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

NCT02867800 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: AAAQ2350
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 7

Brief 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.

Conditions

Sickle Cell Disease; Graft Versus Host Disease

Keywords

Sickle Cell Disease; Graft Versus Host Disease; Abatacept; Hematopoietic Stem Cell Transplantation

Outcome Measures

Primary Outcomes (1)

• Number of patients who tolerate abatacept

  Patients will be deemed to be evaluable for tolerability if they received all prescribed doses of abatacept. Abatacept will deemed to be tolerated, if no more than one dose is withheld per protocol stipulations, no death from an infection that occurs within 30 days of or develops post-transplant lymphoproliferative disease (PTLD) within 100 days of receiving the last prescribed dose of abatacept.

  Within 100 days of receiving the last prescribed dose of abatacept

Secondary Outcomes (2)

• Bearman Scale Score of Regimen-Related Toxicity (RRT)

  Day 42 post-transplant

• Number of infections

  Up to 180 days post transplant

Study Arms (1)

Standard GVHD Prophylaxis + Abatacept

EXPERIMENTAL

Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0.

Drug: Diphenhydramine; Drug: Acetaminophen; Drug: Methylprednisolone; Drug: Meperidine; Drug: Alemtuzumab; Drug: Thymoglobulin; Drug: Fludarabine; Drug: Melphalan; Drug: Thiotepa; Drug: Cyclosporine; Drug: Tacrolimus; Drug: Methotrexate; Drug: Abatacept; Procedure: Marrow infusion; Drug: Sirolimus; Drug: Mycophenolate Mofetil

Interventions

Diphenhydramine DRUG

(Standard of Care) Premedication Diphenhydramine: 1 mg/kg IV or PO q 8 hours (maximum=50 mg)

Also known as: Benadryl

Standard GVHD Prophylaxis + Abatacept

Acetaminophen DRUG

(Standard of Care) Premedication Acetaminophen: 10-15 mg/kg PO q 6 hours (maximum=1000 mg)

Also known as: Tylenol

Standard GVHD Prophylaxis + Abatacept

Methylprednisolone DRUG

(Standard of Care) Premedication Methylprednisolone: 0.25-0.5 mg/kg IV q 6 hours

Also known as: Medrol

Standard GVHD Prophylaxis + Abatacept

Meperidine DRUG

(Standard of Care) Premedication Use as needed (PRN) Meperidine: 0.5 mg/kg IV q 4-6 hours (for rigors)

Also known as: Demerol

Standard GVHD Prophylaxis + Abatacept

Alemtuzumab DRUG

(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.

Also known as: Lemtrada

Standard GVHD Prophylaxis + Abatacept

Thymoglobulin DRUG

(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.

Also known as: Genzyme

Standard GVHD Prophylaxis + Abatacept

Fludarabine DRUG

(Standard Conditioning Regimen) Fludarabine should be administered 30 mg/m2 IV daily for five days. It should be infused over 30 to 60 minutes.

Also known as: Fludara

Standard GVHD Prophylaxis + Abatacept

Melphalan DRUG

(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.

Also known as: Alkeran

Standard GVHD Prophylaxis + Abatacept

Thiotepa DRUG

(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.

Also known as: Thioplex

Standard GVHD Prophylaxis + Abatacept

Cyclosporine DRUG

(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.

Also known as: Neoral

Standard GVHD Prophylaxis + Abatacept

Tacrolimus DRUG

(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.

Also known as: Protopic

Standard GVHD Prophylaxis + Abatacept

Methotrexate DRUG

(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.

Also known as: Trexall

Standard GVHD Prophylaxis + Abatacept

Abatacept DRUG

(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.

Also known as: CTLA4-Ig, Orencia

Standard GVHD Prophylaxis + Abatacept

Marrow infusion PROCEDURE

(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

Also known as: stem cell transplant

Standard GVHD Prophylaxis + Abatacept

Sirolimus DRUG

(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.

Also known as: Rapamune

Standard GVHD Prophylaxis + Abatacept

Mycophenolate Mofetil DRUG

(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.

