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.
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).



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.



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.



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.



NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.
South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio amita.patnaik@start.stoh.com.
A
A
Patnaik
University of Pittsburgh, Pittsburgh.
L J
LJ
Appleman
South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio.
A W
AW
Tolcher
South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio.
K P
KP
Papadopoulos
South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio.
M
M
Beeram
South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio.
D W
DW
Rasco
Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale Cancer Treatment Centers of America, Goodyear.
G J
GJ
Weiss
Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale.
J C
JC
Sachdev
Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale.
M
M
Chadha
Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale.
M
M
Fulk
Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale.
S
S
Ejadi
University of Pittsburgh, Pittsburgh.
J M
JM
Mountz
University of Pittsburgh, Pittsburgh.
M T
MT
Lotze
University of Pittsburgh, Pittsburgh.
F G S
FG
Toledo
University of Pittsburgh, Pittsburgh.
E
E
Chu
Bayer HealthCare Pharmaceuticals, Inc., Whippany, USA.
M
M
Jeffers
Bayer HealthCare Pharmaceuticals, Inc., Whippany, USA.
C
C
Peña
Bayer HealthCare Pharmaceuticals, Inc., Whippany, USA.
C
C
Xia
Bayer Pharma AG, Berlin, Germany.
S
S
Reif
Bayer Pharma AG, Berlin, Germany.
I
I
Genvresse
Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale.
R K
RK
Ramanathan
D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C000589253:copanlisib
PI3K inhibitor; advanced cancer; copanlisib; non-Hodgkin's lymphoma
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