Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy
| Autor: | Alan P Skarbnik, Paul M. Barr, Danielle M. Brander, Hanna Weissbrot, Ian W. Flinn, Peter Sportelli, Suman Kambhampati, Patricia Y. Tsao, Jeffrey Pu, Lindsey E. Roeker, Dana Paskalis, Nicole Lamanna, Stephen J. Schuster, Anthony R. Mato, James A. Reeves, Frederick Lansigan, Bruce D. Cheson, Michael S. Weiss, Nicole LaRatta, Gustavo Fonseca, Hari P. Miskin, Issam Hamadeh, Colleen Dorsey, Andrea Sitlinger, Nilanjan Ghosh, John M. Pagel, Eline T. Luning Prak, Kanti R. Rai, Jakub Svoboda, Jacqueline C. Barrientos |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
education.field_of_study business.industry Immunology Population Phases of clinical research Cell Biology Hematology Neutropenia medicine.disease Biochemistry Gastroenterology Rash Discontinuation hemic and lymphatic diseases Internal medicine Clinical endpoint medicine Progression-free survival Leukocytosis medicine.symptom education business |
| Zdroj: | Blood. 137:2817-2826 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.2020007376 |
| Popis: | Purpose Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in CLL. Umbralisib a novel, highly selective PI3Kδ/CK1e inhibitor, is active and well tolerated in CLL patients. This phase 2 trial evaluated umbralisib in CLL patients who are intolerant to prior BTK or PI3K inhibitor therapy. Patients and methods In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg oral daily in CLL patients requiring therapy per investigator discretion who were intolerant to prior BTK or PI3K inhibitor therapy, until progression or toxicity. Primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure and umbralisib safety profile. DNA isolated from buccal swabs was genotyped for polymorphisms in CYP3A4, CYP3A5 and CYP2D6. Results Fifty-one patients were enrolled (44 BTKi and 7 PI3Kδi intolerant). Median age was 70 years (range 48-96), median of 2 prior lines of therapy (1-7), 24% had del17p and/or TP53 mutation, and 65% were IGHV unmutated. Most common AEs leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median progression free survival (PFS) was 23.5 months (95% CI 13.1-not estimable). 58% of patients were on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib due to an AE. Eight patients (16%) had dose reductions and were successfully re-challenged. Conclusions Umbralisib is safe and effective in this BTK and alternate PI3K inhibitor intolerant CLL population. These are the first prospective data to confirm that switching from a BTK or alternate PI3K inhibitor to umbralisib can result in durable, well tolerated responses. |
| Databáze: | OpenAIRE |
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