Clinical trial • Phase III • Oncology

Radium Ra 223 dichloride for Castration-resistant prostate cancer metastatic to bone

Phase III trial of Radium Ra 223 dichloride for Castration-resistant prostate cancer metastatic to bone.

Overview

Trial Therapeutic Area
Oncology
Trial Disease
Castration-resistant prostate cancer metastatic to bone
Trial Stage
Phase III
Drug Modality
Small molecule|Radiopharmaceutical

Key dates

Initial CTIS Submission Date
14-06-2024
First CTIS Authorization Date
10-07-2024

Trial design

Randomised, two arms: 1) enzalutamide alone (xtandi - 40 mg soft capsules; oral; product max daily dose reported as 160 mg) 2) combination arm: enzalutamide (as above) plus radium-223 dichloride (xofigo 1100 kbq/ml solution for injection; intravenous; dose unit kbq/kg with max per-dose amount reported as 55 kbq/kg).-controlled Phase III trial in Belgium, Denmark, France and others.

Randomised
Yes
Comparator
Two arms: 1) Enzalutamide alone (Xtandi - 40 mg soft capsules; oral; product max daily dose reported as 160 mg) 2) Combination arm: Enzalutamide (as above) plus Radium-223 dichloride (Xofigo 1100 kBq/mL solution for injection; intravenous; dose unit KBq/kg with max per-dose amount reported as 55 KBq/Kg).
Target Sample Size
191

Eligibility

Recruits 191 Participants must be adults ("Patients must be at least 18 years old"); isVulnerablePopulationSelected is false. Written informed consent is required prior to randomization according to ICH/GCP and national/local regulations; specific consent is required for participation in translational research. No assent processes or enrolment of children or other vulnerable groups are indicated..

Vulnerable Population
Participants must be adults ("Patients must be at least 18 years old"); isVulnerablePopulationSelected is false. Written informed consent is required prior to randomization according to ICH/GCP and national/local regulations; specific consent is required for participation in translational research. No assent processes or enrolment of children or other vulnerable groups are indicated.

Inclusion criteria

  • {"criterion_text":"-Histologically confirmed diagnosis of prostate adenocarcinoma\n-Castrate serum levels of testosterone < 50 ng/dL\n-Biochemistry and hematology: -Adequate bone marrow function (absolute neutrophil count (ANC) ≥ 1.5 109/L; platelets ≥ 100 109/L, and hemoglobin ≥ 10.0 g/dl.). -Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN), except for patient with Gilbert's disease where ≤ 5.0 × ULN applies. -Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN. -Creatinine ≤ 1.5 x ULN -Albumin > 25 g/L\n-Normal cardiac function according to local standard by 12-lead ECG (complete, standardized 12-lead recording).\n-Able to swallow the study drug and comply with study requirements\n-Prior or concomitant therapy. -Prior docetaxel is permitted if given in the castration sensitive state and if it was started within 4 months of ADT initiation. Note: patients having received docetaxel for CRPC are excluded. excluded.\n-Prior use of abiraterone is permitted if the patient had a response or stable disease on abiraterone for a minimum of 1 year for metastatic castration sensitive prostate cancer. Note: patients having received abiraterone for CRPC are excluded.\n-Prior treatment with abiraterone is allowed if it was stopped at least 4 weeks prior to randomization.\n-Previous treatment with bicalutamide, or flutamide is allowed if it was stopped at least 48 hours prior to randomization.\n-Corticosteroids are allowed only at a dose ≤ 10 mg of prednisone (or equivalent) no matter the indication.\n-Drugs known to lower the seizure threshold or prolong QT interval are not permitted.\n-Asymptomatic or mildly symptomatic (defined as short form question #3 in Brief Pain Inventory worst pain must be < 4.\n-Participants who have pregnant partners must use a condom and those with partners of childbearing potential must use a condom and another adequate birth control measure if engaging in sexual activities during the study treatment period and for at least 3 months after last dose of enzalutamide and 6 months after the last dose of Ra223. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.\n-Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.\n-Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.\n-For participation in translational research, specific consent must be given.\n-Metastatic to bone with ≥ 4 bone metastases (ambiguous areas of increased uptake on 99mTC Bone Scan (BS) should be confirmed by CT or MRI) with or without additional lymph node metastases. Patients with visceral metastases are not allowed. Patients with multifocal bone lesions are allowed, while patients with diffuse confluent bone lesions (superscan) are not allowed in the trial. Note: Patients must start treatment with a bone protecting agent (at doses used to reduce the incidence of skeletal related events) ideally before or at the time of randomization, if patient is not already on one. A minimum of two doses is recommended before the first administration of Ra223 in the experimental arm. The first administration of Ra223 should be scheduled at least 6 weeks after the first administration of bone protecting agent. Note: For French sites only, patients must not have undergone a PET/CT scan for restaging prostate cancer using radiopharmaceuticals such as 18F-FDG,18F-fluoride, 18F-Fluorocholine or a PSMA (prostate-specific membrane antigen) ligand or any other tracer.\n-Progressive CRPC according to Prostate Cancer Working Group 3 (PCWG3) i.e. either: -For patients who manifest disease progression solely as a rising PSA level, PCWG3 criteria require documentation of a sequence of rising PSA values at a minimum of 1-week intervals with the last value ≥ 2 ng/mL. -For patients with disease progression manifest in the bone, irrespective of progression by rising PSA, PCWG3 guidelines require appearance of 2 or more new lesions. Ambiguous results should be confirmed by other imaging modalities than bone scan (e.g.: CT-scan or MRI). -For patients with disease progression manifest at nodal sites, irrespective of progression by rising PSA, PCWG3 requires progression according to RECIST 1.1.\n-Ongoing androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or bilateral orchiectomy.\n-Patients must be at least 18 years old\n-WHO Performance status 0-1\n-Charlson score ≤ 3\n-T-score ≥ -2.5 on a DXA scan done in the past 12 months. Note: For French sites only, DXA scan done within 6 weeks of randomization."}

Exclusion criteria

  • {"criterion_text":"-Known central nervous system metastases or leptomeningeal tumor spread.\n-Known hypersensitivity to compounds related to enzalutamide or Ra223 .\n-Prior history of malignancies other than prostate adenocarcinoma (except patients with basal cell, squamous cell carcinoma of the skin, insitu carcinoma or low-grade superficial bladder cancer), or the patient has been free of malignancy for a period of 3 years prior to randomization date.\n-History of seizure, including any febrile seizure, loss of consciousness, or transient ischemic attack within 12 months of randomization, OR any condition that may pre-dispose to seizure (e.g., prior stroke, brain arterio-venous malformation, head trauma with loss of consciousness requiring hospitalization).\n-Major surgery within 4 weeks prior to treatment.\n-Drug or alcohol abuse.\n-Other serious illness or medical condition, such as but not limited to: -Any infection ≥ Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4. -No gastrointestinal disorder affecting absorption (e.g., gastrectomy or active peptic ulcer disease). -Crohn's disease or ulcerative colitis. -Osteonecrosis of the jaw. -Any bone disease with an osteoblastic activity. -Bone marrow dysplasia. -Fecal incontinence. -Life-threatening illness unrelated to cancer.\n-Condition which, in the investigator's opinion, makes the patient unsuitable for trial participation.\n-Significant cardiovascular disease including: -Myocardial infarction within 6 months prior to screening. -Uncontrolled angina within 3 months prior to screening. -Congestive heart failure New York Heart Association (NYHA) class III or IV, or patients with history of congestive heart failure NYHA class III or IV in the past, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is ≥ 45% -History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes). -History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place. -Uncontrolled hypertension as indicated by a resting systolic blood pressure > 140 millimeters of mercury (mm Hg) or diastolic blood pressure > 90 mm Hg at screening. Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to randomization. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour. The mean SBP / DBP values from all blood pressure assessment timepoints must be ≤ 140/90 mm Hg in order for a patient to be eligible for the study. -Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening. -Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening ECG and on physical examination.\n-Uncontrolled hyperglycemia as indicated by a fasting glucose ≥ 7 mmol/L.\n-Prior treatment with enzalutamide, apalutamide, darolutamide or Ra223.\n-Concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel) and ketoconazole.\n-Prior hemibody external radiotherapy. Patients who received other types of prior external radiotherapy are allowed provided that the bone marrow function is assessed and meets the protocol requirements for hemoglobin, absolute neutrophil count and platelets.\n-Prior therapy with other radionuclides (e.g., strontium-89, samarium- 153, rhenium-186, or rhenium-188).\n-Involvement in another therapeutic trial involving an experimental drug.\n-Anticancer therapy (except ADT) or treatment with another investigational agent within the last 4 weeks prior to randomization."}

