NCT07162038

Phase I Trial Integrating HLA-Haploidentical Anti-CD19 CAR-T Cells With Post-Transplantation Cyclophosphamide-Based HLA-Haploidentical Hematopoietic Cell Transplantation

Phase I Trial Integrating HLA-Haploidentical Anti-CD19 CAR T Cells With Post-Transplantation Cyclophosphamide-Based HLA-Haploidentical Hematopoietic Cell Transplantation

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 155 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

Background: High-risk blood cancers (leukemias and lymphomas) often come back after treatment, and many cannot be cured with chemotherapy alone. These cancers may be treated and potentially cured in 2 ways: (1) Bone marrow transplant (allogeneic hematopoietic cell transplantation, or alloHCT) gives immune and blood stem cells from a donor. These new cells can attack the cancer and also grow into healthy blood. (2) Chimeric antigen receptor (CAR) T-cell therapy takes immune cells and changes them in a lab to better recognize and target certain cancers. But these 2 treatments are not usually given at the same time. Objective: To test alloHCT and CAR-T cell therapy, used together, in people with high-risk blood cancers. Eligibility: People aged 18 to 75 years with an aggressive blood cancer that has a protein on the surface called CD19. A healthy related donor aged 12 years or older is also needed; this donor may be a parent or child or may be some siblings or even extended family members, but has to be half-matched at something called the HLA (human leukocyte antigen). Design: Participants will be screened. They will have imaging scans, blood tests, and tests of their heart and lung function. They will have eye and dental exams. They may have fluid drawn from around their spinal cord (spinal tap) and tissue taken from inside a bone (bone marrow biopsy). Healthy donors will provide bone marrow, immune cells, and about 9 tablespoons of blood for both the recipient s treatment and for research. They will also provide stool, saliva, and oral swabs just for research. Recipient participants will stay in the hospital for 4 to 6 weeks. They will be given drugs over 6 days to prepare for the cell therapies. Both the donor bone marrow cells and CAR-T-cells will be given through a tube inserted into a vein. They will receive drugs to reduce complications after the treatments. Participants will remain within a 1-hour drive of the hospital for 2 to 3 months after they leave the hospital. They will have frequent visits during that time. They will continue to have periodic follow-up visits for 5 years. ...

Detailed description

Background: * High-risk hematologic malignancies generally are incurable without an allogeneic hematopoietic cell transplant (HCT), but even with HCT they are at high-risk of relapse and poor overall survival. * Chimeric-antigen-receptor (CAR) T-cell therapy can offer a high remission rate for relapsed or refractory B-cell malignancies but is not curative in the majority of patients. * Currently, these two therapies (HCT and CAR-T cells) are used individually or sequentially, with HCT being used as consolidation or salvage post-CAR-T cells or CART cells being used to treat post-HCT relapse. * Allogeneic CAR-T cells may be given to treat post-transplant relapse, but have not been used early post-transplant due to potential increased risk of graft-versus-host disease (GVHD). * Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic GVHD and the immunosuppressive burden after HCT, including allowing LAhaploidentical HCT to be performed safely and routinely worldwide. * In pre-clinical major histocompatibility complex (MHC)-haploidentical HCT models, CAR-T cells can be given on day 0 or day +5 (before or early after PTCy) and exert potent anti-tumor effects without impairing PTCy s efficacy in preventing GVHD. Administration of CAR-T cells on day +9 or +14 was ineffective in eradicating leukemia. * In our preclinical models, administration of CAR-T cells on day 0 (prior to PTCy) surprisingly led to better anti-tumor efficacy than when given on day +5, associated with better early expansion, less CD4+ CAR-T cells with a regulatory phenotype, more activated CD4+ CAR-T cells, and more cytotoxic CD8+ CAR-T cells. * The premise for the clinical application is that the CAR-T cells given in conjunction with or early post-transplant would induce an initial deep remission, while the polyclonal allogeneic T cells contained in the HCT would eliminate escape clones and promote longterm cure. * The direct integration of CAR-T cells with PTCy-based HCT has the potential to provide synergistic reduction of relapse, reduce the duration of treatment, and allow CAR-T cells to persist post-transplant. Objectives: * To identify the safety of donor-derived HLA-haploidentical anti-CD19 CAR-T cells that can be given in combination with PTCy-based HLA-haploidentical allogeneic HCT in participants who have high-risk CD19-expressing hematologic malignancies (Phase I -dose escalation). * To estimate 1 year relapse and survival outcomes at the maximum tolerated dose (MTD) (Phase I - dose expansion) Eligibility: * Adults age 18-75 years * High-risk CD19-expressing hematologic malignancies * Available HLA-haploidentical donor * Adequate organ function * KPS \>= 60% Design: * Open-label, single-center, non-randomized, phase I study * All recipient participants will receive reduced intensity conditioning, HLA-haploidentical bone marrow HCT, GVHD prophylaxis including post-transplantation cyclophosphamide, and allogeneic donor-derived anti-CD19 CAR-T cells. * The study will proceed to a small, four-level phase I dose escalation study based on the standard 3+3 approach. CAR-T cells will be administered on day 0, except in the case of dose de-escalation wherein alternative dose levels would be employed and CAR-T cells would then be administered on day +7. * Dose-escalation will be based on absence of grade III-IV acute GVHD (aGVHD), severe cytokine release syndrome (CRS), severe neurotoxicity or other toxicities as specified, or non-relapse mortality by day +28 * We will expand to include 6 additional participants at the maximum tolerated dose level determined by the phase I dose escalation to better estimate relapse and GVHD outcomes. Recipient participants will be followed for 5 years.

Conditions

• Hematologic Malignancies
• Hematologic Neoplasms

Interventions

Type	Name	Description
BIOLOGICAL	mCD19-CAR-CD28-CD3-zeta.(anti-CD19 CAR) retroviral vector-transduced allogeneic peripheral blood lymphocytes (PBL)	CAR-T cell infusion given at four escalating dose levels (DL1: 3 x 10\^4 cells/kg, DL2: 1 x 10\^5 cells/kg, DL3: 3 x 10\^5 cells/kg, DL4: 1 x 10\^6 cells/kg) with a dose de-escalation dose (DL-1: 1 x 10\^4 cells/kg), if needed.
DRUG	Fludarabine	Pre-transplant: 30 mg/m\^2 IV infusion over 30-60 minutes once daily for 5 days from day -6 through day -2
DRUG	Cyclophosphamide	Pre-transplant: 14.5 mg/kg/day IV daily for 2 days pre-transplant on day -6 and day -5. Post-transplant: 25 mg/kg/day on day +3 and day +4.
DRUG	Mycophenolate Mofetil	15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35 post-transplant.
DRUG	Sirolimus	Loading dose of 6 mg orally given on day +5, then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +60 post-transplant.
DEVICE	CD19 Flow Cytometry Assay	Assay used to determine CD19+ status
DEVICE	CD19 Immunohistochemical Assay	Assay used to determine CD19+ status
RADIATION	Total Body Irradiation	400 centigray (cGy) to be delivered in 2 fractions as 200 cGy per fraction twice a day on Day -1 pre-transplant.

Timeline

• Start date: 2025-11-14
• Primary completion: 2030-11-01
• Completion: 2034-10-01
• First posted: 2025-09-09
• Last updated: 2026-01-23

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study