T Cells Expressing a Fully-Human Anti-CD30 Chimeric Antigen Receptor for Treating CD30-Expressing Lymphomas
Condition: Lymphoma, Large-Cell, Anaplastic; Enteropathy-Associated T-Cell Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Extranodal NK-T-Cell; Lymphoma, T-Cell, Peripheral
MeSH terms: Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Lymphoma, Large-Cell, Anaplastic; Lymphoma, Large B-Cell, Diffuse; Enteropathy-Associated T-Cell Lymphoma; Lymphoma, Extranodal NK-T-Cell
Intervention: Anti-Tumor Necrosis Factor (TNF) Receptor Superfamily Member 8 (CD30) Chimeric Antigen Receptor (CAR) T cells; Cyclophosphamide; Fludarabine
Intervention description: Dose-escalation trial starting dose: 0.3x10^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) (up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0; 300 or 500 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
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Maximum age: 73 Years
Healthy volunteers: No
Keywords: Gray Zone Lymphoma; Immunotherapy; Peripheral T-Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell lymphoma

Summary:

      Background:

        -  Improved treatments for a variety of treatment-resistant, TNFRSF8 (CD30)-expressing
           malignancies including Hodgkin lymphoma, anaplastic large cell lymphoma, and other CD30-
           expressing lymphomas are needed.

        -  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
           B-lymphocyte antigen CD19 (CD19) have caused complete remissions in a small number of
           patients with lymphoma. These results demonstrate that CAR-expressing T cells can have
           anti-lymphoma activity in humans.

        -  CD30 expression can be easily detected by immunohistochemistry on lymphoma cells, which
           allows selection of CD30-expressing malignancies for treatment.

        -  CD30 is not known to be expressed by normal cells except for a small number of activated
           lymphocytes.

        -  We have constructed a novel fully-human anti-CD30 CAR that can specifically recognize
           CD30-expressing target cells in vitro and eradicate CD30-expressing tumors in mice.

        -  This particular CAR has not been tested before in humans.

        -  Possible toxicities include cytokine-associated toxicities such as fever, hypotension,
           and neurological toxicities. Elimination of a small number of normal activated
           lymphocytes is possible, and unknown toxicities are also possible.

      Objectives:

      Primary

      -Determine the safety and feasibility of administering T-cells expressing a novel fully human
      anti-CD30 CAR to patients with advanced CD30-expressing lymphomas.

      Eligibility:

        -  Patients must have anaplastic large cell lymphoma, peripheral T-cell lymphoma not
           otherwise specified, diffuse large B-cell lymphoma not otherwise specified, primary
           mediastinal B-cell lymphoma, grey zone lymphoma, enteropathy associated T-cell lymphoma,
           or extranodal natural killer (NK)/T-cell lymphoma, nasal type

        -  Patients must have malignancy that is both measurable on a computed tomography (CT) scan
           with a largest diameter of at least 1.5 cm and possessing increased metabolic activity
           detectable by positron emission tomography (PET) scan. Alternatively, patients with
           lymphoma detected by flow cytometry of bone marrow are eligible.

        -  Patients must have a creatinine of 1.6 mg/dL or less and a normal cardiac ejection
           fraction.

        -  An Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 is required.

        -  No active infections are allowed including evidence of active human immunodeficiency
           virus (HIV), hepatitis B, or hepatitis C. At the time of protocol enrollment patients
           must be seronegative for cytomegalovirus (CMV) by antibody testing or must have a
           negative blood CMV polymerase chain reaction (PCR).

        -  Absolute neutrophil count greater than or equal to 1000/micro L, platelet count greater
           than or equal to 55,000/micro L, 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 above 5 mg/day of prednisone or equivalent corticosteroid dose) and
           initiation of required leukapheresis.

        -  Clear CD30 expression must be detected on 75% or more of malignant cells from either
           bone marrow or lymphoma mass by flow cytometry or immunohistochemistry. The patient s
           malignancy will need to be assessed for CD30 expression by flow cytometry or
           immunohistochemistry performed at the National Institutes of Health (NIH). If unstained,
           paraffin-embedded bone marrow or lymphoma sections are available from prior biopsies,
           these can be used to determine CD30 expression by immunohistochemistry; otherwise,
           patients will need to come to the NIH for a biopsy to determine CD30 expression. The
           sample for CD30 expression can come from a biopsy obtained at any time before
           enrollment, unless the patient has received a prior anti-CD30 monoclonal antibody, in
           which case the sample must come from a biopsy following completion of the most recent
           anti-CD30 monoclonal antibody treatment.

