Recruitment

Recruitment Status
Recruiting

Inclusion Criteria

No significant circulating disease, defined as an elevated total lymphocyte count above the ULN due to the presence of malignant cells.
Age >=18 years at the time of consent
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 x institutional upper limit of normal (ULN) and Total bilirubin < 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome
...
No significant circulating disease, defined as an elevated total lymphocyte count above the ULN due to the presence of malignant cells.
Age >=18 years at the time of consent
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 x institutional upper limit of normal (ULN) and Total bilirubin < 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome
Hemoglobin (Hgb) >8 grams per deciliter (gm/dl) (transfusions allowed)
Subjects with small lymphocytic lymphoma (SLL) must have progressed after at least 2 prior therapies and prior treatment with or intolerance of both ibrutinib and venetoclax.
Relapsed or refractory disease after two or more lines of systemic therapy
Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method
Laboratory result abnormalities that are considered not clinically significant by the principal investigator AND are not the result of a demonstrated active infection or an active central nervous system condition.
Absolute lymphocyte count > 100/ (microliter)
Positron Emission Tomography (PET) -positive disease according to "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification"
Hematologic function parameters will not be included as a pre-infusion eligibility criterion (because lymphodepletive chemotherapy is expected to cause pancytopenia).
Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of antiCD19 CAR-T cells
For subjects with Mantle cell lymphoma, previous lines of therapy may include multiagent chemotherapy including alkylating agent or anthracycline and anti CD20 antibody therapy and Bruton's tyrosine kinase (BTK) inhibitor therapy.
Primary refractory or early relapse (first remission < 12 months) and not eligible for stem cell transplant
Absolute Neutrophil Count (ANC) > 500/uL
Ability to understand a written informed consent document, and the willingness to sign it.
Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) > 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA)
Eastern Cooperative Oncology Group (ECOG) performance status < 2
Subjects with DLBCL, primary mediastinal B- Cell lymphoma, Burkitt lymphoma and transformed lymphoma must have relapsed or failed to respond to >= 2 prior lines of multiagent chemoimmunotherapy with prior exposure to both an anti-CD20 antibody agent and an anthracycline.
Platelets >50,000/microliter (uL) (transfusions allowed)
Adequate vascular access for leukapheresis procedure (either peripheral line or surgically placed line).
Serum Creatinine < 2 x the institutional ULN
CD19 positive by either immunohistochemistry or flow cytometry analysis on any biopsy. If prior anti-CD19 therapy has been administered, CD19 positivity has to be re-established on the most recent biopsy.
Subjects with indolent lymphomas (follicular lymphoma and lymphoplasmacytic lymphoma) must have relapsed after or been refractory to >=2 prior lines of multi-agent chemoimmunotherapy including prior exposure to rituximab and at least 2 other chemotherapy agents.

Exclusion Criteria

Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
Patients with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.
Neurologic symptoms suggestive of an active central nervous system condition.
...
Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
Patients with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.
Neurologic symptoms suggestive of an active central nervous system condition.
Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test.
Body weight <40 kilograms(kg)
Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements.
History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months.
Autologous transplant within 6 weeks of planned CAR-T cell infusion
Recipient of prior CAR-T cell therapy targeting CD19 outside of this protocol
Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast).
Use of corticosteroids within 7 days prior to infusion (with exception of agents used for prevention of emesis during lymphodepletive chemotherapy).
Signs or laboratory markers of active infection or systemic inflammatory response.
HIV seropositivity

Summary

Conditions
  • Burkitt Lymphoma
  • Diffuse Large B Cell Lymphoma
  • Follicular Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Primary Mediastinal Large B Cell Lymphoma
  • Refractory Non Hodgkin Lymphoma
  • Small Lymphocytic Lymphoma
  • Transformed Lymphoma
Type
Interventional
Phase
Phase 1
Design
  • Allocation: N/A
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label)
  • Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 125 years
Gender
Both males and females

Description

This is an open-label, pilot, phase 1 study to determine the safety profile of anti-CD19 CAR-T cell infusion in participants with R/R B-cell NHL. The dose-finding cohorts in this study will evaluate and define the safe dose of anti-CD19 CAR-T cells. Using a "3+3" design, participants will be enrolle...

