Clinical trial NCT02631590
Conditions: Biliary Carcinoma Gall Bladder Carcinoma Cholangiocarcinoma Gastrointestinal Tumor
Keywords: intra-hepatic biliary system extra-hepatic biliary system gall bladder advanced biliary cancer unresectable locally advanced metastatic disease
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2016-07-05; Completion date: 2021-03-05
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see if an experimental drug, called copanlisib is effective and safe in treating adult participants with cholangiocarcinoma, when used in combination with gemcitabine and cisplatin.

Detailed description:

Arms: arm 1: Treatment Plan: Cisplatin (25 mg/m\^2 ) + Gemcitabine (1000 mg/m\^2) + copanlisib (60 mg) on days 1 and 8 with day 15 off to be administered on an every 21-days schedule.
Interventions: intervention 1: Cisplatin intervention 2: Gemcitabine intervention 3: Copanlisib
Intervention descriptions: intervention 1: Cisplatin administered once as intravenous (IV) infusion over 60 minutes. Treatment is on Days 1 and 8 every 21 days. intervention 2: Gemcitabine administered as 30-min IV infusion. Treatment is on Days 1 and 8 every 21 days. intervention 3: Experimental Drug: Copanlisib administered as an IV over 60-minutes beginning 1 hour after completing gemcitabine infusion. Treatment is on Days 1 and 8 every 21 days.

Protocol documents:
Prot_SAP_000.pdf: 
 
 Phase II Study of Copanlisib (BAY 80-6946) in Combination with 
Gemcitabine and Cisplatin in Advanced Cholangiocarcinoma 
 
 
NCT02631590 
 
Version 5 
March 26, 2018 


1 
 
 
TITLE: Phase II study of copanlisib (BAY 80-6946) in combination with gemcitabine 
and cisplatin in advanced cholangiocarcinoma 
 
 
 
Principal Investigator: 
Richard Kim M.D. 
H. Lee Moffitt Cancer Center 
12902 Magnolia Drive, Tampa, Florida, 33612 
Telephone: 813-745-1277 
Fax: 813-449-8511 
E-mail: Richard.kim@moffitt.org 
 
 
 
Co-Investigators: 
 
Dae Kim  MD 
 
Rutika Mehta 
 
 
 
Participating Institutions: 
 
H. Lee Moffitt Cancer Center 
Richard Kim M.D. 
Richard.kim@moffitt.org 
 
 
 
 
Statistician: 
Jongphil Kim, PhD 
Jongphil.Kim@moffitt.org 
 
 
Protocol Version Date: 
March 26, 2018 
 
Protocol version: 
5.0 


2 
 
Cisplatin (25 mg/m2 ), 
Gemcitabine (1000 mg/m2), and 
copanlisib 60 mg 
(Days 1 and 8 with day 15 off) 
 
SCHEMA 
 
 
Advanced 
cholangiocarcinoma 
n=25 
 
 
 
 
 
 
 
 
 
 
 
Restaging with labs and 
imaging every 3cycles (9 
weeks) 
Progression 
Off 
treatment 


3 
 
 
Synopsis 
 
Title 
Phase II study of copanlisib (BAY 80-6946) in combination with 
gemcitabine and cisplatin in advanced cholangiocarcinoma 
Clinical study phase 
Phase II 
Study objective(s) 
Primary Objective 
• To determine progression free survival (PFS) at 6 months in 
patients with advanced cholangiocarcinoma receiving copanlisib 
in combination with gemcitabine and cisplatin. 
Secondary Objectives 
• To determine response rate, PFS and overall survival (OS) in 
patients with advanced cholangiocarcinoma receiving copanlisib 
in combination with gemcitabine and cisplatin. 
• To determine the safety and tolerability of the combination 
regimen of copanlisib, gemcitabine, and cisplatin. 
Exploratory Objectives 
• To explore potential correlations between PTEN and clinical 
outcome 
• To explore potential correlation between an Illumina custom 
cancer next generation targeted sequencing of 26 genes 
including PI3K, BRAF, and RAS (NRAS and KRAS) and 
clinical outcome 


4 
 
 
Background 
treatment 
Biliary cancer (BC) typically includes intra and extrahepatic 
cholangiocarcinoma(CCA) and cancers of the gallbladder. In  the 
United States an estimated 2,600 intrahepatic cholangiocarcinomas were 
diagnosed in 2014. 
Systemic chemotherapy has historically been disappointing in advanced 
BC, but new combination regimens have shown promise. ABC-02, a 
randomized phase III study published by Valle, et al., enrolled 410 
patients and compared gemcitabine plus cisplatin with gemcitabine 
alone. The median overall survival (OS) and progression-free survival 
(PFS) were greater for gemcitabine plus cisplatin than for gemcitabine 
alone without significantly increased toxicity (OS: 11.7 v 8.1 months; 
log-rank P = .002; PFS: 8.0 v 5.0 months; P = .003). This drug 
combination is now established as the new international standard of care 
for advanced biliary tract cancers. However, survival for advanced BCs 
still rarely exceeds one year. As a result, there remains a significant 
need to identify novel agents that can be incorporated in this cytotoxic 
chemotherapy regimen. 
Phosphatidylinositol 3΄-kinase (PI3K) pathway in 
cholangiocarcinoma 
Cellular metabolism, growth and differentiation depend on signaling 
through the phosphatidylinositol 3΄-kinase (PI3K), serine-threonine 
kinase (AKT) and mammalian target of rapamycin (mTOR) pathways. 
Dysregulation of these pathways has been shown to drive tumorigenesis. 
In CCA there are multiple kinases that are activated in both CCA cell 
lines and human CCA tissues. Predominately, the kinases activated 
downstream were those in the PI3K/Akt signaling pathways. It has been 
shown that PI3K/AKT activation leads to increased resistance to 
radiation therapy and chemotherapy, and inhibition of this pathway can 
sensitize CCA cells to these therapies. Copanlisib is a potent and 
reversible pan-class I PI3K inhibitor with significant activity against 
PI3K- δ and PI3K- α isoforms. In preclinical studies copanlisib 
demonstrated anti-tumor activity in PIK3CA mutated cells particularly 
in biliary tract cancers. Further, in vivo, the combination of gemcitabine 
and copanlisib demonstrated anti-tumor activity in a biliary tract cancer 
model (unpublished data). The maximum tolerated dose (MTD) of 
copanlisib was determined to be 0.8 mg/kg in patients with advanced 
solid tumors. A phase I study of gemcitabine + cisplatin with copanlisib 
was conducted in all solid tumors with expanded cohort of CCA 
patients. Full dose of gemcitabine and cisplatin was tolerated at 0.8 
mg/kg of copanlisib. The results were promising, as four patients with 
CCA who received the treatment as a first line treatment responded 
including a complete radiographic response. Therefore, combining 
copanlisib with DNA-targeting therapies gemcitabine + cisplatin may be 
an effective treatment strategy in anti-cancer therapy and warrants 
further clinical investigation. 


5 
 
 
Indication 
Patients with newly diagnosed advanced cholangiocarcinoma 
Diagnosis and 
main criteria 
for inclusion 
• Age ≥18 years of age. 
• Histologically confirmed advanced or unresectable biliary tract 
or gallbladder cancer 
• Chemotherapy-naïve 
• Adjuvant treatment including chemotherapy plus or minus 
radiation will be allowed but must have relapsed after 6 
months of treatment 
• Measurable disease per RECIST 1.1 criterion. 
• ECOG performance status of 0 or1. 
• Life expectancy of at least 3 months. 
• Adequate bone marrow and organ function with: 
a. ANC ≥ 1000/mm³ 
b. Hemoglobin ≥ 9.0 g/dL 
c. Platelet count ≥100,000/mm³ 
d. Creatinine ≤ 1.5 times upper limit of normal (ULN) 
e. AST and ALT ≤2.5 times ULN (≤ 5 x ULN for 
subjects with liver involvement with cancer) 
f. Total bilirubin ≤ 1.5 times ULN 
• The patient must be using an acceptable/effective method of 
contraception. 
• Female patients of childbearing potential must present negative 
serum pregnancy test within 14 days of entering the protocol. 
• Left ventricular ejection fraction (LVEF) ≥ 45% 
• Tumor tissue sample is mandatory (minimum of 10 unstained 
slides) 
Study design 
This is a multi-institutional phase II single arm two-stage design trial 
using copanlisib in combination with gemcitabine and cisplatin in 
advanced cholangiocarcinoma. 
2 
2 
Cisplatin (25 mg/m ) +Gemcitabine (1000 mg/m ) + Copanlisib 60 mg 
days 1 and 8 with day 15 off. 
1 cycle = 21 days 
After 3 cycles, response and progression will be evaluated using the new 
international criteria proposed by the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guidelines (version 1.1). 


6 
 
 
Number of 
subjects 
25 
Plan for statistical 
analysis 
Based on the ABC-01 and ABC-02 studies, PFS6 for the combination of 
gemcitabine and cisplatin are 57.1% and 59.3%, respectively.1,2 
Therefore, we will consider PFS6 of 57% not warranting further study, 
and we will use PFS6 of 77% as a promising result to pursue further 
study. A single-arm Simon’s two-stage minimax design with one-sided 
10% type I error and 80% power is used. Fourteen eligible patients will 
be enrolled in the first stage. If 8 or more patients (≥57%) are alive and 
progression free at 6 months, 11 additional patients will be enrolled in 
the second stage. If 18 or more (≥72%) of 25 patients are alive and 
progression free at 6 months, the study regimen would be worthy of 
further investigation. Progression-free survival, TTP and OS  curves 
were estimated using the Kaplan–Meier methodology. The documented 
response rate and exact two-sided 95% confidence intervals (CIs) were 
calculated. Unless there are toxicity concerns, the study will not close 
during this interim assessment. 


7 
 
 
Contents 
1. 
Introduction .......................................................................................................... 9 
1.1 
Background .......................................................................................................... 9 
1.2 
Copanlisib ............................................................................................................ 9 
1.3 
Rationale ............................................................................................................ 13 
2. 
Study Objectives ................................................................................................ 13 
3. 
Study Design ...................................................................................................... 13 
4. 
Eligibility ........................................................................................................... 14 
4.1 
Inclusion Criteria ............................................................................................... 14 
4.2 
Exclusion Criteria .............................................................................................. 15 
4.3 
Withdrawal of Subjects from Study ................................................................... 16 
4.3.1 
Withdrawal .................................................................................................................... 16 
4.3.2 
Screen Failures/Dropouts ........................................................................................ 17 
4.3.3 
Replacement ............................................................................................................ 17 
5. 
Treatment[s] ....................................................................................................... 17 
5.1 
Treatments to be administered ........................................................................... 17 
5.2 
Dose Modification for Management of Adverse Events .................................... 18 
5.3 
Dose Modifications for Gemcitabine and Cisplatin ........................................... 19 
5.3.1 
Dose Modification Guidelines for Hematologic Toxicity ....................................... 19 
5.3.2 
Dose Modification Guidelines for Hematologic/Non-Hematologic Toxicity ......... 19 
5.4 
Dose Modifications for Copanlisib .................................................................... 20 
5.5 
Management of Toxicities Associated with Study Drug .................................... 22 
5.6 
Blinding ............................................................................................................. 27 
5.7 
Drug Logistics and Accountability .................................................................... 27 
5.8 
Treatment Compliance ....................................................................................... 28 
5.9 
Post-study Therapy ............................................................................................ 28 
5.10 
Prior and Concomitant Therapy ......................................................................... 28 
6. 
Study Drug ......................................................................................................... 30 
7. 
Visit schedule and Assessments ......................................................................... 32 
7.1 
Screening FirstVvisit .......................................................................................... 32 
7.2 
Cycle 1 and Subsequent Cycles, Days 1 and 8 .................................................. 32 
8. 
Assessment types ................................................................................................ 35 
8.1 
Efficacy ................................................................................................................... 35 
8.2 
Safety ................................................................................................................. 35 
8.3 
Biomarkers .............................................................................................................. 35 


8 
 
9. 
Safety monitoring and reporting ............................................................................ 38 
9.1 
Adverse Events .................................................................................................. 38 
9.1.1 
Definitions............................................................................................................... 38 
9.2 
Safety Monitoring .............................................................................................. 40 
9.3 
Reporting of Serious Adverse Events ................................................................ 40 
9.4 
Pregnancies ........................................................................................................ 41 
10. 
Statistical Methods and Data Analysis .................................................................. 42 
10.1 
Study Design and Sample Size Calculation ....................................................... 42 
10.2 
Analysis of Primary Endpoint ............................................................................ 42 
10.3 
Analysis of Secondary and Exploratory Endpoints ........................................... 42 
11. 
Data Recording .................................................................................................. 43 
11.1 
Institutional Review Board (IRB) Approval and Consent ................................. 43 
11.2 
Required Documentation ................................................................................... 43 
11.3 
Registration Procedures ..................................................................................... 44 
11.4 
Data Management and Monitoring/Auditing ..................................................... 44 
11.5 
Adherence to the Protocol .................................................................................. 45 
11.6 
Emergency Modifications .................................................................................. 45 
11.7 
Record Retention ............................................................................................... 45 
11.8 
Obligations of Investigators ............................................................................... 45 
12. 
Ethical and Legal Aspects .................................................................................. 46 
12.1 
Ethical and Legal Conduct of the Study ............................................................ 46 
12.2 
Subject Information and Consent ....................................................................... 46 
12.3 
Publication policy .............................................................................................. 47 
12.4 
Confidentiality ................................................................................................... 48 
13. 
References .......................................................................................................... 49 
14. 
Appendix ............................................................................................................ 51 


9 
 
1. Introduction 
 
1.1 
Background 
Biliary cancer (BC) typically includes intra and extrahepatic cholangiocarcinoma (CCA) and 
cancers of the gallbladder. In the United States an estimated 2,600 intrahepatic 
cholangiocarcinomas were diagnosed in 2014.3,4 In addition, about 10,000  cases  of 
extrahepatic bile duct cancer are diagnosed annually in the United States, two-thirds of which 
are gallbladder cancers.5 Unfortunately, most patients have advanced disease at presentation 
and relapse despite surgery.6 
 
Systemic chemotherapy has historically been disappointing in advanced BC, but new 
combination regimens have shown promises. ABC-02, a randomized phase III study published 
by Valle, et al., enrolled 410 patients and compared gemcitabine plus cisplatin with gemcitabine 
alone.1 The median overall survival (OS) and progression-free survival (PFS) were greater for 
gemcitabine plus cisplatin than for gemcitabine alone without significantly increased toxicity 
(OS: 11.7 v 8.1 months; log-rank P = .002; PFS: 8.0 v 5.0 months; P = .003). This drug 
combination set a new international standard of care for advanced biliary tract cancers. 
However, survival for advanced BCs still rarely exceeds one year. Moreover, advances have 
been slow in part because of the tumor heterogeneity of BCs and poor penetration and non- 
uniform distribution of drug within the tumor.7,8 As a result, there remains a significant need to 
identify novel agents and novel combination regimens to treat this disease. 
 
 
1.2 
Copanlisib 
Preclinical single agent studies 
Copanlisib is a highly selective and potent class I PI3K inhibitor, with IC50 values of 0.5 to 6.4 
nM. Copanlisib had no inhibitory effect on ~240 other kinases and receptors. Copanlisib 
inhibited proliferation of 160 tumor cell lines (from 14 different cancer types), many with IC50 
values of 1 to 100 nM. Induction of apoptosis was demonstrated in several breast cancer cell 
lines harboring PIK3CA mutations. In addition, copanlisib exhibited potent anti-angiogenic 
activity by blocking VEGF signaling. It was also highly efficacious in nude rat human tumor 
xenograft models of various histologic types with alterations of PI3KCA or PTEN, such as 
H460 NSCLC, HCT116 CRC (PI3KCA mut, KRAS mut), U87MG glioma, and KPL4 breast 
tumor models. Preclinical studies revealed its rapid distribution into tissues and tumors, with a 
tissue-to-plasma ratio of > 10. Copanlisib has low central nervous system (CNS) penetration. 
 
The PI3K pathway is essential for insulin signaling, affecting both glucose uptake (eg, glut-4 
transporter) and various glycolytic enzyme activities. Animals treated with copanlisib 
exhibited an acute increase in insulin and glucose levels. Tumor bearing mice subjected to 
serial 2-deoxy-2[F-18] fluoro-D-glucose positron emission tomography (FDG-PET) scans 
following treatment with copanlisib demonstrated dose and time related decreases in tumor 
FDG uptake. 
 
Clinical studies of Copanlisib 
 
Study 12871, the ongoing first-in-human dose escalation Phase 1 trial in cancer subjects. 
 
This study started accruing subjects in the U.S. in November 2009. Copanlisib (single agent) 
was administered as a 1-hour IV infusion on days 1, 8 and 15, every 28 days. The first dose 
was given following an overnight fast, and the subjects fasted until 2 hours after the dose. 
Blood was sampled at 0, 0.5, 1, 1.5, 2, 3, 5, 8, 11, 25 and 49 hours for PK and plasma glucose. 


10 
 
Plasma insulin was drawn during the fasting period. By January 2011, 17 subjects had been 
dosed at 0.1, 0.2, 0.4, 0.8 and 1.2 mg/kg. 
 
An accelerated design was used with criteria for switching to 3+3 design based on doubling 
plasma insulin or increased plasma glucose by 50 mg/dL during the fasting period. The other 
criteria were occurrence of Grade 2 toxicity in two subjects or Grade 3 toxicity in one subject. 
The starting dose of 0.1 mg/kg was well tolerated in the one subject studied. As no significant 
pharmacodynamic (PD) effect was observed, the dose was increased to 0.2 mg/kg. The first 
subject at this level exhibited a greater than doubling of the baseline insulin level within 2 
hours of the end of infusion. This met the study criteria of a PD effect, and the dose was 
expanded to 3 subjects; all completed at least one 4-week cycle without dose limiting toxicity 
(DLT). Three subjects were then dosed at 0.4 mg/kg; one subject experienced Grade 2 
hypertension (resolved in 24 hours) and one had Grade 2 fasting hyperglycemia (also resolved 
in 24 hours). Of the 7 subjects dosed at 0.8 mg/kg, all received insulin after the first dose for 
postprandial blood glucose levels > 200 mg/dL. In this cohort, peak fasting glucose was 79 to 
157 mg/dL and peak postprandial glucose 165 to 429 mg/dL. Otherwise, there were no 
episodes of hypertension and no DLT. Copanlisib 0.8 mg/kg was considered the maximum 
tolerated dose (MTD). 
 
Three subjects were enrolled at 1.2 mg/kg (only 2 subjects received 1.2 mg/kg dosing). One 
subject was a 65-year-old male with metastatic adenocarcinoma of the appendix and a prior 
history of hypertension. About 8 hours after the copanlisib infusion, he developed signs of 
acute decompensated cardiomyopathy with ischemic changes with an echocardiogram showing 
an LVEF of 10-15% with global hypokinesis and electrocardiogram (ECG) showed ST wave 
elevation. His blood glucose was ~500 mg/dL during his acute illness. He was treated with 
insulin, dobutamine, furosemide and other supportive care. He made clinical recovery over 
several days. Follow-up echocardiogram 13 days after copanlisib dosing showed an LVEF of 
70%. The subject then showed signs of progressive deterioration and expired 21 days after his 
first and only dose of copanlisib. 
 
This constellation of events is consistent with the preclinical findings of increased peripheral 
vascular resistance and hypertension seen in dogs. The DLT in this single subject was felt by 
the investigators and Sponsor to be sufficiently severe to mandate cessation of the 1.2 mg/kg 
dose level. The dose of 0.8 mg was considered the maximal tolerated dose (MTD). A second 
subject who received a dose of 1.2 mg/kg had only Grade 2 hyperglycemia following the dose, 
but her dose was reduced to 0.8 mg/kg following the DLT event described above. A third 
subject received 2 doses of 0.8 mg/kg, given 2 weeks apart. She exhibited hyperglycemia with 
blood glucose >200 mg/dL. 
 
Although an MTD of 0.8 mg/kg had been determined in the dose-escalation portion of the 
study, review of additional interim data for patients in the MTD expansion cohort, as of 
November 2011, has shown significantly increased Cmax in 2 very obese patients. The basis 
for this may be explained by the preclinical biodistribution study, demonstrating that copanlisib 
does not enter adipose tissue to a significant degree. Based on these results, a maximum dose 
of 65 mg will be in effect for subjects scheduled to receive 0.8 mg/kg (and proportionally lower 
doses at lower dose levels—i.e., 49mg at the 0.6mg/kg dose level and 32.5mg at the 0.4mg/kg 
dose level). 
 
Fourteen subjects treated in dose Cohorts 1 through 4 were valid for safety evaluation. The 
median number of cycles completed was 2, with a range of 1 to 9 cycles. Of the 14 subjects, 13 
subjects have discontinued study drug and one subject remains ongoing. Of the 13 subjects 
who have discontinued copanlisib, 10 discontinued due to disease progression, 1 discontinued 


11 
 
due to an adverse event (AE) unrelated to copanlisib, 1 subject had logistical difficulties 
traveling, and 1 subject went to hospice. All subjects had at least one treatment-emergent AE. 
Most of the AEs were Grades 1 and 2 toxicities. There were no Grade 4 AEs. Grade 3 AEs 
included aspiration pneumonia unrelated to copanlisib, which occurred in one subject at Dose 
Level 1 (0.1 mg/kg); anemia, diarrhea and limb edema which occurred in subjects at Dose 
Level 2 (0.2 mg/kg); intermittent right shoulder tendinopathy and hypokalemia unrelated to 
copanlisib occurring in one subject at Dose Level 3 (0.4 mg/kg); and elevated alkaline 
phosphatase (AP), fecal obstruction, hyperglycemia, hypokalemia, ascites, biliary sepsis and 
fever occurring in subjects at Dose Level 4 (0.8 mg/kg). The anemia and diarrhea were 
considered related to copanlisib. There were 14 serious adverse events (SAEs) occurring in 8 
subjects and most of them were unrelated to copanlisib except for Grade 3 anemia and Grade 2 
hypertension. For Cohorts 1 to 4, there were no reported deaths, DLTs or dose reductions. One 
subject discontinued copanlisib due to an AE of Grade 3 enterococcal and polymicrobial sepsis 
considered unrelated to copanlisib. 
 
There was no significant hematologic toxicity with only 1 reported event of Grade 2 
neutropenia and 1 reported event of Grade 2 lymphopenia, both considered unrelated to 
copanlisib. A total of six subjects had anemia and 2 of those subjects developed Grade 3 
anemia reported as related to copanlisib.  There were no reports of Grade 4 hematologic events. 
 
Most of the reported biochemical laboratory AEs were Grade 1 and Grade 2 and included 
elevated amylase (n = 1), elevated bilirubin (n = 2), elevated aspartate aminotransferase (AST) 
(n = 1), hypoalbuminemia (n = 1) and hypomagnesemia (n = 1) which were unrelated to 
copanlisib. Three subjects developed hypokalemia: 1 subject had Grade 3 hypokalemia on two 
separate occasions, a second subject had Grade 1 hypokalemia and the other subject had Grades 
1 and 3 hypokalemia. The hypokalemia was considered unrelated to copanlisib. Three subjects 
were reported to have elevated AP: 1 subject had Grade 1 elevated AP related to study drug, a 
second subject had Grade 3 elevated AP unrelated to study drug and a third subject had Grades 
1 and 3 elevated AP but relationship to copanlisib was not reported. 
 
There have been no significant changes in ECG parameters or MUGA scan results in the 14 
subjects enrolled in dose Cohorts 1 through 4. Serial hemoglobin A1C (HgbA1c) testing has 
shown no instance of rise from a normal baseline value into the abnormal range. 
 
A key design feature of Study 12871 is detection of tumor-specific PD effects by performing 2- 
deoxy-2[F-18] fluoro-D-glucose positron emission tomography/computed tomography (FDG- 
PET/CT) studies at baseline and then 48 hours after the first dose. Subjects were studied in this 
way starting at Dose Level 4. One subject with NSCLC, dosed at 0.8 mg/kg, showed an 
approximate 40% reduction in FDG uptake in a lung lesion. A second subject treated at the 
same dose showed an approximate 23% reduction in FDG uptake in a liver metastasis of 
pancreatic adenocarcinoma. These are considered indicative of a tumor-specific PD effect of 
copanlisib that is persisting for 48 hours after the dose. 
 
Subjects in Study 12871 were evaluated with tumor imaging studies after every even numbered 
cycle. There have been no partial responses by modified Response Evaluation Criteria in Solid 
Tumors (RECIST) criteria. The longest durations of stable disease occurred in a subject with 
esophageal carcinoma (6 months, 0.1 mg/kg) and in a subject with endometrial cancer (8 
months, 0.4 mg/kg) 


12 
 
Phase I study of gemcitabine + cisplatin with copanlisib in all solid tumors 
This study started accruing patients in the US in 2011 and finished accrual in 2013.9 The study 
consisted of two arms. On Treatment A, patients received gemcitabine at 1000 mg/m2 IV and 
copanlisib 0.6 mg /kg or 0.8 mg/kg IV on days 1, 8 and 15 of a 28-day cycle to determine the 
maximum tolerated dose (MTD). Only 2 dose levels were planned as 0.8mg/kg was considered 
MTD as a single agent. On Treatment B, patients received cisplatin at 25 mg/m2, gemcitabine 
1000 mg/m2 IV and copanlisib IV on days 1 and 8 of a 21-day cycle at the MTD determined in 
Treatment A. A standard 3+3 design was used. The primary objective was to determine the 
safety, tolerability, and MTD of copanlisib in combination with gemcitabine and 
gemcitabine/cisplatin. 
 
