Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Non-Hodgkin Lymphoma
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of genetically engineered lymphocyte therapy and to see how well it works after peripheral blood stem cell transplant (PBSCT) in treating patients with high-risk, intermediate-grade, B-cell non-Hodgkin lymphoma (NHL). Genetically engineered lymphocyte therapy may stimulate the immune system in different ways and stop cancer cells from growing. Giving rituximab together with chemotherapy before a PBSCT stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim (G-CSF), or plerixafor helps stem cells move from the bone marrow to the blood so they can be collected and stored. More chemotherapy or radiation therapy is given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Giving genetically engineered lymphocyte therapy after PBSCT may be an effective treatment for NHL.
Detailed description
PRIMARY OBJECTIVES: I. To assess the safety of cellular immunotherapy utilizing ex vivo expanded autologous central memory T cell (TCM)-enriched cluster of differentiation (CD)8+ T cells genetically-modified to express a CD19-specific chimeric antigen receptor (CAR) in conjunction with a standard myeloablative autologous hematopoietic stem cell transplantation (aHSCT) for research participants with high-risk intermediate grade B-lineage non-Hodgkin lymphomas who have relapsed after primary therapy, or who did not achieve complete remission with primary therapy. (Phase I) II. To determine the maximum tolerated dose (MTD) on dose limiting toxicities (DLTs) and to describe the full toxicity profile. (Phase I) III. To determine the rate of research participants receiving TCM-enriched CD8+ T cells genetically-modified to express a CD19-specific CAR for which the transferred cells are detected in the circulation 28 days (+/- 3 days) by woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) quantitative (Q)-polymerase chain reaction (PCR). (Phase II) SECONDARY OBJECTIVES: I. To determine the tempo, magnitude, and duration of engraftment of the transferred T cell product as it relates to the number of cells infused. (Phase II) II. To study the impact of this therapeutic intervention on the development of CD19+ B-cell precursors in the bone marrow as a surrogate for the in vivo effector function of transferred CD19-specific T cells. (Phase II) III. To describe the progression-free and overall survival of treated research participants on this protocol. (Phase II) OUTLINE: This is a phase I, dose-escalation study of genetically engineered lymphocyte therapy followed by a phase II study. Patients receive standard salvage chemotherapy per standard practice and undergo standard mobilization for stem cell collection with filgrastim and/or plerixafor. Some patients may also receive rituximab intravenously (IV) within 4 weeks of transplant. Patients receive standard myeloablative conditioning followed by autologous PBSCT. Patients then undergo infusion of ex vivo expanded autologous TCM-enriched CD8+ T cells expressing CD19-specific CAR on day 2 or 3 after transplant. After completion of study treatment, patients are followed up periodically for at least 15 years.
Interventions
PROCEDUREAutologous Hematopoietic Stem Cell Transplantation
Undergo autologous PBSCT
BIOLOGICALFilgrastim
Given IV
Receive ex vivo expanded autologous TCM-enriched CD8+ T cells expressing CD19-specific CAR
OTHERLaboratory Biomarker Analysis
Correlative studies
PROCEDUREPeripheral Blood Stem Cell Transplantation
Undergo autologous PBSCT
DRUGPlerixafor
Given IV
BIOLOGICALRituximab
Given IV
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* City of Hope (COH) pathology review confirms that research participant's diagnostic material is consistent with history of intermediate grade B-cell NHL (e.g., diffuse B-cell lymphoma, mantle cell lymphoma, transformed follicular lymphoma) * History of relapse after achieving first remission with primary therapy, or failure to achieve remission with primary therapy * Life expectancy \> 16 weeks * Karnofsky performance scale (KPS) \>= 70% * Negative serum pregnancy test for women of childbearing potential * Research participant has an indication to be considered for autologous stem cell transplantation
Exclusion criteria
* Fails to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I/II study; evidence of understanding includes passing the Protocol Comprehensive Screening given by the Research Subject Advocate (RSA); a legal guardian may substitute for the research participant * Any standard contraindications to myeloablative HSCT per standard of care practices at COH * Dependence on corticosteroids * Currently enrolled in another investigational therapy protocol * Human immunodeficiency virus (HIV) seropositive based on testing performed within 4 weeks of enrollment * History of allogeneic HSCT or prior autologous HSCT * Active autoimmune disease requiring systemic immunosuppressive therapy * Research participant(s) who are to receive radioimmunotherapy (Zevalin-based)-based conditioning regimens * Research participant(s) with known active hepatitis B or C infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | Within 28 days of T-cell infusion | Number of DLTs per dose level are reported. A DLT is defined as: Any grade 3 or higher toxicity, with the exception of expected adverse events; and designated as definitely or probably related (level of attribution) to the infusion of the TCM cells; and occurring within 28 days of T-cell infusion; Any toxicity requiring the use of steroids to ablate side effects attributable to the infusion of the TCM cells, and occurring within 28 days of T-cell infusion; Any toxicity which is a lower grade, but that increases in grade to a grade 3 or higher as a direct result of the TCM, and occurring within 28 days of T-cell infusion; Any grade 2 or greater autoimmune toxicity, and occurring within 28 days of T-cell infusion. |
| Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE) Detection Above Background | 28 days post T cell infusion | Peak expansion of WPRE is expressed in CAR copy number/mL of blood is summarized with median and range |
| Number of Days of Quantifiable CD19 CAR Post T-cell Infusion | 28 days post T cell infusion | WPRE persistence of quantifiable CD19 CAR summarized with mean and standard deviation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Failure to Engraft | Within 21 days post T-cell infusion | Count of participants who fail to engraft post transplant. |
