GVAX vs. Placebo for MDS/AML After Allo HSCT

• Safety and toxicity of vaccination, as measured by the development of grade II-IV and III-IV acute graft versus host disease, CTC grade 3 and higher non-hematologic toxicity, or grade 4 and higher hematologic toxicity attributable to vaccination [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  Assessment of the safety of vaccination following allogeneic (ablative or reduced intensity) stem cell transplantation
• Incidence of acute and chronic GVHD [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Assessment of incidence fof grade 2-4 and grade 3-4 acute GVHD, and chronic GVHD after vaccination following allogeneic stem cell transplantation
• PFS after start of vaccination [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Assessment of PFS after start of vaccination
• Relapse and non-relapse mortality [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Assessment of relapse and non-relapse mortality after vaccination
• Overall Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Assessment of overall survival after vaccination
• Biologic activity of GVAX vs. Placebo as assessed by laboratory and histologic analyses of blood before and after vaccination. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Assessment of the biologic activity of GVAX as compared to placebo vaccination after HSCT

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 your MDS or AML from relapsing after your 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 hte vaccine is effective. It also means that the FDA has not yet approved the vaccine for your type of cancer.

You are being asked to participate in this trial because you have advanced myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Your doctor has determined that you are a candidate for an allogeneic stem cell transplant as treatment for your MDS/AML. Allogeneic stem cell transplantation is a standard treatment for MDS/AML. It can be effective because the cells from your donor (also known as the graft) could from a new immune system that can fight against the MDS/AML cells in your body. This is also known as the "graft-versus-leukemia" or "GVL" effect. In patients with advanced MDS or AML that is not in remission at the time of transplantation, as in your case, 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 your 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.

If you participate in this research study, you will be "randomized" to receive either GVAX vaccination or placebo (a saline solution) vaccination. Randomization means that you are put into a group by chance. It is like flipping a coin. There is a 50% chance that you will receive the GVAX vaccine and a 50% chance you will receive placebo. Neither you nor your transplant doctor(s) will know which you 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 enrollment.

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 you will undergo some screening tests to find out if you 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 you are eligible to participate in the research study, you will be enrolled on the trial and randomized to receive either the GVAX vaccine or the placebo vaccine after your transplant. After enrolling in the study you 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 you are admitted to the hospital to receive the chemotherapy and stem cell transplant. In the week before you receive the stem cells, you 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 your immune system so that the donor blood stem cells will not be rejected after transplantation. The chemotherapy may also reduce the number of MDS/AML cancer cells in your 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 your age and other clinical factors, your transplant doctor will decide whether you receive a higher or lower dose of busulfan. Between 1-2 days after you finish the chemotherapy, you will receive the blood stem cell or marrow from your donor. This is given as a transfusion through a central intravenous line (IV usually placed in your chest or arm).

Just prior to and immediately following the infusion of stem cells, you will receive medications to help prevent graft-versus-host disease (GVHD), a common complication of transplant where your donor's immune cells attack your body. The medications you will receive to prevent GVHD will include Tacrolimus and Methotrexate.

You will be closely monitored as per standard transplant care after your stem cell transplant. If you received the higher dose chemotherapy conditioning, you will stay in the hospital for an average of about 3-4 weeks. If you received the lower dose conditioning transplant, your hospital admission for transplant may be shorter, depending on your clinical condition.

After your stem cell infusion, you may receive daily injections of a medication called rhGM-CSF, or Leukine, to help your white blood cells to recover faster. You may receive this medication for up to 2 weeks. You will also be given antiviral and antibiotic medications to prevent infections as per standard practice after transplantation.

Between 20 to 30 days after your stem cell infusion you will have a physical examination, routine blood work and a blood draw for future immune tests.

Between 30 to 45 days after your transplant you 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 your MDS/AML.

Phase 3: Vaccination You may begin receiving the GVAX or placebo vaccination between 30 to 45 days following your transplant, provided your blood counts have recovered, and you do not have any severe side effects from the transplant. If by day 46, your blood counts have not recovered sufficiently, or if you have developed side effects or GVHD from the transplant, and do not meed the conditions necessary to start the vaccination portion of this trial, then you will not receive any vaccinations, and you will be removed from the study. You will continue to receive standard post transplant care.

If you are able to begin the vaccinations between day 30-45 after your transplant, the GVAC or placebo vaccine will be administered as an injection under and into the skin on your 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 as an outpatient in the clinic. On the days you are receiving vaccination, you 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, you will continue to be followed by your doctor at least on a weekly basis to monitor for any transplant of possible vaccine side effects.

Before the first and after the fifth and sixth vaccinations, a small amount of your own leukemia cells (previously collected before transplant and killed with radiation) will be injected under your skin (like a TB test) to see if your body will react against it and cause redness and/or swelling. This is called a delayed-type hypersensitivity (DTH) test. Two to three days after the DTH test, we would encourage you (but not require you) to return to the clinic to have a skin biopsy of the DTH injection site. This will allow researchers to assess whether your new immune system is reacting to the injected leukemia cells under the microscope. At the same time, we may perform a skin biopsy of the GVAX/Placebo vaccination site, especially if there is redness or swelling in the area.

During the course of the study, we will also be drawing your blood on a regular basis to evaluate immune cells and the effect that the vaccinations may have on your new immune system.

If you tolerate the vaccinations well, and do not have GVHD or any severe side effects from the transplant or the vaccinations, you will complete a total of 6 vaccines. However, your vaccination may be terminated earlier if you develop any side effects (from transplant or vaccination) that do not resolve/improve after 2 weeks, or you develop GVHD that requires steroid treatment, or if your MDS/AML relapses and you need to receive more treatment.

Phase 4: Post Vaccination Follow-UP About 1 month after your last vaccination, you will have a physical examination, blood work, immune bloods and bone marrow biopsy and aspirate to assess the status of your disease.

You will also be followed 6, 9, 12 and 18 months following your transplant with physical examinations, blood work and immune bloods. At the 12 and 18 month visit you will also ahve a bone marrow biopsy and aspirate.

• Myelodysplastic Syndrome
• Acute Myeloid Leukemia

• Biological: GVAX
• Biological: Placebo Vaccine
• Procedure: Allogeneic Hematopoietic Stem Cell Transplant
• Drug: Busulfan
• Drug: Fludarabine
• Drug: Tacrolimus
• Drug: Methotrexate

• Active Comparator: GVAX
  GVAX vaccine
  Interventions:

  • Biological: GVAX
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplant
  • Drug: Busulfan
  • Drug: Fludarabine
  • Drug: Tacrolimus
  • Drug: Methotrexate
• Placebo Comparator: Placebo
  Placebo vaccine
  Interventions:

  • Biological: Placebo Vaccine
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplant
  • Drug: Busulfan
  • Drug: Fludarabine
  • Drug: Tacrolimus
  • Drug: Methotrexate

Inclusion Criteria:

• AML, MDS-RAEB not in remission prior to admission for transplant
• HLA 8/8 matched related or unrelated donor available
• Suitable candidate for myeloablative or reduced intensity conditioning allogeneic HSCT using PBSC or marrow as stem cell resource
• ECOG performance status of 0-2
• Normal organ function

Exclusion Criteria:

• Pregnant or breastfeeding
• Leukemia with active CNS involvement
• Positive HIV or HTLV-1 serology
• Prior allogeneic stem cell transplantation
• 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 previous two years