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

Amita Patnaik, L. J. Appleman, A. W. Tolcher, K. P. Papadopoulos, M. Beeram, D. W. Rasco, G. J. Weiss, J. C. Sachdev, M. Chadha, M. Fulk, S. Ejadi, J. M. Mountz, M. T. Lotze, F. G.S. Toledo, E. Chu, M. Jeffers, C. Peña, C. Xia, S. Reif, I. GenvresseR. K. Ramanathan

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78 Scopus citations

Abstract

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 treatmentrelated 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.

Original languageEnglish (US)
Pages (from-to)1928-1940
Number of pages13
JournalAnnals of Oncology
Volume27
Issue number10
DOIs
StatePublished - Jan 1 2016

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Keywords

  • Advanced cancer
  • Copanlisib
  • Non-Hodgkin's lymphoma
  • PI3K inhibitor

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Patnaik, A., Appleman, L. J., Tolcher, A. W., Papadopoulos, K. P., Beeram, M., Rasco, D. W., Weiss, G. J., Sachdev, J. C., Chadha, M., Fulk, M., Ejadi, S., Mountz, J. M., Lotze, M. T., Toledo, F. G. S., Chu, E., Jeffers, M., Peña, C., Xia, C., Reif, S., ... Ramanathan, R. K. (2016). 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, 27(10), 1928-1940. https://doi.org/10.1093/ANNONC/MDW282