Clincosm LogoSign in Get a demo

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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT02311933
Collaborator
(none)
81
Enrollment
567
Locations
2
Arms
86.6
Anticipated Duration (Months)
0.1
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Endoxifen Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Drug: Tamoxifen Citrate
 Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. 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:

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

  2. 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.

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

TERTIARY OBJECTIVES:

  1. 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.

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

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

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

  5. 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.

  6. 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).

  7. 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.

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

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

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

  11. 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 Design

Study Type:
Interventional
Actual Enrollment :
81 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized Phase II Trial of Tamoxifen Versus Z-Endoxifen HCL in Postmenopausal Women With Metastatic Estrogen Receptor Positive, HER2 Negative Breast Cancer
Actual Study Start Date :
Mar 6, 2015
Actual Primary Completion Date :
Nov 6, 2020
Anticipated Study Completion Date :
May 25, 2022

Arms and Interventions

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.

Drug: Endoxifen Hydrochloride
Given PO
Other Names:
  • Z-Endoxifen HCl
  • Z-Endoxifen Hydrochloride

    • Other: Laboratory Biomarker Analysis
    Correlative studies

    Other: Pharmacological Study
    Correlative studies
    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:
  • 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 (PFS) [Assessed up to 5 years]

      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.

    Secondary Outcome Measures

    1. Incidence of Adverse Events, Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [Up to 5 years]

      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.

    2. Tumor Response Rate by Study Arm, Defined as the Number of Patients With a Complete or Partial Response [Up to 5 years]

      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.

    3. Overall Survival Distribution by Study Arm [The time from registration to death due to any cause, assessed up to 5 years]

      The distribution of survival times will be estimated using the method of Kaplan-Meier.

    Other Outcome Measures

    1. Deoxyribonucleic Acid (DNA) Alterations as Measured by Foundation Medicine [Baseline]

      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.

    2. Nuclear Receptor Coactivator 3 (SRC3) Immunohistochemistry Expression Levels [Baseline]

      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.

    3. Change in Biochemical Markers of Bone Turnover [Baseline to week 8 (after course 2)]

      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.

    4. Z-endoxifen Hydrochloride Area Under Curve (AUC) [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]

      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.

    5. Pharmacokinetic (PK) Data [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]

      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.

    6. Pharmacogenetic Data [Baseline]

      Examined in an exploratory and hypothesis-generating fashion.

    7. Pharmacodynamic Data [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]

      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.

