Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Infections

Rare Diseases

Lymphoma

Lymphoma, Non-Hodgkin

Lymphoma, Mantle-Cell

Lymphoma, Follicular

Lymphoma, B-Cell, Marginal Zone

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Lymphoma, Extranodal NK-T-Cell

Burkitt Lymphoma

Neoplasms by Histologic Type

Lymphoma, Large-Cell, Immunoblastic

Neoplasms, Experimental

Lymphomatoid Granulomatosis

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Mantle Cell Lymphoma

Follicular Lymphoma

B-cell Lymphoma

Lymphoma, Large-cell, Immunoblastic

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Bendamustine Hydrochloride

Immunomodulating Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.

Cyclophosphamide \[1.5 g/m\^2 x 1 day Intravenous (IV)\] or Bendamustine \[120 mg/m\^2 x 2 days Intravenous (IV)\] is administered as Pre-treatment medication of CD19-CAR-T.

Cyclophosphamide or Bendamustine

CD19-CAR-T \[1 x 10\^5 cells/kg x 1 day and 2 x 10\^5 cells/kg x 1 day Intravenous (IV)\] are administered.

Dose Level -1

CD19-CAR-T \[1/3 x 10\^6 cells/kg x 1 day and 2/3 x 10\^6 cells/kg x 1 day Intravenous (IV)\] are administered.

Dose Level 1

CD19-CAR-T \[1 x 10\^6 cells/kg x 1 day and 2 x 10\^6 cells/kg x 1 day Intravenous (IV)\] are administered.

Dose Level 2

CD19-CAR-T \[1/3 x 10\^7 cells/kg x 1 day and 2/3 x 10\^7 cells/kg x 1 day Intravenous (IV)\] are administered.

Dose Level 3

Ken Ohmine, MD, PhD

Keiya Ozawa, MD, PhD

The purpose of this study is to evaluate the safety, efficacy and blood kinetics of autologous T cells genetically modified to express anti-CD19 Chimeric Antigen Receptor in patients with relapsed or refractory B-Cell Non-Hodgkin Lymphoma.

Peripheral blood (up to 600 mL) will be collected from a subject after obtaining a written informed consent and completing the 1st registration. Peripheral blood mononuclear cells (PBMCs) and plasma are obtained from the blood, and T cells contained in the PBMCs are transduced with anti-CD19 CAR gene by using SFG-1928z retroviral vector. Anti-CD19 CAR expressing T cells (CD19-CAR-T) will be expanded using a medium containing autologous plasma. After the T cells pass in quality control tests, the subject will go into 2nd registration. Subjects will be hospitalized and administered Cyclophosphamide on Day -2 or Bendamustine on Day -3 to Day -2 intravenously as Pre-treatment, and then subjects will receive 1st infusion of CD19-CAR-T on Day 0 and Day 1 (Day 1：1/3 dose, Day 2：2/3 dose) as a split dose. In case the sufficient cell number of CD19-CAR-T is manufactured, DLT is not observed after CD19-CAR-T infusion, certain clinical effect is observed and additional treatment is preferable, the necessity of 2nd infusion will be assessed. In the case that 2nd infusion is necessary, it is allowed to infuse at appropriate timing.

This study is conducted based on the 3+3 dose escalation scheme. Three subjects are enrolled in each group of Dose Level. If one of the 3 subjects show DLT during DLT assessment period, another 3 subjects will be added; therefore, decision as to whether the next Dose Level can follow or not is made based on the results obtained from the total of 6 subjects.

The investigator assesses the tumor shrinkage effect of CD19-CAR-T in accordance with "Revised response criteria malignant lymphoma", at 12 week after the 1st infusion of CD19-CAR-T (or at the time of termination). The investigator also assesses the safety during the follow-up period. Long-term follow-up study is conducted at frequency of once a year for 15 years after the 1st infusion of CD19-CAR-T in reference to guidelines of FDA.

Gene Therapy for B-Cell Non-Hodgkin Lymphoma Using CD19 CAR Gene Transduced T Lymphocytes

Clinical Research of Gene Therapy for Refractory B-Cell Non-Hodgkin Lymphoma Using Autologous T Cells Expressing a Chimeric Antigen Receptor Specific to the CD19 Antigen

Confirm the toxicity profile with CTCAE ver4.0.

