A Biomarker Study of Standard-of-care Radium-223 Chloride for Metastatic Castration-resistant Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to look for markers of how Ra-223 improves the lives of men with prostate cancer. This study makes use of Ra-223 in the standard FDA-approved way, but adds non-standard testing in an attempt to gain insight about how the drug works and how best to track patients who are receiving the drug.

Detailed Description
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This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. This research study is designed to examine a treatment strategy that is standard but still relatively new. Ra-223 consists of a series of six infusions given once every 4 weeks. It was FDA approved in 2013 for the treatment of prostate cancer that has spread to bone and has grown despite ADT (hormonal therapy). Ra-223 was approved because it was shown to improve the length of the lives of the men with prostate cancer who received it. Despite that important benefit, it is not known to improve other standard markers of prostate cancer such as PSA blood tests (a blood marker that is used to track cancer activity in men who have prostate cancer) and standard imaging scans such as bone scans and computed tomography (CT) scans. If participants and their doctors do not have good markers of whether or not the cancer is responding to therapy, it is harder to make decisions about whether to continue that therapy. This is a current problem. This study makes use of Ra-223 in the standard FDA-approved way, but adds non-standard testing in an attempt to gain insight about how the drug works and how best to track patients who are receiving the drug.

Official Title
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A Single-arm Open Label Biomarker Study of Standard-of-care Radium-223 Chloride for Metastatic Castration-resistant Prostate Cancer

Conditions
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Prostate Cancer, Castration-resistant Prostate Cancer, Castration-resistant Prostate Cancer Metastatic to Bone