    Eligibility Criteria

    Criteria

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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Southern Cancer Center PC-Providence Mobile Alabama United States 36608
    2 Anchorage Associates in Radiation Medicine Anchorage Alaska United States 98508
    3 Anchorage Radiation Therapy Center Anchorage Alaska United States 99504
    4 Alaska Breast Care and Surgery LLC Anchorage Alaska United States 99508
    5 Alaska Oncology and Hematology LLC Anchorage Alaska United States 99508
    6 Alaska Regional Hospital Anchorage Alaska United States 99508
    7 Alaska Women's Cancer Care Anchorage Alaska United States 99508
    8 Anchorage Oncology Centre Anchorage Alaska United States 99508
    9 Katmai Oncology Group Anchorage Alaska United States 99508
    10 Providence Alaska Medical Center Anchorage Alaska United States 99508
    11 Fairbanks Memorial Hospital Fairbanks Alaska United States 99701
    12 Mayo Clinic Hospital in Arizona Phoenix Arizona United States 85054
    13 Mayo Clinic in Arizona Scottsdale Arizona United States 85259
    14 CHI Saint Vincent Cancer Center Hot Springs Hot Springs Arkansas United States 71913
    15 Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro Jonesboro Arkansas United States 72401
    16 Kaiser Permanente-Anaheim Anaheim California United States 92806
    17 PCR Oncology Arroyo Grande California United States 93420
    18 Sutter Auburn Faith Hospital Auburn California United States 95602
    19 Sutter Cancer Centers Radiation Oncology Services-Auburn Auburn California United States 95603
    20 AIS Cancer Center at San Joaquin Community Hospital Bakersfield California United States 93301
    21 Kaiser Permanente-Baldwin Park Baldwin Park California United States 91706
    22 Kaiser Permanente-Bellflower Bellflower California United States 90706
    23 Alta Bates Summit Medical Center-Herrick Campus Berkeley California United States 94704
    24 Providence Saint Joseph Medical Center/Disney Family Cancer Center Burbank California United States 91505
    25 Mills-Peninsula Medical Center Burlingame California United States 94010
    26 Sutter Cancer Centers Radiation Oncology Services-Cameron Park Cameron Park California United States 95682
    27 Eden Hospital Medical Center Castro Valley California United States 94546
    28 Sutter Davis Hospital Davis California United States 95616
    29 Epic Care-Dublin Dublin California United States 94568
    30 Bay Area Breast Surgeons Inc Emeryville California United States 94608
    31 Epic Care Partners in Cancer Care Emeryville California United States 94608
    32 Kaiser Permanente-Fontana Fontana California United States 92335
    33 Kaiser Permanente - Harbor City Harbor City California United States 90710
    34 Kaiser Permanente-Irvine Irvine California United States 92618
    35 UC San Diego Moores Cancer Center La Jolla California United States 92093
    36 Kaiser Permanente Los Angeles Medical Center Los Angeles California United States 90027
    37 Kaiser Permanente West Los Angeles Los Angeles California United States 90034
    38 Contra Costa Regional Medical Center Martinez California United States 94553-3156
    39 Fremont - Rideout Cancer Center Marysville California United States 95901
    40 Mercy UC Davis Cancer Center Merced California United States 95340
    41 Memorial Medical Center Modesto California United States 95355
    42 Palo Alto Medical Foundation-Camino Division Mountain View California United States 94040
    43 Palo Alto Medical Foundation-Gynecologic Oncology Mountain View California United States 94040
    44 Sutter Cancer Research Consortium Novato California United States 94945
    45 Alta Bates Summit Medical Center - Summit Campus Oakland California United States 94609
    46 Bay Area Tumor Institute Oakland California United States 94609
    47 Hematology and Oncology Associates-Oakland Oakland California United States 94609
    48 Palo Alto Medical Foundation Health Care Palo Alto California United States 94301
    49 Kaiser Permanente - Panorama City Panorama City California United States 91402
    50 Kaiser Permanente-Riverside Riverside California United States 92505
    51 Sutter Cancer Centers Radiation Oncology Services-Roseville Roseville California United States 95661
    52 Sutter Roseville Medical Center Roseville California United States 95661
    53 Sutter Medical Center Sacramento Sacramento California United States 95816
    54 University of California Davis Comprehensive Cancer Center Sacramento California United States 95817
    55 Kaiser Permanente-San Diego Mission San Diego California United States 92108
    56 Kaiser Permanente-San Diego Zion San Diego California United States 92120
    57 California Pacific Medical Center-Pacific Campus San Francisco California United States 94115
    58 Kaiser Permanente-San Marcos San Marcos California United States 92078
    59 Palo Alto Medical Foundation-Santa Cruz Santa Cruz California United States 95065
    60 Sutter Pacific Medical Foundation Santa Rosa California United States 95403
    61 Palo Alto Medical Foundation-Sunnyvale Sunnyvale California United States 94086
    62 Gene Upshaw Memorial Tahoe Forest Cancer Center Truckee California United States 96161
    63 Sutter Cancer Centers Radiation Oncology Services-Vacaville Vacaville California United States 95687
    64 Sutter Solano Medical Center/Cancer Center Vallejo California United States 94589
    65 Kaiser Permanente-Woodland Hills Woodland Hills California United States 91367
    66 Penrose-Saint Francis Healthcare Colorado Springs Colorado United States 80907
    67 Rocky Mountain Cancer Centers-Penrose Colorado Springs Colorado United States 80907
    68 Porter Adventist Hospital Denver Colorado United States 80210
    69 Mercy Medical Center Durango Colorado United States 81301
    70 Southwest Oncology PC Durango Colorado United States 81301
    71 Mountain Blue Cancer Care Center Golden Colorado United States 80401
    72 Rocky Mountain Cancer Centers-Lakewood Lakewood Colorado United States 80228
    73 Saint Anthony Hospital Lakewood Colorado United States 80228
    74 Littleton Adventist Hospital Littleton Colorado United States 80122
    75 Longmont United Hospital Longmont Colorado United States 80501
    76 Rocky Mountain Cancer Centers-Longmont Longmont Colorado United States 80501
    77 Parker Adventist Hospital Parker Colorado United States 80138
    78 Rocky Mountain Cancer Centers-Parker Parker Colorado United States 80138
    79 Saint Mary Corwin Medical Center Pueblo Colorado United States 81004
    80 Rocky Mountain Cancer Centers - Pueblo Pueblo Colorado United States 81008
    81 Rocky Mountain Cancer Centers-Thornton Thornton Colorado United States 80260
    82 Smilow Cancer Hospital Care Center at Saint Francis Hartford Connecticut United States 06105
    83 Middlesex Hospital Middletown Connecticut United States 06457
    84 Halifax Health Medical Center-Centers for Oncology Daytona Beach Florida United States 32114
    85 Mayo Clinic in Florida Jacksonville Florida United States 32224-9980
    86 University Cancer and Blood Center LLC Athens Georgia United States 30607
    87 Northside Hospital Atlanta Georgia United States 30342
    88 Augusta University Medical Center Augusta Georgia United States 30912
    89 Northside Hospital-Forsyth Cumming Georgia United States 30041
    90 Dekalb Medical Center Decatur Georgia United States 30033
    91 Pali Momi Medical Center 'Aiea Hawaii United States 96701
    92 Queen's Cancer Center - Pearlridge 'Aiea Hawaii United States 96701
    93 The Cancer Center of Hawaii-Pali Momi 'Aiea Hawaii United States 96701
    94 Hawaii Cancer Care Inc - Waterfront Plaza Honolulu Hawaii United States 96813
    95 Island Urology Honolulu Hawaii United States 96813
    96 Queen's Cancer Cenrer - POB I 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 Hawaii Cancer Care Inc-Liliha Honolulu Hawaii United States 96817
    101 Kuakini Medical Center Honolulu Hawaii United States 96817
    102 Queen's Cancer Center - Kuakini Honolulu Hawaii United States 96817
    103 The Cancer Center of Hawaii-Liliha Honolulu Hawaii United States 96817
    104 Kapiolani Medical Center for Women and Children Honolulu Hawaii United States 96826
    105 Wilcox Memorial Hospital and Kauai Medical Clinic Lihue Hawaii United States 96766
    106 Saint Alphonsus Cancer Care Center-Boise Boise Idaho United States 83706
    107 Saint Luke's Cancer Institute - Boise Boise Idaho United States 83712
    108 Saint Alphonsus Cancer Care Center-Caldwell Caldwell Idaho United States 83605
    109 Kootenai Health - Coeur d'Alene Coeur d'Alene Idaho United States 83814
    110 Walter Knox Memorial Hospital Emmett Idaho United States 83617
    111 Saint Luke's Cancer Institute - Fruitland Fruitland Idaho United States 83619
    112 Idaho Urologic Institute-Meridian Meridian Idaho United States 83642
    113 Saint Luke's Cancer Institute - Meridian Meridian Idaho United States 83642
    114 Saint Alphonsus Medical Center-Nampa Nampa Idaho United States 83686
    115 Saint Luke's Cancer Institute - Nampa Nampa Idaho United States 83686
    116 Kootenai Clinic Cancer Services - Post Falls Post Falls Idaho United States 83854
    117 Kootenai Cancer Clinic Sandpoint Idaho United States 83864
    118 Saint Luke's Cancer Institute - Twin Falls Twin Falls Idaho United States 83301
    119 Rush - Copley Medical Center Aurora Illinois United States 60504
    120 Saint Joseph Medical Center Bloomington Illinois United States 61701
    121 Illinois CancerCare-Bloomington Bloomington Illinois United States 61704
    122 Illinois CancerCare-Canton Canton Illinois United States 61520
    123 Memorial Hospital of Carbondale Carbondale Illinois United States 62902
    124 SIH Cancer Institute Carterville Illinois United States 62918
    125 Illinois CancerCare-Carthage Carthage Illinois United States 62321
    126 Centralia Oncology Clinic Centralia Illinois United States 62801
    127 Northwestern University Chicago Illinois United States 60611
    128 John H Stroger Jr Hospital of Cook County Chicago Illinois United States 60612
    129 University of Chicago Comprehensive Cancer Center Chicago Illinois United States 60637
    130 Presence Saint Joseph Hospital-Chicago Chicago Illinois United States 60657
    131 Carle on Vermilion Danville Illinois United States 61832
    132 Cancer Care Specialists of Illinois - Decatur Decatur Illinois United States 62526
    133 Decatur Memorial Hospital Decatur Illinois United States 62526
    134 Carle Physician Group-Effingham Effingham Illinois United States 62401
    135 Crossroads Cancer Center Effingham Illinois United States 62401
    136 AMITA Health Alexian Brothers Medical Center Elk Grove Village Illinois United States 60007
    137 Illinois CancerCare-Eureka Eureka Illinois United States 61530
    138 Illinois CancerCare-Galesburg Galesburg Illinois United States 61401
    139 Western Illinois Cancer Treatment Center Galesburg Illinois United States 61401
    140 Illinois CancerCare-Kewanee Clinic Kewanee Illinois United States 61443
    141 Illinois CancerCare-Macomb Macomb Illinois United States 61455
    142 Carle Physician Group-Mattoon/Charleston Mattoon Illinois United States 61938
    143 Good Samaritan Regional Health Center Mount Vernon Illinois United States 62864
    144 UC Comprehensive Cancer Center at Silver Cross New Lenox Illinois United States 60451
