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

Phase 1

Recruiting

• Conditions: Recurrent Chronic Lymphocytic Leukemia; Recurrent Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Transformed Chronic Lymphocytic Leukemia; Refractory Mantle Cell Lymphoma; Refractory Transformed Chronic Lymphocytic Leukemia; B-Cell Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Diffuse Large B-Cell Lymphoma
• Interventions: Biological: Autologous BAFFR-targeting CAR T Cells; Drug: Bendamustine; Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration and Biopsy; Procedure: Computed Tomography; Drug: Cyclophosphamide; Procedure: Echocardiography; Drug: Fludarabine; Procedure: Leukapheresis; Procedure: Magnetic Resonance Imaging; Procedure: Positron Emission Tomography

• Registration Number: NCT06191887
• Lead Sponsor: Mayo Clinic

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2023-12-20
• Study First Submitted QC: 2024-01-04
• Study First Posted: 2024-01-05
• Study Start: 2024-03-18
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-12
• Last Update Posted: 2024-07-16
• Primary Completion: 2040-12-31
• Study Completion: 2040-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 27

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (BARRF based chimeric antigen receptor T-cells)	Computed Tomography	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Bone Marrow Aspiration and Biopsy	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Magnetic Resonance Imaging	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Autologous BAFFR-targeting CAR T Cells	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Biopsy	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Biospecimen Collection	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Leukapheresis	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Positron Emission Tomography	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Echocardiography	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Bendamustine	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Cyclophosphamide	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
Treatment (BARRF based chimeric antigen receptor T-cells)	Fludarabine	Patients undergo leukapheresis. Patients then receive cyclophosphamide 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 MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.

Primary Outcome Measures

Name	Time	Method
Incidence of dose-limiting toxicities (DLT)	Up to 28 days after MC10029 (autologous B-cell activating factor receptor [BAFFR]-targeting chimeric antigen receptor [CAR] T cells product) infusion	DLTs are defined per the protocol and assessed by the number of DLTs that occur during the DLT evaluation period and persist beyond the specified duration (relative to the time of onset, defined as within 28 days).
Incidence and severity of treatment emergent adverse events	Up to 15 years	Defined as adverse events (AEs) that occur or worsen in severity on or after MC10029 product infusion.

Secondary Outcome Measures

Name	Time	Method
Overall response rate	Up to 15 years	Will be estimated by the number of patients with an objective status of complete response (CR) or partial response (PR) by the positron emission tomography-computed tomography (PET-CT) based response criteria . Will be assessed according to Lugano criteria for lymphomas (follicular lymphoma \[FL\], mantle cell lymphoma \[MCL\], marginal zone lymphoma \[MZL\], large b-cell lymphoma \[LBCL\]) and International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria for chronic lymphocytic leukemia (CLL).
Progression free survival	Up to 15 years	Defined as the time from initiation of treatment to the occurrence of disease progression or death.
Overall survival	Up to 15 years	Defined as the time from treatment to death, regardless of disease recurrence.
Duration of response	Up to 15 years	Defined as the time from onset of response to progression or death due to any reason, whichever occurs earlier.
Number of conforming versus nonconforming products	Up to 15 years	Will be noted and reported. A conforming cell product product must have met all release criteria for infusion. No patient will receive a non-conforming product under this protocol, thus this endpoint will be evaluated by the Quality Assurance/Quality Control team.
Complete response rate	Up to 15 years	Will be assessed according to Lugano criteria for lymphomas (FL, MCL, MZL, LBCL) and iwCLL 2018 criteria for CLL.

Trial Locations

Locations (1)

Mayo Clinic in Florida; 🇺🇸 Jacksonville, Florida, United States