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

Phase 2

Completed

Conditions: Prostate Cancer

Interventions: Radiation: Samarium Sm 153 lexidronam pentasodium
Biological: Sargramostim
Biological: Recombinant vaccinia-TRICOM vaccine
Biological: Recombinant fowlpox-TRICOM vaccine

Registration Number: NCT00450619

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 44

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A -EDTMP Alone	Samarium Sm 153 lexidronam pentasodium	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.
Arm B - 153SmEDTMP with vaccine	Recombinant vaccinia-TRICOM vaccine	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.
Arm B - 153SmEDTMP with vaccine	Sargramostim	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.
Arm B - 153SmEDTMP with vaccine	Samarium Sm 153 lexidronam pentasodium	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.
Arm B - 153SmEDTMP with vaccine	Recombinant fowlpox-TRICOM vaccine	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.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Stable Disease at 4 Months.	4.7 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.
Progression Free Survival (PFS)	4 months	PFS is defined as the time to progress or die after the start of the therapy.

Secondary Outcome Measures

Name	Time	Method
Toxicity	5 years, 5 months	Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Number of Participants With Prostate-Specific Antigen (PSA) ≥ 30%	4 months	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.
Number of Participants With Prostate-Specific Antigen (PSA) ≥50%	4 months	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.
Overall Survival	From date of randomization until death or last follow up, whichever comes first, assessed up to 14 months.	Time from treatment start date until date of death or date last known alive.
Arm A: Prostate-Specific Antigen (PSA) T-cell Responses Post-vs. Pre-treatment	Approximately 60 days	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).
Arm B: Prostate-Specific Antigen (PSA) T-cell Responses Post-vs. Pre-treatment	Approximately 60 days	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).
Objective Response (Complete Response + Partial Response)	4 weeks	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.
Palliation: Pain at Baseline	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.
Palliation: Improvement in Baseline Pain	post quadramet (samarium)	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.

Trial Locations

Locations (3): University of Chicago
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Chicago, Illinois, United States
Cancer Institute of New Jersey
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New Brunswick, New Jersey, United States
National Institutes of Health Clinical Center, 9000 Rockville Pike
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Bethesda, Maryland, United States