Confirm existence or non-existence of normal B-lymphocytes decrease by flow cytometry.

Confirm replication competent retrovirus (RCR) by PCR.

Confirm clonality by linear amplification mediated (LAM)-PCR.

Transduction efficiency, viability, sterility and potency.

Confirm the efficacy with "Revised response criteria for malignant lymphoma" J Clin Oncol. 25: 579-586 (2007).

Confirm the state of immune mechanism by flow cytometry.

Takara Bio Inc.

Jichi Medical University

Professor

Symptoms and General Pathology

Heart and Blood Diseases

Recurrence

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Waldenstrom Macroglobulinemia

Hematologic Diseases

Disease Attributes

Leukemia, B-Cell

Chronic Disease

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Marginal Zone Lymphoma

Indolent B Cell Lymphoma

Anti-Infective Agents

Analgesics

Aldesleukin

Interleukin-2

Analgesics, Non-Narcotic

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

CHEMOTHERAPY: Patients receive cyclophosphamide IV over 60 minutes.

IMMUNOTHERAPY: Beginning 2 days after completion of cyclophosphamide, patients receive autologous CD20-specific T-cells IV over 30 minutes. Treatment repeats every 2-5 days for 3 courses.

MAINTENANCE THERAPY: Beginning 2 hours after the last T-cell infusion, patients receive low-dose aldesleukin subcutaneously twice daily for 14 days.

Subjects who have achieved at least a partial remission lasting a minimum of 6 months may, on a case-by-case basis, receive additional stored T cells following relapse.

therapeutic autologous lymphocytes

cyclophosphamide

aldesleukin

polymerase chain reaction

gene rearrangement analysis

lymph node biopsy

genetically engineered lymphocyte therapy

bone marrow aspiration

flow cytometry

laboratory biomarker analysis

enzyme-linked immunosorbent assay

Brian Till

This phase I trial is studying the side effects of giving genetically engineered lymphocytes together with cyclophosphamide and aldesleukin in treating patients with relapsed or refractory mantle cell lymphoma or indolent B-cell non-Hodgkin lymphoma. Placing a gene that has been created in the laboratory into white blood cells may make the body build an immune response to kill cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Aldesleukin may stimulate the white blood cells to kill lymphoma cells. Giving genetically engineered lymphocytes together with cyclophosphamide and aldesleukin may be an effective treatment for mantle cell lymphoma and B-cell non-Hodgkin lymphoma

PRIMARY OBJECTIVES:

I. To assess the feasibility, safety and toxicity of cellular immunotherapy utilizing ex-vivo expanded autologous T cells genetically modified to express a "second generation' cluster of differentiation (CD)20-specific scFvFc:CD28:CD137:zeda chimeric immunoreceptor in patients with recurrent or refractory CD20+ mantle cell or indolent lymphoma.

SECONDARY OBJECTIVES:

I. To determine the duration of in vivo persistence of adoptively transferred CD20-specific T cells transfected with a CD20-specific scFvFc:CD28:CD137:zeda chimeric immunoreceptor.

II. To assess the trafficking of CD20-specific T cells to lymphoma masses. III. To evaluate the development of host anti-CD20 scFvFc:CD28:CD137:zeda chimeric immunoreceptor and anti-neomycin-resistance gene (NeoR) immune responses in study subjects.

OUTLINE:

CHEMOTHERAPY: Patients receive cyclophosphamide IV over 60 minutes.

IMMUNOTHERAPY: Beginning 2 days after completion of cyclophosphamide, patients receive autologous CD20-specific T-cells IV over 30 minutes. Treatment repeats every 2-5 days for 3 courses.

MAINTENANCE THERAPY: Beginning 2 hours after the last T-cell infusion, patients receive low-dose aldesleukin subcutaneously twice daily for 14 days.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Subjects who have achieved at least a partial remission lasting a minimum of 6 months may, on a case-by-case basis, receive additional stored T cells following relapse.

After completion of study treatment, patients are followed up weekly for one month, monthly for 1 year, and then annually for up to 2 years.

