T Cell Receptor α/β TCD HCT in Patients With Fanconi Anemia

Study Overview
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Brief Summary
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This is a phase II trial of T cell receptor alpha/beta depletion (α/β TCD) hematopoietic cell transplantation (HCT) transplantation in patients with Fanconi anemia (FA) 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.

Official Title
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T Cell Receptor Alpha/Beta T Cell Depleted (α/β TCD) Hematopoietic Cell Transplantation in Patients With Fanconi Anemia (FA)

Conditions
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Fanconi Anemia, Severe Aplastic Anemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Total Body Irradiation (TBI) (Plan 1)
* Drug: Cyclophosphamide (CY) (Plan 1)
* Drug: Fludarabine (FLU)
* Drug: Methylprednisolone (MP)
* Device: Donor mobilized PBSC infusion
* Drug: G-CSF
* Drug: Cyclophosphamide (CY) (Plan 2)
* Drug: Rituximab
* Drug: Busulfan


Participation Criteria
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Eligibility Criteria
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Patient Selection: Inclusion Criteria: Diagnosis of Fanconi anemia Less than 65 years of age Karnofsky performance status of ≥ 70% or, for children < 16 years of age, Lansky Play Score ≥ 50 Presence of at least one of the following risk factors: Severe aplastic anemia (SAA) defined as: Aplastic anemia is defined as having at least one of the following when not receiving growth factors or transfusions: platelet count <20 x 109/L absolute neutrophil count of <5 x 108/L hemoglobin <8 g/dL Myelodysplastic syndrome (MDS) or acute leukemia High risk genotype Adequate organ function defined as: Bilirubin, AST or ALT, ALP <5 x normal, Cardiac: left ventricle ejection fraction (LEFV) ≥45% by ECHO Pulmonary: DLCO, FEV1, FVC ≥ 40% predicted, and absence of O2 requirements. For children that are not able to cooperate with PFTs, a pulse oximetry with exercise should be attempted. If neither test can be obtained it should be clearly stated in the physician's note. Identification of a suitable donor for peripheral blood cells per match criteria found in Section 5. Females of childbearing potential and males with partners of child-bearing potential must agree to use of contraception for the duration of treatment and 4 months after the transplant Able to provide written voluntary consent prior to the performance of any research related tests or procedures with parental/guardian consent for minor (and assent as appropriate) 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

Ages Eligible for Study
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Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Plan 1: TBI 300 with Thymic Shielding, CY, FLU, MP<br>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 | Drug: Total Body Irradiation (TBI) (Plan 1)<br>* 300 cGy with thymic shielding on day -6<br>* Other names: TBI;Drug: Cyclophosphamide (CY) (Plan 1)<br>* 10 mg/kg IV daily on days -5, -4, -3, and -2<br>* Other names: CY;Drug: Fludarabine (FLU)<br>* 35 mg/m2 IV daily on days -5, -4, -3, and -2<br>* Other names: FLU;Drug: Methylprednisolone (MP)<br>* 1 mg/kg IV q12h on days -5, -4, -3, -2, and -1<br>* Other names: MP;Device: Donor mobilized PBSC infusion<br>* T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation on day 0<br>* Other names: PBSC;Drug: G-CSF<br>* Initiate G-CSF 5mcg/kg per day IV on day +1 (continue until ANC >2.5 x 10^9/L for 3 consecutive days)<br>Drug: Rituximab<br>* 200 mg/m2 IV once on day -1<br>|
| Experimental: Treatment Plan 2: CY, FLU and MP<br>Given to: • HLA-identical sibling donor recipients with aplastic anemia | Drug: Fludarabine (FLU)<br>* 35 mg/m2 IV daily on days -5, -4, -3, and -2<br>* Other names: FLU;Drug: Methylprednisolone (MP)<br>* 1 mg/kg IV q12h on days -5, -4, -3, -2, and -1<br>* Other names: MP;Device: Donor mobilized PBSC infusion<br>* T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation on day 0<br>* Other names: PBSC;Drug: G-CSF<br>* Initiate G-CSF 5mcg/kg per day IV on day +1 (continue until ANC >2.5 x 10^9/L for 3 consecutive days)<br>Drug: Cyclophosphamide (CY) (Plan 2)<br>* 5 mg/kg IV daily on days -5, -4, -3, and -2<br>* Other names: CY;Drug: Rituximab<br>* 200 mg/m2 IV once on day -1<br>|
| Experimental: Treatment Plan 3: BU, Cy, FLU, MP and Rituximab<br>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 | Drug: Cyclophosphamide (CY) (Plan 1)<br>* 10 mg/kg IV daily on days -5, -4, -3, and -2<br>* Other names: CY;Drug: Fludarabine (FLU)<br>* 35 mg/m2 IV daily on days -5, -4, -3, and -2<br>* Other names: FLU;Drug: Methylprednisolone (MP)<br>* 1 mg/kg IV q12h on days -5, -4, -3, -2, and -1<br>* Other names: MP;Drug: Rituximab<br>* 200 mg/m2 IV once on day -1<br>Drug: Busulfan<br>* 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.<br>* Other names: BU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade II-IV acute graft versus host disease (GVHD) | incidence of grade II-IV acute graft versus host disease (GVHD) | Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Acute graft versus host disease (aGVHD) | Incidence of grade III-IV acute graft versus host disease | Day 100 | 
| Chronic graft versus host disease (cGVHD) | Incidence of chronic graft versus host disease after transplant | 1 Year after transplant | 
| Regimen related toxicity | Incidence of regimen related toxicity based on CTCAE v5 | 30 Days after transplant | 
| Bacterial, viral and fungal infections | Incidence of bacterial, viral and fungal infections | 1 Year after transplant | 
| Opportunistic infections | Incidence of opportunistic infections | 100 Days after transplant | 
| Overall survival (OS) | Incidence of overall survival | 1 Year after transplant |