    145 Cancer Care Center of O'Fallon O'Fallon Illinois United States 62269
    146 Illinois CancerCare-Ottawa Clinic Ottawa Illinois United States 61350
    147 Radiation Oncology of Northern Illinois Ottawa Illinois United States 61350
    148 Illinois CancerCare-Pekin Pekin Illinois United States 61554
    149 OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center Pekin Illinois United States 61554
    150 Illinois CancerCare-Peoria Peoria Illinois United States 61615
    151 OSF Saint Francis Radiation Oncology at Peoria Cancer Center Peoria Illinois United States 61615
    152 Methodist Medical Center of Illinois Peoria Illinois United States 61636
    153 OSF Saint Francis Medical Center Peoria Illinois United States 61637
    154 Illinois CancerCare-Peru Peru Illinois United States 61354
    155 Valley Radiation Oncology Peru Illinois United States 61354
    156 Illinois CancerCare-Princeton Princeton Illinois United States 61356
    157 Central Illinois Hematology Oncology Center Springfield Illinois United States 62702
    158 Southern Illinois University School of Medicine Springfield Illinois United States 62702
    159 Springfield Clinic Springfield Illinois United States 62702
    160 Memorial Medical Center Springfield Illinois United States 62781
    161 Southwest Illinois Health Services LLP Swansea Illinois United States 62226
    162 Carle Cancer Center Urbana Illinois United States 61801
    163 The Carle Foundation Hospital Urbana Illinois United States 61801
    164 Rush-Copley Healthcare Center Yorkville Illinois United States 60560
    165 Indiana University/Melvin and Bren Simon Cancer Center Indianapolis Indiana United States 46202
    166 Sidney and Lois Eskenazi Hospital Indianapolis Indiana United States 46202
    167 Springmill Medical Center Indianapolis Indiana United States 46290
    168 Franciscan Saint Anthony Health-Michigan City Michigan City Indiana United States 46360
    169 Woodland Cancer Care Center Michigan City Indiana United States 46360
    170 Memorial Regional Cancer Center Day Road Mishawaka Indiana United States 46545
    171 Reid Health Richmond Indiana United States 47374
    172 Memorial Hospital of South Bend South Bend Indiana United States 46601
    173 Mary Greeley Medical Center Ames Iowa United States 50010
    174 McFarland Clinic PC - Ames Ames Iowa United States 50010
    175 McFarland Clinic PC-Boone Boone Iowa United States 50036
    176 Medical Oncology and Hematology Associates-West Des Moines Clive Iowa United States 50325
    177 Mercy Cancer Center-West Lakes Clive Iowa United States 50325
    178 Alegent Health Mercy Hospital Council Bluffs Iowa United States 51503
    179 Greater Regional Medical Center Creston Iowa United States 50801
    180 Medical Oncology and Hematology Associates-Laurel Des Moines Iowa United States 50314
    181 Mercy Medical Center - Des Moines Des Moines Iowa United States 50314
    182 JCHC McCreery Cancer Center Fairfield Iowa United States 52556
    183 McFarland Clinic PC-Trinity Cancer Center Fort Dodge Iowa United States 50501
    184 McFarland Clinic PC-Jefferson Jefferson Iowa United States 50129
    185 McFarland Clinic PC-Marshalltown Marshalltown Iowa United States 50158
    186 Ottumwa Regional Health Center Ottumwa Iowa United States 52501
    187 Mercy Medical Center-West Lakes West Des Moines Iowa United States 50266
    188 Cancer Center of Kansas - Chanute Chanute Kansas United States 66720
    189 Cancer Center of Kansas - Dodge City Dodge City Kansas United States 67801
    190 Cancer Center of Kansas - El Dorado El Dorado Kansas United States 67042
    191 Cancer Center of Kansas - Fort Scott Fort Scott Kansas United States 66701
    192 Cancer Center of Kansas-Independence Independence Kansas United States 67301
    193 Cancer Center of Kansas-Kingman Kingman Kansas United States 67068
    194 Lawrence Memorial Hospital Lawrence Kansas United States 66044
    195 Cancer Center of Kansas-Liberal Liberal Kansas United States 67905
    196 Cancer Center of Kansas-Manhattan Manhattan Kansas United States 66502
    197 Cancer Center of Kansas - McPherson McPherson Kansas United States 67460
    198 Cancer Center of Kansas - Newton Newton Kansas United States 67114
    199 Cancer Center of Kansas - Parsons Parsons Kansas United States 67357
    200 Cancer Center of Kansas - Pratt Pratt Kansas United States 67124
    201 Cancer Center of Kansas - Salina Salina Kansas United States 67401
    202 Cancer Center of Kansas - Wellington Wellington Kansas United States 67152
    203 Associates In Womens Health Wichita Kansas United States 67208
    204 Cancer Center of Kansas-Wichita Medical Arts Tower Wichita Kansas United States 67208
    205 Ascension Via Christi Hospitals Wichita Wichita Kansas United States 67214
    206 Cancer Center of Kansas - Wichita Wichita Kansas United States 67214
    207 Wichita NCI Community Oncology Research Program Wichita Kansas United States 67214
    208 Cancer Center of Kansas - Winfield Winfield Kansas United States 67156
    209 Flaget Memorial Hospital Bardstown Kentucky United States 40004
    210 Baptist Health Corbin Corbin Kentucky United States 40701
    211 Commonwealth Cancer Center-Corbin Corbin Kentucky United States 40701
    212 Oncology Hematology Care Inc-Crestview Crestview Hills Kentucky United States 41017
    213 Baptist Health Hardin Elizabethtown Kentucky United States 42701
    214 Baptist Health Lexington Lexington Kentucky United States 40503
    215 Saint Joseph Radiation Oncology Resource Center Lexington Kentucky United States 40504
    216 Saint Joseph Hospital East Lexington Kentucky United States 40509
    217 Jewish Hospital Louisville Kentucky United States 40202
    218 Baptist Health Louisville Louisville Kentucky United States 40207
    219 Saints Mary and Elizabeth Hospital Louisville Kentucky United States 40215
    220 Jewish Hospital Medical Center Northeast Louisville Kentucky United States 40245
    221 Baptist Health Madisonville/Merle Mahr Cancer Center Madisonville Kentucky United States 42431
    222 Baptist Health Paducah Paducah Kentucky United States 42003
    223 Jewish Hospital Medical Center South Shepherdsville Kentucky United States 40165
    224 Ochsner Health Center-Summa Baton Rouge Louisiana United States 70809
    225 Ochsner Medical Center Kenner Kenner Louisiana United States 70065
    226 Ochsner Medical Center Jefferson New Orleans Louisiana United States 70121
    227 Harold Alfond Center for Cancer Care Augusta Maine United States 04330
    228 Eastern Maine Medical Center Bangor Maine United States 04401
    229 Lafayette Family Cancer Center-EMMC Brewer Maine United States 04412
    230 Christiana Care - Union Hospital Elkton Maryland United States 21921
    231 Saint Joseph Mercy Hospital Ann Arbor Michigan United States 48106
    232 Bronson Battle Creek Battle Creek Michigan United States 49017
    233 IHA Hematology Oncology Consultants-Brighton Brighton Michigan United States 48114
    234 Saint Joseph Mercy Brighton Brighton Michigan United States 48114
    235 IHA Hematology Oncology Consultants-Canton Canton Michigan United States 48188
    236 Saint Joseph Mercy Canton Canton Michigan United States 48188
    237 Caro Cancer Center Caro Michigan United States 48723
    238 IHA Hematology Oncology Consultants-Chelsea Chelsea Michigan United States 48118
    239 Saint Joseph Mercy Chelsea Chelsea Michigan United States 48118
    240 Hematology Oncology Consultants-Clarkston Clarkston Michigan United States 48346
    241 Newland Medical Associates-Clarkston Clarkston Michigan United States 48346
    242 Beaumont Hospital - Dearborn Dearborn Michigan United States 48124
    243 Ascension Saint John Hospital Detroit Michigan United States 48236
    244 Great Lakes Cancer Management Specialists-Doctors Park East China Township Michigan United States 48054
    245 Genesee Cancer and Blood Disease Treatment Center Flint Michigan United States 48503
    246 Genesee Hematology Oncology PC Flint Michigan United States 48503
    247 Genesys Hurley Cancer Institute Flint Michigan United States 48503
    248 Hurley Medical Center Flint Michigan United States 48503
    249 Mercy Health Saint Mary's Grand Rapids Michigan United States 49503
    250 Spectrum Health at Butterworth Campus Grand Rapids Michigan United States 49503
    251 Academic Hematology Oncology Specialists Grosse Pointe Woods Michigan United States 48236
    252 Great Lakes Cancer Management Specialists-Van Elslander Cancer Center Grosse Pointe Woods Michigan United States 48236
    253 Michigan Breast Specialists-Grosse Pointe Woods Grosse Pointe Woods Michigan United States 48236
    254 Allegiance Health Jackson Michigan United States 49201
    255 West Michigan Cancer Center Kalamazoo Michigan United States 49007
    256 Borgess Medical Center Kalamazoo Michigan United States 49048
    257 Sparrow Hospital Lansing Michigan United States 48912
    258 Hope Cancer Clinic Livonia Michigan United States 48154
    259 Saint Mary Mercy Hospital Livonia Michigan United States 48154
    260 Great Lakes Cancer Management Specialists-Macomb Medical Campus Macomb Michigan United States 48044
    261 Michigan Breast Specialists-Macomb Township Macomb Michigan United States 48044
    262 Saint Mary's Oncology/Hematology Associates of Marlette Marlette Michigan United States 48453
    263 Mid-Michigan Medical Center - Midland Midland Michigan United States 48670
    264 Monroe Cancer Center Monroe Michigan United States 48162
    265 Mercy Health Mercy Campus Muskegon Michigan United States 49444
    266 Lakeland Hospital Niles Niles Michigan United States 49120
    267 21st Century Oncology-Pontiac Pontiac Michigan United States 48341
    268 Hope Cancer Center Pontiac Michigan United States 48341
    269 Newland Medical Associates-Pontiac Pontiac Michigan United States 48341
    270 Saint Joseph Mercy Oakland Pontiac Michigan United States 48341
    271 Lake Huron Medical Center Port Huron Michigan United States 48060
    272 Spectrum Health Reed City Hospital Reed City Michigan United States 49677
    273 Great Lakes Cancer Management Specialists-Rochester Hills Rochester Hills Michigan United States 48309
    274 Ascension Saint Mary's Hospital Saginaw Michigan United States 48601
    275 Oncology Hematology Associates of Saginaw Valley PC Saginaw Michigan United States 48604
    276 Lakeland Medical Center Saint Joseph Saint Joseph Michigan United States 49085
    277 Marie Yeager Cancer Center Saint Joseph Michigan United States 49085
    278 Bhadresh Nayak MD PC-Sterling Heights Sterling Heights Michigan United States 48312
    279 Munson Medical Center Traverse City Michigan United States 49684
    280 Advanced Breast Care Center PLLC Warren Michigan United States 48088
    281 Great Lakes Cancer Management Specialists-Macomb Professional Building Warren Michigan United States 48093
    282 Macomb Hematology Oncology PC Warren Michigan United States 48093
    283 Michigan Breast Specialists-Warren Warren Michigan United States 48093
    284 Saint John Macomb-Oakland Hospital Warren Michigan United States 48093
    285 Saint Mary's Oncology/Hematology Associates of West Branch West Branch Michigan United States 48661
    286 Metro Health Hospital Wyoming Michigan United States 49519
    287 Huron Gastroenterology PC Ypsilanti Michigan United States 48106
    288 IHA Hematology Oncology Consultants-Ann Arbor Ypsilanti Michigan United States 48197
    289 Sanford Joe Lueken Cancer Center Bemidji Minnesota United States 56601
    290 Essentia Health Saint Joseph's Medical Center Brainerd Minnesota United States 56401
    291 Essentia Health Cancer Center Duluth Minnesota United States 55805
    292 Essentia Health Saint Mary's Medical Center Duluth Minnesota United States 55805
    293 Miller-Dwan Hospital Duluth Minnesota United States 55805
    294 Lake Region Healthcare Corporation-Cancer Care Fergus Falls Minnesota United States 56537
    295 Mayo Clinic in Rochester Rochester Minnesota United States 55905
    296 Coborn Cancer Center at Saint Cloud Hospital Saint Cloud Minnesota United States 56303
    297 University of Mississippi Medical Center Jackson Mississippi United States 39216
    298 Singing River Hospital Pascagoula Mississippi United States 39581
    299 Saint Louis Cancer and Breast Institute-Ballwin Ballwin Missouri United States 63011
    300 Central Care Cancer Center - Bolivar Bolivar Missouri United States 65613
    301 Parkland Health Center-Bonne Terre Bonne Terre Missouri United States 63628
    302 Cox Cancer Center Branson Branson Missouri United States 65616
    303 Saint Francis Medical Center Cape Girardeau Missouri United States 63703
    304 Southeast Cancer Center Cape Girardeau Missouri United States 63703
    305 University of Missouri - Ellis Fischel Columbia Missouri United States 65212
    306 Siteman Cancer Center at West County Hospital Creve Coeur Missouri United States 63141
    307 Capital Region Southwest Campus Jefferson City Missouri United States 65109
    308 Freeman Health System Joplin Missouri United States 64804
    309 Mercy Hospital Joplin Joplin Missouri United States 64804
    310 Delbert Day Cancer Institute at PCRMC Rolla Missouri United States 65401
    311 Mercy Clinic-Rolla-Cancer and Hematology Rolla Missouri United States 65401
    312 Saint Louis Cancer and Breast Institute-South City Saint Louis Missouri United States 63109
    313 Washington University School of Medicine Saint Louis Missouri United States 63110
    314 Missouri Baptist Medical Center Saint Louis Missouri United States 63131
    315 Mercy Hospital Saint Louis Saint Louis Missouri United States 63141
    316 Siteman Cancer Center at Saint Peters Hospital Saint Peters Missouri United States 63376
    317 Sainte Genevieve County Memorial Hospital Sainte Genevieve Missouri United States 63670
    318 Mercy Hospital Springfield Springfield Missouri United States 65804
    319 CoxHealth South Hospital Springfield Missouri United States 65807
    320 Missouri Baptist Sullivan Hospital Sullivan Missouri United States 63080
    321 Missouri Baptist Outpatient Center-Sunset Hills Sunset Hills Missouri United States 63127
    322 Community Hospital of Anaconda Anaconda Montana United States 59711
    323 Billings Clinic Cancer Center Billings Montana United States 59101
    324 Saint Vincent Healthcare Billings Montana United States 59101
    325 Bozeman Deaconess Hospital Bozeman Montana United States 59715
    326 Saint James Community Hospital and Cancer Treatment Center Butte Montana United States 59701
    327 Benefis Healthcare- Sletten Cancer Institute Great Falls Montana United States 59405
    328 Great Falls Clinic Great Falls Montana United States 59405
    329 Saint Peter's Community Hospital Helena Montana United States 59601
    330 Kalispell Regional Medical Center Kalispell Montana United States 59901
    331 Saint Patrick Hospital - Community Hospital Missoula Montana United States 59802
    332 Community Medical Hospital Missoula Montana United States 59804
    333 CHI Health Saint Francis Grand Island Nebraska United States 68803
    334 Heartland Hematology and Oncology Kearney Nebraska United States 68845
    335 CHI Health Good Samaritan Kearney Nebraska United States 68847
    336 Saint Elizabeth Regional Medical Center Lincoln Nebraska United States 68510
    337 Alegent Health Immanuel Medical Center Omaha Nebraska United States 68122
    338 Hematology and Oncology Consultants PC Omaha Nebraska United States 68122
    339 Alegent Health Bergan Mercy Medical Center Omaha Nebraska United States 68124
    340 Alegent Health Lakeside Hospital Omaha Nebraska United States 68130
    341 Creighton University Medical Center Omaha Nebraska United States 68131
    342 University of Nebraska Medical Center Omaha Nebraska United States 68198
    343 Midlands Community Hospital Papillion Nebraska United States 68046
    344 Carson Tahoe Regional Medical Center Carson City Nevada United States 89703
    345 Cancer and Blood Specialists-Henderson Henderson Nevada United States 89052
    346 Comprehensive Cancer Centers of Nevada - Henderson Henderson Nevada United States 89052
    347 Las Vegas Cancer Center-Henderson Henderson Nevada United States 89052
    348 21st Century Oncology-Henderson Henderson Nevada United States 89074
    349 Comprehensive Cancer Centers of Nevada-Southeast Henderson Henderson Nevada United States 89074
    350 Cancer and Blood Specialists-Shadow Las Vegas Nevada United States 89106
    351 Radiation Oncology Centers of Nevada Central Las Vegas Nevada United States 89106
    352 21st Century Oncology Las Vegas Nevada United States 89109
    353 HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway Las Vegas Nevada United States 89109
    354 HealthCare Partners Medical Group Oncology/Hematology-San Martin Las Vegas Nevada United States 89113
    355 Radiation Oncology Centers of Nevada Southeast Las Vegas Nevada United States 89119
    356 Cancer Therapy and Integrative Medicine Las Vegas Nevada United States 89121
    357 21st Century Oncology-Vegas Tenaya Las Vegas Nevada United States 89128
    358 Ann M Wierman MD LTD Las Vegas Nevada United States 89128
    359 Cancer and Blood Specialists-Tenaya Las Vegas Nevada United States 89128
    360 Comprehensive Cancer Centers of Nevada - Northwest Las Vegas Nevada United States 89128
    361 HealthCare Partners Medical Group Oncology/Hematology-Tenaya Las Vegas Nevada United States 89128
    362 Comprehensive Cancer Centers of Nevada-Summerlin Las Vegas Nevada United States 89144
    363 Summerlin Hospital Medical Center Las Vegas Nevada United States 89144
    364 Las Vegas Cancer Center-Medical Center Las Vegas Nevada United States 89148-2405
    365 21st Century Oncology-Fort Apache Las Vegas Nevada United States 89148
    366 Comprehensive Cancer Centers of Nevada Las Vegas Nevada United States 89148
    367 OptumCare Cancer Care at Fort Apache Las Vegas Nevada United States 89148
    368 HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills Las Vegas Nevada United States 89149
    369 Comprehensive Cancer Centers of Nevada - Central Valley Las Vegas Nevada United States 89169
    370 Renown Regional Medical Center Reno Nevada United States 89502
    371 Saint Mary's Regional Medical Center Reno Nevada United States 89503
    372 Dartmouth Hitchcock Medical Center Lebanon New Hampshire United States 03756
    373 Norris Cotton Cancer Center-Manchester Manchester New Hampshire United States 03102
    374 Norris Cotton Cancer Center-Nashua Nashua New Hampshire United States 03063
    375 University of New Mexico Cancer Center Albuquerque New Mexico United States 87102
    376 State University of New York Downstate Medical Center Brooklyn New York United States 11203
    377 Northwell Health/Center for Advanced Medicine Lake Success New York United States 11042
    378 AdventHealth Infusion Center Asheville Asheville North Carolina United States 28803
    379 Gaston Hematology and Oncology Associates-Belmont Belmont North Carolina United States 28012
    380 Waverly Hematology Oncology Cary North Carolina United States 27518
    381 UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina United States 27599
    382 Sampson Radiation Oncology Clinton North Carolina United States 28328
    383 Southeastern Medical Oncology Center-Clinton Clinton North Carolina United States 28328
    384 Duke University Medical Center Durham North Carolina United States 27710
    385 CaroMont Regional Medical Center Gastonia North Carolina United States 28054
    386 Gaston Hematology and Oncology Associates Gastonia North Carolina United States 28054
    387 Southeastern Medical Oncology Center-Goldsboro Goldsboro North Carolina United States 27534
    388 Wayne Memorial Hospital Goldsboro North Carolina United States 27534
    389 Wayne Radiation Oncology Goldsboro North Carolina United States 27534
    390 Hendersonville Hematology and Oncology at Pardee Hendersonville North Carolina United States 28791
    391 Margaret R Pardee Memorial Hospital Hendersonville North Carolina United States 28791
    392 AdventHealth Hendersonville Hendersonville North Carolina United States 28792
    393 Maria Parham Hospital Henderson North Carolina United States 27536
    394 Onslow Memorial Hospital Jacksonville North Carolina United States 28546
    395 Southeastern Medical Oncology Center-Jacksonville Jacksonville North Carolina United States 28546
    396 Vidant Oncology-Kinston Kinston North Carolina United States 28501
    397 Scotland Memorial Hospital-Laurinburg Cancer Center Laurinburg North Carolina United States 28352
    398 Southeastern Regional Medical Center Lumberton North Carolina United States 28358
    399 Cleveland Hematology and Oncology Associates PC Shelby North Carolina United States 28150
    400 Johnston Memorial Hospital Smithfield North Carolina United States 27577
    401 Wake Forest University Health Sciences Winston-Salem North Carolina United States 27157
    402 Sanford Bismarck Medical Center Bismarck North Dakota United States 58501
    403 Essentia Health Cancer Center-South University Clinic Fargo North Dakota United States 58103
    404 Sanford Broadway Medical Center Fargo North Dakota United States 58122
    405 Sanford Clinic North-Fargo Fargo North Dakota United States 58122
    406 Sanford Roger Maris Cancer Center Fargo North Dakota United States 58122
    407 Altru Cancer Center Grand Forks North Dakota United States 58201
    408 Cleveland Clinic Akron General Akron Ohio United States 44307
    409 Strecker Cancer Center-Belpre Belpre Ohio United States 45714
    410 Cleveland Clinic Mercy Hospital Canton Ohio United States 44708
    411 Aultman Health Foundation Canton Ohio United States 44710
    412 Dayton Physicians LLC-Miami Valley South Centerville Ohio United States 45459
    413 Miami Valley Hospital South Centerville Ohio United States 45459
    414 Adena Regional Medical Center Chillicothe Ohio United States 45601
    415 Oncology Hematology Care Inc-Eden Park Cincinnati Ohio United States 45202
    416 Oncology Hematology Care Inc-Mercy West Cincinnati Ohio United States 45211
    417 Good Samaritan Hospital - Cincinnati Cincinnati Ohio United States 45220
    418 Oncology Hematology Care Inc-Anderson Cincinnati Ohio United States 45230
    419 Oncology Hematology Care Inc-Kenwood Cincinnati Ohio United States 45236
    420 Bethesda North Hospital Cincinnati Ohio United States 45242
    421 Oncology Hematology Care Inc-Blue Ash Cincinnati Ohio United States 45242
    422 TriHealth Cancer Institute-Westside Cincinnati Ohio United States 45247
    423 TriHealth Cancer Institute-Anderson Cincinnati Ohio United States 45255
    424 Ohio State University Comprehensive Cancer Center Columbus Ohio United States 43210
    425 Mount Carmel East Hospital Columbus Ohio United States 43213
    426 Columbus Oncology and Hematology Associates Inc Columbus Ohio United States 43214
