsea, Michigan, United States, 48118
      • Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
    • Clarkston, Michigan, United States, 48346
      • Hematology Oncology Consultants-Clarkston
    • Clarkston, Michigan, United States, 48346
      • Newland Medical Associates-Clarkston
    • Dearborn, Michigan, United States, 48124
      • Beaumont Hospital - Dearborn
    • Detroit, Michigan, United States, 48236
      • Ascension Saint John Hospital
    • East China Township, Michigan, United States, 48054
      • Great Lakes Cancer Management Specialists-Doctors Park
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Flint, Michigan, United States, 48503
      • Genesee Cancer and Blood Disease Treatment Center
    • Flint, Michigan, United States, 48503
      • Genesee Hematology Oncology PC
    • Flint, Michigan, United States, 48503
      • Genesys Hurley Cancer Institute
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health at Butterworth Campus
    • Grand Rapids, Michigan, United States, 49503
      • Trinity Health Grand Rapids Hospital
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Academic Hematology Oncology Specialists
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Great Lakes Cancer Management Specialists-Van Elslander Cancer Center
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Michigan Breast Specialists-Grosse Pointe Woods
    • Jackson, Michigan, United States, 49201
      • Allegiance Health
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
    • Kalamazoo, Michigan, United States, 49048
      • Borgess Medical Center
    • Lansing, Michigan, United States, 48912
      • University of Michigan Health - Sparrow Lansing
    • Livonia, Michigan, United States, 48154
      • Trinity Health Saint Mary Mercy Livonia Hospital
    • Livonia, Michigan, United States, 48154
      • Hope Cancer Clinic
    • Macomb, Michigan, United States, 48044
      • Great Lakes Cancer Management Specialists-Macomb Medical Campus
    • Macomb, Michigan, United States, 48044
      • Michigan Breast Specialists-Macomb Township
    • Marlette, Michigan, United States, 48453
      • Saint Mary's Oncology/Hematology Associates of Marlette
    • Midland, Michigan, United States, 48670
      • MyMichigan Medical Center Midland
    • Monroe, Michigan, United States, 48162
      • Monroe Cancer Center
    • Muskegon, Michigan, United States, 49444
      • Trinity Health Muskegon Hospital
    • Niles, Michigan, United States, 49120
      • Corewell Health Lakeland Hospitals - Niles Hospital
    • Pontiac, Michigan, United States, 48341
      • Saint Joseph Mercy Oakland
    • Pontiac, Michigan, United States, 48341
      • 21st Century Oncology-Pontiac
    • Pontiac, Michigan, United States, 48341
      • Hope Cancer Center
    • Pontiac, Michigan, United States, 48341
      • Newland Medical Associates-Pontiac
    • Port Huron, Michigan, United States, 48060
      • Lake Huron Medical Center
    • Reed City, Michigan, United States, 49677
      • Corewell Health Reed City Hospital
    • Rochester Hills, Michigan, United States, 48309
      • Great Lakes Cancer Management Specialists-Rochester Hills
    • Saginaw, Michigan, United States, 48601
      • Ascension Saint Mary's Hospital
    • Saginaw, Michigan, United States, 48604
      • Oncology Hematology Associates of Saginaw Valley PC
    • Saint Joseph, Michigan, United States, 49085
      • Lakeland Medical Center Saint Joseph
    • Saint Joseph, Michigan, United States, 49085
      • Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center
    • Sterling Heights, Michigan, United States, 48312
      • Bhadresh Nayak MD PC-Sterling Heights
    • Traverse City, Michigan, United States, 49684
      • Munson Medical Center
    • Warren, Michigan, United States, 48093
      • Saint John Macomb-Oakland Hospital
    • Warren, Michigan, United States, 48088
      • Advanced Breast Care Center PLLC
    • Warren, Michigan, United States, 48093
      • Great Lakes Cancer Management Specialists-Macomb Professional Building
    • Warren, Michigan, United States, 48093
      • Macomb Hematology Oncology PC
    • Warren, Michigan, United States, 48093
      • Michigan Breast Specialists-Warren
    • West Branch, Michigan, United States, 48661
      • Saint Mary's Oncology/Hematology Associates of West Branch
    • Wyoming, Michigan, United States, 49519
      • University of Michigan Health - West
    • Ypsilanti, Michigan, United States, 48197
      • Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
    • Ypsilanti, Michigan, United States, 48106
      • Huron Gastroenterology PC
  • Minnesota
    • Bemidji, Minnesota, United States, 56601
      • Sanford Joe Lueken Cancer Center
    • Brainerd, Minnesota, United States, 56401
      • Essentia Health Saint Joseph's Medical Center
    • Duluth, Minnesota, United States, 55805
      • Essentia Health Cancer Center
