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

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03615144
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arms: 2
• Actual Duration (Months): 27.7
• Patients Per Site Per Month: 0

Study Details

Study Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 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.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: Jul 23, 2018
• Actual Primary Completion Date: Nov 13, 2020
• Actual Study Completion Date: Nov 13, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 69 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial SloanKettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center

Investigators

• Principal Investigator: Maria Cancio, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 2, 2019

More Information

Additional Information:

• Memorial Sloan Kettering Cancer Center

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT03615144
• Other Study ID Numbers: 17-596
• First Posted: Aug 3, 2018
• Last Update Posted: Mar 24, 2021
• Last Verified: Nov 1, 2020

• 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: Hematologic Diseases; Fludarabine; Melphalan; Thiotepa; Clofarabine; Thymoglobulin; Antilymphocyte Serum

Study Results

Participant Flow

Arm/Group Title	Melphalan/Thiotepa/Clofarabine	Melphalan/Thiotepa/ Fludarabine
Arm/Group Description	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. Melphalan: Melphalan 70 mg/m2/day x 2 Thiotepa: Thiotepa 7.5 mg/kg/day x 2 Clofarabine: Clofarabine 20-30 mg/m2/day x 5 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. CliniMACS reagents: Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.	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. Melphalan: Melphalan 70 mg/m2/day x 2 Thiotepa: Thiotepa 7.5 mg/kg/day x 2 Fludarabine: Fludarabine 30 mg/m2/day x 5 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. CliniMACS reagents: Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.
Period Title: Overall Study
STARTED	1	0
COMPLETED	0	0
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Melphalan/Thiotepa/Clofarabine	Melphalan/Thiotepa/ Fludarabine	Total
Arm/Group Description	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. Melphalan: Melphalan 70 mg/m2/day x 2 Thiotepa: Thiotepa 7.5 mg/kg/day x 2 Clofarabine: Clofarabine 20-30 mg/m2/day x 5 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. CliniMACS reagents: Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.	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. Melphalan: Melphalan 70 mg/m2/day x 2 Thiotepa: Thiotepa 7.5 mg/kg/day x 2 Fludarabine: Fludarabine 30 mg/m2/day x 5 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. CliniMACS reagents: Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.	Total of all reporting groups
Overall Participants	1	0	1
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	20	20
Sex: Female, Male (Count of Participants)
Female	1 100%	1 Infinity
Male	0 0%	0 NaN
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 NaN
Not Hispanic or Latino	1 100%	1 Infinity
Unknown or Not Reported	0 0%	0 NaN
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 NaN
Asian	0 0%	0 NaN
Native Hawaiian or Other Pacific Islander	0 0%	0 NaN
Black or African American	0 0%	0 NaN
White	1 100%	1 Infinity
More than one race	0 0%	0 NaN
Unknown or Not Reported	0 0%	0 NaN
Region of Enrollment (Count of Participants)
United States	1 100%	1 Infinity

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	Overall survival is defined as time from transplant to death or last follow-up. Rate greater than 0.75 would be considered a success.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	Melphalan/Thiotepa/Clofarabine	Melphalan/Thiotepa/ Fludarabine
Arm/Group Description	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. Melphalan: Melphalan 70 mg/m2/day x 2 Thiotepa: Thiotepa 7.5 mg/kg/day x 2 Clofarabine: Clofarabine 20-30 mg/m2/day x 5 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. CliniMACS reagents: Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.	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. Melphalan: Melphalan 70 mg/m2/day x 2 Thiotepa: Thiotepa 7.5 mg/kg/day x 2 Fludarabine: Fludarabine 30 mg/m2/day x 5 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. CliniMACS reagents: Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.
Measure Participants	0	0

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	Only 1 participants was accrued before the study was closed to accrual due to low accrual
Arm/Group Title	Melphalan/Thiotepa/Clofarabine		Melphalan/Thiotepa/ Fludarabine
Arm/Group Description	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. Melphalan: Melphalan 70 mg/m2/day x 2 Thiotepa: Thiotepa 7.5 mg/kg/day x 2 Clofarabine: Clofarabine 20-30 mg/m2/day x 5 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. CliniMACS reagents: Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.		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. Melphalan: Melphalan 70 mg/m2/day x 2 Thiotepa: Thiotepa 7.5 mg/kg/day x 2 Fludarabine: Fludarabine 30 mg/m2/day x 5 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. CliniMACS reagents: Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.
All Cause Mortality
	Melphalan/Thiotepa/Clofarabine		Melphalan/Thiotepa/ Fludarabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/0 (NaN)
Serious Adverse Events
	Melphalan/Thiotepa/Clofarabine		Melphalan/Thiotepa/ Fludarabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)
Blood and lymphatic system disorders
Blood and lymphatic system disorders - Other, spec	1/1 (100%)		0/0 (NaN)
Cardiac disorders
Heart failure	1/1 (100%)		0/0 (NaN)
Respiratory, thoracic and mediastinal disorders
Pulmonary hypertension	1/1 (100%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Melphalan/Thiotepa/Clofarabine		Melphalan/Thiotepa/ Fludarabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.