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T Cells Expressing a Fully-Human Anti-CD30 Chimeric Antigen Receptor for Treating CD30-Expressing Lymphomas

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ClinicalTrials.gov Identifier: NCT03049449
Recruitment Status : Recruiting
First Posted : February 10, 2017
Last Update Posted : August 10, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

  • Improved treatments for a variety of treatment-resistant, 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 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 fullyhuman anti-CD30 CAR to patients with advanced CD30-expresssing lymphomas.

Eligibility:

  • Patients must have Hodgkin lymphoma, 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, enteropathyassociated T-cell lymphoma, or extranodal NK/T-cell lymphoma, nasal type
  • Patients must have malignancy that is both measurable on a CT scan with a largest diameter of at least 1.5 cm and possessing increased metabolic activity detectable by PET scan. Alternatively patients with lymphoma detected by flow cytometry of bone marrow

are eligible.

  • Patients must have a creatinine of 1.4 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 any history of HIV, hepatitis B, or hepatitis C. At the time of protocol enrollment patients must be seronegative for CMV by antibody testing or must have a negative blood CMV PCR.
  • Absolute neutrophil count greater than or equal to 1000/micro L, platelet count greater than or equal to 45,000/micro L, hemoglobin greater than or equal to 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 initiation of protocol enrollment.
  • 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 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 Hodgkin lymphoma must fulfill one of the following criteria: 1) have received two prior therapies, one of which must be an autologous stem cell transplant, or 2) have received three prior lines of therapy. Eligible patients with any of the listed peripheral T cell lymphomas or non-Hodgkin lymphomas must have received two lines of prior therapy, at least one of which must contain cytotoxic

chemotherapyPatients 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 an HLA-matched sibling or a 8/8 HLA-matched unrelated donor or 8/8-matched related (not HLA-identical) hematopoietic stem cell transplant are potentially eligible.
  • Women who are pregnant or plan to become pregnant will be excluded.

Design...


Condition or disease Intervention/treatment Phase
Lymphoma, Large-Cell, Anaplasitc Hodgkin Disease Lymphoma, Hodgkins Enteropathy-Associated T-Cell Lymphoma Lymphoma, Extranodal NK-T-Cell Biological: Anti-CD30-CAR T cells Drug: Cyclophosphamide Drug: Fludarabine Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 79 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: T Cells Expressing a Fully-Human Anti-CD30 Chimeric Antigen Receptor for Treating CD30-Expressing Lymphomas
Actual Study Start Date : March 17, 2017
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2022


Arm Intervention/treatment
Experimental: Cohort 1
All patients will be receiving starting dose: 0.3x106 CAR+ T cells/kg (weight based dosing)(up to a maximum dose of 18x106 CAR+ T cells /kg)infuse on day 0 and Cyclophosphamide: 300 mg/m2 IV infusion over 30 minutes on days -5, -4 and -3 and Fludarabine: 30 mg /m2 IV infusion over 30 minutes administered immediately following the cyclophosphamid on days -5, -4,and -3
Biological: Anti-CD30-CAR T cells
Dose-escalation trial starting dose: 0.15x106 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x106 CAR+ T cells/kg)infuse on day 0

Drug: Cyclophosphamide
300 mg/m2 IV infusion over 30 minutes on days -5, -4 and -3

Drug: Fludarabine
30 mg/m2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3




Primary Outcome Measures :
  1. Determine the safety and feasibility of administering T cells expressing a novel fully-human anti-CD30 CAR to patients with advanced CD30-expresssing lymphomas. [ Time Frame: 4-5 weeks after first dose ]
    List of adverse event frequency


Secondary Outcome Measures :
  1. Assess the immunogenicity of the CAR used in this protocol [ Time Frame: 5 years ]
    Amount of anti-CD30-CAR transduced T cells in the blood of patients after infusion.

  2. Evaluate the in vivo persistence and peak blood levels of anti-CD30 CAR T cells after initial and repeated CAR T-cell infusions [ Time Frame: 5 years ]
    Amount of anti-CD30-CAR transduced T cells in the blood of patients after infusion.

  3. Assess for evidence of antilymphoma activity by anti-CD30 CAR T cells [ Time Frame: 5 years ]
    Evidence of anti-lymphoma activity in the blood after anti-CD30 infusion



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 73 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Malignancy Criteria:

  • Patients must have Hodgkin lymphoma, 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 NK/T-cell lymphoma, nasal type
  • 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 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 Hodgkin lymphoma must fulfill one of the following criteria: 1) have received two prior therapies, one of which must be an autologous stem cell transplant, or 2) have received three prior lines of therapy. Eligible patients with any of the listed peripheral T- cell lymphomas or non-Hodgkin lymphomas must have received two lines of prior therapy, at least one of which must contain cytotoxic chemotherapy. 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 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 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 ECOG 0-1
  • 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.)
  • Patients with a known history of hepatitis B or hepatitis C are not eligible due to the risk of re-activation of hepatitis after possible immunosuppression due to anti-CD30 CAR T-cells and chemotherapy administered on this protocol.
  • Seronegative for 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. 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 RNA by RT-PCR and be HCV RNA negative. Patients with a known history of hepatitis C are not eligible.
  • At time of protocol enrollment, the patient should be negative for 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/mm3 without the support of filgrastim or other growth factors.
  • Platelet count greater than or equal to 55,000/mm3 without transfusion support
  • Hemoglobin greater than 8.0 g/dl.
  • Less than 5% malignant cells in the peripheral blood leukocytes
  • Serum ALT and 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 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-PD-1 or anti-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 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 must be willing to undergo endotracheal intubation, mechanical ventilation, dialysis, 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 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 HLA-identical sibling allogeneic hematopoietic stem cell transplant, or an 8/8-matched (HLA-A, B, C, DR) other-than-sibling related donors, or a 8/8-matched (HLA-A, B, C, DR) unrelated donor (URD) allo-HSCT for an eligible CD30+ lymphoma
  • Donor T cell engraftment after allo-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 any dose 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 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 DLIs are not necessary.
  • Either no evidence of 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 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 ventricular tachycardia or ventricular fibrillation; 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).
  • Systemic corticosteroid 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 CNS involvement by malignancy (either by imaging or cerebrospinal fluid involvement or biopsy-proven).
  • Patients currently taking anticoagulants.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03049449


Contacts
Contact: Brenna Hansen (301) 435-5605 hansenb3@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: James N Kochenderfer, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03049449     History of Changes
Other Study ID Numbers: 170048
17-C-0048
First Posted: February 10, 2017    Key Record Dates
Last Update Posted: August 10, 2018
Last Verified: August 8, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Gene Therapy
Adoptive T Cell Therapy
T-cell infusion
Allogeneic Stem Cell Transplantation
Immunohistochemistry

Additional relevant MeSH terms:
Lymphoma
Lymphoma, T-Cell
Hodgkin Disease
Intestinal Diseases
Enteropathy-Associated T-Cell Lymphoma
Lymphoma, Extranodal NK-T-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Gastrointestinal Diseases
Digestive System Diseases
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites