Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML)
Conditions
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
Brief 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.
Interventions
BIOLOGICALWT1:126-134
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.
BIOLOGICALPR1:169-177 Peptide
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.
BIOLOGICALMontanide adjuvant
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.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Diagnosed with MDS (B subtypes Refractory anemia (RA), Refractory anemia with ring sideroblasts (RARS) -Low Risk) (MDS with 5q- must have failed lenalidomide or been ineligible to receive it) OR Diagnosed with AML and in complete remission within 5 years of treatment with less than 5% marrow blasts OR Diagnosed with CML in chronic phase Unsuitable for stem cell transplantation (SCT) (age over sixty or unavailability of a fully-matched donor) or made an informed decision not to undergo the transplant procedure or are between 6 months 3 years following allogeneic SCT and fulfill the following criteria: 100% donor engraftment, Less than 5% blasts in marrow normal marrow cellularity Human leukocyte antigen (HLA-A020 1) positive at one allele Ages 18-85 years old Off all lympho-ablative chemotherapeutic agents
Exclusion criteria
* Hypoplastic MDS * Relapsed AML * CML in accelerated phase or blast crisis * Hypocellular bone marrow (less than 20%) * History of Wegener's granulomatosis * Serologic antibody against proteinase-3 (ANCA positive) * Previous allergic reaction to Montanide Adjuvant * Positive test for HIV * Treatment with systemic corticosteroids or immunosuppressants within 14 days prior to study entry * Co-morbidity of such severity that it would preclude the patient's ability to tolerate protocol therapy * Predicted survival less than 28 days * Pregnant or breast feeding (All female patients must have a urine pregnancy test within 1 week prior to vaccine administration) * Unwilling to practice abstinence or effective contraception (men and women) during the study period. * Enrolled in another drug or vaccine clinical trial during the study period * Inability to comprehend the investigational nature of the study and provide informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Inducing or Boosting of a Cellular Immune Response | 16 weeks | Number of participants diagnosed with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) who experienced an inducing or boosting of a cellular immune response following Wilm's Tumor 1 (WT1) and PR1 vaccine. A T-cell immune response was considered positive if the frequencies of interferon (IFN-γ+) cluster of differentiation (CD8+) T cells in peptide-stimulated peripheral bloody mono-nucleated cells (PBMCs) were 2-fold or more higher than the frequencies of interferon (IFN-γ+) CD8+ T cells in unstimulated PBMCs and if there was a minimum of 0.05% Interferon (IFNγ+) CD8+ T cells (after subtracting the frequencies of interferon (IFNγ+) CD8+ T cells in unstimulated PBMCs). A significant vaccine-induced CD8+ T-cell response was defined as the emergence of detectable PR1 or WT1-specific CD8+ T cells when the pre-study analysis found no response, or a 2-fold increase in frequencies when responses were present before vaccination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Hematological Response | 16 weeks | Number of participants diagnosed with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) who experienced a hematological response following Wilm's Tumor (WT1) and PR1 peptide vaccine. Hematological response is defined by reduction in marrow blast cells, changes in blood counts. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PR1/WT1 Vaccine Response in Participants With Low-Risk Myeloid Cancers Participants were given subcutaneous 6 injections of PR1:169-177 in Montanide adjuvant and 6 doses of WT1:126-134 in Montanide adjuvant at 2 weekly intervals. 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. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Disease progression | 1 |
| Overall Study | Enrolled but not treated | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | PR1/WT1 Vaccine Response in Participants With Low-Risk Myeloid Cancers |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 58.9 years STANDARD_DEVIATION 13.7 |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 4 / 10 |
| serious Total, serious adverse events | 2 / 10 |
Outcome results
Primary
Number of Participants Who Experienced Inducing or Boosting of a Cellular Immune Response
Number of participants diagnosed with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) who experienced an inducing or boosting of a cellular immune response following Wilm's Tumor 1 (WT1) and PR1 vaccine. A T-cell immune response was considered positive if the frequencies of interferon (IFN-γ+) cluster of differentiation (CD8+) T cells in peptide-stimulated peripheral bloody mono-nucleated cells (PBMCs) were 2-fold or more higher than the frequencies of interferon (IFN-γ+) CD8+ T cells in unstimulated PBMCs and if there was a minimum of 0.05% Interferon (IFNγ+) CD8+ T cells (after subtracting the frequencies of interferon (IFNγ+) CD8+ T cells in unstimulated PBMCs). A significant vaccine-induced CD8+ T-cell response was defined as the emergence of detectable PR1 or WT1-specific CD8+ T cells when the pre-study analysis found no response, or a 2-fold increase in frequencies when responses were present before vaccination.
Time frame: 16 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PR1/WT1 Vaccine Response in Participants With Low-Risk Myeloid Cancers | Number of Participants Who Experienced Inducing or Boosting of a Cellular Immune Response | Cellular immune response | 5 participants |
| PR1/WT1 Vaccine Response in Participants With Low-Risk Myeloid Cancers | Number of Participants Who Experienced Inducing or Boosting of a Cellular Immune Response | No cellular immune response | 2 participants |
Secondary
Number of Participants Who Experienced a Hematological Response
Number of participants diagnosed with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) who experienced a hematological response following Wilm's Tumor (WT1) and PR1 peptide vaccine. Hematological response is defined by reduction in marrow blast cells, changes in blood counts.
Time frame: 16 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PR1/WT1 Vaccine Response in Participants With Low-Risk Myeloid Cancers | Number of Participants Who Experienced a Hematological Response | 0 participants |