A Phase III, Randomized, Double-blind, Controlled Multicenter Study of Intravenous PI3K Inhibitor Copanlisib in Combination With Standard Immunochemotherapy Versus Standard Immunochemotherapy in Patients With Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)
Phase: PHASE3
Conditions: Lymphoma, Non-Hodgkin
Sponsor: Bayer

 
Document Type: 
Clinical Study Protocol 
Official Title: 
A Phase III, randomized, double-blind, controlled, multicenter study 
of intravenous PI3K inhibitor copanlisib in combination with 
standard immunochemotherapy versus standard 
immunochemotherapy in patients with relapsed indolent non-
Hodgkin’s lymphoma (iNHL) - CHRONOS-4 
NCT Number: 
NCT02626455 
Document Date: 
21 MAR 2023 
 

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Cover page of integrated protocol 
 
A Phase III, randomized, double-blind, controlled, multicenter study of intravenous 
PI3K inhibitor copanlisib in combination with standard immunochemotherapy versus 
standard immunochemotherapy in patients with relapsed indolent non-Hodgkin’s 
lymphoma (iNHL) - CHRONOS-4 
This protocol version is an integration of the following documents / sections: 
• Original protocol, Version 1.0, dated 23 JUN 2015 
• Amendment 01 (global amendment described in Section 15.1) 
forming integrated protocol Version 2.0, dated 01 SEP 2015 
• Amendment 02 (global amendment described in Section 15.2) 
forming integrated protocol Version 3.0, dated 18 JUL 2016 
• Amendment 03 (global amendment described in Section 15.3) 
forming integrated protocol Version 4.0, dated 30 MAR 2017 
• Amendment 05 (global amendment described in Section 15.4) 
forming integrated protocol Version 5.0, dated 14 AUG 2017 
• Amendment 06 (global amendment described in Section 15.5) 
forming integrated protocol Version 6.0, dated 25 SEP 2018 
• Amendment 08 (global amendment described in Section 15.6) 
forming integrated protocol Version 7.0, dated 14 AUG 2019 
• Amendment 09 (global amendment described in Section 15.7) 
forming integrated protocol Version 8.0, dated 21 MAR 2023 
Amendments not included in the consecutive numbering of amendments are 
local amendments described in Section 15.8 (Country-specific requirements) of this 
integrated global protocol. These are: 
• 
Amendment 04, dated 11 MAY 2017 
(local amendment valid for Japan only) 
• Amendment 07, dated 12 MAR 2019  
(local amendment valid for Germany only) 
 

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1. 
Title page  
A Phase III, randomized, double-blind, controlled, multicenter study of intravenous 
PI3K inhibitor copanlisib in combination with standard immunochemotherapy versus 
standard immunochemotherapy in patients with relapsed indolent non-Hodgkin’s 
lymphoma (iNHL) - CHRONOS-4 
Short title 
Phase III study of copanlisib with standard 
immunochemotherapy in relapsed iNHL 
Acronym 
CHRONOS-4 
Test drug: 
BAY 80-6946 / copanlisib 
Study purpose: 
Dose-finding, efficacy and safety of copanlisib 
Clinical study phase: 
III 
Date: 
21 MAR 2023 
EudraCT no.: 
EU CT no.: 
2015-001088-38 
2023-504155-27-00 
Version no.: 8.0 
Sponsor’s study no.: 
BAY 80-6946 / 17833  
 
 
Sponsor: 
Non-US: Bayer AG, D-51368 Leverkusen, Germany 
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer 
Boulevard, P.O. Box 915, Whippany, NJ 07981-0915, USA 
Sponsor’s medical expert: 
 
  
100 Bayer Boulevard P.O. Box 915 
Whippany, NJ  07981-0915 USA  
Phone: 
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the Trial Master File 
(TMF) and available on request. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation. Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation, or its use for any other purpose, without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
PPD
PPD
PPD

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Signature of principal investigator 
 
The signatory agrees to the content of the final clinical study protocol as presented. 
 
Name: 
 
Affiliation:  
Date: 
 
 
Signature:  
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file. 

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2. 
Synopsis  
Title 
A Phase III, randomized, double-blind, controlled, multicenter study of 
intravenous PI3K inhibitor copanlisib in combination with standard 
immunochemotherapy versus standard immunochemotherapy in patients 
with relapsed indolent non-Hodgkin’s lymphoma (iNHL) - CHRONOS-4 
Short title 
Phase III study of copanlisib with standard immunochemotherapy in 
relapsed iNHL 
Acronym 
CHRONOS-4  
Clinical study phase 
III 
Rationale 
The usual front-line treatment for iNHL consists of the anti-CD20-MAb 
rituximab given together with an alkylating agent (bendamustine, R-B), or 
a chemotherapy combination containing an alkylating agent (CHOP). 
While the R-B combination is preferred in the US, R-CHOP remains the 
first option in the EU. In second line, patients with R-sensitive disease (the 
large majority) would usually receive R-B following R-CHOP, and R-
CHOP following R-B.  
Copanlisib has activity as monotherapy in patients with relapsed or 
refractory iNHL (shown in the results of studies 12781 and 16349 Part A). 
In addition, based on the current metabolism knowledge of each compound 
there is low potential for drug-drug interactions between copanlisib and the 
combination partners. It can therefore be expected that copanlisib would 
increase the activity of standard 1st and 2nd line immunochemotherapy (R-
CHOP/R-B) in patients with relapsed, R-sensitive iNHL warranting re-
treatment with a rituximab based regimen. The clinical benefit should be 
expressed in a prolonged progression-free survival (PFS), and an improved 
quality of life in comparison to the standard immunochemotherapy. 
Study objective(s) 
Safety run-in part 
Primary objective is to determine: 
• The recommended phase III dose (RP3D) of copanlisib in combination 
with standard immunochemotherapy (rituximab and bendamustine [R-
B] or rituximab, cyclophosphamide, doxorubicin, vincristine and 
prednisone [R-CHOP]) to be used in the subsequent phase III part of 
the study 
The secondary objectives are to evaluate (for patients that stay on 
treatment after Cycle 1): 
• Radiological and clinical indicators of treatment efficacy 
• Safety and tolerability of copanlisib in combination with R-B/R-CHOP  
Further objectives are to evaluate: 
• Pharmacokinetics (PK) of copanlisib  
• Biomarkers of efficacy, mode-of-action-related effect, safety, and / or 
the pathomechanism of the disease 
 

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Phase III part (randomized, controlled trial) 
Primary objective is: 
• To evaluate whether copanlisib in combination with standard 
immunochemotherapy, is superior to standard immunochemotherapy in 
prolonging PFS, in patients with relapsed indolent non-Hodgkin’s 
lymphoma, who have received at least one, but at most three lines of 
treatment, including rituximab, and/or rituximab biosimilars, and/or 
anti-CD20 monoclonal antibody -based immunochemotherapy and 
alkylating agents, and for whom the combination of rituximab with 
either bendamustine or CHOP represents a valid therapeutic option 
Secondary objectives are to evaluate: 
• Other radiological and clinical indicators of treatment efficacy 
(objective response rate (ORR), duration of response (DOR), complete 
response rate (CRR), time to progression (TTP), time to next anti-
lymphoma treatment (TTNT), disease control rate (DCR), overall 
survival (OS, 5 year survival rate), time to improvement and the time to 
deterioration in disease-related symptoms - physical) 
• Safety and tolerability of copanlisib in combination with R-B/R-CHOP 
Further objectives are to evaluate: 
• PK of copanlisib 
• Biomarkers of efficacy, mode-of-action-related effect, safety, and / or 
the pathomechanism of the disease 
Test drug(s) 
Copanlisib  
Name of active ingredient 
Copanlisib / BAY 80-6946  
Dose(s) 
Safety run-in part:  
Dosing of copanlisib: 
• in combination with R-B: Starting dose of 45 mg and, if well tolerated, 
60 mg, on Days 1, 8 and 15 of each 28-day cycle or  
• in combination with R-CHOP: Starting dose of 45 mg and, if well 
tolerated, 60 mg, on Days 1 and 8 of each 21-day cycle. 
After Cycle 1, dose reductions to 45 mg (if starting dose is 60 mg) and 
further to 30 mg are possible, should toxicities occur  
Phase III part:  
Dosing of copanlisib: 
• in combination with R-B: Starting dose of 60 mg  
(the determined recommended phase III dose [RP3D] of copanlisib) or 
• in combination with R-CHOP: Starting dose of 60 mg or 45 mg, 
depending on the dose level determined in the safety run-in part  
(RP3D of copanlisib).  
Dose reductions to 45 mg (if RP3D is 60 mg) and further to 30 mg are 
possible, should toxicities occur.  
 

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Copanlisib/Placebo (C/P) dosing 
Cycle 
length (d) 
D1 
D8 
D15 
Cycles 1-6 
 
 
 
 
C/P in combination with R-B 
28 
X 
X 
X 
C/P in combination with R-CHOP 
21 
X 
X 
 
 
 
 
 
 
Cycle 7 onwards 
 
 
 
 
C/P monotherapy 
28 
X 
X 
X 
 
Dosing of immunochemotherapy (Cycles 1-6): 
R-B will be administered every 4 weeks (q4w) as follows: 
• Rituximab intravenous (IV) 375 mg/m2 body surface on Day 1 (D1)  
• Bendamustine IV 90 mg/m2 body surface on D1 and D2  
R-CHOP will be administered q3w as follows: 
• Rituximab IV 375 mg/m2 body surface on D2  
• Cyclophosphamide IV 750 mg/m2 body surface on D2  
• Doxorubicin IV 50 mg/m2 body surface on D2  
• Vincristine IV 1.4 mg/m2 body surface (maximum dose 2.0 mg) on D2  
• Prednisone/prednisolone 100 mg daily orally (PO) from D2 to D6  
Route of administration 
IV infusion 
Duration of treatment 
Combination therapy (copanlisib/placebo with R-B or R-CHOP) will be 
administered for a maximum of 6 cycles (C1-C6). Copanlisib/placebo 
(study drug) monotherapy will be administered from C7 onwards.  
Combination therapy (copanlisib/placebo with R-B or R-CHOP) will be 
continued until the occurrence of progressive disease (PD) (per central 
independent blinded radiology review) as defined in Recommendations for 
Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification (Owen Criteria for 
patients with Waldenström macroglobulinemia [WM]), or clinical 
progression (e.g. Eastern Cooperative Oncology Group [ECOG] 
performance status of ≥ 3), unacceptable toxicity occurs, or until another 
criterion is met for withdrawal from study or up to 6 cycles whichever 
comes first. 
Copanlisib/placebo monotherapy (C7 onwards) will be continued until the 
occurrence of PD (per central independent blinded radiology review) as 
defined in The Lugano Classification (Owen Criteria for patients with 
WM), or clinical progression (e.g. ECOG performance status of ≥ 3), 
unacceptable toxicity occurs, or another criterion is met for withdrawal 
from study or until completion of monotherapy, whichever comes first.  
The maximum duration of treatment with copanlisib/placebo is 12 months 
(including combination therapy and monotherapy). The duration of 
treatment in the safety run-in part will be the same as in the phase III part.  

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Reference drug(s) 
Placebo  
Name of active ingredient 
Not applicable 
Dose(s) 
Safety run-in part: Not applicable 
Phase III part:  
• 
In combination with R-B: Dummy 60 mg. 
• 
In combination with R-CHOP: Dummy 60 mg or 45 mg, 
depending on the copanlisib dose level determined in the safety 
run-in part (RP3D of copanlisib).  
Dummy dose reductions to 45 mg (if starting dose is 60 mg) and further to 
30 mg are possible, should toxicities occur.  
The dosing of placebo during the combination therapy and monotherapy is 
the same as for copanlisib, please see above.  
Dosing of immunochemotherapy: 
Same as in combination with copanlisib, please see above. 
Route of administration 
IV infusion 
Duration of treatment 
Same as for copanlisib, please see above. 
Background treatment 
Immunochemotherapy: rituximab plus B (R-B) or rituximab plus CHOP 
(R-CHOP) for Cycles 1-6. For administration, see above. 
Indication 
Relapsed indolent non-Hodgkin’s lymphoma 

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Diagnosis and main criteria for 
inclusion /exclusion 
Main criteria for inclusion:  
• 
Histologically confirmed diagnosis of CD20 positive iNHL with 
histological subtype limited to: 
o 
Follicular lymphoma (FL) G1, G2, or G3a 
o 
Small lymphocytic lymphoma (SLL) with absolute lymphocyte 
count <5x109/L at study entry 
o 
Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia 
(LPL/WM) 
o 
Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal) 
• 
Patients must have relapsed (recurrence after complete response or 
presented progression after partial response) or progressed after at least 
one but at most three prior lines of therapy, including rituximab, and/or 
rituximab biosimilars, and/or anti-CD20 monoclonal antibody (e.g. 
obinutuzumab) -based immunochemotherapy and alkylating agents (if 
given concomitantly is considered one line of therapy). A previous 
regimen is defined as one of the following: at least 2 months of single-
agent therapy (less than 2 months of therapy with single agent 
rituximab, or rituximab biosimilars, or anti-CD20 monoclonal antibody 
can be considered a previous regimen in the case the patient responded 
to it); at least 2 consecutive cycles of polychemotherapy; autologous 
transplant; radioimmunotherapy. Previous exposure to other PI3K 
inhibitors (except copanlisib) is acceptable provided there is no 
resistance (resistance defined as no response (response defined as 
partial response [PR] or complete response [CR]) at any time during 
therapy, or PD after any response (PR/CR) or after stable disease 
within 6 months from the end of the therapy with a PI3K inhibitor  
.  
• 
Non-WM patients must have at least one bi-dimensionally measurable 
lesion (that has not been previously irradiated) according to the Lugano 
Classification. For patients with splenic MZL this requirement may be 
restricted to splenomegaly alone since that is usually the only 
manifestation of measurable disease. 
• 
Patients affected by WM who do not have at least one bi-dimensionally 
measurable lesion in the baseline radiologic assessment must have 
measurable disease defined as presence of immunoglobulin M (IgM) 
paraprotein with a minimum IgM level ≥ 2 × upper limit of normal and 
positive immunofixation test.  
• 
Male or female patients ≥ 18 years of age. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 
• 
Life expectancy of at least 3 months. 
• 
Availability of fresh tumor tissue and/or archival tumor tissue at 
Screening. 
• 
Adequate baseline laboratory values as assessed within 7 days before 
starting study treatment.  
• 
Left ventricular ejection fraction ≥ 50%.  
Main criteria for exclusion: 
• 
Histologically confirmed diagnosis of follicular lymphoma (FL) grade 
3b or transformed disease, or chronic lymphocytic leukemia. In patients 
with clinical suspicion of transformed disease, a fresh biopsy is 
recommended. 
• Rituximab, or rituximab biosimilars, or anti-CD20 monoclonal 

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antibody (e.g. obinutuzumab) resistance at any line of therapy 
(resistance defined as lack of response, or progression within 6 months 
of the last date of rituximab, or rituximab biosimilars, or anti-CD20 
monoclonal antibody administration, including maintenance with these 
drugs). 
• 
HbA1c > 8.5% at Screening. 
• 
History or concurrent condition of interstitial lung disease and/or 
severely impaired lung function (as judged by the investigator). 
• 
Known lymphomatous involvement of the central nervous system. 
• 
Known history of human immunodeficiency virus (HIV) infection. 
• 
Hepatitis B (HBV) or C (HCV) infection. Patients positive for hepatitis 
B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will 
be eligible if they are negative for HBV-DNA, these patients should 
receive prophylactic antiviral therapy as per rituximab label. Patients 
positive for anti-HCV antibody will be eligible if they are negative for 
HCV-RNA. 
• 
Cytomegalovirus (CMV) infection. Patients who are CMV PCR 
positive at baseline will not be eligible. CMV PCR test is considered 
positive if, the result can be interpreted as a CMV viremia according to 
local standard of care (SOC). 
• 
Congestive heart failure > New York Heart Association (NYHA) 
class 2. 
• 
Uncontrolled hypertension despite optimal medical management (per 
investigator’s assessment). 
Study design 
The study has two parts: safety run-in / dose finding part and double-blind, 
controlled, two-arm phase III part.  
Safety run-in part: 
The study will start with a safety run-in part, where the recommended dose 
of copanlisib in combination with standard immunochemotherapy to be 
administered in phase III part (RP3D) will be determined.  
During the safety run-in part two treatment combinations (copanlisib with 
R-B and copanlisib with R-CHOP), will be tested at two dose levels of 
copanlisib (first dose level 45 mg, second dose level, 60 mg) for safety and 
tolerability. Data Monitoring Committee (DMC) will review all data 
available from the safety run-in part and evaluate whether protocol 
specified treatment combinations are safe and tolerable. When the RP3D of 
copanlisib in combination with R-CHOP or R-B has been defined and 
confirmed by sponsor, principal investigator, and DMC, enrolment in the 
phase III part will start. 
The safety run-in part of this study was completed for copanlisib in 
combination with R-B and in combination with R-CHOP. The DMC 
reviewed the safety data and decided that copanlisib dose of 60 mg plus R-
B or plus R-CHOP is a recommended and approved dose to be used in the 
phase III part.  
Patients recruited into the safety run-in part are treated in an unblinded 
fashion and will thus not be evaluated as part of the phase III part. 
Phase III part: 
This is a double-blind, two-arm phase III study in patients with relapsed, 
rituximab-sensitive iNHL to evaluate efficacy and safety of copanlisib in 

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combination with standard immunochemotherapy (R-B or R-CHOP) in 
comparison to standard immunochemotherapy (R-B or R-CHOP). The 
patients must have relapsed after at least one but at most three previous 
lines of therapy; previous treatments must have included rituximab, and/or 
rituximab biosimilars, and/or anti-CD20 monoclonal antibody -based 
immunochemotherapy and alkylating agents; and patients must not have a 
lack of response, or progression within 6 months of the last date of 
rituximab, or rituximab biosimilars, or anti-CD20 monoclonal antibody 
administration. 
Patients will be stratified by: prior to base treatment regimen 
(R-chemotherapy to R-B, R-B to R-CHOP, and R-B to R-B), 
NHL histology (FL vs. other iNHL) and duration of progression-free 
interval on the last rituximab, or rituximab biosimilars, or anti-CD20 
monoclonal antibody containing regimen (6-12 months vs. >12 months).  
 
Patients who meet the eligibility criteria will be randomly assigned in a 1:1 
ratio to one of the double-blinded treatment arms:  
• Arm 1: copanlisib plus R-CHOP or R-B 
• Arm 2: placebo plus R-CHOP or R-B  
During the phase III part, study DMC will review the unblinded data per 
DMC charter of all patients treated up to that time point (or as needed) to 
ensure that patients are not exposed to undue risk. The investigators, 
patients and the sponsor will remain blinded. 
The study (applicable to safety run-in part and phase III part) is composed 
of the following periods:  
• Screening 
• Treatment 
• Safety-follow-up (patients who discontinue study treatment due to 
progressive disease [PD]) 
• Active follow-up (patients who complete 12 months’ study treatment 
without PD or discontinue study treatment for any other reason than 
PD)  
• Survival follow-up. 
Methodology 
The primary safety variable in the safety run-in part is occurrence of dose-
limiting toxicities in Cycle 1. The primary efficacy variable in the phase III 
part is PFS (for the definition, see below). 
Efficacy will be assessed based on radiological tumor evaluations of neck, 
chest, abdomen and pelvis by using IV [and oral, if indicated, per Imaging 
Manual] contrast enhanced computed tomography/magnetic resonance 
imaging (CT/MRI) and positron emission tomography-computed 
tomography (PET-CT) as a preferred imaging modality. During the 
treatment phase as well as during the active follow-up period, radiological 
tumor assessment will be performed every 12 weeks (±7 days) from 
Cycle 1 Day 1 during Year 1 and 2; every 24 weeks (±7 days) during Year 
3, 4 and 5; and every 24 weeks (±14 days) beyond Year 5. Tumor scans 
will be evaluated locally at the study site and by the blinded independent 
central review. The response assessment will be based on the Lugano 
Classification. For patients with WM, response assessment will be done 
according to the Owen criteria and CT/MRI, if applicable.  
Bone marrow biopsy will be mandatory at Screening and will be sent to 

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central pathology review after local bone marrow assessment. If the 
baseline biopsy is positive for lymphoma infiltration, it will be mandatory 
to perform a local bone marrow biopsy assessment again to confirm the 
first complete response (CR) and also at the investigator’s discretion if 
clinical evaluation leads to suspicion of bone marrow infiltration without 
further radiological findings.  
All patients will be followed off study for overall survival at 3-monthly 
(± 14 days) intervals during the survival follow-up period (up to 10 years 
after the last patient started study treatment), independent of the patient’s 
reason for study termination, except for patients who object to follow-up 
data collection. Patients or their healthcare providers will be contacted 
either in person or by telephone. 
Safety evaluations will be done at Screening, during treatment, and at the 
Safety follow-up visit. During the Active follow-up period, adverse events 
(AEs) and serious adverse events (SAEs) assessed as related to study 
procedures by the investigator will be reported.  
Sparse blood samples for pharmacokinetic (PK) analysis will be collected 
from all patients to characterize the PK of copanlisib and rituximab. Fresh 
tumor tissue and/or archival tumor tissue must be available at Screening for 
central pathology review for an exploratory analysis. In addition, pre-
treatment tumor tissue samples will be collected when available to 
investigate or identify biomarkers that may be predictive of copanlisib 
effects/efficacy in iNHL and to contribute to better understanding the 
disease. Plasma samples for biomarker analyses will be collected from all 
patients at baseline and during treatment. 
In the phase III part, “time to deterioration” and “time to improvement” in 
disease-related symptoms - physical (DRS-P) will be assessed using the 
FLymSI-18 questionnaire. Other efficacy variables are FLymSI-18 
subscale and total score analyses.  
Type of control 
Inactive control: placebo (phase III part) 
Data Monitoring Committee 
Yes  
Number of patients 
Safety run-in part: maximum 2 × 6 patients per combination evaluable for 
the primary endpoint. 
Phase III part: approximately 520 (including FL and other iNHL).  
Patients recruited into the safety run-in part will not be evaluated as part of 
the phase III part. 
Primary variable(s) 
Safety run-in part: The primary safety variable is the occurrence of DLTs 
in Cycle 1.  
Phase III part: The primary efficacy variable is PFS, defined as the time 
(in days) from randomization to PD as assessed by blinded independent 
central review or death from any cause (if no progression is documented).  
Time point/frame of 
measurement for primary 
variable(s) 
Safety run-in part: Approximately 6-8 months 
Phase III part: The study duration for primary completion of PFS is at 
least 52 months with approximately 33 months enrollment period and at 
least 19 months follow-up. 

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Plan for statistical analysis 
Safety run-in part: Safety data will be summarized or listed per dose 
level.  
Phase III part:  
The analysis of efficacy will be done in the full analysis set (FAS), which 
is defined as all patients who are randomized. The primary analysis of PFS 
will be based on tumor assessments of the central independent blinded 
review, and will be performed using a log rank test, stratified by the same 
factors as the stratification factors in randomization.  
Kaplan-Meier estimates and survival curves will also be presented by 
treatment group, as well as the hazard ratios with 95% confidence intervals. 
No formal interim analysis of the primary efficacy endpoint, PFS, is 
planned. 
The sample size calculation is based on the number of events required to 
detect a 50% increase in median PFS time in the FAS, and assumes a 
median PFS of 24 months under the control treatment, a 1-sided alpha of 
0.025, a randomization ratio of 1:1 between the two treatment groups and 
estimates that approximately 280 PFS events in the iNHL popoulation 
(progression based on blinded independent central review or death from 
any cause, whichever occurs first) are required to detect this increase with 
approximately 92% power. The expectation is that approximately 280 PFS 
events in the FAS population will also provide sufficient power for an 
additional PFS analysis in the FL histology population. 
The “time to event” secondary efficacy variables (overall survival, time to 
progression, duration of response, time to next anti-lymphoma treatment, 
time to deterioration and time to improvement in disease-related symptoms 
- physical (DRS-P) of at least 3 points) will be analyzed in a similar way to 
PFS. 
The objective response rate (ORR) and complete response rate (CRR) will 
be compared between the two treatments using a Cochran-Mantel-Haenszel 
test with the randomization factors as strata.  
DCR and CRR will be analyzed in a manner similar to ORR. 
The analysis of safety will be descriptive only (no statistical test will be 
applied). 
 

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Table of contents 
Cover page of integrated protocol .......................................................................................... 1 
1. 
Title page ............................................................................................................................ 2 
Signature of principal investigator ......................................................................................... 3 
2. 
Synopsis .............................................................................................................................. 4 
Table of contents ..................................................................................................................... 13 
Table of tables ......................................................................................................................... 20 
Table of figures ....................................................................................................................... 20 
List of abbreviations ............................................................................................................... 21 
Definitions of terms ................................................................................................................ 25 
3. 
Introduction ..................................................................................................................... 26 
3.1 
Background .................................................................................................................... 26 
3.1.1 
Copanlisib (BAY 80-6946) ........................................................................................ 27 
3.1.2 
Clinical experience ..................................................................................................... 28 
3.2 
Rationale of the study .................................................................................................... 30 
3.3 
Benefit-risk assessment .................................................................................................. 30 
4. 
Study objectives ............................................................................................................... 31 
4.1 
Safety run-in part ........................................................................................................... 31 
4.2 
Phase III part .................................................................................................................. 31 
5. 
Study design ..................................................................................................................... 32 
5.1 
Design overview ............................................................................................................ 32 
5.2 
Safety run-in part ........................................................................................................... 35 
5.3 
Phase III ......................................................................................................................... 37 
5.3.1 
Primary variable ......................................................................................................... 38 
5.3.2 
Justification of the design ........................................................................................... 38 
5.3.3 
End of study ................................................................................................................ 39 
6. 
Study population ............................................................................................................. 39 
6.1 
Inclusion criteria ............................................................................................................ 39 
6.2 
Exclusion criteria ........................................................................................................... 41 
6.3 
Justification of selection criteria .................................................................................... 44 
6.4 
Withdrawal of patients from study ................................................................................ 44 
6.4.1 
Withdrawal ................................................................................................................. 44 
6.4.1.1 
Withdrawal criteria .................................................................................................. 44 
6.4.1.2 
Screening failure ..................................................................................................... 46 
6.4.1.3 
Dropout .................................................................................................................... 48 
6.4.1.4 
General procedures .................................................................................................. 48 
6.4.2 
Replacement ............................................................................................................... 48 
6.5 
Patient identification ...................................................................................................... 49 
7. 
Treatments ....................................................................................................................... 49 

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7.1 
Treatments to be administered ....................................................................................... 49 
7.2 
Identity of study treatment ............................................................................................. 49 
7.3 
Treatment assignment .................................................................................................... 51 
7.3.1 
Safety run-in part ........................................................................................................ 51 
7.3.2 
Phase III part ............................................................................................................... 51 
7.4 
Dosage and administration ............................................................................................. 52 
7.4.1 
Definition of dose-limiting toxicities (DLTs) ............................................................ 54 
7.4.2 
Dose modification ...................................................................................................... 55 
7.4.2.1 
Safety run-in part and phase III part ........................................................................ 56 
7.4.2.2 
Hematological toxicity ............................................................................................ 56 
7.4.2.3 
Non-hematological toxicity ..................................................................................... 57 
7.4.3 
Treatment of toxicities ................................................................................................ 60 
7.4.3.1 
Management of transient post-infusion glucose increases that can occur with 
copanlisib ................................................................................................................ 61 
7.4.3.2 
Management of hyperlipidemia .............................................................................. 62 
7.4.3.3 
Treatment of blood pressure increases associated with copanlisib ......................... 63 
7.4.3.4 
Treatment of vomiting and diarrhea ........................................................................ 63 
7.4.3.5 
Treatment of dermatologic toxicity ......................................................................... 63 
7.4.3.6 
Guidance for monitoring and prophylaxis of opportunistic infection (OI) ............. 64 
7.4.3.6.1 
Monitoring guidelines for OI ............................................................................... 64 
7.4.3.6.2 
Prophylaxis of OI ................................................................................................. 65 
7.5 
Blinding ......................................................................................................................... 66 
7.6 
Drug logistics and accountability................................................................................... 67 
7.7 
Treatment compliance .................................................................................................... 67 
8. 
Non-study therapy ........................................................................................................... 67 
8.1 
Prior and concomitant therapy ....................................................................................... 67 
8.1.1 
Prohibited concomitant therapy .................................................................................. 68 
8.1.2 
Permitted concomitant therapy ................................................................................... 68 
8.2 
Post-study therapy .......................................................................................................... 69 
9. 
Procedures and variables ............................................................................................... 70 
9.1 
Tabular schedule of evaluations .................................................................................... 70 
9.2 
Visit descriptions ........................................................................................................... 81 
9.2.1 
Visit descriptions in safety run-in part and phase III part .......................................... 81 
9.2.1.1 
Screening period ...................................................................................................... 81 
9.2.1.2 
Treatment period ..................................................................................................... 83 
9.2.1.2.1 
Treatment – Cycle 1 ............................................................................................. 84 
9.2.1.2.2 
Treatment – From Cycle 2 to Cycle 6 .................................................................. 87 
9.2.1.2.3 
Treatment – From Cycle 7 onwards (during copanlisib/placebo 
monotherapy) ....................................................................................................... 92 
9.2.1.3 
Tumor assessments .................................................................................................. 94 
9.2.1.4 
End-of-treatment visit ............................................................................................. 95 
9.2.1.5 
Follow-up periods ................................................................................................... 97 
9.2.1.5.1 
Safety follow-up ................................................................................................... 97 
9.2.1.5.2 
Active follow-up .................................................................................................. 97 

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9.2.1.5.3 
Survival follow-up ............................................................................................... 98 
9.3 
Population characteristics .............................................................................................. 99 
9.3.1 
Demographic .............................................................................................................. 99 
9.3.2 
Medical history ........................................................................................................... 99 
9.3.3 
Other baseline characteristics ..................................................................................... 99 
9.4 
Efficacy ........................................................................................................................ 100 
9.4.1 
Primary efficacy variable.......................................................................................... 100 
9.4.2 
Radiological tumor assessments ............................................................................... 100 
9.4.3 
Tumor assessments in patients with WM ................................................................. 102 
9.5 
Pharmacokinetics / pharmacodynamics ....................................................................... 102 
9.5.1 
Sampling ................................................................................................................... 102 
9.5.2 
Analysis .................................................................................................................... 103 
9.6 
Safety ........................................................................................................................... 103 
9.6.1 
Adverse events .......................................................................................................... 103 
9.6.1.1 
Definitions ............................................................................................................. 103 
9.6.1.2 
Classifications for adverse event assessment ........................................................ 105 
9.6.1.2.1 
Seriousness ......................................................................................................... 105 
9.6.1.2.2 
Intensity .............................................................................................................. 105 
9.6.1.2.3 
Causal relationship ............................................................................................. 105 
9.6.1.2.4 
Action taken with study treatment ..................................................................... 107 
9.6.1.2.5 
Other specific treatment(s) of adverse events .................................................... 107 
9.6.1.2.6 
Outcome ............................................................................................................. 107 
9.6.1.3 
Assessments and documentation of adverse events .............................................. 107 
9.6.1.4 
Reporting of serious adverse events ...................................................................... 108 
9.6.1.5 
Expected adverse events ........................................................................................ 109 
9.6.1.6 
Adverse events of special safety interest ............................................................... 109 
9.6.2 
Pregnancies ............................................................................................................... 109 
9.6.3 
Further safety ............................................................................................................ 110 
9.6.3.1 
Laboratory ............................................................................................................. 110 
9.6.3.2 
Glucose measurement on treatment days .............................................................. 111 
9.6.3.3 
Physical examinations ........................................................................................... 112 
9.6.3.3.1 
Complete physical examinations ....................................................................... 112 
9.6.3.3.2 
Brief physical examination and status check ..................................................... 113 
9.6.3.4 
Vital signs .............................................................................................................. 113 
9.6.3.5 
Blood pressure measurement on treatment days ................................................... 113 
9.6.3.6 
12-lead ECG .......................................................................................................... 114 
9.6.3.7 
Cardiac function .................................................................................................... 114 
9.6.3.8 
ECOG performance status ..................................................................................... 114 
9.6.3.9 
Reporting of medical device failures .................................................................... 114 
9.7 
Other procedures and variables .................................................................................... 115 
9.7.1 
Biomarker investigations .......................................................................................... 115 
9.7.2 
Quality of life questionnaire – Phase III part only ................................................... 116 
9.8 
Appropriateness of procedures / measurements .......................................................... 117 
10. Statistical methods and determination of sample size ............................................... 118 

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10.1 General considerations ................................................................................................. 118 
10.2 Analysis sets ................................................................................................................ 118 
10.3 Variables and planned statistical analyses ................................................................... 118 
10.3.1 Safety run-in part ...................................................................................................... 118 
10.3.2 Phase III part ............................................................................................................. 119 
10.3.2.1 Population characteristics ...................................................................................... 119 
10.3.2.2 Primary efficacy variable ...................................................................................... 119 
10.3.2.3 Secondary efficacy variables ................................................................................. 119 
10.3.2.4 Other efficacy variables ........................................................................................ 121 
10.3.2.5 Primary efficacy analysis ...................................................................................... 121 
10.3.2.6 Secondary efficacy analysis .................................................................................. 122 
10.3.2.7 Confirmatory statistical test strategy ..................................................................... 122 
10.3.2.8 Section removed by amendment 3. ........................................................................ 122 
10.3.2.9 Other efficacy analysis .......................................................................................... 122 
10.3.2.10 Subgroup analysis ................................................................................................. 122 
10.3.2.11 Safety variables and analysis ................................................................................. 122 
10.3.2.12 Further variables and their analysis ....................................................................... 123 
10.3.3 Missing data / drop-outs ........................................................................................... 123 
10.4 Determination of sample size....................................................................................... 123 
10.5 Planned interim analyses ............................................................................................. 124 
11. Data handling and quality assurance .......................................................................... 124 
11.1 Data recording .............................................................................................................. 124 
11.2 Monitoring ................................................................................................................... 125 
11.3 Data processing ............................................................................................................ 126 
11.4 Missing data ................................................................................................................. 126 
11.5 Audit and inspection .................................................................................................... 127 
11.6 Archiving ..................................................................................................................... 127 
12. Premature termination of the study ............................................................................ 127 
13. Ethical and legal aspects ............................................................................................... 128 
13.1 Investigator(s) and other study personnel .................................................................... 128 
13.2 Funding and financial disclosure ................................................................................. 129 
13.3 Ethical and legal conduct of the study ......................................................................... 129 
13.4 Patient information and consent .................................................................................. 130 
13.5 Publication policy and use of data ............................................................................... 132 
13.6 Compensation for health damage of patients / insurance ............................................ 132 
13.7 Confidentiality ............................................................................................................. 132 
14. Reference list .................................................................................................................. 133 
15. Protocol amendments .................................................................................................... 135 
15.1 Amendment 1 ............................................................................................................... 135 
15.1.1 Overview of changes to the study............................................................................. 135 
15.1.1.1 Modification 1 – language regarding reconstitution, dilution and storage of 
copanlisib modified ............................................................................................... 135 
15.1.1.2 Modification 2 – language on exclusion criterion clarified .................................. 135 

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15.1.1.3 Modification 3 –dosing criteria modified .............................................................. 136 
15.1.1.4 Modification 4 – adjustment of biomarker sampling time point ........................... 136 
15.1.1.5 Modification 5 – administrative change ................................................................ 136 
15.1.2 Changes to the protocol text ..................................................................................... 136 
15.2 Amendment 2 ............................................................................................................... 136 
15.2.1 Overview of changes ................................................................................................ 136 
15.2.1.1 Modification 1 – update of clinical experience with copanlisib ........................... 136 
15.2.1.2 Modification 2 – definition on rituximab-sensitive iNHL removed ..................... 137 
15.2.1.3 Modification 3 – allowed prior immunochemotherapy regimens and 
treatment assignment clarified .............................................................................. 137 
15.2.1.4 Modification 4 – update to inclusion criteria ........................................................ 138 
15.2.1.5 Modification 5 – modification of exclusion criterion related to arterial 
hypertension .......................................................................................................... 138 
15.2.1.6 Modification 6 – exclusion of patients based on plasma glucose levels 
removed ................................................................................................................. 138 
15.2.1.7 Modification 7 – inclusion of patients with chronic HCV or HBV infection 
and prophylaxis for HBV and monitoring of HBV and HCV added .................... 139 
15.2.1.8 Modification 8 – clarification of exclusion criterion related to proteinuria .......... 139 
15.2.1.9 Modification 9 – language on corticosteroid therapy clarified ............................. 139 
15.2.1.10 Modification 10 – prior treatment with copanlisib prohibited .............................. 140 
15.2.1.11 Modification 11 – updated guidance for management and monitoring of 
glucose increases ................................................................................................... 140 
15.2.1.12 Modification 12 – updated guidance for management and monitoring of 
blood pressure increases ........................................................................................ 141 
15.2.1.13 Modification 13 – fasting requirement for lipid panels revised ............................ 141 
15.2.1.14 Modification 14 – clarification of tumor response language ................................ 141 
15.2.1.15 Modification 15 – guidance for management of toxicities added ......................... 142 
15.2.1.16 Modification 16 – usage of verapamil and diltiazem amended ............................ 142 
15.2.1.17 Modification 17 – guidance for metformin use updated ....................................... 143 
15.2.1.18 Modification 18 – recommendation for prednisone administration removed ....... 143 
15.2.1.19 Modification 19 – reference to the Declaration of Objection form removed ........ 143 
15.2.1.20 Modification 20 – changes in statistical language ................................................ 143 
15.2.1.21 Modification 21 – modification of replacement language .................................... 143 
15.2.1.22 Modification 22 – central pathology review of bone marrow samples clarified... 144 
15.2.1.23 Modification 23 – modification of coagulation language ..................................... 144 
15.2.1.24 Modification 24 – monitoring guidelines for opportunistic infection (OI) 
prophylaxis ............................................................................................................ 144 
15.2.1.25 Modification 25 – clarification of reporting period of adverse events during 
safety follow-up ..................................................................................................... 145 
15.2.1.26 Modification 26– modification of absolute neutrophil count (ANC) criteria 
for copanlisib dosing ............................................................................................. 145 
15.2.1.27 Modification 27– modification of withdrawal criterion and dose adjustment 
in case of non-infectious pneumonitis ................................................................... 145 
15.2.1.28 Modification 28 – change in the timing of the IVRS/IWRS randomization 
transaction ............................................................................................................. 145 