A total of 29 patients were treated with copanlisib. In Treatment A, 8 patients received 
copanlisib at 0.6 mg/kg and 8 at 0.8 mg/kg. One DLT occurred: posterior reversible 
encephalopathy syndrome at the 0.6 mg/kg dose. MTD was not reached. In Treatment B, 13 
patients were dosed at 0.8 mg/kg of copanlisib ( maximum tested dose), with no DLTs seen. 
The most frequently observed drug-related adverse events reported in >20% of the patients 
were hyperglycemia, nausea, diarrhea, anemia, and fatigue. There was no treatment-related 
deaths. Pharmacokinetic evaluations showed comparable results across treatment groups 
indicating the absence of relevant PK interactions. An expansion cohort in patients with BC 
with treatment schedule B has finished accrual and results were presented at American Society 
of Clinical Oncology Meeting in 2014. Unfortunately most of the patients were pre treated with 
gemcitabine and cisplatin. However clinical activity was observed with 1 complete response 
and a total of 4 responses according to RECIST in patients with BC who were chemo naïve. 
 
Phosphatidylinositol 3΄-kinase (PI3K) pathway and PTEN in cholangiocarcinoma 
Cellular metabolism, growth and differentiation depend on signaling through the 
phosphatidylinositol 3΄-kinase (PI3K), serine-threonine kinase (AKT) and mammalian target of 
rapamycin (mTOR) pathways. Dysregulation of these pathways has been shown to drive 
tumorigenesis. Activation of this particular pathway is central to the growth of many human 
cancers, including CCA.10,11 Previous studies demonstrated an activation of the PI3K/AKT 
pathway in human CCA tissues which more than 50 % of cases expressed p-AKT and 
correlated with poor prognosis.12,13 
In CCA there are multiple kinases that are activated in both CCA cell lines and human CCA 
tissues. Predominately, the kinases activated downstream were those in the PI3K/AKT 
signaling pathways. 14 PI3K/AKT activation leads to increased resistance to radiation therapy 
and chemotherapy, and inhibition of this pathway can sensitize CCA cells to these 
therapies.15,16 Furthermore Menakongka, et al., reported hepatocyte growth factor (HGF)- 
induced invasiveness in CCA cell lines which was seen via PI3K/AKT signaling. Inhibition of 
this pathway markedly suppressed HGF-stimulated CCA cell invasion.17 
The expression of PTEN, which was defined as a tumor suppressor and a major negative 
regulator of PI3K/AKT signaling, was investigated by a group from Thailand. 18 The study 
found loss of PTEN expression in the majority of CCA patients (70 %) and consistent with the 
study of Chung and coworkers, which showed the absence of PTEN expression in extrahepatic 
cholangiocarcinoma  patients.19   The   authors   concluded   that   the   constitutive   activation 
of PI3K/AKT pathway in CCA is mainly due to PTEN inactivation by either loss of expression 
or phosphorylation along with an increased expression in its pathway components heralding a 
poor prognosis for CCA patients. 
 
PTEN is one of the potential biomarkers which may identify patients most likely to benefit 
from PI3K inhibitors. Robust evidence supports the predictive capability of these genetic 
aberrations in preclinical models,20,21 but validation in the clinical setting remains limited and, 


13 
 
at times, contradictory.22 The interplay between PTEN loss and activating PIK3CA is an 
interesting example of how a genetic alteration that predicts for sensitivity in one cancer type 
(endometrial cancer) may fail to predict for effıcacy in another (in breast cancer).22 The reason 
for this observation may reside in differences in biologic consequences of each of these specifıc 
mutations. Although activating PIK3CA mutations and PTEN loss, both result in 
PI3K/AKT/mTOR pathway activation, the downstream effects and the mediators recruited by 
these genetic alterations are dissimilar. Therefore the role of PTEN expression/mutation will 
need to be studied further in CCA 
 
1.3 
Rationale 
 
Copanlisib is a potent and reversible pan-class I PI3K inhibitor with significant activity against 
PI3K-d and PI3K-a isoforms. In preclinical studies, copanlisib demonstrated anti-tumor activity 
in PIK3CA mutated cells particularly in biliary tract cancers.23 Further, in vivo, the combination 
of gemcitabine and copanlisib demonstrated anti-tumor activity in a biliary tract cancer model 
(unpublished data).  The maximum tolerated dose (MTD) of copanlisib was determined to be 
0.8 mg/kg in patients with advanced solid tumors in phase I study with promising results. 9 
Four patients with CCA who received the treatment as a first line treatment responded, 
including a complete radiographic response. 
 
Therefore, combining copanlisib with DNA-targeting therapies gemcitabine + cisplatin may be 
an effective treatment strategy in anti-cancer therapy and warrants further clinical investigation. 
We hypothesize that the addition of copanlisib, a PI3K inhibitor will enhance the efficacy of the 
standard regimen of gemcitabine and cisplatin in advanced cholangiocarincinoma. 
 
2. Study Objectives 
 
Primary Objective 
To determine progression free survival at 6 months (PFS6) in patients with advanced biliary 
cancer (BC) receiving copanlisib in combination with gemcitabine and cisplatin. 
 
Secondary Objectives 
1. To determine the response rate, median PFS and overall survival (OS) in patients with 
advanced cholangiocarcinoma receiving copanlisib in combination with gemcitabine and 
cisplatin. 
 
2. To determine the safety and tolerability of the regimen of copanlisib, gemcitabine, and 
cisplatin 
 
Exploratory Objectives 
 
1. To explore potential correlations between PTEN and clinical outcome. 
 
2. To explore potential correlation between an Illumina custom cancer next generation 
targeted sequencing of 26 genetic mutations including PI3K,PTEN, BRAF, RAS (NRAS 
and KRAS) and clinical outcome. 
 
3. Study Design 
 
This is a multi-institutional single arm study using combination of gemcitabine + cisplatin + 
copanlisib in advanced cholangiocarcinoma. A total of 25 patients will be accrued. Patients will 


14 
 
receive Cisplatin (25 mg/m2 ) + Gemcitabine (1000 mg/m2) + copanlisib 60 mg on days 1 and 
8 with day 15 off to be administered on an every 21-day schedule. The FDA has mandated 
that the trial use the fixed dose of copanlisib instead of weight based. Please see appendix 
for explanation. Response and progression will be evaluated using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guidelines (version 1.1).  The primary endpoint is progression free survival at 6 months. 
 
4. Eligibility 
 
4.1 
Inclusion Criteria 
 
• Patients must have histologically or cytologically documented carcinoma primary 
to the intra- or extra-hepatic biliary system or gall bladder with clinical and/or 
radiologic evidence of unresectable, locally advanced or metastatic disease. 
Patients with ampullary carcinoma are not eligible. 
• Patients must not have received any systemic chemotherapy for advanced biliary 
cancer. 
• Patients who received adjuvant chemotherapy plus or minus radiation and had 
evidence of disease recurrence within 6 months of completion of the adjuvant 
treatment are NOT eligible. If patients received adjuvant treatment and had disease 
recurrence after 6 months, patients will be eligible. 
• Age ≥ 18 years. 
• Eastern Cooperative Oncology Group (ECOG) Performance Status Assessment of 
0 or 1. 
• The patient must have radiographic measurable disease per RECIST 1.1 criterion. 
• Life expectancy of at least 12 weeks (3 months). 
• For patients who have received prior radiation,  cryotherapy, radiofrequency 
ablation, therasphere, ethanol injection, transarterial chemoembolization (TACE) 
or photodynamic therapy, the following criteria must be met: 
o 28 days have elapsed since that therapy 
o Lesions that have not  been treated with local therapy must  be present and 
measureable 
• Subjects must be able to understand and be willing to sign the written informed 
consent form. A signed informed consent form must be appropriately obtained 
prior to the conduct of any trial-specific procedure. 
• All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 
Grade 1 or less at the time of signing the Informed Consent Form (ICF) except for 
alopecia. 
• Adequate bone marrow, liver and liver function as assessed by the following 
laboratory requirements: 
o Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) 
o Alanine aminotransferase (ALT) and aspartate amino-transferase (AST)  ≤ 2.5 
x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) 
o Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver 
involvement of their cancer) 
o Serum creatinine ≤ 1.5 x the ULN and 
o Calculated creatinine clearance > 30 ml/min 
 
Calculated creatinine clearance = (140 – age) x t (kg) x [0.85 (if female)] 
72 x creatinine (mg/dL) 
 Platelet count ≥ 100,000 /mm3 
 Hemoglobin (Hb) ≥ 9 g/dL 


15 
 
 Absolute neutrophil count (ANC) ≥1000/mm3 
 Blood transfusion to meet the inclusion criteria will be allowed. 
• Women of childbearing potential must have a negative serum pregnancy test 
performed within 7 days prior to the start of study drug. Post-menopausal women 
(defined as no menses for at least 1 year) and surgically sterilized women are not 
required to undergo a pregnancy test. 
• Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 3 months after the 
last dose of study drug.  The definition of adequate contraception will be based on 
the judgment of the principal investigator or a designated associate. 
• MUGA or ECHO for LVEF ≥ 45%. 
• Subject must be able to swallow and retain oral medication. 
• Availability of archival tumor tissue for biomarkers analysis (minimum of 10 
unstained slides are optional). Specimen from primary site will be allowed. 
 
4.2 
Exclusion Criteria 
 
• Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for 
curatively treated cervical cancer in situ, non-melanoma skin cancer and 
superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and 
T1 (tumor invades lamina propria)]. 
• Congestive heart failure > New York Heart Association (NYHA) class 2. 
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the 
last 3 months). 
• Myocardial infarction less than 6 months before study enrollment 
• Uncontrolled hypertension (blood pressure ≥ 150/90 mmHg despite optimal 
medical management). 
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary 
embolism within the 6 months before enrollment. 
• Non-healing wound, ulcer, or bone fracture. 
• Active clinically serious infections (> CTCAE grade 2). 
• Known history of human immunodeficiency virus (HIV) infection. 
• Known active Hepatitis B or C. 
• Patients with seizure disorder requiring medication. 
• Strong inducers of CYP3A4 are not permitted starting Day -14 of Cycle 1. 
• Patients with evidence or history of bleeding diathesis. Any hemorrhage or 
bleeding event ≥ CTCAE Grade 3 within 4 weeks of start of study enrollment. 
• Substance abuse, medical, psychological or social conditions that may interfere 
with the patient’s participation in the study or evaluation of the study results. 
• Known hypersensitivity to any of the test drugs, test drug classes, or excipients in 
the formulation. 
• History or concurrent condition of interstitial lung disease of any grade or 
severely impaired pulmonary function. 
• Unresolved toxicity higher than CTCAE grade 1 attributed to any prior 
therapy/procedure excluding alopecia. 
• HbA1c >8.5% or fasting plasma glucose > 160 mg/dL at screening. 
• Concurrent diagnosis of pheochromocytoma. 
• Pregnant or breast-feeding patients. Women of childbearing potential must have a 
pregnancy test performed a maximum of 7 days before start of treatment, and a 
negative result must be documented before start of treatment. 


16 
 
• Any illness or medical conditions that are unstable or could jeopardize the safety 
of the patient and his/her compliance in the study. 
• Proteinuria of CTCAE grade 3 or higher (> 3.5 g/24 h, measured by urine protein: 
creatinine ratio on a random urine sample). 
 
Excluded Therapies and Medications for Cancer 
• Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of 
study enrollment.  Subjects must have recovered from the toxic effects of the previous 
anti-cancer chemotherapy or immunotherapy (with the exception of alopecia). Anti- 
cancer therapy is defined as any agent or combination of agents with clinically proven 
anti-tumor activity administered by any route with the purpose of affecting the 
malignancy, either directly or indirectly, including palliative and therapeutic endpoints. 
However, subjects with prostate cancer who are receiving depot LHRH agonist therapy 
may continue on this treatment. 
• Hormonal therapy during the study or within 2 weeks of first study enrollment. 
• Radiotherapy to target lesions during study or within 4 weeks of first study treatment. 
• An irradiated lesion is considered evaluable only if it has shown enlargement since the 
completion of last radiation. 
• Bone marrow transplant or stem cell rescue. 
• Bisphosphonate therapy during the first 2 cycles of treatment. 
• G-CSF and other hematopoietic growth factors may be used in the management of 
acute toxicity such as febrile neutropenia when clinically indicated or at the discretion 
of the principal investigator; however they may not be substituted for a required dose 
reduction.  Erythropoietins are not permitted. 
• Investigational drug therapy outside of this trial during or within 4 weeks of first study  
treatment. 
 
4.3 
Withdrawal of Subjects from Study 
 
4.3.1 Withdrawal 
Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons: 
• Subject withdraws consent from study treatment and study procedures. A subject must 
be removed from the trial at his/her own request or at the request of his/her legally 
acceptable representative.  At any time during the trial and without giving reasons, a 
subject may decline to participate further. The subject will not suffer any disadvantage 
as a result. 
• Pregnancy.  Pregnancy will be reported as an SAE. (Note: subjects who have been 
withdrawn from treatment with study drug because of pregnancy should not undergo CT 
scans [with contrast]/MRI or bone scans while pregnant.) 
• If, in the investigator's opinion, continuation of the trial would be harmful to the 
subject's well-being. 
• Subject is lost to follow-up. 
• Death. 
Subjects may be withdrawn from the study for the following reasons: 
• The subject is non-compliant with study drug, trial procedures, or both; including the 
use of anti-cancer therapy not prescribed by the study protocol. 
• Severe allergic reaction to copanlisib. 
• The development of a second cancer. 


17 
 
• Development of an intercurrent illness or situation which would, in the judgment of 
the investigator, significantly affect assessments of clinical status and trial endpoints. 
• Deterioration of ECOG performance status to 3 or 4. 
• Use of illicit drugs or other substances that may, in the opinion of the investigator, 
have a reasonable chance of contributing to toxicity or otherwise skewing trial result. 
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable. 
Any subject with progression of disease will come off of treatment.In all cases, the reason for 
withdrawal must be recorded in the CRF and in the subject's medical records. 
 
4.3.2 Screen Failures/Dropouts 
 
A subject who discontinues study participation prematurely for any reasons except death, 
disease progression and severe toxicity is defined as a dropout. 
 
A subject who, for any reason (e.g., failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “dropout” (see above) is regarded a “screening 
failure”. 
 
4.3.3 Replacement 
Dropout patients and non-evaluable patients will need to be replaced. 
 
 
5. Treatment[s] 
 
5.1 
Treatments to be administered 
Agents 
Day 1 
Day 8 
Day 15 
Cisplatin (25 mg/m2) 
Gemcitabine (1000 mg/m2) 
X 
X 
X 
X 
copanlisib 60 mg 
X 
X 
Cycle = 21 days 
 
 
The treatment is administered on Days 1 and 8 every 21 days as follows: 
• Hour 0 to 1.0: Cisplatin will be administered once as IV infusion over 60 minutes 
as follows: One liter (L) of 0.9% sodium chloride (NaCl) including 25 mg/m2 
cisplatin, 20 millimole (mmol) of potassium chloride, and 8 mmol of magnesium 
sulfate. 
 
• Hour 1.0 to 1.5: IV infusion of 500 mL of 0.9% NaCl over 30 minutes 
• Hour 1.5 to 2.0: Gemcitabine (1000 mg/m2 as 30-min IV infusion) 
• Hour 3.0 to 4.0: Copanlisib 60 mg will be administered as an IV over 60-minutes 
beginning 1 hour after completing gemcitabine infusion. 


18 
 
 
Treatment continues on days 1 and 8 every 21 days for 24 weeks (8 Cycles). After 24 weeks of 
treatment, gemcitabine and copanlisib, without cisplatin, may continue at the discretion of the 
investigator until disease progression or unacceptable toxicity if a clinical benefit is noted. 
Furthermore copanlisib alone may continue at the discretion of the investigator until disease 
progression or unacceptable toxicity if clinical benefit is noted. 
 
Intravenous glucose-containing solutions should be avoided. Corticosteroids should not 
be given as antiemetics. 
 
On Cycle 1 Day 1, subjects should be fasting (non-sugar containing beverages are allowed, 
such as water, tea and coffee without sugar) for at least 8 hours prior to the first copanlisib 
dose and until 2 hours after completing copanlisib infusion. Guidelines for fasting prior to and 
after subsequent copanlisib doses will be based on the individual’s glucose response to the first 
copanlisib dose and the discretion of the treating physician. 
 
If gemcitabine or cisplatin is discontinued for toxicity, the other drug(s) may continue at the 
discretion of the investigator if clinical benefit is noted. 
 
5.2 
Dose Modification for Management of Adverse Events 
 
It is recognized that attribution of causality of any AE to specifically one or more of the study 
drugs may be difficult. Certain toxicities were seen in relation to only one of the drugs in the 
respective Phase 1 trial; e.g., hyperglycemia, hypertension and cardiac toxicity (observed only 
with 1.2 mg/kg dosing) with copanlisib. As such, dose modification for these events may 
initially be limited to just one of the drugs based on Phase 1 experience. However, if 
improvement doesn’t occur following reduction or cessation of dosing of the suspected 
investigational agent, other drug(s) should be considered as a contributing factor. 
 
Only two dose reductions are allowed for each drug. Treatment can be held until treatment 
criteria are met. If a patient requires a dose delay of > 21 consecutive days of copanlisib, 
gemcitabine or cisplatin, then the patient should be discontinued from the study treatment. In 
exceptional situations, if the patient is clearly benefiting from the study treatment (i.e., stable 
disease, partial response, complete response), and in the opinion of the investigator no safety 
concerns are present, the patient may remain on the study treatment – a decision that is at the 
discretion of the PI. Patients who discontinue from the study for a study-related AE or an 
abnormal laboratory value must be followed. 
 
If gemcitabine and cisplatin needs to be delayed copanlisib can be given by iself. w Also 
gemcitabine and cisplatin can give given without copanlisib if copanlisib needs to be delayed 


19 
 
 
Dose level reductions are as follows: (fixed dose is as per FDA’s guideline) 
 
Dose Level 
Gemcitabine 
Cisplatin 
Copanlisib 
Starting Dose 
1000 mg/m2 
25  mg/m2 
60 mg 
Dose -1 
800 mg/m2 
20 mg/m2 
45 mg 
Dose -2 
600 mg/m2 
15 mg/m2 
30 mg 
 
 
5.3 
Dose Modifications for Gemcitabine and Cisplatin 
 
5.3.1 Dose Modification Guidelines for Hematologic Toxicity 
 
The dose modification guidelines for gemcitabine and cisplatin for hematologic toxicity on day 
1 of each cycle of the treatment is mentioned below. 
 
ANC 
Platelet count 
Gemcitabine 
Cisplatin 
≥1,000/mm3 and 
≥ 100,000/mm3 
Give full dose 
<1,000/mm3 or/and < 100,000/mm3 
Delay t
for nex
reatment by 1 week. Reduce dose by one level 
t treatment. 
 
The dose modification guidelines for gemcitabine and cisplatin for hematologic toxicity on day 
8 of each cycle of the treatment is mentioned below. 
 
ANC 
Platelet count 
Gemcitabine 
Cisplatin 
≥1,000/mm3 And 
≥ 75,000/mm3 
Give full dose 
<1,000/mm3 or/and < 75,000/mm3 
Skip treatment. Reduce dose by one level for next 
treatment. 
 
It is recommended that G-CSF is administered if patients develop neutropenia. 
 
5.3.2 Dose Modification Guidelines for Hematologic/Non-Hematologic Toxicity 
 
The dose modification guidelines for gemcitabine and cisplatin for non-hematologic toxicities 
on day 1 of each cycle of the treatment is mentioned below: 
 
 
 
 
 
 
a   Except for alopecia, clinically insignificant laboratory abnormalities, and 
inadequately treated nausea, vomiting and diarrhea. 
 
The dose modification guidelines for gemcitabine and cisplatin for non-hematologic toxicities 
on day 8  of each cycle of the treatment is mentioned below: 
 
Non Hematologic Toxicitya 
Gemcitabine 
Cisplatin 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Skip treatment until resolves to ≤ Grade 1. Reduce 
dose by one level of the drug depending upon the 
attribution. 
Non Hematologic Toxicitya 
Gemcitabine 
Cisplatin 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Delay treatment until resolves to ≤ Grade 1. Reduce 
dose by one level of the drug depending upon the 
attribution. 


20 
 
a   Except for alopecia, clinically insignificant laboratory abnormalities, and 
inadequately treated nausea, vomiting and diarrhea. 
 
Dose modification for these events may initially be limited to just one of the drugs ( 
gem or cis) based on treating physician’s experience.  However, if improvement 
doesn’t resolve following reduction or cessation of dosing of the suspected 
investigational agent, other drug should be considered as a contributing factor and 
be dosed reduced as well. 
 
 
5.4 
Dose Modifications for Copanlisib 
Hematologic Toxicity 
Currently there is no evidence that copanlisib is toxic for bone marrow. The clinician should 
proceed, as far as copanlisib is concerned, as dictated by the clinical situation, common sense, 
and his experience as an investigator. The guidelines in table 5-1 can be used as support for the 
clinical decision. In case these guidelines are not followed, the rationale for other measures will 
be documented in detail in the patient’s medical record. 
 
Table 5—1: Dose Modification of Copanlisib for Hematological Toxicity 
Hematological Toxicity (any of the following) 
Test drug action 
• Thrombocytopenia <25 x 109/L or Grade 3 with 
bleeding 
• Febrile neutropenia 
• Neutropenia CTC Grade 4 and lasting for 
>3 days a 
• INR or PTT CTC Grade >3 with bleeding 
• CTC Grade 4 anemia b 
• CTC Grade >3 hemorrhage/bleeding 
Hold copanlisib 
Resume when toxicity is resolved 
to 
≤ CTC Grade 1a 
(If recovery within 21 days, 
patient can be treated at one dose 
level lower). 
• Toxicity requiring delay for > 21 days 
Discontinue test drug 
aFor patients who develop a CTC Grade 4 neutropenia, a blood count after 3-5 days is 
recommended 
bHb values of 9 g/dL are acceptable 
 
Non-hematologic toxicity 
 
Subjects who experience non-hematologic copanlisib related grade III and IV toxicity other 
than mentioned below, but show an objective clinical benefit may continue copanlisib at the 
next lower dose level of copanlisib at the discretion of the investigator. The decision whether 
or not to continue copanlisib will be made by the Investigator following discussion of this 
information with the PI. 
 
Dose modifications for Non-Hematologic Toxicities: Hyperglycemia and Hypertension 
 
a) Hyperglycemia 
 
Patients who develop hyperglycemia of CTCAE grade 3 (glucose levels of > 250 mg/dL) after 
copanlisib administration may continue treatment. The next infusion must be delayed until their 
glucose levels return to ≤ 160 mg/dL (fasting) or ≤ 200 mg/dL (non-fasting). Guidelines for the 
treatment of hyperglycemia are given in Table 5-3 and 5-4. 


21 
 
 
Investigators may decrease one to two dose levels of copanlisib if hyperglycemia is not 
manageable, or is difficult to manage, based on the investigator’s judgment. 
 
A dose reduction of copanlisib by one dose level is mandatory in the event of CTCAE Grade 4 
asymptomatic hyperglycemia. No further dose reductions will be allowed in the event of 
reoccurrence of CTCAE Grade 4 asymptomatic hyperglycemia and the patient will be 
permanently discontinued.  In case of symptomatic hyperglycemia CTC grade 4, permanent 
discontinuation of the study drug is mandatory. 
 
b) Hypertension 
 
No dose should be given if the blood pressure is ≥ 150/90 mmHg.  Instructions for blood 
pressure measurement are given in Section 5.5 Table 5-5. 
 
Antihypertensive medication may be given to control the hypertension. Dosing can proceed on 
the scheduled day if there are at least 2 consecutive measurements <150/90 mmHg. Otherwise 
dosing must be delayed. 
 
In case that drug-related hypertension (post-dose blood pressure of CTC grade 3 or 
160/100 mmHg) is not manageable with optimal antihypertensive treatment, the dose for the 
subsequent copanlisib administrations may be reduced by 1 or 2 dose levels. Guidelines for the 
treatment of hypertension are given in Section 5.5 Table 5-5. In patients with a post-dose blood 
pressure of CTC grade 4, i.e., a post-dose blood pressure which may have life-threatening 
consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, 
hypertensive crisis) or where urgent intervention is indicated, permanent discontinuation from 
study drug is mandatory. 
 
Dose Modification for Subsequent Cycles 
 
Lab tests prior to each infusion may be performed either the day before or the planned date of 
infusion, with the exception of blood glucose, which must be performed on the day of infusion. 
On Day 1 of each cycle, the dose of copanlisib will be given only if the criteria described in 
Table 5-2 are met. 


