Clinical trial NCT04597125: Investigation of Radium-223 Dichloride (Xofigo), a Treatment That Gives Off Radiation That Helps Kill Cancer Cells, Compared to a Treatment That Inactivates Hormones (New Antihormonal Therapy, NAH) in Patients With Prostate Cancer That Has Spread to the Bone Getting Worse on or After Earlier NAH
Official title: A Phase 4, Randomized, Open-label, Multicenter Efficacy and Safety Study of Standard Dose of Radium-223 Dichloride vs. Standard Doses of Novel Anti-hormonal Therapy (NAH) in Patients With Bone Dominant Metastatic Castration Resistant Prostate Cancer (mCRPC) Progressing on/After One Line of NAH
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Metastatic Castrate Resistant Prostate Cancer (mCRPC)
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2020-10-22
Enrollment: 696
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Researchers in this study want to compare how well drug radium-223 dichloride (Xofigo) and new (novel) anti-hormonal (NAH) therapy work in participants with prostate gland cancer which has spread to the bone and progressed on or after one line of NAH therapy. Meanwhile researchers want to compare the safety of radium-223 dichloride and NAH therapy. Radium-223 dichloride is known as a radioactive drug that is taken up by bones after it is injected into the body. It works by giving off a type of radioactivity that travels a very short distance and kills the tumor cells that have spread to the bone without major effects to the healthy cells. It has been approved in many countries for the treatment of patients with prostate cancer which has spread to the bone. The NAH drugs used in this study will be either abiraterone acetate (Zytiga) (plus prednisone/prednisolone) or enzalutamide (Xtandi). Both of them are standard approved medications which are used in the treatment of advanced prostate cancer.

Participants in this study will receive either Radium-223 dichloride or a NAH therapy. Radium-223 dichloride will be given as an infusion into one of the veins on Day 1 of each 4-week cycle for a total of up to 6 cycles. Oral NAH therapy will be given per the standard approved dose once daily until the disease has progressed. Participants will visit the hospital or clinic every 2 weeks for the first 6 cycles, and only on the first day of each cycle from cycle 7 and onwards. Observation for each participant will last for about 2 years in total. Blood and urine samples will be collected from the participants and participants will be asked to complete questionnaires about the well-being and the pain.


Eligibility criteria: Inclusion Criteria:

* Participants who have histologically confirmed adenocarcinoma of the prostate.
* Participants with mCRPC progressing on/after one line of an approved NAH (eg. abiraterone, enzalutamide, apalutamide, or darolutamide, after being treated for at least 3 months) in an authorized prostate cancer indication.
* One prior taxane treatment regimen (at least 2 cycles) for metastatic prostate cancer (mHSPC and mCRPC) or refusal or ineligibility of such a regimen.
* Prostate cancer progression documented by PSA according to the Prostate Cancer Working Group 3 (PCWG3) criteria or radiological progression according to RECIST, version 1.1.
* At least 2 bone metastases on bone scan within 4 weeks prior to randomization with no current or history of lung, liver, other visceral, and / or brain metastasis.
* Symptomatic prostate cancer. A worst pain score (WPS) of at least 1 on the Brief Pain Inventory-Short Form (BPI-SF) Question #3 (worst pain in last 24 hours). This is to be assessed once during the Screening period.
* Maintenance of medical castration or surgical castration with testosterone less than 50 ng/dL (1.7 nmol/L). If the participant is being treated with luteinizing hormone releasing hormone (LHRH) agonists or antagonists (participant who has not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to randomization and must be continued throughout the study.
* Participants must be on a BHA treatment, such as bisphosphonates or denosumab treatment unless such treatment is contraindicated or not recommended per investigator's judgement and inclusion is agreed to by the medical monitor.
* Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
* Life expectancy ≥ 6 months.
* Able to swallow abiraterone and prednisone/prednisolone or enzalutamide as whole tablets/capsules.
* Laboratory requirements:

  * Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
  * Platelet count ≥ 100 x 10\^9/L
  * Hemoglobin (Hb) ≥ 9.0 g/dL (90 g/L; 5.6 mmol/L)
  * Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) (except for participants with documented Gilbert's disease)
  * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
  * Creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m\^2 as calculated using the Cockcroft-Gault equation
  * International normalized ratio (INR) of prothrombin time (PT; PT-INR) and partial thromboplastin time (PTT) ≤ 1.5 times the ULN. Participants treated with warfarin or heparin will be allowed to participate in the study if no underlying abnormality in coagulation parameters exists per prior history; weekly evaluation of PT-INR / PTT will be required until stability is achieved (as defined by local standard of care and based on pre-study PT-INR / PTT values)
  * Serum albumin \> 30 g/L
  * Serum potassium ≥ 3.5 mmol/L
* Capable of giving signed informed consent

Exclusion Criteria:

* Active infection or other medical condition that would make prednisone / prednisolone (corticosteroid) use contraindicated.
* Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone / prednisolone equivalent daily for more than 2 months.
* Pathological finding consistent with tumors with predominant neuroendocrine features or small cell carcinoma of the prostate.
* History of osteoporotic fracture
* History of visceral metastasis, or presence of visceral metastasis detected by screening imaging examinations.
* History of or known brain metastasis.
* Malignant lymphadenopathy exceeding 3 cm in short-axis diameter.
* Other malignancy treated within the last 3 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)
* Imminent spinal cord compression based on clinical findings and / or magnetic resonance imaging (MRI). Participants with history of spinal cord compression should have completely recovered.
* Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg). Participants with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment.
* Active or symptomatic viral hepatitis
* History of pituitary or adrenal dysfunction
* Any other serious illness or medical condition such as, but not limited to:

  * Any infection ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 Grade 2
  * Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II to IV heart disease or cardiac ejection fraction measurement of \<50% at baseline
  * Current clinical evidence of any uncontrolled cardiac arrhythmia
  * Crohn's disease or ulcerative colitis
  * Bone marrow dysplasia
  * Moderate and severe hepatic impairment (Child-Pugh Classes B and C)
  * Unmanageable fecal incontinence.
* Any condition, which in the opinion of the investigator would preclude participation in this trial (eg, history of seizure).
* Hypersensitivity to the active substances or to any excipients of radium-223 dichloride, or abiraterone acetate or enzalutamide.
* Prior therapeutic systemic radiation with any radiopharmaceutical medication for the treatment of prostate cancer, including but not limited to lutetium-177, strontium-89, samarium-153, iodine-131, rhenium-186, rhenium-188, or radium-223. Radiopharmaceutical compounds used for diagnosis purposes only are allowed.
* Prior hemibody external radiotherapy is excluded. Participants who received other types of prior external radiotherapy are allowed provided that the bone marrow function is assessed and meets the protocol requirements for Hb, ANC, and platelet count.
* Blood transfusion or erythropoietin stimulating agents 4 weeks prior to Screening and during the whole Screening period before randomization.
* Excessive intake of biotin above the recommended daily dose of 30 μg. Biotin is found in multivitamins, including prenatal multivitamins, biotin supplements, and dietary supplements for hair, skin, and nail growth at levels that may interfere with laboratory tests.
* Prior administration of an investigational therapeutic for CRPC.
* Previous (within the last 4 weeks of randomization) or concurrent participation in any interventional clinical study with investigational study drug administration.

