Bone Marrow Transplantation in Young Adults With Severe Sickle Cell Disease

A Phase II Study of Hematopoietic Stem Cell Therapy for Young Adults With Severe Sickle Cell Disease

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01565616

Acronym

STRIDE

Enrollment

Registered

2012-03-28

Start date

2012-03-31

Completion date

2016-06-30

Last updated

2017-11-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

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

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.

Detailed description

Interventions

DRUGConditioning Regimen with Bone Marrow Transplant

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

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

16 Years to 40 Years

Healthy volunteers

Inclusion criteria

* Diagnosis of severe sickle cell disease and have one or more of the following: 1. Clinically significant neurologic event (stroke) or any neurological deficit lasting \> 24 hours 2. 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. 3. 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). 4. 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) 5. 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: 1. Karnofsky performance score greater than or equal to 60 2. Cardiac function: Left ventricular ejection fraction (LVEF) \> 40%; or LV shortening fraction \> 26% by cardiac echocardiogram or by multigated acquisition (MUGA) scan. 3. 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) 4. 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. 5. 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 6. 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.

Exclusion criteria

* 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

Design outcomes

Primary

Measure	Time frame	Description
Event -Free Survival Rate	1 year after transplant	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.

Secondary

Measure	Time frame	Description
Acute Graft Versus Host Disease (GVHD)	1 year after transplant	Acute GVHD was graded according to the Center for International Blood and Marrow Transplant Research (CIBMTR) consensus criteria. Clinical manifestations of acute GVHD include skin, liver, and gastrointestinal symptoms. Grading of acute GVHD is determined by size of maculopapular rash, bilirubin and stool output. Acute GVHD grades range from 0 to 4 with 0 indicating no GVHD and 4 representing the most severe grade. Grade II is defined as a maculopapular rash over 25-50% of body surface area (BSA), bilirubin of 3.1 to 6 mg/dL, and stool output of 1000-1500 mL/d (for adults). Grade III is defined as a maculopapular rash over more than 50% of BSA, bilirubin of 6.1 to 15 mg/dL, and stool output of greater than 1500 mL/d (for adults). Grade IV is defined as generalized erythroderma with bullous formation, bilirubin greater than 15 mg/dL, and severe abdominal pain with or without ileus.
Chronic Graft Versus Host Disease (GVHD)	1 year after transplant	Chronic GVHD was graded according to the National Institutes of Health (NIH) 2014 Consensus Criteria Diagnosis and scoring the severity of chronic GVHD is determined by evaluating symptoms of the skin, nails, hair, mouth, eyes, genitalia, gastrointestinal tract, liver, lungs, muscles, fascia and joints, immune function as well as other symptoms such as ascites and neuropathy. Chronic GVHD is graded as mild, moderate or severe based on the number of organ sites impacted and the severity of symptoms.
Graft Failure	1 year after transplant	Primary graft failure occurs when a transplant recipient does not achieve donor chimerism following a bone marrow transplant. Secondary graft failure occurs when graft fails after donor chimerism had initially occurred.
Time to Neutrophil and Platelet Engraftment	1 year after transplant	Time to neutrophil engraftment is defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of at least 500/µL after conditioning. Time to Platelet engraftment is defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count \> 50,000/µL, without receiving a platelet transfusion in the previous 7 days.
Transplant Related Outcomes	1 year after transplant	Common transplant related complications were monitored as a secondary outcome measure of this study. These transplant related complications include hepatic veno-occlusive disease (VOD), idiopathic pneumonia syndrome (IPS), central nervous system (CNS) toxicity complications of posterior reversible encephalopathy syndrome (PRES), hemorrhage, and seizures, cytomegalovirus (CMV) infection, adenovirus infection, Epstein-Barr virus (EBV) infection, post-transplant lymphoproliferative disease (PTLD), and invasive fungal infection.
Overall Survival	1 year after transplant	Overall survival is defined as survival with or without sickle cell disease after hematopoietic cell transplantation (HCT).

Countries

United States

Participant flow

Recruitment details

Participants were enrolled from 8 study locations between March, 2012 and June, 2015.

Pre-assignment details

The first component of the study was restricted to 5 patients with a related donor. If no more than 2 of the first 5 patients experienced unacceptable toxicity within six months of transplantation then the safety of the regimen was considered promising and the study could include patients with a related or unrelated HLA matched donor.

Participants by arm

Arm	Count
Bone Marrow Transplant Recipients Individuals receiving a bone marrow transplant at one of 10 study locations, between March 2012 and June, 2015.	22
Total	22

Baseline characteristics

Characteristic	Bone Marrow Transplant Recipients
Age, Customized 16-19 years of age	6 Participants
Age, Customized 20-24 years of age	8 Participants
Age, Customized 24-29 years of age	6 Participants
Age, Customized 30-40 years of age	2 Participants
Donor Relation Related	17 Participants
Donor Relation Unrelated	5 Participants
Indication of Severe Sickle Cell Disease Acute chest syndrome	2 Participants
Indication of Severe Sickle Cell Disease Elevated TRJ Velocity	4 Participants
Indication of Severe Sickle Cell Disease Recurrent pain events	15 Participants
Indication of Severe Sickle Cell Disease Regular RBC transfusion therapy	4 Participants
Indication of Severe Sickle Cell Disease Significant neurological event (stroke)	2 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	22 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	0 Participants
Region of Enrollment United States	22 Participants
Sex: Female, Male Female	14 Participants
Sex: Female, Male Male	8 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	2 / 22
other Total, other adverse events	12 / 22
serious Total, serious adverse events	14 / 22

Outcome results

Primary

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.