ATG Dosing for Blood Cancer

Overseen By Razan Mohty, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alabama at Birmingham

Must be taking: Tacrolimus, Methotrexate

Must not be taking: Investigational drugs

Disqualifiers: HIV, Cirrhosis, 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: 6

Duration: 1 week

56 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should not have received any investigational drugs within 14 days prior to the first day of transplant conditioning.

What data supports the effectiveness of the drug ATG (Anti-Thymocyte Globulin) for blood cancer?

Research shows that ATG can reduce severe acute and chronic graft-versus-host disease (GVHD) in patients undergoing stem cell transplantation, which is often part of blood cancer treatment. In a study, low-dose ATG significantly lowered the incidence of severe GVHD, suggesting its potential benefit in managing complications related to blood cancer therapies. ^{1 2 3 4 5}

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

ATG, also known as Thymoglobulin, has been used safely in humans for various conditions, including organ transplantation and aplastic anemia. Common side effects include fever, cytokine release syndrome (a reaction that can cause fever and low blood pressure), and blood-related issues like low platelet or white blood cell counts. While some patients experience adverse effects, these are often manageable, and the treatment is generally considered safe with proper monitoring. ^{3 5 6 7 8}

How is the drug ATG (Thymoglobulin) unique in treating blood cancer?

ATG (Thymoglobulin) is unique because it is an immunosuppressive drug that targets T-cells, which are part of the immune system, and is used in various conditions like aplastic anemia and organ transplantation. Its dosing and administration are still being optimized, and it can mediate cell destruction at very low concentrations, making it different from other treatments that may not specifically target T-cells. ^{3 7 9 10 11}

What is the purpose of this trial?

In an effort to reduce graft versus host disease (GVHD) and enhance graft versus leukemia (GVL) effect post allogenic hematopoietic stem cell transplantation (AHSCT), recent research has focused on host immune cell depletion. Frame shifting anti-thymocyte globulin (ATG) backwards to earlier days before days 0 can result in deeper host and less graft T-cell depletion, leading to better immune reconstitution. Preliminary data where 80% of the ATG dose is given on days -6,-5,-4 and 20% given on day -1, showed effective prevention of severe acute GVHD, chronic GVHD and favorable early immune reconstitution. We hypothesize that our 2 step ATG dosing platform when combined with standard tacrolimus and mini methotrexate can prevent grade III-IV acute GVHD and chronic GVHD, resulting in improvement of GVHD/relapse free survival at one year post transplant.

Research Team

Razan A Mohty, MD

Principal Investigator

The University of Alabama at Birmingham

Eligibility Criteria

This trial is for individuals with acute leukemia, myeloproliferative disorders, preleukemia, or myelodysplastic syndromes who are undergoing allogeneic stem cell transplant. The study aims to prevent severe graft versus host disease (GVHD). Specific eligibility criteria details were not provided.

Inclusion Criteria

Willingness to sign informed consent and abide by protocol requirements

My lung function tests show at least half the normal capacity.

My liver tests are within the required range.

Exclusion Criteria

I had a stem cell transplant using my own cells less than 3 months ago.

I have had a stem cell transplant from a donor.

I do not have uncontrolled heart problems or abnormal heart rhythms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 2 step ATG dosing combined with tacrolimus and mini methotrexate for prevention of acute GVHD

1 week

Multiple visits for ATG administration on days -6, -5, -4, and -1

Follow-up

Participants are monitored for safety and effectiveness after treatment, focusing on GVHD/relapse free survival

1 year

Treatment Details

Interventions

• ATG

Trial Overview The trial tests a new way of giving anti-thymocyte globulin (ATG) in two steps before the transplant to reduce GVHD while improving immune response and survival without relapse or GVHD at one year post-transplant. It's combined with standard tacrolimus and mini methotrexate.

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 GRFS rate at one-year post transplant. GRFS will be estimated using Kaplan Meier method The reported GRFS with recent phase III trial of PTCY/tac/MMF in transplant from matched related and unrelated donors at 1 year follow up was 52%. We hypothesize that with 2 step ATG/Tac/Mini MTX regimen, we can achieve a one year GRFS of 69%.

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 study of 24 patients with aplastic anemia, the survival rates at 6 months varied among different anti-thymocyte globulin (ATG) preparations, with Lymphoglobulin showing the highest survival rate at 77.8%.

None of the patients treated with ATG-Fresenius (ATG-F) responded to the treatment, indicating it is significantly less effective and should not be used for severe aplastic anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of Jurkat cell-reactive anti-T lymphocyte globulin and fetal anti-thymocyte globulin preparations in the treatment of aplastic anemia. Serefhanoglu, S., Buyukasik, Y., Purnak, T., et al.[2011]

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 29 patients receiving anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG) for aplastic anemia, 62.1% experienced adverse effects, with fever being the most common.

ATG, which is rabbit-derived, was associated with more frequent adverse effects compared to ALG, and shorter intervals between treatment cycles increased the risk of these reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adverse effects of anti-thymocyte globulin/anti-lymphocyte globulin therapy]. Kobayashi, R., Kaneda, M., Watanabe, N., et al.[2006]

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]

References

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

Pharmacokinetics and pharmacodynamics of two antithymocyte globulins in treatment of pediatric aplastic anemia. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

A comparison of Jurkat cell-reactive anti-T lymphocyte globulin and fetal anti-thymocyte globulin preparations in the treatment of aplastic anemia. [2011]

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

Perioperative effects of high doses of intraoperative thymoglobulin induction in liver transplantation. [2020]

4. England pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

Disease-specific impact of anti-thymocyte globulin in allogeneic hematopoietic cell transplantation: a nationwide retrospective study on behalf of the JSTCT, transplant complications working group. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

[Adverse effects of anti-thymocyte globulin/anti-lymphocyte globulin therapy]. [2006]

7. Japan pubmed.ncbi.nlm.nih.gov

Efficacy of combination therapy with anti-thymocyte globulin and cyclosporine A as a first-line treatment in adult patients with aplastic anemia: a comparison of rabbit and horse formulations. [2018]

8. Romania pubmed.ncbi.nlm.nih.gov

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

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

Monitoring of CD3(+) T-cell count in patients receiving antithymocyte globulin induction after cadaveric renal transplantation. [2017]

10. England pubmed.ncbi.nlm.nih.gov

Effect of plasmapheresis on ATG (Thymoglobulin) clearance prior to adoptive T cell transfer. [2022]

11. France pubmed.ncbi.nlm.nih.gov

[Severe quantitative bone marrow insufficiency: results of treatment with high-dose antilymphocyte serum]. [2016]