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.
- 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/mm3
- 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 highly effective contraception (that is, methods with a
failure rate of less than 1% per year) for the duration of study therapy and at least
6 months after the 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.
