High Dose Thymoglobulin for Graft-versus-Host Disease Prophylaxis

(ATG2017 Trial)

Recruiting at 1 trial location

Overseen By Jan Storek, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Must be taking: ATG, CSA, MTX

Must not be taking: Anti-tuberculosis drugs

Disqualifiers: Myelofibrosis, HIV, Severe obesity, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

200 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether compared to our standard low dose ATG with CSA, the high dose ATG with low-dose CSA minimizes the chances of relapse and chronic GVHD, without increasing the chances of other transplant complications.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, since the trial involves specific treatments and conditions, it's best to discuss your current medications with the trial team to ensure there are no conflicts.

What data supports the effectiveness of the drug Thymoglobulin for preventing graft-versus-host disease?

Research shows that Thymoglobulin, a type of rabbit antithymocyte globulin, is commonly used in stem cell transplants to reduce the risk of graft-versus-host disease. Studies indicate that it is effective in preventing both acute and chronic forms of this condition, with similar efficacy to other formulations in terms of survival rates. ^{1 2 3 4 5}

Is high dose Thymoglobulin generally safe for humans?

Thymoglobulin, also known as rabbit antithymocyte globulin, is generally used to prevent or treat conditions like organ rejection and graft-versus-host disease. While it can cause serum sickness (a type of immune reaction) in most patients without additional drugs, serious allergic reactions are rare. Adverse events during infusion may occur but are not significantly different from other similar treatments. ^{1 3 5 6 7}

How is Thymoglobulin different from other drugs for preventing graft-versus-host disease?

Thymoglobulin is unique because it is a rabbit-derived polyclonal antibody used to suppress the immune system, which helps prevent graft-versus-host disease after stem cell transplants. Unlike other treatments, it is specifically designed to target and reduce the activity of T-cells (a type of immune cell), and its dosage and preparation can vary to optimize patient outcomes. ^{1 2 3 8 9}

Research Team

Jan Storek, MD

Principal Investigator

Tom Baker Cancer Centre

Eligibility Criteria

This trial is for adults over 17 who need their first blood stem cell transplant due to a blood cancer. They must have an HLA matched sibling or almost fully matched unrelated donor, and meet specific health criteria like normal liver function tests. People with previous transplants, certain infections (HIV, high-risk CMV), contact with tuberculosis, severe obesity, or women who are pregnant/breastfeeding or not using contraception can't join.

Inclusion Criteria

I am over 17 and getting my first stem cell transplant for blood cancer with a specific treatment plan.

Exclusion Criteria

Nonmyeloablative conditioning. Cord blood or marrow graft. Myelofibrosis being the primary indication for HCT. Previous autologous or allogeneic HCT. Total Bilirubin >1.5-fold above upper normal limit (UNL), ALT >2.0-fold above UNL, or alkaline phosphatase >2.5-fold above UNL. HIV positive by a serologic test that includes detection of both antibody and antigen. Increased risk of tuberculosis, defined as patient requiring an anti-tuberculosis drug peritransplant. All patients with a history of tuberculosis (active or latent) or contact with a person with active tuberculosis will be evaluated by an infectious disease specialist to determine whether treatment or prophylaxis of tuberculosis with an anti-tuberculosis drug peritransplant is needed. The infectious disease specialist will order tests (eg, Mantoux tuberculin skin test or interferon gamma release test) as needed to arrive at the decision on whether an anti-tuberculosis drug peritransplant is needed. High risk of cytomegalovirus (CMV) disease or recurrent CMViremia based on donor negative AND recipient positive CMV serostatus. If recipient serostatus was determined since the presentation of his/her hematologic malignancy more than once and the results are discrepant, the determination performed >4 weeks after a transfusion of platelets or plasma (or before transfusions of platelets or plasma were initiated) is considered valid. If unclear, the CMV serostatus determination will be at the discretion of the treating Investigator. High risk of PTLD based on donor positive AND recipient negative Epstein-Barr virus (EBV) serostatus (EBNA1 or VCA IgG). Hypersensitivity to rabbit blood protein, Thymoglobulin or a Thymoglobulin excipient. Severe obesity, defined as body mass index ≥40 kg/m2. The reason is that obese patients are at risk of achieving a high ATG area under the time vs concentration curve (AUC). This could lead to substantial toxicity (e.g., death due to an infection) when using the studied high dose (10 mg/kg) of ATG. Contraindication to methotrexate: Hypersensitivity to methotrexate or to any ingredient in the formulation or component of the container. Females of childbearing potential who are pregnant, breastfeeding or unwilling to use adequate contraception from the time of enrolment until at least day 100 posttransplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

High dose ATG is infused on days -4, -3, -2, -1, and 0. CSA is given from day 21 to 84, and methotrexate is administered on days 1, 3, 6, and 11.