Primary outcomes:
measure: Overall survival (OS)
timeFrame: Up to five years
Secondary outcomes:
measure: Time to first symptomatic skeletal event (SSE)
timeFrame: Up to five years
measure: Radiological Progression-free survival (rPFS)
timeFrame: Up to five years
measure: Time to pain progression (BPI-SF)
timeFrame: Up to five years
measure: Adverse events assessments using NCI CTCAE (v5.0)
timeFrame: After first administration of study intervention up to 30 days after the last dose of study intervention
measure: Incidence of fractures
timeFrame: Up to five years
measure: Time to deterioration of FACT-P total score
timeFrame: Up to five years
Other outcomes:
Locations:
city: Castle Hill
country: Australia
facility: Specialist Services Medical Group
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: North Tamworth
country: Australia
facility: North West Cancer Centre
state: New South Wales
city: St Leonards
country: Australia
facility: Northern Cancer Institute
state: New South Wales
city: Sydney
country: Australia
facility: Prince of Wales Hospital NSW
state: New South Wales
city: Wollongong
country: Australia
facility: Illawarra Shoalhaven Local Health District
state: New South Wales
city: Brisbane
country: Australia
facility: Icon Cancer Care
state: Queensland
city: Southport
country: Australia
facility: Tasman Health Care
state: Queensland
city: Tugun
country: Australia
facility: The Tweed Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Linz
country: Austria
facility: Kepler Universitätsklinikum Campus III
state: Oberösterreich
city: Wien
country: Austria
facility: Klinik Ottakring - Wilhelminenspital
city: Brno
country: Czechia
facility: Fakultni nemocnice u sv. Anny
city: Chomutov
country: Czechia
facility: Nemocnice Chomutov, o.z.
city: Liberec
country: Czechia
facility: Krajska Nemocnice Liberec
city: Prague
country: Czechia
facility: Fakultni Thomayerova Nemocnice
city: Praha 2
country: Czechia
facility: Urocentrum Praha, s.r.o.
city: Praha 2
country: Czechia
facility: Všeobecná fakultní nemocnice v Praze
city: Praha 8
country: Czechia
facility: Fakultní nemocnice Bulovka
city: Helsinki
country: Finland
facility: Docrates Klinikka
city: Oulu
country: Finland
facility: Oulun yliopistollinen sairaala
city: Seinäjoki
country: Finland
facility: Seinäjoen keskussairaala
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala
city: Bordeaux
country: France
facility: Hôpital Saint André - Bordeaux
city: Brest
country: France
facility: Hôpital Morvan - Brest
city: Caen Cedex 5
country: France
facility: Centre de Lutte Contre le Cancer François Baclesse
city: Creteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: Centre Georges Francois Leclerc Dijon
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire - Grenoble
city: Marseille
country: France
facility: Institut Paoli-Calmettes - Marseille
city: Nice Cedex 2
country: France
facility: Centre Antoine Lacassagne
city: Reims
country: France
facility: Institut de Cancerologie Jean Godinot
city: Rennes Cedex
country: France
facility: Centre Eugène Marquis - Rennes Cedex
city: Strasbourg
country: France
facility: CHU Strasbourg - Hopital Hautepierre
city: Vandoeuvre-les-Nancy
country: France
facility: Institut de Cancérologie de Lorraine - Alexis Vautrin
city: Villejuif Cedex
country: France
facility: Gustave Roussy - Departement Oncologie-Radiotherapie
city: Münster
country: Germany
facility: Universitaetsklinikum Muenster
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg Universität Mainz
state: Rheinland-Pfalz
city: Central
country: Hong Kong
facility: Hong Kong Integrated Oncology Centre (HKIOC)
city: Chai Wan
country: Hong Kong
facility: Pamela Youde Nethersole Eastern Hospital
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: TBC
country: Hong Kong
facility: Tuen Mun Hospital
city: Budapest
country: Hungary
facility: Semmelweis University
city: Szolnok
country: Hungary
facility: Jasz-Nagykun-Szolnok Varmegyei Hetenyi Geza Korhaz
city: Haifa
country: Israel
facility: Lady Davis Carmel Medical Center
city: Tel Aviv
country: Israel
facility: Tel-Aviv Sourasky Medical Center
city: Ferrara
country: Italy
facility: University Hospital Of Ferrara - Oncologia Clinica
state: Emilia-Romagna
city: Modena
country: Italy
facility: Azienda Ospedaliero Universitaria di Modena_Policlinico - Oncologia
state: Emilia-Romagna
city: Parma
country: Italy
facility: Azienda Ospedaliero Universitaria Parma - SC Oncologia Medica
state: Emilia-Romagna
city: Pordenone
country: Italy
facility: Centro di Riferimento Oncologico di Aviano
state: Friuli-Venezia Giulia
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Servizio di Radioterapia Oncologica
state: Lazio
city: Genova
country: Italy
facility: Ente Ospedaliero Ospedali Galliera Di Genova - Oncologia Medica
state: Liguria