    427 Riverside Methodist Hospital Columbus Ohio United States 43214
    428 Grant Medical Center Columbus Ohio United States 43215
    429 The Mark H Zangmeister Center Columbus Ohio United States 43219
    430 Mount Carmel Health Center West Columbus Ohio United States 43222
    431 Doctors Hospital Columbus Ohio United States 43228
    432 Good Samaritan Hospital - Dayton Dayton Ohio United States 45406
    433 Miami Valley Hospital Dayton Ohio United States 45409
    434 Dayton Physician LLC-Miami Valley Hospital North Dayton Ohio United States 45415
    435 Miami Valley Hospital North Dayton Ohio United States 45415
    436 Delaware Health Center-Grady Cancer Center Delaware Ohio United States 43015
    437 Delaware Radiation Oncology Delaware Ohio United States 43015
    438 Grady Memorial Hospital Delaware Ohio United States 43015
    439 Oncology Hematology Care Inc-Healthplex Fairfield Ohio United States 45014
    440 Armes Family Cancer Center Findlay Ohio United States 45840
    441 Blanchard Valley Hospital Findlay Ohio United States 45840
    442 Orion Cancer Care Findlay Ohio United States 45840
    443 Atrium Medical Center-Middletown Regional Hospital Franklin Ohio United States 45005-1066
    444 Dayton Physicians LLC-Atrium Franklin Ohio United States 45005
    445 Dayton Physicians LLC-Wayne Greenville Ohio United States 45331
    446 Wayne Hospital Greenville Ohio United States 45331
    447 Greater Dayton Cancer Center Kettering Ohio United States 45409
    448 First Dayton Cancer Care Kettering Ohio United States 45420
    449 Kettering Medical Center Kettering Ohio United States 45429
    450 Fairfield Medical Center Lancaster Ohio United States 43130
    451 OhioHealth Mansfield Hospital Mansfield Ohio United States 44903
    452 Marietta Memorial Hospital Marietta Ohio United States 45750
    453 OhioHealth Marion General Hospital Marion Ohio United States 43302
    454 Dayton Physicians LLC-Signal Point Middletown Ohio United States 45042
    455 Knox Community Hospital Mount Vernon Ohio United States 43050
    456 Licking Memorial Hospital Newark Ohio United States 43055
    457 Newark Radiation Oncology Newark Ohio United States 43055
    458 Southern Ohio Medical Center Portsmouth Ohio United States 45662
    459 Dayton Physicians LLC-Wilson Sidney Ohio United States 45365
    460 Springfield Regional Cancer Center Springfield Ohio United States 45504
    461 Springfield Regional Medical Center Springfield Ohio United States 45505
    462 ProMedica Flower Hospital Sylvania Ohio United States 43560
    463 ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital Toledo Ohio United States 43606
    464 Dayton Physicians LLC-Upper Valley Troy Ohio United States 45373
    465 Upper Valley Medical Center Troy Ohio United States 45373
    466 Saint Ann's Hospital Westerville Ohio United States 43081
    467 Genesis Healthcare System Cancer Care Center Zanesville Ohio United States 43701
    468 Cancer Centers of Southwest Oklahoma Research Lawton Oklahoma United States 73505
    469 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    470 Saint Alphonsus Medical Center-Baker City Baker City Oregon United States 97814
    471 Saint Charles Health System Bend Oregon United States 97701
    472 Clackamas Radiation Oncology Center Clackamas Oregon United States 97015
    473 Providence Cancer Institute Clackamas Clinic Clackamas Oregon United States 97015
    474 Bay Area Hospital Coos Bay Oregon United States 97420
    475 Providence Newberg Medical Center Newberg Oregon United States 97132
    476 Saint Alphonsus Medical Center-Ontario Ontario Oregon United States 97914
    477 Providence Willamette Falls Medical Center Oregon City Oregon United States 97045
    478 Providence Portland Medical Center Portland Oregon United States 97213
    479 Providence Saint Vincent Medical Center Portland Oregon United States 97225
    480 Abington Memorial Hospital Abington Pennsylvania United States 19001
    481 Lehigh Valley Hospital-Cedar Crest Allentown Pennsylvania United States 18103
    482 Lehigh Valley Hospital - Muhlenberg Bethlehem Pennsylvania United States 18017
    483 Geisinger Medical Center Danville Pennsylvania United States 17822
    484 Doylestown Hospital Doylestown Pennsylvania United States 18901
    485 Geisinger Medical Center-Cancer Center Hazleton Hazleton Pennsylvania United States 18201
    486 Geisinger Medical Oncology-Lewisburg Lewisburg Pennsylvania United States 17837
    487 Lewistown Hospital Lewistown Pennsylvania United States 17044
    488 Geisinger Cancer Services-Pottsville Pottsville Pennsylvania United States 17901
    489 Community Medical Center Scranton Pennsylvania United States 18510
    490 Geisinger Medical Oncology-Selinsgrove Selinsgrove Pennsylvania United States 17870
    491 Geisinger Medical Group State College Pennsylvania United States 16801
    492 Geisinger Wyoming Valley/Henry Cancer Center Wilkes-Barre Pennsylvania United States 18711
    493 Roper Hospital Charleston South Carolina United States 29401
    494 Charleston Oncology - Roper Charleston South Carolina United States 29403
    495 Lowcountry Hematology Oncology PA-North Charleston Charleston South Carolina United States 29406
    496 Bon Secours Saint Francis Hospital Charleston South Carolina United States 29414
    497 Charleston Oncology - Saint Francis Charleston South Carolina United States 29414
    498 Lowcountry Hematology Oncology PA-West Ashley Charleston South Carolina United States 29414
    499 Saint Francis Hospital Greenville South Carolina United States 29601
    500 Saint Francis Cancer Center Greenville South Carolina United States 29607
    501 Self Regional Healthcare Greenwood South Carolina United States 29646
    502 Lowcountry Hematology Oncology PA-Mount Pleasant Mount Pleasant South Carolina United States 29464
    503 Sanford Cancer Center Oncology Clinic Sioux Falls South Dakota United States 57104
    504 Sanford USD Medical Center - Sioux Falls Sioux Falls South Dakota United States 57117-5134
    505 Memorial Hospital Chattanooga Tennessee United States 37404
    506 Pulmonary Medicine Center of Chattanooga-Hixson Hixson Tennessee United States 37343
    507 Memorial GYN Plus Ooltewah Tennessee United States 37363
    508 Saint Joseph Regional Cancer Center Bryan Texas United States 77802
    509 Bon Secours Memorial Regional Medical Center Mechanicsville Virginia United States 23116
    510 Bon Secours Saint Francis Medical Center Midlothian Virginia United States 23114
    511 Bon Secours Saint Mary's Hospital Richmond Virginia United States 23226
    512 Providence Regional Cancer System-Aberdeen Aberdeen Washington United States 98520
    513 Cancer Care Center at Island Hospital Anacortes Washington United States 98221
    514 MultiCare Auburn Medical Center Auburn Washington United States 98001
    515 Virginia Mason Bainbridge Island Medical Center Bainbridge Island Washington United States 98110
    516 Overlake Medical Center Bellevue Washington United States 98004
    517 Swedish Cancer Institute-Eastside Oncology Hematology Bellevue Washington United States 98005
    518 PeaceHealth Saint Joseph Medical Center Bellingham Washington United States 98225
    519 Harrison HealthPartners Hematology and Oncology-Bremerton Bremerton Washington United States 98310
    520 Harrison Medical Center Bremerton Washington United States 98310
    521 Highline Medical Center-Main Campus Burien Washington United States 98166
    522 Providence Regional Cancer System-Centralia Centralia Washington United States 98531
    523 Swedish Cancer Institute-Edmonds Edmonds Washington United States 98026
    524 Saint Elizabeth Hospital Enumclaw Washington United States 98022
    525 Providence Regional Cancer Partnership Everett Washington United States 98201
    526 Virginia Mason Federal Way Medical Center Federal Way Washington United States 98002
    527 Saint Francis Hospital Federal Way Washington United States 98003
    528 Tacoma/Valley Radiation Oncology Centers-Gig Harbor Gig Harbor Washington United States 98332
    529 MultiCare Gig Harbor Medical Park Gig Harbor Washington United States 98335
    530 Swedish Cancer Institute-Issaquah Issaquah Washington United States 98029
    531 Providence Regional Cancer System-Lacey Lacey Washington United States 98503
    532 Saint Clare Hospital Lakewood Washington United States 98499
    533 PeaceHealth Saint John Medical Center Longview Washington United States 98632
    534 Virginia Mason Lynnwood Medical Center Lynnwood Washington United States 98036
    535 Jefferson Healthcare Port Townsend Washington United States 98368
    536 Harrison HealthPartners Hematology and Oncology-Poulsbo Poulsbo Washington United States 98370
    537 Peninsula Cancer Center Poulsbo Washington United States 98370
    538 MultiCare Good Samaritan Hospital Puyallup Washington United States 98372
    539 Tacoma/Valley Radiation Oncology Centers-Puyallup Puyallup Washington United States 98372
    540 Virginia Mason Medical Center Seattle Washington United States 98101
    541 Minor and James Medical PLLC Seattle Washington United States 98104
    542 Pacific Gynecology Specialists Seattle Washington United States 98104
    543 Swedish Medical Center-Ballard Campus Seattle Washington United States 98107
    544 Kaiser Permanente Washington Seattle Washington United States 98112
    545 Swedish Medical Center-First Hill Seattle Washington United States 98122-4307
    546 Providence Regional Cancer System-Shelton Shelton Washington United States 98584
    547 MultiCare Deaconess Cancer and Blood Specialty Center - Valley Spokane Valley Washington United States 99216
    548 MultiCare Deaconess Cancer and Blood Specialty Center - Downtown Spokane Washington United States 99204
    549 Evergreen Hematology and Oncology PS Spokane Washington United States 99218
    550 MultiCare Deaconess Cancer and Blood Specialty Center - North Spokane Washington United States 99218
    551 Tacoma/Valley Radiation Oncology Centers-Jackson Hall Tacoma Washington United States 97405
    552 Franciscan Research Center-Northwest Medical Plaza Tacoma Washington United States 98405
    553 MultiCare Tacoma General Hospital Tacoma Washington United States 98405
    554 Northwest Medical Specialties PLLC Tacoma Washington United States 98405
    555 Northwest NCI Community Oncology Research Program Tacoma Washington United States 98405
    556 Tacoma/Valley Radiation Oncology Centers-Saint Joe's Tacoma Washington United States 98405
    557 PeaceHealth Southwest Medical Center Vancouver Washington United States 98664
    558 Providence Saint Mary Regional Cancer Center Walla Walla Washington United States 99362
    559 North Star Lodge Cancer Center at Yakima Valley Memorial Hospital Yakima Washington United States 98902
    560 Providence Regional Cancer System-Yelm Yelm Washington United States 98597
    561 Ascension Columbia Saint Mary's Hospital Ozaukee Mequon Wisconsin United States 53097
    562 Ascension Columbia Saint Mary's Hospital - Milwaukee Milwaukee Wisconsin United States 53211
    563 Medical College of Wisconsin Milwaukee Wisconsin United States 53226
    564 Aspirus Cancer Care - Wisconsin Rapids Wisconsin Rapids Wisconsin United States 54494
    565 Big Horn Basin Cancer Center Cody Wyoming United States 82414
    566 Billings Clinic-Cody Cody Wyoming United States 82414
    567 Welch Cancer Center Sheridan Wyoming United States 82801