| Progression-free Survival at 1 Year | Up to 1 year | Estimated using the Kaplan-Meier methods. Progression is defined using the revised IWG response criteria, as any new lesion or increase by ≥50% of previously involved sites from nadir. |
Countries
United States
Participant flow
Pre-assignment details
Three additional participants underwent leukapheresis, however, two were ineligible for transplant and the third refused additional treatment and therefore were not assigned a dose level.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 0 (25 x 10^6 CAR+ T-cells) Patients receive standard salvage chemotherapy per standard practice and undergo standard mobilization for stem cell collection with Granulocyte-Colony Stimulating Factor (G-CSF) and/or plerixafor. Some patients may also receive rituximab IV within 4 weeks of transplantation. Patients receive standard myeloablative conditioning followed by autologous Peripheral Blood Stem Cell Transplant (PBSCT). Patients then undergo infusion of ex vivo expanded autologous central memory (TCM)-enriched CD8+ T cells expressing CD19-specific chimeric antigen receptor (CAR) on day 2 or 3 after transplantation. | 1 |
| Dose Level 1 (50 x 10^6 CAR+ T-cells) Patients receive standard salvage chemotherapy per standard practice and undergo standard mobilization for stem cell collection with Granulocyte-Colony Stimulating Factor (G-CSF) and/or plerixafor. Some patients may also receive rituximab IV within 4 weeks of transplantation. Patients receive standard myeloablative conditioning followed by autologous Peripheral Blood Stem Cell Transplant (PBSCT). Patients then undergo infusion of ex vivo expanded autologous central memory (TCM)-enriched CD8+ T cells expressing CD19-specific chimeric antigen receptor (CAR) on day 2 or 3 after transplantation. | 4 |
| Dose Level 2 (100 x 10^6 CAR+ T-cells) Patients receive standard salvage chemotherapy per standard practice and undergo standard mobilization for stem cell collection with Granulocyte-Colony Stimulating Factor (G-CSF) and/or plerixafor. Some patients may also receive rituximab IV within 4 weeks of transplantation. Patients receive standard myeloablative conditioning followed by autologous Peripheral Blood Stem Cell Transplant (PBSCT). Patients then undergo infusion of ex vivo expanded autologous central memory (TCM)-enriched CD8+ T cells expressing CD19-specific chimeric antigen receptor (CAR) on day 2 or 3 after transplantation. | 3 |
| Total | 8 |
Baseline characteristics
| Characteristic | Dose Level 1 (50 x 10^6 CAR+ T-cells) | Dose Level 2 (100 x 10^6 CAR+ T-cells) | Total | Dose Level 0 (25 x 10^6 CAR+ T-cells) |
|---|---|---|---|---|
| Age, Continuous | 60 years | 58 years | 62 years | 75 years |
| Disease histology Diffuse Large B-Cell Lymphoma | 3 Participants | 3 Participants | 7 Participants | 1 Participants |
| Disease histology Mantle Cell Lymphoma | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 8 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 8 Participants | 1 Participants |
| Region of Enrollment United States | 4 participants | 3 participants | 8 participants | 1 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 4 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 1 / 4 | 1 / 3 |
| other Total, other adverse events | 1 / 1 | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 0 / 1 | 2 / 4 | 3 / 3 |
Outcome results
Primary
Number of Days of Quantifiable CD19 CAR Post T-cell Infusion
WPRE persistence of quantifiable CD19 CAR summarized with mean and standard deviation
Time frame: 28 days post T cell infusion
Population: 1 participant in dose level 1 did not have any whole blood samples to analyze. Overall mean was reported due to small samples sizes in each dose level.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 0 (25 x 10^6 CAR+ T-cells) | Number of Days of Quantifiable CD19 CAR Post T-cell Infusion | 18.25 days | Standard Deviation 12.1 |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
Number of DLTs per dose level are reported. A DLT is defined as: Any grade 3 or higher toxicity, with the exception of expected adverse events; and designated as definitely or probably related (level of attribution) to the infusion of the TCM cells; and occurring within 28 days of T-cell infusion; Any toxicity requiring the use of steroids to ablate side effects attributable to the infusion of the TCM cells, and occurring within 28 days of T-cell infusion; Any toxicity which is a lower grade, but that increases in grade to a grade 3 or higher as a direct result of the TCM, and occurring within 28 days of T-cell infusion; Any grade 2 or greater autoimmune toxicity, and occurring within 28 days of T-cell infusion.
Time frame: Within 28 days of T-cell infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 0 (25 x 10^6 CAR+ T-cells) | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Dose Level 1 (50 x 10^6 CAR+ T-cells) | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Dose Level 2 (100 x 10^6 CAR+ T-cells) | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE) Detection Above Background
Peak expansion of WPRE is expressed in CAR copy number/mL of blood is summarized with median and range
Time frame: 28 days post T cell infusion
Population: 1 participant in dose level 1 did not have any whole blood samples to analyze. Overall median was reported due to small samples sizes in each dose level.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 0 (25 x 10^6 CAR+ T-cells) | Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE) Detection Above Background | 280 CAR copy number/mL |
Secondary
Failure to Engraft
Count of participants who fail to engraft post transplant.
Time frame: Within 21 days post T-cell infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 0 (25 x 10^6 CAR+ T-cells) | Failure to Engraft | 0 Participants |
| Dose Level 1 (50 x 10^6 CAR+ T-cells) | Failure to Engraft | 0 Participants |
| Dose Level 2 (100 x 10^6 CAR+ T-cells) | Failure to Engraft | 0 Participants |
Secondary
Progression-free Survival at 1 Year
Estimated using the Kaplan-Meier methods. Progression is defined using the revised IWG response criteria, as any new lesion or increase by ≥50% of previously involved sites from nadir.
Time frame: Up to 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 0 (25 x 10^6 CAR+ T-cells) | Progression-free Survival at 1 Year | 50 percentage of participants |