Alpha/Beta T Cell Depleted Stem Cell Transplant in Treating Patients with Fanconi Anemia or Telomere Biology Disorder
This phase II trial studies how well alpha/beta T cell depleted stem cell transplant works in treating patients with Fanconi anemia or telomere biology disorder . Fanconi anemia and telomere biology disorder are inherited disorders that causes the bone marrow to stop making enough new blood cells (bone marrow failure) or to make abnormal cells (myelodysplastic syndrome or acute leukemia) and the only proven cure is a stem cell transplant. A common risk with a stem cell transplant is graft-versus-host disease (GVHD) which occurs when the donor cells (the graft) see the patient’s body (the host) as foreign and attack it. A method to decrease the risk of GVHD, is to remove most of the lymphocytes, a type of white blood cells, from the donor cell product. There has been a new machine developed which better selects the types of white blood cells to remove from the donor. This type of processing is called T cell receptor (TCR) alpha/beta T cell depletion. The purpose of this study is to learn if removing the donor T cells from the donor product using this new method will be a better way to reduce the risk of GVHD. The benefit of removing these cells with this new method is that they will prevent GVHD without requiring drugs to suppress the immune system. Potentially, the immune system will recover from the transplant faster, which in turn will also lessen the risk of severe infections.
Inclusion Criteria
- Diagnosis of Fanconi anemia.
- FANCONI ANEMIA: Less than 65 years of age.
- FANCONI ANEMIA: Karnofsky performance status of >= 70% or, for children < 16 years of age, Lansky play score >= 50.
- FANCONI ANEMIA: Presence of at least one of the following risk factors: * Single- or multi-lineage hematopoietic failure defined as: ** Platelet count < 20 x 10^9/L. ** Absolute neutrophil count of < 5 x 10^8/L. ** Hemoglobin < 8 g/dL. * Myelodysplastic features (morphologic, cytogenetic, or molecular), myelodysplastic syndrome (MDS) or acute leukemia. * High risk genotype (i.e. FANCD1/BRCA2, FANCN/PALB2). * Immunodeficiency associated with history of recurrent infections.
- FANCONI ANEMIA: Bilirubin < 5 x normal.
- FANCONI ANEMIA: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 5 x normal.
- FANCONI ANEMIA: Alkaline phosphatase (ALP) < 5 x normal.
- FANCONI ANEMIA: Left ventricle ejection fraction (LEFV) >= 45% by echocardiography (ECHO).
- FANCONI ANEMIA: Diffusion capacity of the lung for carbon monoxide (DLCO) >= 40% predicted, and absence of oxygen (O2) requirements. For children that are not able to cooperate with pulmonary function tests (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.
- FANCONI ANEMIA: Forced expiratory volume in one second (FEV1) >= 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.
- FANCONI ANEMIA: Forced vital capacity (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.
- FANCONI ANEMIA: Identification of a suitable donor for peripheral blood cells per match criteria.
- FANCONI ANEMIA: Females of childbearing potential and males with partners of childbearing potential must agree to use of contraception for the duration of treatment and 4 months after the transplant.
- FANCONI ANEMIA: 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).
- Or diagnosis of Telomere biology disorder.
- TELOMERE BIOLOGY DISORDER: Less than 70 years of age.
- TELOMERE BIOLOGY DISORDER: Karnofsky performance status of ≥ 70% or, for children < 16 years of age, Lansky Play Score ≥ 50.
- TELOMERE BIOLOGY DISORDER: Presence of at least one of the following risk factors, with or without clonal cytogenetic abnormalities: * Bone marrow failure defined as having at least one of the following when not receiving growth factors or transfusions: ** Platelet count < 50 x 10^9/L. ** Absolute neutrophil count of < 5 x 10^8/L. ** Hemoglobin < 9 g/dL. * Early Myelodysplastic features (morphologic, cytogenetic, or molecular) not meeting MDS or acute leukemia diagnostic criteria). ** Myelodysplastic syndrome with bone marrow blasts < 5%.
- TELOMERE BIOLOGY DISORDER: Bilirubin < 5 x normal.
- TELOMERE BIOLOGY DISORDER: AST < 5 x normal.