    • Duluth, Minnesota, United States, 55805
      • Essentia Health Saint Mary's Medical Center
    • Duluth, Minnesota, United States, 55805
      • Miller-Dwan Hospital
    • Fergus Falls, Minnesota, United States, 56537
      • Lake Region Healthcare Corporation-Cancer Care
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
    • Saint Cloud, Minnesota, United States, 56303
      • Coborn Cancer Center at Saint Cloud Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
    • Pascagoula, Mississippi, United States, 39581
      • Singing River Hospital
  • Missouri
    • Ballwin, Missouri, United States, 63011
      • Saint Louis Cancer and Breast Institute-Ballwin
    • Bolivar, Missouri, United States, 65613
      • Central Care Cancer Center - Bolivar
    • Bonne Terre, Missouri, United States, 63628
      • Parkland Health Center-Bonne Terre
    • Branson, Missouri, United States, 65616
      • Cox Cancer Center Branson
    • Cape Girardeau, Missouri, United States, 63703
      • Saint Francis Medical Center
    • Cape Girardeau, Missouri, United States, 63703
      • Southeast Cancer Center
    • Columbia, Missouri, United States, 65212
      • MU Health - University Hospital/Ellis Fischel Cancer Center
    • Creve Coeur, Missouri, United States, 63141
      • Siteman Cancer Center at West County Hospital
    • Jefferson City, Missouri, United States, 65109
      • Capital Region Southwest Campus
    • Joplin, Missouri, United States, 64804
      • Freeman Health System
    • Joplin, Missouri, United States, 64804
      • Mercy Hospital Joplin
    • Rolla, Missouri, United States, 65401
      • Delbert Day Cancer Institute at PCRMC
    • Rolla, Missouri, United States, 65401
      • Mercy Clinic-Rolla-Cancer and Hematology
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Medical Center
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
    • Saint Louis, Missouri, United States, 63109
      • Saint Louis Cancer and Breast Institute-South City
    • Saint Peters, Missouri, United States, 63376
      • Siteman Cancer Center at Saint Peters Hospital
    • Sainte Genevieve, Missouri, United States, 63670
      • Sainte Genevieve County Memorial Hospital
    • Springfield, Missouri, United States, 65807
      • CoxHealth South Hospital
    • Springfield, Missouri, United States, 65804
      • Mercy Hospital Springfield
    • Sullivan, Missouri, United States, 63080
      • Missouri Baptist Sullivan Hospital
    • Sunset Hills, Missouri, United States, 63127
      • BJC Outpatient Center at Sunset Hills
  • Montana
    • Anaconda, Montana, United States, 59711
      • Community Hospital of Anaconda
    • Billings, Montana, United States, 59101
      • Billings Clinic Cancer Center
    • Billings, Montana, United States, 59101
      • Saint Vincent Healthcare
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Hospital
    • Butte, Montana, United States, 59701
      • Saint James Community Hospital and Cancer Treatment Center
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic
    • Great Falls, Montana, United States, 59405
      • Benefis Healthcare- Sletten Cancer Institute
    • Helena, Montana, United States, 59601
      • Saint Peter's Community Hospital
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Missoula, Montana, United States, 59804
      • Community Medical Hospital
    • Missoula, Montana, United States, 59802
      • Saint Patrick Hospital - Community Hospital
  • Nebraska
    • Grand Island, Nebraska, United States, 68803
      • CHI Health Saint Francis
    • Kearney, Nebraska, United States, 68847
      • CHI Health Good Samaritan
    • Kearney, Nebraska, United States, 68845
      • Heartland Hematology and Oncology
    • Lincoln, Nebraska, United States, 68510
      • Saint Elizabeth Regional Medical Center
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68124
      • Alegent Health Bergan Mercy Medical Center
    • Omaha, Nebraska, United States, 68122
      • Alegent Health Immanuel Medical Center
    • Omaha, Nebraska, United States, 68130
      • Alegent Health Lakeside Hospital
    • Omaha, Nebraska, United States, 68131
      • Creighton University Medical Center
    • Omaha, Nebraska, United States, 68122
      • Hematology and Oncology Consultants PC
    • Papillion, Nebraska, United States, 68046
      • Midlands Community Hospital
  • Nevada
    • Carson City, Nevada, United States, 89703
      • Carson Tahoe Regional Medical Center
    • Henderson, Nevada, United States, 89052
      • Comprehensive Cancer Centers of Nevada - Henderson
    • Henderson, Nevada, United States, 89052
      • Cancer and Blood Specialists-Henderson
    • Henderson, Nevada, United States, 89052
      • Las Vegas Cancer Center-Henderson
    • Henderson, Nevada, United States, 89074
      • Comprehensive Cancer Centers of Nevada-Southeast Henderson
    • Henderson, Nevada, United States, 89074
