PR1 Vaccination in Myelodysplastic Syndrome (MDS)

Study Overview
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Brief Summary
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Primary aim: To determine the immunologic response, using a PR1-HLA-A2 tetramer assay, to 4 subcutaneous (SQ) injections of TVC-PR1 vaccine formulated in Montanide ISA 51 VG followed by granulocyte macrophage colony-stimulating factor (GM-CSF) in low risk and intermediate-1 myelodysplastic syndrome (MDS) patients. Secondary aims: To determine if non-immunologic responders to 4 subcutaneous (SQ) injections of TVCPR1 vaccine formulated in Montanide ISA 51 VG followed by GM-CSF can be converted to immunologic responders by administering 4 additional doses of TVC-PR1 vaccine formulated in Montanide ISA 51 VG followed by GM-CSF. To determine the clinical response to 4 or 8 subcutaneous (SQ) injections of TVC-PR1 vaccine formulated in Montanide ISA 51 VG followed by GM-CSF in patients low risk and intermediate-1 MDS.

Detailed Description
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MDS cells over-produce proteins found in normal bone marrow cells. These proteins can be used to stimulate the body's immune system to kill the MDS cells. PR-1 is a peptide derived from a protein, and PR1 peptide vaccine is given to help immune cells kill MDS cells. The vaccine is given together with granulocyte macrophage colony stimulating factor (GM-CSF), which increases production of white blood cells and is intended to increase the number of immune cells. Before you can start treatment on the study, you will have screening tests. These tests will help the doctor decide if you are eligible to take part in the study. You will have a bone marrow aspirate (about 1 tablespoon) for routine tests and for special studies. To collect a bone marrow aspirate, an area of the hip is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle. Blood (about 6 tablespoons) will be drawn. The blood tests are being done to compare pre-treatment blood counts to post-treatment counts, and the aspirate is being done to allow comparison of the number of MDS cells before and after treatment. Both the blood counts and aspirate will show whether the therapy was successful. Women who are able to have children must have a negative blood pregnancy test. If you are found to be eligible to take part in this study, you will receive the PR-1 vaccine as an injection under the skin once every 3 weeks. You will receive a total of 4 vaccinations. Each vaccination requires 4 shots: 2 of PR-1 vaccine and 2 of GM-CSF. GM-CSF is given to increase the number of immune cells that might respond to the vaccine and eventually kill MDS cells. PR-1 vaccine is mixed with montanide ISA 51, which is used to dissolve and stabilize the vaccine. Blood (about 1 tablespoon) will be drawn for routine tests 1 time every 3 weeks and (about 3 tablespoons) will be drawn each time before you receive the vaccinations and at follow up visits for the length of the study. You will have a bone marrow aspiration 4 weeks after the 4th and 8th vaccinations (about 1 tablespoon) for routine and for the special tests. These tests will allow researchers to find out if the number of immune cells has increased, whether these cells are able to attack the MDS cells, and whether the cells are related to a change in blood counts. At this time (13 weeks from the first PR-1 vaccine), if your immune system is reacting to the vaccinations, no further vaccinations will be given. This is to avoid production of immune cells that might block the effects of the cells already produced by the first 4 vaccinations. If, at this time (13 weeks from the first PR-1 vaccine), your immune system is not reacting to the drug, you will be offered an additional 4 vaccinations. These additional vaccinations will again be given once every 3 weeks. During this time, blood (about 4 tablespoons) will again be drawn once every 3 weeks for routine and special testing. You will be taken off study at any time if the disease gets worse or intolerable side effects occur. Twenty-nine (29) weeks after beginning the study, blood (about 1 teaspoon) will be drawn to check for a response to the vaccine. If you have not responded, you will be taken off study. If you have responded, you will continue to be followed. Follow-up will involve monthly routine blood tests (1 tablespoon of blood) for 6 months. These can be done at home with results sent to M. D. Anderson. Every 3 months, you will return to M. D. Anderson for a bone marrow aspirate and routine blood tests including the special testing studies. This is an investigational study. This vaccine is authorized for use in research only and is not commercially available. About 30 patients will take part in this multicenter study. About 20 patients will be enrolled at M. D. Anderson.