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15.2.1.29 Modification 29 – clarification on DLT language and transition from safety 
run-in phase to phase III part ................................................................................. 146 
15.2.1.30 Modification 30– modification to criteria for CT-based response assessment ..... 146 
15.2.1.31 Modification 31 – other clarifications and corrections ......................................... 146 
15.2.2 Changes to the protocol text ..................................................................................... 147 
15.3 Amendment 3 ............................................................................................................... 148 
15.3.1 Overview of changes ................................................................................................ 148 
15.3.1.1 Modification 1 – change in the inclusion criterion: prior therapies ...................... 148 
15.3.1.2 Modification 2 – combination with study drug and R-B allowed for patients 
who have received prior treatment with R-B ........................................................ 148 
15.3.1.3 Modification 3 – changes in the statistical analysis and sample size .................... 148 
15.3.1.4 Modification 4 – RP3D for copanlisib in combination with R-B determined ...... 149 
15.3.1.5 Modification 5 – changes in exclusion criteria ..................................................... 149 
15.3.1.6 Modification 6 – patients experiencing disease progression may continue on 
treatment ................................................................................................................ 149 
15.3.1.7 Modification 7 – changes to the safety evaluation schedule ................................. 149 
15.3.1.8 Modification 8 – clarifications related to bone marrow assessments .................... 150 
15.3.1.9 Modification 9 – clarifications to the OI guidance ............................................... 150 
15.3.1.10 Modification 10 – clarification to urinalysis examinations (dipstick) .................. 150 
15.3.1.11 Modification 11 – changes and clarifications to radiological tumor 
assessments ............................................................................................................ 151 
15.3.1.12 Modification 12 – reporting of medical device failures of imported and non-
approved third-party device .................................................................................. 151 
15.3.1.13 Modification 13 – change in the PK sampling schedule ....................................... 151 
15.3.1.14 Modification 14 – a minimum length for the screening period added .................. 152 
15.3.1.15 Modification 15 – changes based on drug-drug interaction data .......................... 152 
15.3.1.16 Modification 16 – possibility to use paper QoL questionnaire in case ePRO 
device is not available ........................................................................................... 152 
15.3.1.17 Modification 17 – other clarifications and corrections ......................................... 152 
15.3.2 Changes to the protocol text ..................................................................................... 153 
15.4 Amendment 5 ............................................................................................................... 154 
15.4.1 Overview of changes ................................................................................................ 154 
15.4.2 Changes to the protocol text ..................................................................................... 154 
15.5 Amendment 6 ............................................................................................................... 155 
15.5.1 Overview of changes ................................................................................................ 155 
15.5.1.1 Modification 1 – updated guidance for management of glucose increases ........... 155 
15.5.1.2 Modification 2 – updated guidance for blood pressure measurements ................. 155 
15.5.1.3 Modification 3 – updated guidance for dermatologic and hematological 
toxicity ................................................................................................................... 156 
15.5.1.4 Modification 4 – clarifications/modifications of inclusion criteria ....................... 156 
15.5.1.5 Modification 5 – clarifications/modifications of exclusion criteria ...................... 156 
15.5.1.6 Modification 6 – clarification of the administration of study treatment ............... 157 
15.5.1.7 Modification 7 – clarification of time window for assessments ........................... 157 
15.5.1.8 Modification 8 – modification of the laboratory assessments ............................... 157 
15.5.1.9 Modification 9 – clarification of tumor assessments ............................................ 158 

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15.5.1.10 Modification 10 – clarification of stratification factor related to treatment-
free interval ........................................................................................................... 158 
15.5.1.11 Modification 11 – administrative change .............................................................. 159 
15.5.1.12 Modification 12 – changes to prohibited concomitant therapy ............................. 159 
15.5.1.13 Modification 13 – other clarifications and corrections ......................................... 159 
15.5.2 Changes to the protocol text ..................................................................................... 160 
15.6 Amendment 8 ............................................................................................................... 160 
15.6.1 Protocol amendment summary of changes table ...................................................... 160 
15.6.2 Changes to the protocol text ..................................................................................... 161 
15.7 Amendment 9 ............................................................................................................... 161 
15.7.1 Protocol amendment summary of changes table ...................................................... 161 
15.7.2 Changes to the protocol text ..................................................................................... 163 
15.8 Country-specific requirements ..................................................................................... 163 
15.8.1 Japan ......................................................................................................................... 164 
15.8.1.1 Overview of Changes ............................................................................................ 164 
15.8.1.1.1 
Modification 1 – Japanese safety run-in (J-SRI) cohort added .......................... 164 
15.8.1.2 Changes to the protocol text .................................................................................. 164 
15.8.1.2.1 
Section 2. Synopsis ............................................................................................ 165 
15.8.1.2.2 
List of abbreviations .......................................................................................... 169 
15.8.1.2.3 
Section 3.3 Benefit-risk assessment ................................................................... 169 
15.8.1.2.4 
Section 4.1.1 Japanese safety run-in (J-SRI) cohort .......................................... 169 
15.8.1.2.5 
Section 5.1 Design overview ............................................................................. 170 
15.8.1.2.6 
Section 5.2.1 Japanese safety run-in (J-SRI) cohort .......................................... 171 
15.8.1.2.7 
Section 5.3 Phase III .......................................................................................... 173 
15.8.1.2.8 
Section 5.3.1 Primary variable ........................................................................... 173 
15.8.1.2.9 
Section 5.3.2 Justification of the design ............................................................ 174 
15.8.1.2.10 Section 6 Study population ................................................................................ 175 
15.8.1.2.11 Section 6.4.1.1 Withdrawal criteria ................................................................... 175 
15.8.1.2.12 Section 6.4.1.3 Drop out .................................................................................... 175 
15.8.1.2.13 Section 6.4.2 Replacement ................................................................................. 175 
15.8.1.2.14 Section 7.1 Treatments to be administered ........................................................ 176 
15.8.1.2.15 Section 7.3.1 Safety run-in part ......................................................................... 176 
15.8.1.2.16 Section 7.4 Dosage and administration .............................................................. 176 
15.8.1.2.17 Section 7.4.1 Definition of dose-limiting toxicities (DLTs) .............................. 177 
15.8.1.2.18 Section 7.4.2 Dose modification ........................................................................ 177 
15.8.1.2.19 Section 7.4.2.1 Safety run-in part and phase III part ......................................... 178 
15.8.1.2.20 Section 7.4.2.2 Hematological toxicity .............................................................. 179 
15.8.1.2.21 Section 7.5 Blinding ........................................................................................... 179 
15.8.1.2.22 Section 9.1 Tabular schedule of evaluations ...................................................... 179 
15.8.1.2.23 Section 9.2.1 Visit descriptions in safety run-in part and phase III part ............ 180 
15.8.1.2.24 Section 9.5.1 Sampling ...................................................................................... 180 
15.8.1.2.25 Section 9.5.2 Analysis ........................................................................................ 180 
15.8.1.2.26 Section 10.1 General considerations .................................................................. 181 
15.8.1.2.27 Section 10.2 Analysis sets .................................................................................. 181 
15.8.1.2.28 Section 10.3.1 Safety run-in part ....................................................................... 182 

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15.8.1.2.29 Section 10.3.2.11 Further variables and their analysis ...................................... 182 
15.8.1.2.30 Section 10.4 Determination of sample size ........................................................ 182 
15.8.2 Germany ................................................................................................................... 183 
15.8.2.1 Overview of Changes ............................................................................................ 183 
15.8.2.1.1 
Modification 1 – Revised blood glucose withdrawal criterion .......................... 183 
15.8.2.1.2 
Modification 2 – New Sponsor Personnel ......................................................... 183 
15.8.2.2 Changes to the protocol text .................................................................................. 183 
15.8.2.2.1 
Section  1. Title page ......................................................................................... 184 
15.8.2.2.2 
Section  Signature of the sponsor’s medically responsible person .................... 184 
15.8.2.2.3 
Section 6.4.1.1 Withdrawal criteria ................................................................... 184 
15.8.2.2.4 
Section 7.4.2.3 Non-hematological toxicity ...................................................... 185 
15.8.2.2.5 
Section 13 Investigator(s) and other study personnel ........................................ 185 
16. Appendices ..................................................................................................................... 186 
16.1 CYP3A4 inhibitors and inducers ................................................................................. 186 
16.2 Section removed by amendment 3. .............................................................................. 186 
16.3 ECOG Performance Status .......................................................................................... 186 
16.4 New York Heart Association (NYHA) Functional Classification ............................... 187 
16.5 Evaluation of tumor response ...................................................................................... 188 
16.6 Quality of life questionnaire: FLymSI-18 section removed ........................................ 191 
16.7 Glomerular filtration rate ............................................................................................. 192 
16.8 The average Glycemic Index of common foods derived from multiple studies by 
different laboratories section removed ......................................................................... 193 
 
Table of tables 
Table 7–1 Dosing of copanlisib/placebo during the study ....................................................... 52 
Table 7–2 Laboratory test criteria for Day 1 dose of subsequent cycles ................................. 54 
Table 7–3 Dose levels of copanlisib and placebo .................................................................... 56 
Table 7–4 Dose modification of copanlisib/placebo for hematological toxicity ..................... 57 
Table 7–5 Dose modification of copanlisib/placebo for non-hematological toxicity .............. 57 
Table 7–6 Dose modification of copanlisib/placebo for dermatologic toxicity ....................... 58 
Table 7–7 Dose adjustment in cases of non-infectious pneumonitis (NIP) ............................. 58 
Table 7–8 Dose modification of study treatment for arterial hypertension ............................. 60 
Table 7–9 Management of transient post-infusion glucose increases ...................................... 61 
Table 7–10 Guidance on treatment of skin toxicities ............................................................... 64 
Table 9–1 Study flow chart – Screening and copanlisib + R-B combination therapy ............. 71 
Table 9–2 Study flow chart – Screening and copanlisib + R-CHOP combination therapy ..... 73 
Table 9–3 Study flow chart – copanlisib/placebo monotherapy (from C7 onwards) .............. 75 
Table 9–4 PK assessments in the safety run-in part and phase III part .................................. 103 
 
Table of figures 
Figure 5-1 Study periods .......................................................................................................... 33 
Figure 5-2 Overall study design of the safety run-in part ........................................................ 36 

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Figure 5-3 Overall study design of Phase III part .................................................................... 38 
 
List of abbreviations 
 
5PS 
5 point score for the visual assessment of PET-CT 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event 
AESI 
adverse event of special interest 
AITL 
angioimmunoblastic T-cell lymphoma 
AKT 
protein kinase B 
ALCL 
anaplastic large cell lymphoma 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
B 
bendamustine hydrochloride 
BCRP 
breast cancer resistance protein 
bid 
twice daily 
BL 
baseline 
BMT 
bone marrow transplant 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
cycle 
CBC 
complete blood count 
CD 
cluster of differentiation 
CD20 
B lymphocyte antigen CD20 
CHOP 
cyclophosphamide, hydroxydoxorubicin, vincristine, prednisone 
c-KIT 
proto-oncogen c-KIT (CD117) 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum drug concentration 
CMR 
complete metabolic response 
CMV 
cytomegalovirus 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
CRR 
complete response rate 
CRu 
complete response unconfirmed 
CT 
computed tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
observed drug concentration measured at the end of the dosing interval 
CXR 
chest X-ray 
CYP3A4 
cytochrome P450 isoenzyme 3A4 
D 
Day 
DDI 
drug-drug-interaction 
dL 
deciliter 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 

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DOR 
duration of response 
DPD 
dihydropyrimidine dehydrogenase 
DPP4 
dipeptidyl peptidase-4 
DRS-E 
disease-related symptoms – emotional (subscale) 
DRS-P, DRSP 
disease-related symptoms – physical (subscale) 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EOT 
end of treatment 
ePRO 
electronic patient-reported outcome 
EU 
European Union 
EU-CTR 
European Union Clinical Trials Regulation 
EudraCT 
European Union Drug Regulating Authorities Clinical Trial 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FFPE 
formalin-fixed paraffin-embedded 
FL 
follicular lymphoma 
FLymSI-18 
NCCN-FACT Lymphoma Symptom Index-18 
FSH 
follicle stimulating hormone 
FU 
follow-up 
FWB 
functional well-being (subscale) 
GCB 
germinal center B-cell 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GFR 
glomerular filtration rate 
GI 
glycemic index 
GMP 
Good Manufacturing Practice 
GPCR 
G protein-coupled receptor 
GPV 
Global Pharmacovigilance 
Gr 
grade 
Hb 
hemoglobin 
HbA1c 
glycated hemoglobin 
HBcAb 
hepatitis B core antibody 
HBe-Ag 
hepatitis B e antigen 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B Virus 
HCG 
β-human chorionic gonadotropin  
HCV 
hepatitis C Virus 
HCV-Ab 
hepatitis C virus-antibody 
HDL 
high-density lipoprotein 
HER 
human epidermal growth factor receptor  
HIV 
human immunodeficiency virus 
HIV-Ag/Ab 
human immunodeficiency virus-antigen/antibody 
IB 
Investigator’s Brochure 
IC 
informed consent 
IC50 
half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
IDMS 
isotope dilution mass spectroscopy 
IEC 
independent ethics committee 

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IGF-1R 
insulin-like growth factor 1 receptor 
IgM 
immunoglobulin M 
IHC 
immunohistochemistry 
iNHL 
indolent non-Hodgkin’s lymphoma 
INR 
international normalized ratio 
I.P 
improvement in disease-related symptoms – physical 
IRB 
institutional review board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV, i.v. 
intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
IxRS 
interactive voice response system / interactive web response system 
LDH 
lactate dehydrogenase 
LDi 
longest diameter 
LDL 
low-density lipoprotein 
LPL 
lymphoplasmacytic lymphoma 
LVEF 
left ventricular ejection fraction 
M-1 
metabolite 1 
MAb 
monoclonal antibody 
MALT 
mucosa-associated lymphoid tissue 
MATE2K 
multidrug and toxin extrusion protein 2 
MCL 
mantle cell lymphoma 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MLBCL 
mediastinal large B cell lymphoma 
MR 
minor response 
MRI 
magnetic resonance imaging 
mTOR 
mammalian target of rapamycin 
MUGA 
multiple gated acquisition 
MZL 
marginal-zone lymphoma 
N 
total number of patients 
NA, N/A 
not available, not applicable 
NaOH 
sodium hydroxide 
NCCN-FACT  
National Comprehensive Cancer Network – Functional Assessment of Cancer Therapy 
NCI 
National Cancer Institute 
NE 
not evaluable (by investigator / oncologist) 
NHL 
non-Hodgkin’s lymphoma 
NIP 
non-infectious pneumonitis 
NMR 
no metabolic response, equivalent with stable disease 
NMZL 
nodal marginal-zone lymphoma 
NOS 
no other specification 
NYHA 
New York Heart Association 
OI 
opportunistic infection 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PDGFR 
platelet-derived growth factor receptor 
PDK1 
phosphoinositide-dependent kinase 1 
PET  
positron emission tomography  
PET-CT 
positron emission tomography-computed tomography 
PFS 
progression-free survival 
P-gp 
permeability glycoprotein 

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pH 
negative log of hydrogen ion concentration 
PH 
pleckstrin homology 
PI3K 
phosphatidylinositol-3-kinase 
PID 
patient identification number 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha 
PIP3 
phosphatidylinositol-3,4,5-trisphosphate 
PK 
pharmacokinetic(s) 
PKAS 
pharmacokinetic analysis set 
PMD 
progressive metabolic disease, equivalent with progressive disease 
PMDA 
Pharmaceuticals and Medical Devices Agency (Japan) 
PMR 
partial metabolic response 
PO 
orally 
PPD 
product of perpendicular diameters 
PR 
partial response 
PRO 
patient-reported outcomes 
PT 
prothrombin time 
PTCL 
peripheral T-cell lymphoma 
PtdIns-4,5-P2 
phosphatidylinositol-4,5-bisphosphate 
PTEN 
phosphatase and tensin homolog 
PTT 
partial thromboplastin time 
q1w 
weekly 
QoL 
quality of life 
QTcB 
QT interval corrected for heart rate - Bazett 
QTcF 
QT interval corrected for heart rate - Fridericia 
R 
rituximab  
RAVE 
validated electronic data capture system used by Bayer 
R-B 
rituximab and bendamustine 
RBC 
red blood cell count 
R-CHOP 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
R-CVP 
rituximab, cyclophosphamide, vincristine, and prednisone 
RNA 
ribonucleic acid 
RP3D 
recommended phase III dose 
RTK 
receptor tyrosine kinase 
SAC 
Statistical Analysis Center 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SAS 
statistical analysis system 
SCR 
serum creatinine 
SD 
stable disease 
SDi 
shortest diameter 
SFU 
safety follow-up 
SGLT2 
sodium/glucose co-transporter 2 
SLL 
small lymphocytic lymphoma 
SmPC 
Summary of Product Characteristics 
SMZL 
splenic marginal-zone lymphoma 
SOC 
standard of care 
SPD 
sum of the product of the diameters 
StiL 
Study Group Indolent Lymphomas 
SUSAR 
suspected, unexpected, serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TSE 
treatment side effects (subscale) 
TTNT 
time to next anti-lymphoma treatment 
TTP 
time to progression 

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UGT 
uridine diphosphate glucuronosyltransferase 
ULN 
upper limit normal 
UPCR 
urine protein to creatinine ratio 
US 
United States (of America) 
VEGF 
vascular endothelial growth factor 
VGPR 
very good partial response 
VPN 
virtual private network 
vs. 
versus 
WBC 
white blood cell count 
WHO 
World Health Organization 
WHO-DD 
WHO Drug Dictionary 
WM 
Waldenström macroglobulinemia 
WOCBP 
woman of childbearing potential 
W.P 
worsening of disease-related symptoms – physical 
 
 
Definitions of terms 
The tumor response assessment will be done according to the Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: 
The Lugano Classification (14), henceforth referred to as the Lugano classification. 
For patients with WM, response assessment will be done according to the Response 
Assessment in Waldenström macroglobulinemia: update from the VIth International 
Workshop (13), henceforth referred to as the Owen criteria. 

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3. 
Introduction 
3.1 
Background 
Lymphomas are a heterogeneous group of malignancies originating from lymphoid tissues. 
Approximately 85% of all lymphomas are non-Hodgkin’s lymphomas (NHL), with different 
subtypes, clinical features and response to therapy (1). The majority of NHLs arises from B-
lymphocytes (85-90%) and can be characterized by cell of origin, tumor proliferation rate and 
histologic pattern of growth.  
It is estimated that worldwide there were around 356,000 new cases of NHLs in 2008 (2). The 
incidence of NHLs is increasing in many regions, but the frequency of specific histologic 
subtypes of lymphoma varies substantially by geographic region. Over two-thirds of patients 
are 60 years and older (3). 
The non-Hodgkin`s lymphoma have distinct clinical features and can be divided according to 
their clinical behavior in two prognostic groups: indolent NHL and aggressive NHL. 
Aggressive NHLs are characterized by high tumor proliferation, symptomatic disease and 
may evolve into a lethal presentation if not immediately treated. However, with modern 
immunochemotherapy regimens and stem cell transplantation a definitive cure can be reached 
in more than 50% of patients (4). Indolent NHLs have a clinical presentation with few 
symptoms and low tumor proliferation, with a relatively good prognosis and median survival 
rates longer than 10 years, but they are not curable with current available therapeutic options, 
especially for those with advanced stages. They respond to standard chemotherapy regimens 
and to radiotherapy, but their natural history is characterized by remissions and relapses. 
Although most relapses can be generally treated with success, the quality and duration of 
remissions decreases over time. Finally, these lymphomas evolve into refractory disease or 
undergo transformation into an aggressive histologic type with poor prognosis. 
The World Health Organization (WHO) lymphoma classification is based on cell of origin 
and pathophysiology of lymphomas. Indolent NHLs are included in this classification as: 
follicular lymphoma (FL), small lymphocytic lymphoma (SLL), lymphoplasmacytic 
lymphoma (LPL), which is defined as Waldenström’s macroglobulinemia (WM) when 
associated with a monoclonal IgM component and bone marrow involvement, splenic 
marginal-zone lymphoma (SMZL), nodal marginal-zone lymphoma (NMZL) and marginal-
zone lymphoma of mucosa-associated lymphoid tissue (MALT) (5). FL is the second most 
common subtype of NHL (22% of newly diagnosed cases), followed by MALT lymphoma 
(7% of all NHL), while other subtypes are rather rare, with SLL, LPL, SMZL and NMZL 
accounting for 3%, 2%, 2% and 1% of NHL patients, respectively (6, 7). 
Despite the indolent nature of indolent lymphomas, treatment is rarely curative. In 
asymptomatic patients with low-burden disease, a “watch and wait” approach is accepted until 
disease accelerates. When patients require therapeutic intervention, several options are 
available, ranging from single agent therapy (rituximab) to immunochemotherapy. Results 
from a prospective randomized study comparing rituximab + cyclophosphamide, 
hydroxydoxorubicin, vincristine and prednisone (R-CHOP) and CHOP for patients with 
follicular lymphoma demonstrated that R-CHOP reduced the relative risk for treatment 
failure, significantly prolonged the time to treatment failure with significantly higher overall 

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response rate and a prolonged duration of remission in patients with advanced-stage follicular 
lymphoma (8). The alkylating agent bendamustine (B) has shown promising results in first-
line treatment and in relapsed patients. The study conducted by StiL (Study Group Indolent 
Lymphomas) comparing R-B with R-CHOP as first-line therapy for iNHL showed significant 
longer progression-free survival and complete response rate in the R-B group compared to R-
CHOP (9).  
For patients with relapsed disease, the same regimen (rituximab in combination with an 
alternative chemotherapy) can be used. The safety and efficacy of R-CHOP and R-B in this 
setting were evaluated, showing satisfactory rates of complete response and overall survival. 
(10, 11). However, it is known that patients will invariably relapse and further active and 
well-tolerated agents are needed to be used in combination with current therapy.  
The high frequency of phosphoinositide 3-kinase (PI3K) pathway alterations in cancer led 
PI3K to be recognized as an attractive molecular target for novel anti-cancer molecules (12). 
In this setting, PI3K inhibitors could improve outcome by prolonging progression-free 
survival and symptom control, thus delaying the need for subsequent treatment. 
3.1.1 
Copanlisib (BAY 80-6946) 
Phosphatidylinositol-3 kinases (PI3Ks) are downstream of most cancer associated tyrosine 
kinase growth factor receptors (RTKs, such as EGFR/HER, IGF-1R, PDGFR, VEGF, c-KIT 
or Met), cell adhesion molecules (such as integrins), G protein-coupled receptors (GPCRs), 
and oncogenes (such as Ras). Once PI3K is activated, it catalyzes the phosphorylation of 
phosphoinositides to generate PIP3 which binds and activates AKT as well as other Pleckstrin 
homology domain (PH-domain) containing proteins such as PDK1, GEF, etc. Activating 
mutations and/or amplification of PI3K alpha isoform, and the deletion of PI3K antagonizing 
tumor suppressor genes PTEN are frequently found in many tumors, which results in the 
constitutive activation of PI3K/AKT and therefore promoting cell survival, proliferation, 
stress adaptation and metastasis. In addition, activation of PI3K/AKT pathway after radio- 
and/or chemotherapies is also one of the major mechanisms by which tumors escape and 
become resistant to chemo- and radio-therapies. 
Four of these PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ) are categorized as class I 
enzymes because they can use phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) as a 
substrate to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). Elevated PIP3 in 
cellular membranes drives several hallmarks of the cancer phenotype: cell proliferation, 
survival, metabolic reprogramming, and migration. PI3Kα and β are ubiquitous, PI3Kγ and δ 
are expressed mostly in the hematopoietic tissue. 
Copanlisib (BAY 80-6946) is a potent pan-class I inhibitor of PI3K with predominant activity 
against the α and δ isoforms, with in vitro IC50s of 0.5 nM and 0.7 nM, respectively. This 
novel PI3K inhibitor is being developed for the treatment of advanced and refractory 
malignancies. Copanlisib is the active ingredient (free base) of BAY 84-1236, the 
dihydrochloride salt, which for clinical use is formulated as an intravenous (IV) drug product 
solution. 
Copanlisib is primarily metabolized by the cytochrome P450 (CYP) 3A4 with minor 
contribution of CYP1A1. There is a low risk for clinical drug-drug interactions of 

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concomitant drug products through inhibition or induction of CYP enzymes, inhibition of 
uridine diphosphate glucuronosyltransferase (UGT) enzymes and inhibition of 
dihydropyrimidine dehydrogenase (DPD) by copanlisib as a perpetrator. Copanlisib is a weak 
substrate of permeability glycoprotein (P-gp) and of breast cancer resistance protein (BCRP). 
Copanlisib inhibited P-gp- and BCRP-mediated transport in in vitro studies. Furthermore, 
copanlisib is a strong inhibitor of the drug transporter multidrug and toxin extrusion protein 2 
(MATE2K).  
3.1.2 
Clinical experience 
As of 01 FEB 2016, approximately 627 patients with advanced cancer have been treated with 
copanlisib (BAY 80-6946) in Phase 1, Phase 2 and Phase 3 studies. More information on 
clinical experience can be found in the investigator’s brochure (IB) for copanlisib.  
Pharmacokinetics 
Pharmacokinetic (PK) results of copanlisib indicate dose proportional increases in maximum 
concentration (Cmax) and area under the curve (AUC) from time zero to 25 hours (AUC(0-25)) 
in the dose range 0.1 to 1.2 mg/kg with a terminal phase half-life (t1/2) of 38.2 hours at 
0.8 mg/kg (n=28). These data indicate that copanlisib is widely distributed in tissues and 
support a once weekly dosing regimen. No accumulation was observed after once weekly 
dosing when comparing PK on Cycle 1 Days 1 and 15 and Cycle 3 Day 15. No evidence of 
time-dependency in the PK of copanlisib was observed.  
Preliminary results of the human ADME (absorption, distribution, metabolism, and excretion) 
study in healthy volunteers indicate that following a single intravenous dose of 12 mg [14C]-
BAY 80-6946, 88.3% of administered dose, with approx. 66.1% of dose excreted in feces, 
and approximately 22.2% of dose excreted in urine was recovered within 34 days. Copanlisib 
was found to be the primary circulating moiety in plasma as well as in excreta. The amount of 
copanlisib excreted unchanged amounts up to 40 to 50%. The morpholinone derivative M-1 
was found to be the only relevant metabolite. Oxidative biotransformation of copanlisib was 
found to be predominantly mediated by cytochrome P450 isoenzyme 3A4 (CYP3A4) and its 
contribution is about 50% of the metabolic pathway. Therefore, a low drug-drug-interaction 
(DDI) potential due to several clearance pathways is anticipated.  
A preliminary population PK analysis revealed no impact of either body weight, body surface 
area, or other body size-related factors was found on the clearance of copanlisib which was 
the basis to switch to a flat-dose regimen of copanlisib.  
The recommended (Phase II) dose of monotherapy copanlisib is 60 mg given IV weekly (q1w) 
in a 3 weeks on/1 week off schedule based on an evaluation of pharmacokinetic and clinical 
data from ongoing single agent studies.  
Study 12871 
As of 10 FEB 2014, a total of 57 cancer patients were treated in the Phase I monotherapy 
study 12871, with 17 patients in the dose escalation cohorts and 34 patients in the maximum 
tolerated dose expansion cohorts (two cohorts including 9 patients with NHL and 25 patients 
with solid tumors), as well as 6 patients with Type II diabetes mellitus in the diabetic 
expansion cohort at 0.4 mg/kg. The maximum tolerated dose of copanlisib, when 

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administered intravenously (IV) over 1 hour, on Days 1, 8 and 15 of every 28 days given as a 
single agent, was determined to be 0.8 mg/kg, with a maximum dose of 65 mg in order to 
control copanlisib exposure in obese patients.  
Preliminary efficacy data are available from the NHL expansion cohort of Study 12871. A 
total of 6 patients with FL and 3 patients with diffuse large B-cell lymphoma (DLBCL) were 
treated, all initially dosed at 0.8 mg/kg. All 6 patients with FL reached a partial response (PR). 
In 5 of the 6 patients with FL, the partial response (PR) was confirmed by a second 
radiological assessment. As of 01 FEB 2015, 2 patients with FL were still on treatment, both 
having an ongoing PR for 1406 and 935 days.  
Out of the 3 patients with DLBCL, 2 dropped out at the end of Cycle 1 and Cycle 2 due to 
progressive disease. The third patient reached PR as best response but not confirmed by a 
second radiological assessment (unconfirmed PR). This patient discontinued the study during 
Cycle 10 due to a perirectal abscess.  
None of the NHLs tested had PIK3CA or PTEN mutations but one FL patient had complete 
PTEN protein loss (as determined by immunohistochemistry [IHC] and 4 had a low PTEN 
(with 1-5% of tumor cells staining positive for PTEN). Among the 3 DLBCL patients, the 
1 patient with sufficient tissue material for gene expression profiling had germinal center B-
cell (GCB) DLBCL.  
Preliminary analysis of the 57 patients showed that the most common treatment-emergent 
adverse events (TEAEs), irrespective of relationship to study drug and grade, occurring in 
≥ 20% of the patients, were hyperglycemia (64.9%), nausea (52.6%), fatigue (40.4%), 
diarrhea (33.3%), hypokalemia (31.6%), hemoglobin (decreased) and hypertension (29.8% 
each), rash / desquamation and vomiting (28.1% each), anorexia (26.3%), constipation 
(24.6%), cough and dehydration (22.8% each), and dyspnea (21.1%). The most common 
drug-related TEAEs, regardless of seriousness and severity, occurring in 5% of the 
57 patients (all cohorts) were hyperglycemia (63.2%), nausea (36.8%), hypertension (21.1%), 
rash / desquamation and diarrhea (15.8% each), vomiting (12.3%), fatigue (10.5%), 
hemoglobin (decreased), alopecia, and taste alteration (8.8% each), pruritus, anorexia, and any 
type of pain (7% each), leukocytes (decreased), neutrophils (decreased), weight loss, rigor / 
chills, and amylase (increased) (5.3% each). 
Three FL patients experienced treatment-emergent pneumonitis, all with a severity of 
Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Grade 3 and assessed as 
serious. Of note, no pneumonitis was reported in the 48 patients with solid tumors treated in 
this study. In 2 asymptomatic cases, diagnosis was based on CT scans performed for restaging 
of lymphoma. Since remedial drug therapies such as antibiotics and / or corticosteroids were 
administered, no definitive conclusion can be drawn whether and to what extent study drug 
interruption or remedial drug therapy contributed to the improvement of pneumonitis. All 
3 events of pneumonitis resolved. The 3 patients were non-smokers. Only one of the 3 FL 
patients with pneumonitis had received prior PI3K inhibitor / mTOR inhibitor treatment more 
than 1 year before the event and one had had prior radiotherapy. The rapid recovery of 
pneumonitis observed in one patient favored a viral infection (viral pneumonitis), whereas the 
2 other events were considered non-infectious pneumonitis (NIP). 

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Study 16349 
As of 28 FEB 2015, a total of 81 patients with various indolent and aggressive lymphomas 
were treated at a starting dose of 0.8 mg/kg in the ongoing study 16349 (part A). The 
objective of the study was to identify activity signals in various histologic NHL subtypes and 
to further explore the safety profile of copanlisib. In the group of patients with indolent NHL, 
the following histologies were represented: FL (16 patients), CLL/SLL (14 patients), and 
MZL (3 patients). Median age was 68 years and 61% of the patients had ≥ 4 previous lines of 
systemic treatment. As of the cut-off date the median duration of copanlisib treatment was 
6 cycles in the indolent group. The objective response rate (ORR) was 40% in FL, 38% in 
CLL, 100% in SLL, and 67% in MZL. 
The most frequent TEAEs, regardless of relationship to study drug, occurring in >20% of the 
whole study population were hyperglycemia (59.3%), hypertension (56.8%), diarrhea 
(40.7%), fatigue (35.8%), nausea (32.1%), neutropenia (28.4%) and anemia (27.2%). The two 
most common study drug-related TEAEs were hyperglycemia (56.8%) and hypertension 
(53.1%). At the time of the cut-off, a total of 75 patients (92.6%), 30 with indolent, and 
45 with aggressive lymphomas, had discontinued the study treatment. Altogether 20 patients 
(24.7%) stopped treatment because of AEs. No conspicuous cluster of AEs causing treatment 
discontinuation emerged. Overall 17 out of 81 patients received treatment with short-acting 
insulin. 
Further details can be found in the IB for copanlisib, which contains comprehensive 
information on the test drug. 
3.2 
Rationale of the study 
The usual front-line treatment for iNHL consists of the anti-CD20-MAb rituximab given 
together with an alkylating agent (bendamustine, R-B), or a chemotherapy combination 
containing an alkylating agent (CHOP). While the R-B combination is preferred in the US, R-
CHOP remains the first option in the EU. In 2nd line, patients with R-sensitive disease (the 
large majority) would usually receive R-B following R-CHOP, and R-CHOP following R-B.  
Copanlisib has activity as monotherapy in patients with relapsed or refractory iNHL (shown 
in the results of studies 12781 and 16349 Part A). In addition, based on the current 
metabolism knowledge of each compound there is low potential for drug-drug interactions 
between copanlisib and the combination partners. It can therefore be expected that copanlisib 
would increase the activity of standard 1st and 2nd line immunochemotherapy (R-CHOP/R-B) 
in patients with relapsed, R-sensitive iNHL warranting re-treatment with a rituximab based 
regimen. The clinical benefit should be expressed in a prolonged PFS, and an improved 
quality of life in comparison to the standard immunochemotherapy.  
3.3 
Benefit-risk assessment 
Advanced indolent NHL remains an incurable disease that will invariably relapse after a 
period of remission. As the efficacy of subsequent lines of therapy decreases over time, 
prolonging progression-free survival, reducing the symptom burden, and delaying the next 
round of anti-lymphoma therapy are relevant goals of treatment. To achieve these goals, new 

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agents with different mechanisms of action and the potential to provide good response with an 
adequate safety profile are needed. The activity of copanlisib as monotherapy in patients with 
relapsed and refractory indolent NHL was demonstrated (see Section 3.1.2). The addition of 
copanlisib to the standard immunochemotherapy is therefore expected to provide a 
supplementary, clinically meaningful benefit in terms of progression-free survival and 
symptom control. The most frequent adverse events of copanlisib (hyperglycemia and 
hypertension) are manageable and not expected to interfere with conducting treatment 
according to plan. In this study, copanlisib-related and other toxicities will be closely 
monitored and managed according to a pre-defined program intended to ensure the patients’ 
safety and to avoid undue risk. Combination of copanlisib with standard 
immunochemotherapy (R-CHOP and R-B) in the safety run-in part is expected to establish a 
recommended phase III dose (RP3D) and indicate that possible overlapping toxicities are 
controllable. The safety and feasibility of these combinations will be evaluated at the end of 
the safety run-in part by a Data Monitoring Committee (DMC). The present study is 
acceptable after considering the risks and benefits associated with it.  
The safety run-in part of this study for copanlisib in combination with R-B and R-CHOP was 
completed. The DMC reviewed the safety data and decided that a copanlisib dose of 60 mg 
plus R-B or plus R-CHOP is a recommended and approved dose to be used in the phase III 
part.  
4. 
Study objectives 
4.1 
Safety run-in part  
The primary objective is to determine:  
• The recommended phase III dose (RP3D) of copanlisib in combination with standard 
immunochemotherapy (R-B or R-CHOP) to be used in the subsequent phase III part of 
the study. 
The secondary objectives are to evaluate (for patients that stay on treatment after 
Cycle 1): 
• Radiological and clinical indicators of treatment efficacy. 
• Safety and tolerability of copanlisib in combination with R-B/R-CHOP. 
Further objectives are to evaluate: 
• Pharmacokinetics (PK) of copanlisib.  
• Biomarkers of efficacy, mode-of-action-related effect, safety, and / or the 
pathomechanism of the disease. 
4.2 
Phase III part  
The primary objective of the phase III part is:  
• To evaluate whether copanlisib in combination with standard immunochemotherapy, 
is superior to standard immunochemotherapy in prolonging progression-free survival 

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(PFS) in patients with relapsed iNHL, who have received at least one, but at most 
three lines of treatment, including rituximab, and/or rituximab biosimilars, and/or anti-
CD20 monoclonal antibody -based immunochemotherapy and alkylating agents, and 
for whom the combination of rituximab with either bendamustine or CHOP represents 
a valid therapeutic option. 
The secondary objectives of the phase III part are to evaluate: 
• Other radiological and clinical indicators of treatment efficacy (objective response rate 
(ORR), duration of response (DOR), complete response rate (CRR), time to 
progression (TTP), time to next anti-lymphoma treatment (TTNT), disease control rate 
(DCR), overall survival (OS, 5 year survival rate), time to improvement and the time 
to deterioration in disease-related symptoms - physical). 
• Safety and tolerability of copanlisib in combination with R-B/R-CHOP. 
The further objectives of the phase III part are to evaluate: 
• Pharmacokinetics of copanlisib.  
• Biomarkers of efficacy, mode-of-action-related effect, safety, and / or the 
pathomechanism of the disease. 
5. 
Study design 
5.1 
Design overview 
This is a double-blind, two-arm phase III study in patients with relapsed, rituximab-sensitive 
iNHL to evaluate efficacy and safety of copanlisib in combination with standard 
immunochemotherapy (R-B or R-CHOP) in comparison to standard immunochemotherapy 
(R-B or R-CHOP). The patients must have relapsed or progressed after at least one, but at 
most three previous lines of therapy; previous treatments must have included rituximab and/or 
rituximab biosimilars, and/or anti-CD20 monoclonal antibody -based immunochemotherapy 
and alkylating agents (if given concomitantly is considered one line of therapy); and patients 
must not have a lack of response, or progression within 6 months of the last date of rituximab, 
or rituximab biosimilars, or anti-CD20 monoclonal antibody administration. For the purpose 
of this protocol, one month is considered to have 30 days.  
The study includes two parts. The safety run-in part will determine the RP3D of copanlisib in 
combination with standard immunochemotherapy (R-B or R-CHOP) to be used in the 
subsequent phase III part. The primary objective of the phase III part is to evaluate whether 
copanlisib in combination with standard immunochemotherapy, is superior to standard 
immunochemotherapy in prolonging progression-free survival (PFS) in patients with relapsed, 
rituximab-sensitive iNHL. The study will accrue patients with FL, MZL, SLL, and LPL/WM. 
In view of the prevalence of various histological types, it is expected that the large majority of 
study participants will be patients with FL. 
The overview of study periods is presented in Figure 5-1. 
 

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Figure 5-1 Study periods 
On study 
Off study 
 
Screening 
 
Treatment 
 
                Safety FU / Active FU a 
 
 
Survival FU 
 
 
 
 
Cycle 1 
 
 
Cycle 2 etc. 
 
EOT  
visit 
 
SFU visit 
Tumor 
assessments  
 
Informed 
Consent 
First dose of 
study 
treatment  
 
Last dose of study 
treatment/ 
End of last cycle 
 
Last protocol-
stipulated 
procedure 
 
EOT = End of treatment; FU = Follow up; SFU = Safety follow-up 
a: SFU for patients who discontinue study treatment due to PD; Active FU for patients who complete 12 months’ study 
treatment without PD or discontinue study treatment for any other reason than PD (includes Safety FU). 
The following design applies to both safety run-in part and the phase III part unless 
otherwise specified.  
The study is composed of the following periods: Screening, Treatment, Safety follow-up, 
Active follow-up (if applicable) and Survival follow-up.  
The start of the study period is defined by signing the informed consent form (ICF). After an 
up to 28-day and a minimum of 7-day screening period, patients who meet the entry criteria 
will be randomized to one of the two arms (only in the phase III part) and start treatment. The 
start of the treatment period is defined by the first administration of study treatment.  
Combination therapy (copanlisib/placebo with R-B or R-CHOP) will be administered for a 
maximum of 6 cycles (C1-C6). Copanlisib/placebo (study drug) monotherapy will be 
administered from C7 onwards.  
Combination therapy (copanlisib/placebo with R-B or R-CHOP) will be continued until the 
occurrence of progressive disease (PD) (per central independent blinded radiology review) 
defined by the Lugano Classification (14) (or Owen criteria for patients with WM [see 
Appendix 16.5]) or clinical progression (e.g. Eastern Cooperative Oncology Group [ECOG] 
performance status of ≥ 3), unacceptable toxicity occurs, or until another criterion is met for 
withdrawal from study (see Section 6.4) or up to 6 cycles whichever comes first.  
Copanlisib/placebo monotherapy (C7 onwards) will be continued until the occurrence of PD 
(per central independent blinded radiology review) as defined in the Lugano Classification 
(Owen Criteria for patients with WM), or clinical progression (e.g. ECOG performance status 
of ≥ 3), unacceptable toxicity occurs, or another criterion is met for withdrawal from study or 
until completion of monotherapy, whichever comes first. 
The maximum duration of treatment with copanlisib/placebo is 12 months (including 
combination therapy and monotherapy).  
An end-of -treatment (EOT) visit will be performed no later than 7 days after the decision is 
made to discontinue study treatment. Following completion of the EOT visit, patients will 
enter either the Safety follow-up or the Active follow-up period, if applicable. In both cases, 
the Safety follow-up visit will take place 30 days (a time window of +5 days is allowed) after 
the last administration of study treatment.  

