High dose thymoglobulin for preventing graft-versus-host disease

A Phase 2, Open-label Study to Evaluate Graft-vs-host Disease Prophylaxis With High Dose Thymoglobulin, Methotrexate, and Low-dose Cyclosporine in Comparison to Historical/Concurrent Controls Who Received Low Dose Thymoglobulin, Methotrexate, and High-dose Cyclosporine

This study is testing if giving a high dose of thymoglobulin along with a low dose of cyclosporine can help prevent graft-versus-host disease in patients receiving a stem cell transplant.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 200 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: AHS Cancer Control Alberta (other)
• Drugs / interventions: methotrexate, fludarabine
• Locations: 1 site (Calgary, Alberta)
• Trial ID: NCT03456817 on ClinicalTrials.gov

What this trial studies

This study aims to evaluate the effectiveness of high dose thymoglobulin (ATG) combined with a low dose of cyclosporine (CSA) in preventing graft-versus-host disease (GVHD) and relapse in patients undergoing allogeneic hematopoietic cell transplantation. The approach involves administering high dose ATG over five days prior to the transplant, while CSA will be given starting from day 21 post-transplant, differing from the standard treatment regimen. Patients will be monitored for the development of acute and chronic GVHD, as well as relapse, and will complete quality of life questionnaires to assess their well-being. The goal is to minimize complications associated with the transplant without increasing the risk of acute GVHD.

Who should consider this trial

Good fit: Ideal candidates for this study are adults over 17 years old undergoing their first allogeneic hematopoietic cell transplantation for hematologic malignancies with an HLA-matched donor.

Not a fit: Patients who have undergone previous transplants, those receiving nonmyeloablative conditioning, or those with specific contraindications such as high bilirubin levels may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly reduce the incidence of relapse and chronic GVHD in transplant patients, improving their overall survival and quality of life.

How similar studies have performed: While the approach of using high dose ATG is being explored, it is a novel strategy compared to standard low dose ATG and CSA regimens, with limited prior studies demonstrating its effectiveness.

Eligibility criteria

Inclusion Criteria:

1. First allogeneic HCT, performed for a hematologic malignancy, using filgrastim-mobilized peripheral blood stem cells (PBSC).
2. Conditioning with fludarabine 50 mg/m2 daily on day -6 to -2, busulfan approximately 3.2 mg/kg daily on day -5 to -2 with PK adjustment (target AUC of 3750 uM\*min/L) and total body irradiation (TBI) 2 Gy x 2 given typically on day -1 and/or day 0 (before graft infusion), ie, our standard myeloablative conditioning.79 Dose and schedule adjustments per Investigator discretion are permitted.
3. Planned GVHD prophylaxis with our standard of low-dose ATG (4.5 mg/kg) + MTX + high-dose CSA.
4. HLA matched sibling donor, or ≥7/8 HLA allele-matched unrelated donor (maximum 1 allele mismatch at HLA-A, B, C, or DRB1).
5. Age \>17 years.

Exclusion Criteria:

1. Nonmyeloablative conditioning.
2. Cord blood or marrow graft.
3. Myelofibrosis being the primary indication for HCT.
4. Previous autologous or allogeneic HCT.
5. Total Bilirubin \>1.5-fold above upper normal limit (UNL), ALT \>2.0-fold above UNL, or alkaline phosphatase \>2.5-fold above UNL.
6. HIV positive by a serologic test that includes detection of both antibody and antigen)
7. 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.
8. High risk of cytomegalovirus (CMV) disease or recurrent CMViremia based on donor negative AND recipient positive CMV serostatus.2 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
9. High risk of PTLD based on donor positive AND recipient negative Epstein-Barr virus (EBV) serostatus (EBNA1 or VCA IgG)80
10. Hypersensitivity to rabbit blood protein, Thymoglobulin or a Thymoglobulin excipient.
11. Severe obesity, defined as body mass index ≥40 kg/m2.81 The reason is that obese patients are at risk of achieving a high ATG area under the time vs concentration curve (AUC).82 This could lead to substantial toxicity (e.g., death due to an infection) when using the studied high dose (10 mg/kg) of ATG.
12. Contraindication to methotrexate:

    1. Hypersensitivity to methotrexate or to any ingredient in the formulation or component of the container.
    2. 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.

Where this trial is running

Calgary, Alberta

• Tom Baker Cancer Centre/Arthur J.E. Child Comprehensive Cancer Centre — Calgary, Alberta, Canada (RECRUITING)

Study contacts

• Principal investigator: Jan Storek, MD — Tom Baker Cancer Centre
• Study coordinator: Jan Storek, MD

Conditions: Graft-versus-host-disease, Relapse