ATG Combination Therapy for Acute GVHD

Overseen By Margaret A Thomas, MPH

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alabama at Birmingham

Must not be taking: Investigational drugs

Disqualifiers: HIV, Non-hematologic malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 1 week

29 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug ATG (Anti-Thymocyte Globulin) for treating acute GVHD?

Research shows that low-dose ATG can reduce the incidence of severe acute and chronic GVHD in patients undergoing stem cell transplantation, particularly when used as a preventive measure. However, in cases of severe acute GVHD, ATG did not show additional benefits over conventional treatments. ^{1 2 3 4 5}

Is ATG (Anti-Thymocyte Globulin) generally safe for humans?

ATG, also known as Thymoglobulin, has a proven safety profile in various treatments, including organ transplantation and GVHD prevention. Common side effects include cytokine release syndrome (a reaction that can cause fever and chills), low platelet count, and low white blood cell count. While there is a risk of infections, modern antiviral treatments can help manage this. ^{1 2 4 6 7}

How is the drug ATG different from other treatments for acute GVHD?

ATG (Anti-Thymocyte Globulin) is unique because it is used to prevent and treat graft-versus-host disease (GVHD) by targeting and reducing the activity of T-cells (a type of immune cell) that cause the condition. Unlike some other treatments, ATG can be used in different doses and has been shown to reduce the severity of both acute and chronic GVHD, especially in patients undergoing stem cell transplantation. ^{1 2 6 8 9}

What is the purpose of this trial?

The purpose of this study is to test whether the combination of the drugs called tacrolimus (Tac), methotrexate (MTX) and new dosing strategy of another drug called (rabbit Anti-thymocyte Globulin \[ATG\]) will help prevent the development and/or improve severity of acute and/or chronic GVHD.

Eligibility Criteria

This trial is for individuals with conditions like Myelodysplastic Syndrome, Preleukemia, or Acute Leukemia who are undergoing a myeloablative allogeneic stem cell transplant. The goal is to prevent acute Graft-versus-Host Disease (GVHD). Specific eligibility criteria details were not provided.

Inclusion Criteria

Calculated creatinine clearance greater than 50 mL/minute

I can carry out normal activities with minimal symptoms.

My liver tests are within the required range.

Exclusion Criteria

Pregnant and/or breastfeeding

Participation in another clinical study with an investigational product during the last 28 days

Known hypersensitivity to the study agent (ATG)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a 2-step ATG dosing regimen combined with tacrolimus and mini methotrexate to prevent acute GVHD post myeloablative allogeneic stem cell transplant

1 week

Multiple visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including immune cell recovery and GVHD prevention

1 year

Regular visits for immune monitoring

Treatment Details

Interventions

• ATG

Trial Overview The study tests if using Anti-thymocyte Globulin (ATG) in a new dosing strategy along with Tacrolimus and Mini Methotrexate can prevent or lessen the severity of acute and/or chronic GVHD after stem cell transplant.

Participant Groups

Group I: phase II single arm study of 2 step ATG dosing in prevention of aGVHD. Experimental Treatment 1 Intervention

The primary outcome for the study is rate of GRFS at one-year post transplant. When accounting for competing risks, any death, relapse, Grade III-IV acute GVHD and cGVHD requiring systemic therapy are competing risks. The reported one year GRFS with the use of standard of care GVHD prevention regimen in MA HSCT (Tac/MTX) was 35%. (El-Jurdi 2023) We hypothesize that with 2 step ATG/Tac/Mini MTX regimen, we can achieve a one year GRFS of 60%.

ATG is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Thymoglobulin for:

• Prevention and treatment of acute rejection in patients undergoing kidney transplantation
• Treatment of aplastic anemia in patients who are not candidates for bone marrow transplantation

Approved in European Union as Thymoglobulin for:

• Prevention and treatment of acute rejection in patients undergoing kidney transplantation
• Treatment of aplastic anemia in patients who are not candidates for bone marrow transplantation

Approved in Canada as Thymoglobulin for:

• Prevention and treatment of acute rejection in patients undergoing kidney transplantation
• Treatment of aplastic anemia in patients who are not candidates for bone marrow transplantation

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Findings from Research

In a multicenter phase II study involving 77 patients undergoing HLA-matched peripheral blood stem cell transplantation (PBSCT), low-dose anti-thymocyte globulin (ATG) significantly reduced the incidence of severe acute graft-versus-host disease (GVHD) to just 1.4% at 100 days, well below the predefined threshold of 18%.

The study also reported a low incidence of chronic GVHD at one year, with only 15.3% of patients experiencing all-grade chronic GVHD and 5.6% experiencing moderate to severe cases, indicating that low-dose ATG is effective in minimizing both acute and chronic GVHD risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose anti-thymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation. Shiratori, S., Sugita, J., Ota, S., et al.[2021]

In a study of 209 patients undergoing allogenic hematopoietic cell transplantation, a single low dose of anti-thymocyte globulin (ATG) significantly reduced the incidence of chronic graft versus host disease (cGVHD) compared to those who did not receive ATG, with rates of 10.1% versus 25%.

Despite the reduction in cGVHD, the use of low dose ATG did not affect overall survival or relapse-free survival rates, indicating that it may be a safe option to minimize cGVHD without compromising patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes with low dose anti-thymocyte globulin in patients undergoing matched unrelated donor allogeneic hematopoietic cell transplantation. Mountjoy, L., Jain, T., Kunze, KL., et al.[2021]

Thymoglobulin is a safe and effective treatment for preventing acute rejection in organ transplantation, with common side effects including cytokine release syndrome and thrombocytopenia, but recent studies suggest that antiviral prophylaxis can mitigate the risk of cytomegalovirus disease associated with its use.

Thymoglobulin may offer advantages over horse ATG in treating aplastic anemia and can reduce the incidence of acute and chronic graft-versus-host disease (GvHD) in patients receiving stem cell transplants, indicating its potential as a versatile immunosuppressant in various therapeutic contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thymoglobulin--new approaches to optimal outcomes. Moicean, AD., Popp, AM., Sinescu, I.[2021]

In a study involving 203 patients undergoing haemopoietic cell transplantation, pretreatment with anti-thymocyte globulin (ATG) significantly increased the likelihood of being free from long-term immunosuppressive treatment after 12 months, with 37% of the ATG group achieving this compared to only 16% in the control group.

While ATG treatment was associated with a higher incidence of Epstein-Barr virus reactivation, the overall safety profile was acceptable, as serious adverse events were similar between the ATG and control groups, indicating that ATG can be safely integrated into transplant regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Walker, I., Panzarella, T., Couban, S., et al.[2017]

References

1. Denmark pubmed.ncbi.nlm.nih.gov

Treatment of severe acute graft-versus-host disease with anti-thymocyte globulin. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Low-dose anti-thymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Low dose anti-thymocyte globulin reduces chronic graft-versus-host disease incidence rates after matched unrelated donor transplantation. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Clinical outcomes with low dose anti-thymocyte globulin in patients undergoing matched unrelated donor allogeneic hematopoietic cell transplantation. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Low-dose thymoglobulin for prevention of chronic graft-versus-host disease in transplantation from an HLA-matched sibling donor. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Low-dose anti-thymocyte globulin reduce severe acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. [2018]

7. Romania pubmed.ncbi.nlm.nih.gov

Thymoglobulin--new approaches to optimal outcomes. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The impact of different doses of antithymocyte globulin conditioning on immune reconstitution upon hematopoietic stem cell transplantation. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. [2017]