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Patients who discontinue study treatment because of PD will enter the Safety-follow up 
period. Patients who complete 12 months’ study treatment without PD or discontinue study 
treatment for reasons other than PD will enter the Active follow-up period (which also serves 
as a Safety follow-up), except for patients who object to follow-up data collection. The 
patients in the Active follow-up will have tumor assessments by central independent blinded 
review as outlined in this protocol until the end of the Active follow-up period, defined as 
when either PD is documented or a new anti-tumor treatment is administered, whichever 
occurs first. 
All patients will be followed off-study for overall survival at 3-month (± 14 days) intervals 
during the Survival follow-up period (up to 10 years after the last patient started study 
treatment), except for patients who object to follow-up data collection. See Section 9.2.1.5.3. 
Efficacy will be evaluated based on radiological tumor evaluations of neck, chest, abdomen 
and pelvis by using contrast enhanced computed tomography/magnetic resonance imaging 
(CT/MRI), and positron emission tomography-computed tomography (PET-CT) as an 
preferred imaging modality (see Section 9.4.2 and Section 9.8). Scans will be performed at 
Screening, during Treatment as well as during the Active follow-up period (Year 1 and 
Year 2: every 12 weeks [± 7 days]; Years 3, 4, and 5: every 24 weeks [± 7 days]; beyond 
Year 5: every 24 weeks [± 14 days]). Response assessment will be based on the 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification (14) and for patients with WM 
according to the Owen Criteria (see Appendix 16.5) and CT/MRI, if applicable. As long as 
the patient has not experienced PD, investigator’s assessment is sufficient for case 
management. In the event of radiological progression, radiological real-time confirmation by 
central independent blinded evaluation is needed before a final decision is made by the 
investigator. The evaluation of treatment response (best response: objective response rate and 
complete response rate) will be also done by central blinded review.  
WM patients who do not have radiologically measurable lesion at Screening will not have 
further radiological assessments as per protocol. Their tumor response will be measured only 
by laboratory/clinical tests and evaluated by investigators. However, because these patients 
may on progression develop measurable disease without simultaneous increase in IgM, the 
imaging material should be submitted for blinded independent central review and PD 
confirmation. WM patients who have radiologically measurable lesion at Screening will 
continue having radiological assessments and, in addition, will have laboratory tests 
performed on the same days. 
Bone marrow biopsy will be mandatory at Screening and will be sent to central pathology 
review after local bone marrow assessment. If the baseline biopsy is positive for lymphoma 
infiltration, it will be mandatory to perform a local bone marrow biopsy assessment again to 
confirm the first complete response (CR) and also at the investigator’s discretion if clinical 
evaluation leads to suspicion of bone marrow infiltration without further radiological findings. 
Safety evaluations will be done at Screening, during treatment and at the Safety follow-up 
visit. NCI-CTCAE version 4.03 will be used to grade toxicities/AEs. Doses may be delayed 
or reduced in cases of clinically significant hematological or other toxicities that are possibly, 

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probably or definitely related to study treatment. The dose modification levels and the delay 
of copanlisib/placebo administration will follow pre-defined rules (see Section 7.4.2). 
Fresh tumor tissue and/or archival tumor tissue must be available at Screening for central 
pathology review for an exploratory analysis. In addition, pre-treatment tumor tissue samples 
will be collected when available to investigate or identify biomarkers that may be predictive 
of copanlisib effects/efficacy in iNHL and to contribute to better understanding the disease. 
See Section 9.7.1. In patients with WM, bone marrow biopsy can be used for histological 
confirmation of the diagnosis and for biomarker analyses. 
Sparse blood samples for pharmacokinetic (PK) analysis will be collected in all patients to 
characterize the PK of copanlisib and rituximab as outlined in Section 9.5. Plasma samples for 
biomarker analyses will be collected from all patients at baseline and during treatment. Blood 
samples for exploratory genetic biomarker analysis will be collected on Cycle 1 Day 1 from 
patients who provide “genetic research” consent (voluntary). See Section 9.7.1. 
In the phase III part, “time to deterioration” and “time to improvement” in disease-related 
symptoms - physical (DRS-P) will be assessed using the FLymSI-18 questionnaire, see 
Section 9.7.2.  
5.2 
Safety run-in part 
The study will start with a safety run-in part, where the recommended dose of copanlisib in 
combination with standard immunochemotherapy to be administered in phase III part will be 
determined, based on an open-label, two dose level, 3+3 design.  
During the safety run-in part two treatment combinations (copanlisib with R-B and copanlisib 
with R-CHOP), will be tested at two dose levels of copanlisib (first dose level of 45 mg and, 
second dose level of 60 mg) for safety and tolerability. The two dose levels will have a 
minimum of 3 and maximum of 6 patients evaluable for dose-limiting toxicity (DLT) during 
Cycle 1.  
The dose levels of copanlisib in the safety run-in part will be as follows:  
Dose level 1: 
45 mg of copanlisib in combination with either R-B or R-CHOP 
Dose level 2: 
60 mg of copanlisib in combination with either R-B or R-CHOP 
 
For the dosing of R-B and R-CHOP in the safety run-in part, please see Section 7.4. For the 
treatment assignment in the safety run-in part, please see Section 7.3.1. 
The dose-finding steps are presented in Figure 5-2.  
Three patients will initially receive 45 mg of copanlisib. If 2 or more of the first 3 patients 
experience DLT (see Section 7.4.1 for DLT definitions) at this dose level, the safety run-in 
would be closed and the combination considered to be not feasible. If 1 out of the first 
3 patients experiences a DLT at the 45 mg dose level, 3 additional patients will need to be 
enrolled at this dose level. If none of the first 3 patients experiences DLT at the 45 mg dose 
level, 3 new patients will start at 60 mg. If 0-1 patient out of the first 3 experiences DLT at the 

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60 mg dose level, the cohort will be expanded and 3 additional patients will receive the dose 
of 60 mg. If 0-1 patient out of 6 experiences DLT, 60 mg will be the recommended dose. If 
2 or more out of 6 patients experience DLT at 60 mg, 3 more patients will be assigned to 
receive the lower dose (45 mg) if there are only 3 patients thus far treated with 45 mg of 
copanlisib. If 0-1/6 patients display DLT at this dose, then 45 mg will be the recommended 
dose. If 2 or more of 6 patients experience DLT at 45 mg, then the safety run-in would be 
closed and the combination considered to be not feasible with the tested schedule. 
Patients treated within the safety run-in part and who in the investigator’s opinion benefit 
from treatment can continue combination therapy (copanlisib plus R-B or R-CHOP) for a 
maximum of 6 cycles followed by copanlisib monotherapy with the same dose of copanlisib 
administered with immunochemotherapy. The maximum duration of treatment with 
copanlisib is 12 months (including combination therapy and monotherapy). 
 
Figure 5-2 Overall study design of the safety run-in part  
 
DLT = dose-limiting toxicity; RP3D = recommended phase III dose 
All patients enrolled in the safety run-in part need to be evaluated for occurrence of DLTs 
during the first cycle. Patients not fully evaluable for occurrence of DLTs during the first 
cycle of therapy will be replaced unless the reason for dropout is a DLT (see Section 6.4.2). 
Any patient who experiences a DLT during first cycle of therapy should not receive further 
administration of copanlisib or any other study treatment. The investigator must notify the 
sponsor immediately of any CTCAE Grade 3 or 4 AEs or clinically relevant laboratory 
abnormalities.  
Transition from safety run-in part to phase III part  
DMC will review all data available from the safety run-in part and evaluate whether protocol 
specified treatment combinations are safe and tolerable. Details of the setup of the DMC and 

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the DMC meeting will be described in the DMC Charter. When the RP3D of copanlisib in 
combination with R-CHOP or R-B has been defined and confirmed by sponsor, and DMC, 
enrolment in the phase III part will start. 
The safety run-in part of this study was completed for copanlisib in combination with R-B 
and in combination with R-CHOP. The DMC reviewed the safety data and decided that a 
copanlisib dose of 60 mg plus R-B or plus R-CHOP is safe to be used in the phase III part. 
Patients recruited into the safety run-in part were treated in an unblinded fashion and will thus 
not be evaluated as part of the phase III part. 
5.3 
Phase III  
Patients will be stratified by: prior to base treatment regimen (R-chemotherapy to R-B, R-B to 
R-CHOP, and R-B to R-B), NHL histology (FL vs. other iNHL) and duration of progression-
free interval on the last rituximab, or rituximab biosimilars, or anti-CD20 monoclonal 
antibody containing regimen (6-12 months vs. >12 months). If the copanlisib 
immunochemotherapy combinations are deemed safe in the safety run-in part of the trial, 
approximately 520 (including FL and other iNHL) patients who meet the eligibility criteria 
will be randomly assigned in a 1:1 ratio to one of the double-blinded treatment arms (approx. 
260 patients per arm) in the phase III part: Arm 1: copanlisib plus R-CHOP or R-B and Arm 
2: placebo plus R-CHOP or R-B, see Figure 5-3.  
• Patients who never received R-B as a previous line of therapy will be randomized to 
copanlisib/placebo + R-B treatment group 
• Patients who received R-B as a previous line of therapy will be randomized to: 
o copanlisib/placebo + R-CHOP treatment group, or  
o copanlisib/placebo + R-B treatment group if ≥ 24 months progression-free 
interval after the last R-B treatment  
During the phase III part DMC will review the unblinded data per DMC charter of all patients 
treated up to that time point (or as needed) and to ensure that patients are not exposed to 
undue risk. The investigators, patients and the sponsor will remain blinded. 

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Figure 5-3 Overall study design of Phase III part  
 
FL = follicular lymphoma; FU = follow-up; iNHL = indolent non-Hodgkin’s lymphoma; N = total number of patients; NHL = non-
Hodgkin’s lymphoma; PD = progressive disease; R-B = rituximab and bendamustine; R-CHOP = rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone; RP3D = recommended phase III dose 
a:The maximum duration of treatment with copanlisib/placebo is 12 months (including combination therapy and monotherapy). 
Study treatment will be continued until occurrence of PD (per central independent blinded radiology review), clinical progression, 
unacceptable toxicity occurs, or until another criterion is met for withdrawal from study or up to 12 months whichever comes first.  
b: Safety follow-up (FU) for patients who discontinue study treatment due to PD; Active FU for patients who complete 
12 months’ study treatment without PD or discontinue study treatment for any other reason than PD (includes Safety FU). 
5.3.1 
Primary variable 
• The primary variable for the safety run-in part is the occurrence of DLTs in Cycle 1. 
• The primary efficacy variable for the phase III part is PFS, defined as the time (in 
days) from randomization to PD as assessed by blinded independent central review or 
death from any cause (if no progression is documented). The main analysis of the 
study will be performed when approximately 280 centrally evaluated PFS events in 
the FAS have occurred in the study. 
5.3.2 
Justification of the design 
No data are available regarding the dose of copanlisib to be used in combination with standard 
immunochemotherapy. This study will have a safety run-in part to establish the RP3D of 
copanlisib to be used in combination with immunochemotherapy. The safety run-in part of 
this study will investigate the two dose-levels of copanlisib considered to be sufficiently 
active for a starting dose, 45 mg and 60 mg in combination with the standard dose of R-B or 
R-CHOP. Therefore patients will only be exposed to treatment that is expected to provide 
clinical benefit. If the initial dose level of 45 mg is well tolerated, the next dose level will be 
60 mg.  
The safety run-in part uses the standard design of dose-finding study, with 3-6 patients per 
dose level, and occurrence of dose-limiting toxicity as primary endpoint. The intensity and 
frequency of AEs as well as the occurrence of new and unexpected AEs will be carefully 
monitored. Those patients who have benefit and will stay on treatment after the 1st Cycle will 

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be also evaluated for treatment efficacy, safety and tolerability of copanlisib in combination 
with R-CHOP/R-B, pharmacokinetics and biomarkers. All these information will be taken 
into account when assessing the performance of the study in the phase III part. 
The phase III part will start after RP3D of copanlisib is defined. The use of placebo can 
minimize investigator bias in assessing treatment effects beyond tumor shrinkage. This is 
particularly important when assessing duration endpoints and patient-reported outcomes. 
Although treatment with copanlisib is associated with infusion-related increases in blood 
glucose and increases in blood pressure, the risk of inadvertent unblinding is low. In the 
majority of the cases, the intensity of both symptoms is low, and both symptoms are not 
infrequent in the age group to which the majority of patients with indolent NHL belong.  
5.3.3 
End of study 
The end of the study as a whole will be reached as soon as the last visit of the last patient has 
been reached in all centers in all participating countries (EU and non-EU). 
Primary completion 
The primary completion event for this study is PFS (progression assessed by blinded 
independent central review or death from any cause, whichever occurs first). The analysis will 
be performed when approximately 280 PFS events in the FAS occur. 
The primary completion date for this study according to the US Food and Drug 
Administration (FDA) Amendment Act is specified in a separate document (not part of this 
study protocol). 
6. 
Study population 
Criteria for patients’ eligibility, withdrawal and, as well as patients’ identification apply to 
both safety run-in part and phase III part, unless otherwise specified. 
6.1 
Inclusion criteria 
1. 
Ability to understand and willingness to sign written informed consent. Signed 
informed consent must be obtained before any study specific procedure. 
2. 
Histologically confirmed diagnosis of CD20 positive iNHL with histological subtype 
limited to: 
• Follicular lymphoma (FL) grade 1, grade 2, or grade 3a 
• Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 × 109/L 
at study entry 
• Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) 
• Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal) 
3. 
Patients must have relapsed (recurrence after complete response or presented 
progression after partial response) or progressed after at least one but at most three prior 
lines of therapy, including rituximab, and/or rituximab biosimilars, and/or anti-CD20 

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monoclonal antibody (e.g. obinutuzumab) -based immunochemotherapy and alkylating 
agents (if given concomitantly is considered one line of therapy). A previous regimen is 
defined as one of the following: at least 2 months of single-agent therapy (less than 2 
months of therapy with single agent rituximab, or rituximab biosimilars, or anti-CD20 
monoclonal antibody can be considered a previous regimen in the case the patient 
responded to it); at least 2 consecutive cycles of polychemotherapy; autologous 
transplant; or radioimmunotherapy. Previous exposure to other PI3K inhibitors (except 
copanlisib) is acceptable provided there is no resistance (resistance defined as no 
response (response defined as PR or CR) at any time during therapy, or PD after any 
response (PR/CR) or after stable disease within 6 months from the end of the therapy 
with a PI3K inhibitor. 
4. 
Non-WM patients must have at least one bi-dimensionally measurable lesion (that has 
not been previously irradiated) according to the Lugano Classification (14). For patients 
with splenic MZL this requirement may be restricted to splenomegaly alone since that is 
usually the only manifestation of measurable disease. 
5. 
Patients affected by WM who do not have at least one bi-dimensionally measurable 
lesion in the baseline radiologic assessment must have measurable disease, defined as 
presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 × 
upper limit of normal (ULN) and positive immunofixation test.  
6. 
Male or female patients ≥ 18 years of age. 
7. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.  
8. 
Life expectancy of at least 3 months. 
9. 
Availability of fresh tumor tissue and/or archival tumor tissue at Screening. 
10. 
Women of childbearing potential (WOCBP) and men must agree to use effective 
contraception when sexually active. This applies for the time period between signing of 
the informed consent form and 12 months (for WOCBP) and 6 months (for men) after 
the last administration of study treatment. A woman is considered of childbearing 
potential, i.e. fertile, following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include but are not limited to 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal 
state is defined as no menses for continuous 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy.  
The investigator or a designated associate is requested to advise the patient how to 
achieve highly effective birth control method (failure rate of less than 1%) e.g. 
intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal 
occlusion, vasectomized partner, and sexual abstinence. The use of condoms by male 
patients is required unless the female partner is permanently sterile. 
11. 
Adequate bone marrow, liver and renal function as assessed by the following laboratory 
requirements conducted within 7 days of starting the study treatment: 

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• 
Total bilirubin < 1.5 × ULN (< 3 × ULN for patients with Gilbert-Meulengracht 
syndrome, patients with cholestasis due to compressive adenopathies of the 
hepatic hilum or documented liver involvement by lymphoma). 
• 
Alanine transaminase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN 
(< 5 × ULN for patients with documented liver involvement or with biliary 
obstruction due to lymphoma). 
• 
Lipase ≤ 1.5 × ULN. 
• 
Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease (MDRD) abbreviated formula. If not on 
target, this evaluation may be repeated once after at least 24 hours either 
according to the MDRD abbreviated formula or by 24 hour sampling. If the latter 
result is within acceptable range, it may be used to fulfill the inclusion criteria 
instead. 
• 
International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) 
≤ 1.5 × ULN. PT can be used instead of INR if PTT ≤ 1.5 × ULN. 
• 
Platelet count ≥ 75,000 /mm3. For patients with lymphomatous bone marrow 
infiltration (local assessment), platelet count ≥ 50,000 /mm3. Platelet transfusion 
should not be given less than 7 days before the exam collection. 
• 
Hemoglobin (Hb) ≥ 8 g/dL. 
• 
Absolute neutrophil count (ANC) ≥ 1,500/mm3. 
12. 
Left ventricular ejection fraction (LVEF) ≥ 50%. 
6.2 
Exclusion criteria  
Patients who meet any of the following criteria at the time of screening will be excluded. 
1. 
Previous assignment to treatment during this study. Patients permanently withdrawn 
from study participation will not be allowed to re-enter the study. 
2. 
Previous (within 28 days or less than 5 half-lives of the drug before start of study 
treatment) or concomitant participation in another clinical study with investigational 
medicinal product(s). 
3. 
Criterion 3 removed in amendment 6  
Excluded medical conditions: 
4. 
Histologically confirmed diagnosis of follicular lymphoma (FL) grade 3b or 
transformed disease, or chronic lymphocytic leukemia. In patients with clinical 
suspicion of transformed disease, a fresh biopsy is recommended. 
5. 
Rituximab, or rituximab biosimilars, or anti-CD20 monoclonal antibody (e.g. 
obinutuzumab) resistance at any line of therapy (resistance defined as lack of response, 
or progression within 6 months of the last date of rituximab, or rituximab biosimilars, or 

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anti-CD20 monoclonal antibody administration, including maintenance with these 
drugs). 
6. 
History or concurrent condition of interstitial lung disease of any severity and/or 
severely impaired lung function (as judged by the investigator). 
7. 
Known lymphomatous involvement of the central nervous system. 
8. 
HbA1c > 8.5% at Screening.  
9. 
Known history of human immunodeficiency virus (HIV) infection. All patients must be 
screened for HIV up to 28 days prior to study drug start using a blood test for HIV 
according to local regulations. 
10. 
Hepatitis B (HBV) or C (HCV) infection. All patients must be screened for HBV and 
HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial 
panel. Patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B core 
antibody (HBcAb) will be eligible if they are negative for HBV-DNA, these patients 
should receive prophylactic antiviral therapy as per rituximab label. Patients positive for 
anti-HCV antibody will be eligible if they are negative for HCV-RNA. 
11. 
Previous or concurrent history of malignancies other than indolent non-Hodgkin’s 
lymphoma within 5 years prior to study treatment except for curatively treated: 
• Cervical carcinoma in situ 
• Non-melanoma skin cancer 
• Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and 
T1 [tumor invades lamina propria]) 
• Localized prostate cancer  
12. 
Congestive heart failure > New York Heart Association (NYHA) class 2. 
13. 
Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 
3 months). Myocardial infarction less than 6 months before start of test drug.  
14. 
Criterion 14 removed in amendment 6. 
15. 
Uncontrolled hypertension despite optimal medical management (per investigator’s 
assessment). 
16. 
Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism 
within 3 months before the start of study medication. 
17. 
Non-healing wound, ulcer, or bone fracture. 
18. 
Active, clinically serious infections (> CTCAE Grade 2). 
19. 
Patients with seizure disorder requiring medication.  
20. 
Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding 
event ≥ CTCAE Grade 3 within 4 weeks of start of study medication. 

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21. 
Known hypersensitivity to any of the study drugs, study drug classes, or excipients in 
the formulation. 
22. 
Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24 h total urine protein quantification 
or estimated by urine protein : creatinine ratio > 3.5 (> 396 mg/mmol) on a random 
urine sample. 
23. 
Unresolved toxicity higher than NCI-CTCAE grade 1 attributed to any prior 
therapy/procedure excluding alopecia. 
24. 
Concurrent diagnosis of pheochromocytoma. 
25. 
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.  
26. 
Substance abuse, medical, psychological or social conditions that may interfere with the 
patient’s participation in the study or evaluation of the study results. 
27. 
Any illness or medical conditions that are unstable or could jeopardize the safety of the 
patients and their compliance in the study.  
Excluded previous therapies and medications: 
28. 
Documented evidence of resistance to prior treatment with idelalisib or other PI3K 
inhibitors defined as: 
• No response (response defined as partial response [PR] or complete response 
[CR]) at any time during therapy, or 
• Progression (PD) after any response (PR/CR) or after stable disease within 6 
months from the end of the therapy with a PI3K inhibitor. 
29. 
Prior treatment with anthracyclines (if patient will be assigned to R-CHOP), if the 
cumulative dose of anthracyclines will exceed 450 mg/m2 (or lower local limit) of 
doxorubicin isotoxic equivalent dose including the predicted 6 cycles of R-CHOP as 
given in this study. 
30. 
Ongoing immunosuppressive therapy. 
31. 
Radiotherapy or immuno-/chemotherapy less than 4 weeks before start of treatment. 
32. 
Radioimmunotherapy or autologous transplant less than 3 months before start of 
treatment. 
33. 
Myeloid growth factors within 14 days prior to treatment start. 
34. 
Blood or platelet transfusion within 7 days prior to treatment start. 
35. 
Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg 
prednisone or equivalent is not allowed. Patients may be using topical or inhaled 
corticosteroids. Previous corticosteroid therapy must be stopped or reduced to the 
allowed dose at least 7 days before performing the screening PET-CT and/or CT/MRI, 
whichever is performed first, and again at least 7 days prior to the first study drug 

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administration. If a patient is on chronic corticosteroid therapy, corticosteroids should 
be de-escalated to the maximum allowed dose after the patient has signed the IC.  
36. 
History of having received an allogeneic bone marrow or organ transplant. 
37. 
Major surgical procedure or significant traumatic injury (as judged by the investigator) 
within 28 days before start of study medication, open biopsy within 7 days before start 
of study medication. 
38. 
Anti-arrhythmic therapy (beta blockers or digoxin are permitted). 
39. 
Use of CYP3A4 inhibitors and inducers (see Appendix 16.1). Copanlisib is primarily 
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, phenytoin, carbamazepine, 
phenobarbital, St. John's Wort) are not permitted from Day -14 of Cycle 1 until the 
safety follow-up visit. 
40. 
Prior treatment with copanlisib. 
Other exclusions: 
41. 
Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at baseline will 
not be eligible. CMV PCR test is considered positive if the result can be interpreted as a 
CMV viremia according to local SOC. 
42. 
Live vaccination, including virus vaccination and yellow fever vaccination, within 
6 months before start of study treatment. 
For prohibited concomitant therapy please refer to Section 8.1.1. 
6.3 
Justification of selection criteria 
The selection criteria are chosen to ensure that patients with specific risks for administration 
of the test drug and / or patients with conditions which may have an impact on the aims of the 
study are excluded, as well as patients with disease considered to be rituximab, and/or 
rituximab biosimilars, and/or anti-CD20 monoclonal antibody-refractory. Patients with an 
ECOG score of ≥ 3 will not be enrolled, as well as patients whose comorbidities may 
compromise safety or the ability to comply with the study procedures. 
6.4 
Withdrawal of patients from study 
6.4.1 
Withdrawal 
6.4.1.1 
Withdrawal criteria 
Patients must be withdrawn from the study treatment if any of the following occurs: 
• At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a patient may decline to participate 
further. The patient will not suffer any disadvantage as a result. Patients who withdraw 
consent from treatment will still participate in the Safety, Active or Survival follow-up 

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unless they object to follow-up data collection. For this, the patient’s oral objection 
may be documented in the patient’s source data. 
• If, in the investigator's opinion, continuation of the study would be harmful to the 
patient's well-being. 
• Disease progression as assessed by blinded independent central review and defined in 
the Lugano Classification and, for patients with WM, according to the Owen Criteria. 
• Occurrence of unacceptable toxicity from any study treatment. 
• CTCAE Grade 4 arterial hypertension. 
• CTCAE Grade 4 dermatologic toxicity. 
• Persistent occurrence of post-infusion blood glucose > 500 mg/dL based on laboratory 
analysis which occurred at the lowest copanlisib/placebo dose level despite optimal 
glucose lowering therapy (after at least one cycle of treatment).  
Definition of persistent occurrence is based on repeated post-infusion blood glucose 
laboratory analysis taken at different time during the whole cycle of treatment. 
• Non-infectious pneumonitis ≥ CTCAE Grade 3.  
• Drug-induced pancreatitis. 
• Development of a malignancy other than indolent B-cell NHL. New malignancy will 
be reported as an SAE. 
• Start of a new anti-cancer regimen. 
• Phase III part: The patient does not tolerate copanlisib/placebo dose of 30 mg.  
Safety run-in part: The patient does not tolerate copanlisib dose of 30 mg after 
Cycle 1. 
• The patient presents during further testing a positive viral load when initial HBV DNA 
and/or HCV RNA testing was negative.  
• Severe allergic reaction to study treatment (such as CTCAE Grade 3 or 4 
hypersensitivity reaction).  
• Severe (life-threatening) reaction to rituximab infusion despite optimal supportive 
treatment. 
• Patient lost to follow-up. 
• Substantial non-compliance with the requirements of the study. 
• Delay in test drug administration due to toxicities for > 28 days (a delay of test drug 
dosing due to reasons other than toxicity is not included in this definition). Except, in 
case of delays due to reactivation of CMV where delays could be up to 2 months. 

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• Development of any intercurrent illness or situation which, in the judgment of the 
investigator, may affect assessments of clinical status and study endpoints to a 
relevant degree. 
• Detection of illicit drugs or other substances that may, in the opinion of the 
investigator, have a reasonable chance of contributing to toxicity or otherwise 
confound results. 
• Patients with a positive β-human chorionic gonadotropin (HCG) test or any other sign 
consistent with pregnancy. Pregnancy will be reported within the same timelines as a 
SAE via the Pregnancy Monitoring Form. 
Patients must be withdrawn from the study if any of the following occurs: 
• At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns). 
For patients who withdraw consent and object to follow-up data collection, no further study 
related procedures will be allowed, and no further data, including survival data, will be 
collected. The patients will not suffer any disadvantage as a result. 
Withdrawal from follow-up period 
Following completion of the EOT visit, patients who discontinue study treatment due to PD 
will enter the Safety follow-up period, and patients who complete 12 months’ study treatment 
without PD or discontinue study treatment for reasons other than PD will enter Active follow-
up period (which also serves as a Safety follow-up). During the Survival follow-up period all 
patients will be contacted every 3 months (± 14 days) to determine survival status (up to 10 
years after the last patient started study treatment). 
Reasons for not performing the Safety follow-up or discontinuation of the Survival follow-up 
include the following: 
• Death 
• Objection to follow-up data collection 
• Lost to follow-up 
Depending on the time point of withdrawal, a withdrawn patient is referred to as either 
“screening failure” (see Section 6.4.1.2) or “dropout” (see Section 6.4.1.3) as specified below: 
6.4.1.2 
Screening failure 
A patient 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 below) is regarded a 
“screening failure”.  

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Re-starting the defined set of screening procedures to enable the “screening failure” patient’s 
participation at a later time point is not allowed – with the following exceptions: 
• The patient had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule. 
• Initial screening occurred too early to complete the required washout period after prior 
therapy. 
• The in- / exclusion criteria preventing the patient’s initial attempt to participate have 
been changed (via protocol amendment). 
• Screening failed due to positive CMV PCR result. 
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the patient to an unjustifiable health risk. Also, for re-screening, the patient has to re-
sign the informed consent form, even if it was not changed after the patient’s previous 
screening.  
Re-screening of patients who have failed screening may only be allowed once after discussion 
with the sponsor’s designated medical representative and after approval by the sponsor. 
Sponsor approval of re-screening for the patient who has failed screening must be 
documented. The screening failure will be registered in IVRS/IWRS to close the patient 
identification number (PID), and rescreening will start again by signing a new ICF and being 
assigned a new PID.  
Laboratory tests at Screening  
All initial screening laboratory tests will need to be taken within 7 days prior to planned Day 
1 of Cycle 1 (C1D1). If one or more screening laboratory tests do not support eligibility, 
laboratory re-test is permitted only once without the need of re-consent. Only the laboratory 
tests with results out of range need to be repeated. Re-testing must be performed within 14 
days of the initial test and with approval from the sponsor. However, if this retesting cannot 
be completed within 7 days of the C1D1, all blood and urinary tests that are required to be 
within 7 days of C1D1 will need to be repeated. Patients may not begin study drug treatment 
until the results of re-testing are available and documented to be within protocol-required 
range. Diagnostic testing performed as part of the original screening or standard of practice 
(e.g. including fresh tumor tissue, CT scans, bone marrow sample, multiple gated acquisition 
[MUGA]/echocardiogram and hepatitis testing) will not need to be repeated during the 14 day 
re-testing period. If re-test laboratory results are still out of eligibility range, this will be 
considered a full screening failure, and only one re-screening will be allowed following the 
rules as outlined above. 
For patients with newly diagnosed diabetes mellitus that cannot meet protocol requirements, a 
single re-screening (which includes all screening procedures) should be performed when the 
patient’s diabetes is controlled and can meet protocol requirements (see Section 6.1 and 6.2). 

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6.4.1.3 
Dropout 
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been randomized (phase III part) /assigned to treatment 
(safety run-in part). 
6.4.1.4 
General procedures 
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in 
the patient's medical records.  
The patient may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4. 
All patients who discontinue due to AEs or clinical laboratory abnormalities should be 
followed up until they recover or stabilize, and the subsequent outcome recorded. If any 
patient dies during the study or within 30 days of the last dose of study drug, the investigator 
or his/her designated associate(s) will inform the sponsor. The cause of death should be 
recorded in detail within 24 h of awareness on an SAE form and transmitted to the sponsor. 
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12 (Premature termination of the study). 
6.4.2 
Replacement 
Safety run-in part 
Replacement if: 
1. 
Termination for disease progression in patients with insufficient treatment exposure in 
Cycle 1 (< 100% of planned dose of the combination)  
2. 
Insufficient treatment exposure due to non-compliance or voluntary withdrawal in 
Cycle 1 (< 100% of planned dose of the combination) 
3. 
Major protocol violation (affecting the primary efficacy variable). This includes wrong 
diagnosis at enrollment, prior anti-tumor therapy not according to protocol, and 
prohibited concomitant anti-tumor therapy during the study. 
Phase III part  
Patients will not be replaced. 

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6.5 
Patient identification 
At Screening upon signing the ICF, each patient will be assigned a unique patient 
identification number (PID) by Interactive Voice Response System /Interactive Web 
Response System (IxRS) for unambiguous identification. 
The patient number is a 9-digit number consisting of: 
Digits 1 to 2  
= Country code 
Digits 3 to 5 
= Center number within the country 
(Digits 1 to 5 = Trial unit) 
Digits 6 to 9 
= Current patient number within the center 
7. 
Treatments 
7.1 
Treatments to be administered 
The study treatment will comprise the following: 
1. 
Test drug copanlisib (BAY 80-6946) administered in combination with standard 
immunochemotherapy (R-B or R-CHOP)  
2. 
Placebo administered in combination with standard immunochemotherapy (R-B or R-
CHOP)  
3. 
Copanlisib administered as monotherapy  
4. 
Placebo administered as monotherapy  
Combination therapy (copanlisib/placebo with R-B or R-CHOP) will be administered for a 
maximum of 6 cycles (C1-C6).  
Copanlisib/placebo (study drug) monotherapy will be administered from C7 onwards. There 
will be no rituximab maintenance therapy administered from C7 onwards. 
The maximum duration of treatment with copanlisib/placebo is 12 months (including 
combination therapy and monotherapy). The duration of treatment in the safety run-in part 
will be the same as in the phase III part. For the dosage and administration please see 
Section 7.4. 
7.2 
Identity of study treatment  
Copanlisib (test drug) 
Copanlisib is supplied as lyophilized preparation in a 6-mL injection vial. The total amount of 
BAY 80-6946 per vial is 60 mg. The solution for IV infusion is obtained after reconstitution 
of the lyophilisate with 0.9% sodium chloride solution.  
Please refer to the Pharmacy Manual for detailed instructions for the reconstitution of the 
lyophilisate and for further dilution of the reconstituted solution. 
Please refer to IB for copanlisib for more details regarding drug properties and formulation. 

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Placebo for copanlisib (only in phase III part) 
Placebo is supplied as lyophilized preparation in a 6 mL injection vial. Placebo treatment will 
follow a dosing scheme to match the active drug product. Accordingly, the developed placebo 
lyophilisate is equivalent to the 60 mg copanlisib formulation, with regard to the composition 
of excipients and the instructions for reconstitution and dose preparation. 
Reconstitution, dilution and storage of placebo preparation should be performed according to 
same instructions as for copanlisib. 
For the guidance on preserving the blinding during handling of the study treatment, refer to 
Section 7.5. 
Background treatment (Cycles 1-6): 
Rituximab 
Rituximab will be sourced centrally or locally depending on the local law and requirements. 
Rituximab biosimilars cannot be prescribed in this study.  For full details on rituximab and 
instructions for dilution, please refer to the current prescribing information / Summary of 
Product Characteristics (SmPC).  
Bendamustine, cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone 
Bendamustine, cyclophosphamide, doxorubicin, vincristine and prednisone will be sourced 
centrally or locally depending on the local law and requirements. For full details on 
bendamustine, cyclophosphamide, doxorubicin and vincristine and instructions for dilution, 
please refer to the current prescribing information / SmPC. In countries where prednisone is 
not available, prednisolone can be administered instead. Prednisone and prednisolone are not 
diluted (oral); for full details on prednisone and prednisolone, please refer to the current 
prescribing information / SmPC.  
All centrally supplied study drugs will be labeled according to the requirements of local law 
and legislation. The label text will be approved according to the sponsor’s agreed procedures, 
and a copy of the labels will be made available to the study site upon request. 
For all centrally supplied study drugs, a system of numbering in accordance with all 
requirements of Good Manufacturing Practice (GMP) will be used, ensuring that each dose of 
study drug can be traced back to the respective bulk batch of the ingredients. Lists linking all 
numbering levels will be maintained by the sponsor’s clinical supplies Quality Assurance 
group.  
A complete record of batch numbers and expiry dates of all centrally supplied study 
treatments as well as the labels will be maintained in the sponsor’s study file. 
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may prepare, supply, or administer study treatment. 
An approved representative at the site will ensure that all received study drugs are stored in a 
secured, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.  

