Radium-223 in Biochemically Recurrent Prostate Cancer
Radium-223 in Biochemically Recurrent Prostate Cancer
Background:

 Some men who have been treated for localized prostate cancer with surgery or radiation still
 show signs of the disease in their blood. This is called biochemically recurrent prostate
 cancer. Radium-223 is a small molecule. It uses radiation to kill cancer cells and improves
 survival in advanced prostate cancer. Researchers want to see if it can treat prostate cancer
 and induced immune changes earlier in the disease when the cancer is only detectable by
 prostate specific antigen (PSA) in the blood.

 Objective:

 To learn how Radium-223 affects men with rising PSA but no evidence of cancer on conventional
 CT or bone scan, but positive findings on PET or molecular imaging in the bones. The primary
 focus is impact on the immune system with secondary focus on impact on PSA and imaging.

 Eligibility:

 Men ages 18 and older with prostate cancer who have had surgery and/or radiation, but their
 PSA is rising even though no disease is visible on routine imaging scans (CT or bone scans).
 Patients are required to have PET or molecular imaging findings in bones, but not organs
 (lymph nodes are allowed).

 Design:

 Participants will be screened with a medical history and physical exam. Their ability to do
 normal tasks will be reviewed. They will give tissue samples or a report from their doctor
 about their cancer. They will have blood and urine tests. They will have an electrocardiogram
 to measure heart function. They will have a scan of their chest and abdomen using radiation
 or magnetic resonance imaging. They will have a bone scan with injection of Tc99. They will
 have a positron emission tomography scan with intravenous (IV) injection of 18F-NaF.

 Participants will get Radium-223 by IV. For this, a small plastic tube is put into an arm
 vein. Radium-223 will be given on Day 1 of each cycle (1 cycle = 4 weeks) for up to 6 cycles.
 Participants will repeat the screening tests during the study. They will also complete
 Quality of Life Surveys and give stool samples.

 After treatment, participants will have long-term follow-up every 6 weeks for the rest of
 their lives.
Background:

 -  Androgen deprivation therapy (ADT) and surveillance are treatment options for prostate
 cancer patients with biochemical progression after localized therapy with either
 definitive radiation or surgery (biochemically recurrent prostate cancer). A primary
 goal in these patients is to prevent morbidity from their cancer that results from
 disease progression and metastatic disease on conventional imaging.

 -  Radium-223 has demonstrated the ability to improve survival in men with symptomatic
 metastatic castration resistant prostate cancer (mCRPC) with a manageable toxicity
 profile, particularly in patients who have not yet received docetaxel.

 -  Radiation, even at low doses can impact immune recognition and immune cell killing of
 cancer cells. Recent findings by the LTIB suggest that radium-223 potentiated T-cell
 killing of prostate cancer cells.

 -  Radium-223 may present an alternative option for patients with BRPC that is not
 associated with substantial toxicity (as seen with ADT) and may have a lasting effect
 due to its potential effect on the immune system and/or the bone microenvironment.

 -  Emerging PET imaging studies will likely find evidence of "micrometastatic" disease,
 often in the bones, in biochemically recurrent prostate cancer patients, although these
 patients will have no standard of care that can be supported by prospective data.

 -  Radium-223 has demonstrated the ability to improve survival in men with symptomatic
 prostate cancer, but it remains unknown what the impact is in patients with
 "micrometastatic" or PET positive prostate cancer in their bones

 -  Preclinical data has suggested that radium-223 can impact the immune system.

 -  In addition, changes in PSA kinetics, changes on PET scan findings, and safety and
 tolerability of radium-223 in this population will also be evaluated.

 Objective:

 - To determine statistically significant changes in immune cell populations compared to
 baseline in patients with biochemically recurrent or 18F NaF PET scan positive prostate
 cancer treated with radium-223

 Eligibility:

 -  Histologically confirmed adenocarcinoma of the prostate

 -  Patients with negative CT Scan and Tc-99m Bone Scan

 -  Patients with positive findings NaF PET imaging.

 -  Patients with a rise in PSA >= 0.8 ng/mL for patients following radical prostatectomy or
 for patients following definitive radiation therapy: a rise in PSA of >= 2 ng/mL above
 the nadir

 -  Patients with a PSA doubling time of 5-15 months

 -  ECOG 0-1

 Design:

 -  Single arm study

 -  Patients will receive 6 injections of radium-223 with monthly assessments of PSA and
 periodic immune response. NaF PET scans will be completed at screening then at 4 and 7
 months after the start of radium-223.

