Pre-transplant Immunosuppression and Donor Stem Cell Transplant for the Treatment of Severe Hemoglobinopathies

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

WITHDRAWN

Clinical Phase

EARLY_PHASE1

Study Classification

INTERVENTIONAL

Study Start Date

2020-12-29

Study Completion Date

2022-12-05

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

This clinical trial studies the effect of pre-transplant immunosuppression (PTIS) and donor stem cell transplant in treating patients with severe blood diseases (hemoglobinopathies). PTIS helps prepare the body for the transplant and lowers the risk of developing graft versus host disease (GVHD). Hematopoietic cells are found in the bone marrow and produce blood cells. Hematopoietic cell transplantation (HCT) injects healthy hematopoietic cells into the body to support blood cell production. PTIS and HCT may help to control severe hemoglobinopathies.

Related Clinical Trials

Explore similar clinical trials based on study characteristics and research focus.

Stem Cell Transplant for Hemoglobinopathy

NCT00176852

Sickle Cell Disease Thalassemia Severe Congenital Neutropenia +2 more

COMPLETED PHASE2/PHASE3

A Reduced Toxicity Allogeneic Unrelated Donor Stem Cell Transplantation (SCT) for Severe Sickle Cell Disease

NCT01279616

Sickle Cell Disease

TERMINATED PHASE2

Treatment of Sickle Cell Anemia With Stem Cell Transplant

NCT01350232

Sickle Cell Anemia Sickle Cell-hemoglobin C Disease Sickle Cell-β0-thalassemia

TERMINATED NA

Reduced Intensity Transplantation for Severe Sickle Cell Disease

NCT04362293

Sickle Cell Disease

SUSPENDED PHASE2

A Pilot Study of HSCT for Patients With High-risk Hemoglobinopathy Using a Nonmyeloablative Preparative Regimen

NCT00427661

Sickle Cell Disease Thalassemia Hemoglobinopathies

COMPLETED NA

Detailed Description

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

PRIMARY OBJECTIVE:

I. To estimate event-free survival (EFS) at 2-years post HCT.

SECONDARY OBJECTIVES:

I. Assess event-free survival (EFS) at 100 days and 1 year post HCT. II. Assess overall survival (OS) at 100 days and 1 year post HCT. III. 30-day transplant-related mortality (TRM). IV. Time to platelet and neutrophil engraftment. V. Rate of graft failure (primary and secondary) through day 100. VI. Incidence of acute graft-versus-host disease (aGVHD) by day 100. VII. Incidence of chronic graft-versus-host disease (cGVHD) by 1 year and 2 years.

VIII. Rate of grade II or greater organ toxicity through day 100. IX. Incidence of hepatic sinusoidal obstruction syndrome (SOS) by day 100. X. Incidence of central nervous system (CNS) toxicities including posterior reversible encephalopathy syndrome (PRES) by day 100.

XI. Incidence of infectious complications through day 100.

EXPLORATORY OBJECTIVES:

I. Effect of HCT on clinical and laboratory manifestations of hemoglobinopathies by 1 and 2 years after HCT.

II. Assess the pharmacokinetic profile of busulfan and thymoglobulin to better understand post-transplant outcomes.

III. Assess immune reconstitution kinetics post HCT.

OUTLINE:

DONOR-SPECIFIC ANTI-HLA DESENSITIZATION: Patients with donor-specific anti-HLA antibody titers \>= 1:3,000 at the start of PTIS receive rituximab intravenously (IV) on days -69, -41, -28, and -13 and bortezomib IV over less than 1 minute on days -68, -65, -40, and -37 in the absence of unacceptable toxicity. Patients with donor-specific anti-HLA antibody titers \> 1:15,000 at the start of PTIS receive receive rituximab IV on days -69, -41, -28, and -13 and bortezomib IV over less than 1 minute on days -68, -65, -62, -58, -40, -37, -34, and -31 in the absence of unacceptable toxicity. Patients with donor-specific anti-HLA antibody titers \> 1:5,000 at the start of conditioning may also undergo plasmapheresis on day -12.