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The investigator or approved representative at the site is responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and final 
disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
7.3 
Treatment assignment 
7.3.1 
Safety run-in part  
During the open-label safety run-in part patients who have given written informed consent 
and who satisfy the entry criteria will be assigned to the combination therapy (copanlisib + 
R-B or copanlisib + R-CHOP): 
• Patients who received R-CHOP or R-CVP as a previous line of therapy will be 
assigned to copanlisib + R-B treatment group  
• Patients who received R-B as a previous line of therapy will be assigned to copanlisib 
+ R-CHOP treatment group 
The dose level of copanlisib will be based on the cohort that is open at the time of the 
patient’s enrollment based on 3+3 design. 
7.3.2 
Phase III part  
At the end of the screening period, eligible patients will be randomly assigned in a 1:1 ratio to 
the two double-blinded treatment arms: copanlisib and R-B/R-CHOP or placebo and R-B/R-
CHOP, respectively.  
At randomization, IVRS/IWRS will stratify patients according to 3 factors based on baseline 
characteristics: 
• Prior to base treatment regimen: R-chemotherapy to R-B, R-B to R-CHOP, and R-B 
to R-B 
• NHL histology 
o FL histology  
o Other iNHL histology (SLL, MZL, LPL/WM) 
• Duration of progression-free interval on the last rituximab, or rituximab biosimilars, 
or anti-CD20 monoclonal antibody containing regimen: 6-12 months versus 
>12 months 
Resulting from the combination of these 3 stratification factors, patients will be grouped into 
12 different strata; within each stratum, patient will be randomized between copanlisib and 
placebo. The randomization must be performed up to maximum 72 hours before the first dose 
of study treatment. 
• Patients who never received R-B as a previous line of therapy will be randomized to 
copanlisib/placebo + R-B treatment group 

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• Patients who received R-B as a previous line of therapy will be randomized to: 
o copanlisib/placebo + R-CHOP treatment group, or  
o copanlisib/placebo + R-B treatment group if ≥ 24 months progression-free 
interval after the last R-B treatment 
Treatment will be assigned based on information obtained from IVRS/IWRS.  
The IVRS/IWRS procedure is described in detail in a separate IVRS/IWRS instruction 
manual. 
Due to the potential of bias or unblinding, the size of randomization blocks within the 
randomization list must not be disclosed to blinded study individuals. 
During the course of the study, the randomization list will be provided to the Statistical 
Analysis Center for the DMC and its meetings, the Bioanalytics group and the 
Pharmacokinetic Evaluator in order to perform the PK analysis. 
7.4 
Dosage and administration 
Copanlisib and placebo 
Copanlisib and placebo for copanlisib (only in phase III part) administration described below 
applies to all patients in the safety run-in part and patients in the phase III part, for as long as 
patients are on treatment with copanlisib or placebo. 
Copanlisib and placebo for copanlisib formulations are administered in a normal saline 
solution, intravenously, over 1 hour. No intravenous glucose preparations should be 
administered on the days of infusion. See Pharmacy Manual for additional details.  
See Table 7–1 and Section 5.2 for the dosing of copanlisib/placebo during the study.  
Table 7–1 Dosing of copanlisib/placebo during the study 
Copanlisib/Placebo (C/P) dosing 
Cycle length 
(d) 
D1 
D8 
D15 
Cycles 1-6 
 
 
 
 
C/P in combination with R-B 
28 
X 
X 
X 
C/P in combination with R-CHOP 
21 
X 
X 
 
 
 
 
 
 
Cycle 7 onwards 
 
 
 
 
C/P monotherapy 
28 
X 
X 
X 
D = day; R-B = rituximab and bendamustine; R-CHOP = rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone 

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Immunochemotherapy (Cycles 1-6) 
R-CHOP will be administered q3w as follows: 
• Rituximab IV 375 mg/m2 body surface on Day 2  
• Cyclophosphamide IV 750 mg/m2 body surface on Day 2 
• Doxorubicin IV 50 mg/m2 body surface on Day 2  
• Vincristine IV 1.4 mg/m2 body surface (max dose 2.0 mg) on Day 2  
• Prednisone/prednisolone 100 mg daily PO from Day 2 to Day 6  
R-B will be administered q4w as follows: 
• Rituximab IV 375 mg/m2 body surface on Day 1 
• Bendamustine IV 90 mg/m2 body surface on Day 1 and Day 2  
Rituximab will be administered taking into account all measures of precaution prescribed by 
the manufacturer to avoid infusion reactions (rate of infusion, premedication, etc.). Patients 
will be monitored according to rituximab SmPC/prescribing information. 
Cyclophosphamide, vincristine, doxorubicin, prednisone/prednisolone will be utilized 
according to the respective SmPC/prescribing information.  
Bendamustine will be utilized according to SmPC/prescribing information. 
Requirements for copanlisib/placebo pre-dose glucose levels 
The copanlisib/placebo will be administered only if pre-dose glucose level is <160 mg/dL 
(fasting) or <200 mg/dL (non-fasting). 
Glucose measurements at the site may be done either by laboratory analysis or in capillary 
blood. 
Because of inhibitory effect on PI3K α-isoform, which is implicated in insulin metabolism, 
copanlisib infusions could be associated with temporarily increase in blood glucose. Addition 
of meal in close proximity to copanlisib/placebo infusion may exacerbate glucose increase. 
On infusion days, a low carbohydrate diet is recommended. The timing and content of meal 
intake and additional glucose testing (if clinically indicated) is managed and monitored by the 
investigators based on glucose response patterns during prior treatment days. Consultation 
with diabetologist or endocrinologist is advised. 
All glucose measurements done at the site, oral glucose lowering medication and/or insulin 
administration, if applicable, fasting/non-fasting status and meal intake timing on infusion 
days will be collected as part of the clinical source documentation.  
Dosing criteria 
Starting from Cycle 1 Day 8, laboratory tests prior to each infusion may be performed and 
assessed either the day before or on the planned day of infusion (see Section 9.1), with the 
exception of blood glucose, which must be performed and assessed on the day of infusion. All 

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laboratory results must be assessed by the investigator/treating physician/sub-investigator 
prior to administration of planned dose.  
On Day 1 of each subsequent cycle, the dose of copanlisib/placebo with 
immunochemotherapy (Cycles 2-6) and copanlisib/placebo (Cycle 7 onwards) will be given 
only if the laboratory test criteria described in Table 7–2 are met. Glucose lowering 
medication can be used to optimize pre-infusion glucoses (see Section 7.4.3.1 for glucose 
management). 
Table 7–2 Laboratory test criteria for Day 1 dose of subsequent cycles 
Laboratory Test f 
Criteria for Day 1 dose (Cycle 2 and higher) 
Glucose  
< 160 mg/dL (fasting) or < 200 mg/dL (non-fasting) 
Hemoglobin  
≥ 8 g/dL a 
ANC 
 ≥ 1,000/mm3 
Platelets 
≥ 75,000/mm3 e 
ALT 
<2.5 × ULN b  
AST 
<2.5 × ULN c 
Total bilirubin 
< 1.5 × ULN d 
GFR (MDRD) 
≥ 40 mL/min/1.73 m2 
ALT = Alanine aminotransferase; ANC = Absolute neutrophil count; AST = Aspartate aminotransferase; 
GFR = Glomerular filtration rate; MDRD = Modification of Diet in Renal Disease; ULN = Upper limit of 
normal. 
a: If hemoglobin is < 8 g/dL but ≥ 6 g/dL on the day of planned study drug administration it is permissible to 
give the study drug dose as scheduled and transfuse within 48 hours after the dose, if the patient is 
hemodynamically stable and in opinion of investigator benefits outweigh risks. Rationale and treatment 
should be recorded in source document and eCRF.  
b: < 5 × ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to 
lymphoma. 
c: < 5 × ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to 
lymphoma. 
d: < 3 × ULN in patients with Gilbert-Meulengracht syndrome, patients with cholestasis due to compressive 
adenopathies of the hepatic hilum or documented liver involvement by lymphoma. 
e: For patients with lymphomatous bone marrow infiltration at study entry (local assessment), platelet count 
≥ 50,000/mm3. This value should be used throughout the study irrespective of bone marrow status 
changes. Platelet transfusion should not be given less than 7 days before the exam collection. 
f: Laboratory tests prior to each infusion may be performed and assessed either the day before or on the 
planned day of infusion with the exception of blood glucose which must be performed and assessed on 
the day of infusion.  
Note: A blood count will be performed and assessed prior to study drug infusion on Days 8 and 15 of each 
cycle. On Days 8 and 15, the dose of copanlisib/placebo will be administered only if ANC ≥ 500/mm3, 
hemoglobin ≥ 8 g/dL and  platelets ≥ 75,000/mm3. 
Doses of copanlisib/placebo scheduled for Days 8 and 15 may be delayed by up to 2 days. A 
delay of more than 2 days will be considered a missed dose. Missed doses will not be 
replaced. The minimum interval needed between two infusions of study drug is 5 days. 
7.4.1 
Definition of dose-limiting toxicities (DLTs) 
Dose-limiting toxicity – safety run-in part 
Dose-limiting toxicity will be defined as any of the following occurring during Cycle 1 at a 
given dose level and regarded by the investigator and/or the sponsor to be possibly, probably, 
or definitely related to copanlisib given in combination with R-B or R-CHOP. NCI-CTCAE 

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Version 4.03 will be used to assess toxicities/adverse events (AEs). The DMC opinion will 
decide in case of persisting disagreement between sponsor's and investigator's assessments. 
General 
• Any grade 5 hematologic or non-hematologic toxicity 
• Any delay of >2 weeks of Cycle 2 due to study treatment-related toxicity  
Non-hematologic DLT: 
• Any non-hematologic toxicity grade ≥ 3, except: 
o Grade 3 nausea/vomiting/diarrhea of < 3 days duration or responsive to medical 
therapy within ≤ 3 days of occurrence 
o Increased glucose levels that returned to ≤ 200 mg/dL with or without the use of 
insulin or oral glucose lowering medications within ≤ 3 days of occurrence 
o Increased blood pressure that returned to <150 mmHg (systolic blood pressure) 
and <90 mmHg (diastolic blood pressure) with or without the use of anti-
hypertensive medication within ≤ 3 days of occurrence 
Hematologic DLT: 
•  Grade 4 absolute neutrophil count decrease lasting >7 days 
• Grade 4 febrile neutropenia 
•  Grade 4 platelet count decreased or Grade 3 platelet count decreased with serious 
bleeding 
•  Signs of serious bleeding and/or international normalized ratio (INR) increased or 
partial thromboplastin time (PTT) prolonged of Grade 3 
For certain toxicities such as laboratory assessments without a clear clinical correlate (e.g. 
lipase increase without signs of a clinical pancreatitis), a discussion between the investigator 
and the sponsor may take place if that adverse event should be assessed as DLT necessitating 
dose reduction. 
7.4.2 
Dose modification  
Dose modifications due to toxicities described below apply to copanlisib and placebo for 
copanlisib (“dummy dose modification”). There will be no dose reductions for rituximab in 
any cycle. For the safety run-in part, there will be no dose reductions of any components of 
CHOP or bendamustine in the first cycle. Modifications for CHOP and bendamustine (safety 
run-in part: Cycle 2 and subsequent cycles, phase III part: all cycles) will be performed 
according to the measures of precaution and toxicity management per local standards of care, 
local prescribing information, and according to investigator’s experience.  
If any of the study treatment (copanlisib/placebo or immunochemotherapy) must be 
permanently discontinued, all other study treatment must be discontinued as well (excluding 
the planned discontinuation of R-B or R-CHOP after Cycle 6).  

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If any drug administration is delayed, all drug combinations (copanlisib/placebo + 
immunochemotherapy) must be delayed. If severe reactions to R-CHOP or R-B occur despite 
maximum supportive treatment patients should be withdrawn from the study treatment. 
It is recognized that attribution of causality of any AE to the test drug specifically may be 
difficult. However, in Phase I and II trials, certain toxicities were seen only in relation to 
copanlisib e.g. transient increases in glucose and blood pressure. Based on this knowledge the 
investigator may decide on the necessary dose modifications. 
Dose modifications and treatment interruptions for copanlisib and placebo must be done 
according to the guidelines in Section 7.4.2.2 and 7.4.2.3. The investigator may judge a more 
conservative dose modification more appropriate. If therefore these guidelines are not 
followed, the rationale for other measures is to be documented in detail in patient’s medical 
record. Deviations from the guidelines must be discussed with the sponsor.  
7.4.2.1 
Safety run-in part and phase III part  
Dose modification levels are outlined in Table 7–3. In the safety run-in part, dose 
modification rules of copanlisib will apply to patients who stay on treatment beyond 1st cycle 
and present toxicities that will need dose adjustments. Dose modification of placebo applies 
only to phase III part.  
Table 7–3 Dose levels of copanlisib and placebo  
If RP3D dose is 45 mg: 
Dose level 1 (starting dose): 
45 mg of copanlisib or placebo 
Dose level -1: 
30 mg of copanlisib or placebo 
 
If RP3D dose is 60 mg: 
Dose level 1 (starting dose): 
60 mg of copanlisib or placebo 
Dose level -1: 
45 mg of copanlisib or placebo 
Dose level -2: 
30 mg of copanlisib or placebo 
 
After having fully recovered from toxicity and in the absence of any criteria for further dose 
reduction or study drug discontinuation, re-escalation from dose level -2 to dose level -1, or 
from dose level -1 to dose level 1 will be allowed at the investigator’s discretion. 
Patients who do not tolerate the copanlisib/placebo dose of 30 mg must discontinue study 
treatment permanently.  
7.4.2.2 
Hematological toxicity 
Neutropenia and febrile neutropenia are listed in the current version of IB as expected adverse 
events. If the guidelines given in Table 7–4 are not followed, the rationale for other measures 
is to be documented in detail in the patient’s medical record. The use of myeloid growth 
factors in the prophylactic and therapeutic setting is allowed during study treatment based on 
local standard of care (SOC) and at investigator’s discretion for safety run-in part and phase 
III part.  

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Table 7–4 Dose modification of copanlisib/placebo for hematological toxicity 
Hematological toxicity (any of the following) 
Study treatment action (for any toxicity) 
• CTCAE Grade ≥ 3 thrombocytopenia (platelet 
< 50,000/mm3)  
• Febrile neutropenia or ANC<500/mm3 a 
• INR or PTT CTCAE Grade ≥ 3 with bleeding b 
• CTCAE Grade ≥ 3 anemia (Hb < 8 g/dL) 
Delay infusion until criteria displayed in  
Table 7–2 are met.d Patient can be treated at one 
dose level lower at the investigator’s discretion.c 
If more dose reductions are required than 
allowed per protocol, discontinue copanlisib 
permanently. The lowest dose level is 30 mg. 
ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria of Adverse Events, version 4.03; 
Hb = hemoglobin; INR = international normalized ratio; PTT = partial thromboplastin time; G-CSF = Granulocyte 
colony-stimulating factor 
a: These patients should recover from neutropenia to ANC≥500/mm3 without fever. G-CSF should be prescribed 
when ANC is <1000/mm3. 
b: International normalized ratio (INR) and partial thromboplastin time (PTT) should have returned to ≤ 1.5 and 
≤ 1.5 × ULN, respectively, with no signs of bleeding. 
c: After having fully recovered from toxicity and in the absence of any criteria for further dose reduction or study 
drug discontinuation, re-escalation is allowed at the investigator’s discretion. 
d: Treatment with transfusion is allowed at the investigator’s discretion. 
7.4.2.3 
Non-hematological toxicity 
Dose modifications for non-hematologic toxicities attributable to copanlisib/placebo except 
for glucose increases, dermatologic toxicity, non-infectious pneumonitis and blood pressure 
increases are outlined in Table 7–5.  
Table 7–5 Dose modification of copanlisib/placebo for non-hematological toxicity  
(except glucose increases, dermatologic toxicity, non-infectious pneumonitis and blood pressure 
increases) 
 
 
Study Drug Action 
Toxicity a 
Occurrence 
For current course of therapy 
For next course of therapy 
Grade 1-2 
Any appearance 
No change 
No change 
Grade 3 b 
1st appearance 
Interruption until Grade  2 
No change 
 
2nd appearance 
Interruption until Grade  2 
Decrease by one dose level c 
 
3rd appearance 
Interruption until Grade  2 
Decrease by one dose level c 
 
4th appearance 
Permanent discontinuation 
–  
Grade 4 
Any appearance 
Permanent discontinuation  
–  
Toxicity requiring delay for > 28 days 
Permanent discontinuation 
–  
CTCAE = Common Terminology Criteria for Adverse Events; CMV = cytomegalovirus 
a: Toxicities according to CTCAE version 4.03 
b: Despite maximum supportive therapy 
c: Not applicable for 30 mg dose level 
A delay >28 days in study drug administration due to toxicities will cause permanent discontinuation of study 
treatment. Except, in case of delays due to reactivation of CMV where delays could be up to 2 months. 
Copanlisib/placebo must be discontinued if the lowest dose level of 30 mg is not tolerated.  
After having fully recovered from toxicity and in the absence of any criteria for further dose reduction or study 
drug discontinuation, re-escalation to dose level -1 or 1 will be allowed at the investigator’s discretion.  
 
 

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Dermatologic toxicity 
The guidelines for dose modifications in cases of dermatologic toxicity are outlined in Table 
7–6. If these guidelines are not followed, the rationale for other measures will be documented 
in detail in the patient’s medical record. 
Table 7–6 Dose modification of copanlisib/placebo for dermatologic toxicity 
Study drug action 
Toxicity a 
(CTCAE severity 
grade) 
Occurrence For current course of 
therapy 
For next course of therapy 
Grade 1 and 2 
Any 
appearance 
No change 
No change 
Grade 3 a  
1st 
Interruption until Grade ≤ 2 
Decrease by one dose level  
 
2nd 
Interruption until Grade ≤ 2 
Decrease by one dose level  
 
3rd 
Permanent discontinuation 
– 
Grade 4 
1st 
Permanent discontinuation 
–  
CTCAE = Common Terminology Criteria for Adverse Events, version 4.03 
a: Despite maximum supportive therapy  
The lowest dose level is 30 mg; if a patient is already on the 30 mg dose level study drug and meets criteria 
for further decrease of dose, study drug will be discontinued permanently. 
Non-infectious pneumonitis  
In the event of suspected NIP, copanlisib/placebo treatment should be followed as Table 7–7. 
Pneumonitis is to be reported as such only in the event of NIP. 
Table 7–7 Dose adjustment in cases of non-infectious pneumonitis (NIP) 
Suspected or confirmed NIP 
per CTCAE 
Action Taken 
Re-treatment dose 
after recovery 
Grade 1 
No Change 
NA 
Grade 2 
Dose Interruption Until recovery 
to ≤ grade 1 
Decrease dose to the next 
lowest dose level a 
Grade 2 second re-occurrence 
Permanent Discontinuation 
NA 
Grade 3 
Permanent Discontinuation 
NA 
Grade 4 
Permanent Discontinuation 
NA 
NA = Not applicable; NIP = Non-infectious pneumonitis; CTCAE = Common Terminology Criteria for Adverse 
Events. 
a: Not applicable for 30 mg dose level. No re-escalation is allowed after the dose reduction. 
The lowest dose level is 30 mg; if a patient is already on the 30 mg dose level and cannot tolerate treatment study 
treatment will be discontinued permanently. 
The investigator is requested to differentiate between non-infectious pneumonitis (NIP), and 
infectious pneumonitis (viral, bacterial, fungal), aspiration pneumonitis, or other pneumonitis 
clearly not due to a potential hypersensitivity reaction to the copanlisib infusion; and provide 
the basis for his/her assessment that it is infectious or other, as appropriate. The investigator is 
requested to report with the most specific clinical terms to describe the condition, not simple 
“pneumonitis”. 

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Glucose increases and arterial hypertension  
a) Glucose increases  
Patients who develop transient post-infusion glucose > 250 mg/dL after copanlisib/placebo 
administration may continue treatment. However, the next infusion must be delayed until the 
patient’s pre-infusion glucose levels return to < 160 mg/dL (fasting) or < 200 mg/dL (non-
fasting). Guidelines for the management of glucose increases are given in Section 7.4.3.1. 
• Continuing occurrence of post-infusion blood glucose > 500 mg/dL based on repeated 
laboratory analysis despite optimal glucose lowering therapy after 2 infusions of 
copanlisib/placebo will require dose reduction by one dose level. 
• Further dose reduction is allowed as long as discontinuation criteria were not met. 
• Dose re-escalation is allowed when a patient has achieved controlled glucose levels 
per investigator’s judgment. 
• Persistent occurrence of post-infusion blood glucose > 500 mg/dL based on laboratory 
analysis which occurred at the lowest copanlisib/placebo dose level despite optimal 
glucose lowering therapy (after at least one cycle of treatment) requires permanent 
discontinuation of the study treatment (see Section 6.4.1.1). 
b) Arterial hypertension  
No copanlisib/placebo dose should be given if blood pressure is ≥ 150/90 mmHg. Instructions 
for blood pressure measurement are given in Section 9.6.3.4. Antihypertensive medication 
may be given to control the increased blood pressure. 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 copanlisib/placebo administrations may be reduced by 1 or 2 dose levels at the 
investigator’s discretion. Guidelines for the treatment of increased blood pressure are given in 
Section 7.4.3.3. Patients with a post-dose blood pressure that may have life-threatening 
consequences (e.g. malignant arterial hypertension, transient or permanent neurologic deficit, 
hypertensive crisis) must permanently discontinue the study drug.  
The guidelines for dose modifications of study treatment in case of arterial hypertension are 
given in Table 7–8. 

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Table 7–8 Dose modification of study treatment for arterial hypertension 
Toxicity  
(CTCAE severity grade) 
Study drug action 
Recommendation 
Pre-dose measurements 
BP ≥ 150/90 mmHg 
No dose should be given 
until recovery to 
< 150/90 mmHg. 
Consider administering BP lowering 
medication. Dosing can proceed on the 
scheduled day if after at least 2 
consecutive measurements BP returns 
to < 150/90 mmHg. If BP doesn’t return 
to < 150/90 mmHg then delay dosing 
until next visit. 
During infusion: 
BP ≥ 160/100 mmHg 
or CTCAE hypertension 
of Grade 3 
Infusion can be 
interrupted or slowed 
down and administration 
of BP lowering therapy 
should be initiated. 
Infusion may be resumed immediately 
when BP has returned to 
< 150/90 mmHg or otherwise skipped. 
Subsequent study drug administrations 
may be reduced by 1 dose level at the 
investigator’s discretionb. 
Post-dose: 
Drug-related BP 
≥ 160/100 mmHga  
or CTCAE hypertension 
of Grade 3 
– 
Administration of BP lowering therapy 
should be initiated according to local 
standard of care.  
Additional measurements to be 
performed as clinically indicated until 
recovery to < 150/90 mmHg.  
Subsequent study drug administrations 
may be reduced by 1 dose level at the 
investigator’s discretionb. 
CTCAE hypertension of 
grade 4 
Permanent 
discontinuation 
– 
BP = Blood pressure; CTCAE severity grade = Common Terminology Criteria for Adverse Events severity 
grade 
a: Not manageable despite optimal antihypertensive treatment. 
b: The lowest dose level is 30 mg; if a patient is already on the 30 mg dose level and experiences post-dose 
hypertension of CTCAE Grade 3 or ≥160/100 mmHg, consider more intensive therapy than previously 
used. 
 
7.4.3 
Treatment of toxicities 
Recommendations for the treatment of toxicities described below apply to copanlisib and 
placebo. For monitoring and management of adverse reactions following R-CHOP and R-B 
administration please refer to the respective drug’s SmPCs/prescribing information. 

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7.4.3.1 
Management of transient post-infusion glucose increases that can occur 
with copanlisib 
Management of transient post-infusion glucose increases on infusion days  
Mild to moderate asymptomatic increases of blood glucose may occur with copanlisib 
infusion, and with larger increases potentially occurring post-prandially. 
The guidelines for management of transient post-infusion glucose increases on infusion days 
are given in Table 7–9. 
Table 7–9 Management of transient post-infusion glucose increases  
Criteria  
Recommendation 
Suggested Treatment 
On infusion days:  
Asymptomatic glucose 
increases ≤ 250 mg/dL 
• Does not generally require treatment 
with glucose lowering medication 
 
None 
Asymptomatic glucose 
increases > 250 mg/dL 
• Should have repeated laboratory 
glucose determination 
• If the repeated glucose value is 
decreasing, the glucose may be 
followed without glucose lowering 
medication treatment if hydration 
status is normal as clinically 
assessed 
• Consultation with diabetologist or 
endocrinologist is recommended 
• Hydration if appropriate  
• When planning next infusion 
consider prophylaxis with oral 
glucose lowering medication 
Symptomatic or persisting 
glucose increases 
> 250 mg/dL 
• Hydration status should be clinically 
assessed 
• If clinical assessment is consistent 
with dehydration, fluids should be 
given as clinically appropriate (orally 
or IV). 
• Laboratory test confirming increase 
should be repeated. If the repeated 
glucose value is > 250 mg/dL and/or 
patient is symptomatic and/or the 
hydration status indicate the need for 
hydration, glucose lowering 
medication should be administered 
• Prompt input from a diabetologist or 
endocrinologist should be obtained.  
• Hydration if appropriate  
• Rapid/short acting insulin may 
be given for glucose persisting 
at > 250 mg/dL, or if the patient 
is symptomatic during the 
infusion day. 
• Rapid/short acting insulin 
according to the institution 
sliding scale coverage of 
glucose persisting at > 250 
mg/dL is recommended, with 
oral or IV hydration as clinically 
appropriate. 
• When planning next infusion 
consider prophylaxis with oral 
glucose lowering medication 

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Table 7–9 Management of transient post-infusion glucose increases  
Criteria  
Recommendation 
Suggested Treatment 
On subsequent days: 
Max post-infusion glucose 
> 200 mg/dL noted on 
subsequent days 
• Oral glucose lowering medication 
recommended on subsequent day 
• Consultation with diabetologist or 
endocrinologist is recommended 
• The use of 
sulphonylurea/metaglinides 
insulin secretagogues 
medications to manage 
increased glucose levels post 
drug infusions is not 
recommended. 
• Treatment with glucose lowering 
medication suggested according 
the local standards of practice.  
• Based on mechanisms of action 
and decreased risk of 
hypoglycemia, metformin, 
SGLT-2-inhibitor or DPP4-
inhibitor might be useful 
treatment options 
DPP4 = Dipeptidyl peptidase-4; IV = intravenous; SGLT-2 = Sodium/glucose co-transporter 2 
 
The need for glucose monitoring at home should be determined by the investigator based on 
post-infusion glucose profile and clinical status of the patient. 
Monitoring of diabetic patients 
If the patient has known diabetes and already monitors his/her blood glucose as part of routine 
diabetes care, the routine measurements should not be replaced by the study-specific 
measurements.  
7.4.3.2 
Management of hyperlipidemia 
As lipids are monitored for the duration of this study it is recommended to treat significant 
deviations from normal range with standard interventions and therapy in standard doses 
according to local medical practice. Goals of therapy are to keep fasting triglycerides 
< 300 mg/dL and low-density lipoproteins (LDL) < 190 mg/dL (lower LDL depending on 
cardiovascular risk) in patients with a life expectancy >1 year. The goals for fasting 
triglycerides can be raised to < 500 mg/dL for patients with life expectancy <1 year (16). 
Although there is a paucity of data on the effects of hyperlipidemia and cancer outcomes, 
these goals have been chosen to decrease risk of established complications of 
hypertriglyceridemia (pancreatitis) and hypercholesterolemia (cardiovascular events). For 
evaluation of lipid-panels including triglycerides patients must be fasting prior to sampling 
according to local standards. For patients who cannot adhere to these fasting requirements the 
evaluation of lipid-panels including triglycerides and determination of treatment is considered 
as not feasible. 

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7.4.3.3 
Treatment of blood pressure increases 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 blood pressure increases following copanlisib/placebo will need to 
be individualized for each patient, but experience in Phase I has suggested the benefit of 
dihydropyridine calcium channel blockers (i.e. amlodipine, felodipine). Nitrates, verapamil 
and diltiazem can also be considered. In general, it is advisable for sites to be prepared, so that 
antihypertensive medication is readily available in case of need.  
7.4.3.4 
Treatment of vomiting and diarrhea 
Hydration status of the patient should be clinically assessed, with fluid replacement (oral or 
IV) as appropriate. Adequate hydration through appropriate fluid maintenance is essential in 
the treatment of diarrhea or vomiting. Anti-diarrhea medications may be introduced if 
symptoms occur. The recommended dose of loperamide is 4 mg at first onset, followed by 
2 mg every 2 to 4 hours until diarrhea-free for 12 hours; a maximum daily dose of 16 mg is 
not to be exceeded. If clinically indicated, diphenoxylate hydrochloride with or without 
atropine sulfate can be used. The routine use of standard antiemetics, including 5-HT3 
blockers is allowed, see Section 8.1.2 for permitted concomitant therapy. In the event of 
CTCAE Grade 3 diarrhea with maximal pharmacological support, the administration of the 
study treatment should be delayed.  
7.4.3.5 
Treatment of dermatologic toxicity 
If dermatologic changes occur, the patient should be treated quickly and aggressively.  
Table 7–10 can be used as guidance. 

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Table 7–10 Guidance on treatment of skin toxicities 
MILD (CTCAE Grade 1) 
Dry Skin/Fissures Emollients, - Eucerin or Aquaphor plus gentle soaps  
(Dove, Cetaphil, Basis), use fragrance free detergents 
Rash 
Topical hydrocortisone 2.5% and/or clindamycin 1% gel plus doxycycline 100 mg 
bid or Minocycline 100 mg bid 
Nail Changes 
Moisturizers 
Pruritus 
Pramoxine 1% cream or Sarna Ultra Cream 
MODERATE (CTCAE Grade 2) 
Dry Skin/Fissures Emollients and topical as above plus Ammonium lactate or Urea 20% 
Rash 
Topical hydrocortisone 2.5% and/or clindamycin 1% gel plus doxycycline 100 mg 
bid or  
Minocycline 100 mg bid  
Nail Changes 
Vinegar soaks (dilute 1:1 white vinegar in water) and  
soak fingers for 10 minutes a day 
Pruritus 
H1-anti-histamines 
SEVERE (CTCAE Grade 3 or 4) 
Dry Skin/Fissures As above for Moderate 
Rash 
As above for Moderate plus Medrol dose pack a 
Nail Changes 
Topical antibacterials/antifungals (ciclopirox) cream or Topical high potency 
steroids (clobetasol ointment)  
Consider dermatology consult for nail avulsion 
Pruritus 
Pregabalin 50-100 mg bid  
bid = twice daily; CTCAE = Common Terminology Criteria for Adverse Events, version 4.03 
a: Cross check with short-term corticosteroid administration (see Section 6.2 and Section 8.1.2) 
Source: (18) 
If concomitant corticosteroids are used for dermatologic conditions, the investigator should be 
alert to potential impact of corticosteroids on increases in blood glucose and in blood 
pressure. Please refer to excluded previous therapies at Section 6.2. If glucose increases or 
blood pressure increases during the period of corticosteroid use, please see Section 7.4.3.1 for 
glucose management, and see Section 7.4.3.3 for blood pressure management. 
7.4.3.6 
Guidance for monitoring and prophylaxis of opportunistic infection 
(OI)  
7.4.3.6.1 Monitoring guidelines for OI 
In addition to the weekly clinical review and laboratory tests outlined in the schedule of 
assessment, the following should be performed in all patients prior to IV infusion of 
copanlisib: 
• Evaluation of any new onset or worsening of pulmonary symptoms (i.e. cough, 
dyspnea or fever) that includes a lung examination at each visit prior to infusion. 
• Laboratory tests: CD4 (for patients with signs of infection), blood cultures if febrile 
neutropenia occurs, PCR for CMV (every cycle on Cycle X Day 1 (time window -1 

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day) during combination therapy and every 3 cycles starting from Cycle 7). CMV can 
be analyzed retrospectively in case the results are not immediately available. 
o Note: If PCR test is positive for CMV, treatment should be delayed until 
recovery. CMV PCR test is considered positive if, the result can be interpreted 
as a CMV viremia according to local SOC. Treatment of CMV should be 
initiated based on local standard of care (SOC). Retreatment with copanlisib 
will be allowed without dose reduction once PCR test for CMV is negative. 
Enhanced monitoring when prior medical history or laboratory parameters could be associated 
with one of the following risk factors: 
• Intensive chemotherapy (≥2 lines of myelosuppressive cytotoxic therapy) 
• History of CMV, herpes 
• History of lower respiratory tract infection, history of immunodeficiency in the last 
12 months (excluding lymphoma) 
• Lymphocytes count < 500/mm3 while on treatment in clinical study. 
For patients with identified risk factors and those who developed OI on study treatment, 
additional assessments can (per institutional recommendation/guideline) include: 
• CD4 and CD8 count and ratio, CRP, blood cultures 
• Any additional laboratory and diagnostic methods according to local SOC reported as 
unscheduled laboratory and diagnostic methods of assessment  
• Radiological imaging (i.e. chest X-ray [CXR] or CT scans) 
o Note: Treatment of developed OI should be based on local SOC. 
7.4.3.6.2 Prophylaxis of OI 
Mandatory prophylactic therapy is not recommended in all patients: 
• Review of copanlisib data does not support risk benefit ratio favoring prophylaxis in 
all patients 
• Mandatory prophylaxis may cause a higher risk of side effects associated with 
supportive treatment where no risk factors are present 
• Currently implemented schedule of assessments and additional enhancements provide 
frequent monitoring and flexibility for prophylaxis based on local SOC. 
Although not mandated in all patients, OI prophylaxis may be initiated at the discretion of the 
treating investigator’s judgment of the benefit/risk ratio in any patient, irrespective of whether 
a high-risk feature is present, per local SOC. If so, treatment, dosage and route of 
administration must be reported on the concomitant medication page of the eCRF. 
Prophylactic treatment of OI should be initiated based on SOC in patients when high risk 
factors are identified (see protocol Section 7.4.3.6.1). Treatment, dosage and route of 
administration must be reported on the concomitant medication page of the eCRF. 

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7.5 
Blinding 
Blinding measures are only applicable for the phase III part which follows double-blind 
design. The safety run-in part is open-label.  
Patients will be randomized to receive copanlisib in combination with R-B/R-CHOP or 
placebo in combination with R-B/R-CHOP, in a double-blinded fashion, so that neither the 
investigator, nor the sponsor, nor the patient will know which agent is being administered. 
The randomization number will be assigned through the IVRS/IWRS based on information 
entered by the site staff when the patient qualifies for study treatment.  
During the phase III part DMC will review the unblinded data per DMC charter of all patients 
treated up to that time point (or as needed) to ensure that patients are not exposed to undue 
risk. The investigators, patients and the sponsor will remain blinded. 
The appearance of the packaging for copanlisib and placebo will be identical in order to 
preserve blinding. Both will be packaged in a drug pack labeled with a unique drug pack 
number which will be pre-printed. The study drug pack number will be assigned to the patient 
through the IVRS/IWRS.  
Because copanlisib solution may have a yellowish color while the placebo solution is 
colorless, measures will be taken to preserve the blind. This includes an unblinded, study-
independent pharmacist (or qualified person) who will handle the preparation of the study 
drug, and independent monitors, separate from the blinded monitoring team, to conduct the 
monitoring of the pharmacy and drug supplies. Additional details will be described in the 
Pharmacy Manual. 
In compliance with applicable regulations, in the event of a suspected, unexpected, serious 
adverse reaction (SUSAR) (see Section 9.6.1.5) related to the blinded treatment, the patient’s 
treatment code will usually be unblinded before reporting to the health authorities, ethic 
committees and investigators (see Section 9.6.1.4). 
Emergency unblinding by the investigator 
Unblinding of the patient’s treatment assignment may be carried out by the investigator for 
emergency purposes only. Investigators should note that the occurrence of an SAE should not 
routinely precipitate the immediate unblinding of the study drug. If unblinding is necessary 
for the treatment of a patient who has experienced an SAE, the treatment assignment of a 
patient will be unblinded via instructions provided through the IVRS/IWRS. This system 
allows the investigator, or other responsible person, to identify the study drug in case of an 
emergency, without jeopardizing the double-blind integrity of the remainder of the study.  
The code can be broken by the investigator, or other responsible person, when knowledge of 
the patient’s treatment is required for the clinical management of the patient. If it becomes 
necessary to know the individual’s treatment during the study and, thus, break the code for 
that patient, the date and reason are to be entered in the relevant eCRF page. The investigator 
is required to promptly document and explain to the sponsor’s designee any premature 
unblinding (e.g. unblinding due to an SAE) of the study drug. At the end of the study access 
to IxRS (which gives access to code break information) for the principal investigator will be 
revoked. 

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7.6 
Drug logistics and accountability 
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practice (GMP) requirements and the instructions 
given by the clinical supplies 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’s study file; the site-relevant elements of this information will be available in the 
investigator site file.  
The responsible site personnel will confirm receipt of all centrally supplied study drugs 
(sponsor supplied) via IVRS/IWRS.  The handling of batch numbers and expiry dates for 
locally supplied (site supplied) background treatments used in the study will be documented 
in the sponsor’s supporting operational procedures/plans. The personnel 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 and specified procedures.   
Written instructions on medication destruction will be made available to affected parties as 
applicable. 
If performing drug accountability implies a potential risk of contamination, a safety process/ 
guidance for handling returned drug will be provided. 
7.7 
Treatment compliance 
The administration of intravenous copanlisib/placebo, immunochemotherapy (R-CHOP or 
R-B) will be performed in the clinic and must be recorded in the source data and in the 
eCRF. Reasons for dose delay, interruption or reduction will also be recorded in the source 
data and in the eCRF.  
Prednisone will be administered PO from Day 2 to Day 6 q3w. In countries where prednisone 
is not available, prednisolone can be administered instead. Only the dose given on Day 2 will 
be administered in the clinic. From Day 3 to Day 6 prednisone will be self-administered by 
the patient at home. For prednisone which is self-administered by the patient at home, the 
patient will return the empty blisters and unused tablets at the visit when the new prednisone 
is supplied. At this visit, site staff will review the returned amount to verify drug compliance. 
This review and count will be documented in source data. Any discrepancies between actual 
and expected amount of returned study medication must be discussed with the patient at the 
time of the visit, and any explanation must be documented in the source records. 
8. 
Non-study therapy 
8.1 
Prior and concomitant therapy 
For prohibited prior therapy please refer to Section 6.2. 

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8.1.1 
Prohibited concomitant therapy 
• CYP3A4 inhibitors and inducers (see Appendix 16.1). Copanlisib is primarily 
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, phenytoin, 
carbamazepine, phenobarbital, St. John's Wort) are not permitted within two weeks 
prior to start of study treatment until the SFU visit. 
• Grapefruit and grapefruit juice (CYP3A4 inhibitor), Seville oranges and star fruit 
consumption is not permitted during the study. 
• Anti-arrhythmic therapy other than beta blockers or digoxin. 
• Concomitant therapy with any anticancer agents, immunosuppressive agents, other 
investigational anticancer therapies.  
• Concomitant radiotherapy (it is assumed that radiation would be indicated only in case 
of progression, when the patient would come off study treatment anyway). Palliative 
radiotherapy is allowed (see Permitted concomitant therapy for details). 
• Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg 
prednisone or equivalent is not allowed. Patients may be using topical or inhaled 
corticosteroids. Previous corticosteroid therapy must be stopped or reduced to the 
allowed dose at least 7 days before performing the screening PET-CT and/or CT/MRI, 
whichever is performed first, and again at least 7 days prior to the first study drug 
administration. If a patient is on chronic corticosteroid therapy, corticosteroids should 
be de-escalated to the maximum allowed dose after the patient has signed the IC. The 
use of corticosteroids as antiemetics prior to copanlisib/placebo administration will not 
be allowed.  
• Since the use of Biotin (vitamin B7) produce high levels of the vitamin, these can 
interfere with the result of the immunoassay tests including biomarker analysis, HBc-
Ab, HBe-Ag, HBs-Ag, HCV-Ab, HIV-Ag/Ab combo, HIV combo, therefore refrain 
the use of Biotin for at least 72 hours prior to immunoassay test collection. 
8.1.2 
Permitted concomitant therapy 
• Standard therapies for concurrent medical conditions. 
• Treatment with non-conventional therapies (for example herbs or acupuncture), and 
vitamin/mineral supplements is acceptable provided that they do not interfere with the 
study endpoints, in the opinion of the Investigator. St John's Wort is not permitted. 
• Bisphosphonates. 
• Patients who are therapeutically treated with an agent such as warfarin or heparin will 
be allowed to participate provided that their medication dose and INR/PTT is stable. 
Close monitoring is recommended according to standard of care. If either of these 
values is above the therapeutic range, the doses should be modified and the 
assessments should be repeated weekly until it is stable. 

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• Antiemetics: prophylactic anti-emetics may be administered according to standard 
practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as 
granisetron, ondansetron, or an equivalent agent, is allowed as needed. The use of 
corticosteroids as antiemetics prior to study drug administration will be not allowed.  
• Palliative and supportive care for the other disease-related symptoms and for toxicity 
associated with treatment will be offered to all patients in this trial. 
• Patients may receive palliative and supportive care for any underlying illness.  
• Palliative irradiation shall be permitted provided that: 
o In the opinion of the investigator, the patient does not have PD. 
o The radiation field does not encompass a target lesion 
o The radiation field does not encompass a lung field (to reduce the risk for 
pneumonitis). 
• Low-dose aspirin (maximum 100 mg/day) and low-dose heparin are permitted. 
• Patients taking narrow therapeutic index medications should be monitored proactively, 
if these medications cannot be avoided. These medications may include quinidine and 
digoxin. 
• Substrates of the renal drug transporter MATE2K (e.g. metformin, cimetidine, 
procainamide and N methylnicotinamide) need to be used with caution. Metformin 
should be temporarily discontinued in patients undergoing radiologic studies involving 
intravascular administration of iodinated contrast. Please refer to prescribing 
information for further information. 
• Calcium channel blockers to control pre-existing hypertension. 
• Short term (up to 7 days) systemic corticosteroids above 15 mg prednisone or 
equivalent will be allowed for the management of acute conditions (e.g. treatment of 
NIP) and as premedication prior to rituximab and bendamustine infusions (if 
considered standard of care) (see Section 9.6.3.2 for the required glucose 
measurements). The investigator should be alert to potential impact of corticosteroids 
on increases in blood glucose and in blood pressure. If glucose increases or blood 
pressure increases during the period of corticosteroid use as premedication described 
above, please see Section 7.4.3.1 for glucose management and see Section 7.4.3.3 for 
blood pressure management. 
• G-CSF is mandatory if ANC<1000/mm3 and should be administered as per label (see 
also Section 7.4 “Dosing criteria”). 
8.2 
Post-study therapy 
After the end of this study, further therapy is at the discretion of the investigator. 

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9. 
Procedures and variables 
In the event of a significant study-continuity issue (e.g. caused by a pandemic), alternate 
strategies for participant visits, assessments, and monitoring may be implemented by the 
Sponsor or the investigator in consultation with the Sponsor, in line with local health 
authority/ethics requirements. 
9.1 
Tabular schedule of evaluations 
This section contains three tabular schedule of evaluations which are valid to both safety run-
in part and phase III part of the study (unless otherwise specified): 
Table 9–1 for copanlisib/placebo + R-B combination therapy, 
Table 9–2 for copanlisib/placebo + R-CHOP combination therapy, and  
Table 9–3 for copanlisib/placebo monotherapy (from C7 onwards).  
The footnotes apply to all tables. 

