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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04776850
Recruitment Status : Recruiting
First Posted : March 2, 2021
Last Update Posted : March 12, 2021
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Beta Thalassemia Major Sickle Beta 0 Thalassemia Sickle Beta Plus Thalassemia Sickle Beta Thalassemia Sickle Cell Disease Sickle Cell-SS Disease Drug: Bortezomib Drug: Busulfan Drug: Cyclophosphamide Drug: Dexamethasone Drug: Fludarabine Phosphate Procedure: Hematopoietic Cell Transplantation Biological: Lapine T-Lymphocyte Immune Globulin Drug: Mycophenolate Mofetil Procedure: Plasmapheresis Biological: Rituximab Drug: Tacrolimus Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pre-Transplant Immunosuppression and Related Haploidentical Hematopoietic Cell Transplantation for Patients With Severe Hemoglobinopathies
Actual Study Start Date : December 29, 2020
Estimated Primary Completion Date : October 31, 2023
Estimated Study Completion Date : October 31, 2023


Arm Intervention/treatment
Experimental: Treatment (PTIS, HCT)
See Detailed Description.
Drug: Bortezomib
Given IV
Other Names:
  • [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
  • LDP 341
  • MLN341
  • PS-341
  • PS341
  • Velcade

Drug: Busulfan
Given IV
Other Names:
  • 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

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-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

Drug: Dexamethasone
Given IV
Other Names:
  • 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

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Procedure: Hematopoietic Cell Transplantation
Undergo HCT
Other Names:
  • HCT
  • Hematopoietic Stem Cell Transplantation
  • HSCT
  • Stem Cell Transplant
  • stem cell transplantation

Biological: Lapine T-Lymphocyte Immune Globulin
Given IV
Other Names:
  • Anti-Thymocyte Globulin Rabbit
  • Grafalon
  • Rabbit Anti-Human Thymocyte Globulin (RATG)
  • Rabbit Anti-Thymocyte Globulin
  • Rabbit Antithymocyte Globulin
  • Rabbit ATG
  • rATG
  • Thymoglobulin

Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • CellCept
  • MMF

Procedure: Plasmapheresis
Undergo plasmapheresis
Other Names:
  • Plasma Exchange
  • Therapeutic Plasma Exchange
  • Therapeutic Plasmapheresis

Biological: Rituximab
Given IV
Other Names:
  • 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

Drug: Tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Fujimycin
  • Hecoria
  • Prograf
  • Protopic




Primary Outcome Measures :
  1. Event-free survival (EFS) [ Time Frame: At 2 years post-hematopoietic cell transplantation (HCT) ]
    EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.


Secondary Outcome Measures :
  1. Event-free survival [ Time Frame: Up to 100 days post-HCT ]
    EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.

  2. Event-free survival [ Time Frame: Up to 1 year post-HCT ]
    EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.

  3. Overall survival [ Time Frame: Up to 100 days post-HCT ]
    Will be summarized by the Kaplan-Meier method.

  4. Overall survival [ Time Frame: Up to 1 year post-HCT ]
    Will be summarized by the Kaplan-Meier method.

  5. Transplant-related mortality [ Time Frame: Up to 30 days post-HCT ]
    Will be summarized by the Kaplan-Meier method.

  6. Time to platelet and neutrophil engraftment [ Time Frame: Up to 2 years post-HCT ]
    Will be estimated using the method of Gooley et al.

  7. Incidence of graft failure (primary and secondary) [ Time Frame: Up to 100 days post-HCT ]
    Will be estimated using the method of Gooley et al.

  8. Incidence of acute graft-versus-host disease [ Time Frame: Up to 100 days post-HCT ]
    Will be estimated using the method of Gooley et al.

  9. Incidence of chronic graft-versus-host disease [ Time Frame: Up to 1 year post-HCT ]
    Will be estimated using the method of Gooley et al.

  10. Incidence of chronic graft-versus-host disease [ Time Frame: Up to 2 years post-HCT ]
    Will be estimated using the method of Gooley et al.

  11. Incidence of grade II or greater organ toxicity [ Time Frame: Up to 100 days post-HCT ]
    Will be reported as counts with percentages.

  12. Incidence of hepatic sinusoidal obstruction syndrome [ Time Frame: Up to 100 days post-HCT ]
    Will be reported as counts with percentages.

  13. Incidence of central nervous system toxicities including posterior reversible encephalopathy syndrome [ Time Frame: Up to 100 days post-HCT ]
    Will be reported as counts with percentages.

  14. Incidence of infectious complications [ Time Frame: Up to 100 days post-HCT ]
    Will be reported as counts with percentages.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   2 Years to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04776850


Contacts
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Contact: Kris M Mahadeo 713-729-2873 kmmahadeo@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Kris M. Mahadeo    713-729-2873      
Principal Investigator: Kris M. Mahadeo         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
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Principal Investigator: Kris M Mahadeo M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04776850    
Other Study ID Numbers: 2020-0952
NCI-2021-00365 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2020-0952 ( Other Identifier: M D Anderson Cancer Center )
First Posted: March 2, 2021    Key Record Dates
Last Update Posted: March 12, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Thalassemia
beta-Thalassemia
Hemoglobinopathies
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Genetic Diseases, Inborn
Mycophenolic Acid
Dexamethasone
Dexamethasone acetate
Cyclophosphamide
Busulfan
Rituximab
Fludarabine
Fludarabine phosphate
Bortezomib
Antineoplastic Agents, Immunological
Tacrolimus
Thymoglobulin
Antilymphocyte Serum
Antibodies
Immunoglobulins
Antibodies, Monoclonal
gamma-Globulins
Immunoglobulins, Intravenous
Rho(D) Immune Globulin
BB 1101
Immunosuppressive Agents