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. Genvresse; R. K. Ramanathan

doi:10.1093/ANNONC/MDW282

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

Research output: Contribution to journal › Article › peer-review

181 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 language	English (US)
Pages (from-to)	1928-1940
Number of pages	13
Journal	Annals of Oncology
Volume	27
Issue number	10
DOIs	https://doi.org/10.1093/ANNONC/MDW282
State	Published - 2016
Externally published	Yes

Keywords

Advanced cancer
Copanlisib
Non-Hodgkin's lymphoma
PI3K inhibitor

ASJC Scopus subject areas

Hematology
Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/ANNONC/MDW282

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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

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. / Patnaik, Amita; Appleman, L. J.; Tolcher, A. W. et al.
In: Annals of Oncology, Vol. 27, No. 10, 2016, p. 1928-1940.

Research output: Contribution to journal › Article › peer-review

Patnaik, A, Appleman, LJ, Tolcher, AW, Papadopoulos, KP, Beeram, M, Rasco, DW, Weiss, GJ, Sachdev, JC, Chadha, M, Fulk, M, Ejadi, S, Mountz, JM, Lotze, MT, Toledo, FGS, Chu, E, Jeffers, M, Peña, C, Xia, C, Reif, S, Genvresse, I & Ramanathan, RK 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, vol. 27, no. 10, pp. 1928-1940. https://doi.org/10.1093/ANNONC/MDW282

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title = "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",

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.",

keywords = "Advanced cancer, Copanlisib, Non-Hodgkin's lymphoma, PI3K inhibitor",

author = "Amita Patnaik and Appleman, {L. J.} and Tolcher, {A. W.} and Papadopoulos, {K. P.} and M. Beeram and Rasco, {D. W.} and Weiss, {G. J.} and Sachdev, {J. C.} and M. Chadha and M. Fulk and S. Ejadi and Mountz, {J. M.} and Lotze, {M. T.} and Toledo, {F. G.S.} and E. Chu and M. Jeffers and C. Pe{\~n}a and C. Xia and S. Reif and I. Genvresse and Ramanathan, {R. K.}",

note = "Publisher Copyright: {\textcopyright} The Author 2016.",

year = "2016",

doi = "10.1093/ANNONC/MDW282",

language = "English (US)",

volume = "27",

pages = "1928--1940",

journal = "Annals of Oncology",

issn = "0923-7534",

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TY - JOUR

T1 - 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

AU - Patnaik, Amita

AU - Appleman, L. J.

AU - Tolcher, A. W.

AU - Papadopoulos, K. P.

AU - Beeram, M.

AU - Rasco, D. W.

AU - Weiss, G. J.

AU - Sachdev, J. C.

AU - Chadha, M.

AU - Fulk, M.

AU - Ejadi, S.

AU - Mountz, J. M.

AU - Lotze, M. T.

AU - Toledo, F. G.S.

AU - Chu, E.

AU - Jeffers, M.

AU - Peña, C.

AU - Xia, C.

AU - Reif, S.

AU - Genvresse, I.

AU - Ramanathan, R. K.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Advanced cancer

KW - Copanlisib

KW - Non-Hodgkin's lymphoma

KW - PI3K inhibitor

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U2 - 10.1093/ANNONC/MDW282

DO - 10.1093/ANNONC/MDW282

M3 - Article

C2 - 27672108

AN - SCOPUS:85009147568

SN - 0923-7534

VL - 27

SP - 1928

EP - 1940

JO - Annals of Oncology

JF - Annals of Oncology

IS - 10

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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