        -  Eligible patients with diffuse large B-cell lymphoma or primary mediastinal B-cell
           lymphoma must have received 2 prior treatment regimens at least 1 of which included an
           anthracycline and an anti-CD20 monoclonal antibody.

        -  Patients who have never had an allogeneic hematopoietic stem cell transplant as well as
           patients who have had a 9/10 or 10/10 human leukocyte antigen (HLA)-matched sibling or a
           9/10 or 10/10 HLA- matched unrelated donor hematopoietic stem cell transplant are
           potentially eligible.

        -  Women who are pregnant or plan to become pregnant will be excluded.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Malignancy Criteria:

          -  Patients must have anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma,
             peripheral T-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma not
             otherwise specified, primary mediastinal B-cell lymphoma, grey zone lymphoma,
             enteropathy-associated T-cell lymphoma, or extranodal natural killer (NK)/T-cell
             lymphoma, nasal type

          -  Clear TNFRSF8 (CD30) expression must be detected on 75% or more of malignant cells
             from either bone marrow or lymphoma mass by flow cytometry or immunohistochemistry.
             The patient's malignancy will need to be assessed for CD30 expression by flow
             cytometry or immunohistochemistry performed at the National Institutes of Health
             (NIH). If unstained, paraffin-embedded bone marrow or lymphoma sections are available
             from prior biopsies, these can be used to determine CD30 expression by
             immunohistochemistry; otherwise, patients will need to come to the NIH for a biopsy to
             determine CD30 expression. The sample for CD30 expression can come from a biopsy
             obtained at any time before enrollment, unless the patient has received a prior
             anti-CD30 monoclonal antibody, in which case the sample must come from a biopsy
             following completion of the most recent anti-CD30 monoclonal antibody treatment.

          -  Eligible patients with diffuse large B-cell lymphoma or primary mediastinal B-cell
             lymphoma must have received 2 prior treatment regimens at least 1 of which included an
             anthracycline and an anti-B-lymphocyte antigen CD20 (CD20) monoclonal antibody.

          -  Patients must have measurable malignancy as defined by at least one of the criteria
             below.

          -  Lymphoma mass that is measurable (minimum 1.5 cm in largest diameter) by computed
             tomography (CT) scan is required unless bone marrow lymphoma is detectable.

          -  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 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.

        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) 0-2

          -  Room air oxygen saturation of 92% or greater

          -  Male patients and must be willing to practice birth control from the time of
             enrollment on this study and for four months following the final CAR T-cell infusion.
             Pre-menopausal patients (female patients who have had a menstrual period within the
             last year) must be willing to practice birth control from the time of enrollment and
             for one year following the final CAR T cell infusion.

          -  Seronegative for 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.)

          -  Seronegative for Human T-cell lymphotropic virus type 1 (HTLV-1).

          -  Negative for hepatitis B surface antigen. Positive hepatitis B tests can be further
             evaluated by confirmatory tests; and if confirmatory tests are negative, the patient
             can be enrolled.

          -  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
             (HCV) RNA negative to be enrolled.

          -  A patient with a prior history of hepatitis B or a prior history of hepatitis C may
             participate, as long as the patient s viral hepatitis has been treated, and the
             patient has no detectable Hepatitis B (HBV) deoxyribonucleic acid (DNA) or HCV RNA.

          -  At time of protocol enrollment, the patient should be negative for cytomegalovirus
             (CMV) by antibody testing or by PCR. In case of disagreement between these 2 CMV
             tests, the tests will be repeated, and Dept. of Laboratory Medicine consulted.

          -  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 55,000/mm^3

          -  Hemoglobin greater than 8.0 g/dl. Transfusion support is allowed.

