Testing the Addition of a New Anti-Cancer Drug, Niraparib, to the Usual Treatment (Hormone and Radiation Therapy) for Prostate Cancer With a High Chance of Recurring
- Conditions
- Prostate AdenocarcinomaStage IIC Prostate Cancer AJCC v8Stage III Prostate Cancer AJCC v8Stage IIIA Prostate Cancer AJCC v8Stage IIIB Prostate Cancer AJCC v8Stage IIIC Prostate Cancer AJCC v8Stage IVA Prostate Cancer AJCC v8
- Interventions
- Biological: Gonadotrophin Releasing HormoneRadiation: Intensity-Modulated Radiation TherapyProcedure: Magnetic Resonance Imaging
- Registration Number
- NCT04037254
- Lead Sponsor
- NRG Oncology
- Brief Summary
This is a phase I-II trial to find the safety and activity of adding a new drug (neratinib) to the usual treatment (radiation combined with male hormone deprivation therapy) in lowering the chance of prostate cancer growing or returning. Niraparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Adding niraparib to the usual care may lower the chance of prostate cancer growing or returning.
- Detailed Description
PRIMARY OBJECTIVES:
I. To establish the preferred dose of niraparib in combination with radiation and antiandrogen therapy (ADT). (Phase I) II. To compare the disease-free state, defined as prostate specific antigen (PSA) remaining \< 0.1 ng/ml at the end of ADT therapy in men with high risk prostate cancer treated with standard therapy with or without the addition of niraparib. (Phase IIR)
SECONDARY OBJECTIVES:
I. To further establish the safety and toxicity profile of standard treatment with radiation and androgen deprivation therapy specifically, two years from initiation of ADT, plus niraparib at the phase II dose.
II. To compare the overall survival, prostate cancer-specific survival, local/regional or distant progression, and distant metastatic disease rates of standard therapy with or without the addition of niraparib.
EXPLORATORY OBJECTIVE:
I. To identify genomic biomarkers of response to combination therapy with radiation, ADT and PARP inhibition.
OUTLINE: This is a phase I, dose-escalation study of niraparib, followed by a randomized phase II study.
PHASE I: Patients receive niraparib orally (PO) once daily (QD) and receive standard of care gonadotrophin releasing hormone (GnRH) agonist androgen suppression therapy. Treatment with niraparib continues for 12 months, and GnRH agonist therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib and GnRH agonist, patients undergo standard of care intensity-modulated radiation therapy (IMRT) 5 days per week for about 6-9 weeks, depending on type of radiation therapy given, in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) on study.
PHASE II: Patients are randomized to 1 of 2 arms:
ARM I: Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8-28 weeks after starting GnRH agonist, patients undergo IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study.
ARM II: Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months, and niraparib PO QD for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study.
After completion of study treatment, patients are followed up every 6 months for 3 years, then annually for 3 years.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Male
- Target Recruitment
- 18
-
Histologically confirmed (within 180 days prior to registration) adenocarcinoma of the prostate at high risk for recurrence as determined by the following criteria, according to American Joint Committee on Cancer (AJCC) 8th edition:
-
Phase I enrollment
- Gleason >= 9, PSA =< 150 ng/mL, any T-stage
-
Phase II enrollment
- Gleason >= 9, PSA =< 150 ng/mL, any T-stage
- Gleason 8, PSA < 20 ng/mL, and >= T2
- Gleason 8, PSA >= 20-150 ng/mL, any T-stage
- Gleason 7, PSA >= 20-150 ng/mL, any T-stage
-
-
No distant metastases as evaluated by:
- Bone scan 90 days prior to registration
- Lymph node assessment by computed tomography (CT) or magnetic resonance (MR) of pelvis or nodal sampling within 90 days prior to registration (Please note: Lymph nodes will be considered negative [N0] if they are < 1.5 cm short axis)
-
History/physical examination within 90 days prior to registration
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Age >= 18
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 180 days prior to registration
-
Pretreatment serum PSA, obtained prior to any androgen suppression therapy and within 180 days of registration
-
Phase I patients: Prior androgen suppression for prostate cancer is not allowed prior to registration
-
Phase II patients: Prior androgen suppression for prostate cancer is allowed =< 45 days prior to registration
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Hemoglobin >= 9.0 g/dL (within 90 days prior to registration)
-
Platelets >= 100,000 cells/mm^3 (within 90 days prior to registration)
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Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 90 days prior to registration)
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Serum creatinine =<1.5 x upper limit of normal (ULN) OR a calculated creatinine clearance >= 30 mL/min estimated using Cockcroft-Gault equation (within 90 days prior to registration)
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Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN (within 90 days prior to registration)
-
Serum albumin >= 3 g/dL (within 90 days prior to registration)
-
Serum potassium >= 3.5 mmol/L (within 90 days prior to registration)
-
Serum total bilirubin =< 1.5 x ULN or direct bilirubin =< 1 x ULN (Note: in subjects with Gilberts syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin, and if direct bilirubin is =< 1.5 x ULN, subject may be eligible) (within 90 days prior to registration)
-
Men of child-producing potential must be willing to consent to use effective contraception while on treatment and for at least 3 months afterwards
