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
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.
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:
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
For Follicular Lymphoma, patients must have received ≥ two prior lines of therapy, including an antibody directed against CD20.
For Mantle Cell Lymphoma, patients must have received ≥ two prior lines of therapy, including an antibody directed against CD20, and a BTK inhibitor.
For Marginal Zone Lymphoma, patients must have received ≥ two prior lines of therapy, including an antibody directed against CD20.
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.
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
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:
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