Genetically Engineered Lymphocytes, Cyclophosphamide, and Aldesleukin in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Indolent B-Cell Non-Hodgkin Lymphoma

A Pilot Study to Evaluate the Safety and Feasibility of Cellular Immunotherapy Using Genetically Modified Autologous CD20-Specific T Cells For Patients With Relapsed or Refractory Mantle Cell and Indolent B Cell Lymphomas

A true grade 3 or higher toxicity rate in excess of 20% attributed to T cell infusions will be considered grounds for stopping the study and amending the protocol to lower the cell infusion doses. If there ever exists sufficient evidence to suggest that the true T cell-related toxicity rate (grade 3 or higher, with the exception of fever \> 40 degrees Celsius lasting less than 24 hours) exceeds 20%, the study will be stopped.

Numbers and percentages of CD20-specific T cells and of malignant B cells will also be quantified in lymph node (LN) and bone marrow (BM).

Means, medians and standard deviation (S.D.) of the Ab titers observed will be computed.

National Cancer Institute (NCI)

Fred Hutchinson Cancer Center

Antibodies

Antibodies, Monoclonal

Rituximab

Plerixafor

Lenograstim

Immunoglobulins

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Adjuvants, Immunologic

Patients receive standard salvage chemotherapy per standard practice and undergo standard mobilization for stem cell collection with G-CSF and/or plerixafor. Some patients may also receive rituximab 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.

Autologous Hematopoietic Stem Cell Transplantation

Filgrastim

Receive ex vivo expanded autologous TCM-enriched CD8+ T cells expressing CD19-specific CAR

Genetically Engineered Lymphocyte Therapy

Laboratory Biomarker Analysis

Peripheral Blood Stem Cell Transplantation

Elizabeth L Budde, MD,PhD

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.

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.

Genetically Engineered Lymphocyte Therapy After Peripheral Blood Stem Cell Transplant in Treating Patients With High-Risk, Intermediate-Grade, B-cell Non-Hodgkin Lymphoma

Phase I/II Study of Cellular Immunotherapy Using Central Memory-Enriched CD8+ T Cells Lentivirally Transduced to Express A CD19-Specific Chimeric Immunoreceptor Following Peripheral Blood Stem Cell Transplantation for Patients With High-Risk Intermediate Grade B-Lineage Non-Hodgkin Lymphoma

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.

Peak expansion of WPRE is expressed in CAR copy number/mL of blood is summarized with median and range

WPRE persistence of quantifiable CD19 CAR summarized with mean and standard deviation

Count of participants who fail to engraft post transplant.

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.

City of Hope Medical Center

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.

Dose Level 0 (25 x 10^6 CAR+ T-cells)

Dose Level 1 (50 x 10^6 CAR+ T-cells)

Dose Level 2 (100 x 10^6 CAR+ T-cells)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Disease histology

Dr. Lwaliw Popplewell

Number of Participants With Dose Limiting Toxicities (DLTs)

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.

peripheral blood stem cell transplantation (PBSCT): Undergo autologous PBSCT

filgrastim: Given IV

polymerase chain reaction: Correlative studies

rituximab: Given IV

genetically engineered lymphocyte therapy: Receive ex vivo expanded autologous central memory (TCM)-enriched CD8+ T cells expressing CD19-specific chimeric antigen receptor (CAR)

laboratory biomarker analysis: Correlative studies

plerixafor: Given IV

autologous hematopoietic stem cell transplantation: Undergo autologous PBSCT

Treatment (Cellular Adoptive Immunotherapy Following PBSCT)

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.

Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE) Detection Above Background

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.

Number of Days of Quantifiable CD19 CAR Post T-cell Infusion

Failure to Engraft

Progression-free Survival at 1 Year

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. All patients 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.

Overall Study

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

0.3 to 3 x 10\^6 autologous CD19-CAR-T cells/kg per patient will be administered intravenously after a conditioning chemotherapy with cyclophosphamide.

cohort -1: 3×10\^5 cells/kg cohort 1: 1×10\^6 cells/kg cohort 2: 3×10\^6 cells/kg.

