BAFFR-targeting CAR T Cells for Patients With Relapsed or Refractory B-NHL

Study Overview
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Brief Summary
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A Phase 1 Study Evaluating BAFFR-targeting CAR T Cells for Patients with Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma (B-NHL)

Detailed Description
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This phase I trial evaluates the side effects and best dose of BAFFR-CAR T cells in treating patients with B-cell Non-Hodgkin's Lymphoma (B-NHL) that has come back (recurrent) or does not respond to treatment (refractory). T cells are infection fighting blood cells that can kill cancer cells. The T cells given in this study will come from the patient and will have a new gene put in them that makes them able to recognize BAFFR, a protein on the surface of cancer cells. These BAFFR-specific T cells may help the body's immune system identify and kill BAFFR+ cancer cells.

Official Title
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A Phase 1 Study Evaluating BAFFR-targeting CAR T Cells for Patients With Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma (B-NHL)

Conditions
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Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Biological: BAFFR-CAR T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Documented informed consent of the participant and/or legally authorized representative. 2. Agreement to allow the use of archival tissue from diagnostic tumor biopsies * If unavailable, exceptions may be granted with Study PI approval. 3. Age: ≥ 18 years 4. ECOG ≤ 2 5. Histologically confirmed diagnosis of B-NHL, as follows: Large B-cell lymphoma (LBCL) patients including the following types defined by World Health Organization (WHO) 2016 classification - DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL) with or without MYC and BCL2 and/or BCL6 rearrangement, transformed follicular lymphoma (tFL), and transformed marginal zone lymphoma (tMZL) - as well as follicular lymphoma (FL) Grade 3b, who have received at least 2 prior lines of standard therapy (described in NCCN guidelines), which must contain an anti-CD20 targeted agent (unless documented CD20 negative) and an anthracycline. Mantle Cell Lymphoma (MCL) patients with: - Primary refractory MCL (with or without prior BTK inhibitor) defined as lymphoma did not respond to a first line therapy or the response did not last longer than 6 months from an initial response, or Relapsed MCL defined as recurrence of disease after an initial response lasting longer than 6 months, must have had at least 1 prior regimen that must include a BTK inhibitor, or Newly diagnosed MCL without standard of care (SOC) options (e.g., TP53 mutation, ineligible for intensive chemotherapy) are eligible after discussion with PI. Follicular lymphoma (FL) Grades 1-3a and marginal zone lymphoma (MZL) patients who are relapsed or refractory to at least one prior systemic treatment regimen which must include an anti-CD20 targeted agent (unless documented CD20 negative), and for whom there is no readily available therapy expected to improve survival (e.g., standard chemotherapy, ASCT). Note: all the above B-NHL subtypes are eligible during the dose-finding portion. During dose expansion, only MCL patients and large B-cell lymphoma (LBCL) patients are eligible. • 6. Evidence of positive BAFF-R expression on the lymphoma cells at the time of enrollment is required. i. Archival tissue is allowed if there is a significant safety risk for a repeat biopsy or if the lymphoma site is not accessible and as long as the patient has not received any anti-BAFFR treatment. ii. Bone marrow biopsy is optional at enrollment IF patient already has biopsy proven active disease elsewhere. 7. Measurable disease by CT scan (≥1.5 cm) or evidence of blood, gastrointestinal, skin, bone marrow or spleen involvement 8. Prior CAR T cell therapy is allowed if at least 3 months have elapsed prior to leukapheresis procedure i. If participant received prior CD19-CAR T cells persistence must be evaluated and found to be <5% prior to leukapheresis procedure 9. Fully recovered from the acute toxic effects (except alopecia) to ≤ Grade 1 to prior anti-cancer therapy 10. No known contraindications to leukapheresis, steroids or tocilizumab. 11. Total bilirubin ≤ 1.5 X ULN (unless has Gilbert's disease), then ≥ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN) 12. Blood counts: Absolute Neutrophil count (ANC ≥1000 cells/ul)* o Growth factor use within 7 days prior screening is not allowed Platelet count ≥75,000/ul. Transfusion with 7 days prior to screening is not allowed* Exception: participants with bone marrow involvement do not need to meet this criteria 13. AST < 3 x ULN 14. ALT < 3 x ULN 15. Creatinine clearance of ≥ 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula 16. Left ventricular ejection fraction (LVEF) ≥ 45% Note: To be performed within 28 days prior to start of protocol therapy. 17. QTc ≤ 480 ms Note: To be performed within 28 days prior to start of protocol therapy. 