      • GenesisCare USA - Henderson
    • Las Vegas, Nevada, United States, 89144
      • Summerlin Hospital Medical Center
    • Las Vegas, Nevada, United States, 89106
      • Radiation Oncology Centers of Nevada Central
    • Las Vegas, Nevada, United States, 89109
      • GenesisCare USA - Las Vegas
    • Las Vegas, Nevada, United States, 89119
      • Radiation Oncology Centers of Nevada Southeast
    • Las Vegas, Nevada, United States, 89128
      • Comprehensive Cancer Centers of Nevada - Northwest
    • Las Vegas, Nevada, United States, 89144
      • Comprehensive Cancer Centers of Nevada-Summerlin
    • Las Vegas, Nevada, United States, 89148
      • Comprehensive Cancer Centers of Nevada
    • Las Vegas, Nevada, United States, 89148
      • OptumCare Cancer Care at Fort Apache
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada - Central Valley
    • Las Vegas, Nevada, United States, 89106
      • Cancer and Blood Specialists-Shadow
    • Las Vegas, Nevada, United States, 89109
      • HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway
    • Las Vegas, Nevada, United States, 89113
      • HealthCare Partners Medical Group Oncology/Hematology-San Martin
    • Las Vegas, Nevada, United States, 89121
      • Cancer Therapy and Integrative Medicine
    • Las Vegas, Nevada, United States, 89128
      • Cancer and Blood Specialists-Tenaya
    • Las Vegas, Nevada, United States, 89128
      • GenesisCare USA - Vegas Tenaya
    • Las Vegas, Nevada, United States, 89128
      • HealthCare Partners Medical Group Oncology/Hematology-Tenaya
    • Las Vegas, Nevada, United States, 89148-2405
      • Las Vegas Cancer Center-Medical Center
    • Las Vegas, Nevada, United States, 89148
      • GenesisCare USA - Fort Apache
    • Las Vegas, Nevada, United States, 89149
      • HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills
    • Las Vegas, Nevada, United States, 89128
      • Ann M Wierman MD LTD
    • Reno, Nevada, United States, 89502
      • Renown Regional Medical Center
    • Reno, Nevada, United States, 89503
      • Saint Mary's Regional Medical Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
    • Manchester, New Hampshire, United States, 03102
      • Norris Cotton Cancer Center-Manchester
    • Nashua, New Hampshire, United States, 03063
      • Dartmouth Cancer Center - Nashua
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • University of New Mexico Cancer Center
  • New York
    • Brooklyn, New York, United States, 11203
      • State University of New York Downstate Medical Center
    • Lake Success, New York, United States, 11042
      • Northwell Health/Center for Advanced Medicine
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • AdventHealth Infusion Center Asheville
    • Belmont, North Carolina, United States, 28012
      • Gaston Hematology and Oncology Associates-Belmont
    • Cary, North Carolina, United States, 27518
      • Waverly Hematology Oncology
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Clinton, North Carolina, United States, 28328
      • Southeastern Medical Oncology Center-Clinton
    • Clinton, North Carolina, United States, 28328
      • Sampson Radiation Oncology
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Gastonia, North Carolina, United States, 28054
      • CaroMont Regional Medical Center
    • Gastonia, North Carolina, United States, 28054
      • Gaston Hematology and Oncology Associates
    • Goldsboro, North Carolina, United States, 27534
      • Southeastern Medical Oncology Center-Goldsboro
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Radiation Oncology
    • Henderson, North Carolina, United States, 27536
      • Maria Parham Hospital
    • Hendersonville, North Carolina, United States, 28791
      • Hendersonville Hematology and Oncology at Pardee
    • Hendersonville, North Carolina, United States, 28791
      • Margaret R Pardee Memorial Hospital
    • Hendersonville, North Carolina, United States, 28792
      • AdventHealth Hendersonville
    • Jacksonville, North Carolina, United States, 28546
      • Southeastern Medical Oncology Center-Jacksonville
    • Jacksonville, North Carolina, United States, 28546
      • Onslow Memorial Hospital
    • Kinston, North Carolina, United States, 28501
      • Vidant Oncology-Kinston
    • Laurinburg, North Carolina, United States, 28352
      • Scotland Memorial Hospital-Laurinburg Cancer Center
    • Lumberton, North Carolina, United States, 28358
      • Southeastern Regional Medical Center
    • Shelby, North Carolina, United States, 28150
      • Cleveland Hematology and Oncology Associates PC
    • Smithfield, North Carolina, United States, 27577
      • Johnston Memorial Hospital
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • Sanford Bismarck Medical Center
    • Fargo, North Dakota, United States, 58122
      • Sanford Roger Maris Cancer Center
