Radium Ra 223 With Enzalutamide Compared to Enzalutamide Alone in Men With Metastatic Castration Refractory Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
Study of Radium Ra 223 dichloride with enzalutamide compared to enzalutamide alone in men with metastatic castration refractory prostate cancer

Official Title
-----------------
A Phase 2 Randomized Study Comparing Radium Ra 223 Dichloride Plus Enzalutamide With Enzalutamide Alone in Men With Metastatic Castration Refractory Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Radium Ra 223 Dichloride
* Drug: Enzalutamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically documented adenocarcinoma of the prostate. Men at least 18 years of age and life expectancy of greater than or equal to 6 months. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. Metastatic disease as evidenced by both lymphadenopathy and bony metastases or just bony metastases on baseline bone scan and/or computed tomography (CT) scan or MRI of the abdomen and pelvis within 28 days of registration. Chest imaging is only required if clinically indicated or if there is known disease in the chest. Castration resistant prostatic adenocarcinoma. Subjects must have castrate levels of serum testosterone (less than 50 ng/dL) achieved by orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy. Previously received docetaxel or are not healthy enough per clinical judgment or declined to receive it Evidence of disease progression on or after the most recent systemic treatment defined by the following criteria: Prostate-Specific Antigen (PSA): Increasing serum PSA levels as defined by the Prostate Cancer Working Group 2 (PCWG2), determined by 2 consecutive measurements (compared to a baseline or nadir value). If the third measurement is below the second, then a fourth measurement must be greater than the second. The confirming third or fourth measurement must be greater or equal to 2 ng/mL. PSA progression must have occurred within 15 months of registration (with at least 7 days between each PSA measurement). Additionally, the PSA progression as described above should have occurred during or after the most recent systemic treatment for prostate cancer. Measurable disease: greater than or equal to 20% increase in the sum of the short axis diameter of all measurable lymph nodes or the development of any new measurable lymphadenopathy by RECIST 1.1 and PCWG2 criteria. Non-measurable disease: Lymph node disease: The appearance of 1 or more new lymphadenopathy, and/or unequivocal worsening of non-measurable disease when compared to imaging studies acquired during castration therapy or against the pre-castration studies if there was no response. Bone disease: Appearance of 2 or more new areas of abnormal uptake on bone scan when compared to imaging studies acquired during castration therapy or against the pre-castration studies if there was no response. Increased uptake of pre-existing lesions on bone scan does not constitute progression. Symptomatic bone metastases Adequate hematologic, renal, and liver function as evidenced by laboratory test results. (Transfusion of blood products are not allowed to normalize blood parameters within 4 weeks of the first radium treatment.) Subjects who have previously received docetaxel or are ineligible for docetaxel and who are candidates for treatment with enzalutamide alone or enzalutamide in combination with Radium-223 Men must agree to use adequate contraception beginning at the signing of the Informed Consent Form until at least 6 months after the last dose of study drug. Because of the potential side effect on spermatogenesis associated with radiation, men who are sexually active must agree to use condoms and their female partners of reproductive potential must agree to use a highly effective contraceptive method during and for 6 months after completing treatment. Able to provide informed consent and have signed an approved consent form that conforms to federal and institutional guidelines to ensure compliance with HIPAA regulations. Exclusion Criteria: The presence of known brain metastases, malignant pleural effusions, or malignant ascites. Brain MRI is required at screening only if clinically indicated. Visceral metastases as assessed by chest, abdominal or pelvic computed tomography (CT) (or other imaging modality) Received systemic therapy with radionuclides (e.g., strontium-89, samarium-153, rhenium-186, or rhenium-188, or Radium Ra 223 dichloride) for the treatment of bony metastases Prior treatment with enzalutamide. Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than the protocol based treatment. LHRH agonist or antagonist therapy, and supportive non-cancer directed therapies like bisphosphonates or denosumab are allowed. Prior cytoxic chemotherapy with the exception of docetaxel or cabazitaxel. Treatment with docetaxel or cabazitaxel must be discontinued greater than 4 weeks from the time of enrollment, and recovery of adverse events (AEs) to grade 1 or baseline (however, ongoing neuropathy is permitted). Major surgery within 30 days prior to start of study drug Current, untreated pathologic long-bone fractures, imminent pathologic long-bone fractures (cortical erosion on radiography greater than 50%). Prior hemi-body external radiotherapy. Subjects who received other types of prior external radiotherapy are allowed provided that bone marrow function is assessed and meets the protocol requirements for hemoglobin, absolute neutrophil count (ANC), and platelets. Use of biologic response modifiers, such as granulocyte macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) within 4 weeks prior to screening Lymphadenopathy exceeding 3 cm in short-axis diameter Any size pelvic lymphadenopathy if it is thought to be a contributor to concurrent hydronephrosis. Current or imminent spinal cord compression based on clinical findings and/or magnetic resonance imaging (MRI). Treatment should be completed for spinal cord compression. Any other serious illness or medical condition in the opinion of the investigator, such as but not limited to: Any greater than or equal to Grade 2 infection as defined by NCI-CTCAE version 4.03. Cardiac failure New York Heart Association (NYHA) III or IV Crohn's disease or ulcerative colitis Bone