Endpoints

Primary endpoints

  • {"endpoint_text":"-Radiological Progression free survival (rPFS1)","definition_or_measurement_approach":"Main objective: To assess if upfront combination of enzalutamide and Ra223 improves radiological progression-free survival (rPFS1) compared to enzalutamide single agent in CRPC patients metastatic to bone."}

Secondary endpoints

  • {"endpoint_text":"-Overall survival","definition_or_measurement_approach":""}
  • {"endpoint_text":"-Prostate-cancer specific survival","definition_or_measurement_approach":""}
  • {"endpoint_text":"-First symptomatic skeletal event (SSE)","definition_or_measurement_approach":""}
  • {"endpoint_text":"-Time and incidence of first skeletal progression-free survival","definition_or_measurement_approach":""}
  • {"endpoint_text":"-Rate of skeletal fractures","definition_or_measurement_approach":""}
  • {"endpoint_text":"-Time to next systemic anti-neoplastic therapy","definition_or_measurement_approach":""}
  • {"endpoint_text":"-Treatments elected after first disease progression","definition_or_measurement_approach":""}
  • {"endpoint_text":"-Second progression-free survival","definition_or_measurement_approach":""}
  • {"endpoint_text":"-Safety according to Common Terminology Criteria for Adverse Events","definition_or_measurement_approach":"Safety assessed using NCI-CTCAE version 4"}
  • {"endpoint_text":"-Pain: Brief Pain Inventory (BPI). In this study only pain related to prostate cancer is considered","definition_or_measurement_approach":"Pain measured by Brief Pain Inventory (BPI); only pain related to prostate cancer is considered."}
  • {"endpoint_text":"-Time to pain progression (defined as an increase of 2 or more points in the \"worst pain in 24 hours\" score from baseline observed at 2 consecutive evaluations ≥ 4 weeks apart OR initiation of short or longacting opioid use for pain)","definition_or_measurement_approach":"Defined as increase of ≥2 points in 'worst pain in 24 hours' from baseline observed at 2 consecutive evaluations ≥4 weeks apart OR initiation of short- or long-acting opioid use for pain."}
  • {"endpoint_text":"-Time to opiate use for cancer-related pain","definition_or_measurement_approach":""}
  • {"endpoint_text":"-Quality of Life (EQ-5D-5L)","definition_or_measurement_approach":"Quality of life assessed by EQ-5D-5L instrument."}

Recruitment

Planned Sample Size
191
Recruitment Window Months
151
Consent Approach
Written informed consent must be given prior to randomization according to ICH/GCP and national/local regulations. Specific (separate) consent is required for participation in translational research. Participants are adults (≥18 years) and provide their own consent; no assent for minors is applicable.

Geography

Total Number Of Sites
30
Total Number Of Participants
255

Belgium

Earliest CTIS Part Ii Submission Date
27-06-2024
Latest Decision Or Authorization Date
16-07-2024
Processing Time Days
19
Number Of Sites
4
Number Of Participants
38

Sites

Site Name
Cliniques Universitaires Saint-Luc
Department Name
Urology & Physiology
Contact Person Name
Bertrand Tombal
Site Name
Centre Hospitalier Universitaire Dinant Godinne Sainte-Elisabeth-UCL-Namur
Department Name
Oncology
Contact Person Name
Lionel D'Hondt
Contact Person Email
lionel.dhondt@uclouvain.be
Site Name
Hopital Erasme
Department Name
Urology
Contact Person Name
Thierry Roumeguere
Site Name
Algemeen Ziekenhuis Groeninge
Department Name
Urology
Contact Person Name
Siska Van Bruwaene

