A Randomized multicenter phase III trial comparing enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer patients metastatic to bone.

Phase 1

Conditions: Castration resistant prostate cancer patients metastatic to bone.
MedDRA version: 21.1Level: PTClassification code 10036909Term: Prostate cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2014-001787-36-IT

Lead Sponsor: EORTC AISBL/IVZW

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Male

Target Recruitment: 560

Inclusion Criteria

¿ Histologically confirmed diagnosis of prostate adenocarcinoma
¿ Asymptomatic or mildly symptomatic (defined as no opioids and short
form question #3 in Brief Pain Inventory worst pain must be < 4.
¿ 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.
¿ 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.
¿ Ongoing androgen deprivation therapy (ADT) with luteinizing
hormone-releasing hormone (LHRH) agonist or antagonist or bilateral
orchiectomy.
Patients must be at least 18 years old
¿ WHO Performance status 0-1
¿ Charlson score = 3
¿ T-score = -2.5 on a DXA scan done in the past 12 months
¿ Castrate serum levels of testosterone < 50 ng/dL
¿ 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
¿ Normal cardiac function according to local standard by 12-lead ECG
(complete, standardized 12-lead recording).
¿ Able to swallow the study drug and comply with study requirements
¿ Prior or concomitant therapy.
-Prior docetaxel or abiraterone 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 or abiraterone for CRPC are
excluded.
¿ Prior treatment with abiraterone is allowed if it was stopped at least 4
weeks prior to randomization.
¿ Previous treatment with bicalutamide, or flutamide is allowed if it was
stopped at least 48 hours prior to randomization.
¿ Corticosteroids are allowed only at a dose = 10 mg of prednisone (or
equivalent) no matter the indication.
¿ Drugs known to lower the seizure threshold or prolong QT interval are
not permitted.
¿ Participants who have pregnant partners must use a condom and those with partners of childbearing potential

Exclusion Criteria

¿ Known central nervous system metastases or leptomeningeal tumor
spread.
¿ 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.
-Uncontrolled hyperglycemia as indicated by a fasting glucose = 7
mmol/L.
¿ Prior treatment with enzalutamide or Ra223.
¿ Concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel)
and ketoconazole.
¿ 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.
¿ Prior therapy with other radionuclides (e.g., strontium-89, samarium-
153, rhenium-186, or rhenium-188).
¿ Involvement in another therapeutic trial involving an experimental
drug.
¿ Anticancer therapy (except ADT) or treatment with another
investigational agent within the last 4 weeks prior to randomization.
¿ Known hypersensitivity to compounds related to enzalutamide or
Ra223 .
¿ 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.
¿ 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).
¿ Major surgery within 4 weeks prior to treatment.
¿ Drug or alcohol abuse.
¿ 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.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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 Objective: To assess if upfront combination of enzalutamide with Ra223 (experimental arm) offers further benefits over enzalutamide alone in terms of the secondary efficacy endpoints listed below, to compare the safety profile of the approaches and to document their impact on patient reported outcomes (pain and quality of life (QoL).;Primary end point(s): Radiological Progression free survival (rPFS1).;Timepoint(s) of evaluation of this end point: Radiological Progression free survival (rPFS1) counted from randomization to the first progression defined as per the Prostate Cancer clinical trials Working Group version 3 and referred to as the PCWG3 for the setting delay/prevent progression or to death from any cause.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Overall survival;<br>2. Prostate-cancer specific survival;<br>3. First symptomatic skeletal event (SSE);<br>4. Time and incidence of first skeletal progression-free survival;<br>5. Time to next systemic anti-neoplastic therapy;<br>6. Treatments elected after first disease progression;<br>7. Second progression-free survival<br>8. Safety according to Common Terminology Criteria for Adverse Events.<br>9. Pain: Brief Pain Inventory (BPI). In this study only pain related to<br>prostate cancer is considered.<br>10. Time to pain progression (defined as an increase of 2 or more points<br>in the worst pain in 24 hours score from baseline observed at 2<br>consecutive evaluations >= 4 weeks apart OR initiation of short or long-acting<br>opioid use for pain)<br>11. Time to opiate use for cancer-related pain<br>12. Quality of Life (EQ-5D-5L)<br>13. Rate of skeletal fractures