- TELOMERE BIOLOGY DISORDER: ALT < 5 x normal.
- TELOMERE BIOLOGY DISORDER: ALP < 5 x normal.
- TELOMERE BIOLOGY DISORDER: Left ventricle ejection fraction (LEFV) ≥ 45% by ECHO.
- TELOMERE BIOLOGY DISORDER: DLCO ≥ 30% 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.
- TELOMERE BIOLOGY DISORDER: FEV1 ≥ 30% 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.
- TELOMERE BIOLOGY DISORDER: FVC ≥ 30% 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.
- TELOMERE BIOLOGY DISORDER: Glomerular filtration rate ≥ 30% predicted.
- TELOMERE BIOLOGY DISORDER: Identification of a suitable donor for peripheral blood cells.
- TELOMERE BIOLOGY DISORDER: 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.
- TELOMERE BIOLOGY DISORDER: 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).
- DONOR: Meets one of the following match criteria: * An human leukocyte antigen (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. Related donors must be screened for the underlying disease of the recipient and be confirmed to not have the same disease.
- DONOR: Body weight of at least 40 kilograms and at least 12 years of age.
- DONOR: Willing and able to undergo mobilized peripheral blood apheresis.
- DONOR: In general good health as determined by the medical provider.
- DONOR: Hemoglobin within 10% of upper and lower limit of normal range of test (gender based for hemoglobin).
- DONOR: White blood cell (WBC) within 10% of upper and lower limit of normal range of test (gender based for hemoglobin).
- DONOR: Platelet within 10% of upper and lower limit of normal range of test (gender based for hemoglobin).
- DONOR: ALT < 2 x upper limit of normal.
- DONOR: Serum creatinine < 1.8 mg/dl.
- DONOR: Performance of a donor infectious disease screen panel including cytomegalovirus (CMV) antibody, hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody, human immunodeficiency virus (HIV) 1/2 antibody, human T-lymphotropic virus (HTLV)A 1/2 antibody, Treponema, and Trypanosoma cruzi (T. Cruzi) plus hepatitis B virus (HBV), hepatitis C virus (HCV), West Nile virus (WNV), human immunodeficiency virus (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.
- DONOR: Not pregnant - females of childbearing potential must have a negative pregnancy test within 7 days of mobilization start.
- DONOR: Voluntary written consent (parent/guardian and minor assent, if < 18 years) prior to the performance of any research related procedure.
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 with expected 3 year survival < 50%.
- Evidence of moderate or severe portal fibrosis or cirrhosis.
Additional locations may be listed on ClinicalTrials.gov for NCT03579875.
Locations matching your search criteria
United States
Minnesota
Minneapolis
PRIMARY OBJECTIVE:
I. To determine the incidence of grade II-IV acute graft versus host disease (GVHD) by day 100 using an alpha/beta T cell depleted (alpha/beta TCD) that retain natural killer (NK) cells, T-cell receptor (TCR) gamma/delta lymphocytes, monocytes, B cells and hematopoietic progenitors, peripheral blood stem cell (PBSC) product and without routine GVHD prophylaxis.
SECONDARY OBJECTIVES:
I. Rate of neutrophil engraftment by 42 days (defined as the first of three consecutive days after hematopoietic cell transplant [HCT] that the patient’s absolute neutrophil counts is >= 0.5 x 10^9 per liter).
II. Time to platelet engraftment (defined as the first of three consecutive days after HCT that the patient’s platelet count >= 20 x 10^9 per liter).
III. Incidence of grade III-IV acute GVHD by day 100.
TRANSPLANT-RELATED OBJECTIVES:
I. Incidence of chronic GVHD at 2 years after transplant.
II. Regimen related toxicity based on Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 within 30 days after transplant.
III. Incidence of bacterial, viral and fungal infections at day 100 after transplant.
IV. Overall survival at 2 years after transplant.
CORRELATIVE OBJECTIVE:
I. Immune recovery at day 100, 6 months, and 1 and 2 years after transplant.
OUTLINE: Patients are assigned to 1 of 5 treatment plans.
