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

• ClinicalTrials.gov Identifier: NCT03579875
• Recruitment Status: Recruiting
• First Posted: July 9, 2018
• Last Update Posted: May 24, 2021
• Sponsor: Masonic Cancer Center, University of Minnesota
• Information provided by (Responsible Party): Masonic Cancer Center, University of Minnesota

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
Fanconi Anemia; Severe Aplastic Anemia; Myelodysplastic Syndromes	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	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 48 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: T Cell Receptor Alpha/Beta T Cell Depleted (α/β TCD) Hematopoietic Cell Transplantation in Patients With Fanconi Anemia (FA)
• Actual Study Start Date: November 13, 2018
• Estimated Primary Completion Date: February 2026
• Estimated Study Completion Date: February 2029

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 Name: TBI; Drug: Cyclophosphamide (CY) (Plan 1); 10 mg/kg IV daily on days -5, -4, -3, and -2; Other Name: CY; Drug: Fludarabine (FLU); 35 mg/m2 IV daily on days -5, -4, -3, and -2; Other Name: FLU; Drug: Methylprednisolone (MP); 1 mg/kg IV q12h on days -5, -4, -3, -2, and -1; Other Name: MP; Device: Donor mobilized PBSC infusion; T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation on day 0; Other Name: PBSC; 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 Name: FLU; Drug: Methylprednisolone (MP); 1 mg/kg IV q12h on days -5, -4, -3, -2, and -1; Other Name: MP; Device: Donor mobilized PBSC infusion; T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation on day 0; Other Name: PBSC; 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 Name: CY; 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 Name: CY; Drug: Fludarabine (FLU); 35 mg/m2 IV daily on days -5, -4, -3, and -2; Other Name: FLU; Drug: Methylprednisolone (MP); 1 mg/kg IV q12h on days -5, -4, -3, -2, and -1; Other Name: MP; 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 Name: BU

Outcome Measures

Primary Outcome Measures :

1. Grade II-IV acute graft versus host disease (GVHD) [ Time Frame: Day 100 ]
   incidence of grade II-IV acute graft versus host disease (GVHD)

Secondary Outcome Measures :

1. Neutrophil engraftment [ Time Frame: 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)
2. Platelet engraftment [ Time Frame: Day 42 ]
   Time to platelet engraftment (First of three consecutive days after HCT that the patient's platelet count ≥ 20x10^9 per liter)
3. Acute graft versus host disease (aGVHD) [ Time Frame: Day 100 ]
   Incidence of grade III-IV acute graft versus host disease
4. Chronic graft versus host disease (cGVHD) [ Time Frame: 1 Year after transplant ]
   Incidence of chronic graft versus host disease after transplant
5. Regimen related toxicity [ Time Frame: 30 Days after transplant ]
   Incidence of regimen related toxicity based on CTCAE v5
6. Bacterial, viral and fungal infections [ Time Frame: 1 Year after transplant ]
   Incidence of bacterial, viral and fungal infections
7. Opportunistic infections [ Time Frame: 100 Days after transplant ]
   Incidence of opportunistic infections
8. Overall survival (OS) [ Time Frame: 1 Year after transplant ]
   Incidence of overall survival

Eligibility Criteria

• Ages Eligible for Study: up to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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

Contacts and Locations

Contacts

Contact: Lisa Burke, RN; 612-273-8482; lburke3@Fairview.org

Locations

United States, Minnesota

Masonic Cancer Center at University of Minnesota; Recruiting

Minneapolis, Minnesota, United States, 55455

Contact: Lisa Burke, RN 612-273-8482 lburke3@Fairview.org

Sponsors and Collaborators

Masonic Cancer Center, University of Minnesota

Investigators

• Principal Investigator: Margaret MacMillan, MD, Msc, FRCPC; Masonic Cancer Center, University of Minnesota

More Information

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT03579875
• Other Study ID Numbers: 2016LS161; MT2017-17 ( Other Identifier: Masonic Cancer Center, University of Minnesota )
• First Posted: July 9, 2018
• Last Update Posted: May 24, 2021
• Last Verified: May 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Fanconi Syndrome; Anemia; Myelodysplastic Syndromes; Anemia, Aplastic; Fanconi Anemia; Hematologic Diseases; Bone Marrow Diseases; Bone Marrow Failure Disorders; Anemia, Hypoplastic, Congenital; Congenital Bone Marrow Failure Syndromes; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Metabolic Diseases; Renal Tubular Transport, Inborn Errors; Kidney Diseases; Urologic Diseases; Methylprednisolone; Cyclophosphamide; Busulfan; Rituximab; Fludarabine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists