Ignite Creation Date:
2024-05-06 @ 9:41 AM
Last Modification Date:
2024-10-26 @ 12:18 PM
Study NCT ID:
NCT03049449
Status:
COMPLETED
Last Update Posted:
2023-01-18
First Post:
2017-02-09
Brief Title:
T Cells Expressing a Fully-Human Anti-CD30 Chimeric Antigen Receptor for Treating CD30-Expressing Lymphomas
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Anti-CD30 CAR T Cells With Fully-human Binding Domains for Treating CD30-expressing Lymphomas Including Anaplastic Large Cell Lymphomas
Status:
COMPLETED
Status Verified Date:
2022-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 NKT-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 15 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 16 mgdL 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 1000micro L platelet count greater than or equal to 55000micro L hemoglobin greater than or equal to 8gdL
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 mgday 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 910 or 1010 human leukocyte antigen HLA-matched sibling or a 910 or 1010 HLA- matched unrelated donor hematopoietic stem cell transplant are potentially eligible
Women who are pregnant or plan to become pregnant will be excluded
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 NKT-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 15 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 16 mgdL 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 1000micro L platelet count greater than or equal to 55000micro L hemoglobin greater than or equal to 8gdL
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 mgday 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 910 or 1010 human leukocyte antigen HLA-matched sibling or a 910 or 1010 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 NKT-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 15 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 16 mgdL 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 1000micro L platelet count greater than or equal to 55000micro L hemoglobin greater than or equal to 8gdL
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 mgday 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 910 or 1010 human leukocyte antigen HLA-matched sibling or a 910 or 1010 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 03x106 CAR T cellskg of recipient bodyweight for Cohort 1 The initial dose level will be 1 x 10 6 CART cellskg 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 08032018 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
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 NKT-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 15 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 16 mgdL 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 1000micro L platelet count greater than or equal to 55000micro L hemoglobin greater than or equal to 8gdL
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 mgday 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 910 or 1010 human leukocyte antigen HLA-matched sibling or a 910 or 1010 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 03x106 CAR T cellskg of recipient bodyweight for Cohort 1 The initial dose level will be 1 x 10 6 CART cellskg 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 08032018 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 17-C-0048 | None | None | None |