Official Title
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Phase 2 Study of Proteinase 3 PR1 Peptide Vaccine in Myelodysplastic Syndrome (MDS)

Conditions
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Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: PR-1 vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must understand and voluntarily sign an informed consent form Age >/= 18 years at the time of signing the informed consent form Must be able to adhere to the study visit schedule and other protocol requirements HLA-A2 positive at one allele Diagnosis of myelodysplastic syndrome (MDS) and must meet all the following criteria French-American-British (FAB) Class Refractory anemia (RA), Refractory Anemia with Excess Blasts (RAEB), refractory anemia with ringed sideroblasts (RARS) World Health Organization(WHO) Classification refractory anemia (RA), refractory anemia with ringed sideroblasts(RARS), refractory cytopenia with multilineage dysplasia (RCMD), refractory cytopenia with ringed sideroblasts (RCMD-RS) , refractory anemia with excess blasts type 1 (RAEB-1) Less than 20% blasts on marrow aspirate International Prognostic Scoring System (IPSS) risk groups Intermediate 1 or transfusion dependent low risk. Both de novo and therapy related MDS are eligible Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1 Women of childbearing potential must have a negative serum pregnancy test within 30 days of starting study drug. A woman of child-bearing potential is a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months) Male or female of child-bearing potential must agree to use adequate contraceptive methods Serum bilirubin < 2 mg/ml Serum creatinine </= 1.5 mg/ml Serum ALT < 2 x upper normal limit anti-neutrophil cytoplasmic antibody (cANCA) negative Not received specific therapy for MDS for 4 weeks. However, supportive therapy is permitted. Exclusion Criteria: Marrow blasts on aspirate >/= 20% Blood blasts > 1% Inaspirable bone marrow Myelosclerosis occupying >30% of marrow space Iron absence on marrow examination or transferrin saturation <20% and serum ferritin <50ng/ml B-12 deficiency Folate deficiency History of immune related hematological disorder [i.e.,immune thrombopenia purpura(ITP),autoimmune hemolytic anemia ( AIHA)] Other causes of cytopenia not related to MDS (i.e., GI blood loss) Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form or that will place the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret the data Prior allogeneic or syngeneic transplant Prior solid organ transplant Life expectancy severely limited by diseases other than MDS Pregnant or lactating females Prior vaccine therapy for MDS Chronic use (>2 weeks) of greater than physiologic doses of a corticosteroid agent (dose equivalent to >10 mg/day of prednisone) within 30 days of the first day of study drug treatment. (Topical and inhaled corticosteroids are permitted) Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for >/= 5 years Known allergy to incomplete Freund's adjuvant Experimental therapy, cyclosporine, antithymocyte globulin, or FK506 within 3 months of study entry Treatment with androgenic hormones, danazol, colony stimulating factors, erythropoietin, thalidomide, arsenic trioxide or other agents used to treat MDS within four weeks of the first day of study treatment refractory anemia with excess blasts in transformation (RAEB-t) (French-American British (FAB) criteria ) or refractory anemia with excess blasts type2 (RAEB-2) (World Health Organization (WHO) criteria) Chloroma Hypercalcemia Progressive viral or bacterial infection. Patients are not eligible unless all infections are resolved and the patient has remained afebrile for seven days without antibiotics Cardiac disease of symptomatic nature or cardiac ejection fraction < 40% Symptomatic pulmonary disease or FEV1, FVC and Carbon Monoxide Diffusing Capacity (DLCO) </= 50% predicted History of Wegener's Granulomatosis or vasculitis History of HIV positivity or AIDS Prior history of AML

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PR-1 vaccine<br>4 injections of 0.5 mg PR1 peptide vaccine every 3 weeks. | Biological: PR-1 vaccine<br>* 0.5 mg injections under the skin once every 3 weeks for a total of 4 vaccinations.<br>* Other names: PR1 Peptide Vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Immunologic Response | Patients assessed after 4th vaccination for immunologic response categorized as 'Immunologic-Responders' or 'Non-Responders.' Immune response defined as an increase of ≥ 0.5 PR1-HLA-A2 tetramer cells/μl compared to the pre study absolute PR1-HLA-A2 tetramer cells/μl. Time period 29 weeks after study entry, with week 0 corresponding to 1st injection, and 8th injection thus being given at week 25, 29 weeks corresponds to 13 weeks after receipt of a 4th injection. | 29 weeks | 
| Number of Patients With Clinical Response | Clinical response based on the International Working Group (IWG) Response Criteria in myelodysplastic syndromes (MDS): 'Complete Response' or Hematologic Improvement' and 'No Clinical Response'. Clinical responses as assessed by standard criteria with bone marrow biopsy, cytogenetic studies (standard chromosome banding) and molecular studies 3 weeks after the last vaccination. | At 29 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, myelodysplastic syndrome, PR1 Peptide Vaccine