Duvelisib, an oral dual PI3K‐δ, γ inhibitor, shows clinical activity in indolent non‐Hodgkin lymphoma in a phase 1 study

Abstract

Duvelisib (IPI‐145) is an oral dual inhibitor of phosphoinositide‐3‐kinase (PI3K)‐δ and ‐γ in clinical development for the treatment of hematologic malignancies, including indolent non‐Hodgkin lymphoma (iNHL). In a Phase 1, open‐label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8‐100 mg BID) in a dose‐escalation phase (n = 31 evaluable patients). Two dose‐limiting toxicities (DLTs), Grade 3 transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD was determined to be 75 mg BID. Across all doses, 58.1% of iNHL patients had a response (19.4% complete, 35.5% partial, and 3.2% minor); median time to response was 1.84 months and duration of response was 16.9 months. Median progression‐free survival was 14.7 months, and the probability of overall survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included elevated liver enzymes (38.7%), diarrhea (25.8%), and neutropenia (29.0%). Three patients, all in the 75 mg BID cohort, experienced fatal AEs: E. coli sepsis, acute respiratory failure, and fungal pneumonia. No iNHL patients experienced Pneumocystis pneumonia. Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high‐risk, heavily pretreated, relapsed/refractory iNHL patients, with 25 mg BID selected for further clinical development.

Duvelisib: A 2018 Novel FDA-Approved Small Molecule Inhibiting Phosphoinositide 3-Kinases

“…As expected, the most common adverse events in pretreated patients were the occurrence of opportunistic infections and cytopenias, with some cases resulting in fatal events [25,26,27,29]. Duvelisib ( 3 ) showed clinical efficacy and acceptable safety for the treatment of heavily pretreated patients with hematological malignancies, showing an overall response rate (ORR) higher than 50% [25,26,27,29].…”

First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas

“…ORRs of ~50% and PFS of ~1 year in relapsed/refractory FL (38)(39)(40). However, treatment was associated with significant toxicity, including hepatitis, gastrointestinal toxicity, risk of infections, and cytopenias.…”

SHC014748M, a novel selective inhi-bitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia

“…Indolent NHL (iNHL) is a set of slow-progressive B-cell malignancies, which mainly include follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma, and Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma [9] , [10] , [11] . Standard treatments for iNHL include monoclonal antibodies (e.g., anti-CD20) often in combination with chemotherapy (chemoimmunotherapy), radioimmunotherapy, and external-beam radiotherapy [12] , [13] , [14] . Despite initial response to first-line therapy, iNHL is generally incurable, and along with the development of the disease, iNHL commonly relapses or becomes refractory [15 , 16] .…”