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The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
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PSA > 150 ng/mL
-
Definitive clinical or radiologic evidence of metastatic disease
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Pathologically positive lymph nodes or nodes > 1.5 cm short axis on CT or MR imaging
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Prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason
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Any active malignancy within 2 years of study registration that may alter the course of prostate cancer treatment
-
Prior systemic therapy for prostate cancer; note that prior therapy for a different cancer is allowable
-
Prior radiotherapy, including brachytherapy, to the region of the prostate that would result in overlap of radiation therapy fields
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Current treatment with first generation anti-androgens (bicalutamide, nilutamide, flutamide). For patients enrolled to phase II, if prior anti-androgens were administered, a washout period of >= 30 days is required prior to enrollment
-
Severe, active co-morbidity, defined as follows:
- Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
- Transmural myocardial infarction within the last 6 months
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
- Uncontrolled acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition
- Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] >=160 mmHg or diastolic BP >= 100 mmHg). Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment
-
Prior allergic reaction to the drugs involved in this protocol (including known allergies, hypersensitivity or intolerance to the excipients of niraparib)
-
Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter
- Note that patients who are HIV positive are eligible, provided they have a CD4 count >= 200 cells/microliter within 90 days prior to registration. Patients receiving treatment with highly active antiretroviral therapy (HAART) will not be eligible due to concern for radiosensitization
- Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be affected by these drugs
-
Any history or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
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Prior or current treatment with PARP inhibitor
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase I (niraparib, GnRH, IMRT) Gonadotrophin Releasing Hormone Patients receive niraparib PO QD and receive standard of care GnRH agonist androgen suppression therapy. Treatment with niraparib continues for 12 months, and GnRH agonist therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib and GnRH agonist, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks, depending on type of radiation therapy given, in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. Phase I (niraparib, GnRH, IMRT) Intensity-Modulated Radiation Therapy Patients receive niraparib PO QD and receive standard of care GnRH agonist androgen suppression therapy. Treatment with niraparib continues for 12 months, and GnRH agonist therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib and GnRH agonist, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks, depending on type of radiation therapy given, in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. Phase I (niraparib, GnRH, IMRT) Magnetic Resonance Imaging Patients receive niraparib PO QD and receive standard of care GnRH agonist androgen suppression therapy. Treatment with niraparib continues for 12 months, and GnRH agonist therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib and GnRH agonist, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks, depending on type of radiation therapy given, in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. Phase I (niraparib, GnRH, IMRT) Niraparib Patients receive niraparib PO QD and receive standard of care GnRH agonist androgen suppression therapy. Treatment with niraparib continues for 12 months, and GnRH agonist therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib and GnRH agonist, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks, depending on type of radiation therapy given, in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. Phase II, Arm I (GnRH, IMRT) Gonadotrophin Releasing Hormone Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8-28 weeks after starting GnRH agonist, patients undergo IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. Phase II, Arm I (GnRH, IMRT) Intensity-Modulated Radiation Therapy Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8-28 weeks after starting GnRH agonist, patients undergo IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. Phase II, Arm I (GnRH, IMRT) Magnetic Resonance Imaging Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months in the absence of disease progression or unacceptable toxicity. Beginning 8-28 weeks after starting GnRH agonist, patients undergo IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. Phase II, Arm II (niraparib, GnRH, IMRT) Gonadotrophin Releasing Hormone Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months, and niraparib PO QD for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. Phase II, Arm II (niraparib, GnRH, IMRT) Intensity-Modulated Radiation Therapy Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months, and niraparib PO QD for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study. Phase II, Arm II (niraparib, GnRH, IMRT) Niraparib Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months, and niraparib PO QD for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy given in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI on study.
