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TCR Alpha Beta T-cell and CD19 B-cell Depleted Peripheral Blood Stem Cell Transplantation Using the CliniMACS System for Patients With Non-Malignant Hematologic Disorders From Matched or Mismatched, Related or Unrelated Donors

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ClinicalTrials.gov Identifier: NCT03615144
Recruitment Status : Recruiting
First Posted : August 3, 2018
Last Update Posted : October 23, 2019
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
The purpose of this study is to find out if removing a specific type of white blood cell (called alpha beta T-cell) that help make up the transplant donor's stem cells can improve results of blood stem cell transplant for the participant's disease.

Condition or disease Intervention/treatment Phase
Non-Malignant Hematologic Disorders Drug: Melphalan Drug: Thiotepa Drug: Clofarabine Drug: Fludarabine Drug: Anti-Thymocyte Globulin (Rabbit) (Thymoglobulin®) Procedure: CliniMACS reagents Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: For this trial, patients will be assigned to receive one of two conditioning regimens, based on their disease, disease severity, organ status and history of red blood cell alloimmunization.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Alpha Beta T-cell and CD19 B-cell Depleted Peripheral Blood Stem Cell Transplantation Using the CliniMACS System for Patients With Non-Malignant Hematologic Disorders From Matched or Mismatched, Related or Unrelated Donors
Actual Study Start Date : July 23, 2018
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Disorders

Arm Intervention/treatment
Active Comparator: Melphalan/Thiotepa/Clofarabine
Melphalan 70 mg/m2/day x 2, Thiotepa 7.5 mg/kg/day x 2 and Clofarabine 20-30 mg/m2/day x 5. Patients will also receive rabbit anti-thymocyte globulin at 2.5 mg/kg/day x 3 doses prior to the start of conditioning.
Drug: Melphalan
Melphalan 70 mg/m2/day x 2

Drug: Thiotepa
Thiotepa 7.5 mg/kg/day x 2

Drug: Clofarabine
Clofarabine 20-30 mg/m2/day x 5

Drug: Anti-Thymocyte Globulin (Rabbit) (Thymoglobulin®)
antithymocyte globulin (ATG) (rabbit ATG 2.5 mg/kg/day x 3 or equine ATG 15 mg/kg/day x 3 (or 40 mg/kg/day x 1 equine ATG if rabbit ATG is not tolerated) during pre-transplant conditioning to deplete host T-cells that could hamper engraftment.

Procedure: CliniMACS reagents
Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.

Active Comparator: Melphalan/Thiotepa/ Fludarabine
Melphalan 70 mg/m2/day x 2, Thiotepa 7.5 mg/kg/day x 2 and Fludarabine 30 mg/m2/day x 5. Patients will also receive rabbit anti-thymocyte globulin at 2.5 mg/kg/day x 3 doses prior to the start of conditioning.
Drug: Melphalan
Melphalan 70 mg/m2/day x 2

Drug: Thiotepa
Thiotepa 7.5 mg/kg/day x 2

Drug: Fludarabine
Fludarabine 30 mg/m2/day x 5

Drug: Anti-Thymocyte Globulin (Rabbit) (Thymoglobulin®)
antithymocyte globulin (ATG) (rabbit ATG 2.5 mg/kg/day x 3 or equine ATG 15 mg/kg/day x 3 (or 40 mg/kg/day x 1 equine ATG if rabbit ATG is not tolerated) during pre-transplant conditioning to deplete host T-cells that could hamper engraftment.

Procedure: CliniMACS reagents
Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.




Primary Outcome Measures :
  1. overall survival (OS) [ Time Frame: 2 years ]
    Overall survival is defined as time from transplant to death or last follow-up. Rate greater than 0.75 would be considered a success.



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Ages Eligible for Study:   1 Year to 69 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Subject Inclusion Criteria:

  • Lethal disorders of Hematopoiesis correctable by transplant for which Alpha βeta T-cell and CD-19 depleted allogeneic hematopoietic stem cell transplantation is indicated including:
  • Sickle cell disease (HbSS, HbSC, HbSB0 thalassemia, HbSB+, HbSD, HbSE) with at least one of the following criteria (Walters et al):

    1. Cerebrovascular accident lasting longer than 24 hours
    2. Impaired neuropsychological function with abnormal brain MRI/MRA
    3. Recurrent hospitalizations (>2 episodes/year over several years) or exchange transfusions for acute chest syndrome
    4. Recurrent priapism
    5. Stage I or II sickle chronic lung disease
    6. Sickle cell nephropathy (moderate to severe proteinuria or glomerular filtration rate 30-50% of predicted normal value for age)
    7. Bilateral proliferative retinopathy with major visual impairment in at least one eye
    8. Osteonecrosis of multiple joints
    9. Red cell alloimmunization during chronic transfusion therapy
  • Thalassemia major with at least one of the following criteria:

