T Cells Expressing a Fully-human AntiCD19 Chimeric Antigen Receptor for Treating B-cell Malignancies

Lymphoma, B-Cell Clinical Trial

Official title: T Cells Expressing a Fully-Human Anti-CD19 Chimeric Antigen Receptor for Treating B-cell Malignancies

Status Completed

Clinical Trial Summary

Background:

The immune system fights infection and can affect cancer cells. T cells are white blood cells that are a major part of the immune system. T cells can destroy tumors. Researchers want to try to manipulate the immune system to better recognize and kill tumor cells.

Objective:

To test the safety of giving T cells expressing a novel fully-human anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) to people with advanced B-cell cancer.

Eligibility:

People ages 18-73 with a B-cell cancer that has not been controlled by other therapies.

Design:

Participants will be screened with:

Physical exam

Blood and urine tests

Heart tests

Bone marrow sample taken

Scans in machines that take pictures

Participants will have apheresis. Blood is removed through a needle in an arm. T cells are removed. The rest of the blood is returned through a needle in the other arm.

The cells will be changed in a laboratory.

Participants will get 2 chemotherapy drugs over 3 days.

Two days later, participants will check into the hospital. They will get an intravenous (IV) catheter in an arm or chest vein. They will get the T cells through the IV in 1 infusion.

After this, participants will stay in the hospital for at least 9 days and stay nearby for 2 weeks. Then they will have blood tests and see a doctor.

Participants will have visits 6 visits for 1 year after the infusion. Some may have more follow-up visits.

Participants may samples taken of spinal fluid, bone marrow, and tumors.

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Clinical Trial Description

Background:

• Improved treatments for a variety of treatment-resistant B-cell malignancies including Bcell 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 cluster of differentiation 19 (CD19) have caused complete remissions in a small number of patients with leukemia or lymphoma. These results demonstrate that anti-CD19 CAR-expressing T cells have antimalignancy activity in humans.

• The vast majority of B-cell malignancies express CD19.

• CD19 is not expressed by normal cells except for B cells.

• We have constructed a novel fully-human anti-CD19 CAR that can specifically recognize CD19-expressing target cells in vitro and eradicate CD19-expressing tumors in mice.

• This fully-human CAR targeting CD19 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.

Objectives:

Primary

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

Secondary

• Evaluate the in vivo persistence and peak blood levels of anti-CD19 CAR T cells after initial and repeated CAR T-cell infusions. CAR T-cell blood levels will be compared retrospectively to results with an anti-CD19 CAR containing an antigen-recognition moiety derived from a murine antibody.

• Assess for evidence of anti-malignancy activity by anti-CD19 CAR T cells

• Assess the impact of repeated CAR T-cell infusions on residual malignancy after an initial CAR T-cell infusion.

• Assess the immunogenicity of the CAR used in this protocol.

Eligibility:

• Patients must have any B-cell lymphoma, or CLL/small lymphocytic lymphoma (SLL). Lower grade lymphomas transformed to DLBCL are potentially eligible as is primary mediastinal B-cell lymphoma and all other subtypes of Diffuse large B-cell lymphoma (DLBCL).

• Patients must have malignancy that is measurable on a computed tomography (CT) scan or by flow cytometry of bone marrow or blood.

• Patients must have a creatinine of 1.4 mg/dL or less and a normal cardiac ejection fraction.

• An Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 is required.

• No active infections are allowed including any history of hepatitis B or hepatitis C.

• Absolute neutrophil count greater than or equal to1000/microliter, platelet count greater than or equal to 45,000/microliter, hemoglobin greater than or equal to 8g/dL

• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (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 initiation of protocol enrollment.

• The patients malignancy will need to be assessed for CD19 expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (NIH). If unstained, paraffinembedded bone marrow or lymphoma sections are available from prior biopsies, these can be used to determine CD19 expression by immunohistochemistry; otherwise, patients will need to come to the NIH for a biopsy to determine CD19 expression. The sample for CD19 expression can come from a biopsy obtained at any time before enrollment.

• Patients who have never had an allogeneic hematopoietic stem cell transplant are potentially eligible.

Design:

• This is a phase I dose-escalation trial

• Patients will undergo leukapheresis

• T-cells obtained by leukapheresis will be genetically modified to express an anti-CD19 CAR

• Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the intent of enhancing the activity of the infused anti-CD19-CAR-expressing T cells.

• The chemotherapy conditioning regimen is cyclophosphamide 300 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.

• Two days after the chemotherapy ends, patients will receive an infusion of anti-CD19-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, 6, 9, and 12 months after the CAR T-cell infusion. Long-term gene-therapy follow-up consisting of yearly visits to a doctor near the patient s home for 4 more years and then yearly telephone contact for 10 additional years will be required.

• Repeat treatments consisting of the conditioning chemotherapy followed by a CAR T-cell infusion are planned for eligible patients with any best responses except continuing complete remission or progressive malignancy.

• Re-enrollment will be allowed for a small number of subjects. ;

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Lymphoma, Non-hodgkins
• Neoplasms

• NCT number: NCT02659943
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: January 21, 2016
• Completion date: December 31, 2022