- Primary Outcome Measures
Name Time Method Maintenance of disease-free state Up to 2 years following the start of antiandrogen therapy Will be characterized by PSA values sustained below 0.1 ng/ml until the completion of treatment. A modified intent-to-treat analysis will be conducted. The proportion of patients disease-free at 24 months will be compared in the two treatment arms using a non continuity-corrected chi-square test. As a secondary analysis, a logistic regression model will be fit to adjust for the stratification factors (risk group and type of radiation therapy).
- Secondary Outcome Measures
Name Time Method Overall survival From randomization until death from any cause, assessed up to 3 years Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test.
Prostate cancer-specific survival From randomization until death from prostate cancer, assessed up to 3 years Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test.
Time to local/regional or distant progression Up to 3 years Cumulative incidence curves will be compared using the Fine-Gray test (Dignam 2008).
Pathologic complete response (pCR) At 24 months Will be assessed among patients undergoing 12-core biopsy. Will be compared using a chi-square test.
Time to distant metastases From randomization until detection of distant metastatic disease, assessed up to 3 years Cumulative incidence curves will be compared using the Fine-Gray test (Dignam 2008).
Biochemical progression-free survival Up to 3 years Will be defined as PSA \>= 2 ng/ml over the nadir PSA, the presence of local, regional, or distant recurrence, or death from prostate cancer. Will consist of comparison of Kaplan-Meier (Kaplan 1958) curves using a logrank test.
Incidence of adverse events (Phase II) Up to 3 years Adverse event (AE) rates in the two treatment arms will be categorized as early (within 90 days of completion of radiotherapy) or late (more than 90 days after the completion of radiotherapy). type, grade, and attribution to treatment. For each type of AE, the worst grade occurring during the early treatment period, late treatment period, or entire treatment period will be determined. For each time period, treatment group comparisons will be conducted using chi-square or Fisher exact tests.
Trial Locations
- Locations (95)
Benefis Sletten Cancer Institute
🇺🇸Great Falls, Montana, United States
Banner MD Anderson Cancer Center
🇺🇸Gilbert, Arizona, United States
University of Arizona Cancer Center-Orange Grove Campus
🇺🇸Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
🇺🇸Tucson, Arizona, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Fremont - Rideout Cancer Center
🇺🇸Marysville, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
City of Hope Upland
🇺🇸Upland, California, United States
Helen F Graham Cancer Center
🇺🇸Newark, Delaware, United States
Medical Oncology Hematology Consultants PA
🇺🇸Newark, Delaware, United States
George Washington University Medical Center
🇺🇸Washington, District of Columbia, United States
Grady Health System
🇺🇸Atlanta, Georgia, United States
Emory University Hospital/Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States
Emory Saint Joseph's Hospital
🇺🇸Atlanta, Georgia, United States
CTCA at Southeastern Regional Medical Center
🇺🇸Newnan, Georgia, United States
Alton Memorial Hospital
🇺🇸Alton, Illinois, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸Iowa City, Iowa, United States
University of Kansas Cancer Center
🇺🇸Kansas City, Kansas, United States
University of Kansas Cancer Center-Overland Park
🇺🇸Overland Park, Kansas, United States
University of Kansas Hospital-Westwood Cancer Center
🇺🇸Westwood, Kansas, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸Baltimore, Maryland, United States
Central Maryland Radiation Oncology in Howard County
🇺🇸Columbia, Maryland, United States
UM Baltimore Washington Medical Center/Tate Cancer Center
🇺🇸Glen Burnie, Maryland, United States
Massachusetts General Hospital Cancer Center
🇺🇸Boston, Massachusetts, United States
McLaren Cancer Institute-Bay City
🇺🇸Bay City, Michigan, United States
Henry Ford Cancer Institute-Downriver
🇺🇸Brownstown, Michigan, United States
McLaren Cancer Institute-Clarkston
🇺🇸Clarkston, Michigan, United States
Henry Ford Macomb Hospital-Clinton Township
🇺🇸Clinton Township, Michigan, United States
