Results from first phase-I study of new PI3K inhibitor copanlisib

Dr Amita Patnaik from the South Texas Accelerated Research Therapeutics Center for Cancer Care, San Antonio, TX, and colleagues recently published data from the first human phase I study of copanlisib (BAY 80-6946) in patients with NHL and advanced solid tumors. Copanlisib is an intravenous pan class-I PI3K inhibitor, previously trialed in animal models. The study had several cohorts and the NHL group contained patients with advanced stage FL and DLBCL who had previously received rituximab.

  • NHL group = 6 FL and 3 DLBCL, 78% (7) advanced stage
  • Copanlisib dose = 0.8 mg/kg as 1 hour intravenous infusion, weekly for 3 weeks
  • FL: ORR = 100%. Post-hoc CR = 2 pts. Initial PR = 5 pts
  • DLBCL: PR = 1 pt
  • Total drug related AE = 89%, grade 3 AE = 56%, grade 4 AE = 11%
  • Most common drug related AEs were hyperglycemia (total 89%, grade 3 = 33%) and nausea (total 78%)
  • All NHL responders had WT PI3KCA
  • The two pts with disease progression had low PTEN expression

The authors concluded that treatment with copanlisib was tolerated well at the dose of 0.8 mg/kg, and was shown to be a promising drug in patients with NHL. The authors also noted that two of the FL patients received this treatment for several years achieving long-term durable responses. More studies are currently being conducted on the effect of copanlisib in NHL and this data will help clarify and confirm the potential efficacy and safety profiles of copanlisib.


Abstract: First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas

Background: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL).

Patients and methods: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1–1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [18F]-fluorodeoxyglucose positron emission tomography (18FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially.

Results: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced 18FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years.

Conclusion: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL.

  1. Patnaik A. et al. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Annals of Oncology. 2016 Oct; 27(10):1928–1940.http://doi.org/10.1093/annonc/mdw282.  
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