PTIS: Patients receive fludarabine phosphate (fludarabine) IV over 1 hour and dexamethasone IV over less than 1 minute on days -68 to -64 and days -40 to -36 in the absence of disease progression or unacceptable toxicity.

CONDITIONING: Patients receive lapine T-lymphocyte immune globulin (rATG) IV over 4-6 hours on days -12 to -10, fludarabine phosphate IV over 1 hour on days -8 to -4, and busulfan IV over 2 hours on days -7 to -4 in the absence of disease progression or unacceptable toxicity.

TRANSPLANT: Patients undergo HCT on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 2-3 hours on days 3 and 4 in the absence of unacceptable toxicity. Beginning on day 5, patients also receive tacrolimus IV continuously daily and then orally (PO) twice daily (BID) at the discretion of the treating physician for up to 12 months, and mycophenolate mofetil IV or PO BID up to day 60 in the absence of unacceptable toxicity.

After completion of HCT, patients are followed up periodically for up to 2 years.

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

Beta Thalassemia Major Sickle Beta 0 Thalassemia Sickle Beta Plus Thalassemia Sickle Beta Thalassemia Sickle Cell Disease Sickle Cell-SS Disease

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Intervention Type DRUG

Given IV or PO

Discover alternative or legacy names that may be used to describe the listed interventions across different sources.

[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid LDP 341 MLN341 PS-341 PS341 Velcade 1, 4-Bis[methanesulfonoxy]butane BUS Bussulfam Busulfanum Busulfex Busulphan CB 2041 CB-2041 Glyzophrol GT 41 GT-41 Joacamine Methanesulfonic Acid Tetramethylene Ester Methanesulfonic acid, tetramethylene ester Mielucin Misulban Misulfan Mitosan Myeleukon Myeloleukon Myelosan Mylecytan Myleran Sulfabutin Tetramethylene Bis(methanesulfonate) Tetramethylene bis[methanesulfonate] WR-19508 (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 Aacidexam Adexone Aknichthol Dexa Alba-Dex Alin Alin Depot Alin Oftalmico Amplidermis Anemul mono Auricularum Auxiloson Baycadron Baycuten Baycuten N Cortidexason Cortisumman Decacort Decadrol Decadron Decadron DP Decalix Decameth Decasone R.p. Dectancyl Dekacort Deltafluorene Deronil Desamethasone Desameton Dexa-Mamallet Dexa-Rhinosan Dexa-Scheroson Dexa-sine Dexacortal Dexacortin Dexafarma Dexafluorene Dexalocal Dexamecortin Dexameth Dexamethasone Intensol Dexamethasonum Dexamonozon Dexapos Dexinoral Dexone Dinormon Dxevo Fluorodelta Fortecortin Gammacorten Hexadecadrol Hexadrol Lokalison-F Loverine Methylfluorprednisolone Millicorten Mymethasone Orgadrone Spersadex TaperDex Visumetazone ZoDex 2-F-ara-AMP 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)- Beneflur Fludara SH T 586 HCT Hematopoietic Stem Cell Transplantation HSCT Stem Cell Transplant stem cell transplantation Anti-Thymocyte Globulin Rabbit Grafalon Rabbit Anti-Human Thymocyte Globulin (RATG) Rabbit Anti-Thymocyte Globulin Rabbit Antithymocyte Globulin Rabbit ATG rATG Thymoglobulin CellCept MMF Plasma Exchange Therapeutic Plasma Exchange Therapeutic Plasmapheresis ABP 798 BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 PF-05280586 Rituxan Rituximab ABBS Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar GB241 Rituximab Biosimilar IBI301 Rituximab Biosimilar JHL1101 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SAIT101 Rituximab Biosimilar SIBP-02 rituximab biosimilar TQB2303 rituximab-abbs RTXM83 Truxima FK 506 Fujimycin Hecoria Prograf Protopic

