NCT02867800

Abatacept for GVHD Prophylaxis After Hematopoietic Stem Cell Transplantation for Pediatric Sickle Cell Disease

Abatacept for Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation for Pediatric Sickle Cell Disease: a Sickle Transplant Alliance for Research Trial

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 24 (actual)
• Sponsor: Monica Bhatia · Academic / Other
• Sex: All
• Age: 3 Years – 20 Years
• Healthy volunteers: Not accepted

Summary

To assess the tolerability of the costimulation blocking agent abatacept (CTLA4-Ig) when added to the standard graft versus host disease (GVHD) prophylaxis regimen of a calcineurin inhibitor and methotrexate in patients receiving early alemtuzumab followed by fludarabine, thiotepa, melphalan, and alemtuzumab for conditioning.

Detailed description

Outcomes of hematopoietic stem cell transplantation (HSCT) for children and adolescents with sickle cell disease (SCD) have improved. Graft versus host disease (GVHD), however, remains a barrier to success. GVHD accounts for most of the transplant related mortality and much of the morbidity in this setting-in part through the injury it directly causes and in part through the deleterious effects of steroids and the other immunosuppressive agents used to prevent and treat it. The results of pre-clinical studies and a phase I clinical study in patients with hematologic malignancies suggest that the costimulation blocking agent CTLA4-Ig may hold promise an agent for GVHD prophylaxis. In the present trial, the investigators are assessing the tolerability of adding abatacept to standard GVHD prophylaxis-a calcineurin inhibitor and methotrexate-in pediatric SCD patients receiving early alemtuzumab (completed by day -18) followed by fludarabine, thiotepa, and melphalan for conditioning. This trial will provide the foundation for subsequent trials designed to test the long-term hypothesis that abatacept is a safe, steroid-sparing effective adjunct to standard GVHD prophylaxis in this setting.

Conditions

• Sickle Cell Disease
• Graft Versus Host Disease

Interventions

Type	Name	Description
DRUG	Diphenhydramine	(Standard of Care) Premedication Diphenhydramine: 1 mg/kg IV or PO q 8 hours (maximum=50 mg)
DRUG	Acetaminophen	(Standard of Care) Premedication Acetaminophen: 10-15 mg/kg PO q 6 hours (maximum=1000 mg)
DRUG	Methylprednisolone	(Standard of Care) Premedication Methylprednisolone: 0.25-0.5 mg/kg IV q 6 hours
DRUG	Meperidine	(Standard of Care) Premedication Use as needed (PRN) Meperidine: 0.5 mg/kg IV q 4-6 hours (for rigors)
DRUG	Alemtuzumab	(Standard of Care) Immunosuppression Alemtuzumab: A test dose of alemtuzumab, 3 mg, should be administered IV over 2 hours the first day. If the test dose is tolerated, administration of three treatment doses should begin within 24 hours. The three treatment doses should be administered on consecutive days. 10 mg/m2 should be given the first day, 15 mg/m2 the second and 20 mg/m2 the third.
DRUG	Thymoglobulin	(Standard of Care) Immunosuppression Thymoglobulin: A 4 mg/kg dose of anti-thymocyte globulin should be administered in place of each alemtuzumab dose not completed.
DRUG	Fludarabine	(Standard Conditioning Regimen) Fludarabine should be administered 30 mg/m2 IV daily for five days. It should be infused over 30 to 60 minutes.
DRUG	Melphalan	(Standard Conditioning Regimen) Melphalan should be administered 140 mg/m2 IV 3 days before marrow infusion. It should be infused within 60 minutes of preparation and over a maximum of 30 minutes. It should be infused immediately after the fludarabine infusion is complete.
DRUG	Thiotepa	(Standard Conditioning Regimen) Thiotepa should be administered 8 mg/kg IV 3 days before marrow infusion. It should be infused immediately after the fludarabine infusion is complete. The thiotepa should be infused over one hour.
DRUG	Cyclosporine	(Standard GVHD Prophylaxis) Calcineurin inhibitor Cyclosporine: Administration will commence no later than at least 36 hours before marrow infusion; Cyclosporine doses will be adjusted to maintain a level of 150-300 ng/ml.
DRUG	Tacrolimus	(Standard GVHD Prophylaxis) Calcineurin inhibitor Tacrolimus: Administration will commence no later than at least 36 hours before marrow infusion; Tacrolimus doses will be adjusted to maintain a level of 8-15 ng/ml.
DRUG	Methotrexate	(Standard GVHD Prophylaxis) Methotrexate will be given at a dose of 15 mg/m2 IV on day 1 and a dose of 10 mg/m2 IV on days 3, 6 and 11. Dosing shall be based on actual weight.
DRUG	Abatacept	(Investigational) Abatacept will be administered intravenously at a dose of 10 mg/kg based on actual weight with a maximum of 750 mg. In cases where the calculated dose is less than or equal to 110% of a simple multiple of a 250 mg vial: 250 mg (275mg), 500 mg (550 mg) or 750 mg (825 mg), the dose may be rounded down to the nearest multiple. No rounding up of the abatacept dose is permitted.
PROCEDURE	Marrow infusion	(Standard) A procedure that infuses healthy cells, called stem cells, into your body to replace damaged or diseased bone marrow. A bone marrow transplant may also be used to treat certain types of cancer
DRUG	Sirolimus	(Standard GVHD Prophylaxis) Calcineurin inhibitor (cyclosporine or tacrolimus or with permission of the sponsor: sirolimus or mycophenolate mofetil (MMF)) administration will commence no later than day -2 (at least 36 hours before the stem cell infusion); cyclosporine doses will be adjusted to maintain a level of 150-300 ng/ml. This range assumes monitoring by mass spectrometry. If an immunoassay is used instead, the equivalent range for that immunoassay should be used.
DRUG	Mycophenolate Mofetil	(Standard GVHD Prophylaxis) Calcineurin inhibitor (cyclosporine or tacrolimus or with permission of the sponsor: sirolimus or mycophenolate mofetil (MMF)) administration will commence no later than day -2 (at least 36 hours before the stem cell infusion); cyclosporine doses will be adjusted to maintain a level of 150-300 ng/ml. This range assumes monitoring by mass spectrometry. If an immunoassay is used instead, the equivalent range for that immunoassay should be used.

Timeline

• Start date: 2016-07-01
• Primary completion: 2021-12-30
• Completion: 2023-12-30
• First posted: 2016-08-16
• Last updated: 2024-06-13

Locations

7 sites across 1 country: United States

Regulatory

• FDA-regulated drug study