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

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ClinicalTrials.gov Identifier: NCT03579875
Recruitment Status : Recruiting
First Posted : July 9, 2018
Last Update Posted : March 19, 2019
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

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 Phase 2

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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


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




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



Information from the National Library of Medicine

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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 - refer to Appendix III
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03579875


Contacts
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Contact: Kim Nelson, RN 612-273-2925 knelso62@fairview.org

Locations
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United States, Minnesota
Masonic Cancer Center at University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Kim Nelson, RN    612-273-2925    knelso62@fairview.org   
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota

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Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT03579875     History of Changes
Other Study ID Numbers: 2016LS161
MT2017-17 ( Other Identifier: Masonic Cancer Center, University of Minnesota )
First Posted: July 9, 2018    Key Record Dates
Last Update Posted: March 19, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Fanconi Syndrome
Anemia
Myelodysplastic Syndromes
Anemia, Aplastic
Fanconi Anemia
Hematologic Diseases
Bone Marrow Diseases
Anemia, Hypoplastic, Congenital
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Metabolism, Inborn Errors
Methylprednisolone
Cyclophosphamide
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
Antineoplastic Agents, Immunological
Anti-Inflammatory Agents