22 
 
 
Table 5-2: Laboratory Test Criteria for First Dose of Any Cycle Dosing 
Laboratory Test 
Criteria for First Dose of Any Cycle 
Dosing 
Glucose 
≤ 160 mg/dL (fasting; ≤200 mg/dL, if 
non-fasting) 
Hemoglobin 
≥ 9 g/dLa 
ANC 
≥ 1,000/mm3 
Platelets 
≥ 75,000/mm3 
ALT 
≤ 2.5 X ULN or 
≤ 5 X ULN in case of liver involvement 
AST 
≤ 2.5 X ULN or 
≤ 5 X ULN in case of liver involvement 
Total bilirubin 
≤ 1.5 X ULN b 
Creatinine 
≤ 1.5 X ULN 
a   If the hemoglobin is < 9 g/dL on the day of planned copanlisib administration, but the 
patient is hemodynamically stable, it is permissible to give the copanlisib dose on 
schedule and transfuse within 48 hours of the dose. 
b   < 3 x ULN for patients with Gilbert-Meulengracht syndrome. 
 
Blood counts will be performed and assessed prior to the subsequent doses in each cycle of 
copanlisib (on Day 8). The study drug will not be administered if, on the day of scheduled 
dosing, any of the following criteria is met: 
• 
Grade 4 ANC (<5000/mm3) 
• 
Platelets are < 25,000/mm3 
• 
Grade 4 anemia 
 
 
Doses scheduled for Day 8 may be delayed by up to 2 days. A delay by more than 
2 days will be considered a missed dose. Missed doses will not be replaced. The minimum 
interval needed between two infusions of copanlisib is 5 days. 
5.5 
Management of Toxicities Associated with Study Drug 
Treatment of Neutropenia 
G-C CSF is allowed for treatment of neutropenia (ANC < 500/mm3). The dose and schedule 
are at the discretion of the investigators.  Treatment, however, can only be administered ≥ 48 
hours post G-CSF.  If G-CSF is given for neutropenia, the subsequent gemcitabine doses 
should be reduced by one dose level. 
 
 
Treatment of Hyperglycemia 
Only the use of rapid or short acting (regular) insulin is allowed for the treatment of transient 
hyperglycemia (glucose intolerance). In the event of post-dose glucose >250 mg/dL on the 
day of infusion, the administration of rapid or short acting (regular) insulin is recommended 
according to the instruction’s insulin sliding scale regimen.  A suggested regimen for the 


23 
 
administration of short acting (regular) insulin for hyperglycemia is shown in Table 5-3. 
Suggested guidelines for copanlisib-induced hyperglycemias are shown in Table 5-4. 
Table 5-3: Recommended treatment for hyperglycemia 
Glucose Level (mg/dL) 
Regular Insulin Dose 
(capillary or blood sample) 
 
(Units) 
< 200 
0 
200 - < 
2 
250 - < 
4 
300 - < 
6 
350 - < 
8 
≥ 400 
10 
 
In the event of rapid or short acting regular insulin administration at any cycle, a minimum 3- 
hour close observation time is required post-administration. Meals should be provided for 
patients who are kept in for continued observation. A low dose carbohydrate diet is 
recommended for the first 48 hours after study drug infusion. Patients will be trained to 
measure their capillary blood glucose levels at home during screening and will be provided with 
glucometer and supplies (lancets, test strips, and diary) to register measured values and record 
insulin administration if applicable. 
 
All non-diabetic patients who experience hyperglycemia >250 mg/dL or require insulin 
administration will be instructed to check blood glucose at home at least 3 times per full day for 
at least 72 hours after the start of the infusion.  This includes fasting glucose (morning before 
breakfast) and 2 further random non-fasting measurements approximately 2 hours after intake 
of food.  If after the required 72 hours the glucose values are not at goal (fasting glucose ≤125 
mg/dL or random non-fasting glucose ≤ 160 mg/dL), this monitoring will continue until blood 
glucose values are at goal. 
 
All diabetic patients will be instructed to check blood glucose at home at least three times per 
full day for at least 72 hours after start of each infusion at all cycles. This includes fasting 
glucose (morning or breakfast) and 2 further random non-fasting measurements approximately 
2 hours after intake of food.  If after the required 72 hours the glucose values are not at goal 
(fasting glucose < 160 mg/dL or random non fasting glucose < 200 mg/dL) this monitoring will 
continue until blood glucose values are at goal and the patient should be immediately referred 
to the local diabetes center/endocrinologist to adjust treatment. All glucose measurements and 
insulin doses, if applicable, will be collected. 
 
If the patient already monitors his/her blood glucose as part of routine antidiabetic care, the 
routine measurements should not be replaced by the study specific measurements. In this 
situation, patients should add the study specific measurements to their routine, if applicable. 
After the required 72 hours, if blood glucose values are at goal (fasting glucose < 160 mg/dL or 
random non-fasting glucose < 200 mg/dL) after each infusion, patients can then stop only the 
study specific measurements until the next day of infusion, but should keep their routine 
measurements unchanged and ongoing as usual. 
 
Sites recruiting patients with diabetes should have the option to extend glucose monitoring 
overnight. 
 
 


24 
 
Table 5-4: Guidelines for Copanlisib-Induced Hyperglycemia 
 
 
• All subjects should be on a low sugar diet starting 12 hours before until 12 
hours after each copanlisib dose. 
• Plasma glucose should be checked on the same day before copanlisib administration. 
Intravenous glucose containing solutions should be avoided. 
• Copanlisib will be administered only if plasma glucose is < 200 mg/dL. 
• Copanlisib will not be administered if plasma glucose is ≥ 200 mg/dL. In this 
case, there are 2 options: 
 Observe the subject in the clinic while fasting and treat if plasma glucose falls 
to < 200 mg/dL. 
 Discharge from clinic and have the subject return the following morning 
after 8 hour fast. Non-sugar beverages, such as water, coffee and tea are 
allowed during the fasting period. 
• Subjects with plasma glucose >150 mg/dL pre copanlisib dose should also be 
monitored in the clinic. If plasma glucose remains < 200 mg/dL for 4 hours post 
completing the copanlisib dose, they can be discharged from clinic without 
further monitoring. If plasma glucose is > 200 mg/dL within 4 hours of 
completing the copanlisib dose, additional 4 hours of monitoring (in the clinic or 
at home) would be necessary. The decision to administer insulin (please see 
Table 5-4) is at the discretion of the Investigator. 
• 
The anti-diabetic regimen is to be continued if glucose values are at goal (fasting 
glucose < 160 mg/dL and random non-fasting glucose < 200 mg/dL). 
• 
If fasting glucose is ≥ 160 mg/dL or random non-fasting glucose is ≥ 200 mg/dL the 
patient should be immediately referred to the local diabetes center/endocrinologist to 
adjust treatment. 
 
 
 
Treatment of Hypertension Associated with Copanlisib 
 
The guidelines for dose modifications of study treatment in case of arterial hypertension are 
given in Table 5-5. 
 
Copanlisib should not be given if BP is ≥ 150/90 mm Hg.  Antihypertensive medication(s) 
should be given to control the hypertension. Copanlisib dosing may proceed if there are at 
least 2 consecutive BP measurements of <150/90 mm Hg (measured at 5 to 10 minute 
intervals).  If blood pressure is ≥150/90mm Hg, the investigator can consider a medical 
intervention (e.g., administration of a dihydropyridine calcium channel blocker) or delaying the 
infusion of study drug.  The patient should rest 5-10 minutes before blood pressure is recorded. 


25 
 
 
Table 5-5 
Dose modification of study treatment for arterial hypertension 
Toxicity (CTCAE v.4.0) 
Study drug action 
Recommendation 
Pre-dose measurements 
BP ≥ 150/90 mmHg 
No dose should be 
given until recovery to 
< 150/90 mmHg. 
Consider a medical intervention. 
Dosing can proceed on the scheduled 
day if after at least 2 consecutive 
measurements blood pressure returns 
to < 150/90 mmHg. If blood pressure 
doesn’t return to < 150/90 mmHg, 
then delay dosing until next visit.  
During infusion: 
CTCAE Grade 3 
arterial hypertension 
(≥ 160/100 mmHg) 
Infusion can be 
interrupted or slowed 
down and 
administration of anti- 
hypertensive therapy 
should be initiated. 
Infusion may be resumed 
immediately when blood pressure 
has returned to < 150/90 mmHg or 
skipped. 
Subsequent study drug 
administrations may be reduced by 1 
dose level at the investigator’s 
discretionb. 
Post-dose: 
Drug related Arterial 
Hypertension of 
CTCAE Grade ≥3 
(≥ 160/100 mmHg)a 
– 
Subsequent study drug 
administrations may be reduced by 1 
dose level at the investigator’s 
discretionb. 
Post-dose: 
CTCAE Grade 4 
Permanent 
discontinuation 
– 
BP = Blood pressure; CTCAE = Common Terminology Criteria for Adverse Events 
a Not manageable despite optimal antihypertensive treatment. 
b The lowest dose level is 45 mg; if a patient is already on the 45 mg dose level and 
experiences post-dose Arterial Hypertension of CTCAE Grade ≥ 3 or ≥160/100 mmHg, 
consider more intensive therapy than previously used. 
No dose should be given if blood pressure is ≥ 150/90 mmHg. Instructions for blood pressure 
measurement are given in Section 5.5 Table 5-6. Antihypertensive medication may be given to 
control the arterial hypertension. Dosing can proceed on the scheduled day if there are at least 2 
consecutive measurements < 150/90 mmHg. Otherwise dosing must be delayed. 
If drug-related arterial hypertension (post-dose blood pressure of CTCAE Grade ≥ 3 or 
≥ 160/100 mmHg) is not manageable with optimal antihypertensive treatment, the dose for the 
subsequent study drug administrations may be reduced by 1 dose level at the investigator’s 
discretion. Patients with a post-dose blood pressure of CTCAE Grade 4, i.e., a post-dose blood 
pressure that may have life-threatening consequences (e.g., malignant arterial hypertension, 
transient or permanent neurologic deficit, hypertensive crisis), or patients who require urgent 
intervention, must permanently discontinue the study drug. 
Guidelines for Treatment of Arterial Hypertension Associated with Copanlisib 
 
It is important that patients with pre-existing arterial hypertension adhere to their regular 
medication schedule, and take their usual doses on the days of study drug infusion. The 
management of acute arterial hypertension following copanlisib will need to be individualized 
for each patient, but the experience in Phase I has suggested the benefit of dihydropyridine 
calcium channel blockers (i.e., amlodipine, felodipine). Topical nitrates should also be 
considered. Verapamil and diltiazem (non-dihydropyridine calcium channel blockers) should be 


26 
 
avoided due to a potential CYP3A4 interaction. In general, it is advisable for sites to be 
prepared so that antihypertensive medication is readily available in case of need.  In the event 
of the occurrence of arterial hypertension ≥ 150/90 mmHg during infusion of copanlisib at any 
cycle antihypertensive treatment is suggested as indicated above. In the event of the occurrence 
of CTCAE Grade 3 arterial hypertension (≥ 160/100 mmHg) during infusion of copanlisib, the 
infusion should be interrupted and antihypertensive treatment as suggested above is 
administered. Infusion can be resumed when blood pressure has returned to <150/90 mmHg. 
 
Dose Modifications for Non-Hematologic Toxicities: Dermatologic Toxicity 
 
Depending on the grade and incidence of dermatologic reaction associated with copanlisib, 
treatment should continue as dictated by the clinical situation. The guidelines in Table 5-6 can 
be used as support for the clinical decision. In case these guidelines are not followed, the 
rationale for other measures will be documented in detail in the patient’s medical record. 


27 
 
Table 5-6: Dose Modification of Copanlisib for Dermatologic Toxicity 
 
Study Drug Action 
Toxicity a 
Occurrence 
for current course of 
therapy 
for next course of therapy 
Grade 1 
No change 
No change 
Grade 2b 1st appearance 
Interruption until Grade ≤ 1 
No change 
2nd appearance 
Interruption until Grade ≤ 1 
Decrease by one dose level 
3rd appearance 
Interruption until Grade ≤ 1 
Decrease by one dose level 
4th appearance 
Permanent discontinue 
-- 
Grade 3 b 1st appearance 
Interruption until Grade ≤ 1 
Decrease by one dose level 
2nd appearance 
Interruption until Grade ≤ 1 
Decrease by one dose level 
3rd appearance 
Permanent discontinue 
-- 
Grade 4 1st appearance 
Permanent discontinue 
a Toxicities according to CTCAE version 4.0 
b Despite maximum supportive therapy 
Treatment of Dermatologic Toxicity 
If dermatologic changes occur, the patient should be treated quickly and aggressively. 
 
 
 
 
 
5.6 
Blinding 
 
This is an open-label trial.  Subjects will be assigned to treatment in order of recruitment into 
the trial in consultation with the sponsor. There will be no randomization or blinding. 
 
5.7 
Drug Logistics and Accountability 
 
All study drugs will be stored at the investigational site in accordance with good clinical 
practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
d


28 
 
department of the sponsor (or its affiliate / Contract Research Organization [CRO]), and will 
be inaccessible to unauthorized personnel.  Special storage conditions and a complete record 
of batch numbers and expiry dates can be found in the sponsor study file; the site-relevant 
elements, of this information will be available in the ISF.  The responsible site personnel will 
confirm receipt of study drug and will use the study drug only within the framework of this 
clinical study and in accordance with this protocol.  Receipt, distribution, return and 
destruction (if any) of the study drug must be properly documented according to the sponsor’s 
agreed upon and specified procedures. 
 
5.8 
Treatment Compliance 
 
The administration of study drugs will be performed in the clinic. 
 
5.9 
Post-study Therapy 
 
After the end of this study, no further study treatment will be administered. 
 
5.10 
Prior and Concomitant Therapy 
Prohibited Concomitant Anti-cancer Therapy: 
CYP3A4 Inhibitors and Inducers 
 
Copanlisib is metabolized by CYP3A4.  Therefore, concomitant use of strong inhibitors of 
CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir 
and saquinavir), and strong inducers of CYP3A4 (e.g., rifampin) are not permitted from 
Day -14 of Cycle 1 and for the duration of the study. Concomitant use of other known 
CYP3A4 inducers (eg, phenytoin, carbamazepine and phenobarbital) should be avoided as 
clinically significant decrease in plasma concentrations of copanlisib cannot be ruled out. 
 
Concomitant use of herbal preparations containing CYP3A4 inducers (e.g., St. John’s 
Wort) are not permitted during the study. 
 
Grapefruit and grapefruit juice (CYP3A4 inhibitor) consumption are not permitted during 
the study. Subjects taking narrow therapeutic index medications (e.g., warfarin, phenytoin, 
quinidine, carbamazepine, phenobarbital, cyclosporine and digoxin) should be monitored 
closely in case these medications cannot be avoided. 


29 
 
CYP3A4 inhibitors and inducers and CYP2C19 inhibitors 
 
 
 
Strong inhibitors and inducers (underlined) are not permitted during this study. 
 
 
 
indinavir
 nelfinavi
r ritonavi
r 
saquinavir 
clarithro mycin 
itraconazole ketoc
onazole 
nefazodone 
erythromycin grap
efruit juice 
verapamil 
diltiazem 
cimetidine 
amiodarone 
fluvoxamine 
troleandomycin 
CYP3A4 inhibitors 
CYP3A4 inducers 
rifampin 
carbamazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin St.Jo
hn's wort 


30 
 
 
 
6. Study Drug 
The following drug supply will be used in the study as study treatment: 
 Copanlisib solution for IV infusion 
The details of the test drug are given in Table 6-1. 
 
Table 6-1: 
Identity of Copanlisib 
Chemical name 
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- 
dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5- 
carboxamide dihydrochloride 
Substance code number(s) 
BAY 84-1236* 
Appearance 
Yellow to colorless solid substance 
Formulation 
Freeze-dried product containing 92.16 mg BAY 84-1236 
(equivalent to 80 mg copanlisib) in a 6 mL injection vial 
Composition 
BAY 84-1236/citric acid/mannitol//NaOH/water 
Type of packaging and 
content 
6 mL injection vial 
*  BAY 84-1236 is the dihydrochloride salt of the base copanlisib 
NaOH = sodium hydroxide 
 
 
 
1. Introduction 
This instruction describes the preparation of solution for injection of Copanlisib from the 
supplied lyophilisate. The lyophilisate will appear as a yellow to colorless solid substance and 
the solution may be slightly yellow. 
2. Composition 
Copanlisib is a lyophilized preparation filled in 6-mL injection vials. After reconstitution with 
4.4 mL of sodium chloride the drug substance concentration amounts to 15 mg/mL Copanlisib. 
The labeled amount per vial is 60 mg Copanlisib, the nominal content due to the technically 
required overfill is 68.4 mg Copanlisib vial. 
3. Storage and Shelf Life 
The prepared solutions are physicially and chemically stable for 24 hours at room temperature. 
To minimize the risk of microbial growth following compounding the prepared solution should 
be stored between 2⁰C and 8⁰C (< 20 hours) and administered immediately thereafter (<4 
hours). It takes approximately 60 minutes for the 100 mL dilution filled in bages to return to 
room temperature after refrigeration. 
4. Materials 
Reconstitution medium for the lyophilisate: 0.9% sodium chloride solution for injection 
(4.4 mL) 
Dilution medium for the reconstituted product: 0.9% sodium chloride solution for injection 
(100 mL) 
Colorless infusion bags (translucent), empty or filled with 100 mL 0.9% NaCl solution, made of 


31 
 
polyethylene (PE), polypropylene (PP), or ethylene vinyl acetate (EVA) 
Colorless infusion tubes (translucent), made of polyethlene (PE), polypropylene (PP) or 
polyvinylchloride (PVC) (DEHP-free) or polyuretane (PU) 
 
 
5. Handling of the Lyophilized Product Copanlisib (BAY 80-6946)- 60 mg 
For the handling of this study medication the following principles have to be followed: 
· Use of sterile disposable gloves and hand hygiene as recommended for current clinical 
practice 
· Disinfection of the septum of the injection stoppers using a swab with an appropriate 
disinfectant (e.g. based on ethanol or isopropoanol) [applies to vials of Copanlisib and 
sodium chloride solution] 
· To ensure product sterility the vial stopper must not be removed during handling 
 
 
5.1 Dosage Preparation 
These instructions are for the preparation of doses 30, 45, and 60 mg Copanlisib in 100 mL 
0.9% NaCl bags. If starting with an empty bag, inject 100 mL of 0.9% NaCl into the bag to 
ensure a volume of not less than 100 mL 
For reconstitution add 4.4 mL of sterile isotonic sodium chloride solution to the lyophilized 
mass of one vial, leading to solutions with a drug substance concentration of 15 mg/mL. The 
reconstituted solution is then diluted to the administration volume of 100 mL using 
physiological saline solution. 
Process 
· Withdraw 4.4 mL of sterile isotonic chloride solution as reconstitution media by using a 5 mL 
sterile syringe 
(Note: the dosing of the reconstituted lyophilisate may alternatively be performed by 
gravimetric means, provided the density of the reconstituted solution is taken into account: 
D20 4= 1.0222 g/mL) 
· Inject the measured volume through the stopper into the 6 mL injection vials using a needle 
· Shake the injection vial vigorously for 30 seconds, and then allow standing for 1 minute to 
let the bubbles rise to the surface 
· Check if any undissolved substance is still seen. If yes, repeat the shaking and settling 
procedure. The reconstituted lyophilisate may only be diluted or withdrawn after the 
solution is clear 
· Withdraw the required amount of the reconstituted lyophilisate with an unused sterile 
syringe: 
Copanlisib dose [mg] 30 45 60 
Reconstituted Copanlisib solution [mL] 2 3 4 
· Connect the syringe to the 100 mL sodium chloride bag and transfer the required amount of 
the reconstituted lyophilisate into the bag 
· Mix the dose well 
· After administration the line is to be flushed to ensure patient gets the complete dose 
6. First Aid Measure in Case of Accidental Skin Contact 
Remove all contaminated clothes and shoes and wash off immediately with soap and plenty of 
water 
7. Comments/Deviations 
 
Every deviation or non-standard occurrence should be documented and justified. All notes 


32 
 
7. should be stored together with study Visit schedule and Assessments 
 
7.1 
Screening First Visit 
Screening examinations will only be performed after having received the subject’s written 
informed consent. 
The following examinations will be performed within 21 days prior to the first treatment: 
 Written subject informed consent to be obtained prior to any screening assessments. 
After the subject starts the study treatment, any new finding discovered not present 
in the patient’s medical history or a worsening of a prior medical history finding 
must be recorded as an AE. 
 Complete medical history and physical examination, including neurologic examination, 
demographics, surgery, therapies, medications, smoking, alcohol history, co-existing 
diseases, allergies, NYHA classification, vital signs (heart rate, respiration rate, 
temperature, and BP), weight and review of systems including neurological status. 
 Baseline toxicities / AEs 
 ECOG Performance Status Assessment 
 12-lead ECG 
 MUGA scan 
 Radiologic assessment: CT scan or MRI with tumor measurement and disease 
assessment of non-measurable disease 
 Coagulation (PT-INR and aPTT) 
 Hemoglobin A1C 
 Thyroid stimulating hormone (TSH), free thyroxine (free T4) 
 Urinalysis (UA) with microscopy (glucose, protein, ketones, pH, bilirubin blood, 
microscopic analysis for white blood cell (WBC), red blood cell (RBC), epithelial 
cells, bacteria, crystals and casts 
 Collection of archived tumor tissue for biomarker analysis 
The following examinations will be performed within 7 days prior to the first treatment: 
 Hematology (hemoglobin, HCT, RBC, WBC count with differential (neutrophils, 
bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
 Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, lactate 
dehydrogenase (LDH), creatine kinase, lipase, amylase, glucose, uric acid, calcium 
phosphate, magnesium, bicarbonate, sodium, potassium, chloride, creatinine, blood 
urea nitrogen (BUN), total protein and albumin 
 
  Baseline Tumor markers including Ca 19-9 
 Serum pregnancy test (if applicable) 
 
7.2 
Cycle 1 and Subsequent Cycles, Days 1 and 8 
 
• History and assessment to include brief examination, vital signs (heart rate, respiration 


33 
 
rate, temperature and BP) and review of systems including neurological status. 
• Toxicity/AE assessment 
• ECOG Performance Status Assessment 
• Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) and platelet count 
• Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, LDH, creatine kinase, 
lipase, amylase glucose, uric acid, calcium, phosphate, magnesium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin 
 
• Hemoglobin A1C to be performed on Day 1 of odd cycles except for cycle 1 (Cycle 3, 
5, etc.) 
• Cisplatin IV infusion 
• Gemcitabine IV infusion 
• Copanlisib IV infusion 
 
At the end of every third cycle (Cycle 3, Cycle 6, etc) 
• MUGA scan/Echo (one test should be used consistently) 
• Tumor measurement/disease assessment according to RECIST 1.1(please see appendix) 
 
• 
Tumor markers  CA 19-9 


34 
 
Visit Evaluation Schedule 
 
Screening 
w/in 21 days 
of C1D1 
Cycle 1 
Day 1 
± 1 day 
Day 8 
± 1 
day 
Day 15 
Cycle 2 and 
beyond day 1 
± 1 day 
Day 8 
± 1 
day 
EOTj 
Post- 
Progression 
Follow-upk 
Complete 
History/Physicala 
X 
X 
History & Assessment 
b 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
ECG 
X 
MUGA/Echo** 
X 
X 
Tumor 
Measurement/Disease 
Assessmentc 
X 
X 
Hematologyd 
X* 
X 
X 
X 
X 
X 
Chemistrye 
X* 
X 
X 
X 
X 
X 
Coagulationf 
X 
X 
Urinalysisg 
X 
X 
HgbA1C 
X(every 
odd cycle 
except for 
1 st cycle) 
TSH, free T4 
X 
Serum Pregnancy, if 
appl. 
X* 
Tumor Tissueh 
X 
Gemcitabine infusion 
X 
X 
X 
X 
Cisplatin 
X 
X 
X 
X 
Copanlisib 
X 
X 
X 
X 
Blood pressurei 
X 
X 
X 
X 
X 
Survival f/u 
X 
Tumor Marker l 
X 
 
 
a. Complete medical history and physical examination including neurologic examination, 
demographics, surgery, therapies, medications, smoking, alcohol history, co-existing 
diseases, allergy, NYHA classification, vital signs (heart rate, respiration rate, 
temperature and BP), height, weight and review of systems including neurological status. 
History and assessment including brief examination, vital signs (as above) and review of 
systems. 
b. Note all toxicities and adverse events, using CTCAE version 4.0. 
c. Data regarding tumor assessment will be collected at Screening, after every 3 cycles and 
as necessary. Tumor response will be assessed using RECIST 1.1 criteria. Tumor 
measurement/disease assessment should be performed within 7 days of the end every 3rd 
cycle.  For end-of-treatment visit, do assessment of tumor lesions according to RECIST 
1.1. 
d. Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils, bands, lymphocytes, monocytes, eosinophils and basophils) and platelet 
count. 


