153Sm-EDTMP With or Without a PSA/TRICOM Vaccine To Treat Men With Androgen-Insensitive Prostate Cancer
153Sm-EDTMP With or Without a PSA/TRICOM Vaccine To Treat Men With Androgen-Insensitive Prostate Cancer
Background:

 -  No treatment is known to improve survival for prostate cancer patients who have not been
 helped by previous treatments with hormones and chemotherapy.

 -  An experimental vaccine called prostate specific antigen (PSA)/TRICOM contains genes for
 a protein produced by prostate cancer cells called prostate-specific antigen (PSA). The
 vaccine can trigger the immune system to make cells that may be able to recognize and
 attack the cancer cells that make PSA.

 -  Granulocyte macrophage colony stimulating factor (GM-CSF) is an approved drug that is
 usually given to increase a patient's white blood cell count or to stimulate the immune
 system.

 -  1Samarium-153-ethylene diamine tetramethylene phosphonate (53Sm-EDTMP) is a radioactive
 drug that has been approved for many years to treat advanced prostate cancer. It is
 given through a vein and can be targeted directly to tumors in the bone where it can
 relieve pain caused by bone lesions. Radiation also increases the level of certain
 proteins inside the tumor, making it easier for the immune system to find and kill the
 tumor cells.

 -  When laboratory mice were given just vaccine, just radiation, or a combination of both,
 the combination was most effective in treating tumors.

 Objectives:

 -To determine if combined treatment with PSA/TRICOM vaccine and 153Sm-EDTMP radiation can
 delay progression of prostate cancer better than radiation alone.

 Eligibility:

 -Patients who have advanced prostate cancer that has worsened despite treatments with
 hormones, have two or more bone lesions related to their prostate cancer, and have had prior
 treatment with docetaxel chemotherapy.

 Design:

 -  Patients are randomly assigned to receive radiation alone (Arm A) or radiation with
 vaccine and sargramostim (Arm B).

 -  Arm A receives 153Sm-EDTMP radiation starting on study day 8 and repeated every 12
 weeks.

 -  Arm B receives a priming vaccine on study day 1 and radiation on day 8. Radiation
 therapy is repeated every 12 weeks. Boosting vaccines are given on days 15 and 29 and
 then monthly. GM-CSF is given with each vaccination (on the day of the vaccination and
 for the next 3 days) to enhance the immune response. Vaccinations and GM-CSF are given
 as injections under the skin, usually in the thigh. Radiation therapy is given through a
 vein.

 -  Patients are monitored regularly with physical examinations, blood and urine tests, and
 scans to evaluate safety and treatment response.

 -  Patients who are human leukocyte antigen serotype within HLA-A A serotype group
 (HLA-A2)-positive undergo apheresis, a procedure similar to donating blood, for
 obtaining immune cells called lymphocytes to measure the immune response to the vaccine.
Background

 -  There are no standard therapy options shown to prolong survival for patients with
 progressive disease on first-line docetaxel-based regimens for men with metastatic
 castration resistant prostate cancer (CRPC).

 -  Ninety percent of men in this population have bone metastasis.

 -  PSA/TRICOM vaccines as single agents can induce generation of PSA-specific T cells in
 the majority of patients and objective responses and PSA declines in a minority of
 patients. Furthermore, the generation of at least a 6-fold increase in PSA-specific T
 cells was significantly correlated with evidence of clinical benefit.

 -  Radiation can alter the phenotype of tumor cells (increase Fas, increase major
 histocompatibility complex (MHC), increase tumor-associated molecules and increase
 ICAM), making them much more amenable to immune-mediated killing.

 -  (153)Sm EDTMP is a beta emitter (with some gamma emissions) that targets osteoblastic
 bone lesions (such as those found in prostate cancer).

 -  (153)Sm EDTMP, at Food And Drug Administration (FDA)-approved doses used clinically for
 palliation of prostate cancer, can cause phenotypic changes in tumor cells, leading to
 improved killing of those cells in a cytotoxic T-cell assay in vitro.