 -  After completion of treatment patient will be followed every 6 (+/- 2 weeks).
-  INCLUSION CRITERIA:

 -  Histopathological confirmation of prostate adenocarcinoma confirmed in either the
 Laboratory of Pathology at the National Institutes of Health (NIH) Clinical Center, or
 Walter Reed National Military Medical Center prior to enrollment. If no pathologic
 specimen is available, patients may enroll with a pathologist s report showing a
 histologic diagnosis of prostate cancer and a clinical course consistent with the
 disease.

 -  Biochemical progression after definitive surgery or radiation defined as follows:

 -  For patients following definitive radiation therapy: a rise in PSA of >= 2 ng/mL above
 the nadir

 -  For patients following radical prostatectomy: a rise in PSA >= 0.8 ng/mL

 -  PSA <= 30 ng/mL

 -  Rising PSA must be confirmed by 3 values a minimum of 1 week apart. All 3 values must
 be obtained over a period greater than 1 month.

 -  PSA doubling time of 5-15 months.

 -  Negative CT scan/MRI and Tc99 bone scan for metastatic prostate cancer. (Only Tc99
 will be used to detect bone lesions, CT/MRI would be used to detect soft tissue
 lesions)

 -  Presence of findings on PET scan (i.e., NaF PET scan) suspicious for metastatic
 prostate cancer in bone. Note: while lymph node findings would be allowed and provide
 the opportunity for the assessment of any abscopal effects, PET scan findings
 suggesting visceral disease will be excluded.

 -  Testosterone >= 100 ng/dL

 -  ECOG performance status of 0 1

 -  Recovery from acute toxicity related to prior therapy, including surgery and
 radiation, (defined as no toxicity >= grade 2).

 -  Hematological eligibility parameters (within 16 days before treatment initiation):

 -  Granulocyte count >= 3,000/mm^3

 -  Absolute neutrophil count (ANC) >= 1,500/mm^3

 -  Platelet count >= 100,000/mm^3

 -  Hgb >= 10 g/dL

 -  Hepatic function eligibility parameters (within 16 days before treatment initiation)

 -  Bilirubin <=1.5 mg/dL (OR in patients with Gilbert s syndrome, a total bilirubin <=
 3.0), AST and ALT <= 2.5 times upper limit of normal.

 -  Adequate renal function defined by eGFR within normal as predicted by the CKD-EPI
 equation (>= 50 mL/min/1.73m^2) or by measure o f creatinine clearance from 24-hour
 urine collection.

 -  No other active malignancies within 36 months of treatment initiation (with the
 exception of nonmelanoma skin cancers or carcinoma in situ of the bladder)

 -  Patients must be >=18 years old. Currently, no dosing or adverse event data is
 available on the use of radium in patients < 18 years of age; therefore, only adults
 are included in this study.

 -  Ability of subject to understand and the willingness to sign a written informed
 consent document.

 -  The effects radium-223 on the developing human fetus are unknown but based on the
 mechanism of action, radium-223 has the potential to cause fetal harm. For this
 reason, men must agree to use condoms for the duration of study therapy and at least 6
 months

 after the last treatment administration. Female partners of reproductive potential must use
 a highly effective method of birth control during treatment and for 6 months after their
 partner s last treatment administration. Should a woman become pregnant or suspect she

 is pregnant while her partner is participating in this study, she should inform her
 treating physician immediately.

 EXCLUSION CRITERIA:

 -  Patients with immunocompromised status due to Human Immunodeficiency Virus (HIV)
 infection or other immunodeficiency diseases because this is a trial with a primary
 endpoint looking at immune response, requiring functional immune systems.

 -  Patients who test positive for HBV or HCV.

 -  Chronic administration (defined as daily or every other day for continued use > 14
 days) of systemic corticosteroids within 28 days of treatment initiation. Use of
 corticosteroids with minimal systemic absorption (e.g., inhaled steroids, nasal
 sprays, intraarticular, and topical agents) is allowed.

 -  Receipt of any organ transplantation, including allogeneic stem-cell transplantation,
 but with the exception of transplants that do not require immunosuppression (e.g.
 corneal transplant, hair transplant).

 -  Serious intercurrent medical illness that, in the judgement of the investigator, would
 interfere with patient s ability to carry out the treatment program.

 -  Subjects required other medications known to alter PSA including 5-alpha reductase
 inhibitors (finasteride and dutasteride) and alternative therapies (e.g.,
 phytoestrogens and saw palmetto).

 -  History of prior chemotherapy.

 -  History of prior systemic therapy with radionuclides (e.g., strontium-89,
 samarium-153, rhenium-186, rhenium-188, or radium 223 dichloride).

 -  Receipt of an investigational agent within 28 days (or 56 days for an antibody-based
 therapy) of treatment initiation.

 -  Major surgery within 28 days prior to treatment initiation.

 -  PET scan findings suggesting visceral disease.