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

NCT ID: NCT03615144

Last Updated: 2021-03-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 1 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-23
• Study Completion Date: 2020-11-13

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.

Conditions

Non-Malignant Hematologic Disorders

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Melphalan

Intervention Type: DRUG

Melphalan 70 mg/m2/day x 2

Thiotepa

Intervention Type: DRUG

Thiotepa 7.5 mg/kg/day x 2

Clofarabine

Intervention Type: DRUG

Clofarabine 20-30 mg/m2/day x 5

Anti-Thymocyte Globulin (Rabbit) (Thymoglobulin®)

Intervention Type: DRUG

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.

CliniMACS reagents

Intervention Type: PROCEDURE

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

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.

Group Type: ACTIVE_COMPARATOR

Melphalan

Intervention Type: DRUG

Melphalan 70 mg/m2/day x 2

Thiotepa

Intervention Type: DRUG

Thiotepa 7.5 mg/kg/day x 2

Fludarabine

Intervention Type: DRUG

Fludarabine 30 mg/m2/day x 5

Anti-Thymocyte Globulin (Rabbit) (Thymoglobulin®)

Intervention Type: DRUG

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.

CliniMACS reagents

Intervention Type: PROCEDURE

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

Interventions

Melphalan

Melphalan 70 mg/m2/day x 2

Intervention Type: DRUG

Thiotepa

Thiotepa 7.5 mg/kg/day x 2

Intervention Type: DRUG

Clofarabine

Clofarabine 20-30 mg/m2/day x 5

Intervention Type: DRUG

Fludarabine

Fludarabine 30 mg/m2/day x 5

Intervention Type: 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.

Intervention Type: DRUG

CliniMACS reagents

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

Intervention Type: PROCEDURE

Eligibility Criteria

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

• 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.

• 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.

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

• 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.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 69 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Memorial Sloan Kettering Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Maria Cancio, MD

Role: PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Locations

Memorial SloanKettering Cancer Center

New York, New York, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.mskcc.org/mskcc/html/44.cfm

Memorial Sloan Kettering Cancer Center

Other Identifiers

17-596

Identifier Type: -

Identifier Source: org_study_id