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Cyclophosphamide

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Escalating dose of anti-CD19 and anti-CD20 CAR T- cells/kg + conditioning chemotherapy

MTD dose or Optimal dose of Anti-CD19 and anti-CD20 CAR T- cells/kg + conditioning chemotherapy

0.66x10\^6 CAR+ T - 10x10\^6 CAR+ T cells/kg (weight based dosing per cohort) infused on day 0

Anti-CD19 and anti-CD20 bicistronic CAR T- cells

500 mg/m\^2 IV infusion over 30 minutes on days -5, -4 and -3

30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3

Genevieve C Fromm

James N Kochenderfer, M.D.

Genevieve Fromm

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.

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.

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

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

.All IPD recorded in the medical record will be shared with intramural investigators upon request.

Adverse Events (AE) by type and grade of toxicity

Complete Response rate (CR) in participants who receive subsequent infusion, up to 5 years after entry date for last participant

Overall Response rate (ORR= CR + PR) will be recorded if ORR occurs at any response assessment time-point.

Duration of response from date of response will be measured for no more than 5 years after the last participant has been enrolled on the trial.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Trial of Anti-CD19 and Anti-CD20 Bicistronic Chimeric Antigen Receptor T Cells for Treating B-Cell Malignancies	NCT05797233	Chronic Lymphoc... B-Cell Chronic ... Lymphoma, B-Cel...	Anti-CD19 and a... Cyclophosphamid... Fludarabine	18 Years - 75 Years	National Institutes of Health Clinical Center (CC)
Trial of Anti-CD19 and Anti-CD20 Bicistronic Chimeric Antigen Receptor T Cells for Treating B-Cell Malignancies	NCT05797233	Chronic Lymphoc... B-Cell Chronic ... Lymphoma, B-Cel...	Anti-CD19 and a... Cyclophosphamid... Fludarabine	18 Years - 75 Years	National Institutes of Health Clinical Center (CC)

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