 -  The combination of vaccine and radiation greatly increases antitumor efficacy in a
 murine subcutaneous tumor model.

 Objectives

 -  Primary-A comparison of progression-free survival at 4 months between Arm A (153)Sm
 EDTMP alone) and Arm B (153Sm EDTMP with vaccine).

 -  Secondary-Objective responses, PSA outcomes, immunologic responses, toxicity, palliation
 and overall survival.

 Eligibility

 -  Patients with metastatic CRPC who have 2 or more bone lesions consistent with prostate
 cancer and who have been treated with a docetaxel-based regimen.

 -  Patients with symptomatic soft tissue disease or parenchymal disease will be excluded.

 Design

 -  Randomized phase 2.5 study.

 -  Sixty-eight patients to be enrolled and randomized to:

 -  Arm A: (153)Sm-EDTMP: 1 mCi/kg intravenous (IV) over one minute on day 8.
 (153)Sm-EDTMP will be repeated every 12 weeks if there is adequate hematologic
 recovery.

 Arm B: PROSTAC-V/TRICOM (vaccinia) 2 x 10^8 plaque forming unit (pfu) subcutaneously on day
 1.

 -  (153)Sm-EDTMP: 1 mCi/kg IV over one minute on day 8. (153)Sm-EDTMP will be repeated
 every 12 weeks if there is adequate hematologic recovery. PROSTVAC-F/TRICOM (fowlpox) 1
 x 10^9 pfu subcutaneously on days 15, 29, and then every 4 weeks.
-  INCLUSION CRITERIA:

 A. Histopathological documentation of prostate cancer confirmed in the Laboratory of
 Pathology at the National Institutes of Health (NIH) Clinical Center, National Institutes
 of Health (NIH), the National Naval Medical Center, or Walter Reed Army Medical Center; or
 participating Institute's Department of Pathology prior to starting this study. 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.

 B. Must have metastatic castration resistant prostate cancer (CRPC) with at least 2 bone
 lesions consistent with prostate cancer metastasis and progressive disease (2 rising PSA
 values separated by at least one week, new or enlarging lesions consistent with prostate
 cancer, or clinical progression) on docetaxel for metastatic prostate cancer or inability
 to tolerate docetaxel.

 C. Life expectancy greater than or equal to 6 months.

 D. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

 E. No systemic steroid or steroid eye drop use within 2 weeks prior to initiation of
 experimental therapy.

 F. Hematological eligibility parameters (within 16 days of starting therapy).

 -  Granulocyte count greater than or equal to 1,500/mm^3

 -  Platelet (PLT) count greater than or equal to 100,000/mm^3

 -  Hemoglobin (Hgb) greater than or equal to 10 Gm/dL (Transfusion may be given to
 accomplish this)

 G. Biochemical eligibility parameters (within 16 days of starting therapy)

 -Hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less
 than 2.5 times upper limit of normal; bilirubin less than 1.5 mg/dL OR in patients with
 Gilbert's syndrome, a total bilirubin less than or equal to 3.0 mg/dL.

 H. No other active malignancies within the past 12 months (with the exception of
 nonmelanoma skin cancers or carcinoma in situ of the bladder and treated with curative
 intent) or life-threatening illnesses.

 I. Willing to travel to the National Institutes of Health (NIH) or participating Institute
 for follow-up visits.

 J. 18 years of age or greater.

 K. Able to understand and sign informed consent.

 L. Agree to use adequate contraception prior to study entry and for at least 4 months
 following the last vaccine injection.

 M. Patients must remain on medical castration therapy with testosterone-suppressing therapy
 (e.g., gonadotropin releasing hormone (GnRH) agonist), unless they have had surgical
 castration.

 N. Patients must have recovered from acute toxicities related to prior therapy or surgery.
 For chemotherapy, typically this is 3 to 4 weeks.

 O. Patients who are incontinent of urine should be willing to undergo bladder
 catheterization to minimize the risk of radioactive contamination of clothing, bed linen,
 and the patient's environment.