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Table 9–1 Study flow chart – Screening and copanlisib + R-B combination therapy  
(for procedures during the copanlisib/placebo monotherapy and after treatment, see Table 9–3) 
 
Screening 
maximum days 
before C1D1 
Treatment during the combination therapy (C1-C6) 
Cycle 1 
Cycle 2 to Cycle 6 
Days 
-28 
-14 
-7 
D1 
D2 
D8 
D15 
D22 ii 
D1 
D2 
D8 
D15 
D22 ii 
Acceptable deviation for study drug 
administration (unless otherwise 
specified) (in days) hh 
 
-1 to + 
2 days 
dd 
 
-1 to + 2 days dd 
-1 to + 2 
days dd 
 
1 to + 2 days dd 
Screening and enrollment 
 
 
Patient informed consent (including 
genetic) a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Check in- and exclusion criteria 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Medical history b 
 
X 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS transaction c 
X 
 
 
Xc 
 
 
 
 
X 
 
 
 
 
HBsAg, HBcAb, and anti-HCV 
antibody (HBV DNA, HCV RNA)aa,hh 
X 
 
 
 
 
 
 
 
Xaa 
 
 
 
 
CMV PCRgg,hh 
X 
 
 
Xee 
 
 
 
 
Xee 
 
 
 
 
HIV test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-2-microglobulin (for patients with 
WM/FL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (if applicable) d 
 
 
X 
 
 
 
 
 
Xd 
 
 
 
 
UPCR/ 24 h total urine protein 
quantification cc,hh 
 
 
X 
 
 
 
 
 
 
 
 
 
 
GFR calculation (MDRD abbreviated 
formula) e 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity / AE assessment f 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
Concomitant medication f 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
Complete physical examination  
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
Brief physical examination and status 
check, including lung examination hh 
 
 
 
 
 
X 
X 
 
 
 
X 
X 
 
12-lead ECG g 
X 
 
 
X 
 
 
 
 
Xg 
 
 
 
 
MUGA scan or echocardiogram h 
 
X 
 
 
 
 
 
 
Xh 
 
 
 
 
Hemoglobin A1c i 
 
 
X 
 
 
 
 
 
Xi 
 
 
 
 
Complete blood count hh 
 
 
X 
X 
 
X 
X 
 
X 
 
X  
X  
 
Chemistry panel k 
 
 
Xk 
 
 
X 
X 
 
Xk 
 
C2 only 
C2 only 
 
Coagulation panel: PTT,PT and INR  
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Urinalysis (dipstick) 
 
 
X 
 
 
 
 
 
X 
 
 
 
 

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Table 9–1 Study flow chart – Screening and copanlisib + R-B combination therapy  
(for procedures during the copanlisib/placebo monotherapy and after treatment, see Table 9–3) 
 
Screening 
maximum days 
before C1D1 
Treatment during the combination therapy (C1-C6) 
Cycle 1 
Cycle 2 to Cycle 6 
Days 
-28 
-14 
-7 
D1 
D2 
D8 
D15 
D22 ii 
D1 
D2 
D8 
D15 
D22 ii 
Acceptable deviation for study drug 
administration (unless otherwise 
specified) (in days) hh 
 
-1 to + 
2 days 
dd 
 
-1 to + 2 days dd 
-1 to + 2 
days dd 
 
1 to + 2 days dd 
CD4 (for patients with signs of 
infection) and blood cultures if 
febrile neutropenia occurs gg,ff,hh 
 
 
 
 
 
 
 
 
 
 
 
Glucose l,hh 
 
 
 
X 
(X)bb 
X 
X 
 
X 
(X)bb 
X 
X 
 
Blood pressure n 
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
Efficacy 
 
 
 
 
CT / MRI and tumor evaluations o  
X 
 
 
Every 12 weeks 
PET-CT 
X 
 
 
If performed at BL, PET-CT should be repeated after the Cycle 6 if a PD is not detected during
the course of treatment and/or to confirm complete response (CR) or disease progression 
Bone marrow biopsy  
X 
 
 
Confirmation of first CR (if positive for lymphoma infiltration at BL) 
Phase III: QoL questionnaire 
(FLymSI-18) p  
 
 
 
X 
 
 
 
 
Xp 
 
 
 
 
Pharmacokinetic sample q 
 
 
 
X 
 
X 
 
 
C6 
 
C3,C6 
 
 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh and/or or archival tumor tissue 
(central pathology and biomarkers) r 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma for tumor genetics s 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Plasma for non-genetic biomarker 
analysis t 
X 
 
 
X 
 
X 
X 
 
C2  
only 
 
C2  
only 
C2  
only 
 
Whole blood for biomarkers u 
 
 
 
X 
 
 
 
 
 
 
 
 
 
For LPL/WM patients only v 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum protein electrophoresis v 
 
Xv 
 
 
 
 
 
 
 
 
 
 
(X)v 
Immunofixation v 
 
Xv 
 
 
 
 
 
 
 
 
 
 
(X)v 
Serum quantitative IgM test v 
 
Xv 
 
 
 
 
 
 
 
 
 
 
(X)v 
Serum or plasma viscosity 
 
Xv 
 
 
 
 
 
 
(X)v 
 
 
 
 
Drug administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copanlisib/placebo  
 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
R-B (Cycles 1-6) : rituximab D1, 
bendamustine D1, D2 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
For abbreviations and footnotes, see Table 9–3. 

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Table 9–2 Study flow chart – Screening and copanlisib + R-CHOP combination therapy  
(for procedures during the copanlisib/placebo monotherapy and after treatment, see Table 9–3) 
 
Screening  
maximum days 
before C1D1 
Treatment during the combination therapy 
Cycle 1 
Cycle 2 to Cycle 6 
Days 
-28 
-14 
-7 
D1 
D2 
D8 
D15 ii 
D1 
D2 
D8 
D15 ii 
Acceptable deviation  for study drug 
administration (unless otherwise 
specified) (in days) hh 
 
-1 to + 2 
days dd 
 
-1 to + 2 days 
dd 
-1 to + 2 
days dd 
 
-1 to + 2 days dd 
Screening and enrollment 
 
Patient informed consent (including 
genetic) a 
X 
 
 
 
 
 
 
 
 
 
 
Check in- and exclusion criteria 
 
X 
X 
X 
 
 
 
 
 
 
 
Medical history b 
 
X 
 
 
 
 
 
 
 
 
 
IVRS/IWRS transaction c 
X 
 
 
Xc 
 
 
 
X 
 
 
 
HBsAg, HBcAb, and anti-HCV 
antibody (HBV DNA, HCV RNA)aa,hh 
X 
 
 
 
 
 
 
Xaa 
 
 
 
CMV PCRgg,hh 
X 
 
 
Xee 
 
 
 
Xee 
 
 
 
HIV test 
X 
 
 
 
 
 
 
 
 
 
 
Beta-2-microglobulin (for patients with 
WM/FL) 
 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (if applicable) d 
 
 
X 
 
 
 
 
Xd 
 
 
 
UPCR/ 24 h total urine protein 
quantificationcc,hh 
 
 
X 
 
 
 
 
 
 
 
 
GFR calculation (MDRD abbreviated 
formula) e 
 
 
X 
 
 
 
 
X 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
Toxicity / AE assessment f 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Concomitant medication f 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Complete physical examination  
 
X 
 
X 
 
 
 
X 
 
 
 
Brief physical examination and status 
check, including lung examination hh 
 
 
 
 
 
X 
 
 
 
X 
 
12-lead ECG g 
X 
 
 
X 
 
 
 
Xg 
 
 
 
MUGA scan or echocardiogram h 
 
X 
 
 
 
 
 
Xh 
 
 
 
Hemoglobin A1c i 
 
 
X 
 
 
 
 
Xi 
 
 
 
Complete blood count hh 
 
 
X 
X 
 
X 
 
X 
 
 X 
 
Chemistry panel k 
 
 
Xk 
 
 
X 
 
Xk 
 
C2 only 
 
Coagulation panel: PTT,PT and INR  
 
 
X 
 
 
 
 
X 
 
 
 
Urinalysis (dipstick) 
 
 
X 
 
 
 
 
X 
 
 
 

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Table 9–2 Study flow chart – Screening and copanlisib + R-CHOP combination therapy  
(for procedures during the copanlisib/placebo monotherapy and after treatment, see Table 9–3) 
 
Screening  
maximum days 
before C1D1 
Treatment during the combination therapy 
Cycle 1 
Cycle 2 to Cycle 6 
Days 
-28 
-14 
-7 
D1 
D2 
D8 
D15 ii 
D1 
D2 
D8 
D15 ii 
Acceptable deviation  for study drug 
administration (unless otherwise 
specified) (in days) hh 
 
-1 to + 2 
days dd 
 
-1 to + 2 days 
dd 
-1 to + 2 
days dd 
 
-1 to + 2 days dd 
CD4 (for patients with signs of 
infection) and blood cultures if 
febrile neutropenia occurs gg,ff,hh 
 
 
 
 
 
 
 
 
 
 
 
Glucose l 
 
 
 
X 
(X)bb 
X 
 
X 
(X)bb 
X 
 
Blood pressure n 
 
 
 
X 
 
X 
 
X 
 
X 
 
Efficacy 
 
 
 
 
CT / MRI and tumor evaluations o  
X 
 
 
                                          Every 12 weeks 
PET-CT 
X 
 
 
If performed at BL, PET-CT should be repeated after the Cycle 6 if a PD is 
not detected during the course of treatment and/or to confirm complete 
response (CR) or disease progression 
Bone marrow biopsy  
X 
 
 
Confirmation of first CR (if positive for lymphoma infiltration at BL) 
Phase III: QoL questionnaire  
(FLymSI-18) p  
 
 
 
X 
 
 
 
Xp 
 
 
 
Pharmacokinetic sample q 
 
 
 
X 
X 
X 
 
 
C6 
C3,C6 
 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
Fresh and/or or archival tumor tissue 
(central pathology and biomarkers) r 
X 
 
 
 
 
 
 
 
 
 
 
Plasma for tumor genetics s 
 
 
 
X 
 
 
 
 
 
 
 
Plasma for non-genetic biomarker 
analysis t 
X 
 
 
X 
 
X 
X 
C2  
only 
 
C2  
only 
C2 z 
only 
Whole blood for biomarkers u 
 
 
 
X 
 
 
 
 
 
 
 
For LPL/WM patients only v 
 
 
 
 
 
 
 
 
 
 
 
Serum protein electrophoresis v 
 
Xv 
 
 
 
 
 
 
 
 
(X)v 
Immunofixation v 
 
Xv 
 
 
 
 
 
 
 
 
(X)v 
Serum quantitative IgM test v 
 
Xv 
 
 
 
 
 
 
 
 
(X)v 
Serum or plasma viscosity v 
 
Xv 
 
 
 
 
 
(X) v 
 
 
 
Drug administration 
 
 
 
 
 
 
 
 
 
 
 
Copanlisib/placebo  
 
 
 
X 
 
X 
 
X 
 
X 
 

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Table 9–2 Study flow chart – Screening and copanlisib + R-CHOP combination therapy  
(for procedures during the copanlisib/placebo monotherapy and after treatment, see Table 9–3) 
 
Screening  
maximum days 
before C1D1 
Treatment during the combination therapy 
Cycle 1 
Cycle 2 to Cycle 6 
Days 
-28 
-14 
-7 
D1 
D2 
D8 
D15 ii 
D1 
D2 
D8 
D15 ii 
Acceptable deviation  for study drug 
administration (unless otherwise 
specified) (in days) hh 
 
-1 to + 2 
days dd 
 
-1 to + 2 days 
dd 
-1 to + 2 
days dd 
 
-1 to + 2 days dd 
R-CHOP (Cycles 1-6): rituximab, 
cyclophosphamide, doxorubicin and  
vincristine on D2, 
prednisone/prednisolone D2-6. 
 
 
 
 
X 
 
 
 
X 
 
 
 
For abbreviations and footnotes, see Table 9–3. 
Table 9–3 Study flow chart – copanlisib/placebo monotherapy (from C7 onwards) 
 
Treatment 
EOT 
Safety FU 
Active 
FU x 
Survival FU y 
Cycle 7 and higher 
Within (days) 
Days 
D1 
D8 
D15 
D22 ii 
7 
after decision
to stop hh 
30 w 
after last 
dose hh 
 
every 3 months
Acceptable deviation  for study drug 
administration (unless otherwise 
specified) (in days) hh 
-1 to + 2 days dd 
 
+ 5 days hh 
 
 14 days 
IVRS/IWRS transaction c 
X 
 
 
 
X 
 
 
 
Serum pregnancy test (if applicable) d 
X d 
 
 
 
X d 
X d 
 
 
GFR calculation (MDRD abbreviated 
formula)e  
X 
 
 
 
 
 
 
 
CMV PCR gg,hh 
Xee 
 
 
 
 
 
 
 
HBsAg, HBcAb, and anti-HCV 
antibody (HBV DNA, HCV RNA)aa 
Xaa 
 
 
 
 
 
Xaa 
 
Safety 
 
 
 
 
 
 
 
 
Toxicity / AE assessment f 
X 
X 
X 
 
X 
X 
(X)f 
 
Concomitant medication f 
X 
X 
X 
 
X 
X 
 
 
Complete physical examination  
X 
 
 
 
X 
 
 
 
Brief physical examination and status 
check, including lung examination hh 
 
X 
X 
 
 
(X) 
 
 

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Table 9–3 Study flow chart – copanlisib/placebo monotherapy (from C7 onwards) 
 
Treatment 
EOT 
Safety FU 
Active 
FU x 
Survival FU y 
Cycle 7 and higher 
Within (days) 
Days 
D1 
D8 
D15 
D22 ii 
7 
after decision
to stop hh 
30 w 
after last 
dose hh 
 
every 3 months
Acceptable deviation  for study drug 
administration (unless otherwise 
specified) (in days) hh 
-1 to + 2 days dd 
 
+ 5 days hh 
 
 14 days 
12-lead ECG g 
X g 
 
 
 
(X)g 
 
 
 
MUGA scan or echocardiogram h 
X h 
 
 
 
(X)h 
 
 
 
Hemoglobin A1c i 
X i 
 
 
 
X 
 
 
 
Complete blood count hh 
X 
X 
X 
 
X 
(X) 
 
 
Chemistry panel k 
X k 
 
 
 
Xk 
(X) 
 
 
Coagulation panel: PTT,PT and INR  
X 
 
 
 
X 
(X) 
 
 
Urinalysis (dipstick) 
X 
 
 
 
X 
 
 
 
CD4 (for patients with signs of 
infection) and blood cultures if 
febrile neutropenia occurs gg,ff, hh 
 
 
 
 
 
 
 
 
Glucose l 
X 
X 
X 
 
 
 
 
 
Blood pressure n 
X 
X 
X 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
CT / MRI and tumor evaluations o  
Every 12 weeks from Cycle 1 Day 1 during 
Year 1 and 2 and every 24 weeks during 
Year 3 and beyond o 
(X)o 
 
Xo 
 
PET-CT 
If performed at BL, PET-CT should be 
repeated after the Cycle 6 if a PD is not 
detected during the course of treatment 
and/or to confirm complete response (CR) 
or disease progression 
(X)o 
 
(X)o 
 
Bone marrow biopsy  
Confirmation of first CR (if positive for 
lymphoma infiltration at BL) 
 
 
 
 
Phase III: QoL questionnaire 
(FLymSI-18) p  
X p 
 
 
 
X 
X 
X 
 
For LPL/WM patients only v 
 
 
 
 
 
 
 
 
Serum protein electrophoresis v 
 
 
 
(X)v 
(X)v 
 
Xv 
 
Immunofixationv 
 
 
 
(X)v 
(X)v 
 
Xv 
 
Serum quantitative IgM test v 
 
 
 
(X)v 
(X)v 
 
Xv 
 
Serum or plasma viscosity v 
(X)v 
 
 
 
(X)v 
 
 
 
Biomarkers  
 
 
 
 
 
 
 
 

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Table 9–3 Study flow chart – copanlisib/placebo monotherapy (from C7 onwards) 
 
Treatment 
EOT 
Safety FU 
Active 
FU x 
Survival FU y 
Cycle 7 and higher 
Within (days) 
Days 
D1 
D8 
D15 
D22 ii 
7 
after decision
to stop hh 
30 w 
after last 
dose hh 
 
every 3 months
Acceptable deviation  for study drug 
administration (unless otherwise 
specified) (in days) hh 
-1 to + 2 days dd 
 
+ 5 days hh 
 
 14 days 
Tumor tissue (central pathology and 
biomarkers) r 
 
 
 
 
(X)r 
 
 
 
Plasma for tumor genetics s, hh 
 
 
 
 
X 
 
 
 
Plasma for non-genetic biomarker 
analysis t,hh 
 
 
 
 
X 
 
 
 
Drug administration 
 
 
 
 
 
 
 
 
Copanlisib/placebo  
X 
X 
X 
 
 
 
 
 
Survival status, new anticancer 
therapy 
 
 
 
 
 
 
 
X 
 
AE = adverse event; BL = baseline; C = cycle; CBC = complete blood count; CD = cluster of differentiation; CMV = cytomegalovirus; CT = computed tomography; 
CR = complete response; CRP = C-reactive protein; CXR = Chest X-ray; D = day; DNA = deoxyribonucleic acid ; ECG = electrocardiogram; EOT = end of 
treatment; FL = follicular lymphoma; FLymSI-18 = NCCN-FACT Lymphoma Symptom Index-18; FU = follow-up; GFR = glomerular filtration rate; HBV = hepatitis 
B virus; HbA1C = glycated hemoglobin; HBcAb  = Hepatitis B core antibody; HBsAg = Hepatitis B surface antigen; HCV = hepatitis C virus; IgM = immunoglobulin 
M; INR = international normalized ratio; IV = intravenous; IVRS = interactive voice response system; IWRS = interactive web response system; LDL = low-density 
lipoprotein; LPL/WM = Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia; LVEF = left ventricular ejection fraction; MDRD = modification of diet in 
renal disease; MRI = magnetic resonance imaging; MUGA = multiple gated acquisition; OI = opportunistic infection; PCR = polymerase chain reaction; PD = 
progressive disease; PET-CT = positron emission tomography-computed tomography; PK = pharmacokinetics; PRO = patient-reported outcomes; 
PT = prothrombin time; PTT = partial thromboplastin time, QoL = quality of life; QTB = QT interval corrected for heart rate – Bazett; QTcF = QT interval corrected 
for heart rate – Fridericia; RNA = ribonucleic acid; SAE = serious adverse event; SFU = safety follow-up; SmPC = summary of product characteristics; 
SOC = standard of care; UPCR = urine protein to creatinine ratio; WM = Waldenström macroglobulinemia. 
a Written patient informed consent must be obtained prior to any study-specific procedures. Certain results from diagnostic testing prior to the informed consent 
date and time may be used to fulfill screening criteria (for further details, see Section 13.4).  
b Complete medical and surgical history including demographics (see Section 9.3.1), relevant medical history findings, concomitant illnesses, allergy history, 
prior surgeries, most recent histology of tumor, most recent staging and grading of tumor, history of anti-cancer treatments (including type of treatment, type of 
response, date and duration of response), and assessment of baseline toxicity.  
c IVRS/IWRS transaction to register the patient in the system will be at Screening. IVRS/IWRS randomization transaction will take place maximum 72 hours 
before the first dose (Cycle 1 Day 1). IVRS/IWRS transactions for medication dispensing at Cycle 2 and above will be on Day 1 of each cycle or as described 
in the Pharmacy Manual. Please refer to the Pharmacy Manual and the relevant SmPCs for detailed instructions regarding the timing requirements for the 

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dose preparation. The transaction to register end of treatment will be at the EOT visit.  
d After Cycle 1 serum pregnancy test is mandatory on Day 1 of every cycle, at the EOT visit and SFU visit for countries where it is required by local regulations. 
See Section 9.6.3.1. 
e If not on target, this evaluation may be repeated once after at least 24 hours either according to the MDRD abbreviated formula or by 24 hour sampling (see 
also Appendix 16.7). 
f 
Contrast media does not need to be recorded as concomitant medication unless there is an AE related to its administration (e.g. allergic reaction). During the 
Active follow-up period, AEs and SAEs assessed as related to study procedures by the investigator will be reported in the usual manner. 
g 12-lead ECG (including QTcB and QTcF evaluation) at Screening (within 28 days of Cycle 1 Day 1), on Cycle 1 Day 1 and on Day 1 of every 3rd cycle starting 
from Cycle 3 (3, 6, 9, etc.), prior to and at the end of copanlisib/placebo infusion (window of up to 2 hours prior to and post- infusion is allowed). At EOT visit, a 
12-lead ECG is necessary only if not recorded within the previous 4 weeks. 
h MUGA scan/echocardiogram to measure LVEF at Screening (within 14 days before Cycle 1 Day 1), and within 7 days prior to dosing on Day 1 of every 3rd 
cycle (3, 6, 9, etc.) and at EOT(if not previously done within 4 weeks). Same modality must be used throughout the study. See Section 9.6.3.7. 
i 
Hemoglobin A1c (HbA1c) at Screening, on Day 1 of every three cycles (4, 7, 10, etc.) starting from Cycle 4 and at the EOT visit (if not performed within 4 
weeks preceding the EOT visit). Final HbA1C test should be performed approximately 3 months after the EOT visit date whenever possible. 
j 
Footnote deleted by amendment 2, please see revised visits for CBC.  
k Complete chemistry panel with triglycerides, LDL cholesterol and total cholesterol will be tested only at Screening, on Day 1 of every second cycle (2, 4, 6 
etc.) starting from Cycle 2, and at EOT visit. On these days the patients must be fasting prior to sampling according to local standards. If a patient cannot 
adhere to fasting requirements, the evaluation of lipid-panels including triglycerides is considered not feasible (see Section 9.6.3.1). 
l 
On Cycle 1 Day 1, glucose will be measured at pre-dose, and post-dose 1 h and 2 h after the end of study drug infusion; and at the end of the rituximab 
infusion (deviation of ± 10 min is allowed); and at the end of bendamustine infusion (±10min) if patient receives corticosteroid premedication prior to 
bendamustine infusion, according to guidance provided in Section 9.6.3.2. On subsequent infusions, glucose will be measured prior to copanlisib/placebo 
infusion and 1 h after the end of copanlisib/placebo infusion; and at the end of the rituximab infusion; and at the end of bendamustine infusion (±10min) if 
patient receives corticosteroid premedication prior to bendamustine infusion. 
m Home glucose monitoring removed by amendment 6 
n Blood pressure will be measured at pre-dose and at specified time points during and after the study drug infusion according to guidance provided in 
Section 9.6.3.5. In addition, on Day 1, blood pressure will be measured 30 minutes after the start of rituximab infusion and at the end of rituximab infusion 
from Cycle 1-6 in the R-B treatment group. 
o The first IV (and oral, if indicated, per Imaging Manual) contrast enhanced CT/MRI and/or PET-CT scans of neck, chest, abdomen and pelvis must be performed 
at Screening (including WM patients). During treatment and Active follow-up period including all patients who discontinued treatment due to any other reason 
than PD, tumor scans will be done with the same modality every 12 weeks (± 7 days) from Cycle 1 Day 1 during Year 1 and 2, every 24 weeks (± 7 days) during 
Year 3, 4, and 5, and every 24 weeks (±14 days) beyond Year 5. CT/MRI scans are not required at the EOT visit if the patient has been radiologically evaluated 
within the 4 weeks preceding EOT. Tumor scans will be done until PD is centrally evaluated and documented and will continue up to 2 years beyond study 
primary completion or until new anti-tumor treatment is administered. PET functional imaging is optional in this study and should be done based on institutional 
standards. PET-CT can be utilized throughout the study if it is considered standard of care at the institution and according to Section 9.8. See Section 9.2.1.3. 
p Phase III: FLymSI-18 questionnaire is to be completed on Day 1 of every cycle, at the EOT visit and Safety FU visit. During the Active FU, patients will 
complete the FLymSI-18 questionnaire at the same visits as follow-up tumor assessments will be done. The FLymSI-18 should be completed for up to at least 

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1 year after study primary completion or until the sponsor advises termination of its collection. Questionnaire should be self-administered by the patient at the 
start of the visit before contact with the investigator or other investigative site personnel. A PRO information sheet will be completed by the study personnel at 
each visit at which FLymSI-18 questionnaire is to be administered, regardless of whether or not the FLymSI-18 questionnaire is completed by the patient.  
q Plasma for PK will be collected as follows: For copanlisib/placebo: Cycle 1 Day 1 and Day 8 of Cycles 1, 3 and 6. For rituximab in R-B treatment group: Cycle 
1 Day 1 and Cycle 6 Day 1, for rituximab in R-CHOP treatment group: Cycle 1 Day 2 and Cycle 6 Day 2. PK sampling time points for copanlisib and rituximab 
are specified in Section 9.5. 
r 
Fresh tumor tissue and/or archival tumor tissue must be available at Screening for central pathology review for an exploratory analysis. In addition, pre-
treatment tumor tissue samples will be collected when available to investigate or identify biomarkers that may be predictive of copanlisib effects/efficacy in 
NHL and to contribute to better understanding the disease (see Section 9.7.1). In patients with WM, bone marrow biopsy can be used for histological 
confirmation of the diagnosis and for biomarker analyses. A tumor biopsy is encouraged at the time of progression (optional) to allow investigation of 
copanlisib resistance.  
s Plasma for tumor genetics: On Cycle 1 Day 1, blood for plasma preparation should be drawn prior to administration of any study treatment. 
t 
Plasma for non-genetic biomarker analysis will be prepared from whole blood samples. On treatment days, blood for plasma preparation should be drawn 
prior to administration of any study treatment. 
u Whole blood for biomarkers: On Day 1 of Cycle 1 (prior to administration of any study treatment), whole blood will be taken only from patients who have 
provided genetic consent.  
v Only for patients affected by LPL/WM: Serum protein electrophoresis, immunofixation and serum quantitative IgM test to be performed at Screening. Serum or 
plasma viscosity to be tested at Screening only if hyperviscosity syndrome is suspected.  
Only for patients affected by WM: Serum protein electrophoresis, immunofixation and serum quantitative IgM test to be performed on the days of radiological 
assessment and at EOT only if the last assessment is older than 4 weeks. Serum or plasma viscosity, if abnormal at baseline, then to be repeated every 3rd 
cycle, starting from Day 1 of Cycle 3, and at EOT. For patients with WM without measurable disease, these procedures will be performed with the same 
frequency as radiologic assessments. 
w The post-treatment follow-up 30 days (window of +5 days allowed) after the last administration of study drug can be conducted via telephone if the patient is 
no longer being actively seen at the clinic, or patient has started another therapy (see Section 9.2.1.5.1). 
x Patients who complete 12 months’ study treatment without PD or discontinue study treatment for reasons other than PD will enter the active follow-up period 
(except for patients who object to follow-up data collection), which also encompasses the safety follow-up period including SFU visit. 
y Patients or their health care providers will be contacted either in person or by telephone (except for patients who object to follow-up data collection). The 
contacts will be made at least every 3 months (± 14 days), until death or until the end of study, whichever occurs first. Duration of survival follow-up period is 
up to 10 years after the last patient started study treatment. See Section 9.2.1.5.3. 

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z Visit added by amendment 1 
aa Blood test for HBV and HCV at Screening (HBsAg, HBcAb and anti-HCV antibody; if HBsAg or HBcAb positive also HBV DNA; if anti-HCV antibody positive 
also HCV RNA). Patients with positive tests for HBsAg and/or HBcAb will be eligible if they are negative for HBV-DNA. These patients should receive 
prophylactic antiviral therapy per rituximab label and should perform HBV DNA test with PCR every cycle (±7 days) through treatment and 12 months 
thereafter. If viral load becomes positive, patient should be withdrawn from the study. Patients with positive test for anti-HCV antibody will be eligible if they 
are negative for HCV-RNA. These patients should perform HCV RNA test with PCR every cycle (±7 days) through treatment and 6 months thereafter. If viral 
load becomes positive, patient should be withdrawn from the study.  
bb On Day 2 of Cycles 1-6: R-B group: glucose test within 30 minutes prior to bendamustine infusion and at the end of the bendamustine infusion (within 30min) 
for patient receiving corticosteroid premedication prior to the bendamustine infusion; R-CHOP group: glucose test within 30 minutes prior to rituximab infusion 
and at the end of rituximab infusion (within 30 min) for patients receiving corticosteroid premedication prior to the rituximab infusion. 
cc Quantification of proteinuria by either a 24 hour total urine protein quantification or by UPCR on a random urine sample preferably taken in mid-morning. This 
should be reported as the ratio of concentrations of total urine protein (in mg/dL) to urine creatinine (in mg/dL), both done in the same sample (see Section 
9.6.3.1). Dipstick analysis is not acceptable to assess proteinuria. 
dd Starting from Cycle 1 Day 8, laboratory tests prior to each infusion may be performed and assessed either the day before or on the planned day of infusion 
with the exception of blood glucose, which must be performed and assessed on the day of infusion.  
ee Blood test for CMV should be performed in all patients prior to IV infusion of copanlisib. Every cycle on Cycle X Day 1 (time window -1 day) during 
combination therapy and every 3 cycles starting from Cycle 7. If PCR test is positive for CMV, treatment should be delayed until recovery. CMV PCR test is 
considered positive if, the result can be interpreted as a CMV viremia according to local SOC.Treatment of CMV should be initiated based on local SOC. Re-
treatment with copanlisib will be allowed without dose reduction once PCR test for CMV is negative. For further details, see Section 7.4.3.6.1. 
ff Blood cultures should be performed as per local SOC if the patient develops febrile neutropenia. CD4 count should be performed for patients with signs of 
infection. 
gg For patients with identified risk factors and those who developed OI, additional assessments can include: (1) CD4 and CD8 count and ratio, CRP, blood 
cultures (2) any additional laboratory and diagnostic methods according to local SOC reported as unscheduled laboratory and diagnostic methods of 
assessments (3) radiological imaging (i.e. CXR or CT scans) (Note: Treatment of developed OI should be based on local SOC). 
hh Modified by amendment 2 
ii 
The safety evaluations to be performed on Day 22 were removed for patients in the copanlisib/placebo + R-B combination therapy group (from C1 to C6) and 
for all patients during copanlisib/placebo monotherapy (from C7 onwards). The safety evaluations to be performed on Day 15 were removed for patients in the 
copanlisib/placebo + R-CHOP combination therapy group (from C1 to C6). 
 

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9.2 
Visit descriptions 
9.2.1 
Visit descriptions in safety run-in part and phase III part  
These apply to both copanlisib/placebo + R-B and copanlisib/placebo + R-CHOP treatment 
groups unless otherwise specified. 
9.2.1.1 
Screening period  
Screening examinations will be performed after the patient has given written informed 
consent. The maximum interval allowed between signature of informed consent and start of 
treatment is 28 days unless written sponsor authorization has been obtained for laboratory 
re-testing or diagnostic testing (up to additional 14 days permitted). The minimum length of 
the screening period is 7 days. Certain results from diagnostic testing performed as part of the 
standard of practice prior to the informed consent date and time may be used to fulfill 
screening criteria. This includes fresh tissue as noted in the protocol as well as results from 
tumor scans (CT/MRI and/or PET-CT), bone marrow sample, MUGA/echocardiogram, HIV 
and hepatitis testing which may also be used provided that they fall into the protocol-specified 
time window. Archival tissue obtained from the patient at any time during the course of their 
iNHL may also be used if performed as part of the standard of practice. However, these 
historical results can only be used after the patient gives informed consent to use them. Tumor 
scans must also meet the quality standards of the Imaging Manual.  
Within 28 days before the first study drug administration: 
• IVRS/IWRS transaction to register the patient in the system (see Section 6.5). 
• Blood test for hepatitis B and C (HBsAg, HBcAb, and anti-HCV antibody; if HBsAg 
or HBcAb positive also HBV DNA; if anti-HCV antibody positive also HCV RNA).  
o Patients with positive tests for HBsAg and/or HBcAb will be eligible if they 
are negative for HBV-DNA. These patients should receive prophylactic 
antiviral therapy per rituximab label and should perform HBV DNA test with 
PCR every cycle (±7 days)  through treatment and 12 months thereafter (27). If 
viral load becomes positive, patient should be withdrawn from the study. 
o Patients with positive test for anti-HCV antibody will be eligible if they are 
negative for HCV-RNA. These patients should perform HCV RNA test with 
PCR every cycle (±7 days)  through treatment and 6 months thereafter (27). If 
viral load becomes positive, patient should be withdrawn from the study. 
• Blood test for Cytomegalovirus (CMV) infection. Patients who are CMV PCR 
positive at baseline will not be eligible. CMV PCR test is considered positive if, the 
result can be interpreted as a CMV viremia according to local SOC. 
• Blood test for HIV according to local regulations. 
• 12-lead ECG (including QTcB and QTcF evaluation) (see Section 9.6.3.6). 
• IV (and oral, if indicated, per Imaging Manual) contrast-enhanced CT/MRI and/or 
PET-CT of neck, chest, abdomen and pelvis (including WM patients) after a 7 days 

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washout of corticosteroids therapy (see Section 6.2). If a PET-CT is performed during 
initial assessment, the CT portion of the PET-CT has to be of diagnostic quality (with 
IV contrast agent and with an acceptable radiation dose). See Section 9.4.2. 
• Bone marrow biopsy: mandatory at Screening and to confirm the first complete 
response if positive for lymphoma infiltration at baseline (see Section 9.2.1.3).  
• Biomarker sampling (see Section 9.7.1): 
o Fresh tumor tissue and/or archival tumor tissue must be available at Screening 
for central pathology review for an exploratory analysis. In addition, pre-
treatment tumor tissue samples will be collected when available to investigate 
or identify biomarkers that may be predictive of copanlisib effects/efficacy in 
NHL and to contribute to better understanding the disease. In patients with 
WM, bone marrow biopsy can be used for histological confirmation of the 
diagnosis and for biomarker analyses. 
o Collection of plasma (from whole blood sample) for non-genetic biomarker 
analysis. 
Within 14 days before the first study drug administration: 
• Check inclusion and exclusion criteria (see Section 6.1 and Section 6.2) 
• Complete medical and surgical history including demographics (see Section 9.3.1), 
relevant medical history findings, concomitant illnesses, allergy history, prior 
surgeries, most recent histology of tumor, most recent staging and grading of tumor, 
history of anti-cancer treatments (including type of treatment, type of response, date 
and duration of response), and assessment of baseline toxicity.  
• Toxicity/AE assessment: any new findings or worsening of any ongoing medical 
history conditions after the patient has signed the informed consent are to be listed as 
adverse events (see Section 9.6.1). 
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an adverse event related to its 
administration. 
• Complete physical examination (see Section 9.6.3.3.1) 
• MUGA scan or echocardiogram to measure LVEF. The method chosen at baseline 
must be the same throughout the whole study period (see Section 9.6.3.7). 
• Only in patients affected by Lymphoplasmacytic lymphoma/Waldenström 
macroglobulinemia (LPL/WM): 
o Serum protein electrophoresis 
o Immunofixation 
o Serum quantitative IgM test 
o Serum or plasma viscosity (if hyperviscosity syndrome is suspected) 

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• Only in patients affected by WM and FL: Beta-2-microglobulin 
Within 7 days before the first study drug administration: 
• Check inclusion and exclusion criteria (see Section 6.1 and Section 6.2) 
• Laboratory (see Section 9.6.3.1): 
o GFR calculation according to MDRD abbreviated formula. If not on target, 
this evaluation may be repeated once after at least 24 hours either according to 
the MDRD abbreviated formula or by 24 hour sampling (see also Appendix 
16.7). 
o Serum pregnancy test (if applicable). 
o Urine protein to creatinine ratio (UPCR)/24 h total urine protein quantification 
measurement  
o Blood tests for complete blood count, complete chemistry and coagulation 
panels (see Section 9.6.3.1). Patients must be fasting prior to sampling 
according to local standards. If a patient cannot adhere to fasting 
requirements, the evaluation of lipid panels including triglycerides is 
considered not feasible 
o Blood test for hemoglobin A1c 
o Urinalysis (dipstick). Microscopy as clinically indicated. 
9.2.1.2 
Treatment period  
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented, the patient will be randomized via IVRS/IWRS. 
Note: Placebo infusion applies only to phase III part. 
The following assessments should be performed at each visit before receiving study drug 
(copanlisib/placebo) 
• Monitoring for OI (see Section 7.4.3.6.1):  
In addition to the weekly clinical review and laboratory tests outlined in the schedule 
of assessments, the following should be performed in all patients prior to IV infusion 
of copanlisib/placebo: 
o Evaluation of any new onset or worsening of pulmonary symptoms (i.e. cough, 
dyspnea or fever) that includes a lung examination at each visit prior to infusion 
o Laboratory tests: CD4 (for patients with signs of infection), blood cultures if 
febrile neutropenia occurs, PCR for CMV (every cycle on Cycle X Day 1 (time 
window -1 day) during combination therapy and every 3 cycles starting from 
Cycle 7). 
▪ Note: If PCR test is positive for CMV, treatment should be delayed 
until recovery. CMV PCR test is considered positive if, the result can 
be interpreted as a CMV viremia according to local SOC. Treatment of 

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CMV should be initiated based on local SOC. Re-treatment with 
copanlisib will be allowed without dose reduction once PCR test for 
CMV is negative. 
9.2.1.2.1 Treatment – Cycle 1  
Cycle 1, Day 1 
Patients can stay overnight at the site, if needed, based on the investigator’s decision 
• Phase III part only: Quality of life (QoL) questionnaire (FLymSI-18): at the start of a 
visit, before the patient sees the physician (see Section 9.7.2).  
• Check inclusion and exclusion criteria. No patient may receive treatment unless 
adherence to all selection criteria as given in Section 6.1 and Section 6.2 is established. 
• IVRS/IWRS randomization transaction. The randomization must be performed up to 
maximum 72 hours before the first dose of study treatment (see Section 7.3). Please 
refer to the Pharmacy Manual and the relevant SmPCs for detailed instructions 
regarding the timing requirements for the dose preparation. IVRS/IWRS transactions 
for medication dispensing at Cycle 2 and above will be on Day 1 of each cycle or as 
described in the Pharmacy Manual (see Section 9.2.1.2.2).  
• Toxicity/ AE assessment: any new findings or worsening of any ongoing medical 
history conditions after the patient signed the informed consent are to be listed as 
adverse events (see Section 9.6.1). 
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
• Complete physical examination (see Section 9.6.3.3.1). 
• 12-lead ECG evaluation (including QTcB and QTcF evaluation) prior to infusion and 
at the end of infusion (window of up to 2 hours prior to and post-infusion is allowed) 
(see Section 9.6.3.6). 
• Laboratory (see Section 9.6.3.1): 
o Complete blood count 
• Monitoring for OI (see Section 7.4.3.6.1) 
• Glucose measurements:  
o On Cycle 1 Day 1 glucose will be measured at pre-dose and post-dose 1 h and 
2 h after the end of study drug infusion; and at the end of the rituximab 
infusion (window of ± 10 min is allowed except for the pre-dose measurement); 
and at the end of the bendamustine infusion (± 10 min) if patient receives 
corticosteroid premedication prior to bendamustine infusion (see Section 
9.6.3.2). Note: If patient needs to take a meal, then glucose test should be taken 
prior to meal intake. 

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o Additional glucose measurements to be performed at the clinic as clinically 
indicated.  
• Blood pressure measurement: at pre-dose and at specified time points during and after 
the study drug infusion according to guidance provided in Section 9.6.3.5. In addition, 
from Cycles 1 to 6 blood pressure will be measured 30 minutes after the start of 
rituximab infusion and at the end of rituximab infusion (see Section 9.6.3.5). 
• PK sampling (see Section 9.5) 
o For copanlisib/placebo : Cycle 1 Day 1: pre-infusion (up to 30 min prior to 
start infusion, 55 min (within 5 min prior to the end of infusion). 
o For rituximab (only for the R-B treatment group): Cycle 1 Day 1: pre-
infusion and end of rituximab infusion (within 5 minutes prior to the end of 
infusion). 
• Biomarker sampling: (see Section 9.7.1)  
Collection of plasma (from whole blood sample) for biomarker analysis prior to 
administration of any study treatment.  
o Plasma for tumor genetics  
o Plasma for non-genetic biomarker analysis 
o Whole blood for genetic biomarker analysis (only from patients who provide a 
separate consent for genetic research) 
For patients receiving copanlisib/placebo + R-CHOP treatment: 
• Copanlisib/placebo infusion.  
For patients receiving copanlisib/placebo + R-B treatment: 
• Copanlisib/placebo infusion, before rituximab and bendamustine infusion. 
• Rituximab and bendamustine infusion (in this order). 
Cycle 1, Day 2 
For patients receiving copanlisib/placebo + R-CHOP treatment: 
• Rituximab, cyclophosphamide, doxorubicin, and vincristine infusion and from Day 2 
to Day 6 prednisone/prednisolone PO.  
• On Day 2 of Cycles 1-6: For patients receiving corticosteroid premedication prior to 
the rituximab infusion:  
o Glucose test within 30 minutes prior to rituximab infusion and at the end of 
rituximab infusion (within 30 min). 
• PK sampling (see Section 9.5) 
o For rituximab: Cycle 1 Day 2: pre-infusion and end of rituximab infusion 
(within 5 minutes prior to the end of infusion). 