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Matthew P Goetz, Alliance for Clinical Trials in Oncology

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT02311933
    Other Study ID Numbers:
    • NCI-2014-02409
    • NCI-2014-02409
    • A011203
    • A011203
    • A011203
    • U10CA180821
    First Posted:
    Dec 9, 2014
    Last Update Posted:
    Sep 28, 2021
    Last Verified:
    Sep 1, 2021
    Additional relevant MeSH terms:
    Breast Neoplasms
    Tamoxifen

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Arm I (Z-endoxifen Hydrochloride) Arm II (Tamoxifen Citrate)
    Arm/Group Description Patients receive 80 mg z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients receive 20 mg 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.
    Period Title: Overall Study
    STARTED 41 40
    COMPLETED 41 40
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Arm I (Z-endoxifen Hydrochloride) Arm II (Tamoxifen Citrate) Total
    Arm/Group Description Patients receive 80 mg z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients receive 20 mg 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. Total of all reporting groups
    Overall Participants 41 40 81
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    64
    66
    65
    Sex: Female, Male (Count of Participants)
    Female
    41
    100%
    40
    100%
    81
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    2.4%
    3
    7.5%
    4
    4.9%
    Not Hispanic or Latino
    39
    95.1%
    36
    90%
    75
    92.6%
    Unknown or Not Reported
    1
    2.4%
    1
    2.5%
    2
    2.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    2.4%
    1
    2.5%
    2
    2.5%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    3
    7.3%
    2
    5%
    5
    6.2%
    White
    36
    87.8%
    36
    90%
    72
    88.9%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    1
    2.4%
    1
    2.5%
    2
    2.5%
    Region of Enrollment (participants) [Number]
    United States
    41
    100%
    40
    100%
    81
    100%