    • Fargo, North Dakota, United States, 58103
      • Essentia Health Cancer Center-South University Clinic
    • Fargo, North Dakota, United States, 58122
      • Sanford Broadway Medical Center
    • Fargo, North Dakota, United States, 58122
      • Sanford Clinic North-Fargo
    • Grand Forks, North Dakota, United States, 58201
      • Altru Cancer Center
  • Ohio
    • Akron, Ohio, United States, 44307
      • Cleveland Clinic Akron General
    • Belpre, Ohio, United States, 45714
      • Strecker Cancer Center-Belpre
    • Canton, Ohio, United States, 44708
      • Cleveland Clinic Mercy Hospital
    • Canton, Ohio, United States, 44710
      • Aultman Health Foundation
    • Centerville, Ohio, United States, 45459
      • Miami Valley Hospital South
    • Centerville, Ohio, United States, 45459
      • Dayton Physicians LLC-Miami Valley South
    • Chillicothe, Ohio, United States, 45601
      • Adena Regional Medical Center
    • Cincinnati, Ohio, United States, 45220
      • Good Samaritan Hospital - Cincinnati
    • Cincinnati, Ohio, United States, 45242
      • Bethesda North Hospital
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care Inc-Blue Ash
    • Cincinnati, Ohio, United States, 45202
      • Oncology Hematology Care Inc-Eden Park
    • Cincinnati, Ohio, United States, 45211
      • Oncology Hematology Care Inc-Mercy West
    • Cincinnati, Ohio, United States, 45230
      • Oncology Hematology Care Inc-Anderson
    • Cincinnati, Ohio, United States, 45236
      • Oncology Hematology Care Inc-Kenwood
    • Cincinnati, Ohio, United States, 45247
      • TriHealth Cancer Institute-Westside
    • Cincinnati, Ohio, United States, 45255
      • TriHealth Cancer Institute-Anderson
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
    • Columbus, Ohio, United States, 43219
      • The Mark H Zangmeister Center
    • Columbus, Ohio, United States, 43214
      • Columbus Oncology and Hematology Associates Inc
    • Columbus, Ohio, United States, 43228
      • Doctors Hospital
    • Columbus, Ohio, United States, 43213
      • Mount Carmel East Hospital
    • Columbus, Ohio, United States, 43215
      • Grant Medical Center
    • Columbus, Ohio, United States, 43222
      • Mount Carmel Health Center West
    • Dayton, Ohio, United States, 45406
      • Good Samaritan Hospital - Dayton
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
    • Dayton, Ohio, United States, 45415
      • Dayton Physician LLC-Miami Valley Hospital North
    • Dayton, Ohio, United States, 45415
      • Miami Valley Hospital North
    • Delaware, Ohio, United States, 43015
      • Delaware Health Center-Grady Cancer Center
    • Delaware, Ohio, United States, 43015
      • Delaware Radiation Oncology
    • Delaware, Ohio, United States, 43015
      • Grady Memorial Hospital
    • Fairfield, Ohio, United States, 45014
      • Oncology Hematology Care Inc-Healthplex
    • Findlay, Ohio, United States, 45840
      • Blanchard Valley Hospital
    • Findlay, Ohio, United States, 45840
      • Armes Family Cancer Center
    • Findlay, Ohio, United States, 45840
      • Orion Cancer Care
    • Franklin, Ohio, United States, 45005-1066
      • Atrium Medical Center-Middletown Regional Hospital
    • Franklin, Ohio, United States, 45005
      • Dayton Physicians LLC-Atrium
    • Greenville, Ohio, United States, 45331
      • Wayne Hospital
    • Greenville, Ohio, United States, 45331
      • Dayton Physicians LLC-Wayne
    • Kettering, Ohio, United States, 45429
      • Kettering Medical Center
    • Kettering, Ohio, United States, 45409
      • Greater Dayton Cancer Center
    • Kettering, Ohio, United States, 45420
      • First Dayton Cancer Care
    • Lancaster, Ohio, United States, 43130
      • Fairfield Medical Center
    • Mansfield, Ohio, United States, 44903
      • OhioHealth Mansfield Hospital
    • Marietta, Ohio, United States, 45750
      • Marietta Memorial Hospital
    • Marion, Ohio, United States, 43302
      • OhioHealth Marion General Hospital
    • Middletown, Ohio, United States, 45042
      • Dayton Physicians LLC-Signal Point
    • Mount Vernon, Ohio, United States, 43050
      • Knox Community Hospital
    • Newark, Ohio, United States, 43055
      • Licking Memorial Hospital
    • Newark, Ohio, United States, 43055
      • Newark Radiation Oncology
    • Portsmouth, Ohio, United States, 45662
      • Southern Ohio Medical Center
    • Sidney, Ohio, United States, 45365
      • Dayton Physicians LLC-Wilson
    • Springfield, Ohio, United States, 45505
      • Springfield Regional Medical Center
    • Springfield, Ohio, United States, 45504
      • Springfield Regional Cancer Center
    • Sylvania, Ohio, United States, 43560
      • ProMedica Flower Hospital
    • Toledo, Ohio, United States, 43606
      • ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
    • Troy, Ohio, United States, 45373