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For patients receiving copanlisib/placebo + R-B treatment: 
• Bendamustine infusion 
• On Day 2 of Cycles 1-6: For patients receiving corticosteroid premedication prior to 
the bendamustine infusion:  
o Glucose test  within 30 minutes prior to bendamustine infusion and at the end 
of bendamustine infusion (within 30 min). 
Cycle 1, Day 8 
Starting from Cycle 1 Day 8, laboratory tests prior to each infusion may be performed and 
assessed either on the day before or on the planned day of infusion, with the exception of 
blood glucose, which must be performed and assessed on the day of infusion. For dosing 
criteria, see Section 7.4. 
• Toxicity/ AE assessment (Section 9.6.1).  
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
• Brief physical examination and status check, including lung examination, see 
Section 9.6.3.3.2. 
• Laboratory (see Section 9.6.3.1): 
o Blood tests for complete blood count and chemistry panel (excluding 
triglycerides, LDL cholesterol and total cholesterol).  
• Monitoring for OI (see Section 7.4.3.6.1)  
• Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo IV infusion (window of  10 min is allowed except for the pre-
dose measurement). Note: If patient needs to take a meal, then glucose test should be 
taken prior to meal intake. Fasting is not required prior to pre-dose glucose 
measurement (see Section 7.4). 
• Blood pressure measurement: at pre-dose and at specified time points during and after 
the study drug infusion according to guidance provided in Section 9.6.3.5.  
• PK sampling 
o Cycle 1 Day 8: Pre- infusion (up to 30 min prior to start infusion), 5 to 15 min, 
55 min (or within 5 min prior to end of infusion) and 1.5 to 5 h after start of 
infusion. 
• Biomarker sampling (see Section 9.7.1):  
o Collection of plasma for non-genetic biomarker analyses prior to 
copanlisib/placebo infusion  
• Copanlisib/placebo infusion.  

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Cycle 1, Day 15 
All patients: 
• Biomarker sampling (see Section 9.7.1):  
o Collection of plasma for non-genetic biomarker analyses. In copanlisib/placebo 
+ R-B treatment group, sample is collected prior to copanlisib/placebo infusion.  
For patients receiving copanlisib/placebo + R-B treatment: 
• Toxicity/ AE assessment (Section 9.6.1). 
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
• Brief physical examination and status check, including lung examination, see 
Section 9.6.3.3.2. 
• Laboratory (see Section 9.6.3.1): 
o Blood tests for complete blood count, chemistry (excluding triglycerides, LDL 
cholesterol and total cholesterol) and coagulation panels. 
• Monitoring for OI (see Section 7.4.3.6.1) 
• Blood pressure measurement: at pre-dose and at specified time points during and after 
the study drug infusion according to guidance provided in Section 9.6.3.5.  
• Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo IV infusion (window of  10 min is allowed except for the pre-
dose measurement) (see Section 9.6.3.2). Note: If patient needs to take a meal, then 
glucose test should be taken prior to meal intake. Patients are not required to be fasting 
prior to pre-dose glucose measurement (see Section 7.4). 
• Copanlisib/placebo infusion  
9.2.1.2.2 Treatment – From Cycle 2 to Cycle 6  
From Cycle 2 to Cycle 6, Day 1 
• Phase III part only: Quality of life (QoL) questionnaire (FLymSI-18): at the start of a 
visit, before the patient sees the physician (see Section 9.7.2). 
• IVRS/IWRS transaction for medication dispensing at Cycle 2 and above will be on 
Day 1 of each cycle or as described in the Pharmacy Manual. Please refer to the 
Pharmacy Manual and the relevant SmPCs for detailed instructions regarding the 
timing requirements for the dose preparation. 
• Toxicity/ AE assessment (see Section 9.6.1). 
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 

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• Complete physical examination (see Section 9.6.3.3.1). 
• Laboratory (see Section 9.6.3.1): 
o Blood tests for complete blood count, chemistry and coagulation panels. Blood 
tests for triglycerides, LDL cholesterol and total cholesterol will be done on 
Day 1 at every second cycle (2, 4, etc.), starting from Cycle 2; on these days 
patients must be fasting prior to sampling according to local standards. If a 
patient cannot adhere to fasting requirements, the evaluation of lipid-panels 
including triglycerides is considered not feasible. 
o Blood test for hemoglobin A1c will be done on Day 1 of every three cycles (4, 
7, 10, etc.) starting from Cycle 4. 
o GFR calculation (see also Appendix 16.7).  
o Urinalysis (dipstick). Microscopy as clinically indicated. 
o Serum pregnancy test: after Cycle 1 serum pregnancy test is mandatory at 
every cycle for countries where it is required by local regulations. 
• For patients with positive tests for HBsAg and/or HBcAb, and negative for HBV-
DNA: these patients should receive prophylactic antiviral therapy per rituximab label 
and should perform HBV DNA test with PCR every cycle (±7 days)  through 
treatment and 12 months thereafter (27). If viral load becomes positive, patient should 
be withdrawn from the study. 
• For patients with positive test for anti-HCV antibody and negative for HCV-
RNA: these patients should perform HCV RNA test with PCR every cycle (±7 days)  
through treatment and 6 months thereafter (27). If viral load becomes positive, patient 
should be withdrawn from the study. 
• Monitoring for OI (see Section 7.4.3.6.1) 
• Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo IV infusion; and at the end of the rituximab infusion (window of 
 10 min is allowed); and at the end of the bendamustine infusion ( 10 min) if patient 
receives corticosteroid premedication prior to bendamustine infusion. Fasting is not 
required prior to pre-dose glucose measurement, see Section 7.4. Note: If patient needs 
to take a meal, then glucose test should be taken prior to meal intake. 
• Blood pressure measurement: at pre-dose and at specified time points during and after 
the study drug infusion according to guidance provided in Section 9.6.3.5. In addition, 
from Cycles 1 to 6 blood pressure will be measured 30 minutes after the start of 
rituximab infusion and at the end of rituximab infusion (see Section 9.6.3.5). 
• 12-lead ECG evaluation (including QTcB and QTcF evaluation) at every 3rd cycle 
from Cycle 3 Day 1 (i.e. Cycles 3, 6, 9, etc.), prior to dosing and at the end of 
copanlisib/placebo infusion (window of up to 2 hours prior to and post-infusion is 
allowed) (see Section 9.6.3.6).  

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• MUGA scan or echocardiogram to measure LVEF, within 7 days prior to Day 1 of 
every 3rd cycle (i.e. Cycles 3, 6, 9, etc.) The method to measure LVEF must be the 
same as at baseline (see Section 9.6.3.7). 
• Only in patients affected by WM: 
o Serum or plasma viscosity: if abnormal at Screening, then every 3rd cycle, 
starting from Day 1 of Cycle 3. 
• Biomarker sampling (see Section 9.7.1)  
o Only in Cycle 2: collection of plasma for non-genetic biomarker analyses prior 
to copanlisib/placebo infusion.  
For patients receiving copanlisib/placebo + R-CHOP treatment: 
• Copanlisib/placebo infusion.  
For patients receiving copanlisib/placebo + R-B treatment: 
• Copanlisib/placebo infusion before rituximab and bendamustine infusion.  
• Rituximab and bendamustine infusion (in this order) 
• PK sampling (see Section 9.5): 
o Only in Cycle 6 Day 1: pre-infusion and end of rituximab infusion (within 
5 minutes prior to the end of infusion).  
From Cycle 2 to Cycle 6, Day 2 
For patients receiving copanlisib/placebo + R-CHOP treatment: 
• Rituximab, cyclophosphamide, doxorubicin, vincristine infusion on Day 2 and from 
Day 2 to Day 6 prednisone/prednisolone PO.  
• On Day 2 of Cycles 1-6: For patients receiving corticosteroid premedication prior to 
the rituximab infusion:  
o Glucose test within 30  minutes prior to rituximab infusion and at the end of 
rituximab infusion (within 30 min). 
• PK sampling: Only in Cycle 6 Day 2: pre-infusion and end of rituximab infusion 
(within 5 minutes prior to the end of infusion). 
For patients receiving copanlisib/placebo + R-B treatment: 
• Bendamustine infusion 
• On Day 2 of Cycles 1-6: For patients receiving corticosteroid premedication prior to 
the bendamustine infusion:  
o Glucose test within 30 minutes prior to bendamustine infusion and at the end 
of bendamustine infusion (within 30 min). 

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From Cycle 2 to Cycle 6, Day 8 
• Toxicity/ AE assessment (see Section 9.6.1) 
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction).  
• Brief physical examination and status check, including lung examination (see Section 
9.6.3.3.2). 
• Laboratory (see Section 9.6.3.1): 
o Complete blood count 
o Cycle 2 only: blood tests for complete chemistry panel (excluding 
triglycerides, LDL cholesterol and total cholesterol)  
• Monitoring for OI (see Section 7.4.3.6.1)  
• Blood pressure measurement: at pre-dose and at specified time points during and after 
the study drug infusion according to guidance provided in Section 9.6.3.5.  
• Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo IV infusion (window of  10 min is allowed except for the pre-
dose measurement). Note: If patient needs to take a meal, then glucose test should be 
taken prior to meal intake. 
• Biomarker sampling (see Section 9.7.1): 
o Only in Cycle 2: collection of plasma for non-genetic biomarker analyses prior 
to copanlisib/placebo infusion.  
• PK sampling (see Section 9.5): 
o For copanlisib / placebo: Day 8 of Cycles 3 and 6: Pre-infusion (up to 30 min 
prior to start infusion) and 55 min (within 5 min prior to the end of infusion. 
• Copanlisib/placebo infusion  
From Cycle 2 to Cycle 6, Day 15 
All patients: 
• Biomarker sampling (see Section 9.7.1) 
o Cycle 2 only: collection of plasma for non-genetic biomarker analyses prior to 
copanlisib/placebo infusion 

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For patients receiving copanlisib/placebo + R-B treatment: 
• Toxicity/ AE assessment (see Section 9.6.1). 
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
• Laboratory (see Section 9.6.3.1): 
o Complete blood count  
o Cycle 2 only: blood tests for chemistry panel (excluding triglycerides, LDL 
cholesterol and total cholesterol). 
• Brief physical examination and status check, including lung examination (see 
Section 9.6.3.3.2). 
• Monitoring for OI (see Section 7.4.3.6.1) 
• Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo IV infusion (see Section 9.6.3.2). (window of  10 min is allowed 
except for the pre-dose measurement). Note: If patient needs to take a meal, then 
glucose test should be taken prior to meal intake  
• Blood pressure measurement: at pre-dose and at specified time points during and after 
the study drug infusion according to guidance provided in Section 9.6.3.5.  
• Copanlisib/placebo IV infusion.  
For patients receiving copanlisib/placebo + R-CHOP treatment: 
• Only for patients affected by WM  
The following procedures will be performed on the days of radiological assessments 
(or with the same frequency as radiologic assessments for patients with WM without 
measurable disease) (see Section 9.2.1.3): 
o Serum protein electrophoresis 
o Immunofixation 
o Serum quantitative IgM test 
From Cycle 2 to Cycle 6, Day 22: 
For patients receiving copanlisib/placebo + R-B treatment: 
• Only for patients affected by WM  
The following procedures will be performed on the days of radiological assessments 
(or with the same frequency as radiologic assessments for patients with WM without 
measurable disease) (see Section 9.2.1.3): 
o Serum protein electrophoresis 
o Immunofixation 

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o Serum quantitative IgM test 
9.2.1.2.3 Treatment – From Cycle 7 onwards (during copanlisib/placebo 
monotherapy)  
From Cycle 7 onwards, Day 1 
• Phase III part only: Quality of life (QoL) questionnaire (FLymSI-18): at the start of a 
visit, before the patient sees the physician (see Section 9.7.2). 
• IVRS/IWRS transaction for medication dispensing at Cycle 2 and above on Day 1 of 
each cycle or as described in the Pharmacy Manual. Please refer to the Pharmacy 
Manual and the relevant SmPCs for detailed instructions regarding the timing 
requirements for the dose preparation. 
• Toxicity/AE assessment (see Section 9.6.1) 
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
• Complete physical examination (see Section 9.6.3.3.1)  
• Monitoring for OI (See Section 7.4.3.6.1)  
• Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo IV infusion (window of  10 min is allowed except for the pre-
dose measurement). Fasting is not required prior to pre-dose glucose measurement, see 
Section 7.4. Note: If patient needs to take a meal, then glucose test should be taken 
prior to meal intake.  
• 12-lead ECG evaluation (including QTcB and QTcF evaluation) at every 3rd cycle 
from Cycle 3 Day 1 (i.e. Cycles 3, 6, 9, etc.), prior to dosing and at the end of 
copanlisib/placebo infusion (window of up to 2 hours prior to and post-infusion is 
allowed) (see Section 9.6.3.6).  
• MUGA scan or echocardiogram to measure LVEF, within 7 days prior to Day 1 of 
every 3rd cycle (i.e. Cycles 3, 6, 9, etc.) The method to measure LVEF must be the 
same as at baseline (see Section 9.6.3.7). 
• Laboratory (see Section 9.6.3.1): 
o Blood tests for complete blood count, chemistry and coagulation panels. Blood 
tests for triglycerides, LDL cholesterol and total cholesterol will be done on 
Day 1 at every second cycle, starting from Cycle 2; on these days patients must 
be fasting prior to sampling according to local standards. If a patient 
cannot adhere to fasting requirements, the evaluation of lipid-panels including 
triglycerides is considered not feasible.  
o Blood test for hemoglobin A1c will be done on Day 1 of every three cycles (4, 
7, 10 etc.) starting from Cycle 4. 

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o Urinalysis (dipstick). Microscopy as clinically indicated. 
o Serum pregnancy test: after Cycle 1 serum pregnancy test is mandatory at 
every cycle for countries where it is required by local regulations. 
o GFR calculation (see Section 9.6.3.1 and Appendix 16.7) 
• For patients with positive tests for HBsAg and/or HBcAb, and negative for HBV-
DNA: these patients should receive prophylactic antiviral therapy per rituximab label 
and should perform HBV DNA test with PCR every cycle (±7 days)  through 
treatment and 12 months thereafter (27). If viral load becomes positive, patient should 
be withdrawn from the study. 
• For patients with positive test for anti-HCV antibody and negative for HCV-
RNA: these patients should perform HCV RNA test with PCR every cycle (±7 days)  
through treatment and 6 months thereafter (27). If viral load becomes positive, patient 
should be withdrawn from the study. 
• Blood pressure measurement: at pre-dose and at specified time points during and after 
the study drug infusion according to guidance provided in Section 9.6.3.5.  
• Only in patients affected by WM: 
o Serum or plasma viscosity: if abnormal at Screening, then every 3rd cycle, 
starting from Day 1 of Cycle 3. 
• Copanlisib/placebo IV infusion.  
Cycle 7 onwards, Day 8 
• Toxicity/ AE assessment (see Section 9.6.1). 
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction).  
• Brief physical examination and status check, including lung examination (see 
Section 9.6.3.3.2). 
• Laboratory (see Section 9.6.3.1): 
o Complete blood count 
• Monitoring for OI (see Section 7.4.3.6.1) 
• Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo IV infusion (window of  10 min is allowed except for the pre-
dose measurement) (see Section 9.6.3.2). Fasting is not required prior to pre-dose 
glucose measurement, see Section 7.4. Note: If patient needs to take a meal, then 
glucose test should be taken prior to meal intake. 
• Blood pressure measurement: at pre-dose and at specified time points during and after 
the study drug infusion according to guidance provided in Section 9.6.3.5.  

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• Copanlisib/placebo IV infusion. 
Cycle 7 onwards, Day 15 
• Toxicity/ AE assessment (see Section 9.6.1). 
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
• Brief physical examination and status check, including lung examination (see Section 
9.6.3.3.2).  
• Laboratory (see Section 9.6.3.1): 
o  Complete blood count 
• Monitoring for OI (see Section 7.4.3.6.1) 
• Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo IV infusion (deviation of  10 min is allowed except for the pre-
dose measurement) (see Section 9.6.3.2). Fasting is not required prior to pre-dose 
glucose measurement, see Section 7.4. Note: If patient needs to take a meal, then 
glucose test should be taken prior to meal intake. 
• Blood pressure measurement: at pre-dose and at specified time points during and after 
the study drug infusion according to guidance provided in Section 9.6.3.5.  
• Copanlisib/placebo IV infusion. 
Cycle 7 onwards, Day 22  
• Only for patients affected by WM  
The following procedures will be performed on the days of radiological assessments 
(or with the same frequency as radiologic assessments for patients with WM without 
measurable disease) (see Section 9.2.1.3): 
o Serum protein electrophoresis 
o Immunofixation 
o Serum quantitative IgM test 
9.2.1.3 
Tumor assessments  
Radiologic tumor evaluations (IV [and oral, if indicated, per Imaging Manual] contrast 
enhanced CT/MRI scans of neck, chest, abdomen and pelvis) will be performed during the 
screening, treatment period as well as during the Active follow-up period at the following 
intervals (see also Section 9.4): 
During screening:  
• CT/MRI and/or PET-CT scans taken within 28 days of starting study treatment (see 
Section 9.2.1.1) 

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During treatment and Active follow-up:  
• CT/MRI scans (starting from Cycle 1 Day 1 each year):  
o Year 1: every 12 weeks (±7 days)  
o Year 2: every 12 weeks (± 7 days) 
o Year 3: every 24 weeks (± 7 days) 
o Year 4: every 24 weeks (±7 days) 
o Year 5: every 24 weeks (±7 days) 
o Beyond Year 5: every 24 weeks (±14 days) 
At EOT visit, CT/MRI scans are not required, if the patient has been radiologically evaluated 
within the 4 weeks preceding EOT. 
PET functional imaging is the preferred modality and should be done based on institutional 
standards. If a PET-CT is performed at the baseline (BL) assessment the recommendation is 
to have it repeated after the Cycle 6 if a PD is not detected during the course of treatment 
and/or to confirm complete response (CR) or disease progression. It is also recommended to 
perform a PET-CT, if at a previous imaging visit the tumor response was derived from PET-
CT and CT/MRI alone shows any change in the response assessment on subsequent imaging 
visits (e.g. PR).  
Bone marrow biopsy  
Bone marrow biopsy will be mandatory at Screening and will be sent to central pathology 
review after local bone marrow assessment. If the baseline biopsy is positive for lymphoma 
infiltration, it will be mandatory to perform a local bone marrow biopsy assessment again to 
confirm the first complete response (CR), and also at the investigator’s discretion if clinical 
evaluation leads to suspicion of bone marrow infiltration without further radiological findings. 
Patients affected by WM 
Patients affected by WM in whom a lesion is found at Screening, radiologic assessments will 
continue as defined above. If no lesion is detected at Screening, no further radiologic 
assessments are necessary as per protocol (for further details see Section 9.4.3). In addition, 
the following procedures will be performed on the days of tumor assessments (if patients 
continue radiologic assessments, otherwise these procedures will be performed with the same 
frequency as radiologic assessments): 
• Serum protein electrophoresis 
• Immunofixation 
• Serum quantitative IgM test 
9.2.1.4 
End-of-treatment visit  
The procedures to be performed at the EOT visit will take place not later than 7 days after the 
decision is made to discontinue the study treatment or when the patient completes 12 months 
of treatment (maximum duration of therapy). 

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They will comprise the following:  
• Phase III part only: Quality of life (QoL) questionnaire (FLymSI-18): at the start of a 
visit, before the patient sees the physician (see Section 9.7.2). 
• IVRS/IWRS transaction to register end of treatment. 
• Toxicity/AE assessment (see Section 9.6.1). 
• Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an adverse event related to its 
administration (e.g. allergic reaction). 
• Complete physical examination (see Section 9.6.3.3.1).  
• Review of the capillary blood glucose measurements/ meal timing/oral glucose 
lowering medication/insulin doses, if applicable (see Section 7.4.3.1). 
• Laboratory (see Section 9.6.3.1): 
o Serum pregnancy test (if applicable) in countries where it is required by local 
regulations. 
o Blood tests for complete blood count, complete chemistry and coagulation 
panels. Patients must be fasting prior to sampling according to local 
standards. If a patient cannot adhere to fasting requirements, the evaluation of 
lipid panels including triglycerides is considered not feasible. 
o Blood test for hemoglobin A1c (not required if previous test was performed 
within 4 weeks preceding the EOT visit). 
o Urinalysis (dipstick). Microscopy as clinically indicated. 
• 12-lead ECG including QTcB and QTcF evaluation (if not previously done within four 
weeks) (see Section 9.6.3.6). 
• MUGA scan or echocardiogram to measure LVEF (if not previously done within four 
weeks) (see Section 9.6.3.7). The method must be the same as used at baseline and 
throughout the whole study (see Section 9.6.3.7).  
• IV (and oral, if indicated, per Imaging Manual) contrast-enhanced CT/MRI of neck, 
chest, abdomen and pelvis. CT/MRI scans are not required, if the patient has been 
radiologically evaluated within the 4 weeks preceding EOT (see Section 9.4.2).  
• If PET-CT was performed at baseline, the recommendation is to confirm complete 
response (CR) or disease progression with PET-CT. It is also recommended to 
perform a PET-CT, if at a previous imaging visit the tumor response was derived from 
PET-CT and CT/MRI alone shows any change in the response assessment on 
subsequent imaging visits (e.g. PR). Please refer to Imaging Manual for details.  
• Only in patients affected by WM  
o Serum protein electrophoresis, immunofixation and serum quantitative IgM 
test (to be performed only if the last assessment is older than 4 weeks). 

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o Serum or plasma viscosity if abnormal at baseline. 
• Biomarker sampling:  
o A tumor biopsy is highly encouraged at the time of progression (optional) to 
allow investigation of copanlisib resistance.  
o Collection of plasma for tumor genetics and non-genetic biomarker analyses 
(see Section 9.7.1)  
9.2.1.5 
Follow-up periods  
An additional contact with the patient may be required before the next scheduled visit or 
telephone call if the most recent data on survival is needed at a specific time point during 
Safety follow-up, Active follow-up or Survival follow-up (e.g. for a DMC meeting or data 
analysis). 
The final HbA1C test should be performed approximately 3 months after the EOT visit date 
whenever possible.  
9.2.1.5.1 Safety follow-up  
If a patient discontinues study treatment at any time during the study for any reason (except 
death or lost to follow-up) a safety follow-up evaluation should be performed 30 days 
(window of + 5 days is allowed) after the last dose of study medication. Please note that 
adverse events should be reported up to 30 days after the last dose of study drug. 
• Phase III part only: Quality of life (QoL) questionnaire (FLymSI-18): at the start of a 
visit, before the patient sees the physician (see Section 9.7.2). 
• Toxicity/AE assessment (see Section 9.6.1).  
• Concomitant medication review. 
• Serum pregnancy test (if applicable) in countries where it is required by local 
regulations. 
If clinically indicated: 
• Brief physical examination and status check (see Section 9.6.3.3.2). 
• Complete blood count (see Section 9.6.3.1) 
• Complete chemistry and coagulation panels (see Section 9.6.3.1) 
If a patient has begun treatment with another anti-cancer agent or is no longer being seen in 
the clinic, the post-treatment safety assessment can be conducted via telephone. In this case 
FLymSI-18 questionnaire does not need to be completed at the safety follow-up visit.  
9.2.1.5.2 Active follow-up  
Patients who complete 12 months’ study treatment without PD or discontinue study drug for 
reasons other than disease progression will enter the Active follow-up period (which also 
serves as a Safety follow-up), except for patients who object to follow-up data collection.  

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The patients in the Active follow-up will have follow-up tumor assessments (also by central 
independent blinded review), including a local bone marrow analysis to confirm the first 
complete response in patients with previous bone marrow infiltration during Screening, as 
outlined in this protocol from the day of randomization until radiological disease progression 
is centrally evaluated and documented or new anti-tumor treatment is administered (see 
Section 9.4.2). Active follow-up for tumor assessments will continue for up to 2 years beyond 
study primary completion. For tumor assessments in patients with WM, see Section 9.4.3.  
During the Active FU, patients will complete the FLymSI-18 questionnaire at the same visits 
as follow-up tumor assessments will be done. The FLymSI-18 should be completed for up to 
at least 1 year after study primary completion or until the sponsor advises termination of 
patient-reported outcome (PRO) collection.  
During the Active follow-up period, AEs and SAEs assessed as related to study procedures by 
the investigator will be reported. AE pages of the eCRF and the SAE Form should be 
completed in the usual manner and forwarded to the applicable sponsor’s Global 
Pharmacovigilance (GPV) department.  
For patients with positive tests for HBsAg and/or HBcAb, and negative for HBV-DNA: 
these patients should receive prophylactic antiviral therapy per rituximab label and should 
perform HBV DNA test with PCR every cycle (±7 days)  through treatment and 12 months 
thereafter (27). If viral load becomes positive, patient should be withdrawn from the study. 
For patients with positive test for anti-HCV antibody and negative for HCV-RNA: these 
patients should perform HCV RNA test with PCR every cycle (±7 days)  through treatment 
and 6 months thereafter (27). If viral load becomes positive, patient should be withdrawn 
from the study. 
The end of the Active follow-up period is defined as (i) when disease progression is 
documented, or (ii) when a new anti-tumor treatment is administered, or (iii) up to 2 years 
beyond primary completion, whichever occurs first. 
9.2.1.5.3 Survival follow-up  
All patients will be followed off study for overall survival at 3-monthly (±14 days) intervals 
during the survival follow-up period (up to 10 years after the last patient started study 
treatment), independent of the reason for study termination, except for patients who object to 
follow-up data collection. Patients or their healthcare providers will be contacted either in 
person or by telephone. 
Information to be recorded at these contacts: 
• Survival status, including date of contact 
• Documentation of the first new anti-cancer treatment regimen, including tumor 
response, if given  
• Date and cause of death, if applicable 
 

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9.3 
Population characteristics 
9.3.1 
Demographic 
Baseline patient data pertaining to demographic information should be documented on the 
eCRFs including the following: 
• Year of birth and age 
• Sex 
• Race (when allowed by local regulation) 
• Ethnicity (when allowed by local regulation) 
9.3.2 
Medical history 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator: 
• Not pertaining to the study indication 
• Start before signing of the informed consent  
• Considered relevant for the patient’s study eligibility 
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1. 
9.3.3 
Other baseline characteristics 
Disease history of the study indication will be recorded: 
• Most recent histology of tumor 
• Most recent staging and grading of tumor  
• History of anti-cancer treatments (including type of treatment, type of response, date 
and duration of response) 
• Assessment of baseline toxicity: any unresolved toxicity CTCAE Grade 1 attributed to 
any prior therapy/procedure, not due to the underlying disease, excluding alopecia.  
• All medications and significant non-drug therapies taken within 30 days before study 
entry must be recorded on the eCRF, including: 
o Trade name of medication 
o Reason for medication (indication) 
o Dose of medication 
o Start date and end date or if continuing at patient's last visit  

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9.4 
Efficacy  
9.4.1 
Primary efficacy variable 
The primary efficacy variable of this study is progression free survival (PFS), defined as the 
time (in days) from randomization to PD as assessed by blinded independent central review or 
death from any cause (if no progression is documented). Radiological progression will be 
confirmed in real-time by blinded independent central review. Biochemical progression in 
patients with WM without lesions evaluable by imaging will be assessed locally.  
For secondary and other efficacy variables please refer to Sections 10.3.2.3 and 10.3.2.4.  
9.4.2 
Radiological tumor assessments 
Radiologic (IV contrast-enhanced CT/MRI) tumor assessments will include neck, chest, 
abdomen and pelvis, and will be evaluated locally at the study site and by the blinded 
independent central review. PET functional imaging is the preferred modality and should be 
done based on institutional standards. PET-CT can be utilized throughout the study if it is 
considered standard of care at the institution and according to Section 9.8. 
Tumor assessment schedule 
The first radiological (IV [and oral, if indicated, per Imaging Manual] contrast-enhanced 
CT/MRI) tumor assessment will be performed at Screening (including WM patients). 
Corticosteroids must be stopped or reduced to the allowed dose (≤ 15 mg of prednisone or 
equivalent) at least 7 days before performing screening PET-CT and/or CT/MRI (if a patient 
is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum 
allowed dose after the patient has signed the IC). Scans done up to 28 days prior to first dose 
can be used as baseline studies. The method chosen at baseline in terms of CT or MRI must 
be the same throughout the study. MRI shall be performed instead of CT when local 
regulations do not permit the use of CT as requested per protocol schedule. 
During the treatment phase as well as during the Active follow-up period, radiological tumor 
assessment will be performed every 12 weeks ( 7 days) from Cycle 1 Day 1 during Year 1 
and 2; every 24 weeks ( 7 days) during Year 3, 4 and 5; and every 24 weeks (±14 days) 
beyond Year 5. CT/MRI scans are not required at the EOT visit if the patient has been 
radiologically evaluated within the 4 weeks preceding EOT. 
If PET-CT is performed at baseline, it should be repeated after the Cycle 6 if a PD is not 
detected during the course of treatment and/or to confirm complete response (CR) or disease 
progression. If a PET-CT is performed, the CT portion of the PET-CT has to be of diagnostic 
quality (with IV contrast agent and with an acceptable radiation dose). CT/MRI and/or PET-
CT scans will be collected by the sponsor from all protocol defined assessments. For details 
please refer to the Imaging Manual.  

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Response assessment 
The response assessment will be done according to the Lugano Classification (14). For 
patients with WM, additional criteria apply (see Section 9.4.3). Detailed instructions on tumor 
assessment are provided in Appendix 16.5. 
At each tumor assessment during the course of the study (from baseline to EOT and during 
active follow up if applicable) radiological measurement of spleen vertical length (from 
cranial to caudal) must be performed and reported. 
As long as the patient has not experienced PD, investigator’s assessment is sufficient for case 
management. In the event of radiological progression, radiological real-time confirmation by 
central independent blinded evaluation is needed before a final decision on treatment 
discontinuation is made by the investigator. The evaluation of treatment response (best 
response: objective response rate and complete response rate) will be also done by central 
blinded review. 
The same technique (e.g. slice thickness, field of view) should be used for all scans during the 
study treatment period. Preferably all scans should be interpreted by the same 
investigator/radiologist during the study whenever possible. CT/MRI scans must be 
performed with contrast agents and must meet the standard of care for imaging of lesions in 
the respective organ system(s). If at baseline IV (or oral) contrast-enhanced CT is medically 
contraindicated, sites may acquire MRI (contrast-enhanced) of the neck, abdomen and pelvis, 
and an unenhanced CT of the chest above lung apices to the bottom of the adrenals. Only if a 
patient develops contra-indication to both CT and MRI contrast medium during the study, the 
case examinations should be continued without contrast medium. 
A prospective planned central image evaluation by independent radiology experts will be 
performed independent from the conduct of the clinical part of the study in order to facilitate 
an independent evaluation of efficacy in this study. All scans obtained for Screening, 
Treatment, End of Treatment (visit) and Active Follow-up including unscheduled scans 
should be forwarded to the designated Imaging Core Laboratory for independent radiology 
evaluation. 
PET-CT is preferred modality and recommended for FDG-avid lymphoma types only like FL 
grade 3a and MZL of nodal type. If obtained, images are to be submitted for independent 
radiology evaluation. CT scans of PET-CT images used for lesion measurements must be of 
diagnostic CT quality (CT is required for lesion measurements). If a PET scan is obtained at 
baseline, all sites of disease selected as target lesions should be preferably PET-positive. PET 
scans must be performed to confirm CR or disease progression if used from baseline. It is also 
recommended to perform a PET-CT, if at a previous imaging visit the tumor response was 
derived from PET-CT and CT/MRI alone shows any change in the response assessment on 
subsequent imaging visits (e.g. PR). An end-of-treatment PET scan will be performed 
according to an institutional standards and according to details as described in the Imaging 
Manual.  
The independent reviewers will be experienced radiologists, who will not have been involved 
in the clinical part of the study and are considered independent from the study. They will be 
blinded to patient data (excluding those who are specified in the Independent Review Charter, 

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e.g. for bone marrow biopsy). The primary efficacy variable will be analyzed based on the 
assessment of the central image evaluation. 
9.4.3 
Tumor assessments in patients with WM 
WM patients who do not have radiologically measurable lesion at Screening will not have 
further radiological assessments as per protocol. Their tumor response will be measured only 
by laboratory/clinical tests, and response assessment will be done according to the Owen 
Criteria. If PD was assessed by an investigator based on laboratory parameters alone, no 
independent confirmation of PD by independent blinded review is necessary. However, 
because these patients may during progression develop measurable disease without 
simultaneous increase in IgM, CT/MRI will be performed according to investigator’s criteria 
and according to details as described in the Imaging Manual. The imaging material should be 
submitted for blinded independent central review and PD confirmation.  
WM patients who have radiologically measurable lesion at Screening will continue having 
radiological assessments and, in addition, will have laboratory tests performed on the same 
days. CT/MRI scans will be done and collected according to the schedule specified in the 
protocol (see Section 9.2.1.3). For patients who have PD assessed based on CT/MRI scans 
must be submitted for review to confirm disease progression by an independent blinded 
radiology review. 
Sites must notify the sponsor about disease progression and follow procedures outlined in the 
protocol. 
Detailed instructions on tumor assessment are provided in Appendix 16.5. 
9.5 
Pharmacokinetics / pharmacodynamics 
9.5.1 
Sampling 
Copanlisib/placebo is given in combination with R-B or R-CHOP from Cycle 1 to Cycle 6 
and as monotherapy from Cycle 7 onwards. A separate IV line should be used for PK draws. 
This line must not be used for IV infusion of the drug. 
PK sampling will be performed as shown in Table 9–4 (see also Sections 9.1 and 9.2). 

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Table 9–4 PK assessments in the safety run-in part and phase III part  
Treatment: copanlisib/placeboa + R-B or copanlisib/placebo + R-CHOP 
PK sampling for copanlisib/placebo 
PK sampling for rituximab 
• 
Cycle 1 Day 1: pre-infusion (up to 30 
min prior to start infusion, 55 min (or 
within 5 min prior to end of infusion) 
• 
Cycle 1 Day 8: pre-infusion (up to 30 
min prior to start infusion), 5 to 15 min, 
55 min (or within 5 min prior to end of 
infusion) and 1.5 to 5 h after start of 
infusion 
• 
Day 8 of Cycle 3 and 6: Pre-infusion 
(up to 30 min prior to start infusion) and 
55 min (within 5 min prior to the end of 
infusion 
R-B 
• 
Cycle 1 Day 1: pre-infusion and end of 
rituximab infusion (within 5 minutes prior 
to the end of infusion)  
• 
Cycle 6 Day 1: pre-infusion and end of 
rituximab infusion (within 5 minutes prior 
to the end of infusion)  
R-CHOP 
• 
Cycle 1 Day 2: pre-infusion and end of 
rituximab infusion (within 5 minutes prior 
to the end of infusion)  
• 
Cycle 6 Day 2: pre-infusion and end of 
rituximab infusion (within 5 minutes prior 
to the end of infusion)  
 
PK = pharmacokinetic(s); R-B = rituximab and bendamustine;  
R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone  
a: applicable to the phase III part only 
Details about the collection, processing, storage and shipment of samples will be provided 
separately (laboratory manual).  
9.5.2 
Analysis 
PK samples will be analyzed for copanlisib, M-1, and other metabolites, as needed, and for 
rituximab. 
Concentration data of copanlisib, its metabolite M-1, and other metabolites, as needed, from 
this study will be analyzed to estimate the individual maximum drug concentration (Cmax) and 
area under the curve (AUC), and to measure the variability of the PK of copanlisib, its 
metabolite M-1 and other metabolites, as needed, in the safety run-in part and phase III 
population. A population pharmacokinetic approach will be used for the analysis. 
The pharmacokinetic serum exposure (Ctrough at pre-infusion and Cmax at the end of infusion) 
of rituximab will be estimated and compared with historical data from monotherapy. 
9.6 
Safety 
9.6.1 
Adverse events 
9.6.1.1 
Definitions 
Definition of adverse event (AE) 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 

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study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
A surgical procedure that was planned prior to the start of the study by any physician treating 
the patient should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE). 
New lesions or disease progression per se (by itself) should not be regarded as AEs. Instead, 
the associated signs and symptoms should be recorded as AEs. 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, laboratory, ECG. 
• Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints). 
• Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis). 
• Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. This includes intercurrent illnesses. 
Definition of serious adverse event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition refers to an event in which the patient was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met: 
o The admission results in a hospital stay of less than 12 hours 
o The admission is pre-planned  
(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2) 
o The admission is not associated with an AE  
(e.g. social hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence. 

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d. Results in persistent or significant disability / incapacity 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
e. Is a congenital anomaly / birth defect 
f. Is another serious or important medical event as judged by the investigator 
9.6.1.2 
Classifications for adverse event assessment 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.  
9.6.1.2.1 Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1. 
9.6.1.2.2 Intensity 
The intensity/severity of an AE will be graded using the NCI-CTCAE, version 4.03. For 
events not listed in the NCI-CTCAE version 4.03, the following scale will be used: 
• Grade 1: Mild 
• Grade 2: Moderate 
• Grade 3: Severe 
• Grade 4: Life-threatening 
• Grade 5: Fatal 
9.6.1.2.3 Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the CRF. 
Causality should be assessed separately for each study treatment as detailed in the CRF. If the 
investigator feels that the event cannot be firmly attributed to one of the study treatments 
(e.g. owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment. 
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question. 
Possible answers are “yes” or “no” 

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An assessment of “no” would include: 
1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site. 
or 
2. Non-plausibility, e.g. the patient is struck by an automobile when there is no indication 
that the drug caused disorientation that may have caused the event; cancer developing a 
few days after the first drug administration. 
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment. 
Important factors to be considered in assessing the relationship of the AE to study treatment 
include: 
• The temporal sequence from drug administration: The event should occur after the 
drug is given. The length of time from drug exposure to event should be evaluated in 
the clinical context of the event. 
• Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Patient’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question. 
• Underlying, concomitant, intercurrent diseases:  
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 
• Concomitant medication or treatment:  
The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might have caused the event in question. 
• Known response pattern for this class of drug: Clinical/preclinical 
• Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event 
• The pharmacology and pharmacokinetics of the study treatment:  
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) 
of the study treatment, coupled with the individual patient’s pharmacodynamics 
should be considered. 
• The assessment is not possible 
Causal relationship to protocol-required procedure(s) 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s). 
Possible answers are “yes” or “no” 

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9.6.1.2.4 Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. 
The study treatment action should be recorded separately for each study treatment as detailed 
in the CRF. 
• Drug withdrawn 
• Drug interrupted 
• Dose reduced 
• Dose not changed 
• Not applicable 
• Unknown 
9.6.1.2.5 Other specific treatment(s) of adverse events 
• None 
• Remedial drug therapy 
• Other 
9.6.1.2.6 Outcome 
The outcome of the AE is to be documented as follows:  
• Recovered/resolved 
• Recovering/resolving 
• Recovered/resolved with sequelae 
• Not recovered/not resolved 
• Fatal 
• Unknown 
9.6.1.3 
Assessments and documentation of adverse events 
AEs observed, mentioned upon open questioning by a member of the investigator team or 
spontaneously reported by the patient will be documented in the patient’s records and the 
appropriate eCRF. AEs will be documented in an event-based manner, using NCI-CTCAE 
v.4.03 guidelines. 
The investigator has to record on the respective CRF pages all adverse events occurring in the 
period that starts with the signing of the informed consent and will end 30 days after the last 
dose of study drug. The safety follow-up will occur 30 days (window of +5 days is allowed) 
after the last dose of study drug. During the active follow-up period, AEs and SAEs assessed 
as related to study procedures by the investigator will be reported. AE pages of the eCRF and 

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the SAE form should be completed in the usual manner and forwarded to the applicable 
sponsor’s GPV department. 
After the end of the follow-up phase there is no requirement to actively collect AEs including 
deaths. The type of information that should be assessed and recorded by the investigator for 
each AE is listed in Section 9.6.1.2.  
“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome of 
underlying AE(s). 
For all serious adverse events (SAEs) the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study drug. 
A laboratory test abnormality considered clinically significant, e.g., causing the patient to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, or 
judged significant by the investigator, should be reported as an AE. Each event should be 
described in detail along with start and stop dates, intensity, relationship to investigational 
product, action taken and outcome. 
9.6.1.4 
Reporting of serious adverse events 
The definition of SAEs is given in Section 9.6.1.1. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient. 
Investigator’s notification of the sponsor 
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigator site file. This information will be updated as needed. 
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File. For this, an AE 
page in the CRF as well as the complementary pages provided in the Investigator File must be 
completed for each SAE.  
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations. 
If disease progression leads to signs and symptoms that meet the criteria for seriousness (see 
Section 9.6.1.1), the associated signs and symptoms, not the underlying cause, should be 
reported as SAE, (i.e. progressive disease should not be recorded as SAE). In this case, 
disease progression should be mentioned on the SAE form as an “alternative explanation”. 
If a new primary malignancy is noted at any time it must be reported as an SAE, whether or 
not it is assessed as related to study therapy. 
In the event of a fatal or life-threatening reaction, the investigator must seek relevant follow-
up information and must complete a follow-up reported to the sponsor as soon as possible but 
not later than 8 calendar days after the initial report is sent. 
For all SAEs, the investigator is required to document in full the course of the SAE and any 
therapy given, including any relevant findings/records in the report. 

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For documentation of laboratory findings as SAE, please refer to Section 9.6.3.1. 
Notification of the Independent Ethics Committees / Institutional Review Boards 
(IECs/IRBs) 
Notification of the IECs / IRBs about all relevant events (e.g. SAEs, SUSARs) will be 
performed by the sponsor and/or by the investigator according to all applicable regulations. 
Notification of the authorities 
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations. 
Sponsor’s notification of the investigational site 
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations. 
9.6.1.5 
Expected adverse events 
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB) for copanlisib / summary of product characteristics (SmPC)/ 
prescribing information for rituximab, bendamustine, cyclophosphamide, doxorubicin, 
vincristine and prednisone. 
Overview listings of frequent events that have occurred so far in the clinical development of 
copanlisib are shown in the current IB. If relevant new safety information is identified, the 
information will be integrated into an update of the IB and distributed to all participating sites. 
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations. 
9.6.1.6 
Adverse events of special safety interest  
Copanlisib is an investigational drug and current knowledge of the AEs associated with this 
compound is limited. As with any new chemical entity, there is always potential for AEs that 
may be class related. Non-infectious pneumonitis (NIP) has been observed with copanlisib, as 
with other PI3K drugs, and since the sponsor wishes to be aware of any such reports rapidly, 
NIP has been designated as an AE of special interest (AESI). 
Regardless of whether an AE consistent with NIP is assessed as causally related/not related to 
study drug, or as serious/non-serious, the investigator should notify the sponsor within 24 
hours as outlined in Section 9.6.1.4. The AESI should be entered in the SAE form, and if the 
event is assessed as non-serious, the non-serious assessment should be noted in the form. The 
AESI will be also entered in the eCRF. 
9.6.2 
Pregnancies 
The investigator must report to the sponsor any pregnancy occurring in a female study patient 
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported. 
For a pregnancy in the partner of a male study patient, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent. 

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For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.  
9.6.3 
Further safety 
9.6.3.1 
Laboratory 
All laboratory analyses will be performed locally. Dipsticks should be available for urinalysis. 
• Complete blood count: hemoglobin, hematocrit, red blood cell (RBC), and white blood 
cell (WBC) (with differential to include absolute neutrophil, lymphocyte, monocyte, 
basophils and eosinophil counts), and platelet count. 
• Complete chemistry panel: calcium, sodium, potassium, chloride, phosphorus, 
magnesium, bicarbonate (or carbon dioxide if bicarbonate is not routinely measured at 
the site), total protein, albumin, glucose, blood urea nitrogen (BUN) (or urea if BUN is 
not routinely measured at the site), creatinine, uric acid, total bilirubin (conjugated and 
unconjugated bilirubin must be calculated if bilirubin > 1.5 × ULN), creatine kinase, 
ALT, AST, lactate dehydrogenase (LDH), alkaline phosphatase, lipase, amylase (or 
pancreatic amylase if amylase is not routinely measured at the site), cholesterol (total 
and LDL) and triglycerides. For evaluation of lipid-panels including triglycerides the 
patient must be fasted prior to sampling according to local standards. For patients 
who cannot adhere to these fasting requirements the evaluation of lipid-panels 
including triglycerides is considered not feasible. 
• Coagulation panel: PT, INR, and PTT. 
• Urinalysis: blood cells (RBC and leukocytes), glucose, ketones, bilirubin (not 
mandatory at urinalysis), protein, and pH (dipstick). Additional microscopic 
examinations will be performed if clinically indicated. 
• Serum pregnancy test in women of childbearing potential (WOCBP). Postmenopausal 
women who have not had periods for more than 1 year or surgically sterilized women 
will not be required to undergo a pregnancy test (this information should be recorded 
under medical history on the eCRF). See also Section 6.1. 
• Quantification of proteinuria by either a 24 hour total urine protein quantification or 
by UPCR on a random urine sample preferably taken in mid-morning. This should be 
reported as the ratio of concentrations of total urine protein to urine creatinine, both 
done in the same sample. Dipstick analysis is not acceptable to assess proteinuria. 
• Measurement of GFR according to the MDRD abbreviated formula (see 
Appendix 16.7).  
• In addition to the weekly clinical review and laboratory tests outlined in the schedule 
of assessments, the following should be performed in all patients prior to IV infusion 
of copanlisib/placebo (see Section 7.4.3.6.1):  
o CD4 (for patients with signs of infection), blood cultures if febrile neutropenia 
occurs, PCR for CMV (every cycle on Cycle X Day 1 (time window -1 day) 
during combination therapy and every 3 cycles starting from Cycle 7). 

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▪ Note: If PCR test is positive for CMV, treatment should be delayed 
until recovery. CMV PCR test is considered positive if, the result can 
be interpreted as a CMV viremia according to local SOC. Treatment 
CMV should be initiated based on local SOC. Re-treatment with 
copanlisib will be allowed without dose reduction once PCR test for 
CMV is negative. 
For patients with identified risk factors and those who developed OI, additional 
laboratory assessments can include (see Section 7.4.3.6.1): 
o CD4 and CD8 count and ratio, CRP, blood cultures 
o Any additional laboratory assessments according to local SOC reported as 
unscheduled laboratory assessments. 
An isolated laboratory abnormality that meets the criteria for a CTCAE Grade 4 classification 
is not reportable as an SAE, unless the investigator assesses that the event meets standard ICH 
criteria for an SAE (SAE definition in Section 9.6.1.1). All laboratory abnormalities, 
including CTCAE Grade 4 abnormalities, will be documented in the laboratory eCRF and will 
be reviewed on a regular basis. 
Baseline laboratory abnormalities that are part of the disease profile should not be reported as 
an AE, specifically when they are allowed or not excluded by the protocol inclusion/exclusion 
criteria. If an investigator is in doubt about the applicable reporting obligations, he / she 
should consult with the study monitor of the sponsor. 
9.6.3.2 
Glucose measurement on treatment days 
For requirements for copanlisib/placebo pre-dose glucose levels, see Section 7.4. 
On Cycle 1 Day 1 glucose will be measured at pre-dose, and post-dose 1 h and 2 h after the 
end of copanlisib/placebo infusion; and at the end of the rituximab infusion (window of ± 10 
min is allowed except for the pre-dose measurement); and at the end of the bendamustine 
infusion (±10 min) if patient receives corticosteroid premedication prior to bendamustine 
infusion. Additional measurements to be performed at the clinic as clinically indicated.  
On subsequent infusions, glucose will be measured prior to copanlisib/placebo infusion and 
1 h after the end of copanlisib/placebo; and at the end of the rituximab infusion (window of 
± 10 min is allowed except for the pre-dose measurement); and at the end of the bendamustine 
infusion (±10 min) if patient receives corticosteroid premedicaion prior to bendamustine 
infusion.  
• On Day 2 of Cycles 1-6: For patients receiving corticosteroid premedication prior to 
the bendamustine infusion:  
o Glucose test within 30 minutes prior to bendamustine infusion and at the end 
of bendamustine infusion (within 30 min). 
• On Day 2 of Cycles 1-6: For patients receiving corticosteroid premedication prior to 
the rituximab infusion:  

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o Glucose test within 30 minutes prior to rituximab infusion and at the end of 
rituximab infusion (within 30 min). 
9.6.3.3 
Physical examinations 
Physical examinations will be performed according to the schedule summarized in the flow 
chart of Section 9.1. 
Abnormal physical examination findings are recorded either as medical history or as adverse 
events (see Section 9.6.1.1). 
9.6.3.3.1 Complete physical examinations 
Complete physical examination includes: 
• Height (only at Screening) 
• Weight 
• ECOG performance status assessment,  
• NYHA classification (see Appendix 16.4) 
• Vital signs (see Section 9.6.3.4) 
• Complete review of body systems. 
All clinical signs and regions that can be brought in context with the underlying disease, with 
the anti-cancer treatment to be administered or with relevant accompanying diseases (if 
present) should be clinically assessed. 
At minimum the following aspects/regions need to be assessed as well: 
• General appearance  
• Skin, hand and feet including clinical assessment of hydration status via hand extensor 
surface skin turgor 
• Eyes  
• Ears, nose, throat (including inspection of oral mucosa for hydration status) 
• Head and neck 
• Lungs 
• Heart 
• Abdomen  
• Lymph nodes 
• Musculoskeletal system and spine 
• Lower legs  
• Neurologic findings 

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9.6.3.3.2 Brief physical examination and status check 
Brief physical examination and status check includes ECOG performance status, vital signs 
(see Section 9.6.3.4), examination of pertinent organ systems, and brief interim history 
(change of symptoms). 
The examination of pertinent organ systems should investigate at minimum: 
• Skin, hand and feet including clinical assessment of hydration status via hand extensor 
surface skin turgor 
• Throat (including inspection of oral mucosa for hydration status) 
• Lungs: evaluation of new onset or worsening of pulmonary symptoms, and lung 
examination. 
• Heart examination and NYHA classification (see Appendix 16.4) 
• Abdomen  
• Neurologic findings 
Other clinical signs and regions might be investigated as well, if clinically indicated. 
9.6.3.4 
Vital signs 
Pulse, blood pressure and temperature will be assessed as part of physical examinations 
according to the schedule summarized in the flow chart of Section 9.1. If clinically indicated, 
it is at the investigator’s discretion to perform these measurements more frequently.  
9.6.3.5 
Blood pressure measurement on treatment days 
• Blood pressure will be measured prior to each copanlisib/placebo dose (no more than 
4 measurements) until there are two consecutive results < 150/90 mmHg with at least 
15 min interval between the measurements, to be able to start copanlisib/placebo 
infusion (pre-dose). The investigator can consider a medical intervention to maintain 
blood pressure values appropriate for infusion. The investigator must delay the 
infusion until blood pressure values are <150/90 mmHg. The patient should rest for 5-
10 minutes before blood pressure is recorded. 
• On infusion days: blood pressure will be measured at pre-dose, 30 min (after the start 
of infusion), right after the end of infusion, and 1 h and 2 hours after the end of 
infusion 
Note: a time window of ±10 min is allowed for all post-dose BP measurements 
• In addition, on Day 1, blood pressure will be measured 30 minutes after the start of 
rituximab infusion and at the end of rituximab infusion (window of ±10 min is 
allowed) from Cycle 1 to Cycle 6 in the R-B treatment groups. 
• For details on the management of arterial hypertension, see also Sections 7.4.2 (dose 
modification) and 7.4.3.3 (treatment of blood pressure increases associated with 
copanlisib). 

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9.6.3.6 
12-lead ECG 
12-lead ECGs (including QTcB and QTcF evaluation) will be performed according to the 
schedule summarized in the flow chart in Section 9.1. The study number, patient number, visit 
and the date of the ECG will be noted on every ECG. 
The patient should rest for 5-10 minutes before the ECG is recorded. 
The overall interpretation of the ECG (normal/abnormal, clinical relevance) and the ECG 
findings will be recorded in the source documentation and in the eCRF. 
9.6.3.7 
Cardiac function 
Cardiac function test: echocardiogram or MUGA scan. The method chosen at baseline (i.e. 
either echocardiogram or MUGA scan) must be used throughout the whole study period. 
Additional cardiac function tests are required if any signs or symptoms of cardiac dysfunction 
occur.  
Echocardiogram/MUGA scan should be performed for determination of LVEF.  
The study number, patient number, visit and the date of the echocardiogram/MUGA scan are 
noted on every echocardiogram/MUGA scan. 
The overall interpretation of the echocardiogram/MUGA scan and findings will be recorded 
in the source documentation and in the eCRF. 
9.6.3.8 
ECOG performance status 
Grading definitions are given in Appendix 16.3. 
9.6.3.9 
Reporting of medical device failures 
To countries where applicable: the investigator must report immediately all non-approved 
medical device failures which could cause health damage, as well as any health damage that 
may be causally associated with a non-approved medical device failure. For this reporting, the 
forms provided are to be used and sent to the designated recipient. 

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9.7 
Other procedures and variables 
9.7.1 
Biomarker investigations 
Overview 
There following biomarker investigations are included in this study: 
1. Tumor-genetic research of fresh (highly preferred) or archival tumor tissue, and 
possibly of circulating tumor DNA isolated from plasma 
2. Non-genetic biomarker testing (may be performed using tumor tissue and/or plasma) 
3. Genetic biomarker research 
Genetic biomarker research of the whole blood requires a separate ‘genetic’ research consent 
(optional testing for research). All other analyses are covered by the main ICF. 
Biomarker investigations 
The planned biomarker analyses utilize tumor tissue, plasma and blood, and involve the 
analysis of protein and nucleic acids (i.e., RNA and/or DNA). Details on the collection, 
processing, storage and shipment of biomarker samples will be provided in separate 
documents (e.g. sample handling sheets or laboratory manual). 
The biomarker results may be reported separately. 
Collection and use of biomarker specimens 
Tumor Tissue: 
Fresh tumor tissue and/or archival tumor tissue must be available at Screening for central 
pathology review for an exploratory analysis (see Section 6.1). Patients without historical 
material or fresh tissue biopsy will not be eligible for randomization. In patients with WM, 
bone marrow biopsy can be used for histological confirmation of the diagnosis and for 
biomarker analyses. 
In addition, one or more of the following pre-treatment tumor tissue samples will be collected 
during Screening when available with the purpose of investigating or identifying biomarkers 
that may be predictive of copanlisib effects/efficacy in NHL and to contribute to better 
understanding the disease. 
• Submission of archival tumor tissue from a biopsy performed within 180 days before 
signing of the informed consent. 
• Submission of fresh tissue from a biopsy performed during Screening (between Day -
28 and Day -8 prior to the start of study treatment) is highly encouraged when the 
above is not available. 
• In the absence of either of the above, submission of an older archival tumor tissue 
sample (collected prior to 180 days before signing of the informed consent) is 
mandatory when available.  
A tumor biopsy is also encouraged at the time of progression (optional) to allow investigation 
of copanlisib resistance.  

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Archival formalin-fixed paraffin-embedded (FFPE) tissue may be supplied as a block 
(preferred) or as precut slides. Details on the preparation of slides and number of slides to be 
prepared as well as detailed guidance on fresh biopsy sample preparation and storage will be 
described in separate documents (e.g. Sample Handling Sheets or laboratory manual). 
All tumor tissues may be used as a source of RNA or protein for the study of gene and protein 
expression. The tumor tissue may also be used as a source of tumor DNA for the evaluation of 
tumor-associated alterations in genes of interest (e.g., PIK3CA and genes associated with 
NHL). 
Plasma for tumor genetic biomarker analysis: Blood samples will be obtained and used for 
plasma preparation at the time points as indicated in the study flow chart (see Section 9.1). 
Plasma may be used as a source of circulating tumor DNA for the evaluation of mutations in 
tumor-related genes of interest. 
Plasma for non-genetic biomarker analysis: Blood samples will be obtained and used for 
plasma preparation at the time points as indicated in the study flow chart (see Section 9.1). 
Plasma may be used to quantify the circulating levels of various proteins. 
Whole blood (only applicable for patients who provided ‘genetic’ research consent): On 
Cycle 1 Day 1, a whole blood sample will be obtained. The blood sample will be used as a 
source of DNA and gene products for the evaluation factors that are associated with the drug 
or the pathomechanisms of the disease. Results will be reported under separate cover. 
In addition to the assays listed above, other biomarkers deemed relevant to gain further 
knowledge about the pathomechanism of the disease or about the drug (i.e. mode of action or 
safety of the drug) may be measured, based on newly emerging data from other ongoing trials 
of these investigational drugs and/or literature data. However, the study sponsors reserve the 
right not to conduct all or part of the aforementioned biomarker analysis. Data from this 
biomarker analysis may be correlated with various other data obtained in this study (e.g., 
clinical efficacy, pharmacokinetics, toxicity). 
If a scheduled biomarker sample collection is missed, this should not be regarded as a 
protocol deviation. 
9.7.2 
Quality of life questionnaire – Phase III part only 
The effect of treatment on the physical symptoms of lymphoma is an important issue for 
patients; therefore the collection of this information is a routine component in many protocols.  
The main purpose of the symptom assessment in this study is to describe any differences 
between the treatment groups in the time to deterioration and time to improvement in disease-
related physical symptoms (DRS-P) of at least 3 points as measured by the DRS-P subscale of 
the FLymSI-18 questionnaire. 
In the phase III part of this study, physical symptoms of lymphoma will be assessed using the 
NCCN-FACT Lymphoma Symptom Index-18 (FLymSI-18), version 2 (NCCN-FACT: 
National Comprehensive Cancer Network - Functional Assessment of Cancer Therapy). 
The FLymSI-18 is an instrument that was developed to assess symptoms of lymphoma, 
symptoms of treatment of lymphoma, and health related QoL of patients with lymphoma. The 

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instrument was developed in accordance with recent Food and Drug administration (FDA) 
guidance for the development of instruments for PROs.  
The instrument contains 18 items, each of which utilizes a Likert scale with 5 possible 
responses ranging from 0 “Not at all” to 4 “Very much”. Nine items reflect DRS-P, and the 
responses to the items are summed to calculate a DRS-P subscale score. Four items represent 
disease-related emotional symptoms (DRS-E), and the responses to those items may be used 
to calculate a DRS-E subscale score. Three items represent treatment side effects, and the 
responses to these items may be summed to calculate a treatment side-effect (TSE) subscale 
score. Finally, two items represent functional well-being (FWB), and responses to those items 
may be summed to calculate a FWB subscale score. The questionnaire allows for calculation 
of total score and four subscales: DRS-P, DRS-E, TSE and FWB (15, 17).  
The FLymSI-18 will be administered in the phase III part according to the schedule specified 
in the study flow chart (see Section 9.1).  
The FLymSI-18 should be completed at the start of the visit before the patient sees the 
physician and before any study-related procedure is conducted, so that any interaction 
between the patient and physicians or other health care providers does not influence the 
response to the FLymSI-18 questionnaire. 
A PRO information sheet will be provided and completed by the study personnel at each visit 
at which the FLymSI-18 questionnaire is to be administered, regardless of whether or not the 
FLymSI-18 questionnaire is completed by the patient. This is to document information such 
as questionnaire completion, date of completion, and reasons for non-completed 
questionnaires. 
9.8 
Appropriateness of procedures / measurements 
The efficacy assessments used in this study include those considered standard for the 
evaluation of objective tumor response in patients with iNHL. The recently published 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification (14) support the use of PET-CT for 
staging and response assessment of routinely FDG-avid histologies, especially in clinical 
trials. PET-CT is preferred modality and will be allowed for indolent FDG-avid histologies 
and should be considered for follicular lymphoma grade 3 and marginal zone lymphoma 
(nodal type). For lymphomas with low FDG avidity, it may be used if there is a suspicion of 
transformed disease. In all the other cases response assessment according to the Lugano 
classification will be performed by CT scan. MRI can be used optionally including in the case 
of contraindication to CT-contrast agents.  
See Section 9.7.2 for the use of FLymSI-18 questionnaire in this study. 

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10. 
Statistical methods and determination of sample size 
10.1 
General considerations 
Statistical analyses will be conducted by or under the supervision of the sponsor’s study 
statistician, except for the analysis of biomarker data, which will be performed by or under the 
direction of the sponsor’s genomics and biomarker statistical expert.  
Statistical analyses will be performed using Statistical Analysis System (SAS); the version 
used will be specified in the statistical analysis plan (SAP). As a general principle, the safety 
run-in part and phase III part will be analyzed separately.  
Further details on the statistical analyses including handling of missing data will be provided 
in the SAP. 
10.2 
Analysis sets 
Safety run-in part:  
Full analysis set (FAS): All patients in the safety run-in part who receive at least one dose of 
study drug. 
Safety analysis set (SAF): All patients in the safety run-in part who receive at least one dose 
of study drug.  
Pharmacokinetic analysis set (PKAS): All patients in the safety run-in part with a valid PK 
profile will be included in the analysis of PK data. 
Phase III part:  
The following statistical analysis sets are defined: 
Full analysis set (FAS): All randomized patients in the phase III part. The FAS is the 
primary population for all efficacy analyses. Patients will be analyzed as randomized. 
Safety analysis set (SAF): All randomized patients in the phase III part who received at least 
one dose of study drug (copanlisib/placebo, R-B or R-CHOP). SAF will be used for the 
analyses of the safety variables. Patients will be analyzed as treated.  
Pharmacokinetic analysis set (PKAS): All patients in the phase III part with a valid PK 
profile will be included in the analysis of PK data.  
10.3 
Variables and planned statistical analyses 
10.3.1 
Safety run-in part  
The recommended dose of copanlisib in combination with standard immunochemotherapy 
will be determined based on a 3+3 design. The primary safety variable is the occurrence of 
DLTs during Cycle 1. Safety variables will include also treatment-emergent AEs, SAEs, 
laboratory parameters, and vital signs. The safety data will be listed by dose level. The best 
overall response will be summarized. For further details on PK and biomarker variables and 
analysis, see Section 10.3.2.12. 

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10.3.2 
Phase III part 
10.3.2.1 
Population characteristics 
Demographics and baseline characteristics will be summarized by descriptive statistics by 
treatment group (copanlisib in combination with R-B or R-CHOP versus placebo in 
combination with R-B or R-CHOP) for the FAS.  
10.3.2.2 
Primary efficacy variable  
The primary efficacy variable is PFS, defined as the time (in days) from randomization to PD 
or death from any cause (if no progression is documented). The primary data for PFS analysis 
will be based on blinded independent central review. Radiological progression will be 
confirmed in real-time by blinded independent central review. Biochemical progression in 
patients with WM without lesions evaluable by imaging will be assessed locally, and the 
confirmation of PD by central review is not needed. 
10.3.2.3 
Secondary efficacy variables  
Secondary efficacy variables are objective response rate (ORR), duration of response (DOR), 
complete response rate (CRR), time to progression (TTP), time to next anti-lymphoma 
treatment (TTNT), disease control rate (DCR), overall survival (OS, 5 year survival rate), 
time to improvement and time to deterioration in disease-related symptoms - physical (DRS-
P) of at least 3 points of lymphoma as measured by the FLymSI-18 questionnaire (FLymSI = 
NCCN-FACT Lymphoma Symptom Index). All secondary efficacy variables will be analyzed 
in the FAS. 
Objective response rate (ORR) 
ORR is defined as the proportion of patients who have a best overall response  
over the whole duration of the study (i.e. up to time of analysis of PFS) of complete 
response (CR) or partial response (PR) according to the Lugano Classification and for 
patients with WM a best overall response of CR, very good partial response (VGPR), PR, or 
minor response (MR) according to the Owen Criteria. 
Duration of response (DOR)  
DOR is defined as the time (in days) from first observed tumor response (CR, VGPR, PR, or 
MR) until PD or death from any cause, whichever is earlier. Patients without PD or death at 
the time of analysis will be censored at the date of their last evaluable tumor assessment. DOR 
will only be analyzed for patients with at least one CR, VGPR, PR, or MR.  
Complete response rate (CRR)  
CRR is defined as the proportion of patients who have a best overall response of CR during 
the study (i.e., up to time of analysis of PFS).  
Time to progression (TTP) 
TTP is defined as the time from randomization to PD or death related to PD, whichever is 
earlier. Death related to PD is considered to be any death except for: 

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a) Death due to an AE unrelated to progression 
b) Death with a specification of “other” as reason (which excludes PD)  
TTP for patients without PD at the time of analysis or death not related to progression will be 
censored at the date of their last tumor assessment. TTP for patients who have neither tumor 
assessments post baseline nor death related to PD will be censored at Day 1. 
Time to next anti-lymphoma treatment (TTNT) 
TTNT is defined as the time from stop of study medication to start of new anti-lymphoma 
therapy. For patients without new anti-lymphoma treatment at the time of analysis, patients 
will be censored at last assessment of new anti-lymphoma treatment. For patients stopping the 
study medication without further assessment of new anti-lymphoma treatment, they will be 
censored at Day 1. Patients still on study treatment at the time of analysis will not be included 
in the analysis. 
Overall survival (OS)  
OS is defined as the time (in days) from randomization until death from any cause. For 
patients alive at the time of analysis, they will be censored at the last known alive date. 
Time to improvement in DRS-P of at least 3 points 
Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 
questionnaire, is defined as time from randomization to first increase in DRS-P score of at 
least 3 points from baseline before progression (radiological progression or biochemical 
progression for WM patients without lesions evaluable by imaging).  
If alive patients without progression and without improvement in DRS-P of at least 3 points at 
the time of analysis, they will be censored at last assessment of DRS-P.  
If progression or death occurs before or without improvement in DRS-P of at least 3 points at 
the time of analysis, i.e., cut-off date, patients will be censored at data cut-off date. For alive 
patients with no baseline or no post-baseline assessment of DRS-P, and do not have PD, they 
will be censored at Day 1. 
This endpoint will be evaluated for patients with a baseline DRS-P score of 30 points or less 
(i.e. patients who still have room for improvement in symptoms). 
Time to deterioration in DRS-P of at least 3 points 
Time to deterioration in DRS-P of at least 3 points is defined as time (in days) from 
randomization to the occurrence of one of the following, whichever occurs earliest: 
• First reduction of DRS-P score from baseline ≥ 3 points 
• Radiological progression or biochemical progression for WM patients without lesions 
evaluable by imaging 
• Death from any cause 
For patients without event of deterioration in DRS-P of at least 3 points at the time of 
analysis, i.e., data cut-off, they will be censored at last assessment of DRS-P. For alive 

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patients with no baseline or no post-baseline assessment of DRS-P, and do not have PD, they 
will be censored at day 1. 
Further sensitivity analyses for the DRS-P analyses may be described in the SAP. Considering 
at least 3 points decline or increase, respectively, to be an important change with regard to 
DRS-P is the current assessment. The important change for DRS-P is however under 
continuing research by the developer of the questionnaire. 
Therefore, the value of 3 points might be updated in the SAP, considering forthcoming 
research findings.  
Disease Control Rate (DCR) 
DCR is defined as the proportion of patients who have a best response rating of CR, VGPR, 
PR, MR, or stable disease (SD) (excluding unconfirmed early SD) that is achieved during 
treatment or within 35 days after termination of study treatment. An unconfirmed early SD is 
defined as SD on or before Study Day 76, with no additional tumor assessment of SD or 
better within the following 25 weeks. 
10.3.2.4 
Other efficacy variables  
FLymSI-18 total and subscale scores (DRS-P, DRS-E, TSE, F/WB). 
10.3.2.5 
Primary efficacy analysis 
All randomized patients (FAS) will be included in the primary efficacy analysis. 
The analysis will be performed when approximately 280 PFS events (PD by blinded 
independent central review or death if death is before PD) in the FAS are observed. For 
patients without documented PD or death at the time of analysis, the PFS time will be 
censored at the date of the last evaluable tumor assessment or last biochemical assessment for 
patients with WM without lesions evaluable by imaging. For patients without post-baseline 
tumor assessments and do not die, PFS time will be censored at day 1. The detailed censoring 
rules will be documented in statistical analysis plan (SAP). 
The date used for the calculation of the PFS is the actual (rather than scheduled) date of 
assessment (i.e., actual scan date); missing tumor assessments are not considered.  
In order to evaluate whether copanlisib in combination with R-B or R-CHOP is superior to 
placebo in combination with R-B or R-CHOP in prolonging progression free survival, the 
following null hypothesis will be tested in the FAS: 
H0, PFS: SCopanlisib+R-B/R-CHOP(t) = SPlacebo+R-B/R-CHOP (t) for all time points t ≥ 0 
The alternative hypothesis will be: 
H1,PFS: SCopanlisib+ R-B/R-CHOP (t) > SPlacebo+ R-B/R-CHOP (t) for at least one time point t ≥ 0, and 
 
SCopanlisib+ R-B/R-CHOP (t) ≥ SPlacebo+ R-B/R-CHOP (t) for all time points t ≥ 0, 
where SCopanlisib+ R-B/R-CHOP denotes the survival function of the copanlisib + R-B or R-CHOP 
group and SPlacebo+ R-B/R-CHOP denotes the survival function of the placebo + R-B or R-CHOP 
group in the FAS. 

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The two treatment groups will be compared using a log-rank test stratified by the same 
stratification variables as for randomization, with one-sided alpha of 0.025 for the FAS. The 
test statistic from stratified log rank test is assumed to be asymptotically normal distribution. 
Kaplan-Meier estimates and survival curves for PFS will also be presented for each treatment 
group. A hazard ratio with a 95% confidence interval derived from a stratified Cox 
proportional hazards model will also be provided. 
10.3.2.6 
Secondary efficacy analysis 
All secondary efficacy endpoints will be analyzed in the FAS at the time as the analysis of the 
primary efficacy endpoint.  
The ORR will be calculated by treatment group, with their 95% confidence interval, as well as 
the differences of objective response rates between treatment groups and their corresponding 
95% confidence intervals in the FAS.  
The comparison of ORR, between the two treatment groups, will be made using the “general 
association Cochran-Mantel-Haenszel statistic” stratified by the same stratification factors 
used in the PFS analysis. 
DCR and CRR will be analyzed in a manner similar to ORR. 
The time to deterioration and time to improvement in DRS-P subscale of FLymSI-18, DOR, 
TTP, and TTNT will be analyzed in a manner similar to PFS. 
OS will be analyzed using a stratified log-rank test, in a manner similar to PFS, and the 5-year 
survival rate will also be provided.  
10.3.2.7 
Confirmatory statistical test strategy 
Details on confirmatory statistical testing strategies will be provided in the SAP. 
10.3.2.8 
Section removed by amendment 3. 
10.3.2.9 
Other efficacy analysis 
An analysis of covariance (ANCOVA) analysis of the physical symptoms of lymphoma (as 
measured using the FLymSI-18 DRS-P subscale) and other subscales if needed will be 
performed to assess differences between treatment arms in the FAS based on AUC using the 
appropriate covariates. Total FLymSI-18 and subscales will be summarized. Further details on 
PRO data analysis will be provided in the SAP. 
10.3.2.10 Subgroup analysis 
Descriptive statistics and hazard ratio estimates with 95% confidence interval will be 
provided for PFS and other secondary endpoints if needed. Subgroups include stratification 
factors and further important demographics and baseline cancer characteristics, as 
appropriate.  
10.3.2.11 Safety variables and analysis 
Safety variables will include treatment-emergent AEs (TEAEs), SAEs, laboratory parameters, 
ECG and vital signs. The severity of AEs will be graded using the NCI-CTCAE version 4.03 

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dictionary. A treatment-emergent AE is defined as any event arising or worsening after start 
of study drug administration until 30 days after the last study drug intake.  
Safety variables will be summarized by means of descriptive statistics and/or frequency tables 
as appropriate. Summaries will be given by treatment group.  
All TEAEs, drug related TEAEs, serious TEAEs will be summarized by Medical Dictionary 
for Regulatory Activities (MedDRA) classification and worst CTCAE grade. The summaries 
of vital signs and ECG will also be provided.  
10.3.2.12 Further variables and their analysis 
Pharmacokinetic (PK) 
Individual PK will be estimated by means of individual maximum drug concentration (Cmax) 
and the area under the curve (AUC) for copanlisib, its metabolite M-1, and other metabolites, 
as needed. Ctrough and Cmax of rituximab will be estimated. See Section 9.5. 
Individual concentration-time data will be provided in a clinical study report appendix. 
A population pharmacokinetic approach will be used for the copanlisib PK analysis, and the 
results will be documented in a separate report.  
The data from the safety run-in part and phase III part will be pooled for PK analysis.  
Biomarkers 
All biomarker analyses that will be performed are considered exploratory; specifics of these 
analyses will be described in the separate Biomarker Evaluation Plan and may be reported 
separately.  
10.3.3 
Missing data / drop-outs 
Drop-out patients will not be replaced in phase III part of the study. Every effort will be made 
to obtain actual tumor assessments date, death date and contact date for alive patients. The 
further imputation rules for missing data will be documented in SAP. Further information 
relating to missing data is given in Section 11.4. 
10.4 
Determination of sample size 
Safety run-in part 
Maximum 2 × 6 evaluable patients per combination (dependent on visibility of DLT) will be 
included into two dose levels to identify the RP3D.  

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Phase III part  
EAST 6.4 was used to calculate a sufficient sample size in the FAS, targeting an increase of 
50% in median PFS time, under the copanlisib + R-B/R-CHOP combination arms. Assuming 
a median PFS of 24 months under the control treatment, 1-sided alpha of 0.025, power of 
90%, and a randomization ratio of 1:1 between the experimental and control arms, 256 events 
(progression based on blinded independent central review or death from any cause, whichever 
occurs first) were required to detect a 50% increase in PFS in the FAS population. The 
number of required PFS events was increased from 256 to approximately 280 events to 
adequately power an analysis of the targeted increase in median PFS time in the FL histology 
population.  
The expected study duration to reach approximately 280 PFS events is at least 52 months, and 
the expected accrual duration was approximately 33 months with a 15 month linear ramp-up 
(maximum accrual rate being approximately 20 patients per month). The monthly dropout 
(loss to follow-up and unevaluable for tumor assessment) rate was assumed to be 0.48%. With 
these assumptions, a total of approximately 520 patients were required to be accrued into the 
two treatment groups, combined. 
10.5 
Planned interim analyses 
No formal interim analysis is planned for the primary efficacy endpoint (i.e. PFS). OS 
analysis will also be performed at the time of final analysis of PFS.  
A DMC will be instituted for independent review of ongoing data from this trial in accordance 
with a separate DMC Charter. The DMC will operate independently of the sponsor and 
investigators. 
11. 
Data handling and quality assurance 
11.1 
Data recording 
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 
from Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies. RAVE allows for the application of 
software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel. Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study. Data queries 
resulting from the application of the software logic are resolved by the site personnel. The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer's internal computer system via a secure Virtual Private 
Network (VPN). 
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel seeking access 
must go through a thorough RAVE training process before they are granted access to RAVE 
for use in Bayer's clinical studies. Training records are maintained. 

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All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner. 
The RAVE system contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
patients enrolled in this study. 
Source documentation 
It is the expectation of the sponsor that key data entered into the CRF has source 
documentation available at the site.  
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at the site 
to identify the source data for key data points collected and the monitor will work with the site 
to complete this. 
Data recorded from screening failures 
Data of 'only screened patients' will be recorded at least as source data, as far as the reason for 
the premature discontinuation is identifiable. At minimum, the following data should be 
recorded in the CRF: 
• Demographic information (patient number; year of birth / age; sex; if applicable race / 
ethnicity) 
• Date of informed consent 
• Reason for premature discontinuation 
• Date of last visit.  
These data will be transferred to the respective database. 
For screening failures with an SAE, the following data should be collected in the CRF in 
addition to the data specified above: 
• All information about the SAE. 
• All information related to the SAE such as:  
o Concomitant medication 
o Medical history 
o Other information needed for SAE complementary page 
11.2 
Monitoring 
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 

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requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items. 
The sponsor/designee will monitor the site activity to verify that the: 
• Data are authentic, accurate and complete.  
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes).  
• Safety and rights of patients are being protected 
• Study is conducted in accordance with the currently approved protocol  
(including study treatment being used in accordance with the protocol) 
• Any other study agreements, GCP, and all applicable regulatory requirements are met. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents. 
11.3 
Data processing 
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures. This is applicable for data recorded on CRF as well as for data from other sources 
(e.g. IVRS, laboratory, ECG, adjudication committees). 
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used. 
Medical Dictionary for Regulatory Activities (MedDRA) will be used for AEs and medical 
history, and WHO-Drug Dictionary (WHO-DD) for concomitant medications. The SAS 
datasets to be used for statistical analysis to be included in the clinical study report will 
remain unmodified after the data is declared clean and ready for analysis. 
After its initial release for biometrical analysis, the clinical database is planned to be re-
opened for the inclusion of the following additional data: pharmacokinetic data, biomarker 
data.  
11.4 
Missing data 
Every effort should be made to document the tumor response even after discontinuation of 
treatment.  
In cases where patients indicate they do not want to “continue”, investigators must determine 
whether this refers to discontinuation of study treatment, unwillingness to attend follow-up 
visits, unwillingness to either have telephone contact, contact with study personnel, or to 
allow contact with a third party (e.g., family member, doctor). In all cases, every effort should 
be made to continue to follow the patients for tumor assessment until patients develop 
radiological progression by blinded independent central review or biomedical progression in 
patients with WM without lesions evaluable by imaging. Survival information including 

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survival status, death date and/or contact date should be determined for all patients during the 
survival follow up. 
11.5 
Audit and inspection 
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome. 
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection. 
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study. 
11.6 
Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period. 
The investigator/institution notifies the sponsor if the archival arrangements change (e.g. 
relocation or transfer of ownership). 
The investigator site file is not to be destroyed without the sponsor’s approval. 
The contract with the investigator/institution will contain all regulations relevant for the study 
center. 
12. 
Premature termination of the study 
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to the 
following reasons:  
• If risk-benefit ratio becomes unacceptable owing to, for example, 
o Safety findings from this study (e.g. SAEs) 
o Results of parallel clinical studies 
• If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame. 

