T Cells Expressing a Fully-human AntiCD19 Chimeric Antigen Receptor for Treating B-cell Malignancies
Condition: Lymphoma, B-Cell; Lymphoma, Non-hodgkins
MeSH terms: Lymphoma; Neoplasms; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell
Intervention: Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells; Cyclophosphamide; Fludarabine
Intervention description: Dose-escalation trial starting dose: 0.66x10^6 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0; 300 mg/m^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3; 30 mg/m^2 intravenous (IV) infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Maximum age: 73 Years
Healthy volunteers: No
Keywords: Gene Therapy; Adoptive T Cell Therapy; Allogeneic Stem Cell Transplantation; T-cell infusion; Residual Malignancy

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.

      ...
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Malignancy criteria:

               -  Patients with the following malignancies are potentially eligible: any B-cell
                  lymphoma, and chronic lymphocytic leukemia (CLL). Patients with indolent
                  malignancies that have transformed to diffuse large B-cell lymphoma are eligible.

               -  Clear cluster of differentiation 19 (CD19) expression must be uniformly detected
                  on 75% or more of malignant cells from either bone marrow or a leukemia or
                  lymphoma mass by flow cytometry or immunohistochemistry. These assays must be
                  performed at the National Institutes of Health. It is preferable but not required
                  that the specimen used for CD19 determination comes from a sample that was
                  obtained after the patient's most recent treatment. If paraffin embedded
                  unstained samples of bone marrow involved with malignancy or a lymphoma mass are
                  available, these can be shipped to the National Institutes of Health (NIH) for
                  CD19 staining; otherwise, new biopsies will need to be performed for
                  determination of CD19 expression.

               -  Diffuse large B-cell lymphoma (DLBCL) patients must have received at least two
                  prior chemotherapy-containing regimens at least one of which must have contained
                  doxorubicin and a monoclonal antibody. Follicular lymphoma patients must have
                  received at least 2 prior regimens including at least 1 regimen with
                  chemotherapy. All other lymphoma and leukemia patients must have had at least 1
                  prior chemotherapy-containing regimen. All patients with CLL or small lymphocytic
                  lymphoma must have had prior treatment with ibrutinib or another signal
                  transduction inhibitor.

               -  Patients 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 computed tomography (CT) scan is required for all diagnoses
                       except CLL. All masses must be less than 10 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.

                    -  For CLL and lymphoma with only bone marrow involvement no mass is necessary,
                       but if a mass is not present, bone marrow malignancy must be detectable by
                       flow cytometry in lymphoma and CLL.

          -  Other inclusion criteria:

               -  Greater than or equal to 18 years of age and less than or equal to age 73.

               -  Able to understand and sign the Informed Consent Document.

               -  Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0-1

               -  Room air oxygen saturation of 92% or greater

               -  Patients of both genders must be willing to practice birth control from the time
                  of enrollment on this study and for four months after receiving the preparative
                  regimen.

               -  Women of child bearing potential must have a negative pregnancy test because of
                  the potentially dangerous effects of the preparative chemotherapy on the fetus.
                  Women of child-bearing potential are defined as all women except women who are
                  post-menopausal or who have had a hysterectomy. Postmenopausal will be defined as
                  women over the age of 55 who have not had a menstrual period in at least 1 year.

               -  Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental
                  treatment being evaluated in this protocol depends on an intact immune system.
                  Patients who are HIV seropositive can have decreased immune -competence and thus
                  are less responsive to the experimental treatment and more susceptible to its
                  toxicities.)

               -  Patients with a known history of hepatitis B or hepatitis C are not eligible due
                  to the risk of re-activation of hepatitis after prolonged B-cell depletion due to
                  anti-CD19 CAR T cells.

               -  Seronegative for hepatitis B antigen, positive hepatitis B tests can be further
                  evaluated by confirmatory tests, and if confirmatory tests are negative, the
                  patient can be enrolled. Patients with a known history of hepatitis B are not
                  eligible.

               -  Seronegative for hepatitis C antibody unless antigen negative. If hepatitis C
                  antibody test is positive, then patients must be tested for the presence of
                  ribonucleic acid (RNA) by reverse transcription polymerase chain reaction
                  (RT-PCR) and be hepatitis C virus (HCV) RNA negative. Patients with a known
                  history of hepatitis C are not eligible.

