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

Last updated: January 31, 2025
Sponsor: National Cancer Institute (NCI)
Overall Status: Active - Not Recruiting

Phase

1

Condition

Lymphoma, B-cell

Lymphocytic Leukemia, Chronic

Lymphoproliferative Disorders

Treatment

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

Fludarabine

Cyclophosphamide

Clinical Study ID

NCT05797233
10001524
001524-C
  • Ages 18-75
  • All Genders

Study 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.

Eligibility Criteria

Inclusion

  • INCLUSION CRITERIA:

Malignancy criteria

  • CD19 and or CD20 expression is required. For all lymphoma types, eligibilitycriteria are met if there is uniform expression of both CD19 and CD20. Eligibilitycriteria are also met with expression of either CD19 or CD20. CD19 and/or CD20expression must be "uniform". "Uniform" CD19 or CD20 expression is defined by CD19and/or CD20 antigen expression on lymphoma cells with no obvious lymphoma populationlacking antigen expression. Antigen expression can be assessed by eitherimmunohistochemistry or flow cytometry.

  • Pathology confirmed B-cell malignancy. Only when insufficient biopsy material isavailable to allow CD19 and CD20 expression assessment at the NIH, CD19 and/or CD20staining performed at another institution can be used.

  • At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids) and protocol-required leukapheresis or start of protocolconditioning chemotherapy.

  • At least sixty days must elapse from therapy with antibodies targeting CD19 or CD20and CAR T-cell infusion.

  • At least 180 days must elapse after any prior CAR T-cell therapy, but otherwise,prior CAR T-cell therapy is allowed.

  • Participants with DLBCL (including all subtypes such as primary mediastinal B-celllymphoma and high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement)must have received at least two prior regimens at least one of which must havecontained doxorubicin and an anti-CD20 monoclonal antibody.

  • Follicular lymphoma participants must have received at least 2 prior regimensincluding at least 1 regimen with chemotherapy and 1 regimen with an anti-CD20monoclonal antibody.

  • Burkitt lymphoma participants must have had at least 1 prior cytotoxic chemotherapy-containing regimen that also contained an anti-CD20 monoclonal antibody.

  • All participants with CLL or small lymphocytic lymphoma must have had at least 1prior line of treatment, and these participants must have had progressive CLL/SLLafter exposure to ibrutinib or another Bruton tyrosine kinase inhibitor andvenetoclax.

  • T-cell rich B-cell lymphoma is eligible if previously treated with at least 2 linesof therapy.

  • Waldenstrom s macroglobulinemia/lymphoplasmacytic lymphoma patients are eligible ifpreviously treated with at least 2 regimens including exposure to a monoclonalantibody, a bruton tyrosine kinase inhibitor, and cytotoxic chemotherapy.

  • Participants with mantle cell lymphoma are eligible after receiving a Brutontyrosine kinase (BTK) inhibitor, an anti-CD20 monoclonal antibody, and at least oneof the following chemotherapy drugs: cytarabine, bendamustine, or an anthracycline.

  • Other B-cell lymphoma types, including B-cell lymphoma unclassifiable with featuresintermediate between DLBCL and Hodgkin lymphoma (Gray zone), that are notspecifically mentioned above are allowed if the participant has received at least 2lines of therapy at least 1 of which must have contained cytotoxic chemotherapy.

  • Primary central nervous system lymphoma patients are not eligible.

All participants must have measurable malignancy as defined by at least one of the criteria below.

  • Lymphoma or leukemia masses that are measurable (minimum 1.5 cm in largest diameter)by CT scan is required for all diagnoses except CLL unless bone marrow or bloodinvolvement with malignancy is detected. All masses must be less than or equal to

10.0 cm in the largest diameter.

  • For a lymphoma mass to count as measurable malignancy, it must have abnormallyincreased metabolic activity when assessed by positron emission tomography (PET)scan. Exceptions to this rule are malignancies that do not consistently displayincreased metabolic activity on PET scans such as CLL/Small lymphocytic lymphoma.

  • For CLL and lymphoma with only bone marrow and/or blood involvement no mass isnecessary, but if a mass is not present, bone marrow and/or blood malignancy must bedetectable by flow cytometry. Note that leukemia cells must make up 1% or less ofperipheral blood lymphocytes within 2 weeks of the time of protocol enrollment inCLL participants for CLL participants to be eligible.

