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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized Phase 2.5 Study of (153)Sm-EDTMP (Quadramet) With or Without a PSA/TRICOM Vaccine in Men With Androgen-Insensitive Metastatic Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Radiation: Samarium Sm 153 lexidronam pentasodium
* Biological: Sargramostim
* Biological: Recombinant vaccinia-TRICOM vaccine
* Biological: Recombinant fowlpox-TRICOM vaccine


Participation Criteria
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Eligibility Criteria
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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.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A -EDTMP Alone<br>Patients receive samarium Sm 153 lexidronam pentasodium 1 mCi/Kg intravenous (IV) over 1 minute on day 8. Treatment repeats every 12 weeks in the absence of disease progression or unacceptable toxicity. | Radiation: Samarium Sm 153 lexidronam pentasodium<br>* 1 mCi/Kg given intravenous (IV)over 1 minute on day 8.<br>|
| Experimental: Arm B - 153SmEDTMP with vaccine<br>Patients receive recombinant vaccinia-TRICOM vaccine 2 x 10^8 PFU subcutaneously (SC) on day 1. Patients also receive recombinant fowlpox-TRICOM vaccine 1 x 10^9 PFU SC on days 15 and 29 and sargramostim (GM-CSF)100 mcg/injection SC x 4 days. Treatment with recombinant fowlpox-TRICOM vaccine and GM-CSF* repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive samarium Sm 153 lexidronam pentasodium 1 mCi/Kg as in arm I. | Radiation: Samarium Sm 153 lexidronam pentasodium<br>* 1 mCi/Kg given intravenous (IV)over 1 minute on day 8.<br>Biological: Sargramostim<br>* 100 mcg/injection x 4 days given subcutaneously<br>Biological: Recombinant vaccinia-TRICOM vaccine<br>* 2 x 10^8 PFU given subcutaneously on day 1.<br>Biological: Recombinant fowlpox-TRICOM vaccine<br>* 1 x 10^9 PFU given subcutaneously on days 15 and 29<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Stable Disease at 4 Months. | Response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Stable disease is neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter (LD) since the treatment started. Partial response (PR) is at least a 30% increase in the sum of the LD of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions on computed tomography (CT) or two or more lesions on bone scan. | 4.7 months | 
| Progression Free Survival (PFS) | PFS is defined as the time to progress or die after the start of the therapy. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 5 years, 5 months | 
| Number of Participants With Prostate-Specific Antigen (PSA) ≥ 30% | PSA is defined by the PSA Working Group criteria. A minimum PSA decline of at least 50% must be confirmed by a second PSA value 4 or more weeks later. | 4 months | 
| Number of Participants With Prostate-Specific Antigen (PSA) ≥50% | PSA is defined by the PSA Working Group criteria. A minimum PSA decline of at least 50% must be confirmed by a second PSA value 4 or more weeks later. | 4 months | 
| Overall Survival | Time from treatment start date until date of death or date last known alive. | From date of randomization until death or last follow up, whichever comes first, assessed up to 14 months. | 
| Arm A: Prostate-Specific Antigen (PSA) T-cell Responses Post-vs. Pre-treatment | PSA T-cell responses were measured by fluorescence activated cell sorting (FACS)-based assay for T-cells expressing type I cytokines interferon (IFN-ϓ), interleukin 2 (IL2), tumor necrosis factor alpha (TNF-a) and/or lysosome-associated membrane protein (CD107a). | Approximately 60 days | 
| Arm B: Prostate-Specific Antigen (PSA) T-cell Responses Post-vs. Pre-treatment | PSA T-cell responses were measured by fluorescence activated cell sorting (FACS)-based assay for T-cells expressing type I cytokines interferon (IFN-ϓ), interleukin 2 (IL2), tumor necrosis factor alpha (TNF-a) and/or lysosome-associated membrane protein (CD107a). | Approximately 60 days | 
| Objective Response (Complete Response + Partial Response) | Objective response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is the disappearance of all target lesions. Partial response (PR) is at least a 30% increase in the sum of the LD of target lesions, taking as reference the baseline sum LD. | 4 weeks | 
| Palliation: Pain at Baseline | Subjective report of participant pain at baseline.This data reflects National Cancer Institute (NCI) patients only. This data was not systematically captured, so these results are based on subjective patient reports of improvement in pain on a scale of 1-10 post quadramet (samarium) as documented in the progress notes. 1-2 equals mild pain and 9-10 equals worst possible pain. | Baseline | 
| Palliation: Improvement in Baseline Pain | Subjective report of participant pain at baseline. This data reflects National Cancer Institute (NCI) patients only. This data was not systematically captured, so these results are based on subjective patient reports of improvement in pain on a scale of 1-10 post quadramet (samarium) as documented in the progress notes. 1-2 equals mild pain and 9-10 equals worst possible pain. | post quadramet (samarium) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radionuclide, Immunotherapy, Radiation, PSA, Hormone Refractory Prostate Cancer, Prostate Cancer