35 
 
e. ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, LDH, creatine kinase, 
lipase, amylase glucose, uric acid, calcium, phosphate, magnesium, bicarbonate, sodium, 
potassium, chloride, creatinine, blood urea nitrogen (BUN), total protein and albumin. 
f. PT-INR and aPTT. 
g. Glucose, protein, ketones, pH, bilirubin, blood, microscopic analysis for WBC, RBC, 
epithelial cells, bacteria, crystals and casts. 
h. Tumor tissue samples will be requested from all subjects and are mandatory. Minimum of 
10 unstained slides will be required. 
i. Copanlisib should not be given if blood pressure is ≥ 150/90 mm Hg. Antihypertensive 
medication(s) should be given to control the hypertension.  Copanlisib dosing may 
proceed if 2 consecutive BP measurements measured at 5 to 10 minute intervals are 
<150/90 mm Hg. 
j. If a subject discontinues treatment due to confirmed PD, only the EOT disease assessment is 
required if it has been > 28 days since the last disease assessment 
k. Can be performed over the phone. After off treatment following disease progression, 
physical assessments (with lab tests performed at the discretion of the treating 
investigator) should take place every 3 months for up to two years or death. 
l. Every 3 cycles 
 
*These screening tests are within 7 days. 
**MUGA or Echo scan to be performed at the end of every 3rd cycle (end of Cycle 3, Cycle 6, 
etc.) 
 
8. Assessment types 
 
8.1 
Efficacy 
Response and progression will be evaluated using the international criteria proposed by 
the  revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).  Changes in the largest diameter (unidimensional measurement) of the 
tumor lesions and the  shortest diameter in the case of malignant lymph nodes are used in 
the RECIST criteria. 
 
8.2 
Safety 
Safety assessments will consist of monitoring and recording all adverse events, including serious 
adverse events, the monitoring of hematology, blood chemistry, Fasting Plasma Glucose, 
Hemoglobin A1c, ECG and the regular monitoring of vital signs, and physical condition as 
shown in corresponding tables. For details on AE collection and reporting, refer to the Safety 
section in the protocol 
8.3 
Biomarkers 
Tumor tissue: 
Samples of tumor tissue for biomarker analysis will be requested from all subjects during 
screening. Tumor tissue submitted for biomarker analysis may be from an archived specimen. 
Attempts should be made to submit samples of all available tumor tissue specimens for 
biomarker analysis. Samples should be submitted either as a tissue block or as freshly cut 
unstained slides ( minimum of 10 slides cut to a thickness of 5 microns). Frozen tissue will 
also be accepted from biomarker analysis. 


36 
 
Send the slides to 
 
Attn: Helen Molina 
H. Lee Moffitt Cancer Center 
12902 Magnolia Dr. 
Tampa, FL 33612 
 
Methods: 
NGS Testing 
The Molecular Pathology laboratory has validated a CLIA grade NGS test using the TruSight 
Tumor panel on the MiSeq instrument ( Illumina, USA). The TruSight Tumor panel targets 26 
genes commonly mutated in solid tumors using 174 amplicons covering 21 kb of the genome. 
The CLIA grade test also includes a custom analysis platform created by PierianDX called 
Clinical Genomicist’s Workstation. The analysis platform has been validated to set cutoff 
criteria for detection of SNPs at a minimum variant allele frequency of 3% at a depth of 1000 
reads and the cutoff criteria for detection of indels at a minimum variant allele frequency of 10% 
and a depth of 2000 reads. Custom reports for each sample are generated programmatically to 
define variants of clinical significance from a manually curated database based on the literature. 


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38 
 
 
9. Safety monitoring and reporting 
 
9.1 
Adverse Events 
 
9.1.1 Definitions 
Information about  all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. An adverse event is any 
undesirable sign, symptom or medical condition occurring after starting study drug (or 
therapy) even if the event is not considered to be related to study drug (or therapy). Study 
drug (or therapy) includes the drug (or therapy) under evaluation, and any reference or 
placebo drug (or therapy) given during any phase of the trial. 
• if it is unclear what study treatment includes, list all drug(s), other therapies, changes to 
existing therapy, diagnostic procedure, etc., that are specified by the protocol 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment. Abnormal laboratory values or 
test results constitute adverse events only if they  induce clinical signs or symptoms or 
require therapy, and are recorded. 
 
A serious adverse event is  an undesirable sign, symptom or medical condition which: 
1. Is fatal or life-threatening. 
2. Requires or prolongs hospitalization. 
3. Results in persistent or significant disability/incapacity. 
4. Constitutes a congenital anomaly or a birth defect. 
5. Is medically significant, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
In addition to the above, fatal events will also be documented by a separate death form, 
instead of reporting them as AE CTCAE grade. 
 
Events not considered to be serious adverse events are hospitalizations for the: 
• Routine  treatment  or  monitoring  of  the  studied  indication,  not  associated  with 
any  deterioration in condition. 
• Treatment, which was elective or pre-planned, for a pre-existing condition that did 
not  worsen. 
• Treatment  on  an  emergency,  outpatient  basis  for  an  event  not  fulfilling  any  of 
the  definitions of serious given above and not resulting in hospital admission. 
Pregnancy, although not itself a serious adverse event, should also be reported on a serious 
adverse event form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects or congenital abnormalities. 
 
Only the serious adverse event occurring after the patient has started taking the study 
medication, and until 4 weeks after the patient has stopped study  participation must be 
reported. The period  after discontinuing study drug may be extended if there is a strong 


39 
 
suspicion that the drug has  not yet been eliminated. 


 
 
9.2 
Safety Monitoring 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology and blood chemistry parameters and 
regular physical examinations. Adverse events will be evaluated continuously throughout the 
study. Safety and tolerability will be assessed according to the NIH/NCI Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v4.0) that is available 
at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
The PMC monitors its assigned ongoing research protocols for: adverse event reporting, data and 
safety monitoring, and internal audit findings. The PMC, upon review of any agenda item, may 
approve the study for continuation, require revisions, suspend or close a protocol. 
 
Investigators of studies which are designated to be reviewed by the PMC for data and safety 
monitoring, shall provide a statistical report of the study’s progress and summary of adverse 
events and deviations based on the phase of the study and the associated risk of the study or more 
often if applicable. The external DSMB (if applicable) shall forward its report for high-risk 
studies designated for external review at least annually or more often if applicable. 
 
Internal Monitoring Plan 
 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be reviewed routinely according to Moffitt’s Monitoring Policies. 
 
 
9.3 
Reporting of Serious Adverse Events 
All AEs will be recorded on the appropriate CRF. The Investigator will also identify the date 
of onset, date of resolution, seriousness, outcome, and the relationship to study drug. Every 
effort should be made to determine the cause of each AE and whether or not it is related to the 
study drug. The relationship of the AE to the study drug must be rated and recorded following 
the guidelines outlined in the CTCAE v4.0. All the AEs will be reviewed by the Principal 
Investigator of the study. The 5 categories for AE grading are: 
 
1. Not related 
2. Not Likely 
3. Possible 
4. Probable 
5. Definite 
 
The definition of serious adverse events (SAEs) is given in Section 8.1.1. 
Each serious adverse event must be followed up until resolution or stabilization, by submission 
of updated reports to the designated person. An isolated laboratory abnormality that is assigned 
grade 4, according to CTC definition, is not reportable as an SAE; unless the investigator 
assesses that the event meets standard ICH criteria for an SAE. CTC grade 4 baseline laboratory 
abnormalities that are part of the disease profile should not be reported as an SAE, specifically 
 
40 


41 
 
when they are allowed or not excluded by the protocol inclusion/exclusion criteria. 
 
To ensure patient safety, each serious adverse event must be reported to the PI and to the sponsor 
expeditiously. Moffitt Cancer Center and all participating sites will report SAEs by completing 
an SAE report in OnCore, the electronic data capture system. The SAE must be reported by 
email (affiliate.research@moffitt.org) to the MCRN within 2 working days. If applicable, the site 
should also follow protocol guidelines for additional reporting to government agencies. 
 
When required, and according to local law and regulations, serious adverse events must be 
reported to the Ethics Committee and Regulatory Authorities. 
 
All serious adverse events should be reported to Bayer within 24 hours.  In the event of such an 
event, the investigator should refer to the Pharmacovigilance section of the contract for reporting 
procedures. 
 
The Investigator may report serious adverse events (SAEs) as described below. 
 
A MedWatch form available at http://www.fda.gov/medwatch/ 
 
All reports shall be sent electronically to: 
 
Electronic Mailbox: 
DrugSafety.GPV.US@bayer.com 
 
Facsimile: 
(973) 709-2185 
 
Address: 
Global Pharmacovigilance - USA 
Mail only: 
Bayer HealthCare Pharmaceuticals Inc. 
P.O. Box 1000 
Montville, NJ 07045-1000 
 
Address: 
340 Changebridge Road 
FDX or UPS only 
Pine Brook, NJ  07058 
 
Reports for all Bayer products can also be phoned in via our Clinical Communications 
Dept: 
 
Phone: 
1-888-765-3203-2937 
 
 
9.4 
Pregnancies 
The investigator must report to Bayer any pregnancy occurring in a study subject, or in his 
partner, during the subject’s participation in this study.  If there is concern for pregnancy after 
the study drug has been started, pregnancy test is required. The report should be submitted 
within the same timelines as an SAE, although a pregnancy per se is not considered an SAE. 
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
abnormal outcome of the mother or the child should be reported. 


42 
 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar 
information on course and outcome, subject to the partner’s consent. 
For all reports, the forms provided are to be used. 
 
 
10. Statistical Methods and Data Analysis 
 
10.1 Study Design and Sample Size Calculation 
Based on the ABC-01 and ABC-02 studies, PFS6 for the combination of gemcitabine and 
cisplatin are 57.1% and 59.3%, respectively. 1,2 Therefore, we will consider PFS6 of 57% not 
warranting further study, and we will use PFS6 of 77% as a promising result to pursue further 
study. A single-arm Simon’s two-stage minimax design with one-sided 10% type I error and 
80% power is used. Fourteen eligible patients will be enrolled in the first stage. If 8 or more 
patients (≥57%) are alive and progression free at 6 months, an additional 11 patients will be 
enrolled in the second stage. If 18 or more (≥72%) of 25 patients are alive and progression free at 
6 months, the study regimen would be worthy of further investigation. If the combination therapy 
is actually effective, then there is a 0.2 probability of concluding that it is not. If the therapy is 
actually not effective, there is a 0.09 probability of concluding that it is. 
. Unless there are toxicity concerns, the study will not close during this interim assessment. 
 
For the correlative endpoint, we will collect at least 10 unstained slides of tumor tissue to evaluate PTEN 
expression by IHC and NGS mutational panel. This will be collected within 28 days of the initiation of 
cycle 1. 
 
10.2 Analysis of Primary Endpoint 
The primary endpoint of the trial is to evaluate the progression free survival at 6 months (PFS6) 
using 
the 
combination 
of 
gemcitabine 
+ 
cisplatin 
with 
copanlisib 
in 
advanced 
cholangiocarcinoma. Same primary endpoint was used in ABC-01 trial.2 Progression-free 
survival (PFS) will be calculated from study entry to documented disease progression, death 
from any cause, or date of last follow-up, whichever comes first. The final analysis will be 
conducted to estimate PFS6 if the second stage is open and the follow-up duration for all subjects 
who are alive and progression free exceeds 6 months. 
 
 
10.3 Analysis of Secondary and Exploratory Endpoints 
The secondary endpoints for efficacy evaluation include the response (CR + PR), overall survival (OS), 
and progression-free survival (PFS). The Kaplan-Meier method and the Cox proportional hazards 
regression model will be used for OS and PFS. The response rate along with 95% confidence interval 
will be reported, based on the exact binomial distribution. The logistic regression model will be used to 
explore the association with the response. A two-sided p-value of <0.05 will be considered 
statistically significant. No multiplicity adjustment is planned. The two sample t-test or Wilcoxon rank- 
sum test will be used to evaluate the correlation between PTEN expression and response. Data 
transformation such as log-transformation of PTEN expression may be considered to apply for parametric 
approaches if necessary. The Anderson-Darling test will be used to test normality assumption. 


43 
 
11. Data Recording 
 
11.1 Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations.  Once this essential information has been provided to the patient and the investigator 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB-approved consent 
form. 
 
11.2 Required Documentation 
Before the study can be initiated at any site, the site will be required to provide regulatory 
documentation to the Moffitt Clinical Research Network (MCRN) at Moffitt Cancer Center. 
Sites must provide a copy of their informed consent to the MCRN Coordinating Center for 
review and approval prior to submission of any documents to the site’s IRB. Any changes      
re- quested by the site’s IRB must be provided to the MCRN staff for review and approval prior 
to resubmission to the IRB. 
 
The MCRN Coordinating Center must receive the following trial specific documents either by 
hardcopy, fax, or email before a site can be activated for any trial: 
 
1. IRB Approval Letter that includes the protocol version and date 
2. FDA Related Forms 1572/1571/310 as appropriate 
3. Signed Protocol Title Page 
4. IRB Approved Consent Form 
5. Site Delegation of Responsibility Log 
6. Signed  Financial Interest Disclosure Forms (principal and sub investigators) 
7. Updated  Investigator/Personnel  documents  (CVs,  licenses,  Conflict  of  Interest 
statements, etc.) as needed 
8. Updated Laboratory Documents (certifications, normal ranges, etc.) as 
needed 
9. Signed protocol specific Task Order 
 
A study initiation visit (or teleconference) will be held prior to the start of any study related 
activity at the site. Attendance i s  r e q u i r e d  f o r :  
• The site PI and appropriate research staff 
• Moffitt PI and MCRN research coordinator 


44 
 
 
The requirements of the protocol and all associated procedures and processes will be 
reviewed and agreed upon prior to the activation of the study. T h e  M C R N  u t iliz e s  th e 
E D C  s ys t e m ,  O nC o r e .  OnCore training will be scheduled if indicated with the 
appropriate staff from the site. 
 
11.3 Registration Procedures 
All subjects must be registered with the MCRN Coordinating Center to be able to participate 
in a trial. The participating site must fax or email the completed study specific eligibility 
checklist and registration forms, supporting documents and signed informed consent to the 
Coordinating Center. Unsigned or incomplete forms will be returned to the site. Once 
documents are received, the MCRN Research Coordinator will review them to confirm 
eligibility and to complete the registration process. If eligibility cannot be confirmed, the 
research coordinator will query the site for clarification or additional documents as needed. 
Subjects failing to meet all study eligibility requirements will not be registered and will 
be unable to participate in the trial. 
 
Upon completion of registration, the MCRN Research Coordinator will provide the 
participating site with the study sequence number and randomization information, if indicated. 
Within 24-48 hours after registration, it is the site’s responsibility to: 
 
• Enter the demographic and on-study patient information into the OnCore 
database. 
• Order investigational agent(s) if indicated per protocol. 
 
It is the responsibility of the participating Investigator or designee to inform the subject of 
the research treatment plan and to conduct the study in compliance with the protocol as 
agreed upon with Moffitt Cancer Center and approved by the site’s IRB. 
 
To register a patient send the completed signed eligibility checklist along with supporting 
documentation to the MCRN via email at affiliate.research@moffitt.org or via fax at 813-745- 
5666, Monday through Friday between 8:00AM and 5:00PM(EST). 
 
11.4 Data Management and Monitoring/Auditing 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be monitored internally according to Moffitt Cancer Center Monitoring 
Policies. Monitoring will be performed regularly to verify data is accurate, complete, and 
verifiable from source documents; and the conduct of the trial is in compliance with the currently 
approved protocol/ amendments, Good Clinical Practice (GCP), and applicable regulatory 
requirements. 
 
To obtain access to OnCore, the site research staff must complete an OnCore Access 
Request Form and a Moffitt Information Systems Confidentiality Agreement (provided in the 
MCRN Handbook at the site initiation visit) and submit both to the Coordinating Center. Once 
the completed forms are received, the site coordinator will receive VPN access, 
logon/password, and information on how to access OnCore using the VPN. The MCRN 


 
Coordinating Center will provide OnCore training to the site once initial access is granted and 
on an ongoing basis, as needed. 
 
11.5 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol. 
 
11.6 Emergency Modifications 
Moffitt Cancer Center and Affiliate investigators may implement a deviation from, or a change 
of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior H. Lee 
Moffitt Cancer Center or their respective institution’s approval/favorable opinion. 
 
For Institutions Relying on Moffitt’s IRB: 
 
For any such emergency modification implemented, a Moffitt IRB modification form must be 
completed by Moffitt Research Personnel within five (5) business days of making the change. 
 
For Institutions Relying on Their Own IRB: 
 
For Affiliate investigators relying on their own instution’s IRB, as soon as possible after the 
modification has been made, the implemented deviation or change and the reasons for it should 
be submitted to Moffitt Principal Investigator for agreement and the Affiliate institution’s IRB 
for review and approval. (Once IRB’s response is received, this should be forwarded to the 
MCRN.) 
 
11.7 Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that all study documentation pertaining 
to the conduct of a clinical trial must be retained by the study investigator. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International Conference 
on Harmonization (ICH) region.  In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
 
11.8 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
 
45 


 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub- 
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered into the eCRFs. Periodically, monitoring visits will 
be conducted and the Principal Investigator will provide access to his/her original records to 
permit verification of proper entry of data. At the completion of the study, all eCRFs will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 
12. Ethical and Legal Aspects 
 
12.1 Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the investigator abide by Good Clinical Practice (GCP) 
guidelines and under the guiding principles detailed in the Declaration of Helsinki. The study 
will also be carried out in keeping with applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating centers 
before start of the study, according to GCP, local laws, regulations and organizations. When 
necessary, an extension, amendment or renewal of the EC/IRB approval must be obtained and 
also forwarded to Bayer. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol. 
Modifications to the study protocol will not be implemented by the investigator without 
discussion and agreement by Bayer. However, the investigator may implement a deviation from, 
or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects without prior 
IEC/IRB/Bayer approval/favorable opinion. As soon as possible, the implemented deviation or 
change, the reasons for it and, if appropriate, the proposed protocol amendment should be 
submitted to the IEC/IRB/head of medical institution. Any deviations from the protocol must be 
explained and documented by the investigator. 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub- 
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and properly documented. 
 
12.2 Subject Information and Consent 
Each subject/legal representative or proxy consenter will have ample time and opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without 
 
46 


47 
 
any disadvantage and without having to provide reasons for this decision. 
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study. Additionally, the 
investigator and other information provider (if any) will personally sign and date the form.  The 
subject/legal representative or proxy consenter will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed consent 
was obtained prior to these procedures. 
1. If the patient is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of Bayer and the investigator). 
This is to be documented by a signature from the informing physician as well as by a 
signature from the witness. 
2. For minors or adults under legal protection, consent shall be given by the legal guardian(s). 
The consent of a minor or adult under legal protection shall also be requested where such a 
person is able to express his/her own will. His/her refusal or the withdrawal of his/her 
consent may not be disregarded. 
3. In emergency situations, when prior consent of the patient is not possible, the consent of the 
patient’s legal representative(s) or proxy consenter, if present, should be requested. The 
patient should be informed about the study as soon as possible and his/her consent to 
continue the study should be requested. 
The informed consent form and any other written information provided to subjects/legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to the 
protocol that necessitates a change to the content of the subject information and/or the written 
informed consent form.  The investigator will inform the subject/legal representative or proxy 
consenter of changes in a timely manner and will ask the subject to confirm his/her participation 
in the study by signing the revised informed consent form. Any revised written informed 
consent form and written information must receive the IEC/IRB`s approval/favorable opinion in 
advance of use. 
 
12.3 Publication policy 
Bayer recognizes the right of the investigator to publish results upon completion of the study. 
However, the investigator must send a draft manuscript of the publication or abstract to Bayer at 
least thirty days in advance of submission in order to obtain approval prior to submission of the 
final version for publication or congress presentation. This will be reviewed promptly and 
approval will not be withheld unreasonably.  In case of a difference of opinion between Bayer 
and the investigator(s), the contents of the publication will be discussed in order to find a 
solution which satisfies both parties. All relevant aspects regarding data reporting and 
publication will be part of the contract between Bayer and the investigator/institution. 
The Principal Investigator should ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov. 


48 
 
12.4 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 


49 
 
13. References 
 
1. 
Valle J, Wasan H, Palmer DH, et al: Cisplatin plus gemcitabine versus 
gemcitabine for biliary tract cancer. N Engl J Med 362:1273-81, 2010 
2. 
Valle JW, Wasan H, Johnson P, et al: Gemcitabine alone or in combination with 
cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract 
tumours: a multicentre randomised phase II study - The UK ABC-01 Study. Br J Cancer 
101:621-7, 2009 
3. 
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 
63:11-30, 2013 
4. 
Shaib YH, Davila JA, McGlynn K, et al: Rising incidence of intrahepatic 
cholangiocarcinoma in the United States: a true increase? J Hepatol 40:472-7, 2004 
5. 
Jemal A, Siegel R, Xu J, et al: Cancer statistics, 2010. CA Cancer J Clin 60:277- 
300, 2010 
6. 
Jarnagin WR, Fong Y, DeMatteo RP, et al: Staging, resectability, and outcome in 
225 patients with hilar cholangiocarcinoma. Ann Surg 234:507-17; discussion 517-9, 2001 
7. 
Faris JE, Zhu AX: Targeted therapy for biliary tract cancers. J Hepatobiliary 
Pancreat Sci 19:326-36, 2012 
8. 
Jain RK: Vascular and interstitial barriers to delivery of therapeutic agents in 
tumors. Cancer Metastasis Rev 9:253-66, 1990 
9. 
Kim RD, Alberts SR, Renshaw GF, et al: Phase 1 dose escalation study of 
copanlisib (BAY 80-6946) in combination with gemcitabine or gemcitabine-cisplatin in 
advanced cancer patients. J Clin Oncol 32:5s, 2014 (suppl; abstr 2610), , 2014 
10. 
Javle MM, Yu J, Khoury T, et al: Hepatology: Akt expression may predict 
favorable prognosis in cholangiocarcinoma. (vol 21, pg 1394, 2006). Journal of Gastroenterology 
and Hepatology 22:145-145, 2007 
11. 
Chen YB, Xu JM, Jhala N, et al: Fas-mediated apoptosis in cholangiocarcinoma 
cells is enhanced by 3,3'-diindolylmethane through inhibition of AKT signaling and FLICE-like 
inhibitory protein. American Journal of Pathology 169:1833-1842, 2006 
12. 
Lee D, Do IG, Choi K, et al: The expression of phospho-AKT1 and phospho- 
MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic 
cholangiocarcinomas. Modern Pathology 25:131-139, 2012 
13. 
Xu XL, Kobayashi S, Qiao WH, et al: Induction of intrahepatic cholangiocellular 
carcinoma by liver-specific disruption of Smad4 and Pten in mice. Journal of Clinical 
Investigation 116:1843-1852, 2006 
14. 
Dokduang H, Juntana S, Techasen A, et al: Survey of activated kinase proteins 
reveals potential targets for cholangiocarcinoma treatment. Tumour Biol 34:3519-28, 2013 
15. 
Tanno S, Yanagawa N, Habiro A, et al: Serine/threonine kinase AKT is 
frequently activated in human bile duct cancer and is associated with increased radioresistance. 
Cancer Research 64:3486-3490, 2004 
16. 
Leelawat K, Narong S, Udomchaiprasertkul W, et al: Inhibition of PI3K increases 
oxaliplatin sensitivity in cholangiocarcinoma cells. Cancer Cell International 9, 2009 
17. 
Menakongka A, Suthiphongchai T: Involvement of PI3K and ERK1/2 pathways 
in hepatocyte growth factor-induced cholangiocarcinoma cell invasion. World Journal of 
Gastroenterology 16:713-722, 2010 
18. 
Yothaisong S, Dokduang H, Techasen A, et al: Increased activation of PI3K/AKT 


50 
 
signaling pathway is associated with cholangiocarcinoma metastasis and PI3K/mTOR inhibition 
presents a possible therapeutic strategy. Tumor Biology 34:3637-3648, 2013 
19. 
Chung JY, Hong SM, Choi BY, et al: The Expression of Phospho-AKT, Phospho- 
mTOR, and PTEN in Extrahepatic Cholangiocarcinoma. Clinical Cancer Research 15:660-667, 
2009 
20. 
Serra V, Markman B, Scaltriti M, et al: NVP-BEZ235, a dual PI3K/mTOR 
inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K 
mutations. Cancer Research 68:8022-8030, 2008 
21. 
Mueller A, Bachmann E, Linnig M, et al: Selective PI3K inhibition by BKM120 
and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human 
gastrointestinal cancer cell lines. Cancer Chemotherapy and Pharmacology 69:1601-1615, 2012 
22. 
Gonzalez-Angulo AM, Blumenschein GR: Defining biomarkers to predict 
sensitivity to PI3K/Akt/mTOR pathway inhibitors in breast cancer. Cancer Treatment Reviews 
39:313-320, 2013 
23. 
Liu N, Haegebarth A, BulCl, et al: BAY 80-6946, a highly potent and efficacious 
class I PI3K inhibitor, induces complete tumor regression or tumor stasis in rat xenograft tumor 
models with PIK3CA mutant or PTEN deletion. AACR 101st Annual Meeting 2010:Apr 17-21, 
2010; Washington, DC, 2010 


51 
 
14. Appendix 
 
RECIST Criteria for Measuring Tumor Response Antitumor Effect 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (Eisenhauer et al., 2009). Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment withcopanlisib. 
 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable for 6 month PFS (primary endpoint): Patients will need to complete at least 3 cycles 
and restaging scan to be considered evaluable for the primary endpoint. Non evaluable patients 
for the primary endpoint will need to be replaced 
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT scan, MRI or 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might be considered 
measurable if the lesion has increased in size since the radiation. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 


52 
 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly should be 
selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow- 
up. 
 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g., for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 


53 
 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be 
performed with breath-hold scanning techniques, if possible. 
 
