Preliminary Safety and Tolerability of CD19x22 CAR T Cells in Adolescent and Adult R/R B-NHL Patients

Study Overview
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Brief Summary
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This open-label, single arm phase 1/1b trial aims to determine the safety and tolerability of anti-CD19 and anti-CD22 chimeric antigen receptor-expressing (CAR) T cells (CD19x22 CAR T) in adolescents and adults with relapsed/refractory (R/R) B-cell Non-Hodgkin Lymphoma (B-NHL). Phase 1 will determine the maximum tolerated dose of CD19x22 CAR T cells using a standard 3+3 trial design. Phase 1b is an expansion phase designed to evaluate the preliminary efficacy of CD19x22 CAR T in CAR-treated and CAR-naïve patients.

Detailed Description
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Phase 1: To determine the safety and tolerability of infusing CD19x22 CAR T, generated using a bicistronic vector, in adolescents and adults with R/R B-NHL, and to determine the Phase 1b recommended dose. Phase 1b (expansion phase): To acquire additional evidence of safety and efficacy of-CD19x22 CAR T infusion in CAR-treated and CAR-naïve R/R B-NHL patients. Secondary objectives for all subjects in Phase 1 and Phase 1b include: 1) Feasibility of manufacturing and infusion, 2) Safety of infusion and 3) Efficacy: Descriptive characterization of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) at Day +90. As well, progression-free survival (PFS), overall survival (OS), duration of remission (DOR) and overall response rate (ORR) will be determined. Efficacy will be descriptively stratified based on prior receipt of CAR-T cell therapy.

Official Title
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Phase 1/1b Study of Bispecific CD19 and CD22 Chimeric Antigen Receptor Co-Expressing T Cells (CD19x22 CAR T) in Adolescent and Adult Patients With Relapsed and/or Refractory B-Non-Hodgkin's Lymphoma (B-NHL)

Conditions
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Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: CD19x22 CAR T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: ≥ 16 years of age with no upper age limit. (NOTE: the first three subjects on this trial must be ≥ 18 years of age.) Histologically confirmed aggressive B-cell NHL including the following types defined by World Health Organization (WHO) 2008: Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein Barr Virus (EBV)+ DLBCL of the elderly; OR Primary mediastinal (thymic) large B cell lymphoma; OR Transformation to DLBCL will also be included. Subjects must not have signs or symptoms of CNS disease or detectable evidence of CNS disease on magnetic resonance imaging (MRI) at screening; subjects who have been previously treated for CNS disease, but have no evidence of disease at screening are eligible. Subjects must have progressed, had stable disease, or recurred after two lines of therapies including an anthracycline and an anti-CD20 monoclonal antibody. Must have evaluable or measurable disease according to the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma;26 lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. Subjects who have undergone autologous stem cell transplantation (SCT) with disease progression or relapse are eligible. Subjects who have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, are: At least 100 days post-transplant, Do not have graft versus host disease (GVHD) At least 14 days or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy (including radiation therapy) at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5 half-lives. At least 7 days must have elapsed since any prior steroid use (dexamethasone or prednisone) prior to apheresis. Physiological replacement doses are allowable with no washout period. Topical or inhaled steroids for localized GVHD is allowable. Peripheral blood CD3 count must be >0.15 x 10^6 cells/mL within 14 days prior to proceeding with apheresis. Toxicities from prior therapy must be stable and recovered to ≤ grade 1 (except for clinically non-significant toxicities such as alopecia). Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, or Karnofsky ≥ 80%. Adequate organ function as defined by: Absolute neutrophil count (ANC) ≥ 750/μL. Platelet count ≥ 50,000/ μL. Renal: Creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 60 mL/min. Hepatic: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 upper limit of normal (ULN). Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert's syndrome where a bilirubin <3.0 will be acceptable. Cardiac: Ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings. Pulmonary: No clinically significant pleural effusion. 1. Baseline oxygen saturation > 92% on room air and; 2. Pulmonary Function Test: Diffuse capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) are all ≥50% of predicted by spirometry after correcting for hemoglobin. 13. Females of childbearing potential must have a negative serum pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential). 14. Subjects of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four (4) months after receiving the preparative regimen; females of childbearing potential must have a negative pregnancy test. 15. Must be able to give informed consent; subjects unable to give informed consent will not be eligible for this study. 16. Be able to consent to long-term follow-up protocol (#20-0188). Exclusion Criteria: Subjects meeting any of the following criteria are not eligible for participation in the study. Age < 16 years of age. Previous CAR T therapy (Phase 1 only). Signs or symptoms of active CNS disease or detectable evidence of CNS disease on MRI at the time of screening. Subjects who have been previously treated for CNS disease, but have no evidence of disease at screening are eligible. History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) unless disease free for at least 3 years. Uncontrolled fungal, bacterial, viral, or other infection requiring antimicrobials for management; simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (hepatitis B surface antigen [HBsAg] positive) or hepatitis C. 8. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment or have cardiac atrial or cardiac ventricular lymphoma involvement. 9. Venous thrombosis or embolism not managed on a stable regimen of anticoagulation. 10. Any medical condition that in the judgement of the sponsor is likely to interfere with assessment of safety or efficacy of study treatment. 11. History of severe immediate hypersensitivity reaction to any of the agents used in this study. 12. Pregnancy (serum pregnancy test must be obtained at time of enrollment for females of childbearing potential and to be repeated 72 hours prior to lymphodepleting chemotherapy regimen); females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be childbearing potential. 13. Lactating. 14. In the investigator's judgment, the subject is unlikely to complete all protocol required study visits or procedures, including follow up visits, or comply with the study requirements for participation. 15. May not have primary immunodeficiency or history of autoimmune disease (e.g., Crohn's Disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years. 16. Unwilling to participate in long-term follow-up protocol that is required if CAR T cell therapy is administered at CU-AMC (#20-0188).

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: The study is a prospective single arm Phase 1/1b with four dose levels. Phase 1 will be the dose finding phase aimed at determining the maximum tolerated dose using a standard 3+3 dose-escalation strategy. Phase 1b will be an expansion phase designed to evaluate the clinical activity of CD19x22 CAR T in CD19 CAR-treated and CAR-naïve B-NHL patients at the maximum tolerated dose.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD19x22 CAR T Cell Infusion<br>Lymphodepleting chemotherapy following by infusion of CD19x22 CAR T Cells | Drug: CD19x22 CAR T Cells<br>* Autologous peripheral blood mononuclear cells transduced with CD19x22 CAR T lentiviral vector.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Overall Tolerability of CD19x22 CAR T Therapy in CAR-naive Subjects as Assessed by Type, Frequency, and Severity of Adverse Events (AEs) | All AEs, including laboratory abnormalities, will be graded using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grading criteria. | 12 Months Post Infusion | 
| Phase 1: Determine the Phase 1b Dose Level | Incidence and frequency of Grade 3-5 toxicity occurring within the dose limiting toxicity (DLT) period post CD19x22 CAR T infusion. Grades 3-5 adverse events (AEs) are defined as Severe, Life-Threatening, and Fatal. | 30 Days Post Infusion | 
| Phase 1b: Establish Evidence of Tolerability of CD19x22 CAR T Cells in a Broader Sample of CAR-naive Subjects Versus Those who have Previously Received CD19 CAR T Cell Therapy | Frequency and severity of all adverse events (AEs) and serious adverse events (SAEs). All AEs and SAEs will be graded using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grading criteria. | 12 Months Post Infusion | 
| Phase 1b: Evaluate the Clinical Efficacy of CD19x22 CAR T through Calculating Proportion of CR, PR, SD, and PD. | Efficacy of treatment will be quantified by calculating the proportion of subjects who achieved a response, such as a complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) at Day +90, 6 months, and 1 year. | 12 Months Post Infusion | 
| Phase 1b: Evaluate the Clinical Efficacy of CD19x22 CAR T through Reporting ORR, PFS, DOR, and OS | Reporting of overall response rate (ORR), progression free survival (PFS), duration of response (DOR), and overall survival (OS) at 1 year. | 12 Months Post Infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients for Whom the Desired Dose of CAR T Cells was Successfully Produced | The feasibility of manufacturing the desired dose of anti-CD19x22 CAR T cells will be established using the percentage of patients for whom the desired dose of CAR T cells was successfully produced. | Day 0 (Infusion) | 
| Evaluate Clinical Efficacy of CD19x22 CAR T | Clinical efficacy is defined through Lugano response criteria at Day +90, 6 months, and 1 year. Efficacy in the phase 1b portion will be stratified based on prior receipt of CD19 CAR T cell therapy. | 12 Months Post Infusion | 
| Percentage of Study Participants who Receive CD19x22 CAR T Cell Infusion without Infusion Reaction |  | 30 Days Post Infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed, Refractory