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 : September 25, 2018
- 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.
-Determine the safety and feasibility of administering T-cells expressing a novel fullyhuman anti-CD30 CAR to patients with advanced CD30-expresssing lymphomas.
- 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
- 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.
|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|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|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|
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
300 mg/m2 IV infusion over 30 minutes on days -5, -4 and -3
30 mg/m2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3
- 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
- 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.
- 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.
- 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
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
|Contact: Brenna Hansen||(240) firstname.lastname@example.org|
|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|
|Principal Investigator:||James N Kochenderfer, M.D.||National Cancer Institute (NCI)|