 P. Concurrent treatment with bisphosphonates is allowed. If bisphosphonates have been given
 within 2 weeks prior to planned (153)Sm-EDTMP, then a 99Tc whole-body scintigraphy (bone
 scan) will be performed to confirm uptake into lesions. Bisphosphonates will not be given
 within 48 hours after (153)Sm-EDTMP administration.

 Q. Serum creatinine less than or equal to 1.5 times upper limit of normal OR creatinine
 clearance on a 24-h urine collection of greater than or equal to 60 mL/min.

 EXCLUSION CRITERIA:

 A. Patients should have no evidence, as listed below, of being immunocompromised:

 -  Human immunodeficiency virus (HIV) positivity due to the potential for decreased
 tolerance and risk for severe side effects.

 -  Hepatitis B or C positivity.

 -  Concurrent use of topical steroids (including steroid eye drops) or systemic steroids.
 This is to avoid immunosuppression which may lead to potential complications with
 vaccinia (priming vaccination). Nasal or inhaled steroid use is permitted.

 B. Patients should have no autoimmune diseases that have required treatment, such as
 Addison's disease, Hashimoto's thyroiditis, systemic lupus erythematosus, Sjogren's
 syndrome, scleroderma, myasthenia gravis, Goodpasture's syndrome, or active Grave's
 disease. Patients with a history of autoimmunity that has not required systemic
 immunosuppressive therapy or does not threaten vital organ function, including central
 nervous system (CNS), heart, lungs, kidneys, skin, and gastrointestinal tract (GI) tract,
 will be allowed.

 C. History of allergy or untoward reaction to prior vaccination with vaccinia virus or to
 any component of the vaccinia vaccine regimen. Note: prior vaccination with vaccinia is not
 required.

 D. Do not administer the recombinant vaccinia vaccine if the recipient or, for at least 3
 weeks after vaccination, their close household contacts (close household contacts are those
 who share housing or have close physical contact), are persons with active or a history of
 eczema or other eczematoid skin disorders; those with other acute, chronic or exfoliative
 skin conditions (e.g., atopic dermatitis, burns, impetigo, varicella zoster, severe acne,
 or other open rashes or wounds) until condition resolves; pregnant or nursing women;
 children 3 years of age and under; and immunodeficient or immunosuppressed persons (by
 disease or therapy), including HIV infection.

 E. Serious intercurrent medical illness (e.g., one that requires treatment) which would
 interfere with the ability of the patient to carry out the treatment program, including,
 but not limited to, inflammatory bowel disease, Crohn's disease, ulcerative colitis, or
 active diverticulitis.

 F. Patients with a history of cardiomyopathy or symptomatic congestive heart failure
 (unless stable on treatment), symptomatic arrhythmia not controlled by medication. Unstable
 atherosclerotic heart disease (e.g. unstable angina) who require active intervention and
 history of myocardial infarction or embolic stroke within the past 6 months.

 G. Patients with cardiac disease who have fatigue, palpitation, dyspnea or angina with
 ordinary physical activity (New York Heart Association class 2 or greater) are not
 eligible.

 H. Patients with a history of congestive heart failure or who have objective evidence of
 congestive heart failure by physical exam or imaging are not eligible, unless the
 underlying cause has been treated and patient has documented normal ejection fraction.

 I. Patients with pulmonary disease who have fatigue or dyspnea with ordinary physical
 activity are not eligible.

 J. Concurrent chemotherapy.

 K. No brain metastasis or history of seizures, encephalitis, or multiple sclerosis.

 L. Serious hypersensitivity reaction to egg products.

 M. Prior splenectomy.

 N. Contraindicated in patients who have known hypersensitivity to EDTMP or similar
 phosphonate compounds.

 O. Patients with symptomatic soft tissue disease or parenchymal disease will be excluded.

 P. Radiation therapy to bone within 4 weeks of study entry.

 Q. Patients previously treated with (153)Sm-EDTMP will be excluded.

 R. Patients requiring urgent local radiotherapy or orthopedic stabilization.