A Randomized Placebo-controlled Phase II Trial of Irradiated, Adenovirus Vector Transferred GM-CSF Secreting Autologous Leukemia Cell Vaccination (GVAX) Versus Placebo Vaccination in Patients With Advanced MDS/AML After Allogeneic Hematopoietic Stem Cell Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 123
- 试验地点
- 4
- 主要终点
- 18-Month Progression Free Survival
研究概览
简要总结
This research study is a Phase II clinical trial. Phase II clinical trials test the effectiveness of an investigational intervention to learn whether the intervention, in this case, the GVAX vaccine, works in preventing MDS, CMML, or AML from relapsing after allogeneic stem cell transplantation. "Investigational" means that the vaccine is still being studied and that research doctors are trying to find out more about it-such as the side effects it may cause, and if the vaccine is effective. It also means that the FDA has not yet approved the vaccine for these types of cancer.
Participants are being asked to participate in this trial because they have advanced myelodysplastic syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), or acute myeloid leukemia (AML). Investigators have determined that participants are a candidate for an allogeneic stem cell transplant as treatment for MDS/CMML/AML. Allogeneic stem cell transplantation is a standard treatment for MDS/CMML/AML. It can be effective because the cells from the donor (also known as the graft) could form a new immune system that can fight against the MDS/CMML/AML cells in the body. This is also known as the "graft-versus-leukemia" or "GVL" effect. In patients with advanced MDS, CMML, or AML that is not in remission at the time of transplantation, relapse remains the number one cause of transplant failure. As such, this clinical trial is designed to assess whether adding a leukemia vaccine early after transplantation could stimulate donor cells to fight cancer and improve transplant outcomes.
In recent years, researchers at the Dana-Farber Cancer Institute have discovered that GVAX, a vaccine made from the patient's own cancer cells engineered to produce a protein called GM-CSF, can be effective in stimulating a powerful immune response specific to that cancer. GM-CSF is a naturally occurring hormone in the body that helps the immune system fight infections and diseases. The GVAX vaccine is made in the laboratory by using a virus (called adenovirus, which has been modified so it cannot cause illness) to insert the GM-CSF gene into tumor cells. The cells are then irradiated, which prevents them from being able to grow, before being administered to patients in a series of vaccinations.
A previous phase I clinical trial using this GVAX vaccine in patients with MDS/AML after allogeneic transplantation demonstrated that the GVAX vaccine is safe, and the survival outcomes were encouraging. The current randomized phase II study will investigate this vaccine further and gather more information to assess the activity.
Participants in this study will be "randomized" to receive either GVAX vaccination or placebo (a saline solution) vaccination. Randomization means participants are put into a group by chance. It is like flipping a coin. There is a 50% chance they will receive the GVAX vaccine and a 50% chance they will receive placebo. Neither participants nor investigators will know which participants will be receiving.
The primary goal of this trial is to assess if there will be a difference in the percentage of cancer free survivors in the vaccinated vs. placebo group at 18 months after transplant.
详细描述
This trial can be divided into four phases: 1) Pre-Transplant; 2) Allogeneic Transplant; 3) Vaccination; and 4) Post-Vaccination Follow-Up.
Phase 1: Pre-Transplant After signing the consent form participants will undergo some screening tests to find out if they can be in this research study. These tests include a medical history, physical examination, performance status, bone marrow aspirate and biopsy, blood tests, tuberculosis skin test, HLA antibody test, pregnancy test, urine test, ECHO, MUGA or RVG to measure heart function, chest x-ray, pulmonary function tests and dental consult. If these tests show that participants are eligible to participate in the research study, they will be enrolled on the trial and randomized to receive either the GVAX vaccine or the placebo vaccine after their transplant. After enrolling in the study participants will undergo additional research procedures including a blood draw and leukemia cell collection.
Phase 2: Allogeneic Transplant The transplant phase of the study will begin when participants are admitted to the hospital to receive the chemotherapy and stem cell transplant. In the week before participants receive the stem cells, they will be treated with chemotherapy. The combination of chemotherapy given before the donor cells are infused is called the conditioning regimen. The chemotherapy conditioning is given to suppress the immune system so that the donor blood stem cells will not be rejected after transplantation. The chemotherapy may also reduce the number of MDS/CMML/AML cancer cells in participants' body.
In this study the condition regimen will include 2 chemotherapy drugs: busulfan (twice a day or four times a day for 4 days) and fludarabine (once daily for 4 days). Depending on participants' age and other clinical factors, the transplant doctor will decide whether they receive a higher or lower dose of busulfan. Between 1-2 days after participants finish the chemotherapy, they will receive the blood stem cell or marrow from the donor. This is given as a transfusion through a central intravenous line (IV usually placed in the chest or arm).
