Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders

University of Minnesota (UMN)

Status and phase: Enrolling; Phase 2

Conditions: Fanconi Anemia; Bone Marrow Failure; Telomere Biology Disorder; T Cell Receptor Alpha/Beta Depletion; Dyskeratosis Congenita; Myelodysplastic Syndromes; Severe Aplastic Anemia

Treatments: Device: Donor mobilized PBSC infusion; Drug: Busulfan; Drug: Fludarabine (FLU); Drug: Alemtuzumab; Drug: Total Body Irradiation (TBI) (Plan 1); Drug: Rituximab; Drug: Methylprednisolone (MP); Drug: Cyclophosphamide (CY) (Plan 2); Drug: Cyclophosphamide (CY) (Plan 1); Drug: G-CSF; Drug: Melphalan

Study type: Interventional

Funder types: Other

Identifiers

NCT03579875

MT2017-17 (Other Identifier)

2016LS161

Details and patient eligibility

About

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.

Enrollment: 48 estimated patients

Sex: All

Ages: Under 65 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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48 participants in 5 patient groups

Treatment Plan 1: TBI 300 with Thymic Shielding, CY, FLU, MP in patients with Fanconi Anemia

Experimental group

Description:

Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type OR * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia

Treatment:

Drug: G-CSF

Drug: Cyclophosphamide (CY) (Plan 1)

Drug: Methylprednisolone (MP)

Drug: Rituximab

Drug: Total Body Irradiation (TBI) (Plan 1)

Drug: Fludarabine (FLU)

Device: Donor mobilized PBSC infusion

Treatment Plan 2: CY, FLU and MP in patients with Fanconi Anemia

Experimental group

Description:

Given to: • HLA-identical sibling donor recipients with aplastic anemia

Treatment:

Drug: G-CSF

Drug: Cyclophosphamide (CY) (Plan 2)

Drug: Methylprednisolone (MP)

Drug: Rituximab

Drug: Fludarabine (FLU)

Device: Donor mobilized PBSC infusion

Treatment Plan 3: BU, Cy, FLU, MP and Rituximab in patients with Fanconi Anemia

Experimental group

Description:

Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type who cannot tolerate TBI * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia who cannot tolerate TBI * Per treating physician preference

Treatment:

Drug: Cyclophosphamide (CY) (Plan 1)

Drug: Methylprednisolone (MP)

Drug: Rituximab

Drug: Busulfan

Drug: Fludarabine (FLU)

Treatment Plan 4: CY, FLU, and alemtuzumab

Experimental group

Description:

given to TBD patients with: * Bone marrow failure AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 3 patients would be treated per year. Statistical outcomes will be descriptive.

Treatment:

Drug: Cyclophosphamide (CY) (Plan 1)

Drug: Alemtuzumab

Drug: Fludarabine (FLU)

Treatment Plan 5: CY, FLU, melphalan (MEL), and alemtuzumab.

Experimental group

Description:

given to TBD patients with: * Early MDS features (with or without cytogenetic abnormalities) AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 2 patients would be treated per year. Statistical outcomes will be descriptive.

Treatment:

Drug: Melphalan

Drug: Cyclophosphamide (CY) (Plan 1)

Drug: Alemtuzumab

Drug: Fludarabine (FLU)