 
Response Criteria Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression.) 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the Principal Investigator. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 


54 
 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
Progression-Free Survival (PFS) 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
55 


1 
 
 
TITLE: Phase II study of copanlisib (BAY 80-6946) in combination with gemcitabine 
and cisplatin in advanced cholangiocarcinoma 
 
 
 
Principal Investigator: 
Richard Kim M.D. 
H. Lee Moffitt Cancer Center 
12902 Magnolia Drive, Tampa, Florida, 33612 
Telephone: 813-745-1277 
Fax: 813-449-8511 
E-mail: Richard.kim@moffitt.org 
 
 
 
Co-Investigators: 
 
Dae Kim  MD 
 
Rutika Mehta 
 
 
 
Participating Institutions: 
 
H. Lee Moffitt Cancer Center 
Richard Kim M.D. 
Richard.kim@moffitt.org 
 
 
 
 
Statistician: 
Jongphil Kim, PhD 
Jongphil.Kim@moffitt.org 
 
 
Protocol Version Date: 
March 26, 2018 
 
Protocol version: 
5.0 


2 
 
Cisplatin (25 mg/m2 ), 
Gemcitabine (1000 mg/m2), and 
copanlisib 60 mg 
(Days 1 and 8 with day 15 off) 
 
SCHEMA 
 
 
Advanced 
cholangiocarcinoma 
n=25 
 
 
 
 
 
 
 
 
 
 
 
Restaging with labs and 
imaging every 3cycles (9 
weeks) 
Progression 
Off 
treatment 


3 
 
 
Synopsis 
 
Title 
Phase II study of copanlisib (BAY 80-6946) in combination with 
gemcitabine and cisplatin in advanced cholangiocarcinoma 
Clinical study phase 
Phase II 
Study objective(s) 
Primary Objective 
• To determine progression free survival (PFS) at 6 months in 
patients with advanced cholangiocarcinoma receiving copanlisib 
in combination with gemcitabine and cisplatin. 
Secondary Objectives 
• To determine response rate, PFS and overall survival (OS) in 
patients with advanced cholangiocarcinoma receiving copanlisib 
in combination with gemcitabine and cisplatin. 
• To determine the safety and tolerability of the combination 
regimen of copanlisib, gemcitabine, and cisplatin. 
Exploratory Objectives 
• To explore potential correlations between PTEN and clinical 
outcome 
• To explore potential correlation between an Illumina custom 
cancer next generation targeted sequencing of 26 genes 
including PI3K, BRAF, and RAS (NRAS and KRAS) and 
clinical outcome 


4 
 
 
Background 
treatment 
Biliary cancer (BC) typically includes intra and extrahepatic 
cholangiocarcinoma(CCA) and cancers of the gallbladder. In  the 
United States an estimated 2,600 intrahepatic cholangiocarcinomas were 
diagnosed in 2014. 
Systemic chemotherapy has historically been disappointing in advanced 
BC, but new combination regimens have shown promise. ABC-02, a 
randomized phase III study published by Valle, et al., enrolled 410 
patients and compared gemcitabine plus cisplatin with gemcitabine 
alone. The median overall survival (OS) and progression-free survival 
(PFS) were greater for gemcitabine plus cisplatin than for gemcitabine 
alone without significantly increased toxicity (OS: 11.7 v 8.1 months; 
log-rank P = .002; PFS: 8.0 v 5.0 months; P = .003). This drug 
combination is now established as the new international standard of care 
for advanced biliary tract cancers. However, survival for advanced BCs 
still rarely exceeds one year. As a result, there remains a significant 
need to identify novel agents that can be incorporated in this cytotoxic 
chemotherapy regimen. 
Phosphatidylinositol 3΄-kinase (PI3K) pathway in 
cholangiocarcinoma 
Cellular metabolism, growth and differentiation depend on signaling 
through the phosphatidylinositol 3΄-kinase (PI3K), serine-threonine 
kinase (AKT) and mammalian target of rapamycin (mTOR) pathways. 
Dysregulation of these pathways has been shown to drive tumorigenesis. 
In CCA there are multiple kinases that are activated in both CCA cell 
lines and human CCA tissues. Predominately, the kinases activated 
downstream were those in the PI3K/Akt signaling pathways. It has been 
shown that PI3K/AKT activation leads to increased resistance to 
radiation therapy and chemotherapy, and inhibition of this pathway can 
sensitize CCA cells to these therapies. Copanlisib is a potent and 
reversible pan-class I PI3K inhibitor with significant activity against 
PI3K- δ and PI3K- α isoforms. In preclinical studies copanlisib 
demonstrated anti-tumor activity in PIK3CA mutated cells particularly 
in biliary tract cancers. Further, in vivo, the combination of gemcitabine 
and copanlisib demonstrated anti-tumor activity in a biliary tract cancer 
model (unpublished data). The maximum tolerated dose (MTD) of 
copanlisib was determined to be 0.8 mg/kg in patients with advanced 
solid tumors. A phase I study of gemcitabine + cisplatin with copanlisib 
was conducted in all solid tumors with expanded cohort of CCA 
patients. Full dose of gemcitabine and cisplatin was tolerated at 0.8 
mg/kg of copanlisib. The results were promising, as four patients with 
CCA who received the treatment as a first line treatment responded 
including a complete radiographic response. Therefore, combining 
copanlisib with DNA-targeting therapies gemcitabine + cisplatin may be 
an effective treatment strategy in anti-cancer therapy and warrants 
further clinical investigation. 


5 
 
 
Indication 
Patients with newly diagnosed advanced cholangiocarcinoma 
Diagnosis and 
main criteria 
for inclusion 
• Age ≥18 years of age. 
• Histologically confirmed advanced or unresectable biliary tract 
or gallbladder cancer 
• Chemotherapy-naïve 
• Adjuvant treatment including chemotherapy plus or minus 
radiation will be allowed but must have relapsed after 6 
months of treatment 
• Measurable disease per RECIST 1.1 criterion. 
• ECOG performance status of 0 or1. 
• Life expectancy of at least 3 months. 
• Adequate bone marrow and organ function with: 
a. ANC ≥ 1000/mm³ 
b. Hemoglobin ≥ 9.0 g/dL 
c. Platelet count ≥100,000/mm³ 
d. Creatinine ≤ 1.5 times upper limit of normal (ULN) 
e. AST and ALT ≤2.5 times ULN (≤ 5 x ULN for 
subjects with liver involvement with cancer) 
f. Total bilirubin ≤ 1.5 times ULN 
• The patient must be using an acceptable/effective method of 
contraception. 
• Female patients of childbearing potential must present negative 
serum pregnancy test within 14 days of entering the protocol. 
• Left ventricular ejection fraction (LVEF) ≥ 45% 
• Tumor tissue sample is mandatory (minimum of 10 unstained 
slides) 
Study design 
This is a multi-institutional phase II single arm two-stage design trial 
using copanlisib in combination with gemcitabine and cisplatin in 
advanced cholangiocarcinoma. 
2 
2 
Cisplatin (25 mg/m ) +Gemcitabine (1000 mg/m ) + Copanlisib 60 mg 
days 1 and 8 with day 15 off. 
1 cycle = 21 days 
After 3 cycles, response and progression will be evaluated using the new 
international criteria proposed by the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guidelines (version 1.1). 


6 
 
 
Number of 
subjects 
25 
Plan for statistical 
analysis 
Based on the ABC-01 and ABC-02 studies, PFS6 for the combination of 
gemcitabine and cisplatin are 57.1% and 59.3%, respectively.1,2 
Therefore, we will consider PFS6 of 57% not warranting further study, 
and we will use PFS6 of 77% as a promising result to pursue further 
study. A single-arm Simon’s two-stage minimax design with one-sided 
10% type I error and 80% power is used. Fourteen eligible patients will 
be enrolled in the first stage. If 8 or more patients (≥57%) are alive and 
progression free at 6 months, 11 additional patients will be enrolled in 
the second stage. If 18 or more (≥72%) of 25 patients are alive and 
progression free at 6 months, the study regimen would be worthy of 
further investigation. Progression-free survival, TTP and OS  curves 
were estimated using the Kaplan–Meier methodology. The documented 
response rate and exact two-sided 95% confidence intervals (CIs) were 
calculated. Unless there are toxicity concerns, the study will not close 
during this interim assessment. 


7 
 
 
Contents 
1. 
Introduction .......................................................................................................... 9 
1.1 
Background .......................................................................................................... 9 
1.2 
Copanlisib ............................................................................................................ 9 
1.3 
Rationale ............................................................................................................ 13 
2. 
Study Objectives ................................................................................................ 13 
3. 
Study Design ...................................................................................................... 13 
4. 
Eligibility ........................................................................................................... 14 
4.1 
Inclusion Criteria ............................................................................................... 14 
4.2 
Exclusion Criteria .............................................................................................. 15 
4.3 
Withdrawal of Subjects from Study ................................................................... 16 
4.3.1 
Withdrawal .................................................................................................................... 16 
4.3.2 
Screen Failures/Dropouts ........................................................................................ 17 
4.3.3 
Replacement ............................................................................................................ 17 
5. 
Treatment[s] ....................................................................................................... 17 
5.1 
Treatments to be administered ........................................................................... 17 
5.2 
Dose Modification for Management of Adverse Events .................................... 18 
5.3 
Dose Modifications for Gemcitabine and Cisplatin ........................................... 19 
5.3.1 
Dose Modification Guidelines for Hematologic Toxicity ....................................... 19 
5.3.2 
Dose Modification Guidelines for Hematologic/Non-Hematologic Toxicity ......... 19 
5.4 
Dose Modifications for Copanlisib .................................................................... 20 
5.5 
Management of Toxicities Associated with Study Drug .................................... 22 
5.6 
Blinding ............................................................................................................. 27 
5.7 
Drug Logistics and Accountability .................................................................... 27 
5.8 
Treatment Compliance ....................................................................................... 28 
5.9 
Post-study Therapy ............................................................................................ 28 
5.10 
Prior and Concomitant Therapy ......................................................................... 28 
6. 
Study Drug ......................................................................................................... 30 
7. 
Visit schedule and Assessments ......................................................................... 32 
7.1 
Screening FirstVvisit .......................................................................................... 32 
7.2 
Cycle 1 and Subsequent Cycles, Days 1 and 8 .................................................. 32 
8. 
Assessment types ................................................................................................ 35 
8.1 
Efficacy ................................................................................................................... 35 
8.2 
Safety ................................................................................................................. 35 
8.3 
Biomarkers .............................................................................................................. 35 


8 
 
9. 
Safety monitoring and reporting ............................................................................ 38 
9.1 
Adverse Events .................................................................................................. 38 
9.1.1 
Definitions............................................................................................................... 38 
9.2 
Safety Monitoring .............................................................................................. 40 
9.3 
Reporting of Serious Adverse Events ................................................................ 40 
9.4 
Pregnancies ........................................................................................................ 41 
10. 
Statistical Methods and Data Analysis .................................................................. 42 
10.1 
Study Design and Sample Size Calculation ....................................................... 42 
10.2 
Analysis of Primary Endpoint ............................................................................ 42 
10.3 
Analysis of Secondary and Exploratory Endpoints ........................................... 42 
11. 
Data Recording .................................................................................................. 43 
11.1 
Institutional Review Board (IRB) Approval and Consent ................................. 43 
11.2 
Required Documentation ................................................................................... 43 
11.3 
Registration Procedures ..................................................................................... 44 
11.4 
Data Management and Monitoring/Auditing ..................................................... 44 
11.5 
Adherence to the Protocol .................................................................................. 45 
11.6 
Emergency Modifications .................................................................................. 45 
11.7 
Record Retention ............................................................................................... 45 
11.8 
Obligations of Investigators ............................................................................... 45 
12. 
Ethical and Legal Aspects .................................................................................. 46 
12.1 
Ethical and Legal Conduct of the Study ............................................................ 46 
12.2 
Subject Information and Consent ....................................................................... 46 
12.3 
Publication policy .............................................................................................. 47 
12.4 
Confidentiality ................................................................................................... 48 
13. 
References .......................................................................................................... 49 
14. 
Appendix ............................................................................................................ 51 


9 
 
1. Introduction 
 
1.1 
Background 
Biliary cancer (BC) typically includes intra and extrahepatic cholangiocarcinoma (CCA) and 
cancers of the gallbladder. In the United States an estimated 2,600 intrahepatic 
cholangiocarcinomas were diagnosed in 2014.3,4 In addition, about 10,000  cases  of 
extrahepatic bile duct cancer are diagnosed annually in the United States, two-thirds of which 
are gallbladder cancers.5 Unfortunately, most patients have advanced disease at presentation 
and relapse despite surgery.6 
 
Systemic chemotherapy has historically been disappointing in advanced BC, but new 
combination regimens have shown promises. ABC-02, a randomized phase III study published 
by Valle, et al., enrolled 410 patients and compared gemcitabine plus cisplatin with gemcitabine 
alone.1 The median overall survival (OS) and progression-free survival (PFS) were greater for 
gemcitabine plus cisplatin than for gemcitabine alone without significantly increased toxicity 
(OS: 11.7 v 8.1 months; log-rank P = .002; PFS: 8.0 v 5.0 months; P = .003). This drug 
combination set a new international standard of care for advanced biliary tract cancers. 
However, survival for advanced BCs still rarely exceeds one year. Moreover, advances have 
been slow in part because of the tumor heterogeneity of BCs and poor penetration and non- 
uniform distribution of drug within the tumor.7,8 As a result, there remains a significant need to 
identify novel agents and novel combination regimens to treat this disease. 
 
 
1.2 
Copanlisib 
Preclinical single agent studies 
Copanlisib is a highly selective and potent class I PI3K inhibitor, with IC50 values of 0.5 to 6.4 
nM. Copanlisib had no inhibitory effect on ~240 other kinases and receptors. Copanlisib 
inhibited proliferation of 160 tumor cell lines (from 14 different cancer types), many with IC50 
values of 1 to 100 nM. Induction of apoptosis was demonstrated in several breast cancer cell 
lines harboring PIK3CA mutations. In addition, copanlisib exhibited potent anti-angiogenic 
activity by blocking VEGF signaling. It was also highly efficacious in nude rat human tumor 
xenograft models of various histologic types with alterations of PI3KCA or PTEN, such as 
H460 NSCLC, HCT116 CRC (PI3KCA mut, KRAS mut), U87MG glioma, and KPL4 breast 
tumor models. Preclinical studies revealed its rapid distribution into tissues and tumors, with a 
tissue-to-plasma ratio of > 10. Copanlisib has low central nervous system (CNS) penetration. 
 
The PI3K pathway is essential for insulin signaling, affecting both glucose uptake (eg, glut-4 
transporter) and various glycolytic enzyme activities. Animals treated with copanlisib 
exhibited an acute increase in insulin and glucose levels. Tumor bearing mice subjected to 
serial 2-deoxy-2[F-18] fluoro-D-glucose positron emission tomography (FDG-PET) scans 
following treatment with copanlisib demonstrated dose and time related decreases in tumor 
FDG uptake. 
 
Clinical studies of Copanlisib 
 
Study 12871, the ongoing first-in-human dose escalation Phase 1 trial in cancer subjects. 
 
This study started accruing subjects in the U.S. in November 2009. Copanlisib (single agent) 
was administered as a 1-hour IV infusion on days 1, 8 and 15, every 28 days. The first dose 
was given following an overnight fast, and the subjects fasted until 2 hours after the dose. 
Blood was sampled at 0, 0.5, 1, 1.5, 2, 3, 5, 8, 11, 25 and 49 hours for PK and plasma glucose. 


10 
 
Plasma insulin was drawn during the fasting period. By January 2011, 17 subjects had been 
dosed at 0.1, 0.2, 0.4, 0.8 and 1.2 mg/kg. 
 
An accelerated design was used with criteria for switching to 3+3 design based on doubling 
plasma insulin or increased plasma glucose by 50 mg/dL during the fasting period. The other 
criteria were occurrence of Grade 2 toxicity in two subjects or Grade 3 toxicity in one subject. 
The starting dose of 0.1 mg/kg was well tolerated in the one subject studied. As no significant 
pharmacodynamic (PD) effect was observed, the dose was increased to 0.2 mg/kg. The first 
subject at this level exhibited a greater than doubling of the baseline insulin level within 2 
hours of the end of infusion. This met the study criteria of a PD effect, and the dose was 
expanded to 3 subjects; all completed at least one 4-week cycle without dose limiting toxicity 
(DLT). Three subjects were then dosed at 0.4 mg/kg; one subject experienced Grade 2 
hypertension (resolved in 24 hours) and one had Grade 2 fasting hyperglycemia (also resolved 
in 24 hours). Of the 7 subjects dosed at 0.8 mg/kg, all received insulin after the first dose for 
postprandial blood glucose levels > 200 mg/dL. In this cohort, peak fasting glucose was 79 to 
157 mg/dL and peak postprandial glucose 165 to 429 mg/dL. Otherwise, there were no 
episodes of hypertension and no DLT. Copanlisib 0.8 mg/kg was considered the maximum 
tolerated dose (MTD). 
 
Three subjects were enrolled at 1.2 mg/kg (only 2 subjects received 1.2 mg/kg dosing). One 
subject was a 65-year-old male with metastatic adenocarcinoma of the appendix and a prior 
history of hypertension. About 8 hours after the copanlisib infusion, he developed signs of 
acute decompensated cardiomyopathy with ischemic changes with an echocardiogram showing 
an LVEF of 10-15% with global hypokinesis and electrocardiogram (ECG) showed ST wave 
elevation. His blood glucose was ~500 mg/dL during his acute illness. He was treated with 
insulin, dobutamine, furosemide and other supportive care. He made clinical recovery over 
several days. Follow-up echocardiogram 13 days after copanlisib dosing showed an LVEF of 
70%. The subject then showed signs of progressive deterioration and expired 21 days after his 
first and only dose of copanlisib. 
 
This constellation of events is consistent with the preclinical findings of increased peripheral 
vascular resistance and hypertension seen in dogs. The DLT in this single subject was felt by 
the investigators and Sponsor to be sufficiently severe to mandate cessation of the 1.2 mg/kg 
dose level. The dose of 0.8 mg was considered the maximal tolerated dose (MTD). A second 
subject who received a dose of 1.2 mg/kg had only Grade 2 hyperglycemia following the dose, 
but her dose was reduced to 0.8 mg/kg following the DLT event described above. A third 
subject received 2 doses of 0.8 mg/kg, given 2 weeks apart. She exhibited hyperglycemia with 
blood glucose >200 mg/dL. 
 
Although an MTD of 0.8 mg/kg had been determined in the dose-escalation portion of the 
study, review of additional interim data for patients in the MTD expansion cohort, as of 
November 2011, has shown significantly increased Cmax in 2 very obese patients. The basis 
for this may be explained by the preclinical biodistribution study, demonstrating that copanlisib 
does not enter adipose tissue to a significant degree. Based on these results, a maximum dose 
of 65 mg will be in effect for subjects scheduled to receive 0.8 mg/kg (and proportionally lower 
doses at lower dose levels—i.e., 49mg at the 0.6mg/kg dose level and 32.5mg at the 0.4mg/kg 
dose level). 
 
Fourteen subjects treated in dose Cohorts 1 through 4 were valid for safety evaluation. The 
median number of cycles completed was 2, with a range of 1 to 9 cycles. Of the 14 subjects, 13 
subjects have discontinued study drug and one subject remains ongoing. Of the 13 subjects 
who have discontinued copanlisib, 10 discontinued due to disease progression, 1 discontinued 


11 
 
due to an adverse event (AE) unrelated to copanlisib, 1 subject had logistical difficulties 
traveling, and 1 subject went to hospice. All subjects had at least one treatment-emergent AE. 
Most of the AEs were Grades 1 and 2 toxicities. There were no Grade 4 AEs. Grade 3 AEs 
included aspiration pneumonia unrelated to copanlisib, which occurred in one subject at Dose 
Level 1 (0.1 mg/kg); anemia, diarrhea and limb edema which occurred in subjects at Dose 
Level 2 (0.2 mg/kg); intermittent right shoulder tendinopathy and hypokalemia unrelated to 
copanlisib occurring in one subject at Dose Level 3 (0.4 mg/kg); and elevated alkaline 
phosphatase (AP), fecal obstruction, hyperglycemia, hypokalemia, ascites, biliary sepsis and 
fever occurring in subjects at Dose Level 4 (0.8 mg/kg). The anemia and diarrhea were 
considered related to copanlisib. There were 14 serious adverse events (SAEs) occurring in 8 
subjects and most of them were unrelated to copanlisib except for Grade 3 anemia and Grade 2 
hypertension. For Cohorts 1 to 4, there were no reported deaths, DLTs or dose reductions. One 
subject discontinued copanlisib due to an AE of Grade 3 enterococcal and polymicrobial sepsis 
considered unrelated to copanlisib. 
 
There was no significant hematologic toxicity with only 1 reported event of Grade 2 
neutropenia and 1 reported event of Grade 2 lymphopenia, both considered unrelated to 
copanlisib. A total of six subjects had anemia and 2 of those subjects developed Grade 3 
anemia reported as related to copanlisib.  There were no reports of Grade 4 hematologic events. 
 
Most of the reported biochemical laboratory AEs were Grade 1 and Grade 2 and included 
elevated amylase (n = 1), elevated bilirubin (n = 2), elevated aspartate aminotransferase (AST) 
(n = 1), hypoalbuminemia (n = 1) and hypomagnesemia (n = 1) which were unrelated to 
copanlisib. Three subjects developed hypokalemia: 1 subject had Grade 3 hypokalemia on two 
separate occasions, a second subject had Grade 1 hypokalemia and the other subject had Grades 
1 and 3 hypokalemia. The hypokalemia was considered unrelated to copanlisib. Three subjects 
were reported to have elevated AP: 1 subject had Grade 1 elevated AP related to study drug, a 
second subject had Grade 3 elevated AP unrelated to study drug and a third subject had Grades 
1 and 3 elevated AP but relationship to copanlisib was not reported. 
 
There have been no significant changes in ECG parameters or MUGA scan results in the 14 
subjects enrolled in dose Cohorts 1 through 4. Serial hemoglobin A1C (HgbA1c) testing has 
shown no instance of rise from a normal baseline value into the abnormal range. 
 
A key design feature of Study 12871 is detection of tumor-specific PD effects by performing 2- 
deoxy-2[F-18] fluoro-D-glucose positron emission tomography/computed tomography (FDG- 
PET/CT) studies at baseline and then 48 hours after the first dose. Subjects were studied in this 
way starting at Dose Level 4. One subject with NSCLC, dosed at 0.8 mg/kg, showed an 
approximate 40% reduction in FDG uptake in a lung lesion. A second subject treated at the 
same dose showed an approximate 23% reduction in FDG uptake in a liver metastasis of 
pancreatic adenocarcinoma. These are considered indicative of a tumor-specific PD effect of 
copanlisib that is persisting for 48 hours after the dose. 
 
Subjects in Study 12871 were evaluated with tumor imaging studies after every even numbered 
cycle. There have been no partial responses by modified Response Evaluation Criteria in Solid 
Tumors (RECIST) criteria. The longest durations of stable disease occurred in a subject with 
esophageal carcinoma (6 months, 0.1 mg/kg) and in a subject with endometrial cancer (8 
months, 0.4 mg/kg) 


12 
 
Phase I study of gemcitabine + cisplatin with copanlisib in all solid tumors 
This study started accruing patients in the US in 2011 and finished accrual in 2013.9 The study 
consisted of two arms. On Treatment A, patients received gemcitabine at 1000 mg/m2 IV and 
copanlisib 0.6 mg /kg or 0.8 mg/kg IV on days 1, 8 and 15 of a 28-day cycle to determine the 
maximum tolerated dose (MTD). Only 2 dose levels were planned as 0.8mg/kg was considered 
MTD as a single agent. On Treatment B, patients received cisplatin at 25 mg/m2, gemcitabine 
1000 mg/m2 IV and copanlisib IV on days 1 and 8 of a 21-day cycle at the MTD determined in 
Treatment A. A standard 3+3 design was used. The primary objective was to determine the 
safety, tolerability, and MTD of copanlisib in combination with gemcitabine and 
gemcitabine/cisplatin. 
 
A total of 29 patients were treated with copanlisib. In Treatment A, 8 patients received 
copanlisib at 0.6 mg/kg and 8 at 0.8 mg/kg. One DLT occurred: posterior reversible 
encephalopathy syndrome at the 0.6 mg/kg dose. MTD was not reached. In Treatment B, 13 
patients were dosed at 0.8 mg/kg of copanlisib ( maximum tested dose), with no DLTs seen. 
The most frequently observed drug-related adverse events reported in >20% of the patients 
were hyperglycemia, nausea, diarrhea, anemia, and fatigue. There was no treatment-related 
deaths. Pharmacokinetic evaluations showed comparable results across treatment groups 
indicating the absence of relevant PK interactions. An expansion cohort in patients with BC 
with treatment schedule B has finished accrual and results were presented at American Society 
of Clinical Oncology Meeting in 2014. Unfortunately most of the patients were pre treated with 
gemcitabine and cisplatin. However clinical activity was observed with 1 complete response 
and a total of 4 responses according to RECIST in patients with BC who were chemo naïve. 
 
Phosphatidylinositol 3΄-kinase (PI3K) pathway and PTEN in cholangiocarcinoma 
Cellular metabolism, growth and differentiation depend on signaling through the 
phosphatidylinositol 3΄-kinase (PI3K), serine-threonine kinase (AKT) and mammalian target of 
rapamycin (mTOR) pathways. Dysregulation of these pathways has been shown to drive 
tumorigenesis. Activation of this particular pathway is central to the growth of many human 
cancers, including CCA.10,11 Previous studies demonstrated an activation of the PI3K/AKT 
pathway in human CCA tissues which more than 50 % of cases expressed p-AKT and 
correlated with poor prognosis.12,13 
In CCA there are multiple kinases that are activated in both CCA cell lines and human CCA 
tissues. Predominately, the kinases activated downstream were those in the PI3K/AKT 
signaling pathways. 14 PI3K/AKT activation leads to increased resistance to radiation therapy 
and chemotherapy, and inhibition of this pathway can sensitize CCA cells to these 
therapies.15,16 Furthermore Menakongka, et al., reported hepatocyte growth factor (HGF)- 
induced invasiveness in CCA cell lines which was seen via PI3K/AKT signaling. Inhibition of 
this pathway markedly suppressed HGF-stimulated CCA cell invasion.17 
The expression of PTEN, which was defined as a tumor suppressor and a major negative 
regulator of PI3K/AKT signaling, was investigated by a group from Thailand. 18 The study 
found loss of PTEN expression in the majority of CCA patients (70 %) and consistent with the 
study of Chung and coworkers, which showed the absence of PTEN expression in extrahepatic 
cholangiocarcinoma  patients.19   The   authors   concluded   that   the   constitutive   activation 
of PI3K/AKT pathway in CCA is mainly due to PTEN inactivation by either loss of expression 
or phosphorylation along with an increased expression in its pathway components heralding a 
poor prognosis for CCA patients. 
 
PTEN is one of the potential biomarkers which may identify patients most likely to benefit 
from PI3K inhibitors. Robust evidence supports the predictive capability of these genetic 
aberrations in preclinical models,20,21 but validation in the clinical setting remains limited and, 


13 
 
at times, contradictory.22 The interplay between PTEN loss and activating PIK3CA is an 
interesting example of how a genetic alteration that predicts for sensitivity in one cancer type 
(endometrial cancer) may fail to predict for effıcacy in another (in breast cancer).22 The reason 
for this observation may reside in differences in biologic consequences of each of these specifıc 
mutations. Although activating PIK3CA mutations and PTEN loss, both result in 
PI3K/AKT/mTOR pathway activation, the downstream effects and the mediators recruited by 
these genetic alterations are dissimilar. Therefore the role of PTEN expression/mutation will 
need to be studied further in CCA 
 
1.3 
Rationale 
 
Copanlisib is a potent and reversible pan-class I PI3K inhibitor with significant activity against 
PI3K-d and PI3K-a isoforms. In preclinical studies, copanlisib demonstrated anti-tumor activity 
in PIK3CA mutated cells particularly in biliary tract cancers.23 Further, in vivo, the combination 
of gemcitabine and copanlisib demonstrated anti-tumor activity in a biliary tract cancer model 
(unpublished data).  The maximum tolerated dose (MTD) of copanlisib was determined to be 
0.8 mg/kg in patients with advanced solid tumors in phase I study with promising results. 9 
Four patients with CCA who received the treatment as a first line treatment responded, 
including a complete radiographic response. 
 
Therefore, combining copanlisib with DNA-targeting therapies gemcitabine + cisplatin may be 
an effective treatment strategy in anti-cancer therapy and warrants further clinical investigation. 
We hypothesize that the addition of copanlisib, a PI3K inhibitor will enhance the efficacy of the 
standard regimen of gemcitabine and cisplatin in advanced cholangiocarincinoma. 
 
2. Study Objectives 
 
Primary Objective 
To determine progression free survival at 6 months (PFS6) in patients with advanced biliary 
cancer (BC) receiving copanlisib in combination with gemcitabine and cisplatin. 
 
Secondary Objectives 
1. To determine the response rate, median PFS and overall survival (OS) in patients with 
advanced cholangiocarcinoma receiving copanlisib in combination with gemcitabine and 
cisplatin. 
 
2. To determine the safety and tolerability of the regimen of copanlisib, gemcitabine, and 
cisplatin 
 
Exploratory Objectives 
 
1. To explore potential correlations between PTEN and clinical outcome. 
 
2. To explore potential correlation between an Illumina custom cancer next generation 
targeted sequencing of 26 genetic mutations including PI3K,PTEN, BRAF, RAS (NRAS 
and KRAS) and clinical outcome. 
 
3. Study Design 
 
This is a multi-institutional single arm study using combination of gemcitabine + cisplatin + 
copanlisib in advanced cholangiocarcinoma. A total of 25 patients will be accrued. Patients will 


14 
 
receive Cisplatin (25 mg/m2 ) + Gemcitabine (1000 mg/m2) + copanlisib 60 mg on days 1 and 
8 with day 15 off to be administered on an every 21-day schedule. The FDA has mandated 
that the trial use the fixed dose of copanlisib instead of weight based. Please see appendix 
for explanation. Response and progression will be evaluated using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guidelines (version 1.1).  The primary endpoint is progression free survival at 6 months. 
 
4. Eligibility 
 
4.1 
Inclusion Criteria 
 
• Patients must have histologically or cytologically documented carcinoma primary 
to the intra- or extra-hepatic biliary system or gall bladder with clinical and/or 
radiologic evidence of unresectable, locally advanced or metastatic disease. 
Patients with ampullary carcinoma are not eligible. 
• Patients must not have received any systemic chemotherapy for advanced biliary 
cancer. 
• Patients who received adjuvant chemotherapy plus or minus radiation and had 
evidence of disease recurrence within 6 months of completion of the adjuvant 
treatment are NOT eligible. If patients received adjuvant treatment and had disease 
recurrence after 6 months, patients will be eligible. 
• Age ≥ 18 years. 
• Eastern Cooperative Oncology Group (ECOG) Performance Status Assessment of 
0 or 1. 
• The patient must have radiographic measurable disease per RECIST 1.1 criterion. 
• Life expectancy of at least 12 weeks (3 months). 
• For patients who have received prior radiation,  cryotherapy, radiofrequency 
ablation, therasphere, ethanol injection, transarterial chemoembolization (TACE) 
or photodynamic therapy, the following criteria must be met: 
o 28 days have elapsed since that therapy 
o Lesions that have not  been treated with local therapy must  be present and 
measureable 
• Subjects must be able to understand and be willing to sign the written informed 
consent form. A signed informed consent form must be appropriately obtained 
prior to the conduct of any trial-specific procedure. 
• All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 
Grade 1 or less at the time of signing the Informed Consent Form (ICF) except for 
alopecia. 
• Adequate bone marrow, liver and liver function as assessed by the following 
laboratory requirements: 
o Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) 
o Alanine aminotransferase (ALT) and aspartate amino-transferase (AST)  ≤ 2.5 
x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) 
o Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver 
involvement of their cancer) 
o Serum creatinine ≤ 1.5 x the ULN and 
o Calculated creatinine clearance > 30 ml/min 
 
Calculated creatinine clearance = (140 – age) x t (kg) x [0.85 (if female)] 
72 x creatinine (mg/dL) 
 Platelet count ≥ 100,000 /mm3 
 Hemoglobin (Hb) ≥ 9 g/dL 


15 
 
 Absolute neutrophil count (ANC) ≥1000/mm3 
 Blood transfusion to meet the inclusion criteria will be allowed. 
• Women of childbearing potential must have a negative serum pregnancy test 
performed within 7 days prior to the start of study drug. Post-menopausal women 
(defined as no menses for at least 1 year) and surgically sterilized women are not 
required to undergo a pregnancy test. 
• Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 3 months after the 
last dose of study drug.  The definition of adequate contraception will be based on 
the judgment of the principal investigator or a designated associate. 
• MUGA or ECHO for LVEF ≥ 45%. 
• Subject must be able to swallow and retain oral medication. 
• Availability of archival tumor tissue for biomarkers analysis (minimum of 10 
unstained slides are optional). Specimen from primary site will be allowed. 
 
4.2 
Exclusion Criteria 
 
• Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for 
curatively treated cervical cancer in situ, non-melanoma skin cancer and 
superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and 
T1 (tumor invades lamina propria)]. 
• Congestive heart failure > New York Heart Association (NYHA) class 2. 
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the 
last 3 months). 
• Myocardial infarction less than 6 months before study enrollment 
• Uncontrolled hypertension (blood pressure ≥ 150/90 mmHg despite optimal 
medical management). 
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary 
embolism within the 6 months before enrollment. 
• Non-healing wound, ulcer, or bone fracture. 
• Active clinically serious infections (> CTCAE grade 2). 
• Known history of human immunodeficiency virus (HIV) infection. 
• Known active Hepatitis B or C. 
• Patients with seizure disorder requiring medication. 
• Strong inducers of CYP3A4 are not permitted starting Day -14 of Cycle 1. 
• Patients with evidence or history of bleeding diathesis. Any hemorrhage or 
bleeding event ≥ CTCAE Grade 3 within 4 weeks of start of study enrollment. 
• Substance abuse, medical, psychological or social conditions that may interfere 
with the patient’s participation in the study or evaluation of the study results. 
• Known hypersensitivity to any of the test drugs, test drug classes, or excipients in 
the formulation. 
• History or concurrent condition of interstitial lung disease of any grade or 
severely impaired pulmonary function. 
• Unresolved toxicity higher than CTCAE grade 1 attributed to any prior 
therapy/procedure excluding alopecia. 
• HbA1c >8.5% or fasting plasma glucose > 160 mg/dL at screening. 
• Concurrent diagnosis of pheochromocytoma. 
• Pregnant or breast-feeding patients. Women of childbearing potential must have a 
pregnancy test performed a maximum of 7 days before start of treatment, and a 
negative result must be documented before start of treatment. 


16 
 
• Any illness or medical conditions that are unstable or could jeopardize the safety 
of the patient and his/her compliance in the study. 
• Proteinuria of CTCAE grade 3 or higher (> 3.5 g/24 h, measured by urine protein: 
creatinine ratio on a random urine sample). 
 
Excluded Therapies and Medications for Cancer 
• Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of 
study enrollment.  Subjects must have recovered from the toxic effects of the previous 
anti-cancer chemotherapy or immunotherapy (with the exception of alopecia). Anti- 
cancer therapy is defined as any agent or combination of agents with clinically proven 
anti-tumor activity administered by any route with the purpose of affecting the 
malignancy, either directly or indirectly, including palliative and therapeutic endpoints. 
However, subjects with prostate cancer who are receiving depot LHRH agonist therapy 
may continue on this treatment. 
• Hormonal therapy during the study or within 2 weeks of first study enrollment. 
• Radiotherapy to target lesions during study or within 4 weeks of first study treatment. 
• An irradiated lesion is considered evaluable only if it has shown enlargement since the 
completion of last radiation. 
• Bone marrow transplant or stem cell rescue. 
• Bisphosphonate therapy during the first 2 cycles of treatment. 
• G-CSF and other hematopoietic growth factors may be used in the management of 
acute toxicity such as febrile neutropenia when clinically indicated or at the discretion 
of the principal investigator; however they may not be substituted for a required dose 
reduction.  Erythropoietins are not permitted. 
• Investigational drug therapy outside of this trial during or within 4 weeks of first study  
treatment. 
 
4.3 
Withdrawal of Subjects from Study 
 
4.3.1 Withdrawal 
Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons: 
• Subject withdraws consent from study treatment and study procedures. A subject must 
be removed from the trial at his/her own request or at the request of his/her legally 
acceptable representative.  At any time during the trial and without giving reasons, a 
subject may decline to participate further. The subject will not suffer any disadvantage 
as a result. 
• Pregnancy.  Pregnancy will be reported as an SAE. (Note: subjects who have been 
withdrawn from treatment with study drug because of pregnancy should not undergo CT 
scans [with contrast]/MRI or bone scans while pregnant.) 
• If, in the investigator's opinion, continuation of the trial would be harmful to the 
subject's well-being. 
• Subject is lost to follow-up. 
• Death. 
Subjects may be withdrawn from the study for the following reasons: 
• The subject is non-compliant with study drug, trial procedures, or both; including the 
use of anti-cancer therapy not prescribed by the study protocol. 
• Severe allergic reaction to copanlisib. 
• The development of a second cancer. 


17 
 
• Development of an intercurrent illness or situation which would, in the judgment of 
the investigator, significantly affect assessments of clinical status and trial endpoints. 
• Deterioration of ECOG performance status to 3 or 4. 
• Use of illicit drugs or other substances that may, in the opinion of the investigator, 
have a reasonable chance of contributing to toxicity or otherwise skewing trial result. 
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable. 
Any subject with progression of disease will come off of treatment.In all cases, the reason for 
withdrawal must be recorded in the CRF and in the subject's medical records. 
 
4.3.2 Screen Failures/Dropouts 
 
A subject who discontinues study participation prematurely for any reasons except death, 
disease progression and severe toxicity is defined as a dropout. 
 
A subject who, for any reason (e.g., failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “dropout” (see above) is regarded a “screening 
failure”. 
 
4.3.3 Replacement 
Dropout patients and non-evaluable patients will need to be replaced. 
 
 
5. Treatment[s] 
 
5.1 
Treatments to be administered 
Agents 
Day 1 
Day 8 
Day 15 
Cisplatin (25 mg/m2) 
Gemcitabine (1000 mg/m2) 
X 
X 
X 
X 
copanlisib 60 mg 
X 
X 
Cycle = 21 days 
 
 
The treatment is administered on Days 1 and 8 every 21 days as follows: 
• Hour 0 to 1.0: Cisplatin will be administered once as IV infusion over 60 minutes 
as follows: One liter (L) of 0.9% sodium chloride (NaCl) including 25 mg/m2 
cisplatin, 20 millimole (mmol) of potassium chloride, and 8 mmol of magnesium 
sulfate. 
 
• Hour 1.0 to 1.5: IV infusion of 500 mL of 0.9% NaCl over 30 minutes 
• Hour 1.5 to 2.0: Gemcitabine (1000 mg/m2 as 30-min IV infusion) 
• Hour 3.0 to 4.0: Copanlisib 60 mg will be administered as an IV over 60-minutes 
beginning 1 hour after completing gemcitabine infusion. 


18 
 
 
Treatment continues on days 1 and 8 every 21 days for 24 weeks (8 Cycles). After 24 weeks of 
treatment, gemcitabine and copanlisib, without cisplatin, may continue at the discretion of the 
investigator until disease progression or unacceptable toxicity if a clinical benefit is noted. 
Furthermore copanlisib alone may continue at the discretion of the investigator until disease 
progression or unacceptable toxicity if clinical benefit is noted. 
 
Intravenous glucose-containing solutions should be avoided. Corticosteroids should not 
be given as antiemetics. 
 
On Cycle 1 Day 1, subjects should be fasting (non-sugar containing beverages are allowed, 
such as water, tea and coffee without sugar) for at least 8 hours prior to the first copanlisib 
dose and until 2 hours after completing copanlisib infusion. Guidelines for fasting prior to and 
after subsequent copanlisib doses will be based on the individual’s glucose response to the first 
copanlisib dose and the discretion of the treating physician. 
 
If gemcitabine or cisplatin is discontinued for toxicity, the other drug(s) may continue at the 
discretion of the investigator if clinical benefit is noted. 
 
5.2 
Dose Modification for Management of Adverse Events 
 
It is recognized that attribution of causality of any AE to specifically one or more of the study 
drugs may be difficult. Certain toxicities were seen in relation to only one of the drugs in the 
respective Phase 1 trial; e.g., hyperglycemia, hypertension and cardiac toxicity (observed only 
with 1.2 mg/kg dosing) with copanlisib. As such, dose modification for these events may 
initially be limited to just one of the drugs based on Phase 1 experience. However, if 
improvement doesn’t occur following reduction or cessation of dosing of the suspected 
investigational agent, other drug(s) should be considered as a contributing factor. 
 
Only two dose reductions are allowed for each drug. Treatment can be held until treatment 
criteria are met. If a patient requires a dose delay of > 21 consecutive days of copanlisib, 
gemcitabine or cisplatin, then the patient should be discontinued from the study treatment. In 
exceptional situations, if the patient is clearly benefiting from the study treatment (i.e., stable 
disease, partial response, complete response), and in the opinion of the investigator no safety 
concerns are present, the patient may remain on the study treatment – a decision that is at the 
discretion of the PI. Patients who discontinue from the study for a study-related AE or an 
abnormal laboratory value must be followed. 
 
If gemcitabine and cisplatin needs to be delayed copanlisib can be given by iself. w Also 
gemcitabine and cisplatin can give given without copanlisib if copanlisib needs to be delayed 


19 
 
 
Dose level reductions are as follows: (fixed dose is as per FDA’s guideline) 
 
Dose Level 
Gemcitabine 
Cisplatin 
Copanlisib 
Starting Dose 
1000 mg/m2 
25  mg/m2 
60 mg 
Dose -1 
800 mg/m2 
20 mg/m2 
45 mg 
Dose -2 
600 mg/m2 
15 mg/m2 
30 mg 
 
 
5.3 
Dose Modifications for Gemcitabine and Cisplatin 
 
5.3.1 Dose Modification Guidelines for Hematologic Toxicity 
 
The dose modification guidelines for gemcitabine and cisplatin for hematologic toxicity on day 
1 of each cycle of the treatment is mentioned below. 
 
ANC 
Platelet count 
Gemcitabine 
Cisplatin 
≥1,000/mm3 and 
≥ 100,000/mm3 
Give full dose 
<1,000/mm3 or/and < 100,000/mm3 
Delay t
for nex
reatment by 1 week. Reduce dose by one level 
t treatment. 
 
The dose modification guidelines for gemcitabine and cisplatin for hematologic toxicity on day 
8 of each cycle of the treatment is mentioned below. 
 
ANC 
Platelet count 
Gemcitabine 
Cisplatin 
≥1,000/mm3 And 
≥ 75,000/mm3 
Give full dose 
<1,000/mm3 or/and < 75,000/mm3 
Skip treatment. Reduce dose by one level for next 
treatment. 
 
It is recommended that G-CSF is administered if patients develop neutropenia. 
 
5.3.2 Dose Modification Guidelines for Hematologic/Non-Hematologic Toxicity 
 
The dose modification guidelines for gemcitabine and cisplatin for non-hematologic toxicities 
on day 1 of each cycle of the treatment is mentioned below: 
 
 
 
 
 
 
a   Except for alopecia, clinically insignificant laboratory abnormalities, and 
inadequately treated nausea, vomiting and diarrhea. 
 
The dose modification guidelines for gemcitabine and cisplatin for non-hematologic toxicities 
on day 8  of each cycle of the treatment is mentioned below: 
 
Non Hematologic Toxicitya 
Gemcitabine 
Cisplatin 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Skip treatment until resolves to ≤ Grade 1. Reduce 
dose by one level of the drug depending upon the 
attribution. 
Non Hematologic Toxicitya 
Gemcitabine 
Cisplatin 
Grade 1 or 2 
Treat as scheduled 
Grade 3 or 4 
Delay treatment until resolves to ≤ Grade 1. Reduce 
dose by one level of the drug depending upon the 
attribution. 


20 
 
a   Except for alopecia, clinically insignificant laboratory abnormalities, and 
inadequately treated nausea, vomiting and diarrhea. 
 
Dose modification for these events may initially be limited to just one of the drugs ( 
gem or cis) based on treating physician’s experience.  However, if improvement 
doesn’t resolve following reduction or cessation of dosing of the suspected 
investigational agent, other drug should be considered as a contributing factor and 
be dosed reduced as well. 
 
 
5.4 
Dose Modifications for Copanlisib 
Hematologic Toxicity 
Currently there is no evidence that copanlisib is toxic for bone marrow. The clinician should 
proceed, as far as copanlisib is concerned, as dictated by the clinical situation, common sense, 
and his experience as an investigator. The guidelines in table 5-1 can be used as support for the 
clinical decision. In case these guidelines are not followed, the rationale for other measures will 
be documented in detail in the patient’s medical record. 
 
Table 5—1: Dose Modification of Copanlisib for Hematological Toxicity 
Hematological Toxicity (any of the following) 
Test drug action 
• Thrombocytopenia <25 x 109/L or Grade 3 with 
bleeding 
• Febrile neutropenia 
• Neutropenia CTC Grade 4 and lasting for 
>3 days a 
• INR or PTT CTC Grade >3 with bleeding 
• CTC Grade 4 anemia b 
• CTC Grade >3 hemorrhage/bleeding 
Hold copanlisib 
Resume when toxicity is resolved 
to 
≤ CTC Grade 1a 
(If recovery within 21 days, 
patient can be treated at one dose 
level lower). 
• Toxicity requiring delay for > 21 days 
Discontinue test drug 
aFor patients who develop a CTC Grade 4 neutropenia, a blood count after 3-5 days is 
recommended 
bHb values of 9 g/dL are acceptable 
 
Non-hematologic toxicity 
 
Subjects who experience non-hematologic copanlisib related grade III and IV toxicity other 
than mentioned below, but show an objective clinical benefit may continue copanlisib at the 
next lower dose level of copanlisib at the discretion of the investigator. The decision whether 
or not to continue copanlisib will be made by the Investigator following discussion of this 
information with the PI. 
 
Dose modifications for Non-Hematologic Toxicities: Hyperglycemia and Hypertension 
 
a) Hyperglycemia 
 
Patients who develop hyperglycemia of CTCAE grade 3 (glucose levels of > 250 mg/dL) after 
copanlisib administration may continue treatment. The next infusion must be delayed until their 
glucose levels return to ≤ 160 mg/dL (fasting) or ≤ 200 mg/dL (non-fasting). Guidelines for the 
treatment of hyperglycemia are given in Table 5-3 and 5-4. 


21 
 
 
Investigators may decrease one to two dose levels of copanlisib if hyperglycemia is not 
manageable, or is difficult to manage, based on the investigator’s judgment. 
 
A dose reduction of copanlisib by one dose level is mandatory in the event of CTCAE Grade 4 
asymptomatic hyperglycemia. No further dose reductions will be allowed in the event of 
reoccurrence of CTCAE Grade 4 asymptomatic hyperglycemia and the patient will be 
permanently discontinued.  In case of symptomatic hyperglycemia CTC grade 4, permanent 
discontinuation of the study drug is mandatory. 
 
b) Hypertension 
 
No dose should be given if the blood pressure is ≥ 150/90 mmHg.  Instructions for blood 
pressure measurement are given in Section 5.5 Table 5-5. 
 
Antihypertensive medication may be given to control the hypertension. Dosing can proceed on 
the scheduled day if there are at least 2 consecutive measurements <150/90 mmHg. Otherwise 
dosing must be delayed. 
 
In case that drug-related hypertension (post-dose blood pressure of CTC grade 3 or 
160/100 mmHg) is not manageable with optimal antihypertensive treatment, the dose for the 
subsequent copanlisib administrations may be reduced by 1 or 2 dose levels. Guidelines for the 
treatment of hypertension are given in Section 5.5 Table 5-5. In patients with a post-dose blood 
pressure of CTC grade 4, i.e., a post-dose blood pressure which may have life-threatening 
consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, 
hypertensive crisis) or where urgent intervention is indicated, permanent discontinuation from 
study drug is mandatory. 
 
Dose Modification for Subsequent Cycles 
 
Lab tests prior to each infusion may be performed either the day before or the planned date of 
infusion, with the exception of blood glucose, which must be performed on the day of infusion. 
On Day 1 of each cycle, the dose of copanlisib will be given only if the criteria described in 
Table 5-2 are met. 


22 
 
 
Table 5-2: Laboratory Test Criteria for First Dose of Any Cycle Dosing 
Laboratory Test 
Criteria for First Dose of Any Cycle 
Dosing 
Glucose 
≤ 160 mg/dL (fasting; ≤200 mg/dL, if 
non-fasting) 
Hemoglobin 
≥ 9 g/dLa 
ANC 
≥ 1,000/mm3 
Platelets 
≥ 75,000/mm3 
ALT 
≤ 2.5 X ULN or 
≤ 5 X ULN in case of liver involvement 
AST 
≤ 2.5 X ULN or 
≤ 5 X ULN in case of liver involvement 
Total bilirubin 
≤ 1.5 X ULN b 
Creatinine 
≤ 1.5 X ULN 
a   If the hemoglobin is < 9 g/dL on the day of planned copanlisib administration, but the 
patient is hemodynamically stable, it is permissible to give the copanlisib dose on 
schedule and transfuse within 48 hours of the dose. 
b   < 3 x ULN for patients with Gilbert-Meulengracht syndrome. 
 
Blood counts will be performed and assessed prior to the subsequent doses in each cycle of 
copanlisib (on Day 8). The study drug will not be administered if, on the day of scheduled 
dosing, any of the following criteria is met: 
• 
Grade 4 ANC (<5000/mm3) 
• 
Platelets are < 25,000/mm3 
• 
Grade 4 anemia 
 
 
Doses scheduled for Day 8 may be delayed by up to 2 days. A delay by more than 
2 days will be considered a missed dose. Missed doses will not be replaced. The minimum 
interval needed between two infusions of copanlisib is 5 days. 
5.5 
Management of Toxicities Associated with Study Drug 
Treatment of Neutropenia 
G-C CSF is allowed for treatment of neutropenia (ANC < 500/mm3). The dose and schedule 
are at the discretion of the investigators.  Treatment, however, can only be administered ≥ 48 
hours post G-CSF.  If G-CSF is given for neutropenia, the subsequent gemcitabine doses 
should be reduced by one dose level. 
 
 
Treatment of Hyperglycemia 
Only the use of rapid or short acting (regular) insulin is allowed for the treatment of transient 
hyperglycemia (glucose intolerance). In the event of post-dose glucose >250 mg/dL on the 
day of infusion, the administration of rapid or short acting (regular) insulin is recommended 
according to the instruction’s insulin sliding scale regimen.  A suggested regimen for the 


23 
 
administration of short acting (regular) insulin for hyperglycemia is shown in Table 5-3. 
Suggested guidelines for copanlisib-induced hyperglycemias are shown in Table 5-4. 
Table 5-3: Recommended treatment for hyperglycemia 
Glucose Level (mg/dL) 
Regular Insulin Dose 
(capillary or blood sample) 
 
(Units) 
< 200 
0 
200 - < 
2 
250 - < 
4 
300 - < 
6 
350 - < 
8 
≥ 400 
10 
 
In the event of rapid or short acting regular insulin administration at any cycle, a minimum 3- 
hour close observation time is required post-administration. Meals should be provided for 
patients who are kept in for continued observation. A low dose carbohydrate diet is 
recommended for the first 48 hours after study drug infusion. Patients will be trained to 
measure their capillary blood glucose levels at home during screening and will be provided with 
glucometer and supplies (lancets, test strips, and diary) to register measured values and record 
insulin administration if applicable. 
 
All non-diabetic patients who experience hyperglycemia >250 mg/dL or require insulin 
administration will be instructed to check blood glucose at home at least 3 times per full day for 
at least 72 hours after the start of the infusion.  This includes fasting glucose (morning before 
breakfast) and 2 further random non-fasting measurements approximately 2 hours after intake 
of food.  If after the required 72 hours the glucose values are not at goal (fasting glucose ≤125 
mg/dL or random non-fasting glucose ≤ 160 mg/dL), this monitoring will continue until blood 
glucose values are at goal. 
 
All diabetic patients will be instructed to check blood glucose at home at least three times per 
full day for at least 72 hours after start of each infusion at all cycles. This includes fasting 
glucose (morning or breakfast) and 2 further random non-fasting measurements approximately 
2 hours after intake of food.  If after the required 72 hours the glucose values are not at goal 
(fasting glucose < 160 mg/dL or random non fasting glucose < 200 mg/dL) this monitoring will 
continue until blood glucose values are at goal and the patient should be immediately referred 
to the local diabetes center/endocrinologist to adjust treatment. All glucose measurements and 
insulin doses, if applicable, will be collected. 
 
If the patient already monitors his/her blood glucose as part of routine antidiabetic care, the 
routine measurements should not be replaced by the study specific measurements. In this 
situation, patients should add the study specific measurements to their routine, if applicable. 
After the required 72 hours, if blood glucose values are at goal (fasting glucose < 160 mg/dL or 
random non-fasting glucose < 200 mg/dL) after each infusion, patients can then stop only the 
study specific measurements until the next day of infusion, but should keep their routine 
measurements unchanged and ongoing as usual. 
 
Sites recruiting patients with diabetes should have the option to extend glucose monitoring 
overnight. 
 
 


24 
 
Table 5-4: Guidelines for Copanlisib-Induced Hyperglycemia 
 
 
• All subjects should be on a low sugar diet starting 12 hours before until 12 
hours after each copanlisib dose. 
• Plasma glucose should be checked on the same day before copanlisib administration. 
Intravenous glucose containing solutions should be avoided. 
• Copanlisib will be administered only if plasma glucose is < 200 mg/dL. 
• Copanlisib will not be administered if plasma glucose is ≥ 200 mg/dL. In this 
case, there are 2 options: 
 Observe the subject in the clinic while fasting and treat if plasma glucose falls 
to < 200 mg/dL. 
 Discharge from clinic and have the subject return the following morning 
after 8 hour fast. Non-sugar beverages, such as water, coffee and tea are 
allowed during the fasting period. 
• Subjects with plasma glucose >150 mg/dL pre copanlisib dose should also be 
monitored in the clinic. If plasma glucose remains < 200 mg/dL for 4 hours post 
completing the copanlisib dose, they can be discharged from clinic without 
further monitoring. If plasma glucose is > 200 mg/dL within 4 hours of 
completing the copanlisib dose, additional 4 hours of monitoring (in the clinic or 
at home) would be necessary. The decision to administer insulin (please see 
Table 5-4) is at the discretion of the Investigator. 
• 
The anti-diabetic regimen is to be continued if glucose values are at goal (fasting 
glucose < 160 mg/dL and random non-fasting glucose < 200 mg/dL). 
• 
If fasting glucose is ≥ 160 mg/dL or random non-fasting glucose is ≥ 200 mg/dL the 
patient should be immediately referred to the local diabetes center/endocrinologist to 
adjust treatment. 
 
 
 
Treatment of Hypertension Associated with Copanlisib 
 
The guidelines for dose modifications of study treatment in case of arterial hypertension are 
given in Table 5-5. 
 
Copanlisib should not be given if BP is ≥ 150/90 mm Hg.  Antihypertensive medication(s) 
should be given to control the hypertension. Copanlisib dosing may proceed if there are at 
least 2 consecutive BP measurements of <150/90 mm Hg (measured at 5 to 10 minute 
intervals).  If blood pressure is ≥150/90mm Hg, the investigator can consider a medical 
intervention (e.g., administration of a dihydropyridine calcium channel blocker) or delaying the 
infusion of study drug.  The patient should rest 5-10 minutes before blood pressure is recorded. 


25 
 
 
Table 5-5 
Dose modification of study treatment for arterial hypertension 
Toxicity (CTCAE v.4.0) 
Study drug action 
Recommendation 
Pre-dose measurements 
BP ≥ 150/90 mmHg 
No dose should be 
given until recovery to 
< 150/90 mmHg. 
Consider a medical intervention. 
Dosing can proceed on the scheduled 
day if after at least 2 consecutive 
measurements blood pressure returns 
to < 150/90 mmHg. If blood pressure 
doesn’t return to < 150/90 mmHg, 
then delay dosing until next visit.  
During infusion: 
CTCAE Grade 3 
arterial hypertension 
(≥ 160/100 mmHg) 
Infusion can be 
interrupted or slowed 
down and 
administration of anti- 
hypertensive therapy 
should be initiated. 
Infusion may be resumed 
immediately when blood pressure 
has returned to < 150/90 mmHg or 
skipped. 
Subsequent study drug 
administrations may be reduced by 1 
dose level at the investigator’s 
discretionb. 
Post-dose: 
Drug related Arterial 
Hypertension of 
CTCAE Grade ≥3 
(≥ 160/100 mmHg)a 
– 
Subsequent study drug 
administrations may be reduced by 1 
dose level at the investigator’s 
discretionb. 
Post-dose: 
CTCAE Grade 4 
Permanent 
discontinuation 
– 
BP = Blood pressure; CTCAE = Common Terminology Criteria for Adverse Events 
a Not manageable despite optimal antihypertensive treatment. 
b The lowest dose level is 45 mg; if a patient is already on the 45 mg dose level and 
experiences post-dose Arterial Hypertension of CTCAE Grade ≥ 3 or ≥160/100 mmHg, 
consider more intensive therapy than previously used. 
No dose should be given if blood pressure is ≥ 150/90 mmHg. Instructions for blood pressure 
measurement are given in Section 5.5 Table 5-6. Antihypertensive medication may be given to 
control the arterial hypertension. Dosing can proceed on the scheduled day if there are at least 2 
consecutive measurements < 150/90 mmHg. Otherwise dosing must be delayed. 
If drug-related arterial hypertension (post-dose blood pressure of CTCAE Grade ≥ 3 or 
≥ 160/100 mmHg) is not manageable with optimal antihypertensive treatment, the dose for the 
subsequent study drug administrations may be reduced by 1 dose level at the investigator’s 
discretion. Patients with a post-dose blood pressure of CTCAE Grade 4, i.e., a post-dose blood 
pressure that may have life-threatening consequences (e.g., malignant arterial hypertension, 
transient or permanent neurologic deficit, hypertensive crisis), or patients who require urgent 
intervention, must permanently discontinue the study drug. 
Guidelines for Treatment of Arterial Hypertension Associated with Copanlisib 
 
It is important that patients with pre-existing arterial hypertension adhere to their regular 
medication schedule, and take their usual doses on the days of study drug infusion. The 
management of acute arterial hypertension following copanlisib will need to be individualized 
for each patient, but the experience in Phase I has suggested the benefit of dihydropyridine 
calcium channel blockers (i.e., amlodipine, felodipine). Topical nitrates should also be 
considered. Verapamil and diltiazem (non-dihydropyridine calcium channel blockers) should be 


26 
 
avoided due to a potential CYP3A4 interaction. In general, it is advisable for sites to be 
prepared so that antihypertensive medication is readily available in case of need.  In the event 
of the occurrence of arterial hypertension ≥ 150/90 mmHg during infusion of copanlisib at any 
cycle antihypertensive treatment is suggested as indicated above. In the event of the occurrence 
of CTCAE Grade 3 arterial hypertension (≥ 160/100 mmHg) during infusion of copanlisib, the 
infusion should be interrupted and antihypertensive treatment as suggested above is 
administered. Infusion can be resumed when blood pressure has returned to <150/90 mmHg. 
 
Dose Modifications for Non-Hematologic Toxicities: Dermatologic Toxicity 
 
Depending on the grade and incidence of dermatologic reaction associated with copanlisib, 
treatment should continue as dictated by the clinical situation. The guidelines in Table 5-6 can 
be used as support for the clinical decision. In case these guidelines are not followed, the 
rationale for other measures will be documented in detail in the patient’s medical record. 


27 
 
Table 5-6: Dose Modification of Copanlisib for Dermatologic Toxicity 
 
Study Drug Action 
Toxicity a 
Occurrence 
for current course of 
therapy 
for next course of therapy 
Grade 1 
No change 
No change 
Grade 2b 1st appearance 
Interruption until Grade ≤ 1 
No change 
2nd appearance 
Interruption until Grade ≤ 1 
Decrease by one dose level 
3rd appearance 
Interruption until Grade ≤ 1 
Decrease by one dose level 
4th appearance 
Permanent discontinue 
-- 
Grade 3 b 1st appearance 
Interruption until Grade ≤ 1 
Decrease by one dose level 
2nd appearance 
Interruption until Grade ≤ 1 
Decrease by one dose level 
3rd appearance 
Permanent discontinue 
-- 
Grade 4 1st appearance 
Permanent discontinue 
a Toxicities according to CTCAE version 4.0 
b Despite maximum supportive therapy 
Treatment of Dermatologic Toxicity 
If dermatologic changes occur, the patient should be treated quickly and aggressively. 
 
 
 
 
 
5.6 
Blinding 
 
This is an open-label trial.  Subjects will be assigned to treatment in order of recruitment into 
the trial in consultation with the sponsor. There will be no randomization or blinding. 
 
5.7 
Drug Logistics and Accountability 
 
All study drugs will be stored at the investigational site in accordance with good clinical 
practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
d


28 
 
department of the sponsor (or its affiliate / Contract Research Organization [CRO]), and will 
be inaccessible to unauthorized personnel.  Special storage conditions and a complete record 
of batch numbers and expiry dates can be found in the sponsor study file; the site-relevant 
elements, of this information will be available in the ISF.  The responsible site personnel will 
confirm receipt of study drug and will use the study drug only within the framework of this 
clinical study and in accordance with this protocol.  Receipt, distribution, return and 
destruction (if any) of the study drug must be properly documented according to the sponsor’s 
agreed upon and specified procedures. 
 
5.8 
Treatment Compliance 
 
The administration of study drugs will be performed in the clinic. 
 
5.9 
Post-study Therapy 
 
After the end of this study, no further study treatment will be administered. 
 
5.10 
Prior and Concomitant Therapy 
Prohibited Concomitant Anti-cancer Therapy: 
CYP3A4 Inhibitors and Inducers 
 
Copanlisib is metabolized by CYP3A4.  Therefore, concomitant use of strong inhibitors of 
CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir 
and saquinavir), and strong inducers of CYP3A4 (e.g., rifampin) are not permitted from 
Day -14 of Cycle 1 and for the duration of the study. Concomitant use of other known 
CYP3A4 inducers (eg, phenytoin, carbamazepine and phenobarbital) should be avoided as 
clinically significant decrease in plasma concentrations of copanlisib cannot be ruled out. 
 
Concomitant use of herbal preparations containing CYP3A4 inducers (e.g., St. John’s 
Wort) are not permitted during the study. 
 
Grapefruit and grapefruit juice (CYP3A4 inhibitor) consumption are not permitted during 
the study. Subjects taking narrow therapeutic index medications (e.g., warfarin, phenytoin, 
quinidine, carbamazepine, phenobarbital, cyclosporine and digoxin) should be monitored 
closely in case these medications cannot be avoided. 


29 
 
CYP3A4 inhibitors and inducers and CYP2C19 inhibitors 
 
 
 
Strong inhibitors and inducers (underlined) are not permitted during this study. 
 
 
 
indinavir
 nelfinavi
r ritonavi
r 
saquinavir 
clarithro mycin 
itraconazole ketoc
onazole 
nefazodone 
erythromycin grap
efruit juice 
verapamil 
diltiazem 
cimetidine 
amiodarone 
fluvoxamine 
troleandomycin 
CYP3A4 inhibitors 
CYP3A4 inducers 
rifampin 
carbamazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin St.Jo
hn's wort 


30 
 
 
 
6. Study Drug 
The following drug supply will be used in the study as study treatment: 
 Copanlisib solution for IV infusion 
The details of the test drug are given in Table 6-1. 
 
Table 6-1: 
Identity of Copanlisib 
Chemical name 
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- 
dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5- 
carboxamide dihydrochloride 
Substance code number(s) 
BAY 84-1236* 
Appearance 
Yellow to colorless solid substance 
Formulation 
Freeze-dried product containing 92.16 mg BAY 84-1236 
(equivalent to 80 mg copanlisib) in a 6 mL injection vial 
Composition 
BAY 84-1236/citric acid/mannitol//NaOH/water 
Type of packaging and 
content 
6 mL injection vial 
*  BAY 84-1236 is the dihydrochloride salt of the base copanlisib 
NaOH = sodium hydroxide 
 
 
 
1. Introduction 
This instruction describes the preparation of solution for injection of Copanlisib from the 
supplied lyophilisate. The lyophilisate will appear as a yellow to colorless solid substance and 
the solution may be slightly yellow. 
2. Composition 
Copanlisib is a lyophilized preparation filled in 6-mL injection vials. After reconstitution with 
4.4 mL of sodium chloride the drug substance concentration amounts to 15 mg/mL Copanlisib. 
The labeled amount per vial is 60 mg Copanlisib, the nominal content due to the technically 
required overfill is 68.4 mg Copanlisib vial. 
3. Storage and Shelf Life 
The prepared solutions are physicially and chemically stable for 24 hours at room temperature. 
To minimize the risk of microbial growth following compounding the prepared solution should 
be stored between 2⁰C and 8⁰C (< 20 hours) and administered immediately thereafter (<4 
hours). It takes approximately 60 minutes for the 100 mL dilution filled in bages to return to 
room temperature after refrigeration. 
4. Materials 
Reconstitution medium for the lyophilisate: 0.9% sodium chloride solution for injection 
(4.4 mL) 
Dilution medium for the reconstituted product: 0.9% sodium chloride solution for injection 
(100 mL) 
Colorless infusion bags (translucent), empty or filled with 100 mL 0.9% NaCl solution, made of 


31 
 
polyethylene (PE), polypropylene (PP), or ethylene vinyl acetate (EVA) 
Colorless infusion tubes (translucent), made of polyethlene (PE), polypropylene (PP) or 
polyvinylchloride (PVC) (DEHP-free) or polyuretane (PU) 
 
 
5. Handling of the Lyophilized Product Copanlisib (BAY 80-6946)- 60 mg 
For the handling of this study medication the following principles have to be followed: 
· Use of sterile disposable gloves and hand hygiene as recommended for current clinical 
practice 
· Disinfection of the septum of the injection stoppers using a swab with an appropriate 
disinfectant (e.g. based on ethanol or isopropoanol) [applies to vials of Copanlisib and 
sodium chloride solution] 
· To ensure product sterility the vial stopper must not be removed during handling 
 
 
5.1 Dosage Preparation 
These instructions are for the preparation of doses 30, 45, and 60 mg Copanlisib in 100 mL 
0.9% NaCl bags. If starting with an empty bag, inject 100 mL of 0.9% NaCl into the bag to 
ensure a volume of not less than 100 mL 
For reconstitution add 4.4 mL of sterile isotonic sodium chloride solution to the lyophilized 
mass of one vial, leading to solutions with a drug substance concentration of 15 mg/mL. The 
reconstituted solution is then diluted to the administration volume of 100 mL using 
physiological saline solution. 
Process 
· Withdraw 4.4 mL of sterile isotonic chloride solution as reconstitution media by using a 5 mL 
sterile syringe 
(Note: the dosing of the reconstituted lyophilisate may alternatively be performed by 
gravimetric means, provided the density of the reconstituted solution is taken into account: 
D20 4= 1.0222 g/mL) 
· Inject the measured volume through the stopper into the 6 mL injection vials using a needle 
· Shake the injection vial vigorously for 30 seconds, and then allow standing for 1 minute to 
let the bubbles rise to the surface 
· Check if any undissolved substance is still seen. If yes, repeat the shaking and settling 
procedure. The reconstituted lyophilisate may only be diluted or withdrawn after the 
solution is clear 
· Withdraw the required amount of the reconstituted lyophilisate with an unused sterile 
syringe: 
Copanlisib dose [mg] 30 45 60 
Reconstituted Copanlisib solution [mL] 2 3 4 
· Connect the syringe to the 100 mL sodium chloride bag and transfer the required amount of 
the reconstituted lyophilisate into the bag 
· Mix the dose well 
· After administration the line is to be flushed to ensure patient gets the complete dose 
6. First Aid Measure in Case of Accidental Skin Contact 
Remove all contaminated clothes and shoes and wash off immediately with soap and plenty of 
water 
7. Comments/Deviations 
 
Every deviation or non-standard occurrence should be documented and justified. All notes 


32 
 
7. should be stored together with study Visit schedule and Assessments 
 
7.1 
Screening First Visit 
Screening examinations will only be performed after having received the subject’s written 
informed consent. 
The following examinations will be performed within 21 days prior to the first treatment: 
 Written subject informed consent to be obtained prior to any screening assessments. 
After the subject starts the study treatment, any new finding discovered not present 
in the patient’s medical history or a worsening of a prior medical history finding 
must be recorded as an AE. 
 Complete medical history and physical examination, including neurologic examination, 
demographics, surgery, therapies, medications, smoking, alcohol history, co-existing 
diseases, allergies, NYHA classification, vital signs (heart rate, respiration rate, 
temperature, and BP), weight and review of systems including neurological status. 
 Baseline toxicities / AEs 
 ECOG Performance Status Assessment 
 12-lead ECG 
 MUGA scan 
 Radiologic assessment: CT scan or MRI with tumor measurement and disease 
assessment of non-measurable disease 
 Coagulation (PT-INR and aPTT) 
 Hemoglobin A1C 
 Thyroid stimulating hormone (TSH), free thyroxine (free T4) 
 Urinalysis (UA) with microscopy (glucose, protein, ketones, pH, bilirubin blood, 
microscopic analysis for white blood cell (WBC), red blood cell (RBC), epithelial 
cells, bacteria, crystals and casts 
 Collection of archived tumor tissue for biomarker analysis 
The following examinations will be performed within 7 days prior to the first treatment: 
 Hematology (hemoglobin, HCT, RBC, WBC count with differential (neutrophils, 
bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
 Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, lactate 
dehydrogenase (LDH), creatine kinase, lipase, amylase, glucose, uric acid, calcium 
phosphate, magnesium, bicarbonate, sodium, potassium, chloride, creatinine, blood 
urea nitrogen (BUN), total protein and albumin 
 
  Baseline Tumor markers including Ca 19-9 
 Serum pregnancy test (if applicable) 
 
7.2 
Cycle 1 and Subsequent Cycles, Days 1 and 8 
 
• History and assessment to include brief examination, vital signs (heart rate, respiration 


33 
 
rate, temperature and BP) and review of systems including neurological status. 
• Toxicity/AE assessment 
• ECOG Performance Status Assessment 
• Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) and platelet count 
• Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, LDH, creatine kinase, 
lipase, amylase glucose, uric acid, calcium, phosphate, magnesium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin 
 
• Hemoglobin A1C to be performed on Day 1 of odd cycles except for cycle 1 (Cycle 3, 
5, etc.) 
• Cisplatin IV infusion 
• Gemcitabine IV infusion 
• Copanlisib IV infusion 
 
At the end of every third cycle (Cycle 3, Cycle 6, etc) 
• MUGA scan/Echo (one test should be used consistently) 
• Tumor measurement/disease assessment according to RECIST 1.1(please see appendix) 
 
• 
Tumor markers  CA 19-9 


34 
 
Visit Evaluation Schedule 
 
Screening 
w/in 21 days 
of C1D1 
Cycle 1 
Day 1 
± 1 day 
Day 8 
± 1 
day 
Day 15 
Cycle 2 and 
beyond day 1 
± 1 day 
Day 8 
± 1 
day 
EOTj 
Post- 
Progression 
Follow-upk 
Complete 
History/Physicala 
X 
X 
History & Assessment 
b 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
ECG 
X 
MUGA/Echo** 
X 
X 
Tumor 
Measurement/Disease 
Assessmentc 
X 
X 
Hematologyd 
X* 
X 
X 
X 
X 
X 
Chemistrye 
X* 
X 
X 
X 
X 
X 
Coagulationf 
X 
X 
Urinalysisg 
X 
X 
HgbA1C 
X(every 
odd cycle 
except for 
1 st cycle) 
TSH, free T4 
X 
Serum Pregnancy, if 
appl. 
X* 
Tumor Tissueh 
X 
Gemcitabine infusion 
X 
X 
X 
X 
Cisplatin 
X 
X 
X 
X 
Copanlisib 
X 
X 
X 
X 
Blood pressurei 
X 
X 
X 
X 
X 
Survival f/u 
X 
Tumor Marker l 
X 
 
 
a. Complete medical history and physical examination including neurologic examination, 
demographics, surgery, therapies, medications, smoking, alcohol history, co-existing 
diseases, allergy, NYHA classification, vital signs (heart rate, respiration rate, 
temperature and BP), height, weight and review of systems including neurological status. 
History and assessment including brief examination, vital signs (as above) and review of 
systems. 
b. Note all toxicities and adverse events, using CTCAE version 4.0. 
c. Data regarding tumor assessment will be collected at Screening, after every 3 cycles and 
as necessary. Tumor response will be assessed using RECIST 1.1 criteria. Tumor 
measurement/disease assessment should be performed within 7 days of the end every 3rd 
cycle.  For end-of-treatment visit, do assessment of tumor lesions according to RECIST 
1.1. 
d. Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils, bands, lymphocytes, monocytes, eosinophils and basophils) and platelet 
count. 


35 
 
e. ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, LDH, creatine kinase, 
lipase, amylase glucose, uric acid, calcium, phosphate, magnesium, bicarbonate, sodium, 
potassium, chloride, creatinine, blood urea nitrogen (BUN), total protein and albumin. 
f. PT-INR and aPTT. 
g. Glucose, protein, ketones, pH, bilirubin, blood, microscopic analysis for WBC, RBC, 
epithelial cells, bacteria, crystals and casts. 
h. Tumor tissue samples will be requested from all subjects and are mandatory. Minimum of 
10 unstained slides will be required. 
i. Copanlisib should not be given if blood pressure is ≥ 150/90 mm Hg. Antihypertensive 
medication(s) should be given to control the hypertension.  Copanlisib dosing may 
proceed if 2 consecutive BP measurements measured at 5 to 10 minute intervals are 
<150/90 mm Hg. 
j. If a subject discontinues treatment due to confirmed PD, only the EOT disease assessment is 
required if it has been > 28 days since the last disease assessment 
k. Can be performed over the phone. After off treatment following disease progression, 
physical assessments (with lab tests performed at the discretion of the treating 
investigator) should take place every 3 months for up to two years or death. 
l. Every 3 cycles 
 
*These screening tests are within 7 days. 
**MUGA or Echo scan to be performed at the end of every 3rd cycle (end of Cycle 3, Cycle 6, 
etc.) 
 