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia s.r.l
state: Lombardia
city: Alessandria
country: Italy
facility: Azienda Ospedaliero-Universitaria Ss.Antonio E Biagio E C.Arrigo Alessandria_Presidio Civile - Oncologia
state: Piemonte
city: Trento
country: Italy
facility: Azienda Provinciale Per I Servizi Sanitari_Ospedale Santa Chiara - UO Oncologia Medica
state: Trentino-Alto Adige
city: Padova
country: Italy
facility: Istituto Oncologico Veneto_Padova - UOC Oncologia 1
state: Veneto
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggido
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggido
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's Hospital
state: Seocho-Gu
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul Teugbyeolsi
city: Kaunas
country: Lithuania
facility: The Hospital of Lithuanian University of Health SciencesLUHS
city: Klaipeda
country: Lithuania
facility: PI Klaipedos University Hospital
city: Vilnius
country: Lithuania
facility: National Cancer Institute
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santaros Klinikos
city: Koszalin
country: Poland
facility: Szpital Wojewodzki im. Mikolaja Kopernika w Koszalinie - Oddzial Dzienny Chemioterapii
city: Krakow
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie
city: Lublin
country: Poland
facility: Scanmed SA ZOZ Gastromed
city: Warszawa
country: Poland
facility: Szpital Grochowski im. dr.med. Rafala Masztaka
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny UM we Wroclawiu
city: Chelyabinsk
country: Russian Federation
facility: Chelyabinsk Regional Oncology Dispensary
city: Obninsk
country: Russian Federation
facility: National Medical Research Radiology Center
city: Singapore
country: Singapore
facility: National Cancer Center Singapore
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Santiago de Compostela
country: Spain
facility: Hospital Clínico Universitario de Santiago de Compostela
state: A Coruña
city: Cadiz
country: Spain
facility: Hospital Universitario Puerta del Mar
state: Andalucía
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
state: Asturias
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Palma De Mallorca
country: Spain
facility: Hospital Universitari Son Espases - Oncologia
state: Illes Baleares
city: Majadahonda
country: Spain
facility: Hospital Universitario Clinica Puerta de Hierro
state: Madrid
city: Malaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria | Cardiology Department
state: Málaga
city: A Coruña
country: Spain
facility: Centro Oncológico de Galicia
city: Barcelona
country: Spain
facility: Ciutat Sanitaria i Universitaria de la Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau | Gynecology Department
city: Castellón
country: Spain
facility: Consorcio Hospitalario Provincial de Castellón
city: Girona
country: Spain
facility: I.C.O Girona
city: Jaén
country: Spain
facility: Hospital Universitario De Jaen - Oncologia
city: Lugo
country: Spain
facility: Hospital Lucus Augustí
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
state: Kaohsiung
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital at Linkou
city: Adana
country: Turkey
facility: Baskent Universitesi Seyhan Hastanesi
city: Ankara
country: Turkey
facility: Ankara Yildirim Beyazit Universitesi Tip Fakültesi
city: Ankara
country: Turkey
facility: Ankara Universitesi Tip Fakultesi Hastanesi
city: Ankara
country: Turkey
facility: Hacettepe Universitesi Tip Fakultesi
city: Edirne
country: Turkey
facility: Trakya Univ. Tip Fak.
city: Gaziantep
country: Turkey
facility: Gaziantep Universitesi Tip Fakultesi
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Istanbul Tip Fakultesi
city: Istanbul
country: Turkey
facility: Istanbul Egitim ve Arastirma Hastanesi
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Cerrahpasa-Cerrahpasa Tip Fakultesi
city: Istanbul
country: Turkey
facility: TC Saglik Bakanligi Goztepe ProfDr Suleyman Yalcin Sehir Has
city: Istanbul
country: Turkey
facility: Medipol Universitesi Tip Fakultesi
city: Istanbul
country: Turkey
facility: Marmara University Medical Faculty | Pediatric Nephrology
city: Izmir
country: Turkey
facility: Dokuz Eylul Universitesi Tip Fakultesi
city: Izmir
country: Turkey
facility: Ege Universitesi Tip Fakultesi
city: Izmir
country: Turkey
facility: Izmir Tepecik Egitim ve Arastirma Hastanesi
city: Izmir
country: Turkey
facility: Izmir Ekonomi Universitesi Medikal Point Hastanesi
city: Kayseri
country: Turkey
facility: Erciyes Universitesi Tip Fakultesi
city: Mersin
country: Turkey
facility: Mersin Universitesi Tip Fakultesi
city: Samsun
country: Turkey
facility: Ondokuz Mayis Uni Tip Fakultesi
city: Reading
country: United Kingdom
facility: Royal Berkshire NHS Foundation Trust¦Royal Berkshire Hospital - Oncology
state: Berkshire
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
Study officials:
References: