Trials / Recruiting

RecruitingNCT06364423

Anti-CD19 Chimeric Antigen Receptor T-Cell Immunotherapy for Leukemias

Phase I/II Trial of Anti-CD19 Chimeric Antigen Receptor T-Cell Immunotherapy for B-cell Leukemias

Status: Recruiting
Phase: Phase 1 / Phase 2
Study type: Interventional
Enrollment: 132 (estimated)

Sponsor: National Cancer Institute (NCI) · NIH
Sex: All
Age: 18 Years – 120 Years
Healthy volunteers: Not accepted

Summary

Background: Chronic lymphocytic leukemia (CLL),small lymphocytic lymphoma (SLL) and B-cell acute lymphoblastic leukemia or lymphoma (ALL) are blood cancers that affect certain white blood cells. Advanced forms of these diseases are difficult to treat. CD19 is a protein often found on the surfaces of these cancer cells. Researchers can modify a person's own immune cells (T cells) to target CD19. When these modified T cells are returned to the body-a treatment called anti-CD19 chimeric antigen receptor (CAR) T cell therapy-they may help kill cancer cells. Objective: To test anti-CD19 CAR T cell therapy in people with CLL or SLL and ALL. Eligibility: People aged 18 years and older with CLL or SLL and ALL that has not been controlled with standard drugs. Design: Participants will be screened. They will have imaging scans and tests of their heart function. If a sample of tissue from their tumor is not available, a new one may be taken; the sample will be tested for CD19. Participants will receive a drug to reduce the leukemia cells in their blood. Then they will undergo apheresis: Blood will be taken from the body through a needle. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different needle. The collected T cells will be gene edited to make them attack cells with CD19. Participants will take drugs to prepare them for treatment for 3 days. These drugs will start 5 days before the treatment. Then their own modified CAR T cells will be returned to their bloodstream. Participants will stay in the hospital for at least 9 days after the treatment. Follow-up visits will continue for 5 years.

Detailed description

Background: * Improved treatments for relapsed and refractory chronic lymphocytic leukemia/Small lymphocytic leukemia (CLL/SLL) and B-cell acute lymphoblastic leukemia or lymphoma (ALL) are needed. * T cells can be genetically modified to express chimeric antigen receptors (CARs) that specifically target malignancy-associated antigens. * Autologous T cells genetically modified to express CARs targeting the B-cell antigen CD19 have caused complete remissions in patients with leukemia or lymphoma. Responses to CAR T-cell therapy in CLL/SLL have historically been lower than in other B-cell malignancies. * CD19 is uniformly expressed on CLL/SLL and ALL. * CD19 is not expressed by normal cells except for B cells, follicular dendritic cells,and some plasma cells. * We have constructed a novel gene therapy construct that encodes a fully-human anti-CD19 CAR. * The conditioning regimen for this trial will include rituximab, fludarabine, and cyclophosphamide. * Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and neurological toxicities. Elimination of normal B cells is probable, and unknown toxicities are also possible. Primary objective, Phase I: -Determine the safety of administering T cells expressing an anti-CD19 CAR with a fully-human single chain variable fragment (scFv) to participants with advanced CLL/SLL(cohort 1) or ALL (cohort 3). Primary objective, Phase II: -Determine the overall response rate (ORR) of a novel conditioning regimen and T cells expressing the Hu19-CD828Z CAR for participants with advanced CLL/SLL and ALL. Eligibility: * Participant must have CD19+ and CD20+ CLL/SLL, or CD19+ and CD20+ B-cell ALL. * Age \>= 18 years of age * Participants must have malignancy that is measurable on a CT scan or by flow cytometry of bone marrow or blood. * Participant must have a creatinine less than 1.5 X institutional ULN and a normal cardiac ejection fraction. Participants with creatinine \>= 1.5 X institutional ULN may participate if serum creatinine eGFR is \>=50 mL/min/1.73m\^2 by 2021 CKD-EPI equation. * An ECOG performance status of 0-1 is required. * No active infections are allowed including hepatitis B or hepatitis C. * Absolute neutrophil count \>= 1000/microL, platelet count \>= 50,000/microL, hemoglobin \>= 8g/dL * Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal unless liver involvement by malignancy is demonstrated. * At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids) and the first dose of protocol-required rituximab, with the exceptions of Bruton s tyrosine kinase inhibitors (BTKi) for CLL/SLL and tyrosine kinase inhibitors (TKI) for ALL. * Prior CAR T-cell therapy is not allowed. * Demonstration of CD19 and CD20 expression on malignant cells is required for eligibility. * CD19 expression must be "uniform". "Uniform" CD19 expression is defined as no obvious CD19-negative malignant cells being present. CD20 expression must be demonstrated in at least 20% of malignant cells for all participants. Design: * This is a phase I dose-escalation trial with expansion cohorts (Phase II portion) * T cells obtained by leukapheresis will be genetically modified to express the Hu19-CD828Z CAR. * Participants will receive 2 doses of rituximab and a lymphocyte-depleting chemotherapy conditioning regimen with the intent of decreasing the burden of leukemia, which might reduce toxicity and improve anti-leukemia outcomes. * Rituximab will be given in 2 doses, of 375 mg/m\^2 for the first dose and 500 mg/m\^2 (for CLL) or 375 mg/m\^2 (for ALL) for the second dose. * The chemotherapy conditioning regimen is cyclophosphamide 500 mg/m\^2 daily for 3 days and fludarabine 30 mg/m\^2 daily for 3 days. Fludarabine will be given on the same days as the cyclophosphamide. * Three days after the chemotherapy ends, participants will receive an infusion of CAR T cells. * The initial dose level of this dose-escalation trial will be 1.0x10\^6 CAR+ T cells/kg of recipient bodyweight for both the CLL/SLL and the ALL cohorts. * The CAR T-cell cell dose administered will be escalated until a maximum tolerated dose or an optimal dose is determined for each cohort. * Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to monitor for toxicity. * Outpatient follow-up is planned for 2 weeks and 1, 2, 3, 4, 6, 9, and 12 months after the CAR T-cell infusion; less frequent follow-up is required more than 1 year after infusion. Long-term gene-therapy follow-up for a total of 15 years after infusion is required.

Conditions

Interventions

Type	Name	Description
BIOLOGICAL	Autologous HuCD19 ( Anti-CD19)CAR T cells	1.0x10\^6 CAR+T-cells - 12x10\^6 CAR+ T cells/kg (weight based dosing per cohort) infused on day 0
DRUG	Cyclophosphamide	500 mg/m\^2 IV infusion over 30 minutes on days -5, -4 and -3
DRUG	Fludarabine	30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3
DRUG	Rituximab	500 mg/m\^2 IV infusion over 30 minutes on day -5; 375 mg/m\^2 IV infusion over 30 minutes on days 2-9 prior to apheresis

Timeline

Start date: 2024-09-03
Primary completion: 2029-07-01
Completion: 2030-07-01
First posted: 2024-04-15
Last updated: 2026-03-02

Locations

1 site across 1 country: United States

Regulatory

FDA-regulated drug study

Source: ClinicalTrials.gov record NCT06364423. Inclusion in this directory is not an endorsement.