      • Upper Valley Medical Center
    • Troy, Ohio, United States, 45373
      • Dayton Physicians LLC - Troy
    • Westerville, Ohio, United States, 43081
      • Saint Ann's Hospital
    • Zanesville, Ohio, United States, 43701
      • Genesis Healthcare System Cancer Care Center
  • Oklahoma
    • Lawton, Oklahoma, United States, 73505
      • Cancer Centers of Southwest Oklahoma Research
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Baker City, Oregon, United States, 97814
      • Saint Alphonsus Medical Center-Baker City
    • Bend, Oregon, United States, 97701
      • Saint Charles Health System
    • Clackamas, Oregon, United States, 97015
      • Clackamas Radiation Oncology Center
    • Clackamas, Oregon, United States, 97015
      • Providence Cancer Institute Clackamas Clinic
    • Coos Bay, Oregon, United States, 97420
      • Bay Area Hospital
    • Newberg, Oregon, United States, 97132
      • Providence Newberg Medical Center
    • Ontario, Oregon, United States, 97914
      • Saint Alphonsus Medical Center-Ontario
    • Oregon City, Oregon, United States, 97045
      • Providence Willamette Falls Medical Center
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
    • Portland, Oregon, United States, 97225
      • Providence Saint Vincent Medical Center
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Jefferson Abington Hospital
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Hospital-Cedar Crest
    • Bethlehem, Pennsylvania, United States, 18017
      • Lehigh Valley Hospital - Muhlenberg
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Doylestown, Pennsylvania, United States, 18901
      • Doylestown Hospital
    • Hazleton, Pennsylvania, United States, 18201
      • Geisinger Medical Center-Cancer Center Hazleton
    • Lewisburg, Pennsylvania, United States, 17837
      • Geisinger Medical Oncology-Lewisburg
    • Lewistown, Pennsylvania, United States, 17044
      • Lewistown Hospital
    • Pottsville, Pennsylvania, United States, 17901
      • Geisinger Cancer Services-Pottsville
    • Scranton, Pennsylvania, United States, 18510
      • Community Medical Center
    • Selinsgrove, Pennsylvania, United States, 17870
      • Geisinger Medical Oncology-Selinsgrove
    • State College, Pennsylvania, United States, 16801
      • Geisinger Medical Group
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Geisinger Wyoming Valley/Henry Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29401
      • Roper Hospital
    • Charleston, South Carolina, United States, 29406
      • Lowcountry Hematology Oncology PA-North Charleston
    • Charleston, South Carolina, United States, 29414
      • Bon Secours Saint Francis Hospital
    • Charleston, South Carolina, United States, 29414
      • Lowcountry Hematology Oncology PA-West Ashley
    • Charleston, South Carolina, United States, 29403
      • Charleston Oncology - Roper
    • Charleston, South Carolina, United States, 29414
      • Charleston Oncology - Saint Francis
    • Greenville, South Carolina, United States, 29607
      • Saint Francis Cancer Center
    • Greenville, South Carolina, United States, 29601
      • Saint Francis Hospital
    • Greenwood, South Carolina, United States, 29646
      • Self Regional Healthcare
    • Mount Pleasant, South Carolina, United States, 29464
      • Lowcountry Hematology Oncology PA-Mount Pleasant
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5134
      • Sanford USD Medical Center - Sioux Falls
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Cancer Center Oncology Clinic
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Memorial Hospital
    • Hixson, Tennessee, United States, 37343
      • Pulmonary Medicine Center of Chattanooga-Hixson
    • Ooltewah, Tennessee, United States, 37363
      • Memorial GYN Plus
  • Texas
    • Bryan, Texas, United States, 77802
      • Saint Joseph Regional Cancer Center
  • Virginia
    • Mechanicsville, Virginia, United States, 23116
      • Bon Secours Memorial Regional Medical Center
    • Midlothian, Virginia, United States, 23114
      • Bon Secours Saint Francis Medical Center
    • Richmond, Virginia, United States, 23226
      • Bon Secours Saint Mary's Hospital
  • Washington
    • Aberdeen, Washington, United States, 98520
      • Providence Regional Cancer System-Aberdeen
    • Anacortes, Washington, United States, 98221
      • Cancer Care Center at Island Hospital
    • Auburn, Washington, United States, 98001
      • MultiCare Auburn Medical Center
    • Bainbridge Island, Washington, United States, 98110
      • Virginia Mason Bainbridge Island Medical Center
    • Bellevue, Washington, United States, 98004
      • Overlake Medical Center
    • Bellevue, Washington, United States, 98005
      • Swedish Cancer Institute-Eastside Oncology Hematology
    • Bellingham, Washington, United States, 98225