Denmark

Earliest CTIS Part Ii Submission Date
27-06-2024
Latest Decision Or Authorization Date
12-07-2024
Processing Time Days
15
Number Of Sites
1
Number Of Participants
11

Sites

Site Name
Rigshospitalet
Department Name
Medical Oncology
Contact Person Name
Gedske Daugaard

France

Earliest CTIS Part Ii Submission Date
27-06-2024
Latest Decision Or Authorization Date
23-08-2024
Processing Time Days
57
Number Of Sites
7
Number Of Participants
51

Sites

Site Name
Institut Regional Du Cancer De Montpellier
Department Name
/
Contact Person Name
Emmanuel Deshayes
Site Name
Institut Gustave Roussy
Department Name
Medical Oncology
Contact Person Name
Yohann Loriot
Contact Person Email
Yohann.LORIOT@gustaveroussy.fr
Site Name
Assistance Publique Hopitaux De Paris
Department Name
Medical Oncology
Contact Person Name
Carolina Saldana
Contact Person Email
carolina.saldana@aphp.fr
Site Name
Centre Francois Baclesse
Department Name
Medical Oncology
Contact Person Name
Florence Joly - Lobbedez
Contact Person Email
f.joly@baclesse.unicancer.fr
Site Name
Institut De Cancerologie De L Ouest
Department Name
Medical Oncology
Contact Person Name
Remy Delva
Contact Person Email
remy.delva@ico.unicancer.fr
Site Name
Institut De Cancerologie De L Ouest
Department Name
Medical Oncology
Contact Person Name
Emmanuelle Bompas
Site Name
Les Hopitaux Universitaires De Strasbourg
Department Name
/
Contact Person Name
Philippe Barthelemy
Contact Person Email
p.barthelemy@icans.eu

Ireland

Earliest CTIS Part Ii Submission Date
27-06-2024
Latest Decision Or Authorization Date
10-07-2024
Processing Time Days
13
Number Of Sites
3
Number Of Participants
17

Sites

Site Name
Cork University Hospital
Department Name
Radiotherapy
Contact Person Name
Muhammad Faisal Jamaluddin
Contact Person Email
faisal.jamaluddin@hse.ie
Site Name
Tallaght University Hospital
Department Name
Medical Oncology
Contact Person Name
Ray McDermott
Contact Person Email
ray.mcdermott@tuh.ie
Site Name
St Vincent's University Hospital
Department Name
Medical Oncology
Contact Person Name
Ray McDermott
Contact Person Email
ray.mcdermott@tuh.ie

Italy

Earliest CTIS Part Ii Submission Date
27-06-2024
Latest Decision Or Authorization Date
16-07-2024
Processing Time Days
19
Number Of Sites
3
Number Of Participants
29

Sites

Site Name
Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori IRST S.r.l.
Department Name
Medical Oncology
Contact Person Name
Ugo De Giorgi
Contact Person Email
u.degiorgi@irst.emr.it
Site Name
European Institute Of Oncology S.r.l.
Department Name
Urogenital and Head and Neck Tumors
Contact Person Name
Franco Nole
Contact Person Email
franco.nole@ieo.it
Site Name
Azienda Unita Sanitaria Locale Di Modena
Department Name
Internal Medicine
Contact Person Name
Claudia Mucciarini
Contact Person Email
c.mucciarini@ausl.mo.it

Spain

Earliest CTIS Part Ii Submission Date
27-06-2024
Latest Decision Or Authorization Date
16-07-2024
Processing Time Days
19
Number Of Sites
9
Number Of Participants
90