marrow dysplasia Fecal incontinence Concomitant use of narrow therapeutic index drugs that are metabolized by CYP3A4 (i.e. alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (phenytoin, warfarin), and CYP2C19 (S-mephenytoin). [Note: Patients on stable doses of anti-coagulation with warfarin and fentanyl will be eligible, as long as they are monitored closely with additional international normalized ratio (INR) monitoring]. Any infection requiring parenteral antibiotic therapy or causing fever (temperature greater than 100.5 degrees F or 38.1 degrees C) within 1 week prior to registration. Concurrent other malignancy with the exception of: a) cutaneous squamous cell and basal carcinomas, b) adequately treated stage 1-2 malignancy , c) adequately treated stage 3-4 malignancy that had been in remission for greater than or equal to 2 years at the time of registration. Inability to comply with the protocol and/or not willing or not available for follow-up assessments Any medical intervention or other condition which, in the opinion of the Principal Investigator could compromise adherence with study requirements or otherwise compromise the study's objectives

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radium Ra 223 Dichloride and Enzalutamide<br>Radium Ra 223 Dichloride and Enzalutamide administered concurrently for 6 28-day cycles. | Drug: Radium Ra 223 Dichloride<br>* Radium Ra 223 Dichloride, 55 kilobecquerel (kBq)/kg body weight, administered as a bolus intravenous (IV) injection (up to 1 minute) on Day 1 of each cycle for 6 cycles.<br>* Other names: Alpharadin;Drug: Enzalutamide<br>* Enzalutamide 160 mg administered orally once a day (continuously) for 6 cycles.<br>* Other names: Xtandi;|
| Active Comparator: Enzalutamide alone<br>Enzalutamide administered as a single agent for 6 28-day cycles. | Drug: Enzalutamide<br>* Enzalutamide 160 mg administered orally once a day (continuously) for 6 cycles.<br>* Other names: Xtandi;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fold Change in Serum N-telopeptides From Baseline | Patients had serum N-telopeptide labs drawn prior to the start of treatment and at the End of Treatment visit or at disease progression, whichever occurred first. The mean and standard deviation of the differences were calculated on a log 2 scale. Fold changes (post/pre) and 95% confidence intervals are reported. | From prior to start of treatment to end of treatment or disease progression (approximately 6 months) | 
| Number of Participants With Adverse Events | Adverse Events were assessed from start of Radium Ra 223 Dichloride or Enzalutamide treatment (whichever was started first) through 30 days after the last dose of either drug or until start of a new anti-cancer therapy, whichever came first. Adverse events were assessed using the Common Terminology for Adverse Events (CTCAE) version 4.0. Each event was assigned a grade (1-5), with lower grades indicating milder events. All adverse events were recorded, regardless of attribution to study treatment. Reported below are the number of patients who experienced any grade 3-5 non-hematological AE. A full listing of AEs affecting 5% or more participants are listed in the Adverse Events module of the Results section. | From first dose of study treatment to 30 days following last dose (approximately 7 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate Specific Antigen (PSA) Progression Free Survival (PFS) | Prostate Specific Antigen (PSA) Progression Free Survival (PFS) is the time during with participants did not experience PSA progression. This is measured from the start of study therapy to the time of PSA progression. PSA progression is defined as a rise in PSA of at least 25% and at least 2 ng/ml from baseline or nadir. Kaplan-Meier methods were used. | Up to 2 years (24 months) | 
| Radiographic Progression Free Survival (PFS) | Radiographic Progression Free Survival (PFS) is the time during with participants did not experience disease progression based on study imaging. This is measured from the start of study therapy to the time of radiographic progression. Radiographic progression was defined by the Prostate Cancer Working Group 2 (PCWG2) criteria, in which soft tissue disease is evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and bone lesions are evaluated separately under PCWG2 criteria. PCWG2 and RECIST 1.1 are established radiographic assessment protocols. Kaplan-Meier methods were used. | Up to 2 years (24 months) | 
| Bone Alkaline Phosphatase (ALP) Progression Free Survival (PFS) | Bone Alkaline Phosphatase (ALP) Progression Free Survival (PFS) is the time during with participants did not experience Bone ALP progression. This is measured from the start of study therapy to the time of Bone ALP progression. Bone ALP progression defined as a rise in Bone ALP of at least 25% and at least 2 micrograms (mcg)/L from baseline or nadir. Kaplan-Meier methods were used. | Up to 2 years (24 months) | 
| Count of Prostate Specific Antigen (PSA) Responses | Prostate Specific Antigen (PSA) Responses in participants were categorized based on decrease from baseline: less than 30% (<30%) decrease (including increases from baseline), greater than or equal to 30% (>=30%) decrease, greater than or equal to 50% (>=50%) decrease, and greater than or equal to 90% (>=90%) decrease. Count of participants in each category are provided | Up to 2 years after start of study treatment | 
| Count of Radiographic Responses | Radiographic Responses in participants were assessed using the Prostate Cancer Working Group 2 (PCWG2) criteria. Possible responses include Complete Response (CR) (complete disappearance of all metastatic disease on imaging), Partial Response (PR) (improvement in metastatic disease on imaging), Stable Disease (SD) (neither worsening nor improvement of metastatic disease on imaging), and Progressive Disease (PD) (worsening of metastatic disease on imaging). A count of participants in each category is provided here. | Up to 2 years after start of study treatment | 
| Overall Survival (OS) | Overall Survival (OS) is the time during which participants did not pass away. This is measured from the start of study therapy to the time of death from any cause. Kaplan-Meier methods were used. | Up to 40 months |