      • PeaceHealth Saint Joseph Medical Center
    • Bremerton, Washington, United States, 98310
      • Harrison HealthPartners Hematology and Oncology-Bremerton
    • Bremerton, Washington, United States, 98310
      • Harrison Medical Center
    • Burien, Washington, United States, 98166
      • Highline Medical Center-Main Campus
    • Centralia, Washington, United States, 98531
      • Providence Regional Cancer System-Centralia
    • Edmonds, Washington, United States, 98026
      • Swedish Cancer Institute-Edmonds
    • Enumclaw, Washington, United States, 98022
      • Saint Elizabeth Hospital
    • Everett, Washington, United States, 98201
      • Providence Regional Cancer Partnership
    • Federal Way, Washington, United States, 98002
      • Virginia Mason Federal Way Medical Center
    • Federal Way, Washington, United States, 98003
      • Saint Francis Hospital
    • Gig Harbor, Washington, United States, 98332
      • Tacoma/Valley Radiation Oncology Centers-Gig Harbor
    • Gig Harbor, Washington, United States, 98335
      • MultiCare Gig Harbor Medical Park
    • Issaquah, Washington, United States, 98029
      • Swedish Cancer Institute-Issaquah
    • Lacey, Washington, United States, 98503
      • Providence Regional Cancer System-Lacey
    • Lakewood, Washington, United States, 98499
      • Saint Clare Hospital
    • Longview, Washington, United States, 98632
      • PeaceHealth Saint John Medical Center
    • Lynnwood, Washington, United States, 98036
      • Virginia Mason Lynnwood Medical Center
    • Port Townsend, Washington, United States, 98368
      • Jefferson Healthcare
    • Poulsbo, Washington, United States, 98370
      • Harrison HealthPartners Hematology and Oncology-Poulsbo
    • Poulsbo, Washington, United States, 98370
      • Peninsula Cancer Center
    • Puyallup, Washington, United States, 98372
      • MultiCare Good Samaritan Hospital
    • Puyallup, Washington, United States, 98372
      • Tacoma/Valley Radiation Oncology Centers-Puyallup
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
    • Seattle, Washington, United States, 98107
      • Swedish Medical Center-Ballard Campus
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center-First Hill
    • Seattle, Washington, United States, 98112
      • Kaiser Permanente Washington
    • Seattle, Washington, United States, 98104
      • Minor and James Medical PLLC
    • Seattle, Washington, United States, 98104
      • Pacific Gynecology Specialists
    • Shelton, Washington, United States, 98584
      • Providence Regional Cancer System-Shelton
    • Spokane, Washington, United States, 99218
      • Evergreen Hematology and Oncology PS
    • Spokane, Washington, United States, 99204
      • MultiCare Deaconess Cancer and Blood Specialty Center - Downtown
    • Spokane, Washington, United States, 99218
      • MultiCare Deaconess Cancer and Blood Specialty Center - North
    • Spokane Valley, Washington, United States, 99216
      • MultiCare Deaconess Cancer and Blood Specialty Center - Valley
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties PLLC
    • Tacoma, Washington, United States, 98405
      • MultiCare Tacoma General Hospital
    • Tacoma, Washington, United States, 98405
      • Tacoma/Valley Radiation Oncology Centers-Saint Joe's
    • Tacoma, Washington, United States, 97405
      • Tacoma/Valley Radiation Oncology Centers-Jackson Hall
    • Tacoma, Washington, United States, 98405
      • Franciscan Research Center-Northwest Medical Plaza
    • Tacoma, Washington, United States, 98405
      • Northwest NCI Community Oncology Research Program
    • Vancouver, Washington, United States, 98664
      • PeaceHealth Southwest Medical Center
    • Walla Walla, Washington, United States, 99362
      • Providence Saint Mary Regional Cancer Center
    • Yakima, Washington, United States, 98902
      • North Star Lodge Cancer Center at Yakima Valley Memorial Hospital
    • Yelm, Washington, United States, 98597
      • Providence Regional Cancer System-Yelm
  • Wisconsin
    • Mequon, Wisconsin, United States, 53097
      • Ascension Columbia Saint Mary's Hospital Ozaukee
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin
    • Milwaukee, Wisconsin, United States, 53211
      • Ascension Columbia Saint Mary's Hospital - Milwaukee
    • Wisconsin Rapids, Wisconsin, United States, 54494
      • Aspirus Cancer Care - Wisconsin Rapids
  • Wyoming
    • Cody, Wyoming, United States, 82414
      • Big Horn Basin Cancer Center
    • Cody, Wyoming, United States, 82414
      • Billings Clinic-Cody
    • Sheridan, Wyoming, United States, 82801
      • Welch Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• PRE-REGISTRATION ELIGIBILITY CRITERIA
• Women who agree to undergo a standard of care core biopsy of recurrent or metastatic breast cancer to confirm the ER+ (>= 10% nuclear staining) and HER2 negative status