               -  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 45,000/mm(3) without transfusion support

               -  Hemoglobin greater than 8.0 g/dl.

               -  Less than 5% malignant cells in the peripheral blood leukocytes

               -  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.

               -  Serum creatinine less than or equal to 1.4 mg/dL.

               -  Total bilirubin less than or equal to 2.0 mg/dl.

               -  At least 14 days must have elapsed since any prior systemic therapy prior to
                  apheresis and prior to the initiation of chemotherapy (including systemic
                  corticosteroids at any dose). Because this protocol requires collection of
                  autologous blood cells by leukapheresis in order to prepare CAR T cells, systemic
                  anti-malignancy therapy including systemic corticosteroid therapy of any dose are
                  not allowed within 14 days prior to the required leukapheresis. NOTE: Because of
                  the long half-life and potential to affect CAR T cells, 60 days must elapse from
                  the time of administration of anti-Programmed cell death protein 1 (PD-1) or
                  anti-Programmed death-ligand 1 (PD-L1) antibodies or other agents that in the
                  opinion of the PI can stimulate immune activity and infusion of CAR T cells.

               -  Normal cardiac ejection fraction (greater than or equal to 55% by
                  echocardiography) and no evidence of hemodynamically significant pericardial
                  effusion as determined by an echocardiogram within 4 weeks of the start of the
                  treatment protocol.

               -  Patients must not take corticosteroids including prednisone, dexamethasone or any
                  other corticosteroid for 14 days before apheresis and CAR T-cell infusion.
                  Patients must also not take corticosteroids at doses higher than 5 mg/day of
                  prednisone or equivalent at any time after the CAR T cell infusion.

               -  Patients who have been treated on other protocols of genetically-modified T cells
                  at the NIH only are potentially eligible under these conditions:

                    -  At least 6 months have elapsed since the last genetically-modified T-cell
                       therapy that the patient received and there is no evidence of
                       replication-competent retroviruses (evidence must be provided from prior NIH
                       gene-therapy protocol Principal Investigator) and persisting
                       genetically-modified T cells are not detectable in the patient's blood
                       (evidence must be provided by prior NIH gene-therapy protocol Principal
                       Investigator).

        EXCLUSION CRITERIA:

          -  Patients that require urgent therapy due to tumor mass effects or spinal cord
             compression.

          -  Patients that have active hemolytic anemia.

          -  Patients with second malignancies in addition to their B-cell malignancy are not
             eligible if the second malignancy has required treatment (including maintenance
             therapy) within the past 4 years or is not in complete remission. There are two
             exceptions to this criterion: successfully treated non-metastatic basal cell or
             squamous cell skin carcinoma.

          -  Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

          -  Active uncontrolled systemic infections (defined as infections causing fevers and
             infections requiring intravenous antibiotics when intravenous antibiotics have been
             administered for less than 72 hours), active coagulation disorders or other major
             uncontrolled medical illnesses of the cardiovascular, respiratory, endocrine, renal,
             gastrointestinal, genitourinary or immune system, history of myocardial infarction,
             history of ventricular tachycardia or ventricular fibrillation, active cardiac
             arrhythmias (active atrial fibrillation is not allowed, resolved atrial fibrillation
             not requiring current treatment is allowed (anticoagulants count as current treatment)
             ), active obstructive or restrictive pulmonary disease, active autoimmune diseases
             such as rheumatoid arthritis.

          -  Patients will not be seen for screening appointments or enrolled on the protocol if
             they have been hospitalized within the 7 days prior to the screening appointment or
             the date of protocol enrollment.

          -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
             Disease).

          -  Systemic corticosteroid steroid therapy of any dose is not allowed within 14 days
             prior to the required leukapheresis, or the initiation of the conditioning
             chemotherapy regimen. Corticosteroid creams, ointments, and eye drops are allowed.

          -  History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          -  Patients with current central nervous system (CNS) involvement by malignancy (either
             by imaging or cerebrospinal fluid involvement or biopsy-proven).