    1. Age <16 years
    2. Available HLA-identical sibling
    3. Red blood cell transfusion dependency
    4. Lucarelli class 1 or 2 risk status (i.e. with only 0-2 of the following factors: hepatomegaly, portal fibrosis, or poor response to chelation therapy)
    5. Recurrence of disease after previous stem cell transplant
  • Bone Marrow Failure Syndromes:

    1. Aplastic anemia refractory to immunosuppressive therapy
    2. Diamond Blackfan Anemia refractory to conventional therapy
    3. Shwachman-Diamond Syndrome
    4. Severe Congenital Neutropenia
    5. Congenital Amegakaryocytic Thrombocytopenia
    6. Thrombocytopenia Absent Radii syndrome
    7. Other marrow failure disorders not otherwise specified
  • Autoimmune cytopenias refractory to all conventional treatments

    1. Autoimmune hemolytic anemia
    2. Immune thrombocytopenia
    3. Evan's syndrome
    4. Pure red cell aplasia
  • Histiocytic disorders:

    1. Hemophagocytic lymphohistiocytosis
    2. High risk, recurrent or refractory Langerhans cell histiocytosis
    3. Secondary HLH

Subject Inclusion Criteria:

  • Recipient's age birth to < 70 years old
  • Patients must have adequate organ function measured by:
  • Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 50% and must improve with exercise.
  • Hepatic: < 3x ULN AST and ≤ 1.5 mg/dl total serum bilirubin, unless there is congenital benign hyperbilirubinemia or if the hyperbilirubinemia is directly caused by the disease in which the patient is receiving a transplant for. Patients with higher bilirubin levels due to causes other than active liver disease are also eligible with PI approval e.g. patients with PNH, Gilbert‟s disease or other hemolytic disorders.
  • Pulmonary: asymptomatic or if symptomatic, DLCO ≥ 50% of predicted (corrected for hemoglobin).
  • Renal: serum creatinine ≤1.5x normal for age. If serum creatinine is outside the normal range, then CrCl > 70 mL/min/1.73m2 (calculated or estimated) or GFR (mL/min/1.72m2) >30% of predicted normal for age.
  • Normal GFR in Children and Young Adults.

Donor Inclusion Criteria:

  • Each donor must meet criteria outlined by institutional guidelines and be medically eligible to donate according to NMDP (or equivalent donor search organization) criteria including testing for antibodies to Human TLymphotrophic Virus Types I & II (Anti-HTLV-I/II) and screening for West Nile Virus, Creutzfeldt-Jakob disease and Zika.
  • Pediatric donors should weigh ≥ 25.0 kg, have adequate peripheral venous catheter access for leukapheresis or must agree to placement of a central catheter.
  • Donor should be healthy and agree to receive G-CSF followed by donation of peripheral blood stem cells.
  • Donors must agree to anesthesia and marrow donation (in cases of inadequate PBSC collection).
  • Related or unrelated donors who are 7/8 or 8/8 HLA-antigen matched for haplotypes A, B, C, DRB1 OR Related donors who are 4-6/8 HLA-antigen matched.

Subject Exclusion Criteria:

  • Female patients who are pregnant or breast-feeding
  • Active viral, bacterial or fungal infection
  • Patient seropositive for HIV-I/II; HTLV-I/II
  • Karnofsky (adult)/Lansky (pediatric) < 70%
  • Inherited DNA repair deficiency: Fanconi Anemia and Dyskeratosis Congenita. These are presently undergoing transplantation based on a multi-center protocol
  • Patients with Thalassemia major with Pesaro risk score >II
  • Inherited metabolic disorders: Hurler Syndrome, Sly syndrome (MPSVIII), α-Mannosidosis, X- ALD, Osteopetrosis

Donor Exclusion Criteria:

  • Donors who are seropositive for HIV-I/II or HTLV-I/II and female patients who are pregnant or breastfeeding will not be eligible for this study.

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): NCT03615144


Contacts
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Contact: Maria Cancio, MD 212-639-2446 canciom@mskcc.org
Contact: Farid Boulad, MD 212-639-6684

Locations
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United States, New York
Memorial SloanKettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Maria Cancio, MD    212-639-2446      
Contact: Farid Boulad, MD    212-639-6684      
Principal Investigator: Maria Cancio, MD         
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Investigators
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Principal Investigator: Maria Cancio, MD Memorial Sloan Kettering Cancer Center

Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03615144     History of Changes
Other Study ID Numbers: 17-596
First Posted: August 3, 2018    Key Record Dates
Last Update Posted: October 23, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Memorial Sloan Kettering Cancer Center:
T-cell
B-cell
CliniMACS System
Melphalan
Thiotepa
Clofarabine
Fludarabine
17-596
Additional relevant MeSH terms:
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Hematologic Diseases
Vidarabine
Fludarabine
Fludarabine phosphate
Melphalan
Clofarabine
Thiotepa
Thymoglobulin
Antilymphocyte Serum
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists