Phase 1a/1b Dose Escalation and Cohort Expansion Study of the Safety and Efficacy of B-Cell Activating Factor Receptor (BAFFR)-Based Chimeric Antigen Receptor T-Cells (MC10029) in Subjects With Relapsed or Refractory BAFFR-Expressing B-Cell Hematologic Malignancies
This phase I trial tests safety, side effects and best dose of B-cell activating factor receptor (BAFFR)-based chimeric antigen receptor T-cells, with fludarabine and cyclophosphamide lymphodepletion, for the treatment of patients with B-cell hematologic malignancies that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). BAFFR-based chimeric antigen receptor T-cells is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving chemotherapy, such as fludarabine and cyclophosphamide, helps ill cancer cells in the body and helps prepare the body to receive the BAFFR based chimeric antigen receptor T-cells. Giving BAFFR based chimeric antigen receptor T-cells with fludarabine and cyclophosphamide for lymphodepletion may work better for the treatment of patients with relapsed or refractory B-cell hematologic malignancies.
• PRE-REGISTRATION: Age ≥ 18 years
• PRE-REGISTRATION: Confirmed diagnosis of 1 of the following relapsed or refractory B-cell hematologic malignancies: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or large B cell lymphoma (LBCL) including Richter's transformation from CLL/SLL
‣ For CD19+ B cell malignancies; relapsed or refractory disease is defined by one of the following histopathology:
• Biopsy proven SLL or flow cytometry proven CLL; relapsed or refractory disease is defined as:
∙ Demonstration of progressive or stable disease by positron emission tomography/computed tomography (PET/CT) or computed tomography (CT) criteria according to the international workshop on chronic lymphocytic leukemia (iwCLL) 2018 criteria
∙ Biopsy proven B-cell non-Hodgkin lymphoma (NHL) of any histopathology (including Richter Transformation of CLL); relapsed or refractory disease is defined as:
∙ Demonstration of progressive or stable disease by PET/CT or CT criteria as the best response to the most recent chemotherapy regimen according to the revised Lugano Response Criteria for Malignant Lymphoma
• PRE-REGISTRATION: Disease Specific prior lines of therapies below:
‣ For CLL/SLL, patients must have received ≥ two prior lines of therapy, and/or ≥ 6 months of second line prior BTK inhibition (e.g. ibrutinib or other such as acalabrutinib or zanubrutinib) and must have failed to respond to venetoclax or be intolerant. Exception: Patients in stable disease (SD) or partial response (PR) with a known ibrutinib resistance mutation (BTK or phospholipase Cγ2) may be included even if on ibrutinib therapy for less than 6 months
• These patients may or may not have received prior antibody directed against cluster of differentiation 20 (CD20).
⁃ For Follicular Lymphoma, patients must have received ≥ two prior lines of therapy, including an antibody directed against CD20.
• NOTE: Prior cluster of differentiation 19 (CD19) directed chimeric antigen receptor T-cell therapy (CART) must have a 100-day washout period.
⁃ For Mantle Cell Lymphoma, patients must have received ≥ two prior lines of therapy, including an antibody directed against CD20, and a BTK inhibitor.
• NOTE: Prior CD19 directed CART must have a 100-day washout period.
⁃ For Marginal Zone Lymphoma, patients must have received ≥ two prior lines of therapy, including an antibody directed against CD20.
• NOTE: Prior CD19 directed CART must have a 100-day washout period.
⁃ For Large B cell Lymphoma, patients must have received ≥ two prior lines of therapy, including an antibody directed against CD20. Prior exposure to CD19 directed CART will be allowed at the discretion of the Principal Investigator.
• NOTE: Prior failed CD19 directed CART must have a 100-day washout period
⁃ For Richter's Transformation, patients must have received ≥two prior lines of therapy, including an antibody directed against CD20.
⁃ 100-day washout period starts from the date of the last prior CAR-T infusion.
• PRE-REGISTRATION: Measurable disease
• REGISTRATION: Positive BAFFR test
• REGISTRATION: Measurable disease
• REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• REGISTRATION: Hemoglobin ≥ 9.0 g/dL (unless due to documented marrow involvement with disease) obtained ≤14 days prior to registration
• REGISTRATION: Absolute neutrophil count (ANC) ≥ 1500/mm\^3 (unless due to documented marrow involvement with disease) obtained ≤14 days prior to registration
• REGISTRATION: Platelet count ≥100,000/mm\^3 (unless due to documented marrow involvement with disease) obtained ≤ 14 days prior to registration
• REGISTRATION: Total bilirubin ≤ 1.5 x upper limits of normal (ULN) (Subjects with Gilbert's Syndrome may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN) obtained ≤ 14 days prior to registration
• REGISTRATION: Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement) obtained ≤ 14 days prior to registration
• REGISTRATION: Prothrombin time (PT)/international normalized ratio (INR) /activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy obtained ≤ 14 days prior to registration
‣ Patients on a stable, maintenance regimen of anticoagulant therapy for ≥ 30 days prior to registration may have PT/INR measurements \> 1.5 X ULN if, in the judgment of the investigator, the patient is suitable for the study
• REGISTRATION: Calculated creatinine clearance ≥45 ml/min using the Cockcroft-Gault formula obtained ≤ 14 days prior to registration
• REGISTRATION: Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• REGISTRATION: Provide written informed consent understand and comply with protocol-required study procedures
• REGISTARTION: Patients must have an ejection fraction (EF) of ≥ 45%
• REGISTRATION: Patients must have pulse ox measurements of \> 92% on room air
• REGISTRATION: Willingness to provide mandatory blood specimens for correlative research
• REGISTRATION: Willing to return to enrolling institution for study follow-up