CD34 Selected Allogeneic HCT w/ Myeloablative Conditioning Plus CD8+ Memory TCell Infusion in MDS, AL and CML

Phase 2

Completed

• Conditions: Acute Myeloid Leukemia; Acute Leukemia; Chronic Myeloid Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndromes
• Interventions: Drug: CD8+ Memory T Cell Infusion; Drug: Thiotepa; Drug: Fludarabine; Radiation: Hyperfractionated TBI; Drug: Busulfan; Drug: Cyclophosphamide

• Registration Number: NCT04151706
• Lead Sponsor: Robert Lowsky

Brief Summary

This study will evaluate combining stem cells from the patient's matched sibling donor (a standard CD34-selected transplant) with a second infusion of white blood cells called "CD8 memory T-cells" from their sibling donor.

Detailed Description

Primary Objective: To determine the rate of graft versus host disease (GvHD) free, relapse free survival (GRFS) at one year following CD34 selected allogeneic hematopoietic cell transplantation using myeloablative conditioning combined with an infusion of phenotypic CD8+ memory T cells from human leukocyte antigen (HLA) matched donors for patients with myelo...

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2019-11-01
• Study First Submitted QC: 2019-11-01
• Study First Posted: 2019-11-05
• Study Start: 2020-02-27
• Primary Completion: 2023-09-08
• Study Completion: 2023-09-08
• Results First Submitted: 2024-09-09
• Status Verified: 2024-10
• Results First Submitted QC: 2024-10-15
• Last Update Submitted: 2024-10-15
• Results First Posted: 2024-10-17
• Last Update Posted: 2024-10-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 7

Inclusion Criteria

• Acute leukemia, in morphologic complete remission, OR myelodysplasia with < 10% blasts in the marrow, and no circulating blasts that contain auer rods. Patients with chronic myelomonocytic leukemia (CMML) must have a WBC count ≤ 10,000 cells/μL and < 10% blasts in the marrow.
• Planned myeloablative conditioning regimen at Stanford University Medical Center.
• Karnofsky or Lansky Performance Score ≥ 70%.
• Must have an HLA related donor as follows: onor must be an 8/8 match for HLA A, B and C at intermediate (or higher) resolution, and DRB1 at high resolution using DNA based typing. The donors must be willing to receive G CSF followed by collection of cells by apheresis, and must meet the Program's criteria for donation.
• Cardiac function: Ejection fraction at rest ≥ 40%.
• Serum creatinine value of < 1.5 mg/dL, or an estimated creatinine clearance greater than 50 mL/minute (using the Stanford calculator for eGFR available in EPIC)
• Diffusing capacity of the lungs for carbon monoxide (DLCO) ≥ 50% (adjusted for Hgb)
• Forced vital capacity (FVC) ≥ 50%.
• Forced expiratory volume (FEV1) ≥ 50%.
• Total bilirubin < 2 times the upper limit of normal (ULN) (unless the elevated bilirubin is attributed to Gilbert's Syndrome)
• Alanine aminotransferase (ALT) < 2.5 x ULN
• Aspartate aminotransferase (AST) < 2.5 x ULN
• Total bilirubin < 2 times the upper limit of normal (unless elevated bilirubin is attributed to Gilbert's Syndrome)
• Signed informed consent

Recipient

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Exclusion Criteria

• Prior autologous or allogeneic hematopoietic stem cell transplant
• Prior malignancies, except resected non melanoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously is allowed. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs
• Active central nervous system (CNS) involvement by malignant cells
• Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
• Requirement for supplemental oxygen
• Uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment
• History of uncontrolled autoimmune disease or on active treatment (defined as > 5 mg prednisone daily)
• Seropositive for HIV 1 or 2
• Seropositive for HTLV I or -II
• Active Hepatitis B or C viral replication by polymerase chain reaction (PCR)
• Documented allergy to iron dextran or murine proteins
• Pregnant (positive serum or urine βHCG) or breastfeeding)
• Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use an effective form of birth control or abstinence for one year after transplantation
• Unable to comply with the treatment protocol, including appropriate supportive care, follow up and research tests.
• Planned to receive post transplant maintenance therapy except for fms-like tyrosine kinase 3 (FLT3) inhibitors or BCR ABL tyrosine kinase inhibitors (TKIs).

Donor Inclusion Criteria:

• HLA matched donor (matching at 8/8 antigens or alleles including HLA A, B, C, and -DRB1).
• ≥ 18 years to < 66.0 years
• State of general good health
• Completed a donor evaluation with history, medical examination and standard blood tests within 60 days of starting the hematopoietic cell collection procedure. In order to fairly represent the interests of the donor, the donor evaluation and consent will be performed by a study team member other than the recipient's attending physician.
• Hepatitis A, B and C, HIV 1 and 2, HTLV, VZV, EBV, HSV, West Nile virus, Syphilis Treponema, T cruzi (Chagas), CMV, and the MPX NAT IDT (HIV/HCV/HBV) will be tested as per national standard of care guidelines for transplant donors. Donors who are HIV positive will be excluded. Donors who are positive by serology for Hepatitis B or C are eligible as long as PCR for RNA/DNA is negative
• White blood cell count > 3.5 x 109/L
• Platelets > 150 x 109/L
• Hematocrit > 35%
• Capable of undergoing leukapheresis
• Able to understand and sign informed consent

Donor Exclusion Criteria:

• Psychological traits or psychological or medical conditions which make them unlikely to tolerate the procedure
• Pregnant or lactating female

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
fTBI/Thiotepa/fludarabine	CD8+ Memory T Cell Infusion	Participants will be infused on Day 0 with donor derived CD34+ selected cells combined with CD8+CD45RA- T cells {CD Memory T Cells} following a standard myeloablative conditioning regimen that might consist of fTBI, Thiotepa, and Fludarabine or Busulfan and Cyclophosamide.
fTBI/Thiotepa/fludarabine	Hyperfractionated TBI	Participants will be infused on Day 0 with donor derived CD34+ selected cells combined with CD8+CD45RA- T cells {CD Memory T Cells} following a standard myeloablative conditioning regimen that might consist of fTBI, Thiotepa, and Fludarabine or Busulfan and Cyclophosamide.
fTBI/Thiotepa/fludarabine	Busulfan	Participants will be infused on Day 0 with donor derived CD34+ selected cells combined with CD8+CD45RA- T cells {CD Memory T Cells} following a standard myeloablative conditioning regimen that might consist of fTBI, Thiotepa, and Fludarabine or Busulfan and Cyclophosamide.
fTBI/Thiotepa/fludarabine	Thiotepa	Participants will be infused on Day 0 with donor derived CD34+ selected cells combined with CD8+CD45RA- T cells {CD Memory T Cells} following a standard myeloablative conditioning regimen that might consist of fTBI, Thiotepa, and Fludarabine or Busulfan and Cyclophosamide.
fTBI/Thiotepa/fludarabine	Fludarabine	Participants will be infused on Day 0 with donor derived CD34+ selected cells combined with CD8+CD45RA- T cells {CD Memory T Cells} following a standard myeloablative conditioning regimen that might consist of fTBI, Thiotepa, and Fludarabine or Busulfan and Cyclophosamide.
fTBI/Thiotepa/fludarabine	Cyclophosphamide	Participants will be infused on Day 0 with donor derived CD34+ selected cells combined with CD8+CD45RA- T cells {CD Memory T Cells} following a standard myeloablative conditioning regimen that might consist of fTBI, Thiotepa, and Fludarabine or Busulfan and Cyclophosamide.

Primary Outcome Measures

Name	Time	Method
Number of Participants Achieving Graft-versus-Host Disease-Free and Relapse-Free Survival (GRFS) Through 1 Year Post-Transplant	1 year	The rate of participants who do not experience GvHD and also do not experience relapse are collectively considered to be GRFS. Relapse will be assessed according to the myelodysplastic syndrome or leukemia response criteria. The participants will be assessed for GRFS though 1 year post transplant. The outcome will be reported as the number of participants, a...

Secondary Outcome Measures

Name	Time	Method
Number of Participants Experiencing Graft Rejection Through 1 Year Post-Transplant	1 year	Graft rejection will be determined on the basis of reaction against the donor hematopoietic cells. The outcome will be reported as the number of participants who experience graft rejection though 1 year post transplant, a number without dispersion
Number of Participants Experiencing Acute Graft-versus-Host Disease (GvHD) Through 1 Year Post-Transplant	1 year	The participants will be assessed for acute graft versus host disease (GvHD) though 1 year post transplant. The outcome will be reported as the number of participants who experience acute GvHD, a number without dispersion.
Number of Participants With Chronic, Steroid-Requiring Graft-versus-Host Disease (GvHD) Through 1 Year Post-Transplant	1 year	The participants will be assessed for chronic, steroid requiring graft versus host disease (GvHD) though 1 year post transplant. The outcome will be reported as the number of participants who experience chronic GvHD, a number without dispersion.
Number of Participants With Non-Relapse Mortality Through 1 Year Post-Transplant Without Recurrence of Myelodysplastic Syndrome or Leukemia	1 year	Non relapse mortality will be assessed as the number of participants who have died though 1 year post transplant, without a relapse or recurrence of their myelodysplastic syndrome or leukemia. Relapse will be assessed according to the myelodysplastic syndrome or leukemia response criteria. The outcome will be reported as the number of affected participants, ...
Number of Participants Who Experience Relapse Through 1 Year Post-Transplant	1 year	Relapse will be assessed according to the myelodysplastic syndrome or leukemia response criteria. The outcome will be reported as the number of participants who experience relapse though 1 year post transplant, a number without dispersion.
Overall Survival (OS)	1 year	Overall Survival (OS) will be assessed as the number of participants who remain alive at 1 year post transplant. The outcome will be reported as a number without dispersion.

Trial Locations

Locations (1)

Stanford Medical Center; 🇺🇸 Stanford, California, United States