This is an open-label, pilot, phase 1 study to determine the safety profile of anti-CD19 CAR-T cell infusion in participants with R/R B-cell NHL. The dose-finding cohorts in this study will evaluate and define the safe dose of anti-CD19 CAR-T cells. Using a "3+3" design, participants will be enrolled sequentially to each dose level. A dose expansion will then occur at the maximum tolerated dose (MTD) and dose levels that have not exceeded the MTD. Up to 36 participants will be enrolled and treated. Each subject will provide consent and be evaluated for study eligibility. Eligible subjects will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. The CAR T cells will be produced using the Miltenyi Prodigy and an FDA compliant Lentigen CD19 targeted lentiviral vector. After successful generation of the anti-CD19 CAR-T cells (drug product (DP)), subjects will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-CD19 CAR-T cells at the starting dose of 5 x 105 cells/kg will be given on Day=0. Following treatment with DP, subjects will be followed on this study for 12 months for safety, disease status, and survival. For long term follow-up, participants will be followed for 15 years. For participants whose dose does not meet the target dose, enrollment into a conforming product low-dose cohort, at minimum dose level - 1 and that has not exceeded the MTD will occur. This conforming product low-dose cohort will be evaluated for toxicity and efficacy of those lower dose levels as part of the primary safety and secondary objectives. For participants whose CAR-T product does not meet the pre-specified release criteria, enrollment into a non-conforming product cohort, at a minimum dose level - 1 and that has not exceeded the MTD will occur. This non-conforming product cohort will be evaluated for toxicity and efficacy of the non-conforming product cohort as part of the exploratory objectives PRIMARY OBJECTIVES To evaluate the safety of administering chimeric antigen receptor T cells targeting CD-19 to patients with relapsed or refractory CD19+ B-cell nonHodgkin lymphoma (NHL). To determine the recommended phase 2 dose (RP2D) for this cellular therapy. SECONDARY OBJECTIVES To assess the safety and toxicity of cell collection and infusion of CAR-T cells targeting CD19 in patients with relapsed or refractory CD19+ B cell NHL. To describe the efficacy of chimeric antigen receptor T cells targeting CD-19 in patients with relapsed or refractory CD19+ B cell NHL. To evaluate the feasibility of CD19 CAR T cell manufacturing for patients with relapsed or refractory CD19+ B cell NHL of local manufacturing and ability to produce adequate quantities of vector positive T-cells

Inclusion Criteria

No significant circulating disease, defined as an elevated total lymphocyte count above the ULN due to the presence of malignant cells.
Age >=18 years at the time of consent
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 x institutional upper limit of normal (ULN) and Total bilirubin < 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome
...
No significant circulating disease, defined as an elevated total lymphocyte count above the ULN due to the presence of malignant cells.
Age >=18 years at the time of consent
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 x institutional upper limit of normal (ULN) and Total bilirubin < 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome
Hemoglobin (Hgb) >8 grams per deciliter (gm/dl) (transfusions allowed)
Subjects with small lymphocytic lymphoma (SLL) must have progressed after at least 2 prior therapies and prior treatment with or intolerance of both ibrutinib and venetoclax.
Relapsed or refractory disease after two or more lines of systemic therapy
Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method
Laboratory result abnormalities that are considered not clinically significant by the principal investigator AND are not the result of a demonstrated active infection or an active central nervous system condition.
Absolute lymphocyte count > 100/ (microliter)
Positron Emission Tomography (PET) -positive disease according to "Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification"
Hematologic function parameters will not be included as a pre-infusion eligibility criterion (because lymphodepletive chemotherapy is expected to cause pancytopenia).
Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of antiCD19 CAR-T cells
For subjects with Mantle cell lymphoma, previous lines of therapy may include multiagent chemotherapy including alkylating agent or anthracycline and anti CD20 antibody therapy and Bruton's tyrosine kinase (BTK) inhibitor therapy.
Primary refractory or early relapse (first remission < 12 months) and not eligible for stem cell transplant
Absolute Neutrophil Count (ANC) > 500/uL
Ability to understand a written informed consent document, and the willingness to sign it.
Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) > 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA)
Eastern Cooperative Oncology Group (ECOG) performance status < 2
Subjects with DLBCL, primary mediastinal B- Cell lymphoma, Burkitt lymphoma and transformed lymphoma must have relapsed or failed to respond to >= 2 prior lines of multiagent chemoimmunotherapy with prior exposure to both an anti-CD20 antibody agent and an anthracycline.
Platelets >50,000/microliter (uL) (transfusions allowed)
Adequate vascular access for leukapheresis procedure (either peripheral line or surgically placed line).
Serum Creatinine < 2 x the institutional ULN
CD19 positive by either immunohistochemistry or flow cytometry analysis on any biopsy. If prior anti-CD19 therapy has been administered, CD19 positivity has to be re-established on the most recent biopsy.
Subjects with indolent lymphomas (follicular lymphoma and lymphoplasmacytic lymphoma) must have relapsed after or been refractory to >=2 prior lines of multi-agent chemoimmunotherapy including prior exposure to rituximab and at least 2 other chemotherapy agents.

Exclusion Criteria

Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
Patients with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.
Neurologic symptoms suggestive of an active central nervous system condition.
...
Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
Patients with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease.
Neurologic symptoms suggestive of an active central nervous system condition.
Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test.
Body weight <40 kilograms(kg)
Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements.
History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months.
Autologous transplant within 6 weeks of planned CAR-T cell infusion
Recipient of prior CAR-T cell therapy targeting CD19 outside of this protocol
Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast).
Use of corticosteroids within 7 days prior to infusion (with exception of agents used for prevention of emesis during lymphodepletive chemotherapy).
Signs or laboratory markers of active infection or systemic inflammatory response.
HIV seropositivity

Locations

San Francisco, California, 94143
San Francisco, California, 94143

Tracking Information

NCT #
NCT04545762
Collaborators
University of California, Davis
Investigators
  • Principal Investigator: C. Babis Andreadis, MD University of California, San Francisco
  • C. Babis Andreadis, MD University of California, San Francisco