Bone Marrow Transplantation in Young Adults With Severe Sickle Cell Disease

NCT01565616 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: IRB000682871R34HL108761-01
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 8

Brief Summary

This is a Phase II, single arm, multi-center trial. It is designed to estimate the efficacy and toxicity of hematopoietic stem cell transplantation (HSCT) in patients with sickle cell disease (SCD) who have high risk features. The primary goal of this multi-center Phase II study is to determine the safety and feasibility of a conditioning regimen consisting of busulfan (Bu)/ fludarabine (Flu)/ anti-thymocyte globulin (ATG) in adult patients with severe SCD. A two-component design will be used for this study. The first component will be restricted to patients who have an HLA-identical sibling donor. Five patients will be transplanted during the first component of the study. If no more than 2 of the first 5 patients experience unacceptable toxicity, including death, within the first six months after transplantation, then the safety of the regimen will be considered promising in adult SCD patients. The second component will include patients who have a related or an unrelated human leukocyte antigen (HLA) matched donor. Up to 15 additional patients will be transplanted in this component of the study which will evaluate the safety and feasibility of unrelated donor hematopoietic cell transplantation (HCT) in adults with SCD. Data related to study endpoints for 1 year after transplantation will be collected; however, participating centers will be encouraged to conduct long-term follow-up evaluations of patients according to standard institutional guidelines. The purpose of this pilot safety trial is to see if this approach is feasible and meets accrual goals lending support to the development of a subsequent full scale investigation of HCT and comparing outcomes in a transplantation cohort to a control cohort of adults eligible for, but unwilling or unable to receive HCT treated by supportive therapy with a primary endpoint of five years survival for this full scale comparative trial.

Conditions

Sickle Cell Disease

Keywords

Severe Sickle Cell Disease; Hematopoietic cell transplantation (HCT); Hematopoietic Stem Cell Therapy; Bone Marrow Transplant; Hematologic Diseases; Genetic Diseases; Anemia; Hemolytic; Congenital; Human Leukocyte Antigen; HLA

Outcome Measures

Primary Outcomes (1)

• Event -Free Survival Rate

  Event-free survival is defined as stable donor erythropoiesis with no new clinical evidence of sickle cell disease. Primary or late graft rejection, disease recurrence, and death are considered events for this endpoint.

  1 year after transplant

Secondary Outcomes (6)

• Graft Failure

  1 year after transplant

• Acute Graft Versus Host Disease (GVHD)

  1 year after transplant

• Chronic Graft Versus Host Disease (GVHD)

  1 year after transplant

• Overall Survival

  1 year after transplant

• Time to Neutrophil and Platelet Engraftment

  1 year after transplant

Study Arms (1)

Bone Marrow Transplant Recipients

EXPERIMENTAL

Adults with sickle cell disease undergoing a bone marrow transplant from an HLA-identical sibling donor or an unrelated HLA-matched donor.

Drug: Conditioning Regimen with Bone Marrow Transplant

Interventions

Conditioning Regimen with Bone Marrow Transplant DRUG

The bone marrow transplant regimen is below. Day 0 is the day of the transplant. The - sign is the number of days before and the + sign is the number of days after the transplant. Day -8 BU 3.2 mg/ kg/dose IV Day -7 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV Day -6 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV, ATG 0.5mg/kg IV Day -5 BU 3.2 mg/kg/dose IV, FLU 35mg/m2 IV, ATG 1.0mg/kg IV Day -4 FLU 35mg/m2 IV, ATG 1.5mg/kg IV Day -3 FLU 35mg/m2 IV, ATG 1.5mg/kg IV Day -2 ATG 1.5mg/kg IV Day -1 Rest Day 0 Stem cell infusion Graft Versus Host Disease (GVHD) Regimen Day -3 Calcineurin Inhibitor (Cyclosporine or Tacrolimus) therapeutic doses through day 180, then taper Day 0 Stem cell infusion Day +1 Methotrexate 7.5 mg/m2 IV Day +3 Methotrexate 7.5 mg/m2 IV Day +6 Methotrexate 7.5 mg/m2 IV Day+11 Methotrexate 7.5 mg/m2 IV

Also known as: Busulfan (BU), Myleran, Busulfex IV, Fludarabine (FLU), Fludara, Rabbit Anti-thymocyte globulin (ATG), Thymoglobulin

