GVAX vs. Placebo for MDS/AML After Allo HSCT

NCT ID: NCT01773395

Last Updated: 2022-07-18

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 123 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-08
• Study Completion Date: 2021-11-24

Brief Summary

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.

Detailed Description

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.

Conditions

Myelodysplastic Syndrome; Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

GVAX

Intervention Type: BIOLOGICAL

GVAX or placebo vaccination will begin between 30 to 60 days following participant's transplant, provided participant meets vaccination initiation criteria. Only participants in the GVAX arm will receive GVAX vaccine.

Allogeneic Hematopoietic Stem Cell Transplant

Intervention Type: PROCEDURE

Between 1-2 days after participant finishes the chemotherapy, the participant will receive the blood stem cell or marrow from their donor. This is given as a transfusion through a central intravenous line (IV usually placed in the chest or arm).

Busulfan

Intervention Type: DRUG

In this study the condition regimen will include 2 chemotherapy drugs: busulfan (twice a day or four times a day for 5 days) and fludarabine (once daily for 4 days). Depending on participant's age, and other clinical factors, the transplant doctor will decide whether the participant will receive a higher or lower dose of busulfan.

Fludarabine

Intervention Type: DRUG

In this study the condition regimen will include 2 chemotherapy drugs: busulfan (twice a day or four times a day for 5 days) and fludarabine (once daily for 4 days). Depending on participant's age, and other clinical factors, the transplant doctor will decide whether the participant will receive a higher or lower dose of busulfan.

Tacrolimus

Intervention Type: DRUG

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

• Tacrolimus- This will be taken orally twice daily start 3 days before the transplant, and will continue for about 6-9 months.
• Methotrexate- This will be given a short intravenous infusion on days 1, 3, 6, and 11 after the transplant.

Methotrexate

Intervention Type: DRUG

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

• Tacrolimus- This will be taken orally twice daily start 3 days before the transplant, and will continue for about 6-9 months.
• Methotrexate- This will be given a short intravenous infusion on days 1, 3, 6, and 11 after the transplant.

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.

Group Type: PLACEBO_COMPARATOR

Placebo Vaccine

Intervention Type: BIOLOGICAL

GVAX or placebo vaccination will begin between 30 to 60 days following participant's transplant, provided participant meets vaccination initiation criteria. Only participants in the placebo arm will receive placebo vaccine.

Allogeneic Hematopoietic Stem Cell Transplant

Intervention Type: PROCEDURE

Between 1-2 days after participant finishes the chemotherapy, the participant will receive the blood stem cell or marrow from their donor. This is given as a transfusion through a central intravenous line (IV usually placed in the chest or arm).

Busulfan

Intervention Type: DRUG

In this study the condition regimen will include 2 chemotherapy drugs: busulfan (twice a day or four times a day for 5 days) and fludarabine (once daily for 4 days). Depending on participant's age, and other clinical factors, the transplant doctor will decide whether the participant will receive a higher or lower dose of busulfan.

Fludarabine

Intervention Type: DRUG

In this study the condition regimen will include 2 chemotherapy drugs: busulfan (twice a day or four times a day for 5 days) and fludarabine (once daily for 4 days). Depending on participant's age, and other clinical factors, the transplant doctor will decide whether the participant will receive a higher or lower dose of busulfan.

Tacrolimus

Intervention Type: DRUG

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

• Tacrolimus- This will be taken orally twice daily start 3 days before the transplant, and will continue for about 6-9 months.
• Methotrexate- This will be given a short intravenous infusion on days 1, 3, 6, and 11 after the transplant.

Methotrexate

Intervention Type: DRUG

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

• Tacrolimus- This will be taken orally twice daily start 3 days before the transplant, and will continue for about 6-9 months.
• Methotrexate- This will be given a short intravenous infusion on days 1, 3, 6, and 11 after the transplant.

Interventions

GVAX

GVAX or placebo vaccination will begin between 30 to 60 days following participant's transplant, provided participant meets vaccination initiation criteria. Only participants in the GVAX arm will receive GVAX vaccine.

Intervention Type: BIOLOGICAL

Placebo Vaccine

GVAX or placebo vaccination will begin between 30 to 60 days following participant's transplant, provided participant meets vaccination initiation criteria. Only participants in the placebo arm will receive placebo vaccine.

Intervention Type: BIOLOGICAL

Allogeneic Hematopoietic Stem Cell Transplant

Between 1-2 days after participant finishes the chemotherapy, the participant will receive the blood stem cell or marrow from their donor. This is given as a transfusion through a central intravenous line (IV usually placed in the chest or arm).

Intervention Type: PROCEDURE

Busulfan

In this study the condition regimen will include 2 chemotherapy drugs: busulfan (twice a day or four times a day for 5 days) and fludarabine (once daily for 4 days). Depending on participant's age, and other clinical factors, the transplant doctor will decide whether the participant will receive a higher or lower dose of busulfan.

Intervention Type: DRUG

Fludarabine

In this study the condition regimen will include 2 chemotherapy drugs: busulfan (twice a day or four times a day for 5 days) and fludarabine (once daily for 4 days). Depending on participant's age, and other clinical factors, the transplant doctor will decide whether the participant will receive a higher or lower dose of busulfan.

Intervention Type: DRUG

Tacrolimus

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

• Tacrolimus- This will be taken orally twice daily start 3 days before the transplant, and will continue for about 6-9 months.
• Methotrexate- This will be given a short intravenous infusion on days 1, 3, 6, and 11 after the transplant.

Intervention Type: DRUG

Methotrexate

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

• Tacrolimus- This will be taken orally twice daily start 3 days before the transplant, and will continue for about 6-9 months.
• Methotrexate- This will be given a short intravenous infusion on days 1, 3, 6, and 11 after the transplant.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Massachusetts General Hospital

OTHER

Sponsor Role: collaborator

Beth Israel Deaconess Medical Center

OTHER

Sponsor Role: collaborator

Dana-Farber Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Vincent T. Ho, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Vincent Ho, MD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Countries

United States

References

Ho VT, Kim HT, Brock J, Galinsky I, Daley H, Reynolds C, Weber A, Pozdnyakova O, Severgnini M, Nikiforow S, Cutler C, Koreth J, Alyea EP, Antin JH, Gooptu M, Romee R, Shapiro R, Chen YB, Rosenblatt J, Avigan D, Hodi FS, Dranoff G, Wu CJ, Ritz J, Soiffer RJ. GM-CSF secreting leukemia cell vaccination for MDS/AML after allogeneic HSCT: a randomized, double-blinded, phase 2 trial. Blood Adv. 2022 Apr 12;6(7):2183-2194. doi: 10.1182/bloodadvances.2021006255.

Reference Type: DERIVED

PMID: 34807983 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

12-217

Identifier Type: -

Identifier Source: org_study_id