Just prior to and immediately following the infusion of stem cells, participants receive medications to help prevent graft-versus-host disease (GVHD), a common complication of transplant where the donor's immune cells attack the body. The medications participants receive to prevent GVHD will include Tacrolimus and Methotrexate.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •AML, CMML-with excess blasts, MDS-RAEB not in remission prior to leukemia cell harvest
- •HLA 8/8 or 7/8 matched related or unrelated donor available
- •ECOG performance status of 0-2
- •Suitable candidate for myeloablative or reduced intensity conditioning allogeneic HSCT using PBSC or marrow as stem cell resource
- •Normal organ function
排除标准
- •Pregnant or breastfeeding
- •Leukemia with active CNS involvement
- •Positive HIV or HTLV-1 serology
- •History of allergic reactions to compounds of similar chemical or biologic composition to GM-CSF
- •Uncontrolled intercurrent illness
- •History of different malignancy except if disease free for at least two years or cervical cancer in situ, basal or squamous cell carcinoma of the skin diagnosed and treated within the past two years
- •Prior allogeneic transplant
研究组 & 干预措施
GVAX
GVAX vaccine
Participants in the GVAX vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. GVAX arm participants meeting criteria to begin vaccinations will be administered the GVAX vaccine at established study time points.
干预措施: GVAX (Biological)
GVAX
GVAX vaccine
Participants in the GVAX vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. GVAX arm participants meeting criteria to begin vaccinations will be administered the GVAX vaccine at established study time points.
干预措施: Allogeneic Hematopoietic Stem Cell Transplant (Procedure)
GVAX
GVAX vaccine
Participants in the GVAX vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. GVAX arm participants meeting criteria to begin vaccinations will be administered the GVAX vaccine at established study time points.
干预措施: Busulfan (Drug)
GVAX
GVAX vaccine
Participants in the GVAX vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. GVAX arm participants meeting criteria to begin vaccinations will be administered the GVAX vaccine at established study time points.
干预措施: Fludarabine (Drug)
GVAX
GVAX vaccine
Participants in the GVAX vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. GVAX arm participants meeting criteria to begin vaccinations will be administered the GVAX vaccine at established study time points.
干预措施: Tacrolimus (Drug)
GVAX
GVAX vaccine
Participants in the GVAX vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. GVAX arm participants meeting criteria to begin vaccinations will be administered the GVAX vaccine at established study time points.
干预措施: Methotrexate (Drug)
Placebo
Placebo vaccine
Participants in the Placebo vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. Placebo vaccine arm participants meeting criteria to begin vaccinations will be administered the placebo vaccine at established study time points.
干预措施: Placebo Vaccine (Biological)
Placebo
Placebo vaccine
Participants in the Placebo vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. Placebo vaccine arm participants meeting criteria to begin vaccinations will be administered the placebo vaccine at established study time points.
干预措施: Allogeneic Hematopoietic Stem Cell Transplant (Procedure)
Placebo
Placebo vaccine
Participants in the Placebo vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. Placebo vaccine arm participants meeting criteria to begin vaccinations will be administered the placebo vaccine at established study time points.
干预措施: Busulfan (Drug)
Placebo
Placebo vaccine
Participants in the Placebo vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. Placebo vaccine arm participants meeting criteria to begin vaccinations will be administered the placebo vaccine at established study time points.
干预措施: Fludarabine (Drug)
Placebo
Placebo vaccine
Participants in the Placebo vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. Placebo vaccine arm participants meeting criteria to begin vaccinations will be administered the placebo vaccine at established study time points.
干预措施: Tacrolimus (Drug)
Placebo
Placebo vaccine
Participants in the Placebo vaccine arm will undergo a conditioning regimen with busulfan and fludarabine prior to allogeneic hematopoietic stem cell transplant. Immediately after allogeneic hematopoietic stem cell transplant participants will start tacrolimus and methotrexate to prevent GVHD. Placebo vaccine arm participants meeting criteria to begin vaccinations will be administered the placebo vaccine at established study time points.
干预措施: Methotrexate (Drug)
结局指标
主要结局
18-Month Progression Free Survival
时间窗: 18 months
Progression-Free Survival (PFS) at 18 months after randomization. Progression-free survival is defined as time from randomization to progression of disease or death whichever occurs first. Patients with relapse/progressive disease who re-enter remission after vaccination or upon withdrawal of immune suppression alone will not be considered as having disease progression. The primary analysis will be performed using the modified intention-to-treat (ITT) principle, i.e., all transplanted and eligible patients who receive at least one vaccination will be included in the analysis according to the treatment arm they are randomized to. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free. Progression is defined by either morphological evidence of acute leukemia or MDS consistent with pre-transplant features is defined by either morphological evidence of acute leukemia or MDS consistent with pre-transplant features
次要结局
- 18-Month Overall Survival(18 Month)
- Percentage of Participants Experiencing Grade 3 or Higher Non-Hematologic or Grade 4 or Higher Hematologic Adverse Events(18 Months)
- Percentage of Participants Experiencing Acute and Chronic Graft-Versus-Host Disease(1 and 3 years)
- Percentage of Participants With Relapse and/or Non-Relapse Mortality(18 Months)
研究者
Vincent T. Ho, MD
Principal Investigator
Dana-Farber Cancer Institute