Pre-transplant Immunosuppression and Donor Stem Cell Transplant for the Treatment of Severe Hemoglobinopathies
Primary Purpose
Beta Thalassemia Major, Sickle Beta 0 Thalassemia, Sickle Beta Plus Thalassemia
Status
Withdrawn
Phase
Early Phase 1
Locations
Study Type
Interventional
Intervention
Bortezomib
Busulfan
Cyclophosphamide
Dexamethasone
Fludarabine Phosphate
Hematopoietic Cell Transplantation
Lapine T-Lymphocyte Immune Globulin
Mycophenolate Mofetil
Plasmapheresis
Rituximab
Tacrolimus
Sponsored by
About this trial
This is an interventional treatment trial for Beta Thalassemia Major
Eligibility 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
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (PTIS, HCT)
Arm Description
See Detailed Description.
Outcomes
Primary Outcome Measures
Event-free survival (EFS)
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
Event-free survival
EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
Event-free survival
EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
Overall survival
Will be summarized by the Kaplan-Meier method.
Overall survival
Will be summarized by the Kaplan-Meier method.
Transplant-related mortality
Will be summarized by the Kaplan-Meier method.
Time to platelet and neutrophil engraftment
Will be estimated using the method of Gooley et al.
Incidence of graft failure (primary and secondary)
Will be estimated using the method of Gooley et al.
Incidence of acute graft-versus-host disease
Will be estimated using the method of Gooley et al.
Incidence of chronic graft-versus-host disease
Will be estimated using the method of Gooley et al.
Incidence of chronic graft-versus-host disease
Will be estimated using the method of Gooley et al.
Incidence of grade II or greater organ toxicity
Will be reported as counts with percentages.
Incidence of hepatic sinusoidal obstruction syndrome
Will be reported as counts with percentages.
Incidence of central nervous system toxicities including posterior reversible encephalopathy syndrome
Will be reported as counts with percentages.
Incidence of infectious complications
Will be reported as counts with percentages.
Full Information
NCT ID
NCT04776850
First Posted
February 8, 2021
Last Updated
February 16, 2023
Sponsor
M.D. Anderson Cancer Center
1. Study Identification
Unique Protocol Identification Number
NCT04776850
Brief Title
Pre-transplant Immunosuppression and Donor Stem Cell Transplant for the Treatment of Severe Hemoglobinopathies
Official Title
Pre-Transplant Immunosuppression and Related Haploidentical Hematopoietic Cell Transplantation for Patients With Severe Hemoglobinopathies
Study Type
Interventional
2. Study Status
Record Verification Date
November 2022
Overall Recruitment Status
Withdrawn
Why Stopped
Competing protocol opened in Adult SCT that will include pediatric patients and is now multi-center. No patients enrolled on study.
Study Start Date
December 29, 2020 (Actual)
Primary Completion Date
December 5, 2022 (Actual)
Study Completion Date
December 5, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Beta Thalassemia Major, Sickle Beta 0 Thalassemia, Sickle Beta Plus Thalassemia, Sickle Beta Thalassemia, Sickle Cell Disease, Sickle Cell-SS Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment (PTIS, HCT)
Arm Type
Experimental
Arm Description
See Detailed Description.
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, Velcade
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Hematopoietic Cell Transplantation
Other Intervention Name(s)
HCT, Hematopoietic Stem Cell Transplantation, HSCT, Stem Cell Transplant, stem cell transplantation
Intervention Description
Undergo HCT
Intervention Type
Biological
Intervention Name(s)
Lapine T-Lymphocyte Immune Globulin
Other Intervention Name(s)
Anti-Thymocyte Globulin Rabbit, Grafalon, Rabbit Anti-Human Thymocyte Globulin (RATG), Rabbit Anti-Thymocyte Globulin, Rabbit Antithymocyte Globulin, Rabbit ATG, rATG, Thymoglobulin
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Other Intervention Name(s)
CellCept, MMF
Intervention Description
Given IV or PO
Intervention Type
Procedure
Intervention Name(s)
Plasmapheresis
Other Intervention Name(s)
Plasma Exchange, Therapeutic Plasma Exchange, Therapeutic Plasmapheresis
Intervention Description
Undergo plasmapheresis
Intervention Type
Biological
Intervention Name(s)
Rituximab
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
FK 506, Fujimycin, Hecoria, Prograf, Protopic
Intervention Description
Given IV or PO
Primary Outcome Measure Information:
Title
Event-free survival (EFS)
Description
EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
Time Frame
At 2 years post-hematopoietic cell transplantation (HCT)
Secondary Outcome Measure Information:
Title
Event-free survival
Description
EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
Time Frame
Up to 100 days post-HCT
Title
Event-free survival
Description
EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
Time Frame
Up to 1 year post-HCT
Title
Overall survival
Description
Will be summarized by the Kaplan-Meier method.
Time Frame
Up to 100 days post-HCT
Title
Overall survival
Description
Will be summarized by the Kaplan-Meier method.
Time Frame
Up to 1 year post-HCT
Title
Transplant-related mortality
Description
Will be summarized by the Kaplan-Meier method.
Time Frame
Up to 30 days post-HCT
Title
Time to platelet and neutrophil engraftment
Description
Will be estimated using the method of Gooley et al.
Time Frame
Up to 2 years post-HCT
Title
Incidence of graft failure (primary and secondary)
Description
Will be estimated using the method of Gooley et al.
Time Frame
Up to 100 days post-HCT
Title
Incidence of acute graft-versus-host disease
Description
Will be estimated using the method of Gooley et al.
Time Frame
Up to 100 days post-HCT
Title
Incidence of chronic graft-versus-host disease
Description
Will be estimated using the method of Gooley et al.
Time Frame
Up to 1 year post-HCT
Title
Incidence of chronic graft-versus-host disease
Description
Will be estimated using the method of Gooley et al.
Time Frame
Up to 2 years post-HCT
Title
Incidence of grade II or greater organ toxicity
Description
Will be reported as counts with percentages.
Time Frame
Up to 100 days post-HCT
Title
Incidence of hepatic sinusoidal obstruction syndrome
Description
Will be reported as counts with percentages.
Time Frame
Up to 100 days post-HCT
Title
Incidence of central nervous system toxicities including posterior reversible encephalopathy syndrome
Description
Will be reported as counts with percentages.
Time Frame
Up to 100 days post-HCT
Title
Incidence of infectious complications
Description
Will be reported as counts with percentages.
Time Frame
Up to 100 days post-HCT
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kris M Mahadeo
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
12. IPD Sharing Statement
Links:
URL
http://www.mdanderson.org
Description
MD Anderson Cancer Center
Learn more about this trial
Pre-transplant Immunosuppression and Donor Stem Cell Transplant for the Treatment of Severe Hemoglobinopathies
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