Sites

Site Name
Hospital Del Mar
Department Name
Medical Oncology
Contact Person Name
Alejo Rodriguez-Vida
Site Name
Hospital De La Santa Creu I Sant Pau
Department Name
Medical Oncology
Contact Person Name
Pablo Maroto
Contact Person Email
jmaroto@santpau.cat
Site Name
Hospital Universitario De Navarra
Department Name
Medical Oncology
Contact Person Name
Nuria Lainez Milagro
Site Name
Parc Tauli Hospital Universitari
Department Name
Oncology
Contact Person Name
Enrique Gallardo Diaz
Contact Person Email
egallardo@tauli.cat
Site Name
Hospital Universitario De Salamanca
Department Name
Urology
Contact Person Name
Muhammad Manuel Herrero Polo
Contact Person Email
m.herreropolo@gmail.com
Site Name
Hospital Clinic De Barcelona
Department Name
Medical Oncology
Contact Person Name
Begona Mellado
Contact Person Email
BMELLADO@clinic.cat
Site Name
Hospital Universitario Quironsalud Madrid
Department Name
Medical Oncology
Contact Person Name
Elena Almagro Casado
Contact Person Email
elena.almagro@quironsalud.es
Site Name
Hospital Universitari Vall D Hebron
Department Name
Oncology
Contact Person Name
Macarena Gonzalez Rodriguez
Contact Person Email
macarenagonzalez@vhio.net
Site Name
Hospital Universitario De La Princesa
Department Name
Radiation Oncology
Contact Person Name
Almudena Zapatero

Norway

Earliest CTIS Part Ii Submission Date
27-06-2024
Latest Decision Or Authorization Date
12-07-2024
Processing Time Days
15
Number Of Sites
2
Number Of Participants
9

Sites

Site Name
Sorlandet Sykehus HF
Department Name
Oncology
Contact Person Name
Christoph Mueller
Contact Person Email
christoph.muller@sshf.no
Site Name
Universitetssykehuset Nord-Norge HF
Department Name
Oncology
Contact Person Name
Hege Sagstuen Haugnes
Contact Person Email
hege.sagstuen.haugnes@unn.no

Poland

Earliest CTIS Part Ii Submission Date
27-06-2024
Latest Decision Or Authorization Date
06-08-2024
Processing Time Days
40
Number Of Sites
1
Number Of Participants
10

Sites

Site Name
Narodowy Instytut Onkologii Im. Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy
Department Name
Oncology Diagnostics, Cardiooncology and Palliative Care
Contact Person Name
Iwona Skoneczna
Contact Person Email
iwona.skoneczna@nio.gov.pl

Sponsor

Primary sponsor

Full Name
European Organisation For Research And Treatment Of Cancer
Organisation Type
Patient organisation/association
Country Of Registered Address
Belgium

Third parties

  • {"country":"France","full_name":"Keosys","duties_or_roles":"Central imaging platform","organisation_type":"Non-Pharmaceutical company"}
  • {"country":"United Kingdom","full_name":"Klinikos Limited","duties_or_roles":"1","organisation_type":"Pharmaceutical company"}
  • {"country":"France","full_name":"Creapharm Clinical Supplies","duties_or_roles":"Enzalutamide clinical trial labeling, QP release, distribution","organisation_type":"Pharmaceutical company"}
  • {"country":"United Kingdom","full_name":"Theradex (Europe) Limited","duties_or_roles":"6;7","organisation_type":"Pharmaceutical company"}
  • {"country":"France","full_name":"Unicancer","duties_or_roles":"1","organisation_type":"Hospital/Clinic/Other health care facility"}
  • {"country":"Ireland","full_name":"Cancer Trials Ireland","duties_or_roles":"1;12;15 (including Irish site agreement negotiations and signature)","organisation_type":"Patient organisation/association"}
  • {"country":"Netherlands","full_name":"OncoDrugConsult B.V.","duties_or_roles":"1","organisation_type":"Pharmaceutical company"}

Investigational products

Investigational Product Name
Xofigo 1100 kBq/mL solution for injection
Active Substance
Radium Ra 223 dichloride
Modality
Radiopharmaceutical
Routes Of Administration
Intravenous use
Route
Intravenous
Authorisation Status
Marketing authorisation EU/1/13/873/001
Maximum Dose
55 KBq/Kg per dose; max total amount reported 330
Investigational Product Name
Xtandi - 40 mg soft capsules
Active Substance
Enzalutamide
Modality
Small molecule
Routes Of Administration
Oral
Route
Oral
Authorisation Status
Marketing authorisation EU/1/13/846/001
Maximum Dose
160 mg per day
Combination Treatment
Yes

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