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
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      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, 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

        -  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.

      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-CD30
           CAR.

        -  Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the
           intent of enhancing the activity of the infused anti-CD30 CAR-expressing T cells.

        -  A chemotherapy conditioning regimen of cyclophosphamide and fludarabine will be
           administered prior to all CAR T-Cell infusions. Fludarabine will be given on the same
           days as the cyclophosphamide.

        -  Two days after the chemotherapy ends, patients will receive an infusion of
           anti-CD30-CAR-expressing T cells.

        -  The initial dose level of this dose-escalation trial will be 0.3x10(6) CAR+ T cells/kg
           of recipient bodyweight for Cohort 1. The initial dose level will be 1 x 10 (6) CAR+T
           cells/kg for Cohort 2.

        -  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. Long-term gene-therapy follow-up consisting of yearly visits to
           a doctor near the patients home for 4 more years and then yearly telephone contact for
           10 additional years will be required.

        -  As of Amendment E (Protocol version: 08/03/2018), repeat treatments consisting of the
           conditioning chemotherapy followed by a CAR T-cell infusion at the maximum tolerated
           dose (MTD) for the patients cohort are allowed 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.
    

Intervention name(s): Anti-Tumor Necrosis Factor (TNF) Receptor Superfamily Member 8 (CD30) Chimeric Antigen Receptor (CAR) T cells; Cyclophosphamide; Fludarabine
Intervention type(s): Biological; Drug; Drug
Intervention description(s): 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
Other intervention name(s): Cytoxan; Fludara
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Gray Zone Lymphoma; Immunotherapy; Peripheral T-Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell lymphoma