    Outcome Measures

    1. Primary Outcome
    Title Progression Free Survival (PFS)
    Description 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.
    Time Frame Assessed up to 5 years

    Outcome Measure Data

    Analysis Population Description
    All patients registered who began protocol treatment and were eligible for assessment were included in this analysis. One patient in Arm I was ineligible, two patients in Arm II were ineligible and one patient in Arm II did not receive treatment.
    Arm/Group Title Arm I (Z-endoxifen Hydrochloride) Arm II (Tamoxifen Citrate)
    Arm/Group Description Patients receive 80 mg z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients receive 20 mg 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.
    Measure Participants 40 37
    Median (95% Confidence Interval) [days]
    130
    42
    2. Secondary Outcome
    Title Incidence of Adverse Events, Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
    Description 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.
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    3. Secondary Outcome
    Title Tumor Response Rate by Study Arm, Defined as the Number of Patients With a Complete or Partial Response
    Description 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.
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    4. Secondary Outcome
    Title Overall Survival Distribution by Study Arm
    Description The distribution of survival times will be estimated using the method of Kaplan-Meier.
    Time Frame The time from registration to death due to any cause, assessed up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    5. Other Pre-specified Outcome
    Title Deoxyribonucleic Acid (DNA) Alterations as Measured by Foundation Medicine
    Description 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.
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Other Pre-specified Outcome
    Title Nuclear Receptor Coactivator 3 (SRC3) Immunohistochemistry Expression Levels
    Description 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.
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    7. Other Pre-specified Outcome
    Title Change in Biochemical Markers of Bone Turnover
    Description 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.
    Time Frame Baseline to week 8 (after course 2)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Other Pre-specified Outcome
    Title Z-endoxifen Hydrochloride Area Under Curve (AUC)
    Description 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.
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Other Pre-specified Outcome
    Title Pharmacokinetic (PK) Data
    Description 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.
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Other Pre-specified Outcome
    Title Pharmacogenetic Data
    Description Examined in an exploratory and hypothesis-generating fashion.
    Time Frame Baseline