• Patient must have been previously treated with an aromatase inhibitor (either letrozole, anastrozole or exemestane) either in the adjuvant or metastatic setting, and have one of the following types of primary or secondary endocrine resistant disease

  • Primary clinical resistance is defined as one of the following:

    • Recurrence within the first 2 years of adjuvant endocrine therapy while on aromatase inhibitor therapy
    • Progression within first 6 months of initiating first-line endocrine therapy (either aromatase inhibitor or fulvestrant containing regimen) for the treatment of metastatic breast cancer

  • Secondary clinical resistance is defined as one of the following:

    • Recurrence after year 2 while receiving adjuvant aromatase inhibitor therapy, or within 12 months of completing adjuvant aromatase inhibitor therapy
    • Progression occurring 6 or more months after initiating the first endocrine therapy for metastatic disease (either fulvestrant or aromatase inhibitor containing regimen)
• Patients with a history of measurable disease as defined by RECIST criteria or bone only disease are eligible; Note: those patients with non-measurable disease and bone metastases are eligible
• No history of tumors involving spinal cord or heart
• No current evidence of visceral crisis or lymphangitic spread
• No known brain metastases

• Women must be postmenopausal

  • Postmenopausal status is verified by:

    • Prior bilateral surgical oophorectomy, or
    • Age >= 60 years, or
    • Age < 60 with no menses for > 1 year with follicle-stimulating hormone (FSH) and estradiol levels within post menopausal range, according to institutional standard

• Prior treatment

  • No more than two prior chemotherapy regimens in the metastatic setting
  • Prior treatment with an aromatase inhibitor (either anastrozole, letrozole or exemestane), either in the adjuvant or metastatic setting is required
  • Unlimited prior endocrine regimens in the metastatic setting, which may have included an everolimus or cyclin dependent kinase (CDK) 4/6 inhibitor (such as palbociclib, abemaciclib or ribociclib) containing regimen
  • Prior tamoxifen treatment is allowed in the adjuvant setting, but patients must not have experienced relapse within 1 year of stopping tamoxifen
  • No prior treatment with tamoxifen in the metastatic setting
  • No prior treatment with endoxifen

  • Patients who have not fully recovered from acute, reversible effects of prior therapy regardless of interval since last treatment are not eligible to participate in this study

    • EXCEPTION: neuropathies-if grade 2 neuropathies have been stable for at least 3 months since completion of prior treatment patient is eligible
• Not receiving any medications or substances that are strong inhibitors of cytochrome P450 family 2, subfamily D, polypeptide 6 (CYP2D6)
• Not receiving any other investigational agents

• No uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Uncontrolled symptomatic cardiac arrhythmia
  • Uncontrolled hypertension (defined as blood pressure > 160/90)

• None of the following co-morbid conditions:

  • Cataracts of grade 2 or greater as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

  • Retinopathy of grade 2 or greater as per CTCAE version 4.0

    • Note: patients that have cataracts that do not require surgery are eligible
    • Note: serious adverse events will be reported on CTEP-Adverse Event Reporting System (AERS) using CTCAE version (v)5.0

  • Deep vein thrombosis/pulmonary embolism (DVT/PE) within the past 6 months

    • Note: patients that are on anticoagulant therapy for maintenance are eligible as long as the DVT and/or PE occurred > 6 months prior to enrollment, and there is no evidence for active thrombosis (either DVT or PE)
• No other active second malignancy other than non-melanoma skin cancers within 3 years of pre-registration; a second malignancy is not considered active if all treatment for that malignancy is completed and the patient has been disease-free for at least 3 years prior to pre-registration
• Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
• Able to swallow oral formulation of the study agent
• Hemoglobin >= 9 g/dL
• Platelet count >= 75,000/mm^3
• Creatinine =< 1.5 x upper limits of normal (ULN)
• Total bilirubin =< 1.5 x upper limits of normal (ULN)
• Aspartate aminotransferase (AST) =< 2.5 x upper limits of normal (ULN); for patients with liver metastasis: =< 5 x upper limits of normal (ULN)
• REGISTRATION ELIGIBILITY CRITERIA

• Patients with either measurable disease as defined by RECIST criteria or bone only disease are eligible; Note: those patients with both non-measurable disease and bone metastases are eligible

  • Non-measurable bone only disease: Non-measurable bone only disease may include any of the following: blastic bone lesions, lytic bone lesions without a measurable soft-tissue component, or mixed lytic-blastic bone lesions without a measurable soft-tissue component
  • Lytic bone lesions, with an identifiable soft tissue component, evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), can be considered as measurable lesions if the soft tissue component otherwise meets the definition of measurability previously described
• No tumors involving spinal cord or heart
• No visceral crisis, lymphangitic spread or known brain metastases: visceral crisis is not the mere presence of visceral metastases, but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of disease
• Histologic confirmation, from the A011203 pre-registration biopsy, by institutional/local pathologist of either locally advanced or metastatic breast cancer that is estrogen receptor positive and HER2 negative; those patients with bone only disease with either no tumor or insufficient tumor for ER/progesterone receptor (PR) and HER2 staining after the bone biopsy are still eligible to participate in this study
• Estrogen receptor positive disease is defined as > 10% nuclear staining

• HER2 negative disease as per 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, one of the following must apply:

  • 0 or 1+ by immunohistochemistry (IHC) and not amplified by in situ hybridization (ISH)
  • 0 or 1+ by IHC and ISH not done
  • 2+ by IHC and not amplified by ISH or
  • IHC not done and not amplified by ISH

• None of the following therapies are allowed prior to registration:

  • Chemotherapy =< 2 weeks
  • Immunotherapy =< 2 weeks
  • Biologic therapy =< 2 weeks
  • Hormonal therapy =< 2 weeks
  • Monoclonal antibodies =< 2 weeks
  • Radiation therapy =< 2 weeks

  • Anti-Her-2 or other "targeted" (e.g. mammalian target of rapamycin [mTOR]) therapy =< 2 weeks