Also known as: MMF

Standard GVHD Prophylaxis + Abatacept

Eligibility Criteria

• Age: 3 Years - 20 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients with hemoglobin (Hgb) SS or SB0 thalassemia between the ages of 3 and 20.99 years who are at least 10 kg getting an human leukocyte antigen (HLA) matched bone marrow transplant, will be eligible if they are at increased risk for graft versus host disease (GVHD) and have severe SCD.
• (a) Patients falling into one of the following three groups will be considered to be at increased risk for GVHD:
• (i) Are between 10 and 20.99 years and receiving their transplant from an HLA matched related donor.
• (ii) Are between 3 and 9.99 years and receiving their transplant from an HLA matched related donor who is at least 10 years.
• (iii) Are between 3 and 20.99 years and receiving their transplant from an HLA matched unrelated donor. Donors must be matched at the A, B, C and DRB1 loci at the allele level.
• (b) Patients who meet one of the following criteria will qualify as having severe SCD:
• (i) Previous clinical stroke, as evidenced by a neurological deficit lasting longer than 24 hours, which is accompanied by radiographic evidence of ischemic brain injury and cerebral vasculopathy.
• (ii) Asymptomatic cerebrovascular disease, as evidenced by one the following:
• Progressive silent cerebral infarction, as evidenced by serial MRI scans that demonstrate the development of a succession of lesions (at least two temporally discreet lesions, each measuring at least 3 mm in greatest dimension on the most recent scan) or the enlargement of a single lesion, initially measuring at least 3 mm). Lesions must be visible on T2-weighted MRI sequences.
• Cerebral arteriopathy, as evidenced by abnormal transcranial doppler (TCD) testing (confirmed elevated velocities in any single vessel of time-averaged maximum mean velocities (TAMMV) \> 200 cm/sec for non-imaging TCD) or by significant vasculopathy on magnetic resonance angiogram (MRA) (greater than 50% stenosis of \> 2 arterial segments or complete occlusion of any single arterial segment).
• (iii) Frequent ( ≥ 3 per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting ≥ 4 hours and requiring hospitalization or outpatient treatment with parenteral opioids). If patient is on hydroxurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 2 years prior to the start of this drug.
• (iv) Recurrent ( ≥ 3 in lifetime) acute chest syndrome events which have necessitated erythrocyte transfusion therapy.
• (v) Any combination of ≥ 3 acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above) yearly for 3 years. If patient is on hydroxurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 3 years prior to the start of this drug.
• All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• Must have been evaluated and adequately counseled regarding treatment options for severe SCD by a pediatric hematologist.

You may not qualify if:

• Bridging (portal to portal) fibrosis or cirrhosis of the liver.
• Parenchymal lung disease stemming from SCD or other process defined as a diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin) or forced vital capacity of less than 45% of predicted. Children unable to perform pulmonary function testing will be excluded if they require daytime oxygen supplementation.
• Renal dysfunction with an estimated glomerular filtration rate (GFR) \< 50% of predicted normal for age.
• Cardiac dysfunction with shortening fraction \< 25%.
• Neurologic impairment other than hemiplegia, defined as full-scale IQ ≤70, quadriplegia or paraplegia, inability to ambulate, or any impairment resulting in decline of Lansky performance score to \< 70%.
• Clinical stroke within 6 months of anticipated transplant.
• Karnofsky or Lansky functional performance score \< 70%.
• Patient is human immunodeficiency virus (HIV) infected.
• Donor is HIV infected.
• Donor has Hgb SS, SC or SB0 thalassemia.
• Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate bone marrow transplantation.
• Patient or patient's guardian(s) unable to understand the nature and risks inherent in the bone marrow transplant (BMT) process.
• History of lack of compliance with medical care that would jeopardize transplant course.
• Donor who for psychological, physiologic, or medical reasons is unable to tolerate a bone marrow harvest or receive general anesthesia.
• Active viral, bacterial, fungal or protozoal infection.

Sponsors & Collaborators

• Monica Bhatia: lead

Study Sites (7)

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Floating Hospital for Children at Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

North Carolina Cancer Hospital

Chapel Hill, North Carolina, 27514, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

MeSH Terms

Conditions

Anemia, Sickle Cell; Graft vs Host Disease

Interventions

Diphenhydramine; Acetaminophen; Methylprednisolone; Meperidine; Alemtuzumab; thymoglobulin; fludarabine; fludarabine phosphate; Melphalan; Thiotepa; Cyclosporine; Tacrolimus; Methotrexate; Abatacept; Stem Cell Transplantation; Sirolimus; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immune System Diseases

Intervention Hierarchy (Ancestors)

Ethylamines; Amines; Organic Chemicals; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Acetanilides; Anilides; Amides; Aniline Compounds; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Isonipecotic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Piperidines; Heterocyclic Compounds, 1-Ring; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Phosphoramides; Organophosphorus Compounds; Triethylenephosphoramide; Aziridines; Azirines; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Peptides; Macrolides; Lactones; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Immunoconjugates; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Study Officials

• Monica Bhatia, MD

  Columbia University

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics at the Columbia University Medical Center

Study Record Dates

• First Submitted: August 11, 2016
• First Posted: August 16, 2016
• Study Start: July 1, 2016
• Primary Completion: December 30, 2021
• Study Completion: December 30, 2023
• Last Updated: June 13, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)