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Other Pre-specified Outcome
    Title Pharmacodynamic Data
    Description 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.
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
    Adverse Event Reporting Description Adverse events were collected at the end of every 3 week cycle (up to a max 92 cycles). The data reported here for the primary submission is through 8/18/2021.
    Arm/Group Title Arm I (Z-endoxifen Hydrochloride) Arm II (Tamoxifen Citrate)
    Arm/Group Description Patients receive 80 mg z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients receive 20 mg 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.
    All Cause Mortality
    Arm I (Z-endoxifen Hydrochloride) Arm II (Tamoxifen Citrate)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/41 (2.4%) 0/39 (0%)
    Serious Adverse Events
    Arm I (Z-endoxifen Hydrochloride) Arm II (Tamoxifen Citrate)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/41 (19.5%) 11/39 (28.2%)
    Blood and lymphatic system disorders
    Anemia 1/41 (2.4%) 1 0/39 (0%) 0
    Cardiac disorders
    Aortic valve disease 0/41 (0%) 0 1/39 (2.6%) 1
    Cardiac disorders - Other, specify 0/41 (0%) 0 1/39 (2.6%) 1
    Heart failure 0/41 (0%) 0 1/39 (2.6%) 1
    Myocardial infarction 0/41 (0%) 0 1/39 (2.6%) 1
    Eye disorders
    Eye disorders - Other, specify 0/41 (0%) 0 1/39 (2.6%) 1
    Gastrointestinal disorders
    Abdominal pain 1/41 (2.4%) 1 1/39 (2.6%) 1
    Ascites 0/41 (0%) 0 1/39 (2.6%) 1
    Colitis 0/41 (0%) 0 1/39 (2.6%) 1
    Diarrhea 0/41 (0%) 0 1/39 (2.6%) 1
    Dysphagia 1/41 (2.4%) 1 0/39 (0%) 0
    Nausea 0/41 (0%) 0 3/39 (7.7%) 3
    Vomiting 0/41 (0%) 0 2/39 (5.1%) 2
    General disorders
    Chills 0/41 (0%) 0 1/39 (2.6%) 1
    Fatigue 1/41 (2.4%) 1 1/39 (2.6%) 1
    Fever 0/41 (0%) 0 1/39 (2.6%) 1
    Infections and infestations
    Bladder infection 0/41 (0%) 0 1/39 (2.6%) 1
    Infections and infestations - Oth spec 1/41 (2.4%) 1 0/39 (0%) 0
    Lung infection 1/41 (2.4%) 1 0/39 (0%) 0
    Sepsis 0/41 (0%) 0 2/39 (5.1%) 2
    Urinary tract infection 1/41 (2.4%) 1 0/39 (0%) 0
    Injury, poisoning and procedural complications
    Wound complication 0/41 (0%) 0 1/39 (2.6%) 1
    Investigations
    Aspartate aminotransferase increased 1/41 (2.4%) 1 0/39 (0%) 0
    Creatinine increased 1/41 (2.4%) 1 0/39 (0%) 0
    Metabolism and nutrition disorders
    Anorexia 0/41 (0%) 0 2/39 (5.1%) 2
    Dehydration 0/41 (0%) 0 2/39 (5.1%) 2
    Hypercalcemia 1/41 (2.4%) 1 1/39 (2.6%) 1
    Hyperglycemia 1/41 (2.4%) 1 1/39 (2.6%) 1
    Hypophosphatemia 0/41 (0%) 0 1/39 (2.6%) 3
    Musculoskeletal and connective tissue disorders
    Muscle weakness upper limb 1/41 (2.4%) 1 0/39 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, mal, uncpec - Oth spec 1/41 (2.4%) 1 0/39 (0%) 0
    Nervous system disorders
    Stroke 0/41 (0%) 0 1/39 (2.6%) 1
    Psychiatric disorders
    Delirium 1/41 (2.4%) 1 0/39 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 1/41 (2.4%) 1 0/39 (0%) 0
    Urinary tract obstruction 1/41 (2.4%) 1 0/39 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 1/41 (2.4%) 1 2/39 (5.1%) 2
    Pleural effusion 1/41 (2.4%) 2 1/39 (2.6%) 1
    Pneumonitis 0/41 (0%) 0 1/39 (2.6%) 1
    Pneumothorax 1/41 (2.4%) 1 0/39 (0%) 0
    Pulmonary edema 0/41 (0%) 0 1/39 (2.6%) 1
    Respiratory failure 0/41 (0%) 0 1/39 (2.6%) 2
    Skin and subcutaneous tissue disorders
    Skin ulceration 1/41 (2.4%) 1 0/39 (0%) 0
    Other (Not Including Serious) Adverse Events
    Arm I (Z-endoxifen Hydrochloride) Arm II (Tamoxifen Citrate)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 34/41 (82.9%) 36/39 (92.3%)
    Blood and lymphatic system disorders
    Anemia 5/41 (12.2%) 6 4/39 (10.3%) 20
    Blood and lymph sys disorders - Oth Spec 0/41 (0%) 0 1/39 (2.6%) 4
    Cardiac disorders
    Atrial fibrillation 0/41 (0%) 0 1/39 (2.6%) 2
    Sinus bradycardia 1/41 (2.4%) 1 1/39 (2.6%) 1
    Sinus tachycardia 0/41 (0%) 0 1/39 (2.6%) 2
    Eye disorders
    Blurred vision 0/41 (0%) 0 2/39 (5.1%) 8
    Dry eye 0/41 (0%) 0 1/39 (2.6%) 4
    Eye disorders - Other, specify 1/41 (2.4%) 1 0/39 (0%) 0
    Gastrointestinal disorders
    Abdominal distension 2/41 (4.9%) 2 0/39 (0%) 0
    Abdominal pain 1/41 (2.4%) 1 3/39 (7.7%) 8
    Constipation 6/41 (14.6%) 13 1/39 (2.6%) 1
    Diarrhea 1/41 (2.4%) 7 1/39 (2.6%) 1
    Dyspepsia 5/41 (12.2%) 23 3/39 (7.7%) 8
    Gastroesophageal reflux disease 1/41 (2.4%) 2 0/39 (0%) 0
    Gastrointestinal disorders - Oth spec 0/41 (0%) 0 1/39 (2.6%) 2
    Mucositis oral 0/41 (0%) 0 2/39 (5.1%) 4
    Nausea 5/41 (12.2%) 10 7/39 (17.9%) 11
    Oral dysesthesia 0/41 (0%) 0 1/39 (2.6%) 1
    Rectal hemorrhage 0/41 (0%) 0 1/39 (2.6%) 1
    Vomiting 0/41 (0%) 0 1/39 (2.6%) 1
    General disorders
    Chills 1/41 (2.4%) 1 0/39 (0%) 0
    Edema limbs 2/41 (4.9%) 6 0/39 (0%) 0
    Fatigue 16/41 (39%) 57 7/39 (17.9%) 48
    Fever 1/41 (2.4%) 1 0/39 (0%) 0
    Flu like symptoms 2/41 (4.9%) 2 1/39 (2.6%) 2
    Gen disord and admin site conds-Oth spec 0/41 (0%) 0 1/39 (2.6%) 1
    Pain 1/41 (2.4%) 5 1/39 (2.6%) 1
    Immune system disorders
    Allergic reaction 0/41 (0%) 0 1/39 (2.6%) 1
    Infections and infestations
    Bronchial infection 0/41 (0%) 0 1/39 (2.6%) 1
    Infections and infestations - Oth spec 0/41 (0%) 0 1/39 (2.6%) 1
    Otitis externa 1/41 (2.4%) 2 0/39 (0%) 0
    Tooth infection 0/41 (0%) 0 1/39 (2.6%) 1
    Upper respiratory infection 1/41 (2.4%) 1 1/39 (2.6%) 1
    Urinary tract infection 1/41 (2.4%) 2 3/39 (7.7%) 6
    Vaginal infection 0/41 (0%) 0 1/39 (2.6%) 1
    Vulval infection 0/41 (0%) 0 1/39 (2.6%) 1
    Injury, poisoning and procedural complications
    Fracture 0/41 (0%) 0 1/39 (2.6%) 2
    Investigations
    Alanine aminotransferase increased 0/41 (0%) 0 2/39 (5.1%) 2
    Alkaline phosphatase increased 3/41 (7.3%) 11 3/39 (7.7%) 10
    Aspartate aminotransferase increased 9/41 (22%) 26 14/39 (35.9%) 57
    Blood bilirubin increased 1/41 (2.4%) 1 2/39 (5.1%) 2
    Cholesterol high 2/41 (4.9%) 7 2/39 (5.1%) 4
    Creatinine increased 2/41 (4.9%) 4 1/39 (2.6%) 1
    Lipase increased 1/41 (2.4%) 1 0/39 (0%) 0
    Lymphocyte count decreased 4/41 (9.8%) 24 3/39 (7.7%) 5
    Neutrophil count decreased 1/41 (2.4%) 1 2/39 (5.1%) 6
    Platelet count decreased 2/41 (4.9%) 2 3/39 (7.7%) 4
    Weight loss 1/41 (2.4%) 4 1/39 (2.6%) 1
    White blood cell decreased 1/41 (2.4%) 1 2/39 (5.1%) 8
    Metabolism and nutrition disorders
    Anorexia 7/41 (17.1%) 24 3/39 (7.7%) 7
    Hypercalcemia 1/41 (2.4%) 1 0/39 (0%) 0
    Hyperglycemia 4/41 (9.8%) 14 4/39 (10.3%) 11
    Hyperkalemia 1/41 (2.4%) 2 2/39 (5.1%) 4
    Hypernatremia 0/41 (0%) 0 2/39 (5.1%) 3
    Hypertriglyceridemia 16/41 (39%) 61 13/39 (33.3%) 84
    Hypoalbuminemia 5/41 (12.2%) 11 4/39 (10.3%) 9
    Hypocalcemia 1/41 (2.4%) 2 4/39 (10.3%) 8
    Hypoglycemia 0/41 (0%) 0 1/39 (2.6%) 1
    Hypokalemia 0/41 (0%) 0 1/39 (2.6%) 1
    Hypomagnesemia 0/41 (0%) 0 2/39 (5.1%) 4
    Hyponatremia 0/41 (0%) 0 3/39 (7.7%) 6
    Hypophosphatemia 0/41 (0%) 0 2/39 (5.1%) 5
    Musculoskeletal and connective tissue disorders
    Arthralgia 6/41 (14.6%) 10 1/39 (2.6%) 7
    Back pain 1/41 (2.4%) 2 1/39 (2.6%) 1
    Bone pain 2/41 (4.9%) 2 2/39 (5.1%) 2
    Musculoskeletal, conn tissue - Oth spec 1/41 (2.4%) 1 1/39 (2.6%) 3
    Myalgia 2/41 (4.9%) 3 4/39 (10.3%) 10
    Pain in extremity 1/41 (2.4%) 1 3/39 (7.7%) 8
    Nervous system disorders
    Dizziness 2/41 (4.9%) 4 2/39 (5.1%) 6
    Dysgeusia 3/41 (7.3%) 16 2/39 (5.1%) 23
    Headache 1/41 (2.4%) 2 3/39 (7.7%) 6
    Peripheral sensory neuropathy 2/41 (4.9%) 7 0/39 (0%) 0
    Spasticity 0/41 (0%) 0 1/39 (2.6%) 2
    Stroke 0/41 (0%) 0 1/39 (2.6%) 1
    Syncope 0/41 (0%) 0 1/39 (2.6%) 1
    Vasovagal reaction 0/41 (0%) 0 1/39 (2.6%) 1
    Psychiatric disorders
    Anxiety 1/41 (2.4%) 1 1/39 (2.6%) 1
    Insomnia 1/41 (2.4%) 1 5/39 (12.8%) 24
    Irritability 0/41 (0%) 0 1/39 (2.6%) 4
    Renal and urinary disorders
    Urinary frequency 1/41 (2.4%) 4 1/39 (2.6%) 2
    Urinary incontinence 0/41 (0%) 0 1/39 (2.6%) 7
    Urinary tract pain 1/41 (2.4%) 1 1/39 (2.6%) 1
    Urinary urgency 1/41 (2.4%) 2 1/39 (2.6%) 2
    Reproductive system and breast disorders
    Breast pain 0/41 (0%) 0 1/39 (2.6%) 1
    Vaginal discharge 0/41 (0%) 0 4/39 (10.3%) 30
    Vaginal dryness 1/41 (2.4%) 1 1/39 (2.6%) 5
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis 1/41 (2.4%) 1 0/39 (0%) 0
    Cough 6/41 (14.6%) 7 2/39 (5.1%) 8
    Dyspnea 2/41 (4.9%) 2 3/39 (7.7%) 7
    Hoarseness 1/41 (2.4%) 1 0/39 (0%) 0
    Nasal congestion 0/41 (0%) 0 1/39 (2.6%) 1
    Sore throat 1/41 (2.4%) 2 1/39 (2.6%) 1
    Wheezing 0/41 (0%) 0 1/39 (2.6%) 1
    Skin and subcutaneous tissue disorders
    Alopecia 3/41 (7.3%) 6 1/39 (2.6%) 2
    Pruritus 1/41 (2.4%) 1 1/39 (2.6%) 1
    Rash acneiform 1/41 (2.4%) 1 1/39 (2.6%) 1
    Rash maculo-papular 0/41 (0%) 0 2/39 (5.1%) 3
    Skin and subcut tissue disord - Oth spec 1/41 (2.4%) 1 0/39 (0%) 0
    Skin hyperpigmentation 1/41 (2.4%) 1 0/39 (0%) 0
    Skin ulceration 1/41 (2.4%) 1 0/39 (0%) 0
    Surgical and medical procedures
    Surgical and medical proced - Oth spec 0/41 (0%) 0 1/39 (2.6%) 2
    Vascular disorders
    Hot flashes 25/41 (61%) 115 20/39 (51.3%) 178
    Hypertension 2/41 (4.9%) 10 4/39 (10.3%) 8
    Thromboembolic event 1/41 (2.4%) 4 3/39 (7.7%) 14

    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.

    Results Point of Contact

    Name/Title Matthew P. Goetz, MD
    Organization Alliance for Clinical Trials in Oncology
    Phone : 507-284-2511
    Email goetz.matthew@mayo.edu
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT02311933
    Other Study ID Numbers:
    • NCI-2014-02409
    • NCI-2014-02409
    • A011203
    • A011203
    • A011203
    • U10CA180821
    First Posted:
    Dec 9, 2014
    Last Update Posted:
    Sep 28, 2021
    Last Verified:
    Sep 1, 2021