          -  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 1.6 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
             doses greater than prednisone 5 mg/day or the equivalent corticosteroid doses).
             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 at doses greater than prednisone 5 mg/day or the equivalent
             corticosteroid doses is not allowed within 14 days prior to the required
             leukapheresis. NOTE: Because of the long half-life and potential to affect CAR
             T-cells, 30 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 50% 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 at doses higher than 5 mg/day of prednisone or
             the equivalent for 14 days before apheresis, and for 14 days prior to the conditioning
             chemotherapy regimen.

          -  Patients must be willing to undergo endotracheal intubation, mechanical ventilation,
             dialysis, cardiopulmonary resuscitation (CPR), and electrical defibrillation. Patients
             must be willing to receive vasopressor drugs and all other standard intensive care
             unit interventions. Any living will must be amended to allow these interventions, or
             the patient will not eligible.

          -  Patients who have been treated on other protocols of genetically-modified T-cells at
             the National Institutes of Health (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).

        Additional Inclusion Criteria Pertinent Only for Patients with Prior Allogeneic
        Transplantation:

          -  Recipients must have received an 9/10 or 10/10 HLA-matched sibling allogeneic
             hematopoietic stem cell transplant, or a 9/10 or 10/10 HLA-matched unrelated donor
             (URD) allo-HSCT for an eligible CD30+ lymphoma.

          -  Donor T cell engraftment after allo-Hematopoietic stem-cell transplantation
             (HSCT)(>90% donor chimerism of the T-cell compartment).

          -  Patients must be at least 90 days post-transplant.

          -  Patients must be off all systemic immunosuppressive drugs including corticosteroids at
             doses of greater than 5 mg/day prednisone or equivalent, if given for treatment of
             graft versus host disease, for at least 28 days prior to protocol enrollment and must
             remain off immunosuppressive drugs while enrolled on the protocol. Patients must not
             be taking any systemic steroids at doses greater than 5 mg/day prednisone or
             equivalent at all for 14 days prior to apheresis and initiation of chemotherapy.
             Topical corticosteroid preparations applied to the skin such as solutions, creams, and
             ointments are allowed. Inhaled corticosteroids are allowed, and corticosteroid eye
             drops are allowed.

          -  Prior donor lymphocyte infusions (DLIs) are not necessary.

          -  Either no evidence of graft versus host (GVHD) or minimal clinical evidence of acute
             GVHD and chronic GVHD while off of systemic immunosuppressive therapy for at least 28
             days. Minimal clinical evidence of acute GVHD defined as grade 0 to I acute GVHD 109
             Minimal evidence of chronic GVHD is defined as mild global score chronic GVHD (as
             defined by the 2005 NIH consensus project) or no chronic GVHD .107 Subjects with
             disease that is controlled to stage I acute GVHD or to mild global score chronic GVHD
             with local topical cutaneous steroids will be eligible for enrollment.

        EXCLUSION CRITERIA:

          -  Patients with Hodgkin lymphoma are no longer eligible for participation (as of
             amendment G, Protocol version: 08/12/2019).

          -  Patients that require urgent therapy due to tumor mass effects or spinal cord
             compression.

          -  Patients with lymphoma masses 10.0 cm or larger in longest diameter will not be
             eligible.

          -  Patients that have active hemolytic anemia.

          -  Patients who are currently taking any medications for systemic anticoagulation other
             than aspirin will not be eligible.

          -  Patients with second malignancies in addition to their lymphoma 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.
             Women of child-bearing potential are defined as all women except women who are
             postmenopausal 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.

          -  Active uncontrolled systemic infections (defined as infections causing fevers and
             infections requiring intravenous antibiotics when the 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 idiopathic ventricular tachycardia or ventricular fibrillation in the past
             12 months or history of ventricular tachycardia or ventricular fibrillation (VT/VF)
             associated with VT/VF risk factors (e.g., QT prolongation and cardiomyopathy); active
             cardiac arrhythmias (Active atrial fibrillation is not allowed, but resolved atrial
             fibrillation is allowed.); active obstructive or restrictive pulmonary disease; or
             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) , unless the immunodeficiency has been cured by allogeneic stem cell
             transplant.

          -  Systemic corticosteroid therapy at doses greater than 5 mg/day of prednisone or the
             equivalent 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).

          -  Patients currently taking anticoagulants.