Bone Marrow Transplant Recipients

Eligibility Criteria

• Age: 16 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnosis of severe sickle cell disease and have one or more of the following:
• Clinically significant neurologic event (stroke) or any neurological deficit lasting \> 24 hours
• History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea). Acute Chest Syndrome (ACS) is defined as new pulmonary alveolar consolidation (or infiltrate) involving at least one complete lung segment associated with acute symptoms including one or more of the following: fever ≥ 38.5 Celsius, chest pain, tachypnea per age adjusted normal, intercostal retractions/nasal flaring/use of accessory muscles of respiration, wheezing, rales or cough that is not attributed to asthma or bronchiolitis.
• History of three or more severe pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea). Pain Crisis is defined as new onset of pain that last for at least 2 hours for which there is no other explanation (i.e. vaso-occlusive, priapism).
• Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving 8 or more transfusions per year for greater than or equal to 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome)
• Trans-thoracic echocardiograph evidence of tricuspid valve regurgitant jet (TRJ) velocity greater than or equal to 2.7 m/sec.
• Adequate physical function as measured by:
• Karnofsky performance score greater than or equal to 60
• Cardiac function: Left ventricular ejection fraction (LVEF) \> 40%; or LV shortening fraction \> 26% by cardiac echocardiogram or by multigated acquisition (MUGA) scan.
• Pulmonary function: Pulse oximetry with a baseline O2 saturation of greater than or equal to 85% and diffusing capacity of the lungs for carbon monoxide (DLCO) \> 40% (corrected for hemoglobin)
• Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and 24-hour urine creatinine clearance \> 70 mL/min/1.73 m2 by radionuclide glomerular filtration rate (GFR); or GFR \> 70 mL/min/1.73 m2 by radionuclide GFR.
• Hepatic function: Serum conjugated (direct) bilirubin \< 2x upper limit of normal for age as per local laboratory; and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 5 times upper limit of normal as per local laboratory. Patients whose hyperbilirubinemia is the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded
• If the patient has been receiving chronic transfusion therapy for greater than or equal to 1 year and has clinical evidence of iron overload by serum ferritin (mean of 3 ferritin levels \>1000 and chronic transfusions \>20 in a lifetime or MRI), evaluation by liver biopsy is required. Histological examination of the liver must document the absence of cirrhosis, bridging fibrosis and active hepatitis. The absence of bridging fibrosis will be determined using the histological grading and staging scale as described by Ishak and colleagues (1995).
• Patients must have a related or unrelated bone marrow donor with HLA-matched at 8 of 8 HLA-A, B, C, and DRB1 loci by allelic testing. Umbilical cord blood or peripheral blood stem cell donors will not be accepted.

You may not qualify if:

• Patients with cirrhosis of the liver, uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment, or seropositivity for HIV
• Patients who have received prior HCT
• Patients who within 3 months of enrollment have participated in another clinical trial in which the patient received an investigational drug or device or off-label use of a drug or device
• Patients who demonstrate lack of compliance with prior medical care
• Patients who are unwilling to use approved contraception for at least 6 months after transplant
• Patients who have a history of substance abuse in the last 5 years that interferes with their care
• Patients who are pregnant or breast feeding
• Patients unable to provide consent

Sponsors & Collaborators

• Emory University: lead
• National Institutes of Health (NIH): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (8)

Children's Hospital of Oakland

Oakland, California, 94609, United States

Location

Children's National Medical Center

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

Location

University of Miami

Miami, Florida, 33136, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Chidren's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

MeSH Terms

Conditions

Anemia, Sickle Cell; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Hemolysis

Interventions

Transplantation Conditioning; Bone Marrow Transplantation; Busulfan; fludarabine; fludarabine phosphate; Antilymphocyte Serum; thymoglobulin

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemic and Lymphatic Diseases; Hemoglobinopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Immunosuppression Therapy; Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques; Tissue Transplantation; Cell- and Tissue-Based Therapy; Transplantation; Surgical Procedures, Operative; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures

Results Point of Contact

• Title: Lakshmanan Krishnamurti, MD
• Organization: Emory University

lakshmanan.krishnamurti@emory.edu

Study Officials

• Lakshmanan Krishnamurti, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 26, 2012
• First Posted: March 28, 2012
• Study Start: March 1, 2012
• Primary Completion: June 30, 2016
• Study Completion: June 30, 2016
• Last Updated: November 21, 2017
• Results First Posted: September 29, 2017

Record last verified: 2017-10

Locations

US (8)