8. Assessment types 
 
8.1 
Efficacy 
Response and progression will be evaluated using the international criteria proposed by 
the  revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).  Changes in the largest diameter (unidimensional measurement) of the 
tumor lesions and the  shortest diameter in the case of malignant lymph nodes are used in 
the RECIST criteria. 
 
8.2 
Safety 
Safety assessments will consist of monitoring and recording all adverse events, including serious 
adverse events, the monitoring of hematology, blood chemistry, Fasting Plasma Glucose, 
Hemoglobin A1c, ECG and the regular monitoring of vital signs, and physical condition as 
shown in corresponding tables. For details on AE collection and reporting, refer to the Safety 
section in the protocol 
8.3 
Biomarkers 
Tumor tissue: 
Samples of tumor tissue for biomarker analysis will be requested from all subjects during 
screening. Tumor tissue submitted for biomarker analysis may be from an archived specimen. 
Attempts should be made to submit samples of all available tumor tissue specimens for 
biomarker analysis. Samples should be submitted either as a tissue block or as freshly cut 
unstained slides ( minimum of 10 slides cut to a thickness of 5 microns). Frozen tissue will 
also be accepted from biomarker analysis. 


36 
 
Send the slides to 
 
Attn: Helen Molina 
H. Lee Moffitt Cancer Center 
12902 Magnolia Dr. 
Tampa, FL 33612 
 
Methods: 
NGS Testing 
The Molecular Pathology laboratory has validated a CLIA grade NGS test using the TruSight 
Tumor panel on the MiSeq instrument ( Illumina, USA). The TruSight Tumor panel targets 26 
genes commonly mutated in solid tumors using 174 amplicons covering 21 kb of the genome. 
The CLIA grade test also includes a custom analysis platform created by PierianDX called 
Clinical Genomicist’s Workstation. The analysis platform has been validated to set cutoff 
criteria for detection of SNPs at a minimum variant allele frequency of 3% at a depth of 1000 
reads and the cutoff criteria for detection of indels at a minimum variant allele frequency of 10% 
and a depth of 2000 reads. Custom reports for each sample are generated programmatically to 
define variants of clinical significance from a manually curated database based on the literature. 


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38 
 
 
9. Safety monitoring and reporting 
 
9.1 
Adverse Events 
 
9.1.1 Definitions 
Information about  all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. An adverse event is any 
undesirable sign, symptom or medical condition occurring after starting study drug (or 
therapy) even if the event is not considered to be related to study drug (or therapy). Study 
drug (or therapy) includes the drug (or therapy) under evaluation, and any reference or 
placebo drug (or therapy) given during any phase of the trial. 
• if it is unclear what study treatment includes, list all drug(s), other therapies, changes to 
existing therapy, diagnostic procedure, etc., that are specified by the protocol 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment. Abnormal laboratory values or 
test results constitute adverse events only if they  induce clinical signs or symptoms or 
require therapy, and are recorded. 
 
A serious adverse event is  an undesirable sign, symptom or medical condition which: 
1. Is fatal or life-threatening. 
2. Requires or prolongs hospitalization. 
3. Results in persistent or significant disability/incapacity. 
4. Constitutes a congenital anomaly or a birth defect. 
5. Is medically significant, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
In addition to the above, fatal events will also be documented by a separate death form, 
instead of reporting them as AE CTCAE grade. 
 
Events not considered to be serious adverse events are hospitalizations for the: 
• Routine  treatment  or  monitoring  of  the  studied  indication,  not  associated  with 
any  deterioration in condition. 
• Treatment, which was elective or pre-planned, for a pre-existing condition that did 
not  worsen. 
• Treatment  on  an  emergency,  outpatient  basis  for  an  event  not  fulfilling  any  of 
the  definitions of serious given above and not resulting in hospital admission. 
Pregnancy, although not itself a serious adverse event, should also be reported on a serious 
adverse event form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects or congenital abnormalities. 
 
Only the serious adverse event occurring after the patient has started taking the study 
medication, and until 4 weeks after the patient has stopped study  participation must be 
reported. The period  after discontinuing study drug may be extended if there is a strong 


39 
 
suspicion that the drug has  not yet been eliminated. 


 
 
9.2 
Safety Monitoring 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology and blood chemistry parameters and 
regular physical examinations. Adverse events will be evaluated continuously throughout the 
study. Safety and tolerability will be assessed according to the NIH/NCI Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v4.0) that is available 
at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
The PMC monitors its assigned ongoing research protocols for: adverse event reporting, data and 
safety monitoring, and internal audit findings. The PMC, upon review of any agenda item, may 
approve the study for continuation, require revisions, suspend or close a protocol. 
 
Investigators of studies which are designated to be reviewed by the PMC for data and safety 
monitoring, shall provide a statistical report of the study’s progress and summary of adverse 
events and deviations based on the phase of the study and the associated risk of the study or more 
often if applicable. The external DSMB (if applicable) shall forward its report for high-risk 
studies designated for external review at least annually or more often if applicable. 
 
Internal Monitoring Plan 
 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be reviewed routinely according to Moffitt’s Monitoring Policies. 
 
 
9.3 
Reporting of Serious Adverse Events 
All AEs will be recorded on the appropriate CRF. The Investigator will also identify the date 
of onset, date of resolution, seriousness, outcome, and the relationship to study drug. Every 
effort should be made to determine the cause of each AE and whether or not it is related to the 
study drug. The relationship of the AE to the study drug must be rated and recorded following 
the guidelines outlined in the CTCAE v4.0. All the AEs will be reviewed by the Principal 
Investigator of the study. The 5 categories for AE grading are: 
 
1. Not related 
2. Not Likely 
3. Possible 
4. Probable 
5. Definite 
 
The definition of serious adverse events (SAEs) is given in Section 8.1.1. 
Each serious adverse event must be followed up until resolution or stabilization, by submission 
of updated reports to the designated person. An isolated laboratory abnormality that is assigned 
grade 4, according to CTC definition, is not reportable as an SAE; unless the investigator 
assesses that the event meets standard ICH criteria for an SAE. CTC grade 4 baseline laboratory 
abnormalities that are part of the disease profile should not be reported as an SAE, specifically 
 
40 


41 
 
when they are allowed or not excluded by the protocol inclusion/exclusion criteria. 
 
To ensure patient safety, each serious adverse event must be reported to the PI and to the sponsor 
expeditiously. Moffitt Cancer Center and all participating sites will report SAEs by completing 
an SAE report in OnCore, the electronic data capture system. The SAE must be reported by 
email (affiliate.research@moffitt.org) to the MCRN within 2 working days. If applicable, the site 
should also follow protocol guidelines for additional reporting to government agencies. 
 
When required, and according to local law and regulations, serious adverse events must be 
reported to the Ethics Committee and Regulatory Authorities. 
 
All serious adverse events should be reported to Bayer within 24 hours.  In the event of such an 
event, the investigator should refer to the Pharmacovigilance section of the contract for reporting 
procedures. 
 
The Investigator may report serious adverse events (SAEs) as described below. 
 
A MedWatch form available at http://www.fda.gov/medwatch/ 
 
All reports shall be sent electronically to: 
 
Electronic Mailbox: 
DrugSafety.GPV.US@bayer.com 
 
Facsimile: 
(973) 709-2185 
 
Address: 
Global Pharmacovigilance - USA 
Mail only: 
Bayer HealthCare Pharmaceuticals Inc. 
P.O. Box 1000 
Montville, NJ 07045-1000 
 
Address: 
340 Changebridge Road 
FDX or UPS only 
Pine Brook, NJ  07058 
 
Reports for all Bayer products can also be phoned in via our Clinical Communications 
Dept: 
 
Phone: 
1-888-765-3203-2937 
 
 
9.4 
Pregnancies 
The investigator must report to Bayer any pregnancy occurring in a study subject, or in his 
partner, during the subject’s participation in this study.  If there is concern for pregnancy after 
the study drug has been started, pregnancy test is required. The report should be submitted 
within the same timelines as an SAE, although a pregnancy per se is not considered an SAE. 
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
abnormal outcome of the mother or the child should be reported. 


42 
 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar 
information on course and outcome, subject to the partner’s consent. 
For all reports, the forms provided are to be used. 
 
 
10. Statistical Methods and Data Analysis 
 
10.1 Study Design and Sample Size Calculation 
Based on the ABC-01 and ABC-02 studies, PFS6 for the combination of gemcitabine and 
cisplatin are 57.1% and 59.3%, respectively. 1,2 Therefore, we will consider PFS6 of 57% not 
warranting further study, and we will use PFS6 of 77% as a promising result to pursue further 
study. A single-arm Simon’s two-stage minimax design with one-sided 10% type I error and 
80% power is used. Fourteen eligible patients will be enrolled in the first stage. If 8 or more 
patients (≥57%) are alive and progression free at 6 months, an additional 11 patients will be 
enrolled in the second stage. If 18 or more (≥72%) of 25 patients are alive and progression free at 
6 months, the study regimen would be worthy of further investigation. If the combination therapy 
is actually effective, then there is a 0.2 probability of concluding that it is not. If the therapy is 
actually not effective, there is a 0.09 probability of concluding that it is. 
. Unless there are toxicity concerns, the study will not close during this interim assessment. 
 
For the correlative endpoint, we will collect at least 10 unstained slides of tumor tissue to evaluate PTEN 
expression by IHC and NGS mutational panel. This will be collected within 28 days of the initiation of 
cycle 1. 
 
10.2 Analysis of Primary Endpoint 
The primary endpoint of the trial is to evaluate the progression free survival at 6 months (PFS6) 
using 
the 
combination 
of 
gemcitabine 
+ 
cisplatin 
with 
copanlisib 
in 
advanced 
cholangiocarcinoma. Same primary endpoint was used in ABC-01 trial.2 Progression-free 
survival (PFS) will be calculated from study entry to documented disease progression, death 
from any cause, or date of last follow-up, whichever comes first. The final analysis will be 
conducted to estimate PFS6 if the second stage is open and the follow-up duration for all subjects 
who are alive and progression free exceeds 6 months. 
 
 
10.3 Analysis of Secondary and Exploratory Endpoints 
The secondary endpoints for efficacy evaluation include the response (CR + PR), overall survival (OS), 
and progression-free survival (PFS). The Kaplan-Meier method and the Cox proportional hazards 
regression model will be used for OS and PFS. The response rate along with 95% confidence interval 
will be reported, based on the exact binomial distribution. The logistic regression model will be used to 
explore the association with the response. A two-sided p-value of <0.05 will be considered 
statistically significant. No multiplicity adjustment is planned. The two sample t-test or Wilcoxon rank- 
sum test will be used to evaluate the correlation between PTEN expression and response. Data 
transformation such as log-transformation of PTEN expression may be considered to apply for parametric 
approaches if necessary. The Anderson-Darling test will be used to test normality assumption. 


43 
 
11. Data Recording 
 
11.1 Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations.  Once this essential information has been provided to the patient and the investigator 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB-approved consent 
form. 
 
11.2 Required Documentation 
Before the study can be initiated at any site, the site will be required to provide regulatory 
documentation to the Moffitt Clinical Research Network (MCRN) at Moffitt Cancer Center. 
Sites must provide a copy of their informed consent to the MCRN Coordinating Center for 
review and approval prior to submission of any documents to the site’s IRB. Any changes      
re- quested by the site’s IRB must be provided to the MCRN staff for review and approval prior 
to resubmission to the IRB. 
 
The MCRN Coordinating Center must receive the following trial specific documents either by 
hardcopy, fax, or email before a site can be activated for any trial: 
 
1. IRB Approval Letter that includes the protocol version and date 
2. FDA Related Forms 1572/1571/310 as appropriate 
3. Signed Protocol Title Page 
4. IRB Approved Consent Form 
5. Site Delegation of Responsibility Log 
6. Signed  Financial Interest Disclosure Forms (principal and sub investigators) 
7. Updated  Investigator/Personnel  documents  (CVs,  licenses,  Conflict  of  Interest 
statements, etc.) as needed 
8. Updated Laboratory Documents (certifications, normal ranges, etc.) as 
needed 
9. Signed protocol specific Task Order 
 
A study initiation visit (or teleconference) will be held prior to the start of any study related 
activity at the site. Attendance i s  r e q u i r e d  f o r :  
• The site PI and appropriate research staff 
• Moffitt PI and MCRN research coordinator 


44 
 
 
The requirements of the protocol and all associated procedures and processes will be 
reviewed and agreed upon prior to the activation of the study. T h e  M C R N  u t iliz e s  th e 
E D C  s ys t e m ,  O nC o r e .  OnCore training will be scheduled if indicated with the 
appropriate staff from the site. 
 
11.3 Registration Procedures 
All subjects must be registered with the MCRN Coordinating Center to be able to participate 
in a trial. The participating site must fax or email the completed study specific eligibility 
checklist and registration forms, supporting documents and signed informed consent to the 
Coordinating Center. Unsigned or incomplete forms will be returned to the site. Once 
documents are received, the MCRN Research Coordinator will review them to confirm 
eligibility and to complete the registration process. If eligibility cannot be confirmed, the 
research coordinator will query the site for clarification or additional documents as needed. 
Subjects failing to meet all study eligibility requirements will not be registered and will 
be unable to participate in the trial. 
 
Upon completion of registration, the MCRN Research Coordinator will provide the 
participating site with the study sequence number and randomization information, if indicated. 
Within 24-48 hours after registration, it is the site’s responsibility to: 
 
• Enter the demographic and on-study patient information into the OnCore 
database. 
• Order investigational agent(s) if indicated per protocol. 
 
It is the responsibility of the participating Investigator or designee to inform the subject of 
the research treatment plan and to conduct the study in compliance with the protocol as 
agreed upon with Moffitt Cancer Center and approved by the site’s IRB. 
 
To register a patient send the completed signed eligibility checklist along with supporting 
documentation to the MCRN via email at affiliate.research@moffitt.org or via fax at 813-745- 
5666, Monday through Friday between 8:00AM and 5:00PM(EST). 
 
11.4 Data Management and Monitoring/Auditing 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database. Regulatory documents and 
case report forms will be monitored internally according to Moffitt Cancer Center Monitoring 
Policies. Monitoring will be performed regularly to verify data is accurate, complete, and 
verifiable from source documents; and the conduct of the trial is in compliance with the currently 
approved protocol/ amendments, Good Clinical Practice (GCP), and applicable regulatory 
requirements. 
 
To obtain access to OnCore, the site research staff must complete an OnCore Access 
Request Form and a Moffitt Information Systems Confidentiality Agreement (provided in the 
MCRN Handbook at the site initiation visit) and submit both to the Coordinating Center. Once 
the completed forms are received, the site coordinator will receive VPN access, 
logon/password, and information on how to access OnCore using the VPN. The MCRN 


 
Coordinating Center will provide OnCore training to the site once initial access is granted and 
on an ongoing basis, as needed. 
 
11.5 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol. 
 
11.6 Emergency Modifications 
Moffitt Cancer Center and Affiliate investigators may implement a deviation from, or a change 
of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior H. Lee 
Moffitt Cancer Center or their respective institution’s approval/favorable opinion. 
 
For Institutions Relying on Moffitt’s IRB: 
 
For any such emergency modification implemented, a Moffitt IRB modification form must be 
completed by Moffitt Research Personnel within five (5) business days of making the change. 
 
For Institutions Relying on Their Own IRB: 
 
For Affiliate investigators relying on their own instution’s IRB, as soon as possible after the 
modification has been made, the implemented deviation or change and the reasons for it should 
be submitted to Moffitt Principal Investigator for agreement and the Affiliate institution’s IRB 
for review and approval. (Once IRB’s response is received, this should be forwarded to the 
MCRN.) 
 
11.7 Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that all study documentation pertaining 
to the conduct of a clinical trial must be retained by the study investigator. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International Conference 
on Harmonization (ICH) region.  In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
 
11.8 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
 
45 


 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub- 
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered into the eCRFs. Periodically, monitoring visits will 
be conducted and the Principal Investigator will provide access to his/her original records to 
permit verification of proper entry of data. At the completion of the study, all eCRFs will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 
12. Ethical and Legal Aspects 
 
12.1 Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the investigator abide by Good Clinical Practice (GCP) 
guidelines and under the guiding principles detailed in the Declaration of Helsinki. The study 
will also be carried out in keeping with applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating centers 
before start of the study, according to GCP, local laws, regulations and organizations. When 
necessary, an extension, amendment or renewal of the EC/IRB approval must be obtained and 
also forwarded to Bayer. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol. 
Modifications to the study protocol will not be implemented by the investigator without 
discussion and agreement by Bayer. However, the investigator may implement a deviation from, 
or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects without prior 
IEC/IRB/Bayer approval/favorable opinion. As soon as possible, the implemented deviation or 
change, the reasons for it and, if appropriate, the proposed protocol amendment should be 
submitted to the IEC/IRB/head of medical institution. Any deviations from the protocol must be 
explained and documented by the investigator. 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub- 
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and properly documented. 
 
12.2 Subject Information and Consent 
Each subject/legal representative or proxy consenter will have ample time and opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without 
 
46 


47 
 
any disadvantage and without having to provide reasons for this decision. 
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study. Additionally, the 
investigator and other information provider (if any) will personally sign and date the form.  The 
subject/legal representative or proxy consenter will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed consent 
was obtained prior to these procedures. 
1. If the patient is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of Bayer and the investigator). 
This is to be documented by a signature from the informing physician as well as by a 
signature from the witness. 
2. For minors or adults under legal protection, consent shall be given by the legal guardian(s). 
The consent of a minor or adult under legal protection shall also be requested where such a 
person is able to express his/her own will. His/her refusal or the withdrawal of his/her 
consent may not be disregarded. 
3. In emergency situations, when prior consent of the patient is not possible, the consent of the 
patient’s legal representative(s) or proxy consenter, if present, should be requested. The 
patient should be informed about the study as soon as possible and his/her consent to 
continue the study should be requested. 
The informed consent form and any other written information provided to subjects/legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to the 
protocol that necessitates a change to the content of the subject information and/or the written 
informed consent form.  The investigator will inform the subject/legal representative or proxy 
consenter of changes in a timely manner and will ask the subject to confirm his/her participation 
in the study by signing the revised informed consent form. Any revised written informed 
consent form and written information must receive the IEC/IRB`s approval/favorable opinion in 
advance of use. 
 
12.3 Publication policy 
Bayer recognizes the right of the investigator to publish results upon completion of the study. 
However, the investigator must send a draft manuscript of the publication or abstract to Bayer at 
least thirty days in advance of submission in order to obtain approval prior to submission of the 
final version for publication or congress presentation. This will be reviewed promptly and 
approval will not be withheld unreasonably.  In case of a difference of opinion between Bayer 
and the investigator(s), the contents of the publication will be discussed in order to find a 
solution which satisfies both parties. All relevant aspects regarding data reporting and 
publication will be part of the contract between Bayer and the investigator/institution. 
The Principal Investigator should ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov. 


48 
 
12.4 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 


49 
 
13. References 
 
1. 
Valle J, Wasan H, Palmer DH, et al: Cisplatin plus gemcitabine versus 
gemcitabine for biliary tract cancer. N Engl J Med 362:1273-81, 2010 
2. 
Valle JW, Wasan H, Johnson P, et al: Gemcitabine alone or in combination with 
cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract 
tumours: a multicentre randomised phase II study - The UK ABC-01 Study. Br J Cancer 
101:621-7, 2009 
3. 
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 
63:11-30, 2013 
4. 
Shaib YH, Davila JA, McGlynn K, et al: Rising incidence of intrahepatic 
cholangiocarcinoma in the United States: a true increase? J Hepatol 40:472-7, 2004 
5. 
Jemal A, Siegel R, Xu J, et al: Cancer statistics, 2010. CA Cancer J Clin 60:277- 
300, 2010 
6. 
Jarnagin WR, Fong Y, DeMatteo RP, et al: Staging, resectability, and outcome in 
225 patients with hilar cholangiocarcinoma. Ann Surg 234:507-17; discussion 517-9, 2001 
7. 
Faris JE, Zhu AX: Targeted therapy for biliary tract cancers. J Hepatobiliary 
Pancreat Sci 19:326-36, 2012 
8. 
Jain RK: Vascular and interstitial barriers to delivery of therapeutic agents in 
tumors. Cancer Metastasis Rev 9:253-66, 1990 
9. 
Kim RD, Alberts SR, Renshaw GF, et al: Phase 1 dose escalation study of 
copanlisib (BAY 80-6946) in combination with gemcitabine or gemcitabine-cisplatin in 
advanced cancer patients. J Clin Oncol 32:5s, 2014 (suppl; abstr 2610), , 2014 
10. 
Javle MM, Yu J, Khoury T, et al: Hepatology: Akt expression may predict 
favorable prognosis in cholangiocarcinoma. (vol 21, pg 1394, 2006). Journal of Gastroenterology 
and Hepatology 22:145-145, 2007 
11. 
Chen YB, Xu JM, Jhala N, et al: Fas-mediated apoptosis in cholangiocarcinoma 
cells is enhanced by 3,3'-diindolylmethane through inhibition of AKT signaling and FLICE-like 
inhibitory protein. American Journal of Pathology 169:1833-1842, 2006 
12. 
Lee D, Do IG, Choi K, et al: The expression of phospho-AKT1 and phospho- 
MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic 
cholangiocarcinomas. Modern Pathology 25:131-139, 2012 
13. 
Xu XL, Kobayashi S, Qiao WH, et al: Induction of intrahepatic cholangiocellular 
carcinoma by liver-specific disruption of Smad4 and Pten in mice. Journal of Clinical 
Investigation 116:1843-1852, 2006 
14. 
Dokduang H, Juntana S, Techasen A, et al: Survey of activated kinase proteins 
reveals potential targets for cholangiocarcinoma treatment. Tumour Biol 34:3519-28, 2013 
15. 
Tanno S, Yanagawa N, Habiro A, et al: Serine/threonine kinase AKT is 
frequently activated in human bile duct cancer and is associated with increased radioresistance. 
Cancer Research 64:3486-3490, 2004 
16. 
Leelawat K, Narong S, Udomchaiprasertkul W, et al: Inhibition of PI3K increases 
oxaliplatin sensitivity in cholangiocarcinoma cells. Cancer Cell International 9, 2009 
17. 
Menakongka A, Suthiphongchai T: Involvement of PI3K and ERK1/2 pathways 
in hepatocyte growth factor-induced cholangiocarcinoma cell invasion. World Journal of 
Gastroenterology 16:713-722, 2010 
18. 
Yothaisong S, Dokduang H, Techasen A, et al: Increased activation of PI3K/AKT 


50 
 
signaling pathway is associated with cholangiocarcinoma metastasis and PI3K/mTOR inhibition 
presents a possible therapeutic strategy. Tumor Biology 34:3637-3648, 2013 
19. 
Chung JY, Hong SM, Choi BY, et al: The Expression of Phospho-AKT, Phospho- 
mTOR, and PTEN in Extrahepatic Cholangiocarcinoma. Clinical Cancer Research 15:660-667, 
2009 
20. 
Serra V, Markman B, Scaltriti M, et al: NVP-BEZ235, a dual PI3K/mTOR 
inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K 
mutations. Cancer Research 68:8022-8030, 2008 
21. 
Mueller A, Bachmann E, Linnig M, et al: Selective PI3K inhibition by BKM120 
and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human 
gastrointestinal cancer cell lines. Cancer Chemotherapy and Pharmacology 69:1601-1615, 2012 
22. 
Gonzalez-Angulo AM, Blumenschein GR: Defining biomarkers to predict 
sensitivity to PI3K/Akt/mTOR pathway inhibitors in breast cancer. Cancer Treatment Reviews 
39:313-320, 2013 
23. 
Liu N, Haegebarth A, BulCl, et al: BAY 80-6946, a highly potent and efficacious 
class I PI3K inhibitor, induces complete tumor regression or tumor stasis in rat xenograft tumor 
models with PIK3CA mutant or PTEN deletion. AACR 101st Annual Meeting 2010:Apr 17-21, 
2010; Washington, DC, 2010 


51 
 
14. Appendix 
 
RECIST Criteria for Measuring Tumor Response Antitumor Effect 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (Eisenhauer et al., 2009). Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment withcopanlisib. 
 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable for 6 month PFS (primary endpoint): Patients will need to complete at least 3 cycles 
and restaging scan to be considered evaluable for the primary endpoint. Non evaluable patients 
for the primary endpoint will need to be replaced 
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT scan, MRI or 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might be considered 
measurable if the lesion has increased in size since the radiation. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 


52 
 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly should be 
selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow- 
up. 
 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g., for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 


53 
 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be 
performed with breath-hold scanning techniques, if possible. 
 
 
Response Criteria Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression.) 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the Principal Investigator. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 


54 
 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
Progression-Free Survival (PFS) 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
55