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Title: CPI-818, an oral interleukin-2-inducible T-cell kinase inhibitor, is well-tolerated and active in patients with T-cell lymphoma.
Epworth Authors: Yannakou, Costas
Other Authors: Khodadoust, Michael
Feldman, Tatyana
Yoon, Dok
Radeski, Dejan
Kim, Youn
Mehta Shah, Meta
Khot, Amit
Wilcox, Ryan
King, Won
Horwitz, Steven
Buggy, Joseph
Hotson, Andrew
Hill, Craig
Munneke, Brian
Mahabhashyam, Suresh
Miller, Richard
Janc, James
Mobasher, Merhdad
Keywords: CPI-818
Oral Interleukin-2-Inducible T-Cell Kinase Inhibitor
T-Cell Lymphoma
Interleukin-2-Inducible T-Cell Kinase (ITK)
Tec-Family, Non-Receptor Tyrosine Kinase Expressed in T-cells
T-Cell Receptor (TCR) Signaling
Development and Differentiation of T-Cells Development and Differentiation of T-Cells
T-Cell Lymphoproliferative Disorders
TCR Expression
Malignant T cells
Phase 1/1b Trial
PTCL-NOS and CTCL Patients
Non-Receptor Tyrosine Kinase Expressed in T-Cells
Cutaneous and Peripheral T-Cell Lymphoma
Maximum Tolerated Dose (MTD)
Inflammatory T cell pathways
Epworth Centre for Immunotherapies and Snowdome Laboratories
Molecular Oncology and Cancer Immunology
Cancer Services Clinical Institute, Epworth HealthCare, Victoria, Australia
Issue Date: Nov-2020
Publisher: American Society of Hematology (ASH)
Citation: Blood (2020) 136 (Supplement 1): 19–20.
Abstract: Interleukin-2-Inducible T-Cell Kinase (ITK) is a Tec-family, non-receptor tyrosine kinase expressed in T-cells that plays a key role in T-cell receptor (TCR) signaling, which is required for development and differentiation of T-cells. In T-cell lymphoproliferative disorders, expression of the TCR and its downstream signaling components, including ITK, are maintained which suggests malignant T cells exploit this growth and survival pathway to their advantage. Antigen-presenting cells, abundant in the lymphoma microenvironment, also may provide antigen to drive TCR signaling through ITK. CPI-818 is a first-in-class, irreversible ITK inhibitor with selectivity for ITK. In preclinical studies, CPI-818 blocks TCR signaling in vitro and is efficacious in murine models and canines with T-cell lymphomas. We report results from the dose escalation portion of an ongoing phase 1/1b trial of CPI-818 in patients with relapsed/refractory T-cell lymphoma (CPI-818-001 study, NCT03952078). The trial is being conducted at sites in the United States, Australia, and South Korea. In dose-escalation, cohorts (3+3 design) enrolled patients with cutaneous and peripheral T-cell lymphoma who have progressed on, refractory to, relapsed, or intolerant to at least 2 standard therapies; age ≥ 18 years; ECOG status 0-1; and adequate organ function. CPI-818 was administered in ascending dose levels (100, 200, 400, 600mg BID) continuously for up to sixteen 21-day cycles, until progression or unacceptable toxicity. In dose expansion, PTCL-NOS and CTCL patients are receiving CPI-818 at a dose of 600 mg BID. The primary objectives of the study are to evaluate the safety and to establish the maximum tolerated dose (MTD) or the maximum administered dose of CPI-818. Safety events will be assessed according to the NCI-CTCAEv5. Secondary objectives include evaluating pharmacokinetics and efficacy as assessed by the investigator using standard response criteria at the end of every 3 cycles. ITK occupancy in peripheral blood T cells and tumor tissue as well as biomarkers associated with anti-tumor activity in tumor and blood samples are being evaluated. The dose-escalation part of the CPI-818-001 trial demonstrated that the 100, 200, 400 and 600 mg BID doses are well tolerated. Clinical activity was observed in both PTCL-NOS and CTCL. Reduction of serum levels of canonical T cell cytokines is consistent with on-mechanism drug inhibition of inflammatory T cell pathways. Disease specific expansion cohorts for PTCL-NOS and CTCL are enrolling patients at a dose of 600 mg BID.
DOI: 10.1182/blood-2020-137782
ISSN: 0006-4971
Journal Title: Blood
Type: Journal Article
Affiliated Organisations: Division of Medical Oncology, Stanford University School of Medicine, Stanford, CA.
John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ.
Asan Medical Center/University of Ulsan College of Medicine, Seoul, Korea, Republic of (South)
Linear Clinical Research and Sir Charles Gairdner Hospital, Nedlands, Australia
Stanford University School of Medicine and Stanford Cancer Institute, Stanford, CA
Division of Medical Oncology, Washington University School of Medicine, St Louis, MO
Department of Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
Rogel Cancer Center, University of Michigan, Ann Arbor, MI.
Hematology and Oncology, Department of Medicine, Samsung Medical Center, Seoul, Korea, Republic of (South)
Corvus Pharmaceuticals, Inc., Burlingame, CA
Type of Clinical Study or Trial: Clinical Trial
Appears in Collections:Cancer Services

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