Intervention / Treatment
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* Procedure: Blood Tests
* Procedure: CT scan
* Procedure: FACBC PET/MRI in a subset of participants
* Drug: Radium-223 dichloride
* Procedure: bone scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male age ≥ 18 years. Histologically or cytologically confirmed adenocarcinoma of the prostate. Life expectancy of at least 6 months. ECOG performance status of zero, one, or two. Bone-predominant metastatic CRPC: at least two skeletal metastases on bone scan with no lung, liver, and/or brain metastasis (lymph node metastasis is allowed). Symptomatic as defined by either of the following: (a) Regular use of analgesic medication for cancer-related bone pain (≥ level 1; WHO ladder for cancer pain), or (b) Treatment with EBRT for bone pain (though EBRT must be completed ≥12 weeks prior to enrollment in this trial). Judged by investigator to have progressive disease sufficient to clinically justify standard-of-care radium-223 treatment. Subjects must be able to understand and be willing to sign the written informed consent form. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less at the time of signing the Informed Consent Form (ICF). No intention to use cytotoxic chemotherapy within the next 6 months. Subjects must agree to use adequate contraception beginning at the signing of the ICF until at least 6 months after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator. Acceptable hematology and serum biochemistry screening values: White Blood Cell Count (WBC) ≥ 3,000/mm3 Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 Platelet (PLT) count ≥ 100,000/mm3 Hemoglobin (HGB) ≥10 g/dl (Please note: it is acceptable from the standpoint of study eligibility to undergo transfusion in order to achieve hemoglobin ≥ 10 g/dl) Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN Creatinine ≤ 1.5 x ULN Albumin > 25 g/L Willing and able to comply with the protocol, including follow-up visits and examinations. Exclusion Criteria: Treatment with cytotoxic chemotherapy within previous 28 days, or failure to recover from AEs due to cytotoxic chemotherapy administered more than 28 days previous (however, ongoing neuropathy is permitted). Received any investigational compound within 28 days prior to the first dose of study drug or planned during the treatment period or follow-up. 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. Received previous radiotherapy to approximately >25% of bone marrow. Other malignancy treated within the last 3 years (except non melanoma skin cancer or low-grade superficial bladder cancer). Visceral metastases as assessed by abdominal or pelvic computed tomography (CT) or other imaging modality. Presence of brain metastases. Lymphadenopathy exceeding 6 cm in short-axis diameter. Any size pelvic lymphadenopathy if it is thought to be a contributor to concurrent hydronephrosis. 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, such as but not limited to: Any infection ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 Grade 2 Cardiac failure New York Heart Association (NYHA) III or IV Crohn's disease or ulcerative colitis Known bone marrow dysplasia Fecal incontinence. Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radium-223 dichloride<br>After the screening procedures confirm that a patient is eligible to participate in the research study. Ra-223- Each treatment cycle lasts 4 weeks during which the patient receives Ra-223 by intravenous infusion on day 1 only. Treatments are given every 4 weeks for a total of 6 treatments. These treatments are designed to be entirely standard. Extra testing during and after that six month period will be added to standard testing and monitoring. Blood Tests CT scan Bone scan FACBC PET/MRI in a subset of participants | Procedure: Blood Tests<br>* Blood will be drawn for standard and nonstandard testing on day one, day 4, and weeks 5, 9, 13, 17, 21, 25, 37, and 93.<br>Procedure: CT scan<br>* Standard CT scans will be carried out prior to treatment, week 9, and week 25.<br>Procedure: FACBC PET/MRI in a subset of participants<br>* Approximately half of the study patients (n=10) will undergo experimental FACBC PET/MRI testing at 2 time points each: (1) prior to therapy, and (2) week 9.<br>Drug: Radium-223 dichloride<br>* Ra-223- Each treatment cycle lasts 4 weeks during which the patient receives Ra-223 at a dose of 50 kBq/kg body weight by intravenous infusion on day 1 only. Treatments are given every 4 weeks for a total of 6 treatments.<br>* Other names: Xofigo;Procedure: bone scan<br>* Standard bone scans will be carried out prior to treatment, week 9, and week 25.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone Scan Index | Automated bone scan index (aBSI) is an imaging prognostic biomarker used to quantitatively assess effect of therapy. aBSI expresses the tumor burden in bone as a percent of the total skeletal mass. An aBSI value of 1.0 indicates the tumor(s) to be present in 1% of the entire skeleton (arms and legs included). | Baseline to 2 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Skeletal Mass Occupied by a Lesion, Stratified by 18 Month Survival Status | Mean change in automated bone scan index (aBSI) at 2 months (i.e. approximately week 9) as assessed by aBSI will be described by 18 month survival status. In other words, decline in aBSI at 2 months on therapy will be evaluated as a predictive biomarker of survival at 18 months. | Baseline and 2 months | 
| Circulating Tumor Cell (CTC) Number | The presence of circulating tumor cells (CTCs) in the peripheral blood, will be assessed by by the FDA-approved assay CELLSEARCH® CTC Test, is associated with decreased progression-free survival and decreased overall survival in patients treated for metastatic prostate cancer. | Baseline/Day 1, Day 30, Day 60 | 
| Circulating Biomarkers of the Tumor Microenvironment | Bone turnover markers (i.e., serum bone specific alkaline phosphatase and N-telopeptide) and plasma biomarkers of inflammation and angiogenesis will be assessed serially. Our analyses of circulating biomarkers of the tumor microenvironment were more limited than originally planned due to a freezer malfunction that compromised our frozen samples that had been saved for later batched analyses. The reported values within the table below reflect CTCm score which is a previously described analysis that uses droplet digital PCR to assess gene expression from circulating tumor cells (CTCs) isolated using the microfluidic CTC-iChip. CTCm score, by published convention, does not have units and does not have a normal range. In the present study, the normalized CTCm score was calculated as described previously using weighting coefficients. It is considered better to have a lower CTCm score. The table contains [mean (standard deviation)] of CTCm score for each group at the specified timepo | Baseline/Day 1, Day 30, Day 60 | 
| Baseline Pain Score Evaluation as a Predictor of Survival | Pain and narcotic analgesic use was assessed by the 4-item Brief Pain Inventory (BPI). This instrument contains 4 items, with each item reported on a scale of 0-10, meaning that total possible range is 0-40. For each question's 0-10 response scale, 0 meant no pain/interference and 10 meant worst pain imaginable/complete interference. Overall survival (OS) was defined as the interval between the start of therapy and the date of death or censor. For the analysis presented in the table, the algorithm of Contal-O'Quigley was applied to the data using leave-one-out jack-knife resampling to determine the optimal division points according to pain score on 4-item BPI at baseline. Each iteration of the algorithm produced an estimate of the best division point based on the data. With this method, optimal cut-point for this cohort was baseline total BPI score < 8 vs ≥8. Median survival for each sub-group is reported as months (with range in parentheses). | Baseline through study completion, up to approximately 5 years | 
| Baseline Global Health Score Evaluation as a Predictor of Survival | Baseline Global Health Score was reported by participants on a scale of 0 (The worst health you can imagine) to 100 (The best health you can imagine). Overall survival (OS) was defined as the interval between the start of therapy and the date of death or censor, expressed here in months. For the analysis presented in the table, the algorithm of Contal-O'Quigley was applied to the data using leave-one-out jack- knife resampling to determine the optimal division points according to Global Health Score at baseline. Each iteration of the algorithm produced an estimate of the best division point based on the data. With this method, optimal cut-point for this cohort was baseline Global Health Score ≥95 or <95. Median survival for each sub-group is reported as months (with range in parentheses). | Baseline through study completion, up to approximately 5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, Castration-resistant prostate cancer, Castration-resistant prostate cancer metastatic to bone