GVAX vs. Placebo for MDS/AML After Allo HSCT

Myelodysplastic Syndrome, Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia

Advanced

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.

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. Participants will be closely monitored as per standard transplant care after their stem cell transplant. If participants received the higher dose chemotherapy conditioning, they will stay in the hospital for an average of about 3-4 weeks. If they received the lower dose conditioning transplant, their hospital admission for transplant may be shorter depending on clinical condition. After participants' stem cell infusion, they may receive daily injections of a medication called rhGM-CSF, or Leukine, to help their white blood cells to recover faster. participants may receive this medication for up to 2 weeks. They will also be given antiviral and antibiotic medications to prevent infections as per standard practice after transplantation. Between 20 to 30 days after stem cell infusion participants will have a physical examination, routine blood work and a blood draw for future immune tests. Between 30 to 60 days after transplant participants will return to clinic for a visit that will include a physical examination, routine blood work, a blood draw for future immune tests and a bone marrow biopsy and aspirate to assess their MDS/CMML/AML. Phase 3: Vaccination Participants may begin receiving the GVAX or placebo vaccination between 30 to 60 days following their transplant, provided their blood counts have recovered, and do not have any severe side effects from the transplant. If by day 61, participants' blood counts have not recovered sufficiently, or if they have developed side effects or GVHD from the transplant, and do not meet the conditions necessary to start the vaccination portion of this trial, then they will not receive any vaccinations and will be removed from the study. Participants will continue to receive standard post transplant care. If participants are able to begin the vaccinations between day 30-60 after their transplant, the GVAX or placebo vaccine will be administered as an injection under and into the skin on the forearms or thighs, 6 times over a period of 9 weeks. The first 3 vaccinations will be administered once a week for 3 consecutive weeks and the last 3 vaccines will be given once every other week over 6 weeks. All vaccinations will be given either as an inpatient or outpatient in the clinic. On the days participants receive vaccination, they may have to wait several hours in the clinic while the laboratory makes final preparations on the vaccine/placebo. During this 9 week period of vaccination, participants will continue to be followed by their doctor at least on a weekly basis to monitor for any transplant or possible vaccine side effects. Two to three days after the first and fifth vaccinations, investigators would encourage (but do not require) participants to return to the clinic to have a skin biopsy of the GVAX/Placebo vaccination site, especially if there is redness or swelling in the area. This will allow researchers to assess whether the new immune system is reacting to the injected leukemia cells under the microscope. During the course of the study, investigators will also be drawing participants' blood on a regular basis to evaluate immune cells and the effect that the vaccinations may have on their new immune system. If participants tolerate the vaccinations well, and do not have GVHD or any severe side effects from the transplant or the vaccinations, they will complete a total of 6 vaccines. However, vaccination may be terminated earlier if they develop any side effects (from transplant or vaccination) that do not resolve/improve after 2 weeks, if they develop GVHD that requires steroid treatment, or if their MDS/CMML/AML relapses and need to receive more treatment. Phase 4: Post Vaccination Follow-Up About 1 month after the last vaccination, participants will have a physical examination, blood work, immune bloods and bone marrow biopsy and aspirate to assess the status of Their disease. Participants will be followed at an appointment 6, 9, 12 and 18 months following their transplant with physical examinations, blood work and immune bloods. At the 12 and 18 month visit they will have a bone marrow biopsy and aspirate to assess the status of their AMLCMML//MDS.

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