12 weeks

Multiple visits for infusions and monitoring

Follow-up

Participants are monitored for the development of acute and chronic GVHD, and for relapse. Quality of life is assessed 2 years post-transplant.

2 years

Treatment Details

Interventions

• Thymoglobulin

Trial Overview The study compares two approaches to prevent graft-versus-host disease after a stem cell transplant: the usual low dose of Thymoglobulin plus standard drugs versus a high dose of Thymoglobulin with a lower dose of these drugs. The goal is to see if the higher Thymoglobulin dose better prevents relapse and chronic disease without increasing other complications.

Participant Groups

Group I: Treatment Arm - High dose ATG, Low dose CSA Experimental Treatment 1 Intervention

High dose ATG will be infused on days -4, -3, -2, -1 and 0. Before each infusion of ATG (thymoglobulin), patient will receive medications preventing side effects from the ATG, including diphenhydramine (Benadryl), an antipyretic (ibuprofen or acetaminophen) and methylprednisolone (Solumedrol). The high dose ATG will be given into patient's vein via central venous catheter. Each infusion of ATG will take 4-8 hours. CSA (cyclosporine A) will be given from day 21. Standard dose methotrexate will be given.

Group II: Control Arm - Standard of care Experimental Treatment 1 Intervention

Low dose ATG (thymoglobulin) will be infused on days -2, -1 and 0, and CSA (cyclosporine A) will be given from day -1 through day 84. Standard dose methotrexate will also be given.

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

Approved in United States as Thymoglobulin for:

• Prophylaxis and treatment of renal transplant acute rejection in conjunction with concomitant immunosuppression
• Severe aplastic anemia

Approved in European Union as Thymoglobulin for:

• Prevention and treatment of acute cellular rejection after renal transplantation
• Severe aplastic anemia

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Findings from Research

Rabbit-derived antithymocyte globulin (ATG) can induce a strong immune response in patients, leading to the production of antibodies against specific rabbit glycoprotein epitopes, which may compromise its effectiveness in treating conditions like type 1 diabetes.

The study found that patients developed significant levels of antibodies against these rabbit-specific epitopes after ATG treatment, suggesting that using IgGs without these xenoantigens could enhance the safety and efficacy of ATG therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. Salama, A., Evanno, G., Lim, N., et al.[2022]

In a study of 352 patients undergoing HLA-mismatched allogeneic hematopoietic stem cell transplantation, low to medium doses of rabbit anti-thymocyte globulin (ATG) (2.5 to 7.5 mg/kg) were associated with higher 5-year overall survival rates compared to other doses.

Patients receiving low to medium doses of ATG also experienced lower rates of extensive chronic graft-versus-host disease (ecGVHD), suggesting that these doses improve patient outcomes without increasing relapse rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical impact of anti-thymocyte globulin on survival and graft-versus-host disease in patients undergoing human leukocyte antigen mismatched allogeneic stem cell transplantation. Kim, T., Choi, Y., Lee, JH., et al.[2021]

In a study involving 59 pediatric patients undergoing allogeneic hematopoietic stem cell transplantation, high doses of rabbit antithymocyte globulin (ATG-G) were found to significantly impair the regeneration of T cell subsets compared to ATG-F, particularly affecting CD8(+) and CD4(+) T cells.

Patients treated with ATG-G showed an increased risk of Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorder (PTLD), indicating that ATG-G may pose greater safety concerns than ATG-F in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of different rabbit ATG preparation effects on early lymphocyte subset recovery after allogeneic HSCT and its association with EBV-mediated PTLD. Mensen, A., Na, IK., Häfer, R., et al.[2021]

A systematic review of 6 phase III randomized controlled trials found that rabbit antithymocyte globulin (ATG) formulations, particularly anti-T lymphocyte globulin (ATLG), are effective in preventing graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, showing significantly better outcomes compared to standard treatments.