    • NOTE : Any toxicities derived from these therapies must be =< grade 2 prior to starting study therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (z-endoxifen hydrochloride); Patients receive z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Endoxifen Hydrochloride; Given PO; Other Names: Z-Endoxifen HCl; Z-Endoxifen Hydrochloride
Experimental: Arm II (tamoxifen citrate); Patients receive tamoxifen citrate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Tamoxifen Citrate; Given PO; Other Names: Nolvadex; TAM; Soltamox; Apo-Tamox; Clonoxifen; Dignotamoxi; Ebefen; Emblon; Estroxyn; Fentamox; Gen-Tamoxifen; Genox; ICI 46,474; ICI-46474; Jenoxifen; Kessar; Ledertam; Lesporene; Nolgen; Noltam; Nolvadex-D; Nourytam; Novo-Tamoxifen; Novofen; Noxitem; Oestrifen; Oncotam; PMS-Tamoxifen; Tamax; Tamaxin; Tamifen; Tamizam; Tamofen; Tamoxasta; Tamoxifeni Citras; Zemide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	The primary endpoint is progression-free survival (PFS) defined as the time from randomization to documentation of local, regional or distant disease progression or death without progression of disease.	Assessed up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events, Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0	For a given adverse event (AE), the proportion of patients on each treatment arm who report developing a grade 2-5 of this AE will be determined.	Up to 5 years
Tumor Response Rate by Study Arm, Defined as the Number of Patients With a Complete or Partial Response	Defined by Response Evaluation Criteria in Solid Tumors on 2 consecutive evaluations at least 6 weeks apart, divided by the total number of eligible patients who began study treatment. A 90% binomial confidence interval will be constructed for the true response rate.	Up to 5 years
Overall Survival Distribution by Study Arm	The distribution of survival times will be estimated using the method of Kaplan-Meier.	The time from registration to death due to any cause, assessed up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Deoxyribonucleic Acid (DNA) Alterations as Measured by Foundation Medicine	Data will be returned as presence or absence of various DNA alterations, along with description of type and location of the alteration. The nature of alterations in each pathway and gene will be described in tabular format. Association of presence or absence of DNA alterations with PFS will be assessed overall, by pathway, and by gene via Cox regression with the goal of evaluating hazard ratio estimates and confidence intervals. Alterations will be considered together as well as by type. Model fit and stability evaluated, and exact methods used if needed. Performed for both arms and within arms.	Baseline
Nuclear Receptor Coactivator 3 (SRC3) Immunohistochemistry Expression Levels	Within each treatment arm, a point and interval estimate of the difference in tumor response rate between those with metastatic SRC3-positive disease and those with metastatic SRC3-negative disease will be constructed using the properties of the binomial distribution. Also, a point and interval estimate of the odds of disease progression among those with metastatic SRC3-positive disease relative to those with metastatic SRC3-negative disease will be ascertained from the parameter estimates of fitting a proportional hazard model to the progression data.	Baseline
Change in Biochemical Markers of Bone Turnover	For each of the markers of bone formation, the percent change after 2 courses of treatment from pre-treatment levels will be determined. A two-sided alpha = 0.01 z-test will be used to assess whether the percent change in a given bone absorption biomarkers differs with respect to treatment.	Baseline to week 8 (after course 2)
Z-endoxifen Hydrochloride Area Under Curve (AUC)	A population PK will be developed using the software program NONMEM, Version 7. The model will be parameterized in terms of AUC (the primary endpoint), as well as clearance and volume of distribution. Criteria for model selection will include the likelihood ratio test, shrinkage estimates, reasonableness of parameter estimates, as well as goodness-of-fit plots. Attempts will be made to identify the covariates that affect drug behavior or those that explain variability in this patient population.	Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9
Pharmacokinetic (PK) Data	Examined in an exploratory and hypothesis-generating fashion. Pharmacokinetic-pharmacodynamic (PD) relationships will be explored for effects of endoxifen on efficacy-related, adverse events or laboratory parameters of clinical interest. Exploratory/graphical analyses will be conducted for PK/PD evaluations and may be followed by model-based analyses. The data may be pooled with data from other/future studies for additional population PK/PD analyses.	Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9
Pharmacogenetic Data	Examined in an exploratory and hypothesis-generating fashion.	Baseline
Pharmacodynamic Data	PK/PD relationships will be explored for effects of endoxifen on efficacy-related, adverse events or laboratory parameters of clinical interest. Exploratory/graphical analyses will be conducted for PK/PD evaluations and may be followed by model-based analyses. The data may be pooled with data from other/future studies for additional population PK/PD analyses.	Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Matthew P Goetz, Alliance for Clinical Trials in Oncology

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2015
• Primary Completion (Actual): November 6, 2020
• Study Completion (Estimated): February 4, 2025

Study Registration Dates

• First Submitted: December 8, 2014
• First Submitted That Met QC Criteria: December 8, 2014
• First Posted (Estimated): December 9, 2014

Study Record Updates

• Last Update Posted (Actual): April 4, 2024
• Last Update Submitted That Met QC Criteria: April 3, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Tamoxifen
• Other Study ID Numbers: NCI-2014-02409 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180821 (U.S. NIH Grant/Contract); A011203 (Other Identifier: CTEP)