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

A 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 Genvresse, R K Ramanathan, A 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 Genvresse, R K Ramanathan

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 [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-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 (18)FDG-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.

Clinicaltrialsgov: NCT00962611; https://ichgcp.net/clinical-trials-registry/NCT00962611.

Keywords: PI3K inhibitor; advanced cancer; copanlisib; non-Hodgkin's lymphoma.

© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Geometric mean (standard deviation) plasma concentration–time profiles for copanlisib at the maximum tolerated dose expansion dose (0.8 mg/kg) on cycle 1 (at the 96-h time point, samples were collected 72–120 h following the start of infusion), day 1 (A), cycle 1, day 15 (B), and cycle 3, day 15 (C). NHL, non-Hodgkin's lymphoma.
Figure 2.
Figure 2.
Radiologic response to copanlisib with corresponding status of tumor PIK3CA mutation, PTEN protein loss by immunohistochemistry, and PTEN mutation (A) and metabolic response to copanlisib (percentage change from baseline in SUVmax from 18FDG-PET) with corresponding status of tumor PIK3CA, PTEN, and KRAS alteration (B), in patients with solid tumors, and radiologic response to copanlisib with corresponding status of tumor PIK3CA mutation, PTEN protein loss by immunohistochemistry, and PTEN mutation in patients from the NHL expansion cohort (C), treated with 0.8 mg/kg copanlisib. aLoss defined as 0% of tumor cells staining positive for PTEN by immunohistochemistry; bpositive defined as ≥5% of tumor cells staining positive for PTEN by immunohistochemistry; clow defined as 1% to <5% of tumor cells staining positive for PTEN by immunohistochemistry. 18FDG-PET, [18F]-fluorodeoxyglucose positron emission tomography; Bl, bladder cancer; Br, breast cancer; Chol, cholangiocarcinoma; CR, complete response; DLBCL, diffuse large B-cell lymphoma; End, endometrial carcinoma; Esoph, esophageal cancer; FL, follicular lymphoma; Gast, gastric cancer; NA, not available; NHL, non-Hodgkin's lymphoma; NSCLC, non-small-cell lung cancer; Ov, ovarian cancer; Panc, pancreatic cancer; PD, progressive disease; PI3K, phosphatidylinositol 3-kinase; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; SUVmax, maximum standardized uptake value; Thy, thyroid carcinoma.
Figure 2.
Figure 2.
Radiologic response to copanlisib with corresponding status of tumor PIK3CA mutation, PTEN protein loss by immunohistochemistry, and PTEN mutation (A) and metabolic response to copanlisib (percentage change from baseline in SUVmax from 18FDG-PET) with corresponding status of tumor PIK3CA, PTEN, and KRAS alteration (B), in patients with solid tumors, and radiologic response to copanlisib with corresponding status of tumor PIK3CA mutation, PTEN protein loss by immunohistochemistry, and PTEN mutation in patients from the NHL expansion cohort (C), treated with 0.8 mg/kg copanlisib. aLoss defined as 0% of tumor cells staining positive for PTEN by immunohistochemistry; bpositive defined as ≥5% of tumor cells staining positive for PTEN by immunohistochemistry; clow defined as 1% to <5% of tumor cells staining positive for PTEN by immunohistochemistry. 18FDG-PET, [18F]-fluorodeoxyglucose positron emission tomography; Bl, bladder cancer; Br, breast cancer; Chol, cholangiocarcinoma; CR, complete response; DLBCL, diffuse large B-cell lymphoma; End, endometrial carcinoma; Esoph, esophageal cancer; FL, follicular lymphoma; Gast, gastric cancer; NA, not available; NHL, non-Hodgkin's lymphoma; NSCLC, non-small-cell lung cancer; Ov, ovarian cancer; Panc, pancreatic cancer; PD, progressive disease; PI3K, phosphatidylinositol 3-kinase; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; SUVmax, maximum standardized uptake value; Thy, thyroid carcinoma.
Figure 2.
Figure 2.
Radiologic response to copanlisib with corresponding status of tumor PIK3CA mutation, PTEN protein loss by immunohistochemistry, and PTEN mutation (A) and metabolic response to copanlisib (percentage change from baseline in SUVmax from 18FDG-PET) with corresponding status of tumor PIK3CA, PTEN, and KRAS alteration (B), in patients with solid tumors, and radiologic response to copanlisib with corresponding status of tumor PIK3CA mutation, PTEN protein loss by immunohistochemistry, and PTEN mutation in patients from the NHL expansion cohort (C), treated with 0.8 mg/kg copanlisib. aLoss defined as 0% of tumor cells staining positive for PTEN by immunohistochemistry; bpositive defined as ≥5% of tumor cells staining positive for PTEN by immunohistochemistry; clow defined as 1% to <5% of tumor cells staining positive for PTEN by immunohistochemistry. 18FDG-PET, [18F]-fluorodeoxyglucose positron emission tomography; Bl, bladder cancer; Br, breast cancer; Chol, cholangiocarcinoma; CR, complete response; DLBCL, diffuse large B-cell lymphoma; End, endometrial carcinoma; Esoph, esophageal cancer; FL, follicular lymphoma; Gast, gastric cancer; NA, not available; NHL, non-Hodgkin's lymphoma; NSCLC, non-small-cell lung cancer; Ov, ovarian cancer; Panc, pancreatic cancer; PD, progressive disease; PI3K, phosphatidylinositol 3-kinase; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; SUVmax, maximum standardized uptake value; Thy, thyroid carcinoma.

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