Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma

Abstract

BackgroundCopanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms.Patients and methodsThis phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis.ResultsThirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2–138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0–874) and 70 days (range 0–897), respectively; median duration of response was 390 days (range 0–825) and 166 days (range 0–786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression.ConclusionIntravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing.This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).

Choosing ibrutinib wisely

“…Median PFS was 4.6 months, and time to next treatment was 16 months. These results are consistent in terms of their duration of response and PFS when compared with those reported from other similar studies of novel agents such as idelalisib, 3 copanlisib, 4 umbralisib, 5 and venetoclax, 6 in patients with relapsed or refractory FL, which reflects the challenging clinical scenario.…”

Efficacy of phosphatidylinositol‐3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells

“…It shows high in vitro and in vivo potency against multiple myeloma and various tumor cell lines . The intravenous PI3K inhibitor copanlisib has also been investigated in phase I/II trials for activity against solid and hematological tumors …”

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

“…An open-label phase II trial of copanlisib (CHRONOS-1, NCT01660451) examined efficacy and safety in patients who failed at least two prior lines of therapy for indolent or aggressive NHL (part A) with a second portion of the study specifically devoted to patients with relapsed/refractory indolent lymphoma (part B). Results from part A demonstrated an ORR of 44% in the indolent lymphoma cohort (n = 33) and 27% in the aggressive lymphoma cohort (n = 51) [89]. Toxicities (all grades/grade ≥3) included hyperglycemia (60%/25%), hypertension (55%/41%), neutropenia (35%/30%), diarrhea (41%/4.8%), transaminitis (26%/3%), and pneumonitis (3.6%/2.4%).…”