Trial of Anti-CD19 and Anti-CD20 Bicistronic Chimeric Antigen Receptor T Cells for Treating B-Cell Malignancies

Chronic Lymphocytic Leukemia Clinical Trial

Official title: A Phase I Trial of Anti-CD19 and Anti-CD20 Bicistronic Chimeric Antigen Receptor T- Cells for Treating B-cell Malignancies

Status Recruiting

Clinical Trial Summary

Background:

About 23,000 people die from B-cell cancers in the US each year. These cancers, often called leukemia or lymphoma, affect a type of white blood cell called B cells. These cancers are difficult to treat, and the therapies used can have bad side effects. Researchers want to try a new type of treatment. This new treatment uses a patient s own immune cells (T cells) that are modified to carry genes (chimeric antigen receptor, or CAR T cells) to kill cancer cells.

Objective:

To test a treatment using CAR T cells in people with B-cell cancers.

Eligibility:

People aged 18 to 75 years with a B-cell cancer that has not been controlled with standard therapies.

Design:

Participants will be screened. They will have:

Blood and urine tests.

A needle will be inserted to draw a sample of tissue from inside the hip bone.

For some patients, a needle will be inserted into their lower back to get a sample of the fluid around their spinal cord.

A tumor biopsy might be needed.

Imaging scans.

Tests of their heart function.

Participants will undergo apheresis: Blood will be drawn from a needle in an arm. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a second needle.

Participants will receive 2 chemotherapy drugs once a day for 3 days.

Participants will be admitted to the hospital for at least 9 days. Their T cells, now modified, will be infused back into their bloodstream through a tube placed in a large vein.

Follow-up visits will continue for 5 years, but patients will need to stay in touch with the CAR treatment team for 15 year.

Clinical Trial Description

Background:

• Improved treatments for a variety of treatment-resistant malignancies including B-cell lymphomas, and chronic lymphocytic leukemia (CLL) are needed.

• A particular need is development of new treatments for chemotherapy-refractory B- cell malignancies.

• 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. These results have established anti-CD19 CAR T- cells as an important therapy for relapsed lymphoma, but only about 40% of patients receiving anti-CD19 CAR T- cells have durable complete remissions.

• Most B-cell malignancies express CD19 and CD20, but expression of CD19 and CD20 can be lost or diminished.

• CD19 and CD20 are not expressed by normal cells except for B cells and some plasma cells.

• We have constructed a novel gene therapy construct that encodes a fully-human anti- CD19 CAR with a CD28 domain and a fully-human anti-CD20 CAR with a 4-1BB domain.

• T -cells expressing this CAR construct, called Hu1928-Hu20BB-Long, can specifically recognize CD19 and CD20-expressing target cells in vitro and eradicate CD19 or CD20-expressing tumors in mice.

• One CAR expressed in this CAR construct, Hu19-CD828Z has been tested in humans before. The other CAR in the total construct, Hu20-CD8BBZ-Long, has not been tested in humans before.

• 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.

Objective:

• Determine the safety of administering T-cells expressing a novel fully-human anti- CD19 and anti-CD20 CAR construct to participant with advanced B-cell malignancies.

Eligibility:

• Participant must have any B-cell lymphoma, or CLL/small lymphocytic lymphoma (SLL), or Gray-zone lymphoma. Lower grade lymphomas transformed to diffuse large B-cell lymphoma (DLBCL) are potentially eligible.

• Age >= 18 years of age and <=75 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 protocol-required leukapheresis or CAR T-cell infusion. In addition, sixty days must elapse from therapy with antibodies targeting CD19 or CD20 and CAR T-cell infusion, and at least 180 days must elapse since any prior CAR T-cell therapy or checkpoint therapy.

• The participant s malignancy will need to be assessed for CD19 and C20 expression by flow cytometry or immunohistochemistry performed at the NIH. If unstained, paraffin- embedded bone marrow or lymphoma tissue sections are available from prior biopsies, these can be used to determine CD19 and CD20 expression by immunohistochemistry; otherwise, Participant will need to come to the NIH for a biopsy to determine CD19 and CD20 expression. The sample for CD19 and CD20 expression must come from a biopsy obtained after any CD19 or CD20-targeted therapies such as monoclonal antibodies if such antibodies or CAR T-cell therapies have been received by the Participant.

• Either CD19 or CD20 expression must be uniform . Uniform CD19 or CD20 expression is defined as no obvious lymphoma population lacking antigen expression can be present.

Design:

• This is a phase I dose-escalation trial

• T-cells obtained by leukapheresis will be genetically modified to express the Hu1928- Hu20BB-Long CAR construct.

• Participants will receive a lymphocyte-depleting chemotherapy conditioning regimen with the intent of enhancing the activity of the infused CAR-expressing T- cells.

• 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 anti- CAR- expressing T- cells .

• The initial dose level of this dose-escalation trial will be 0.66x10^6 CAR+ T- cells/kg of recipient bodyweight.

• The cell dose administered will be escalated until a maximum tolerated 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
• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma, B-Cell

• NCT number: NCT05797233
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Genevieve C Fromm
• Phone: (240) 858-3663
• Email: NCICAR@mail.nih.gov
• Status: Recruiting
• Phase: Phase 1
• Start date: August 28, 2023
• Completion date: December 30, 2029