While both ATLG and Thymoglobulin (Thymo) had similar effects on transplantation-related mortality, Thymo showed a trend towards better overall survival, suggesting that Thymo may be a preferable option for improving long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Different Rabbit Anti-Thymocyte Globulin Formulations in Allogeneic Stem Cell Transplantation: Systematic Literature Review and Network Meta-Analysis. Gagelmann, N., Ayuk, F., Wolschke, C., et al.[2018]

A study comparing four batches of antithymocyte globulins (ATGs) showed that both ATG-Fresenius and Thymoglobulin had consistent binding and functional properties when interacting with human leukocytes, suggesting similar clinical efficacy across different batches.

The research utilized flow cytometric assays to analyze the reactivity of ATGs with leukocytes, indicating that variations in batch preparation are unlikely to impact their effectiveness in preventing allograft rejection and graft versus host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of batch to batch variation in polyclonal antithymocyte globulin preparations. Popow, I., Leitner, J., Majdic, O., et al.[2014]

A serious anaphylactic reaction occurred in a patient during renal transplantation after the first injection of Thymoglobulin, highlighting the potential risk even though such reactions are rare.

The case emphasizes the need for thorough allergy screening for rabbit allergens in patients before administering Thymoglobulin, as it is contraindicated in individuals with a history of hypersensitivity to rabbit proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An avoidable cause of thymoglobulin anaphylaxis. Brabant, S., Facon, A., Provôt, F., et al.[2020]

In a study of 30 patients undergoing allogeneic hematopoietic stem cell transplantation, Thymoglobulin and ATG-F showed comparable outcomes in terms of overall survival, disease-free survival, and transplant-related complications after a median follow-up of 3.3 years.

Although adverse events were more frequently reported during Thymoglobulin infusion, the difference was not statistically significant, suggesting that both treatments are similarly safe and effective for preventing graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies. Paiano, S., Roosnek, E., Tirefort, Y., et al.[2020]

The study found that mATG effectively depletes T cells in the blood, spleen, lymph nodes, and bone marrow within one day at doses as low as 1 mg/kg, indicating its strong immunosuppressive capability.

Despite its effectiveness in depleting T cells, mATG does not deplete thymocytes in vivo, suggesting limited access to the thymus, and it preferentially depletes naïve T cells while sparing other immune cell types like B cells and macrophages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin. Ruzek, MC., Neff, KS., Luong, M., et al.[2021]

In a study comparing two doses of antithymocyte globulin (7.5 mg/kg vs 10 mg/kg) in patients undergoing haploidentical hematopoietic stem cell transplantation, both doses showed similar effectiveness in preventing graft-versus-host disease, with no significant differences in acute or chronic cases.

The lower dose of 7.5 mg/kg was associated with a trend towards a reduced incidence of hemorrhagic cystitis compared to the higher dose, suggesting it may be a safer option without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of 2 Different Doses of Antithymocyte Globulin in Conditioning Regimens for Haploidentical Hematopoietic Stem Cell Transplantation. Wang, M., Fang, X., Jiang, Y., et al.[2022]

References

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

Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. [2022]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Clinical impact of anti-thymocyte globulin on survival and graft-versus-host disease in patients undergoing human leukocyte antigen mismatched allogeneic stem cell transplantation. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

Comparison of different rabbit ATG preparation effects on early lymphocyte subset recovery after allogeneic HSCT and its association with EBV-mediated PTLD. [2021]

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

Comparison of Different Rabbit Anti-Thymocyte Globulin Formulations in Allogeneic Stem Cell Transplantation: Systematic Literature Review and Network Meta-Analysis. [2018]

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

Assessment of batch to batch variation in polyclonal antithymocyte globulin preparations. [2014]

6. England pubmed.ncbi.nlm.nih.gov

An avoidable cause of thymoglobulin anaphylaxis. [2020]

7. Egypt pubmed.ncbi.nlm.nih.gov

Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies. [2020]

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

In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin. [2021]

9. Turkey pubmed.ncbi.nlm.nih.gov

Comparison of 2 Different Doses of Antithymocyte Globulin in Conditioning Regimens for Haploidentical Hematopoietic Stem Cell Transplantation. [2022]