18. O2 saturation > 91% on room air. 19. Seronegative for HIV Ag/Ab combo, HCV*, active HBV (Surface Antigen Negative) *If seropositive for HIV, HCV or HBV (surface antigen or core antibody positive), nucleic acid quantitation must be performed. Viral load must be undetectable. 20. Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. *If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 21. Agreement by females and males of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy. Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only). Exclusion Criteria: 1. Prior allogeneic stem cell transplant. 2. Autologous stem cell transplant within 6 months prior to leukapheresis 3. Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of inhaled steroids is not exclusionary. Physiologic replacement of steroids (i.e., prednisone ≤ 7.5 mg/day or hydrocortisone ≤ 20 mg/day) is allowed. During study participation, participants may receive systemic corticosteroids as needed for treatment-emergent comorbid conditions. 4. Cardiac lymphoma involvement 5. Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression 6. Auto-immune disease or condition requiring systemic immunosuppressant therapy, including uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP). 7. Primary immunodeficiency 8. Class III/IV cardiovascular disability according to the New York Heart Association (NYHA) Classification. 9. History of clinically significant arrhythmia. Paroxysmal atrial fibrillation or flutter that is stable on medical management at least 2 weeks prior to enrollment is allowed. 10. History or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, including seizure disorder. 11. History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent, including lymphodepletion agents and tocilizumab. 12. History of stroke or intracranial hemorrhage within 6 months of enrollment. 13. History of venous thrombotic embolism (VTE) within 6 months of enrollment with exception of central line associated VTE. 14. History of other malignancies, except for malignancy surgically resected (or treated with other modalities) with curative intent, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer; malignancy treated with curative intent with no known active disease present for ≥ 3 years. 15. Clinically significant uncontrolled illness. 16. Active systemic uncontrolled infection requiring antimicrobials. 17. Active CNS MCL or History of CNS MCL within 3 months prior to screening 18. Females only: Pregnant or breastfeeding i. Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures. 19. Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: B-cell activating factor receptor-Chimeric antigen receptor T cells [BAFFR-CAR T cells]<br>BAFFR-CAR T cells in participants with r/r B-NHL | Biological: BAFFR-CAR T cells<br>* First-in-human trial examining the safety and preliminary efficacy of BAFFR-CAR T cells in participants with r/r B-NHL<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Assess the safety of administering BAFFR-CAR T cells in participants with relapsed or refractory (r/r) B-cell Non-Hodgkin's Lymphoma (B-NHL) and it's subtypes. Toxicity will be graded per Common Terminology Criteria for Adverse Events version 5.0, Cytokine Release Syndrome (CRS) and neurotoxicity which use the American Society for Transplantation and Cellular Therapy Consensus Criteria (ASTCT) and Graft versus Host Disease (GVHD) criteria. Toxicities will be followed from the start of lymphodepletion until the end of the study. | Up to 1 year post treatment | 
| Maximum Tolerated Dose (MTD) | Determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of BAFFR-CAR T cells. Toxicity will be graded per Common Terminology Criteria for Adverse Events version 5.0, Cytokine Release Syndrome (CRS) and neurotoxicity which use the American Society for Transplantation and Cellular Therapy Consensus Criteria (ASTCT) and Graft versus Host Disease (GVHD) criteria. Toxicities will be followed from the start of lymphodepletion until the end of the study. | Up to 1 year post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Response | Defined as achieving a best response of complete response or partial response per Lugano Criteria | Up to 1 year post treatment | 
| Minimal Residual Disease (MRD) | Negative MRD is defined by malignant cells < 0.01% by flow cytometry or clonoSEQ. | Up to 1 year post treatment | 
| B Cell Quantification | Measured by flow cytometry | Up to 1 year post treatment | 
| Progression-free survival (PFS) | Kaplan-Meier product limit method with log-log transformation for the confidence interval will be used to estimate PFS. | From CAR T cell infusion to the first observation of disease relapse/progression or death from any cause, whichever occurs first, assessed up to 15 years. | 
| Overall Survival (OS) | Kaplan-Meier product limit method with log-log transformation for the confidence interval will be used to estimate OS. | From the day of BAFFR-CAR T cell infusion to death from any cause assessed, up to 15 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MCL, Relapsed or Refractory, Mantle Cell Lymphoma, BAFFR-CAR T cells, B-cell Non-Hodgkin's Lymphoma, B-NHL, BAFFR, LBCL