Phase 2A Study of Copanlisib, a Novel PI3K Inhibitor, in Patients with Indolent Lymphoma
Authors: Dreyling Martin , Cunningham David , Bouabdallah Krimo , Assouline Sarit , Van den Neste Eric , Vitolo Umberto , Giurescu Marius , Mappa Silvia , Grunert Julia , Childs Barrett H. , Morschhauser Franck 
Published: October 2019

Abstract
Background: Copanlisib is a novel pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with potent preclinical inhibitory activity against both PI3K-d and PI3K-α isoforms. Preliminary results from a phase II study of copanlisib in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) have been reported (Dreyling et al., ASH 2013), with an expansion cohort for patients with aggressive lymphoma still ongoing. We report here the final results of this exploratory study for patients with indolent NHL or CLL treated with copanlisib.
Methods: Patients with histologically confirmed indolent NHL or CLL and relapsed or refractory to ≥2 prior lines of treatment were eligible. Copanlisib was administered at a dose of 0.8 mg/kg as a 1 hour intravenous infusion on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as assessed per independent radiologic review according to the response criteria for lymphoma (Cheson et al., JCO 17:1244,1999) or the guidelines for diagnosis and treatment of CLL (Hallek et al., Blood 111:5446-56, 2008). Secondary endpoints included progression-free survival (PFS) and duration of response (DOR), safety and tolerability.
Results: A total of 33 patients were treated in the indolent group, including: follicular NHL (FL) = 16, CLL = 13, marginal zone lymphoma (MZL) = 3, and small lymphocytic lymphoma (SLL) = 1. Median age was 68 years (range 46-89), M/F= 15/18. The median number of previous lines of treatment was 4. Thirty patients (91%) were previously exposed to rituximab. The median number of cycles received was 5.7 (mean 7.2); the median dose and median cumulative dosage of copanlisib administered were 52 mg (87% of planned dose) and 687 mg, respectively. Five patients were dose reduced to 0.6 mg/kg and 1 to 0.4 mg/kg. The ORR as determined by independent radiologic review in 32 evaluable patients was 47%, with 1 CR, 1 uCR, and 13 PRs. By histology, there were 1 CR, 1 uCR and 5 PRs for patients with FL (ORR 47%), and 2/3 PRs for patients with MZL and 1/1 PR for the patient with SLL, for an overall ORR for patients with indolent NHL (excluding CLL) of 53%. The ORR for patients with CLL was 38% (all PRs). Overall, the median DOR was 287 days (95% CI: 56; not yet reached); median PFS was 240 days (95% CI: 173; 419). The most common adverse events (AEs) of all grades were hyperglycemia (70%), hypertension (70%), fatigue (64%), diarrhea (36%), neutropenia (36%) and anemia (33%). Grade 3-4 AEs occurring in >10% of patients included: hypertension (49% grade 3), neutropenia (30%), hyperglycemia (30% grade 3), and anemia (15%). Dose reductions, interruptions, or permanent discontinuations due to AEs were reported in 4 (12%), 21 64%), and 11 (33%) patients, respectively. There was one drug-related grade-5 event; meningitis in a heavily-pretreated CLL patient with longstanding disease-related immunodeficiency, occurring shortly after first administration of copanlisib.
Conclusions: Copanlisib is active as a single-agent in heavily pretreated, advanced refractory/relapsed FL, MZL, SLL, and CLL. Copanlisib exhibited an acceptable toxicity profile, consistent with previous reports. Based on the results of this exploratory study, a phase 2B study of copanlisib in relapsed or refractory indolent NHL (after prior treatment with an alkylating agent and rituximab) has been initiated and is ongoing.

Disclosures
Dreyling: Bayer HealthCare: Scientific advisory board/consultant Other. Cunningham:Roche: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Merck Serono: Research Funding; Novartis: Research Funding; Astra Zeneca: Research Funding. Giurescu:Bayer Pharma AG: Employment. Mappa:Bayer S.p.A.: Employment. Grunert:Bayer Pharma AG: Employment. Childs:Bayer HealthCare Pharmaceuticals: Employment.