Other inclusion criteria:

  • Greater than or equal to 18 years of age and less than or equal to 75 years of age.

  • Clinical performance status of ECOG 0-1.

  • Absolute neutrophil count greater than or equal to 1000/mm^3 without the support offilgrastim or other growth factors

  • Platelet count greater than or equal to 50,000/mm^3 without transfusion support

  • Hemoglobin greater than 8.0 g/dl

  • Serum ALT and AST less or equal to 3 times the upper limit of the institutionalnormal unless liver involvement by malignancy is demonstrated. If liver involvementwith malignancy is detected, ALT and AST must be less than or equal to 5 times theupper limit of normal.

  • Serum creatinine less than or equal to 1.5 mg/dl

  • Total bilirubin less than or equal to 2.0 mg/dl

  • Room air oxygen saturation of 92% or greater

  • Participants of child-bearing or child-fathering potential must be willing topractice birth control from the time of enrollment on this study and for four monthsafter receiving the protocol treatment.

  • A participant with a negative blood PCR test for hepatitis B DNA test can beenrolled. If hepatitis B DNA (PCR) testing is not available, participants with anegative hepatitis B surface antigen and negative hepatitis B core antibody can beenrolled. after exposure to ibrutinib or another Bruton tyrosine kinase inhibitor and
venetoclax.
 

  • T-cell rich B-cell lymphoma is eligible if previously treated with at least 2 lines
of therapy.
 

  • Waldenstrom s macroglobulinemia/lymphoplasmacytic lymphoma patients are eligible if
previously treated with at least 2 regimens including exposure to a monoclonal
antibody, a bruton tyrosine kinase inhibitor, and cytotoxic chemotherapy.
 

  • Participants with mantle cell lymphoma are eligible after receiving a Bruton
tyrosine kinase (BTK) inhibitor, an anti-CD20 monoclonal antibody, and at least one
of the following chemotherapy drugs: cytarabine, bendamustine, or an anthracycline.
 

  • Other B-cell lymphoma types, including B-cell lymphoma unclassifiable with features
intermediate between DLBCL and Hodgkin lymphoma (Gray zone), that are not
specifically mentioned above are allowed if the participant has received at least 2
lines of therapy at least 1 of which must have contained cytotoxic chemotherapy.
 

  • Primary central nervous system lymphoma patients are not eligible.
 
 All participants must have measurable malignancy as defined by at least one of the
 criteria below.
 

  • Lymphoma or leukemia masses that are measurable (minimum 1.5 cm in largest diameter)
by CT scan is required for all diagnoses except CLL unless bone marrow or blood
involvement with malignancy is detected. All masses must be less than or equal to
 
 10.0 cm in the largest diameter.
 

  • For a lymphoma mass to count as measurable malignancy, it must have abnormally
increased metabolic activity when assessed by positron emission tomography (PET)
scan. Exceptions to this rule are malignancies that do not consistently display
increased metabolic activity on PET scans such as CLL/Small lymphocytic lymphoma.
 

  • For CLL and lymphoma with only bone marrow and/or blood involvement no mass is
necessary, but if a mass is not present, bone marrow and/or blood malignancy must be
detectable by flow cytometry. Note that leukemia cells must make up 1% or less of
peripheral blood lymphocytes within 2 weeks of the time of protocol enrollment in
CLL participants for CLL participants to be eligible.
 
 Other inclusion criteria:
 

  • Greater than or equal to 18 years of age and less than or equal to 75 years of age.
 

  • Clinical performance status of ECOG 0-1.
 

  • Absolute neutrophil count greater than or equal to 1000/mm^3 without the support of
filgrastim or other growth factors
 

  • Platelet count greater than or equal to 50,000/mm^3 without transfusion support
 

  • Hemoglobin greater than 8.0 g/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. If liver involvement
with malignancy is detected, ALT and AST must be less than or equal to 5 times the
upper limit of normal.
 