PLAN I: Patients undergo total body irradiation with thymic shielding on day -6, receive cyclophosphamide intravenously (IV) over 2 hours on days -5 to -2, fludarabine IV over 60 minutes on days -5 to -2, methylprednisolone IV over 30 minutes every 12 hours on days -5 to -1, rituximab IV on day -1, undergo transplantation of peripheral blood stem cells on day 0, and receive G-CSF IV daily until absolute neutrophil count (ANC) >= 2.5 x 10^9/L for 3 consecutive days or single day ANC > 3000. Patients whose final graft product contains > 2 x 10^5 TCR alpha/beta T cells/kg recipient weight receive mycophenolate mofetil IV or orally (PO) for 30 days followed by a taper through day 60. Patients undergo computed tomography (CT) scan during screening bone marrow biopsy and aspiration during screening and as indicated, and blood sample collection throughout the study.
PLAN II: Patients receive cyclophosphamide IV over 2 hours on days -5 to -2, fludarabine IV over 60 minutes on days -5 to -2, methylprednisolone IV over 30 minutes every 12 hours on days -5 to -1, rituximab IV on day -1, undergo transplantation of peripheral blood stem cells on day 0, and receive G-CSF IV daily until ANC >= 2.5 x 10^9/L for 3 consecutive days or single day ANC > 3000. Patients whose final graft product contains > 2 x 10^5 TCR alpha/beta T cells/kg recipient weight receive mycophenolate mofetil IV or PO for 30 days followed by a taper through day 60. Patients undergo CT scan during screening bone marrow biopsy and aspiration during screening and as indicated, and blood sample collection throughout the study.
PLAN III: Patients receive busulfan IV over 2 hours every 12 hours on days -7 and -6, cyclophosphamide IV over 2 hours on days -5 to -2, fludarabine IV over 60 minutes on days -5 to -2, methylprednisolone IV over 30 minutes on days -5 to -1, rituximab IV on day -1, undergo transplantation of peripheral blood stem cells on day 0, and receive G-CSF IV daily until ANC >= 2.5 x 10^9/L for 3 consecutive days or single day ANC > 3000. Patients whose final graft product contains > 2 x 10^5 TCR alpha/beta T cells/kg recipient weight receive mycophenolate mofetil IV or PO for 30 days followed by a taper through day 60. Patients undergo CT scan during screening bone marrow biopsy and aspiration during screening and as indicated, and blood sample collection throughout the study.
PLAN IV: Patients receive alemtuzumab IV over 2 hours on days -10 to -6, cyclophosphamide IV over 2 hours on day -7, and fludarabine IV over 60 minutes on days -5 to -3, undergo transplantation of peripheral blood stem cells on day 0, and receive G-CSF IV daily until ANC >= 2.5 x 10^9/L for 3 consecutive days or single day ANC > 3000. Patients whose final graft product contains > 2 x 10^5 TCR alpha/beta T cells/kg recipient weight receive mycophenolate mofetil IV or PO for 30 days followed by a taper through day 60. Patients undergo CT scan during screening bone marrow biopsy and aspiration during screening and as indicated, and blood sample collection throughout the study.
PLAN V: Patients receive alemtuzumab IV over 2 hours on days -10 to -6, cyclophosphamide IV over 2 hours on day -7, fludarabine IV over 60 minutes on days -6 to -3, and melphalan IV over 30 minutes on day -2, undergo transplantation of peripheral blood stem cells on day 0, and receive G-CSF IV daily until ANC >= 2.5 x 10^9/L for 3 consecutive days or single day ANC > 3000. Patients whose final graft product contains > 2 x 10^5 TCR alpha/beta T cells/kg recipient weight receive mycophenolate mofetil IV or PO for 30 days followed by a taper through day 60. Patients undergo CT scan during screening bone marrow biopsy and aspiration during screening and as indicated, and blood sample collection throughout the study.
After completion of study treatment, patients are followed up at days 7, 14, 21, 28, 35, 42, 60, and at 3, 6, 9, 12 months, and 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Minnesota/Masonic Cancer Center
Principal InvestigatorMargaret L. MacMillan
- Primary ID2016LS161
- Secondary IDsNCI-2019-02906, MT2017-17
- ClinicalTrials.gov IDNCT03579875