B-Cell Activating Factor Receptor (BAFFR)-Based Chimeric Antigen Receptor T-Cells With Fludarabine and Cyclophosphamide Lymphodepletion for the Treatment of Relapsed or Refractory B-cell Hematologic Malignancies

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of (MC10029) autologous BAFFR-targeting chimeric antigen receptor (CAR) T cells following lymphodepleting (LD) therapy in subjects with relapsed or refractory BAFFR expressing B-cell hematologic malignancies.

II. To determine the recommended dose for phase 1b (dose expansion) and recommend phase 2 dose.

SECONDARY OBJECTIVES:

I. To assess the efficacy and antitumor activity of MC10029 in subjects with relapsed or refractory BAFFR-expressing B-cell hematologic malignancies.

II. To determine long-term toxicities in MC10029 recipients. III. To determine feasibility of manufacturing success rate of MC10029.

CORRELATIVE RESEARCH OBJECTIVES:

I. To evaluate the pharmacokinetics of MC10029 in peripheral blood samples. II. To study the relationship between BAFFR expression and clinical activity of MC10029.

OUTLINE:

Patients undergo leukapheresis. Patients then receive cyclophosphamide intravenously (IV), over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and magnetic resonance imaging (MRI) at screening, computed tomography (CT) scan, positron emission tomography (PET) scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.

After completion of study treatment, patients followed up at day 1, 2, 3, 4, 8, 11, 14, 21, 28, 60, 90, 180, 270, 365, 545 and 730 and then periodically for up to 15 years.

Inclusion criteria

• 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

Exclusion criteria

• PRE-REGISTRATION: Prior solid organ transplantation
• PRE-REGISTRATION: Unstable angina, clinically significant arrhythmia, or myocardial infarction ≤ 6 months of prior to pre-registration, or grade 3 or higher pericardial effusion at the time of pre-registration
• PRE-REGISTRATION: Prior anti-BAFF-R therapies
• PRE-REGISTRATION: Known contraindication to lymphodepleting (LD) chemotherapy
• PRE-REGISTRATION: Use of systemic antitumor therapy or investigational agent ≤ 14 days, prior to pre-registration
• PRE-REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the BAFF-R
• PRE-REGISTRATION: Autologous HCT ≤ 60 days prior to pre-registration
• PRE-REGISTRATION: Uncontrolled intercurrent non-cardiac illness including, but not limited to:

• Previous or concurrent malignancy
• Ongoing or active infection
• Psychiatric illness/social situations
• Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy * Persons of childbearing potential who are pregnant or breastfeeding
• Life Expectancy of < 6 weeks
• Persons requiring systemic corticosteroids (>10 mg prednisone or equivalent per day) and/or other immunosuppressive therapy. Patients are allowed to use topical corticosteroids
• Any other conditions that would limit compliance with study requirements
• PRE-REGISTRATION: Detectable malignant cells from cerebrospinal fluid (CSF) or magnetic resonance imaging (MRI) indicating brain metastases during screening, or a history of central nervous system (CNS) involvement by malignancy (CSF or imaging) with still active disease. Note: Patients with a history of CNS involvement resolving after treatment and without active disease will be considered eligible if other inclusion criteria are met
• PRE-REGISTRATION: History of a seizure disorder, major cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
• PRE-REGISTRATION: Radiation therapy ≤ 14 days prior to pre-registration
• PRE-REGISTRATION: Prior allogeneic hematopoietic stem cell transplant (HCT) in ≤ 6 months prior to pre-registration; patients with active graft versus host disease (GVHD) will not be eligible regardless of duration from prior allogeneic HCT
• PRE-REGISTRATION: Human immunodeficiency virus (HIV) positive patients
• PRE-REGISTRATION: Subjects with New York Health Association (NYHA) class III or greater heart failure
• REGISTRATION: Eligible for auto-HCT based on investigator judgement
• REGISTRATION: Presence of active bacterial, viral, or fungal infection that is uncontrolled, based on investigator judgment
• REGISTRATION: Patients with active hepatitis B or hepatitis C infections are excluded from the study. Patients who are documented to be HIV positive or proven HIV infection from testing are ineligible for the study. Infectious disease testing (HIV-1, HIV-2, hepatitis C virus (HCV) antibody and polymerase chain reaction (PCR), hepatitis B virus (HBV) surface antigen, HBV surface antibody, HBV core antibody) performed ≤ 45 days prior to registration may be considered for subject eligibility
• REGISTRATION: Previous or concurrent malignancy, except basal cell or squamous cell skin carcinoma, adequately resected and in situ carcinoma of cervix, or a previous malignancy that was completely resected and has been in remission for ≥ 5 years prior to registration
• REGISTRATION: Persons of childbearing potential who are pregnant or breastfeeding
• REGISTRATION: Life expectancy of < 6 weeks