  • Serum creatinine less than or equal to 1.5 mg/dl
 

  • Total bilirubin less than or equal to 2.0 mg/dl
 

  • Room air oxygen saturation of 92% or greater
 

  • Participants of child-bearing or child-fathering potential must be willing to
practice birth control from the time of enrollment on this study and for four months
after receiving the protocol treatment.
 

  • A participant with a negative blood PCR test for hepatitis B DNA test can be
enrolled. If hepatitis B DNA (PCR) testing is not available, participants with a
negative hepatitis B surface antigen and negative hepatitis B core antibody can be
enrolled.
 

  • Participants must be tested for the presence of Hepatitis C antigen by PCR and beHCV RNA negative in order to be eligible. Only if Hepatitis C PCR testing is notavailable ina timely manner, participants who are Hepatitis C antibody-negative canbe enrolled.

  • Cardiac ejection fraction of greater than or equal to 50% by echocardiography and noevidence of hemodynamically significant pericardial effusion as determined by anechocardiogram within 4 weeks of treatment start.

  • Participants must be able to understand and be willing to sign a written informedconsent.

  • Participants who have either been previously treated with genetically-modified T-cells including CAR T -cells of any specificity are potentially eligible if at least 180 days have elapsed since the prior infusion of genetically-modified T- cells. Anexception to this is patients previously treated on this protocol can be re-treatedon this protocol 8 weeks or more after the first treatment on this protocol.

Exclusion

EXCLUSION CRITERIA:

  • Participants that require urgent therapy due to tumor mass effects or spinal cordcompression.

  • Participants must not have received any anti-CD20 or anti-CD19 antibody products inthe past 60 days prior to CAR T-cell infusion.

  • Participants that have active hemolytic anemia.

  • HIV-positive patients.

  • Participants with second malignancies in addition to their B-cell malignancy are noteligible if the second malignancy has required treatment (including maintenancetherapy) within the past 3 years or is not in complete remission. There are twoexceptions to this criterion: successfully treated non-metastatic basal cell orsquamous cell skin carcinoma.

  • Currently pregnant (confirmed with beta-HCG serum or urine pregnancy test performedat screening) or breastfeeding.

  • Active uncontrolled systemic infections (defined as infections causing fevers within 48 hours of the date of planned protocol chemotherapy start and infections requiringintravenous antibiotics when intravenous antibiotics have been administered for lessthan 72 hours at the time of protocol chemotherapy start).

  • Active coagulation disorders or other major uncontrolled medical illnesses of thecardiovascular, respiratory, endocrine, renal, gastrointestinal, genitourinary orimmune system, history of myocardial infarction, history of ventricular tachycardiaor ventricular fibrillation, active cardiac arrhythmias (active atrial fibrillationis not allowed, resolved atrial fibrillation not requiring current treatment isallowed (anticoagulants count as current treatment), active obstructive orrestrictive pulmonary disease, active autoimmune diseases such as rheumatoidarthritis.

  • Significant neurologic disorders that are not completely and permanently resolvedand not requiring current treatment.

  • Any form of primary immunodeficiency (such as Severe Combined ImmunodeficiencyDisease).

  • Prior allogeneic stem cell transplant

  • Systemic corticosteroid steroid therapy of any dose greater than 5 mg/day or more ofprednisone or equivalent is not allowed within 14 days prior to the requiredleukapheresis, or the initiation of the conditioning chemotherapy regimen.Corticosteroid creams, ointments, and eye drops are allowed.

  • Participants on systemic anticoagulant therapy except aspirin.

  • History of severe immediate hypersensitivity reaction to any of the agents used inthis study.

  • Active central nervous system/brain metastases or cerebrospinal fluid malignancy.

  • Checkpoint inhibitor drugs such as pembrolizumab or nivolumab or other antibodiestargeting PD-1 or PDL-1 within 180 days of protocol enrollment. This is because ofpossible effects checkpoint inhibitor therapy could have on the patient s T- cells.

Study Design

Total Participants: 58
Treatment Group(s): 3
Primary Treatment: Anti-CD19 and anti-CD20 bicistronic CAR T- cells
Phase: 1
Study Start date:
August 28, 2023
Estimated Completion Date:
December 30, 2029

Study 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.

Connect with a study center

  • National Institutes of Health Clinical Center

    Bethesda, Maryland 20892
    United States

    Site Not Available

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