Henry Ford Medical Center-Fairlane
🇺🇸Dearborn, Michigan, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
Weisberg Cancer Treatment Center
🇺🇸Farmington Hills, Michigan, United States
McLaren Cancer Institute-Flint
🇺🇸Flint, Michigan, United States
Singh and Arora Hematology Oncology PC
🇺🇸Flint, Michigan, United States
Karmanos Cancer Institute at McLaren Greater Lansing
🇺🇸Lansing, Michigan, United States
Mid-Michigan Physicians-Lansing
🇺🇸Lansing, Michigan, United States
McLaren Cancer Institute-Lapeer Region
🇺🇸Lapeer, Michigan, United States
McLaren Cancer Institute-Macomb
🇺🇸Mount Clemens, Michigan, United States
Henry Ford Medical Center-Columbus
🇺🇸Novi, Michigan, United States
McLaren Cancer Institute-Northern Michigan
🇺🇸Petoskey, Michigan, United States
McLaren-Port Huron
🇺🇸Port Huron, Michigan, United States
Henry Ford Macomb Health Center - Shelby Township
🇺🇸Shelby, Michigan, United States
Henry Ford West Bloomfield Hospital
🇺🇸West Bloomfield, Michigan, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Siteman Cancer Center at West County Hospital
🇺🇸Creve Coeur, Missouri, United States
University of Kansas Cancer Center - North
🇺🇸Kansas City, Missouri, United States
University of Kansas Cancer Center - Lee's Summit
🇺🇸Lee's Summit, Missouri, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center-South County
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center at Saint Peters Hospital
🇺🇸Saint Peters, Missouri, United States
AtlantiCare Health Park-Cape May Court House
🇺🇸Cape May Court House, New Jersey, United States
AtlantiCare Surgery Center
🇺🇸Egg Harbor Township, New Jersey, United States
Rutgers New Jersey Medical School
🇺🇸Newark, New Jersey, United States
Holy Name Hospital
🇺🇸Teaneck, New Jersey, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
The New York Hospital Medical Center of Queens
🇺🇸Flushing, New York, United States
Highland Hospital
🇺🇸Rochester, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
Stony Brook University Medical Center
🇺🇸Stony Brook, New York, United States
Summa Health System - Akron Campus
🇺🇸Akron, Ohio, United States
Summa Health System - Barberton Campus
🇺🇸Barberton, Ohio, United States
University of Cincinnati Cancer Center-UC Medical Center
🇺🇸Cincinnati, Ohio, United States
Case Western Reserve University
🇺🇸Cleveland, Ohio, United States
Summa Health Medina Medical Center
🇺🇸Medina, Ohio, United States
University of Cincinnati Cancer Center-West Chester
🇺🇸West Chester, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Christiana Care Health System-Concord Health Center
🇺🇸Chadds Ford, Pennsylvania, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Penn State Milton S Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
Geisinger Medical Oncology-Lewisburg
🇺🇸Lewisburg, Pennsylvania, United States
Lewistown Hospital
🇺🇸Lewistown, Pennsylvania, United States
Eastern Regional Medical Center
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)
🇺🇸Pittsburgh, Pennsylvania, United States
UPMC-Shadyside Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Geisinger Wyoming Valley/Henry Cancer Center
🇺🇸Wilkes-Barre, Pennsylvania, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Prisma Health Cancer Institute - Faris
🇺🇸Greenville, South Carolina, United States
Saint Francis Cancer Center
🇺🇸Greenville, South Carolina, United States
Prisma Health Cancer Institute - Eastside
🇺🇸Greenville, South Carolina, United States
Self Regional Healthcare
🇺🇸Greenwood, South Carolina, United States
Prisma Health Cancer Institute - Greer
🇺🇸Greer, South Carolina, United States
Prisma Health Cancer Institute - Seneca
🇺🇸Seneca, South Carolina, United States
West Virginia University Healthcare
🇺🇸Morgantown, West Virginia, United States
Froedtert Menomonee Falls Hospital
🇺🇸Menomonee Falls, Wisconsin, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Zablocki Veterans Administration Medical Center
🇺🇸Milwaukee, Wisconsin, United States
Drexel Town Square Health Center
🇺🇸Oak Creek, Wisconsin, United States
ProHealth Oconomowoc Memorial Hospital
🇺🇸Oconomowoc, Wisconsin, United States
UW Cancer Center at ProHealth Care
🇺🇸Waukesha, Wisconsin, United States
Froedtert West Bend Hospital/Kraemer Cancer Center
🇺🇸West Bend, Wisconsin, United States
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada