CLBR001 and SWI019 in Patients With Relapsed / Refractory B-cell Malignancies

Study Overview
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Brief Summary
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CLBR001 + SWI019 is an combination investigational immunotherapy being evaluated as a potential treatment for patients diagnosed with B cell malignancies who are refractory or unresponsive to salvage therapy or who cannot be considered for or have progressed after autologous hematopoietic cell transplantation. This first-in-human study will assess the safety and tolerability of CLBR001 + SWI019 and is designed to determine the maximum tolerated dose (MTD) or optimal SWI019 dose (OSD). Patients will be administered a single infusion of CLBR001 cells followed by cycles of SWI019. The study will also assess the pharmacokinetics and pharmacodynamics of CLBR001 + SWI019.

Detailed Description
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CLBR001 + SWI019 is a two-component therapy comprising an autologous chimeric antigen receptor T (CAR-T) cell product (CLBR001, the switchable CAR-T cell (sCAR-T)) and an anti-CD19 (cluster of differentiation antigen 19) antibody (SWI019, the switch, a biologic). In combination, SWI019 acts as an adapter molecule that controls the activity of the CLBR001 CAR-T cell product.

Official Title
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A Phase 1, Open-label, Dose Escalating Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the Combination of CLBR001 and SWI019 in Patients With Relapsed/Refractory B-cell Malignancies

Conditions
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Relapsed/Refractory B-cell Lymphomas, Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Chronic Lymphocytic Leukemia (CLL), Marginal Zone Lymphoma (MZL), Mantle Cell Lymphoma, Small Lymphocytic Lymphoma (SLL), Primary Mediastinal Large B Cell Lymphoma, Transformed Follicular Lymphoma, Waldenstrom Macroglobulinemia, Lymphoplasmacytic Lymphoma, Burkitt Lymphoma

Intervention / Treatment
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* Combination Product: CLBR001 and SWI019


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with relapsed / refractory previously treated B cell malignancies (according to the World Health Organization classification; 2017) Patients must have received adequate prior therapy including at least two lines of prior therapies including anthracycline or bendamustine-containing chemotherapy, anti-CD20 (cluster of differentiation antigen 20) therapies and/or Brutton's tyrosine kinase (BTK) inhibitors Patients treated with prior CD19 targeted molecules (e.g., Blincyto) must have confirmed CD19+ disease Patients must be ineligible for allogeneic stem cell transplant (SCT) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 Estimated life expectancy of ≥ 12 weeks from the first day of SWI019 dose administered Willing to undergo pre- and post-treatment core needle biopsy Adequate hematological, renal, pulmonary, cardiac, and liver function Resolved adverse events of any prior therapy to either baseline or CTCAE Grade ≤1 Women of childbearing potential, a negative pregnancy test and must agree to practice effective birth control Men sexually active with female partners of child bearing potential must agree to practice effective contraception Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other procedures Exclusion Criteria: Patients diagnosed with certain disease histologies including pediatric lymphomas/leukemias, monoclonal gammopathy of undetermined significance (MGUS), T-cell histiocyte large B cell lymphoma Pregnant or lactating women Active bacterial, viral, and fungal infections History of allogeneic stem cell transplantation Treatment with any prior lentiviral or retroviral based CAR-T Patients receiving live (attenuated) vaccines within 4 weeks of screening visit or need for live vaccine on study Patients with known active central nervous system (CNS) disease. Patients with prior CNS disease that has been effectively treated may be eligible History of Class III or IV New York Heart Association (NYHA) heart failure, myocardial infarction, unstable angina or other significant cardiac disease within 6 months of screening Involvement of cardiac tissue by lymphoma Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP) HIV-1 and HIV-2 antibody positive patients

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>CLBR001 + SWI019 is administered via infusion with ascending dose levels to determine the maximum tolerated dose (MTD) or optimal SWI019 dose (OSD) | Combination Product: CLBR001 and SWI019<br>* Investigational immunotherapy for B cell malignancies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency, relatedness, severity and duration of treatment emergent and treatment related adverse events | To determine the frequency, relatedness, severity and duration of treatment emergent and treatment related adverse events | 35 days | 
| Number of first cycle dose limiting toxicities (DLT) as assessed by Common Terminology Criteria for Adverse Events (CTCAE) | Based on the number of first cycle dose limiting toxicities (DLT) as assessed by CTCAE to determine maximum tolerated dose (MTD) | up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum drug concentration (Cmax) of SWI019 | To determine the maximum concentration of SWI019 in a patient's peripheral blood | up to Day 35 | 
| Area under the curve (AUC) of SWI019 | To quantify the cumulative amount of SWI019 in a patient's peripheral blood over time | up to Day 35 | 
| Time to reach Cmax (Tmax) of SWI019 | To identify the time point when the concentration of SWI019 reaches maximum in a patient's peripheral blood | up to Day 35 | 
| Clearance (CL) of SWI019 | To determine the clearance factor of SWI019 in a patient's peripheral blood | up to Day 35 | 
| Apparent elimination half-life (t1/2) of SWI019 | To identify the time point when the concentration of SWI019 reaches half of maximum in a patient's peripheral blood | up to Day 35 | 
| Quantification of CLBR001 cells in peripheral blood | To quantify CLBR001 in a patient's peripheral blood at different time points | up to 1 year | 
| Phenotype of CLBR001 in peripheral blood and/or tumor/bone marrow biopsies | To evaluate the phenotype of CLBR001 in a patient's peripheral blood at different time points by flow cytometry | up to 1 year | 
| Immunogenic response to CLBR001 | To evaluate the anti-drug antibodies in response to CLBR001 administration in a patient's peripheral blood | up to 1 year | 
| Immunogenic response to SWI019 | To evaluate the anti-drug antibodies in response to SWI019 administration in a patient's peripheral blood | up to 1 year | 
| Serum cytokine concentrations | To measure the cytokine levels (e.g. TNFa, IL-6, IL-1, IL-2, etc.) in a patient's peripheral blood at different time points | up to 1 year | 
| Overall (best) objective response by the Response Evaluation Criteria in Lymphoma (RECIL) and Lugano criteria | To determine the overall (best) objective anti-cancer response by RECIL and Lugano criteria | up to 1 year | 
| Duration of response (DOR) | To evaluate the duration of anti-cancer response after CLBR001 and SWI019 administration | up to 1 year | 
| Progression free survival (PFS) | To evaluate the duration of patient's progression-free survival | up to 1 year | 
| Overall survival (OS) | To evaluate the overall duration of patient's survival | up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR-T Cell Therapy, Switchable CAR-T Cell, Autologous Cell Therapy, CD19 Positive Disease, CD19 CAR-T Cell, Blood Cancer, Hematological malignancy, Neoplasms