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Duvelisib, a novel oral dual inhibitor of PI3K-?,?, is clinically active in advanced hematologic malignancies.

ABSTRACT: Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-? (PI3K-?) and PI3K-? in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the dose escalation phase (n = 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion phase (n = 179), patients with indolent non-Hodgkin lymphoma (iNHL), chronic lymphocytic leukemia (CLL), or T-cell lymphoma (TCL) were treated with 25 or 75 mg duvelisib twice daily continuously. Single-dose duvelisib was rapidly absorbed (time to maximum concentration, 1-2 hours), with a half-life of 5.2 to 10.9 hours. PD results showed inhibition of phospho-AKT (S473) in CLL tumor cells following a single dose and near-complete inhibition of CLL proliferation (Ki-67) by cycle 2. Clinical responses were seen across a range of doses and disease subtypes: iNHL overall response rate, 58% (n = 31) with 6 complete responses (CRs); relapsed/refractory CLL, 56% (n = 55) with 1 CR; peripheral TCL, 50% (n = 16) with 3 CR; and cutaneous TCL, 32% (n = 19). Median time to response was ?1.8 months. Severe (grade ?3) adverse events occurred in 84% of patients: neutropenia (32%), alanine transaminase increase (20%), aspartate transaminase increase (15%), anemia and thrombocytopenia (each 14%), diarrhea (11%), and pneumonia (10%). These data support further investigation of duvelisib in phase 2 and 3 studies. This trial was registered at clinicaltrials.gov as #NCT01476657.

SUBMITTER: Flinn IW

PROVIDER: S-EPMC6033052 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies.

Flinn Ian W IW O'Brien Susan S Kahl Brad B Patel Manish M Oki Yasuhiro Y Foss Francine F FF Porcu Pierluigi P Jones Jeffrey J Burger Jan A JA Jain Nitin N Kelly Virginia M VM Allen Kerstin K Douglas Mark M Sweeney Jennifer J Kelly Patrick P Horwitz Steven S

Blood 20171130 8

Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the dose escalation phase (n = 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion ...[more]

PMID: 29191916

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Project description:BackgroundDuvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-δ) and PI3K-gamma (PI3K-γ). Although many clinical studies support the efficacy of duvelisib, the safety of duvelisib remains with great attention. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of duvelisib in treating different relapsed or refractory (RR) lymphoid neoplasm types.MethodsWe searched prospective clinical trials from PUBMED, EMBASE, Cochrane Library, and ClinicalTrials.gov. For efficacy analysis, Overall response rate (ORR), complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), rate of progressive disease (PDR), median progression-free survival (mPFS), 12-/24-month PFS, and 12-month overall survival (OS) were assessed. For safety analysis, the incidences of any grade and grade ≥3 adverse events (AEs), serious AEs, and treatment-related discontinuation and death were evaluated. Subgroup analysis based on the disease type was performed.ResultsWe included 11 studies and 683 patients, including 305 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 187 B-cell indolent non-Hodgkin lymphoma (iNHL), 39 B-cell aggressive non-Hodgkin lymphoma (aNHL), and 152 T-cell non-Hodgkin lymphoma (T-NHL) patients. The pooled ORR in CLL/SLL, iNHL, aNHL and T-NHL was 70%, 70%, 28% and 47%, respectively. Additionally, the pooled ORR in CLL/SLL patients with or without TP53 mutation/17p-deletion (62% vs. 74%, p=0.45) and in follicular lymphoma (FL) or other iNHL (69% vs. 57%, p=0.38) had no significant differences. Mantle cell lymphoma (MCL) patients had higher pooled ORR than other aNHL (68% vs. 17%, p=0.04). Angioimmunoblastic TCL (AITL) patients had higher pooled ORR than other PTCL patients (67% vs. 42%, p=0.01). The pooled incidence of any grade, grade ≥3, serious AEs, treatment-related discontinuation and death was 99%, 79%, 63%, 33% and 3%, respectively. The most frequent any-grade AEs were diarrhea (47%), ALT/AST increase (39%), and neutropenia (38%). The most frequent grade ≥3 AEs were neutropenia (25%), ALT/AST increased (16%), diarrhea (12%), and anemia (12%).ConclusionGenerally, duvelisib could offer favorable efficacy in patients with RR CLL/SLL, iNHL, MCL, and AITL. Risk and severity in duvelisib treatment may be mitigated through proper identification and management.

Dataset Information

Duvelisib, a novel oral dual inhibitor of PI3K-?,?, is clinically active in advanced hematologic malignancies.

Publications

Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies.

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