Peptide Vaccinations to Treat Patients With Low-Risk Myeloid Cancers
Condition: Myelodysplastic Syndrome (MDS); Acute Myeloid Leukemia (AML); Chronic Myeloid Leukemia (CML)
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myelodysplastic Syndromes; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will test the safety and effectiveness of two vaccines on slowing disease
      progression, improving blood counts, reducing the need for transfusions of blood and
      platelets, or achieving remission in patients with myelodysplastic syndrome (MDS, also known
      as myelodysplasia), acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). The
      vaccines consist of peptides (parts of proteins) found in MDS, AML and CML stem cells,
      combined with a substance called "MontanideTM". They are administered with granulocyte-
      macrophage colony- stimulating factor (GM-CSF). The Montanide and the GM-CSF help the immune
      system respond to the vaccines.

      People 18 years of age or older with MDS, AML or CML may be eligible for this study.

      Participants receive six injections of the vaccines, one dose every other week for a total of
      10 weeks. The injections are given in the upper arm, upper leg, or abdomen. A separate
      injection of GM-CSF is given in the same area as the vaccine injections. Subjects are
      observed for 2 hours after the first vaccination and at least 30 minutes after each
      subsequent vaccination for allergic reactions. In addition to the vaccination, subjects
      undergo the following:

        -  History and physical exam, chest x-ray, blood tests and bone marrow aspirate and biopsy
           before starting the vaccinations.

        -  Safety monitoring during vaccine administration (every other week for 10 weeks) with
           blood tests and check of vital signs.

        -  Follow-up safety monitoring (weeks 12 and 16) with blood tests every visit, chest x-ray
           at week 12 and bone marrow biopsy visit 16.
    

Detailed description: 
      Leukemias and the related disorders myelodysplastic syndrome and myeloproliferative diseases
      represent a wide group of bone marrow stem cell malignancies. Some patients can be cured with
      chemotherapy or by allogeneic stem cell transplantation. However standard treatment
      approaches are not effective for patients who become refractory to chemotherapy, those who
      relapse after transplantation and those with progressive disease. The management of such
      patients remains unsatisfactory and requires new treatment approaches other than
      chemotherapy.

      The immunological graft-versus-leukemia (GVL) effect seen after allogeneic stem cell
      transplantation suggests that stimulating the patient's own T cell responses to MDS and
      leukemia with a vaccine might also retard disease progression and even achieve disease
      remissions. Peptide (WT1) and peptide (PR1) were identified as target antigens because both
      antigens are highly expressed by cluster of differentiation 34 (CD34) plus stem cells of most
      patients with myeloid malignancies but not by normal marrow cells. An immunotherapeutic
      approach to vaccinate against PR1 and WT1 antigens could induce T cell response against MDS
      and leukemic cells while sparing normal cells and by using a combination of two antigens the
      risk of disease escape by antigen down regulation should be further diminished. Indeed in a
      safety study of one dose of a combination of peptide (PRl) and (WT1) vaccination, we
      demonstrated that immunological response against one or both vaccines could be induced in all
      subjects who were vaccinated. This immunological response was associated with a transient
      reduction in the leukemia burden. Furthermore the vaccine combination was well tolerated.

      Therefore we propose this Phase II trial, the third in a series of planned peptide vaccine
      research protocols, which will evaluate the safety and efficacy associated with an
      immunotherapy approach using two peptide vaccines, namely PR 1 : 169- 177 and WT-1: 126-1 34
      in Montanide adjuvant, administered concomitantly with GM-CSF (Sargramostim), every 2 weeks
      for 10 weeks (6 doses WT1 plus 6 doses PRl plus GM-CSF) in select patients diagnosed with
      MDS, AML or CML. Subjects with immunological response to one or both peptide vaccines will
      have the option of receiving an additional 6 boosters of the WT-1:126-135 and PR1:169-177
      peptide vaccines at 3 monthly intervals.

