Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders

Myelodysplastic Syndromes Clinical Trial

Official title:

MT2017-17:T Cell Receptor Alpha/Beta T Cell Depleted Hematopoietic Cell Transplantation in Patients With Inherited Bone Marrow Failure (BMF) Disorders

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03579875
• Other study ID #: 2016LS161
• Secondary ID: MT2017-17
• Status: Recruiting
• Phase: Phase 2
• Start date: November 13, 2018
• Est. completion date: January 5, 2029

Study information

• Verified date: June 2024
• Source: Masonic Cancer Center, University of Minnesota
• Contact: Margaret MacMillan, MD, Msc, FRCPC
• Phone: 612-626-2961
• Email: macmi002[@]umn.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase II trial of T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation in patients with inherited bone marrow failure (BMF) disorders to eliminate the need for routine graft-versus-host disease (GVHD) immune suppression leading to earlier immune recovery and potentially a reduction in the risk of severe infections after transplantation.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 48
• Est. completion date: January 5, 2029
• Est. primary completion date: January 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 65 Years

Eligibility

Patient Selection:

Inclusion Criteria:

For FA patients:

• Diagnosis of Fanconi anemia

• Age <65 years of age

• Has one of the following risk factors:

• Severe aplastic anemia (SAA)

• Myelodysplastic syndrome (MDS)

• High risk genotype

• Immunodeficiency associated with history of recurrent infections

• Karnofsky performance status = 70% if = 16 years of age or Lansky play score = 50% for patients <16 years of age

• Adequate pulmonary, cardiac and liver function

• Voluntary written consent (minor assent if appropriate) prior to the performance of any study related procedures not part of standard medical care

For TBD patients:

• Diagnosis of TBD

• Age <70 years of age

• Has one of the following risk factors:

• Severe aplastic anemia (SAA)

• Myelodysplastic syndrome (MDS)

• Karnofsky performance status = 70% if = 16 years of age or Lansky play score

= 50% for patients <16 years of age

• Adequate pulmonary, cardiac and liver function

• Voluntary written consent (minor assent if appropriate) prior to the performance of any study related procedures not part of standard medical care

Exclusion Criteria:

• Pregnant or breastfeeding as the treatment used in this study are Pregnancy Category D. Females of childbearing potential must have a negative pregnancy test (serum or urine) within 14 days of study registration

• Active, uncontrolled infection within 1 week prior to starting study therapy

• Malignant solid tumor cancer within previous 2 years

Donor Selection (Inclusion Criteria): meets one of the following match criteria:

• an HLA-A, B, DRB1 matched sibling donor (matched sibling)

• an HLA-A, B, DRB1 matched related donor (other than sibling)

• a related donor mismatched at 1 HLA-A, B, C and DRB1 antigen

• 7-8/8 HLA-A,B,C,DRB1 allele matched unrelated donor per current institutional guidelines Patients and donors are typed for HLA-A and B using serological or molecular techniques and for DRB1 using high resolution molecular typing. If a donor has been selected on the basis of HLA-A, B, C and DRB1 typing as above, preference will be made for donors matched at the HLA-C locus.

• Body weight of at least 40 kilograms and at least 12 years of age

• Willing and able to undergo mobilized peripheral blood apheresis

• In general good health as determined by the medical provider

• Adequate organ function defined as:

• Hematologic: hemoglobin, WBC, platelet within 10% of upper and lower limit of normal range of test (gender based for hemoglobin)

• Hepatic: ALT < 2 x upper limit of normal

• Renal: serum creatinine < 1.8 mg/dl

• Performance of a donor infectious disease screen panel including CMV Antibody, Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis C Antibody, HIV 1/2 Antibody, HTLVA 1/2 Antibody, Treponema, and Trypanosoma Cruzi (T. Cruzi) plus HBV, HCV, WNV, HIV by nucleic acid testing (NAT); and screening for evidence of and risks factors for infection with Zika virus, or per current standard institutional donor screen - must be negative for HIV and active hepatitis B

• Not pregnant - females of childbearing potential must have a negative pregnancy test within 7 days of mobilization start

• Voluntary written consent (parent/guardian and minor assent, if < 18 years) prior to the performance of any research related procedure

Related Conditions & MeSH terms

• Anemia
• Anemia, Aplastic
• Bone Marrow Failure
• Bone Marrow Failure Disorders
• Dyskeratosis Congenita
• Fanconi Anemia
• Myelodysplastic Syndromes
• Pancytopenia
• Severe Aplastic Anemia

Intervention

Drug:
• Total Body Irradiation (TBI) (Plan 1)
300 cGy with thymic shielding on day -6
• Cyclophosphamide (CY) (Plan 1)
10 mg/kg IV daily on days -5, -4, -3, and -2
• Fludarabine (FLU)
35 mg/m2 IV daily on days -5, -4, -3, and -2
• Methylprednisolone (MP)
1 mg/kg IV q12h on days -5, -4, -3, -2, and -1

Device:
• Donor mobilized PBSC infusion
T cell receptor alpha/beta depletion (a/ß TCD) peripheral blood stem cell (PBSC) transplantation on day 0

Drug:
• G-CSF
Initiate G-CSF 5mcg/kg per day IV on day +1 (continue until ANC >2.5 x 10^9/L for 3 consecutive days)
• Cyclophosphamide (CY) (Plan 2)
5 mg/kg IV daily on days -5, -4, -3, and -2
• Rituximab
200 mg/m2 IV once on day -1
• Busulfan
Busulfan 0.6 mg/kg if > 4 years old and/or >12 kg (0.8 mg/kg IV if = 4 years old and/or = 12 kg) is given IV over 2 hours every 12 hours for 2 days.
• Alemtuzumab
Alemtuzumab 0.2 mg/kg is given IV over 2 hours daily for 5 days (total dose 1 mg/kg)
• Melphalan
If available, MEL dosing will be model-based using Bayesian methodology. If Bayesian methodology is unavailable, MEL dosing will be weight-based: MEL 70 mg/m2 for patients =10 kg (2.35 mg/kg for patients <10 kg^) IV for one dose over 30 minutes.

Locations

Country	Name	City	State
United States	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Masonic Cancer Center, University of Minnesota

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Grade II-IV acute graft versus host disease (GVHD)	incidence of grade II-IV acute graft versus host disease (GVHD)	Day 100
Secondary	Neutrophil engraftment	Rate of neutrophil engraftment (defined as the first of three consecutive days after HCT that the patient's absolute neutrophil counts is = 0.5x109 per liter)	Day 42
Secondary	Platelet engraftment	Time to platelet engraftment (First of three consecutive days after HCT that the patient's platelet count = 20x10^9 per liter)	Day 42
Secondary	Acute graft versus host disease (aGVHD)	Incidence of grade III-IV acute graft versus host disease	Day 100
Secondary	Chronic graft versus host disease (cGVHD)	Incidence of chronic graft versus host disease after transplant	1 Year after transplant
Secondary	Regimen related toxicity	Incidence of regimen related toxicity based on CTCAE v5	30 Days after transplant
Secondary	Bacterial, viral and fungal infections	Incidence of bacterial, viral and fungal infections	1 Year after transplant
Secondary	Opportunistic infections	Incidence of opportunistic infections	100 Days after transplant
Secondary	Overall survival (OS)	Incidence of overall survival	1 Year after transplant