Phase-I portion:

Cyclophosphamide is administered for conditioning medication of TBI1501, that is CD19-CAR-T cells, (cohort -1: 3×10\^5 cells/kg, cohort 1: 1×10\^6 cells/kg, cohort 2: 3×10\^6 cells/kg).

Phase-II portion:

Recommended dose of Phase-II part will be administered. Cyclophosphamide will be administered as conditioning. The end of study will be Week 52 after administration of TBI-1501.

TBI-1501

Evaluate the safety (P-I), pharmacokinetics and anti-tumor effect of immunotherapy of autologous T cells genetically modified to express anti-CD19 chimeric antigen receptor (CAR) (TBI-1501) for relapsed or refractory CD19+ B-cell acute lymphoblastic leukemia.

Enroll patients after confirming eligibility. Following enrollment, peripheral blood mononuclear cells and blood plasma will be obtained from each subject by apheresis to start the manufacturing of TBI-1501.

Before TBI-1501 administration, it is necessary to pass the quality tests. Subject will be hospitalized from Day -3 to Day 28, and administered Cyclophosphamide (1,000 mg/m2/day×2 days) on Day -3 and Day -2.

Peripheral blood will be collected from a subject after obtaining a written informed consent. Peripheral blood mononuclear cells (PBMCs) and plasma are obtained from the blood, and T cells contained in the PBMCs are transduced with anti-CD19 CAR gene by using retroviral vector.

Cyclophosphamide will be administered after obtaining a written informed consent and completing registration.

CD19-CAR-T will be administered in the split dose. Phase 2 recommended dose will be applied for phase 1 portion. The investigator assesses efficacy of CD19-CAR-T in accordance with study-specific criteria, at 8 week after the infusion of CD19-CAR-T (or at the time of termination). The investigator also assesses the safety during the follow-up period. Long-term follow-up study is conducted at frequency of once a year for 15 years after the infusion of CD19-CAR-T in reference to guidelines of FDA.

Study of TBI-1501 for Relapsed or Refractory Acute Lymphoblastic Leukemia

A Multicenter Phase I/II Study for Relapsed or Refractory CD19+ B-acute Lymphoblastic Leukemia

Adverse event (frequency, seriousness, duration, causality, severity, classification), mortality, severe adverse event, discontinuation due to adverse event.

Complete Remission (CR)+Complete Remission with Incomplete Blood Count Recovery (CRi) , as determined by assessments of peripheral blood and bone marrow.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Gene Therapy for B-Cell Non-Hodgkin Lymphoma Using CD19 CAR Gene Transduced T Lymphocytes	NCT02134262	Relapsed or Ref...	Cyclophosphamid... Dose Level -1 Dose Level 1 Dose Level 2 Dose Level 3	20 Years - 70 Years	Jichi Medical University
Genetically Engineered Lymphocytes, Cyclophosphamide, and Aldesleukin in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Indolent B-Cell Non-Hodgkin Lymphoma	NCT00621452	B-cell Chronic ... Extranodal Marg... Nodal Marginal ... Recurrent Grade... Recurrent Grade... Recurrent Mantl... Recurrent Margi... Recurrent Small... Refractory Chro... Splenic Margina... Waldenström Mac...	therapeutic aut... cyclophosphamid... aldesleukin polymerase chai... gene rearrangem... lymph node biop... genetically eng... bone marrow asp... flow cytometry laboratory biom... enzyme-linked i...	-	Fred Hutchinson Cancer Center
Genetically Engineered Lymphocyte Therapy After Peripheral Blood Stem Cell Transplant in Treating Patients With High-Risk, Intermediate-Grade, B-cell Non-Hodgkin Lymphoma	NCT01318317	Recurrent Grade... Recurrent Grade... Recurrent Grade... Recurrent Mantl... Recurrent Non-H...	Autologous Hema... Filgrastim Genetically Eng... Laboratory Biom... Peripheral Bloo... Plerixafor Rituximab	18 Years -	City of Hope Medical Center
Study of TBI-1501 for Relapsed or Refractory Acute Lymphoblastic Leukemia	NCT03155191	Lymphoblastic L...	TBI-1501	16 Years -	Takara Bio Inc.

Spots Global Cancer Trial Database for genetically engineered lymphocyte therapy