Clinical trial NCT04450069: CLBR001 and SWI019 in Patients With Relapsed / Refractory B-cell Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Keywords: CAR-T Cell Therapy
Switchable CAR-T Cell
Autologous Cell Therapy
CD19 Positive Disease
CD19 CAR-T Cell
Blood Cancer
Hematological malignancy
Neoplasms
Lead sponsor: Calibr, a division of Scripps Research
Sponsor class: OTHER
First posted: 2020-06-29
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Frequency, relatedness, severity and duration of treatment emergent and treatment related adverse events
timeFrame: 35 days
measure: Number of first cycle dose limiting toxicities (DLT) as assessed by Common Terminology Criteria for Adverse Events (CTCAE)
timeFrame: up to 1 year
Secondary outcomes:
measure: Maximum drug concentration (Cmax) of SWI019
timeFrame: up to Day 35
measure: Area under the curve (AUC) of SWI019
timeFrame: up to Day 35
measure: Time to reach Cmax (Tmax) of SWI019
timeFrame: up to Day 35
measure: Clearance (CL) of SWI019
timeFrame: up to Day 35
measure: Apparent elimination half-life (t1/2) of SWI019
timeFrame: up to Day 35
measure: Quantification of CLBR001 cells in peripheral blood
timeFrame: up to 1 year
measure: Phenotype of CLBR001 in peripheral blood and/or tumor/bone marrow biopsies
timeFrame: up to 1 year
measure: Immunogenic response to CLBR001
timeFrame: up to 1 year
measure: Immunogenic response to SWI019
timeFrame: up to 1 year
measure: Serum cytokine concentrations
timeFrame: up to 1 year
measure: Overall (best) objective response by the Response Evaluation Criteria in Lymphoma (RECIL) and Lugano criteria
timeFrame: up to 1 year
measure: Duration of response (DOR)
timeFrame: up to 1 year
measure: Progression free survival (PFS)
timeFrame: up to 1 year
measure: Overall survival (OS)
timeFrame: up to 1 year
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: San Diego
country: United States
facility: University of California at San Diego
state: California
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Weill Cornell Medical College - New York Presbyterian Hospital
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute - Tennessee Oncology
state: Tennessee
city: San Antonio
country: United States
facility: Sarah Cannon Research Institute - Texas Transplant Institute
state: Texas
Study officials:
References:
citation: Rodgers DT, Mazagova M, Hampton EN, Cao Y, Ramadoss NS, Hardy IR, Schulman A, Du J, Wang F, Singer O, Ma J, Nunez V, Shen J, Woods AK, Wright TM, Schultz PG, Kim CH, Young TS. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):E459-68. doi: 10.1073/pnas.1524155113. Epub 2016 Jan 12.
citation: Viaud S, Ma JSY, Hardy IR, Hampton EN, Benish B, Sherwood L, Nunez V, Ackerman CJ, Khialeeva E, Weglarz M, Lee SC, Woods AK, Young TS. Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory. Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):E10898-E10906. doi: 10.1073/pnas.1810060115. Epub 2018 Oct 29.
citation: Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.