      The primary objective will be to evaluate the efficacy and toxicity associated with 6 doses
      of a combination of WT-1: 126-134 and PRl: 169-177 peptide vaccines in Montanide adjuvant
      administered concomitantly with GMCSF (Sargramostim) in selected patients with myeloid
      malignancies (MDS, AML, CML).

      The primary endpoint will be immune response (studying changes in the frequencies of
      circulating PR1 and WT1 specific T cells) which will serves as a surrogate for evaluating for
      the efficacy of the study.

      Secondary Endpoints will include changes in marrow blast cells, blood counts, transfusion
      dependence, time to disease progression and survival.
    

Intervention name(s): WT1:126-134; PR1:169-177 Peptide; GM-CSF (Sargramostim); Montanide adjuvant
Intervention type(s): Biological; Biological; Drug; Biological
Intervention description(s): Subjects were given 6 doses of PR1:169-177 in "Montanide" adjuvant and 6 doses of WT1:126-134 in "Montanide" adjuvant at 2 weekly intervals. The peptides were injected in the deep subcutaneous tissue of the anterior abdominal wall, the thighs or the upper arms near the deltoid region. The sites of injection were rotated every 2 weeks. GM-CSF (Sargramostim) was co administered with each vaccine dose. Subjects with immunological response to one or both peptide vaccines had the option of receiving a maximum of 6 additional boosters of the WT-1:126-134 and PR1:169-177 peptide vaccines at 3 monthly intervals.; Subjects were given 6 doses of PR1:169-177 in montanide adjuvant and 6 doses of WT-1:126-134 in Montanide adjuvant at 2 weekly intervals. The peptides were injected in the deep subcutaneous tissue of the anterior abdominal wall, the thighs or the upper arms near the deltoid region. The sites of injection were rotated every 2 weeks. GM-CSF (Sargramostim) was co administered with each vaccine dose. Subjects with immunological response to one or both peptide vaccines had the option of receiving a maximum of 6 additional boosters of the WT-1:126-134 and PR1:169-177 peptide vaccines at 3 monthly intervals.; Subjects were given 6 doses of PR1:169-177 in montanide adjuvant and 6 doses of WT-1:126-134 in Montanide adjuvant at 2 weekly intervals. The peptides were injected in the deep subcutaneous tissue of the anterior abdominal wall, the thighs or the upper arms near the deltoid region. The sites of injection were rotated every 2 weeks. GM-CSF (Sargramostim) was co administered with each vaccine dose. Subjects with immunological response to one or both peptide vaccines had the option of receiving a maximum of 6 additional boosters of the WT-1:126-134 and PR1:169-177 peptide vaccines at 3 monthly intervals.; Subjects were given 6 doses of PR1:169-177 in montanide adjuvant and 6 doses of WT-1:126-134 in Montanide adjuvant at 2 weekly intervals. The peptides were injected in the deep subcutaneous tissue of the anterior abdominal wall, the thighs or the upper arms near the deltoid region. The sites of injection were rotated every 2 weeks. GM-CSF (Sargramostim) was co administered with each vaccine dose. Subjects with immunological response to one or both peptide vaccines had the option of receiving a maximum of 6 additional boosters of the WT-1:126-134 and PR1:169-177 peptide vaccines at 3 monthly intervals.
Other intervention name(s): Wilms' tumor 1: 126-134 (WT1:126-134) Peptide; peptide (PR1:169-177); granulocyte macrophage colony- stimulating factor (GM-CSF)
Intervention MeSH terms: Molgramostim; Sargramostim; Monatide (IMS 3015)
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Myelodysplastic Syndrome (MDS); Acute Myeloid Leukemia (AML); Chronic Myeloid Leukemia (CML); Wilm's Tumor-1; Proteinase-3; Myelodysplastic Syndrome; MDS; Acute Myeloid Leukemia; AML; Chronic Myeloid Leukemia; CML