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

Inclusion Criteria

* Patients 2-30 years-of-age with confirmed sickle cell disease (SCD) (SS \& sickle beta \[SB\]-thalassemia, both sickle beta 0 \[SB0\] and sickle beta plus \[SB+\]) or severe B-thalassemia major are potentially eligible
* Patients with SCD should also meet the following eligibility criteria as outlined by the Center for Medicaid and Medicare Services: sickle cell disease and at least one of the following:

* Stroke or neurological deficit lasting \> 24 hours
* Recurrent acute chest syndrome (ACS): 2 or more episodes of ACS in 2-year period preceding enrollment
* Recurrent vaso-occlusive pain crises: 3 or more episodes per year in 2-year period preceding enrollment or recurrent priapism (3 or more episodes in the 2 years preceding enrollment)
* Chronic transfusion program defined as 8 or more packed red blood cells (PRBC) transfusions per year to prevent central nervous system and/or vaso-occlusive complications in 1-year period preceding enrollment
* Impaired neuropsychological function and abnormal cerebral magnetic resonance imaging (MRI) scan (silent strokes)
* Stage I or II sickle lung disease
* Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50% of predicted normal value)
* Bilateral proliferative retinopathy and major visual impairment in at least one eye
* Osteonecrosis of multiple joints
* Echocardiographic finding of tricuspid valve regurgitant jet velocity (TRJV) \>= 2.7 m/sec
* Patients with B-thalassemia are considered as severe if they are/have any of the following:

* Transfusion-dependent
* Evidence of extra-medullary hematopoiesis
* Pesaro Class III
* Patients shall not proceed to HCT without confirmation of primary diagnosis by review of available newborn screening results or hemoglobin electrophoresis and/or genetic testing
* DONOR: High resolution HLA typing will be performed on all willing and available biologic parents and siblings without clinically significant hemoglobinopathy. Preference will be given to donors with the lowest number of HLA-allele mismatches
* DONOR: Donor-specific anti-HLA antibodies will be obtained and analyzed from all patients. Preference will be given to donors with absent or low titer anti HLA-donor specific antibody levels when possible

Exclusion Criteria

* Uncontrolled infection
* Females who are pregnant and/or unwilling to cease breastfeeding
* Seropositivity for human immunodeficiency virus (HIV)
* Lansky or Karnofsky performance status \< 70%
* Life expectancy severely limited by concomitant illness
* Uncontrolled arrhythmias or symptomatic cardiac disease
* Uncontrolled symptomatic pulmonary disease
* Evidence of chronic active hepatitis or cirrhosis
* Serum conjugated (direct) bilirubin \> 2 x upper limit of normal for age. Participants are not excluded if the serum conjugated (direct) bilirubin is \> 2 x the upper limit of normal for age as per local laboratory and:

* There is evidence of a hyperhemolytic reaction after a recent red blood cell (RBC) transfusion, OR
* There is evidence of moderate direct hyperbilirubinemia defined as direct serum bilirubin \< 5 times upper limit of normal (ULN) and not caused by underlying hepatic disease
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \> 5 x upper limit of normal for age
* Serum creatinine \> 1.5 x upper limit of normal for age AND estimated or measure creatinine clearance \< 70 mL/min/1.72 m\^2
* Patient, parent or guardian unable/unwilling to provide consent and when indicated, assent
* Patients with available HLA-matched related donor
* Prior receipt of gene therapy
* DONOR: All potential donors shall be tested by hemoglobin electrophoresis. Any potential donor with a clinically significant hemoglobinopathy will be deemed ineligible. Donors with sickle cell trait and beta thalassemia trait are eligible to donate

Minimum Eligible Age

2 Years

Maximum Eligible Age

30 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No