Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy.
Anthony R MatoNilanjan GhoshStephen J SchusterNicole LamannaJohn M PagelIan W FlinnJacqueline C BarrientosKanti R RaiJames A ReevesBruce D ChesonPaul M BarrSuman KambhampatiFrederick LansiganJeffrey J PuAlan P SkarbnikLindsey RoekerGustavo A FonsecaAndrea SitlingerIssam S HamadehColleen DorseyNicole LaRattaHanna WeissbrotEline T Luning PrakPatricia TsaoDana PaskalisPeter SportelliHari P MiskinMichael S WeissJakub SvobodaDanielle M BranderPublished in: Blood (2021)
Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1-not estimable), with 58% of patients 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 because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki-intolerant CLL population can result in durable well-tolerated responses.
Keyphrases
- end stage renal disease
- ejection fraction
- newly diagnosed
- chronic kidney disease
- atrial fibrillation
- peritoneal dialysis
- prognostic factors
- heart failure
- clinical trial
- intensive care unit
- mesenchymal stem cells
- stem cells
- emergency department
- machine learning
- acute coronary syndrome
- venous thromboembolism
- artificial intelligence
- left ventricular
- patient reported outcomes
- study protocol
- circulating tumor cells
- nucleic acid