T Cell Receptor α/β TCD HCT in Patients With Fanconi Anemia
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment Plan 1: TBI 300 with Thymic Shielding, CY, FLU, MP 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)
300 cGy with thymic shielding on day -6
Other Names:
Drug: Cyclophosphamide (CY) (Plan 1)
10 mg/kg IV daily on days -5, -4, -3, and -2
Other Names:
Drug: Fludarabine (FLU)
35 mg/m2 IV daily on days -5, -4, -3, and -2
Other Names:
Drug: Methylprednisolone (MP)
1 mg/kg IV q12h on days -5, -4, -3, -2, and -1
Other Names:
Device: Donor mobilized PBSC infusion
T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation on day 0
Other Names:
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)
Drug: Rituximab
200 mg/m2 IV once on day -1
|
| Experimental: Treatment Plan 2: CY, FLU and MP Given to: • HLA-identical sibling donor recipients with aplastic anemia |
Drug: Fludarabine (FLU)
35 mg/m2 IV daily on days -5, -4, -3, and -2
Other Names:
Drug: Methylprednisolone (MP)
1 mg/kg IV q12h on days -5, -4, -3, -2, and -1
Other Names:
Device: Donor mobilized PBSC infusion
T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation on day 0
Other Names:
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)
Drug: Cyclophosphamide (CY) (Plan 2)
5 mg/kg IV daily on days -5, -4, -3, and -2
Other Names:
Drug: Rituximab
200 mg/m2 IV once on day -1
|
| Experimental: Treatment Plan 3: BU, Cy, FLU, MP and Rituximab 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)
10 mg/kg IV daily on days -5, -4, -3, and -2
Other Names:
Drug: Fludarabine (FLU)
35 mg/m2 IV daily on days -5, -4, -3, and -2
Other Names:
Drug: Methylprednisolone (MP)
1 mg/kg IV q12h on days -5, -4, -3, -2, and -1
Other Names:
Drug: Rituximab
200 mg/m2 IV once on day -1
Drug: 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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Grade II-IV acute graft versus host disease (GVHD) [Day 100]
incidence of grade II-IV acute graft versus host disease (GVHD)
Secondary Outcome Measures
- Neutrophil engraftment [Day 42]
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)
- Platelet engraftment [Day 42]
Time to platelet engraftment (First of three consecutive days after HCT that the patient's platelet count ≥ 20x10^9 per liter)
- Acute graft versus host disease (aGVHD) [Day 100]
Incidence of grade III-IV acute graft versus host disease
- Chronic graft versus host disease (cGVHD) [1 Year after transplant]
Incidence of chronic graft versus host disease after transplant
- Regimen related toxicity [30 Days after transplant]
Incidence of regimen related toxicity based on CTCAE v5
- Bacterial, viral and fungal infections [1 Year after transplant]
Incidence of bacterial, viral and fungal infections
- Opportunistic infections [100 Days after transplant]
Incidence of opportunistic infections
- Overall survival (OS) [1 Year after transplant]
Incidence of overall survival
Eligibility Criteria
Criteria
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
- 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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Masonic Cancer Center at University of Minnesota | Minneapolis | Minnesota | United States | 55455 |
Sponsors and Collaborators
- Masonic Cancer Center, University of Minnesota
Investigators
- Principal Investigator: Margaret MacMillan, MD, Msc, FRCPC, Masonic Cancer Center, University of Minnesota
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2016LS161
- MT2017-17