Anti-CD19 Chimeric Antigen Receptor T-Cell Immunotherapy for Chronic Lymphocytic Leukemia (CLL)

B-Cell Chronic Lymphocytic Leukemia Clinical Trial

Official title: Phase I/II Trial of Anti-CD19 Chimeric Antigen Receptor T-Cell Immunotherapy for Chronic Lymphocytic Leukemia (CLL)

Status Not yet recruiting

Clinical Trial Summary

Background:

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) 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.

Eligibility:

People aged 18 years and older with CLL or SLL 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.

Clinical Trial Description

Background:

• Improved treatments for relapsed and refractory chronic lymphocytic leukemia (CLL) 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. However, there is no FDA-approved CAR T-cell product for CLL. Responses to CAR T-cell therapy in CLL have historically been lower than in other B-cell malignancies.

• CD19 is uniformly expressed on CLL.

• 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 a novel conditioning regimen and T cells expressing the Hu19-CD828Z CAR to participants with advanced CLL.

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.

Eligibility:

• Participant must have CLL or small lymphocytic lymphoma (SLL).

• Age >= 18 years of age at time of enrollment

• Participant must have malignancy that is measurable on a CT scan or by flow cytometry of bone marrow or blood.

• Participant must have a creatinine of 1.5 mg/dL or less and a normal cardiac ejection fraction.

• 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. In addition, 60 days must elapse from therapy with antibody-based treatments targeting CD19 and CAR T-cell infusion.

• Prior CAR T-cell therapy is not allowed.

• Demonstration of CD19 expression by the CLL/SLL is required for eligibility.

• CD19 expression must be uniform . Uniform CD19 expression is defined as no obvious CD19-negative CLL/SLL being present.

Design:

• This is a phase I dose-escalation trial with an expansion cohort (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 CLL, 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 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.

• The CAR T-cell cell dose administered will be escalated until a maximum tolerated dose or an optimal dose is determined.

• 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. ;

Related Conditions & MeSH terms

• B-Cell Chronic Lymphocytic Leukemia
• B-Lymphocytic Leukemia, Chronic
• Leukemia
• Leukemia, B-Cell
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

• NCT number: NCT06364423
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Micaela A Ganaden, R.N.
• Phone: (240) 858-3654
• Email: micaela.ganaden@nih.gov
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: June 26, 2024
• Completion date: July 1, 2030