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Beta Thalassemia MajorEarly Phase 1NCT04776850

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

A Early Phase 1 study testing Bortezomib, Busulfan and Cyclophosphamide in people with Beta Thalassemia Major and Sickle Beta 0 Thalassemia, run by M.D. Anderson Cancer Center.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 2 to 30 years
What is being tested?
Bortezomib, Busulfan and Cyclophosphamide
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
29 Dec 2020to 5 Dec 2022
Phase
Early Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 2 to 30 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
Show all 17Show fewer
  • 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

About this study

Official title: Pre-Transplant Immunosuppression and Related Haploidentical Hematopoietic Cell Transplantation for Patients With Severe Hemoglobinopathies

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.

Read the detailed description

PRIMARY OBJECTIVE:

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

SECONDARY OBJECTIVES:

  1. 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:

  1. 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.

Medical subject headings
beta-Thalassemia, Anemia, Sickle Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BortezomibDrug

    Also called [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341

    Given IV

  • BusulfanDrug

    Also called 1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum

    Given IV

  • CyclophosphamideDrug

    Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida

    Given IV

  • DexamethasoneDrug

    Also called Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex

    Given IV

  • Fludarabine PhosphateDrug

    Also called 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara

    Given IV

  • Hematopoietic Cell TransplantationProcedure or surgery

    Also called HCT, Hematopoietic Stem Cell Transplantation, HSCT, Stem Cell Transplant

    Undergo HCT

  • Lapine T-Lymphocyte Immune GlobulinBiological

    Also called Anti-Thymocyte Globulin Rabbit, Grafalon, Rabbit Anti-Human Thymocyte Globulin (RATG), Rabbit Anti-Thymocyte Globulin

    Given IV

  • Mycophenolate MofetilDrug

    Also called CellCept, MMF

    Given IV or PO

  • PlasmapheresisProcedure or surgery

    Also called Plasma Exchange, Therapeutic Plasma Exchange, Therapeutic Plasmapheresis

    Undergo plasmapheresis

  • RituximabBiological

    Also called ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody

    Given IV

  • TacrolimusDrug

    Also called FK 506, Fujimycin, Hecoria, Prograf

    Given IV or PO

Study groups in NCT04776850
Study groupRoleWhat they receive
Treatment (PTIS, HCT)ExperimentalSee Detailed Description.
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: At 2 years post-hematopoietic cell transplantation (HCT)

Secondary outcomes (14)
  1. 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.

    Measured: Up to 100 days post-HCT

  2. 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.

    Measured: Up to 1 year post-HCT

  3. Overall survival

    Will be summarized by the Kaplan-Meier method.

    Measured: Up to 100 days post-HCT

  4. Overall survival

    Will be summarized by the Kaplan-Meier method.

    Measured: Up to 1 year post-HCT

  5. Transplant-related mortality

    Will be summarized by the Kaplan-Meier method.

    Measured: Up to 30 days post-HCT

  6. Time to platelet and neutrophil engraftment

    Will be estimated using the method of Gooley et al.

    Measured: Up to 2 years post-HCT

  7. Incidence of graft failure (primary and secondary)

    Will be estimated using the method of Gooley et al.

    Measured: Up to 100 days post-HCT

  8. Incidence of acute graft-versus-host disease

    Will be estimated using the method of Gooley et al.

    Measured: Up to 100 days post-HCT

  9. Incidence of chronic graft-versus-host disease

    Will be estimated using the method of Gooley et al.

    Measured: Up to 1 year post-HCT

  10. Incidence of chronic graft-versus-host disease

    Will be estimated using the method of Gooley et al.

    Measured: Up to 2 years post-HCT

  11. Incidence of grade II or greater organ toxicity

    Will be reported as counts with percentages.

    Measured: Up to 100 days post-HCT

  12. Incidence of hepatic sinusoidal obstruction syndrome

    Will be reported as counts with percentages.

    Measured: Up to 100 days post-HCT

  13. Incidence of central nervous system toxicities including posterior reversible encephalopathy syndrome

    Will be reported as counts with percentages.

    Measured: Up to 100 days post-HCT

  14. Incidence of infectious complications

    Will be reported as counts with percentages.

    Measured: Up to 100 days post-HCT

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Mar 2021
  2. Study start29 Dec 2020
  3. Primary completion5 Dec 2022
  4. Study completion5 Dec 2022 (estimated)

Why it stopped: Competing protocol opened in Adult SCT that will include pediatric patients and is now multi-center. No patients enrolled on study.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04776850
Sponsor's protocol ID
2020-0952
Other IDs
NCI-2021-00365, 2020-0952
Status last verified
Nov 2022
First submitted
8 Feb 2021
Last updated
24 Oct 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Bortezomib, Busulfan and Cyclophosphamide in people with Beta Thalassemia Major and Sickle Beta 0 Thalassemia, run by M.D. Anderson Cancer Center.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 24 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Event-free survival (EFS) (time frame: At 2 years post-hematopoietic cell transplantation (HCT)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Oct 2024.

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