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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Ann+Oncol
2016 ; 27
(10
): 1928-40
Nephropedia Template TP
gab.com Text
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English Wikipedia
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
#MMPMID27672108
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 FG
; Chu E
; Jeffers M
; Peņa C
; Xia C
; Reif S
; Genvresse I
; Ramanathan RK
Ann Oncol
2016[Oct]; 27
(10
): 1928-40
PMID27672108
show ga
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://clinicaltrials.gov/ct2/show/NCT00962611.
|Administration, Intravenous
[MESH]
|Adult
[MESH]
|Aged
[MESH]
|Class I Phosphatidylinositol 3-Kinases/*antagonists & inhibitors/genetics
[MESH]