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The investigator has the right to close his/her center at any time. 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties. Final decision 
on the closure must be in writing. 
• All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law. 
• All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction. 
• In the event of a partial study closure, ongoing patients, including those in post study 
follow-up, must be taken care of in an ethical manner. 
Details for individual patient's withdrawal can be found in Section 6.4.1. 
13. 
Ethical and legal aspects 
13.1 
Investigator(s) and other study personnel 
Study personnel are identified in a separate personnel list (not part of this clinical study 
protocol) as appropriate. This list will be updated as needed; an abbreviated version with 
personnel relevant for the centers will be available in each center’s investigator site file. 
Whenever the term “investigator” is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site. 
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 
before patient recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center. 
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file. 
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages. 
External data evaluation bodies 
Data Monitoring Committee (DMC) 
A DMC will be established that will closely interact with the sponsor’s Global 
Pharmacovigilance (GPV) department in order to assess all safety-relevant information.  
The DMC will review study data and provide an independent recommendation on the 
advisability of continuing the study as planned. Reviews will take place as outlined in the 

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DMC charter. The DMC will conduct its reviews based on data summaries and on an 
individual case basis. The summaries (i.e., tables and listings) will be generated by external 
Statistical Analysis Center (SAC). Details will be decided based on the sponsor’s currently 
valid operational instruction manual. The format and content of these data summaries will be 
specified by the sponsor in conjunction with the DMC and may change during the study if 
indicated. All summaries will be based on data provided by the sponsor from the study 
database. The sponsor will be blinded to phase III part of the study. 
Decisions on trial termination, amendment, or cessation of patient recruitment based on 
risk/benefit assessment will be made after recommendations from the DMC have been 
assessed by the sponsor.  
Central radiological evaluation  
Radiological evaluation of CT/MRI scans and PET-CT scans if performed will be performed 
centrally. 
Central pathology review  
The retrospective confirmation of histopathological diagnosis will be performed centrally and 
analyzed only as an exploratory analysis. 
13.2 
Funding and financial disclosure 
Funding 
This study will be funded by its sponsor. 
Financial disclosure  
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research patients has to provide a financial disclosure 
according to all applicable legal requirements. All relevant documentation will be filed in the 
trial master file. 
13.3 
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 sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and 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/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB approval 
must be obtained and also forwarded to the sponsor. The responsible unit (e.g. IEC/IRB, head 
of the study center/medical institution) must supply to the sponsor, upon request, a list of the 
IEC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is 
organized and operates according to GCP and applicable laws and regulations. 

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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 either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial patients without prior IEC/IRB/sponsor 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/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator. 
Details on discontinuation of the entire study or parts thereof can be found in Section 12. 
13.4 
Patient information and consent 
All relevant information on the study will be summarized in an integrated patient information 
sheet and informed consent form provided by the sponsor or the study center. There will be 
two informed consent forms in this study: Patients will be asked to provide a “general” 
consent for participation to the study and for their specimens to be collected and used in 
protein analyses and tumor DNA/RNA analyses. In addition, an optional “genetic” consent is 
for patient specimens to be used in analyses involving nucleic acids. A sample patient 
information and informed consent form is provided as a document separate to this protocol. 
Based on this patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient / legal representative or proxy consenter (if the patient is 
under legal protection), prior to his/her entry into the study (i.e. before any examinations and 
procedures associated with the selection for the study are performed or any study-specific data 
is recorded on study-specific forms). 
The investigator will also mention that written approval of the IRB/IEC has been obtained. 
Each patient / legal representative or proxy consenter will be informed about the following 
aspects of premature withdrawal: 
• Each patient has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.  
• The patient’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9 to be conducted after withdrawal of consent.  
• The patient’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the statistical analysis plan.  
• Patient-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such 
as blood, urine or tissues); these data would also be retained and statistically analyzed 
in accordance with the statistical analysis plan. The patient has the right to object to 

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the generation and processing of this post-withdrawal data. For this, the patient’s oral 
objection may be documented in the patient’s source data. 
Each patient / legal representative or proxy consenter will have ample time and opportunity to 
ask questions. 
Only if the patient / 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 will personally sign and date the form. The patient / 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 patient’s clinical record must clearly show that informed 
consent was obtained prior to these procedures. Certain results from diagnostic testing 
performed as part of the standard of practice prior to the informed consent date and time may 
be used to fulfill screening criteria. This includes fresh tissue as noted in the protocol as well 
as results from tumor scans (CT/MRI and/or PET-CT), bone marrow sample, 
MUGA/echocardiogram, HIV and hepatitis testing which may also be used provided that they 
fall into the protocol-specified time window. Archival tissue obtained from the patients at any 
time during the course of their iNHL may also be used if performed as part of the standard of 
practice. However, these historical results can only be used after the patient gives informed 
consent to use them. Tumor scans must also meet the quality standards of the Imaging 
Manual. 
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 the sponsor and the 
investigator). This is to be documented by a signature from the informing physician as well as 
by a signature from the witness. 
For adults under legal protection, consent shall be given by the legal guardian(s). The consent 
of an 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. 
The informed consent form and any other written information provided to patients / legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the patient’s consent, or there is an amendment to 
the protocol that necessitates a change to the content of the patient information and / or the 
written informed consent form. The investigator will inform the patient / legal representative 
or proxy consenter of changes in a timely manner and will ask the patient 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. 

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13.5 
Publication policy and use of data 
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.  
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators. 
Bayer fulfills its commitment to publicly disclose study results through posting the result of 
the studies on public registries in accordance with applicable law and regulations. 
In accordance with the current European Union Clinical Trials Regulation (EU-CTR), result 
summaries will be submitted within one year from the end of the study in all participating 
countries. No preliminary data analysis (e.g. on EU data only) will be performed, as this 
might compromise data integrity and the scientific validity of the study. 
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study. However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission. To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract. 
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.  
Non-study-related use of data, samples or images 
Encoded images may be used to underline the results of the study in scientific publications or 
for other scientific purposes like training of doctors on the appearance or characteristics of 
disease on images. See also Section 9.7.1. 
13.6 
Compensation for health damage of patients / insurance 
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed. 
13.7 
Confidentiality 
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Patient names will not be supplied to the sponsor. Only the patient number will be recorded in 
the CRF, and if the patient name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the patients will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. 

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If the results of the study are published, the patient’s identity will remain confidential. 
The investigator will maintain a list to enable patients to be identified. 
14. 
Reference list 
1. 
Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's 
lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's 
Lymphoma Classification Project. J Clin Oncol.1998; (8):2780-95  
2. 
Ferlay J, Bray F, Forman D, Mathers C, Parkin D. GLOBOCAN 2008 v1.2, Cancer 
Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet] Available 
from: http://globocan.iarc.fr. 
3. 
Shankland KR, Armitage JO, Hancock BW. Non-Hodgkin lymphoma. Lancet. 
2012;380(9844):848-57. 
4. 
Armitage JO. My treatment approach to patients with diffuse large B-cell lymphoma. 
Mayo Clin Proc. 2012;87(2):161-71. 
5. 
Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO 
classification of lymphoid neoplasms and beyond: evolving concepts and practical 
applications. Blood. 2011;117(19):5019-32. 
6. 
A clinical evaluation of the International Lymphoma Study Group classification of 
non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. 
Blood. 1997;89(11):3909-18. 
7. 
Gascoyne RD. Hematopathology approaches to diagnosis and prognosis of indolent 
B-cell lymphomas. Hematology Am Soc Hematol Educ Program. 2005:299-306. 
8. 
Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, et al. 
Frontline therapy with rituximab added to the combination of cyclophosphamide, 
doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome 
for patients with advanced-stage follicular lymphoma compared with therapy with 
CHOP alone: results of a prospective randomized study of the German Low-Grade 
Lymphoma Study Group Blood. 2005;106(12):3725-32. 
9. 
Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, et 
al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment 
for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, 
randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-10.  
10. 
Domingo-Domènech E, González-Barca E, Estany C, Sureda A, Besalduch J, 
Fernández de Sevilla A. Combined treatment with anti-CD20 (rituximab) and CHOP 
in relapsed advanced-stage follicular lymphomas. Haematologica. 2002;87(11):1229-
30 
11. 
Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, Josten 
KM, Dürk H, Rost A, Neise M, von Grünhagen U, Chow KU, Hansmann ML, 
Hoelzer D,Mitrou PS. Bendamustine plus rituximab is effective and has a favorable 
toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's 
lymphoma. J Clin Oncol. 2005 May 20;23(15):3383-9. 

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12. 
Courtney K, Corcoran R, and Engelman J. The PI3K Pathway As Drug Target in 
Human Cancer. J Clin Oncol. 2010;28(6):1075-83  
13. 
Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, et al. Response 
assessment in Waldenstrom macroglobulinaemia: update from the VIth International 
Workshop. British journal of haematology. 2013;160(2):171-6. 
14. 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 
2014; 32(27):3059-3067. 
15. 
Hlubocky FJ, Webster K, Beaumont J, Cashy J, Paul D, Abernethy A, et al. A 
preliminary study of a health related quality of life assessment of priority symptoms 
in advanced lymphoma: the National Comprehensive Cancer Network-Functional 
Assessment of Cancer Therapy - Lymphoma Symptom Index. Leuk Lymphoma. 
2013;54(9):1942-6. 
16. 
Busaidy NL, Farooki A, Dowlati A, Perentesis JP, Dancey JE, Doyle LA, et al. 
Management of metabolic effects associated with anticancer agents targeting the 
PI3K-Akt-mTOR pathway. J Clin Oncol. 2012;30:2919-28. 
17. 
Cella D, Rosenbloom SK, Beaumont JL, Yount SE, Paul D, Hampton D, et al. 
Development and validation of 11 symptom indexes to evaluate response to 
chemotherapy for advanced cancer. J Natl Compr Canc Netw. 2011;9(3):268-78. 
18. 
Lacouture ME, Wu S, Robert C, Atkins MB, Kong HH, Guitart J, et al. Evolving 
strategies for the management of hand-foot skin reaction associated with the 
multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 2008;13:1001-
1011. 
19. 
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 
9 ed: Boston: Little Brown & Co; 1994. 
20. 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate 
method to estimate glomerular filtration rate from serum creatinine: a new prediction 
equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 
30:461-70. 
21. 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Chronic 
Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine 
values in the modification of diet in renal disease study equation for estimating 
glomerular filtration rate. Ann Intern Med. 2006;145:247-54. 
22. 
National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney 
disease: Evaluation, classification, and stratification. Part 4. Definition and 
classification of stages of chronic kidney disease. Am J Kidney Dis. 2002;39:S46-
S75. 
23. 
Food and Drug Administration (FDA), Guidance for Industry, Drug Interaction 
Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling 

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Recommendations Center for Drug Evaluation and Research (CDER), Draft 
Guidance (2012). Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/ucm292362.pdf 
24. 
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers. Available from: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/drugin
teractionslabeling/ucm093664.htm 
25. 
Metabolism and Transport Drug Interaction Database, University of Washington, 
Department of Pharmaceutics (2008) www.druginteractioninfo.org (Last update: July, 
2014) 
26. 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine (2007) Last updated: July 2013.- Available from: 
http://medicine.iupui.edu/flockhart/table.htm 
27. 
National Comprehensive Cancer Network (NCCN): NCCN Guidelines version 
2.2015, Prevention and treatment of cancer-related infections. Available online: 
http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf.  
 
15. 
Protocol amendments 
15.1 
Amendment 1 
Amendment 1 is a global amendment dated 01 SEP 2015. 
15.1.1 
Overview of changes to the study 
15.1.1.1 
Modification 1 – language regarding reconstitution, dilution and 
storage of copanlisib modified 
Detailed information regarding reconstitution and dilution of copanlisib and the storage of 
copanlisib solution was removed from the protocol; this information can be found in the 
Pharmacy Manual or in the IB. The rationale for the text deletion was to avoid future protocol 
amendments due to changes in this language. 
Clinical study protocol section affected by this modification:  
Section 7.2 Identity of study treatment 
15.1.1.2 
Modification 2 – language on exclusion criterion clarified 
Language related to exclusion criterion regarding previous treatment with bendamustine was 
clarified to be consistent with the language provided in Section 7.3 Treatment assignment. 
Patients who had previous treatment with bendamustine are excluded from the study, if 
bendamustine-based therapy was followed by a treatment-free interval of less than 12 months 
following that R-B course and patients have also received a cumulative dose of doxorubicin 
> 250 mg/m2. 

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Clinical study protocol section affected by this modification:  
Section 6.2 Exclusion criteria 
15.1.1.3 
Modification 3 –dosing criteria modified 
Language was modified to clarify that blood count must be performed and assessed on the day 
of infusion, and not the day before the infusion. This modification was done to be consistent 
with the recommendation given in Section 7.4 regarding Table 7-3. 
Clinical study protocol sections affected by this modification:  
Section 7.4 Dosage and administration 
Section 9.2.1.2.1 Treatment – Cycle 1 – Cycle 1, Day 8 
15.1.1.4 
Modification 4 – adjustment of biomarker sampling time point 
One additional plasma collection for non-genetic biomarker analysis was added to Cycle 2 
Day 15 (C2D15) for patients in the R-CHOP treatment group. This modification was done to 
have the same biomarker sampling time points in the R-CHOP treatment group as in the R-B 
treatment group and to better align the biomarker plasma collection time points in the present 
study with the time points used in the Phase 2 trial of copanlisib in NHL (Study 16349). 
Clinical study protocol sections affected by this modification:  
Section 9.1 Tabular schedule of evaluations – Table 9-2 Study flow chart 
Section 9.2.1.2.2 Treatment – From Cycle 2 to Cycle 6 
15.1.1.5 
Modification 5 – administrative change 
The sponsor’s medically responsible person was changed. 
Clinical study protocol sections affected by this modification:  
Signature of the sponsor’s medically responsible person 
15.1.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 1 are provided in Section 15.1.2 of the 
Amendment 1. 
15.2 
Amendment 2 
Amendment 2 is a global amendment dated 18 JUL 2016. 
15.2.1 
Overview of changes 
15.2.1.1 
Modification 1 – update of clinical experience with copanlisib 
Introductory information on the number of patients treated with copanlisib was updated based 
on most recent data. The results from copanlisib study 16349 part A were also updated. 
Section affected by this modification: 3.1.2 Clinical experience. 

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15.2.1.2 
Modification 2 – definition on rituximab-sensitive iNHL removed 
Rituximab (R)-sensitive iNHL is defined as patients that do not have R-resistance (rituximab 
resistance defined as lack of response to a rituximab-containing regimen, or progression 
within 6 months of treatment with a rituximab-containing regimen). For consistency, text 
about R-sensitive iNHL was withdrawn from Section 3.2 “Rationale of the study” because it 
was not according to the definition of resistance. 
Section affected by this modification: 3.2 Rationale of the study. 
15.2.1.3 
Modification 3 – allowed prior immunochemotherapy regimens and 
treatment assignment clarified 
• It was clarified that R-B, R-CVP or R-CHOP are allowed as prior lines of 
immunochemotherapies. This change was done according to the standard treatment for 
indolent NHL. Text describing the rules for randomization based on prior 
immunochemotherapy and exclusion criterion 29 regarding the prior treatment with 
bendamustine were modified accordingly. 
• Language regarding the cumulative dose of anthracyclines was also updated. This study 
will include patients after least 1 but at most 3 previous lines of treatment. According to 
the new treatment assignment, if a patient received previous treatment with a scheme 
containing anthracycline (except CHOP) and can be included in R-CHOP group (also 
received bendamustine), the equivalent cumulative dose of anthracyclines should be 
calculated due to the risk of cardiomyopathy. In this case, the remaining dose must be 
sufficient for 6 cycles of R-CHOP.  
• It was also clarified that patients must have relapsed or progressed after at least one but at 
most three prior lines of therapy. Relapse is a term used for return of the disease in 
patients that achieved complete remission, but it can be attributed to patients that 
achieved a sustained remission (not complete). The more appropriate term in this case is 
progressive disease. Patients with relapsed or progressive disease are allowed in the study 
if they are not resistant to rituximab. 
• The definition of resistance to a prior treatment with other PI3K inhibitors was also 
modified in the inclusion criterion to be consistent with the definition given in exclusion 
criterion.  
• Exclusion criteria were clarified; patients with evidence of progression since last 
treatment will have the same washout period for previous treatments as patients 
without evidence of progression. This change was made to ensure a minimum washout 
period for all patients. 
Sections affected by this modification: Synopsis, 4.2 Phase III part, 5.1 Design overview, 
5.3 Phase III, 6.1 Inclusion criteria, 6.2 Exclusion criteria, 7.3.1 Safety run-in part, 
7.3.2 Phase III part. 

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15.2.1.4 
Modification 4 – update to inclusion criteria 
• Even though SLL and CLL have the same tissue infiltration morphology and 
immunophenotype, they mainly differentiate between cytopenias and absolute 
peripheral B lymphocyte count. Patients previously diagnosed with CLL would be 
allowed to enter the study if they have at the study entry the diagnosis of SLL with 
absolute lymphocyte count < 5 × 109/L. Requirement for the absolute lymphocyte 
count at diagnosis was removed from the inclusion criterion.  
• Clarification was added that WM patients who do not have radiologically measurable 
lesion should have a positive immunofixation test result in addition to elevated IgM 
levels (≥ 2 × ULN) at Screening to indicate the presence of IgM paraprotein. The 
modification was done because IgM level alone does not show that the protein is 
clonal. Immunofixation establishes that the elevated IgM is clonal and therefore a real 
paraprotein. 
• The inclusion criteria referring to platelet count in patients with confirmed 
lymphomatous bone marrow infiltration was also updated and clarified in order to 
ensure consistency across all copanlisib studies being done by the sponsor at this time. 
Dosing criterion in Table 7-3 was modified accordingly. 
• The description of effective contraception and the definition of a woman of 
childbearing potential (WOCBP) and a post-menopausal state were clarified. In 
addition, it was clarified that the use of condoms by male patients is required unless 
the female partner is permanently sterile to ensure the effective contraception for 
males who appear to mainly confer risk to females (WOCBP) via exposure to 
copanlisib in seminal fluid. These changes were made according to recommendations 
related to contraception and pregnancy testing in clinical trials by the Clinical Trial 
Facilitating Group. 
Section affected by these modifications: 6.1 Inclusion criteria. 
15.2.1.5 
Modification 5 – modification of exclusion criterion related to arterial 
hypertension  
Following the investigators’ and lymphoma specialists’ feedback, the eligibility criteria was 
revised to eliminate the conservative requirement for blood pressure levels during eligibility 
evaluation considering the most important safety points are appropriate blood pressure levels 
prior to study treatment and available prophylactic treatments. 
Section affected by this modification: Synopsis, 6.2 Exclusion criteria. 
15.2.1.6 
Modification 6 – exclusion of patients based on plasma glucose levels 
removed 
• Exclusion of patients with fasting plasma glucose > 160 mg/dL at Screening was 
removed. The rationale for this change was to eliminate the eligibility evaluation 
requirement for plasma glucose testing considering the study patient population and to 
ensure enrollment of patients with diabetes mellitus in a compensation state that will 
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overview of the average blood glucose for the past 2 to 3 months, allowing exclusion 
of patients with insufficient glucose control. Such information is not provided by 
fasting plasma glucose. It was also clarified that the HbA1c >8.5% level concerns all 
patients, not only patients with diabetes mellitus. 
Section affected by this modification: Synopsis, 6.2 Exclusion criteria. 
15.2.1.7 
Modification 7 – inclusion of patients with chronic HCV or HBV 
infection and prophylaxis for HBV and monitoring of HBV and HCV 
added 
Patients with chronic HCV or HBV infection will be included in the study, as study 
population should be similar to general population. It was also clarified that patients with 
active (chronic or acute) HCV or HBV (HBV DNA test positive or HCV RNA test positive) 
will be excluded. 
Requirement was added that prophylactic antiviral therapy should be given per local standard 
of care for patients who are positive for HBsAg or HBcAb at screening. Further, monthly 
monitoring of HBV and HCV (HBV DNA test for patients positive for HBsAg and/or 
HBcAb; and HCV-RNA test for patients positive for anti-HCV antibody) was added to the 
protocol; also included recurrence as withdrawal criteria. The change was made because 
patients with HBV and HCV are at risk of recurrence while receiving rituximab.  
Sections affected by this modification: Synopsis, 6.2 Exclusion criteria, 6.4.1.1 Withdrawal 
criteria, 9.1 Tabular schedule of evaluations, 9.2.1.1 Screening period. 
15.2.1.8 
Modification 8 – clarification of exclusion criterion related to 
proteinuria 
Exclusion criterion was modified to clarify that laboratory method used to assess proteinuria 
is not limited to UPCR only. Based on investigator feedback, the criterion was amended to 
make the patient evaluation more flexible and feasible. 
In addition, it was clarified how the tests should be performed and reported to avoid 
misunderstandings and errors in collection. 
Section affected by this modification: 6.2 Exclusion criteria, 9.1 Tabular schedule of 
evaluations, 9.2.1.1 Screening period, 9.6.3.1 Laboratory. 
15.2.1.9 
Modification 9 – language on corticosteroid therapy clarified 
It was clarified in the protocol that previous corticosteroid therapy must be stopped or reduced 
to the allowed dose at least 7 days prior to the screening tumor scan, and again at least 7 days 
prior to the first study drug administration. This modification was made to eliminate a bias in 
the tumor response assessment; as to not potentially change the lesion status from time of 
baseline scan to study treatment start. 
It was also clarified that short term systemic corticosteroids will be allowed as premedication 
prior to bendamustine infusions. This change was made based on investigator’s feedback of 
the use of corticosteroids as premedication due to infusion reactions in the standard of care.  

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Guidance was added in case the use of corticosteroids as premedication leads to increases of 
glucose or blood pressure. 
Sections affected by this modification: 6.2 Exclusion criteria, Section 8.1.1 Prohibited 
concomitant therapy, 8.1.2 Permitted concomitant therapy. 
15.2.1.10 Modification 10 – prior treatment with copanlisib prohibited  
Copanlisib was included to the list of prohibited previous therapies and medications. 
Inclusion criterion for prior line of therapy was revised accordingly. Modification was done 
because prior treatment with copanlisib could jeopardize the clinical assessment of the study 
drug.  
Sections affected by this modification: 6.1 Inclusion criteria, 6.2 Exclusion criteria. 
15.2.1.11 Modification 11 – updated guidance for management and monitoring 
of glucose increases 
An updated guidance for the management of transient glucose increases was provided to 
ensure the patient safety. These changes were made based on updated clinical data and the 
feedback from the investigators.  
Changes include: 
• Management of transient glucose increases should be based on persistent post-infusion 
blood glucose results. 
• Additional guidance regarding meal timing was provided. 
• An updated guidance on dose modification for transient glucose increases was 
provided. 
• Additional information regarding glucose monitoring at home was provided. 
• The withdrawal criterion “CTCAE Grade ≥ 3 glucose (and glucose > 250 mg/dL 
value confirmed by repeated laboratory analysis) despite optimal glucose lowering 
therapy at 30 mg dose level” was revised to align with a new guidance for the 
transient glucose increases management. 
• Incorrect sentence regarding high glycemic index foods was removed from Appendix 
16.8. High glycemic index foods have a glucose reference index greater than 70. 
• Glucose measurements related to rituximab infusion and bendamustine infusion were 
added to monitor the effects of corticosteroids used as premedication and to monitor 
the rituximab effect on glucose levels. 
Sections affected by this modification: 6.4.1.1 Withdrawal criteria, 7.4 Dosage and 
administration, 7.4.2.3 Non-hematological toxicity, 7.4.3.1 Management of transient post-
infusion glucose increases that can occur with copanlisib, 8.1.2 Permitted concomitant 
therapy, 9.1 Tabular schedule of evaluations, 9.2.1.2.1 Treatment – Cycle 1, 
9.2.1.2.2 Treatment – From Cycle 2 to Cycle 6, 9.2.1.2.3 Treatment – From Cycle 7 onwards 
(during copanlisib/placebo monotherapy), 9.6.3.2 Glucose measurement on treatment days, 

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16.8 The average Glycemic Index of common foods derived from multiple studies by 
different laboratories. 
15.2.1.12 Modification 12 – updated guidance for management and monitoring 
of blood pressure increases 
Changes were made to reflect updated copanlisib safety information pertaining to potential 
drug-related transient blood pressure increases and feedback from investigators/lymphoma 
specialists regarding hypertension monitoring and management to make the process more 
feasible without compromising patient safety. 
Sections affected by this modification: 7.4.2.3 Non-hematological toxicity, 9.6.3.5 Blood 
pressure measurement on treatment days. 
15.2.1.13 Modification 13 – fasting requirement for lipid panels revised 
The 11 h fasting requirement for lipid panels was revised; patients must be fasting prior to 
lipid sampling according to local standards. This change was made to allow the 
implementation of local standards for fasting requirements for lipid panel testing. 
Sections affected by this modification: 7.4.3.2 Management of hyperlipidemia, 9.1 Tabular 
schedule of evaluations, 9.2.1.1 Screening period, 9.2.1.2.2 Treatment – From Cycle 2 to 
Cycle 6, 9.2.1.2.3 Treatment – From Cycle 7 onwards (during copanlisib/placebo 
monotherapy), 9.2.1.4 End-of-treatment (EOT) visit and 9.6.3.1 Laboratory. 
15.2.1.14 Modification 14 – clarification of tumor response language 
• 
Table for the CT and/or MRI response assessment criteria was updated 
o 
Language in column “Spleen” for PD was updated; a rule was added to minimize 
any measurements errors, and the value of ≥ 1 cm was used after advice from 
professor Cheson, the author of the Lugano classification (14). The total value of 
increase is also in line with the total increase required for the bigger lesions, i.e. 
lesions > 2 cm. 
o 
A footnote regarding the longest diameter (LDi) was added to provide more 
details as was outlined in the table; the rule or the content was not changed. 
o 
A note was added to further clarify the evaluation provided in the response table, 
which is especially important for patients who do not have a lesion in the spleen. 
• 
Table for the PET-CT response assessment criteria was updated 
o Guidance was added for the investigator to clarify how to evaluate the response. 
This modification is based on the webinar content presented by professor Cheson 
in October 2014.  
o A clarification of PET-avid lesions was added to initiate a common understanding 
what the general term “PET-avid or PET-positive lesions” means with regard to 
the scoring system. 

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o Rules for the response assessment were added to provide clear guidance as this 
was not covered by the response table. This modification did not change any 
overall rules for the assessment. 
• 
In addition, the response assessment based on PET-CT and CT/MRI scans was clarified; 
in cases where CT shows unequivocal progression, the response is PD, independent from 
the response of the previous PET-CT response.  
• 
Tumor assessment language was modified; the requirement that tumor assessments 
should be performed “within 7 days” after the last dose and “starting from Cycle 3” was 
removed to be feasible with different cycle lengths between R-B (every 4 weeks) and R-
CHOP (every 3 weeks).  
• 
It was also clarified that the types of indolent FDG-avid histologies where PET-CT 
should be considered include follicular lymphoma grade 3 and marginal zone lymphoma 
(nodal type). This modification was done to be consistent with imaging manual (by 
GCIS). 
• 
Modifications were also done to harmonize the language across the protocol and with 
other copanlisib protocols, e.g. in Synopsis, and in Section 9.4.2 “Radiological tumor 
assessments”.  
• 
In general, CT/MRI needs to be performed with i.v. contrast agents. A clarification was 
added to explain, in which situations the switch from CT to MRI is required and when to 
proceed after the first treatment without a contrast-enhanced CT/MRI. 
Sections affected by this modification: Synopsis, 5.1 Design overview, 9.1 Tabular schedule 
of evaluations, 9.2.1.3 Tumor assessments, 9.4.2 Radiological tumor assessments, 
9.8 Appropriateness of procedures / measurements, 16.5 Evaluation of tumor response. 
15.2.1.15 Modification 15 – guidance for management of toxicities added 
Guidance for dose modifications for CHOP and bendamustine in case of toxicities was added 
to Section 7.4.2 Dose modification. This change was made to clarify that dose modifications 
regarding CHOP and bendamustine can be done according to prescribing information and 
investigator’s experience.  
Guidance in Table 7-5 “Dose modification of copanlisib/placebo for hematological toxicity” 
was updated: language related to dose reduction/ re-escalation of copanlisib/placebo was 
added to make dose modification more clear, clarification of concomitant medication to treat 
hematological toxicity was added, and criterion for INR or PTT was revised to update 
information.  
Sections affected by this modification: 7.4.2 Dose modification,7.4.2.2 Hematological 
toxicity. 
15.2.1.16 Modification 16 – usage of verapamil and diltiazem amended 
The text was modified to state that verapamil and diltiazem (non-dihydropyridine calcium 
channel blockers) should be used with caution instead of should be avoided because 
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Sections affected by this modification: 7.4.3.3 Treatment of blood pressure increases 
associated with copanlisib, 8.1.2 Permitted concomitant therapy. 
15.2.1.17 Modification 17 – guidance for metformin use updated 
Language related to interruption of metformin when receiving ionidated contrast media was 
modified; metformin should be temporarily discontinued in patients undergoing radiologic 
studies involving intravascular administration of iodinated contrast and prescribing 
information should be checked for further information. This change was made to recommend 
metformin use according to the prescribing information at the site, because differences 
regarding the time of temporary discontinuation can occur among metformin prescribing 
information. 
Section affected by this modification: 8.1.2 Permitted concomitant therapy, 9.4.2 Radiological 
tumor assessments. 
15.2.1.18 Modification 18 – recommendation for prednisone administration 
removed 
Recommendation to administer the first dose of prednisone before rituximab infusion on D2 
was removed. This change was done to allow the decision to be made by the investigator.  
Section affected by this modification: 9.2.1.2.2 Treatment – From Cycle 2 to Cycle 6. 
15.2.1.19 Modification 19 – reference to the Declaration of Objection form 
removed 
The reference to the Declaration of Objection to the Collection of Study Data after 
Withdrawal of Consent was removed from the study protocol since this form is not used 
anymore according to sponsor’s standard operating procedures.  
Sections affected by this modification: 6.4.1.1 Withdrawal criteria, 13.4 Patient information 
and consent. 
15.2.1.20 Modification 20 – changes in statistical language 
Figure ”Confirmatory testing strategy” was replaced with a new one; the new figure is 
equivalent to the old one statistically, but easier to understand. 
Description of the testing hierarchy was revised and clarifications and corrections were made. 
Sample size description and time point of measurement for primary variable for the phase III 
part were updated. This change was made due to a new accrual pattern based on knowledge 
from a competitor study and site feedback. 
Sections affected by this modification: Synopsis, 5.3 Phase III, 5.3.1 Primary variable, 5.3.3 
End of study, 10.3.2.5 Primary efficacy analysis, 10.3.2.7 Confirmatory statistical test 
strategy, 10.4 Determination of sample size. 
15.2.1.21 Modification 21 – modification of replacement language  
Replacement criterion for the safety run-in part was updated to clarify that patients with 
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modification was done because patients who discontinue during the first cycle due to reasons 
other than toxicity need to be replaced in order to ensure adequate number of subjects 
evaluable for safety. 
Section affected by this modification: 6.4.2 Replacement. 
15.2.1.22 Modification 22 – central pathology review of bone marrow samples 
clarified 
Language was modified to clarify that central pathology review of bone marrow samples shall 
be performed for baseline, and after the first complete response if the baseline sample was 
positive. 
Sections affected by this modification: Synopsis, 5.1 Design overview, 9.2.1.3 Tumor 
assessments. 
15.2.1.23 Modification 23 – modification of coagulation language  
Inclusion criterion was updated to clarify that INR should be ≤ 1.5 at Screening and PT can be 
used instead of INR if PTT ≤ 1.5 × ULN. The modification was done because previous 
language (INR ≤ 1.5 × ULN) allowed patients with INR of 1.8 to be eligible. INR and PT 
may be used interchangeably, since the INR is a standardized prothrombin time (which was 
initially designed to account for differences in thromboplastin). 
Furthermore, “PT ratio or PT Quick method” was removed from the coagulation panel to 
avoid redundant testing report on the coagulation method. 
Sections affected by this modification: 6.1 Inclusion criteria, 7.4.2.2 Hematological toxicity, 
9.6.3.1 Laboratory. 
15.2.1.24 Modification 24 – monitoring guidelines for opportunistic infection 
(OI) prophylaxis 
Language provides guidance and clarification to the use of prophylactic treatment in patients 
at risk for opportunistic infections while on study treatment. 
Following Health Authority alerts related to safety issues with Zydelig (idelalisib, a PI3K 
inhibitor) treatment in clinical trials, Section 7.4.3.6 was added to provide guidance for 
monitoring and prophylaxis of opportunistic infections in patients who are at risk for 
opportunistic infection development while on study treatment. 
Also exclusion and withdrawal criteria were modified: patients with cytomegalovirus (CMV) 
infection are to be excluded from the study (re-screening is allowed once), and delay in test 
drug administration due to reactivation of CMV can be up to 2 months. These criteria were 
modified to avoid worsening of CMV infection in patients with active CMV and to harmonize 
the protocol with other CHRONOS studies. 
Laboratory tests for OI were added and tabular schedule of evaluations was modified to be 
consistent with the OI guidance. 
Sections affected by this modification: Synopsis, 6.2 Exclusion criteria, 6.4.1.1 Withdrawal 
criteria, 6.4.1.2 Screening failure, 7.4.2.3 Non-hematological toxicity, 7.4.3.6 Guidance for 

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monitoring and prophylaxis of opportunistic infection (OI), 9.1 Tabular schedule of 
evaluations, 9.2.1.1 Screening period, 9.2.1.2 Treatment period, 9.2.1.2.1 Treatment - Cycle 1, 
9.2.1.2.2 Treatment - From Cycle 2 to Cycle 6, 9.2.1.2.3 Treatment – From Cycle 7 onwards 
(during copanlisib/placebo monotherapy), 9.6.3.1 Laboratory, 9.6.3.3.2 Brief physical 
examination and status check. 
15.2.1.25 Modification 25 – clarification of reporting period of adverse events 
during safety follow-up  
Language was modified to clarify that adverse events should be collected and recorded until 
30 days after last treatment with study drug though safety follow-up visit may occur 30 days 
(a time window of +5 days is allowed) after last treatment.  
Sections affected by this modification: 5.1 Design overview, 9.1 Tabular schedule of 
evaluations, 9.2.1.5.1 Safety follow-up, 9.6.1.3 Assessments and documentation of adverse 
events. 
15.2.1.26 Modification 26– modification of absolute neutrophil count (ANC) 
criteria for copanlisib dosing 
ANC laboratory test criteria were modified for copanlisib/placebo dosing; the ANC limit was 
lowered to ≥1000/mm3 for Day 1 (from Cycle 2 onwards) and to ≥500/mm3 for Day 8 and 15. 
G-CSF was added to be mandatory if ANC<1000/mm3 as per label. Neutropenia can be 
managed by G-CSF in many cases and data shows that the ANC nadir coincides with 
copanlisib administration (Days 8 and 15), therefore, a strict ANC dosing criteria may be 
unnecessarily limiting for copanlisib dosing and therefore compromise the potential efficacy 
of the drug. Table 7-5 Dose modification for hematological toxicity was also modified 
accordingly. 
Sections affected by this modification: 7.4 Dosage and administration, 7.4.2.2 Hematological 
toxicity, 8.1.2 Permitted concomitant therapy. 
15.2.1.27 Modification 27– modification of withdrawal criterion and dose 
adjustment in case of non-infectious pneumonitis 
To allow patients with low grades of NIP (CTCAE Grade 1 and 2) to pursue treatment and to 
align the protocol with other CHRONOS studies, the withdrawal criterion was modified to 
withdraw only patients with NIP ≥ CTCAE Grade 3. A new table was added to Section 
7.4.2.3 for guidance of dose adjustment in cases of NIP. 
Sections affected by this modification: 6.4.1.1 Withdrawal criteria, 7.4.2.3 Non-hematological 
toxicity. 
15.2.1.28 Modification 28 – change in the timing of the IVRS/IWRS 
randomization transaction 
The timing of IVRS/IWRS randomization transaction before the first dose (Cycle 1 Day 1) 
was increased from maximum 48 to maximum 72 hours, to allow more flexibility.  
Sections affected by this modification: 7.3.2 Phase III part, 9.1 Tabular schedule of 
evaluations, 9.2.1.2.1 Treatment – Cycle 1. 

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15.2.1.29 Modification 29 – clarification on DLT language and transition from 
safety run-in phase to phase III part 
It was clarified that in the safety-run in part, dose reduction is only allowed after Cycle 1 and 
that the DLTs are evaluated during Cycle 1. The DLT definition on abnormal lab values was 
also added. 
The specific laboratory values were removed from the defined hematologic DLTs to avoid 
redundancy. 
Clarification was added that the evaluation of the RP3D of copanlisib by DMC could be 
performed separately for R-B and for R-CHOP since recruitment speed for these cohorts is 
different. This change was made to avoid a potential delay to the start of the phase III part. 
Sections affected by this modification: Synopsis, 5.2 Safety run-in part, 7.4.1 Definition of 
dose-limiting toxicities (DLTs). 
15.2.1.30 Modification 30– modification to criteria for CT-based response 
assessment  
It was clarified that in addition to a negative IHC confirmation for CR, a negative PCR is also 
acceptable for evaluation of the bone marrow.  
Section affected by this modification: 16.5 Evaluation of tumor response. 
15.2.1.31 Modification 31 – other clarifications and corrections 
• It was clarified in the Section 7.4 “Dosage and administration - Dosing criteria” that in 
addition to the investigator, laboratory results can be also assessed by the treating 
physician or sub-investigator prior to administration of planned dose. It was also 
emphasized that on D8 and D15, laboratory test criteria described in Table 7-3 must be 
met before copanlisib/placebo will be administered. 
• References to footnotes in Table 9-3 for procedures “Plasma for tumor genetics” and 
“Plasma for non-genetic biomarker analysis” were corrected for consistency.  
• The word “Less than” was replaced with word “Within” in Section 9.2.1.1 “Screening 
period” to clarify the maximum allowed time for procedures performed before first 
study drug administration.  
• The exclusion criterion “HIV infection” was changed to “Known history of HIV 
infection” to keep language consistent across the program. 
• It was clarified in Section 6.4.1.1 “Withdrawal criteria” that patients must (not may) 
be withdrawn from the study at the specific request of the sponsor and in liaison with 
the investigator. Duplicate criterion regarding withdrawal in the case when 
investigator considers the study harmful to patient was removed. 
• The withdrawal criterion regarding delay in test drug administration was clarified; 
patient must be withdrawn from study treatment if the delay due to toxicities is 
>28 days instead on >21 days (21 days plus 1 week of washout is 28 days). 

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• Language was clarified without changing the content in the Table 7-6 “Dose 
modification of copanlisib/placebo for non-hematological toxicity” to harmonize the 
language with other dose modification tables.  
• It was clarified in Section 5.1 “Design overview” that the evaluation of WM patients 
without radiological disease will be performed by investigators based on the 
laboratory/clinical tests. 
• Text regarding the examination of skin was combined with the examination of hand 
and feet in Section 9.6.3.3.1 and Section 9.6.3.3.2 to avoid repetition.  
• An adjustment was made to Tables 9-1, 9-2 and 9-3 in Section 9.1 “Tabular schedule 
of evaluation” stating that acceptable deviation of -1 days to + 2 days is applicable to 
all visits during the treatment unless otherwise specified. This change was made to be 
more flexible and feasible for the sites to perform the procedures. Footnote “dd” was 
added to flowcharts in Section 9.1 to clarify the timing for laboratory tests prior to 
each infusion.  
• Wording “dose reductions” for CHOP and bendamustine was changed to “dose 
modifications” in Section 7.4.2.3 “Non-hematological toxicity” as there can be also 
other modifications than reductions. 
• It was clarified in Section 7.5 “Blinding” that also placebo is given in combination 
with R-B/R-CHOP. 
• It was clarified in Section 7.1 “Treatments to be administered” that there will be no 
rituximab maintenance therapy administered from C7 onwards. 
• Administrative change was done; the study medical expert was changed. 
• Due to sponsor name change, sponsor information and sponsor logo were changed on 
Title page.  
• It was clarified in Section 7.4.3.3 “Treatment of blood pressure increases associated 
with copanlisib” that nitrates instead of topical nitrates should be considered for the 
management of acute blood pressure increases following copanlisib/placebo 
administration. 
• Clarification was made in Section 9.7.2 that time to improvement and the time to 
deterioration in disease-related symptoms –physical are measured by the DRS-P 
subscale of the FLymSI-18 questionnaire.  
15.2.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 2 are provided in Section 15.2.2 of the 
Amendment 2. 
 

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15.3 
Amendment 3 
Amendment 3 is a global amendment dated 30 MAR 2017. 
15.3.1 
Overview of changes 
15.3.1.1 
Modification 1 – change in the inclusion criterion: prior therapies 
The study eligibility criteria were modified to include patients who have received prior 
treatment with rituximab-based immunochemotherapy and alkylating agents. The change was 
done since the previous criterion (rituximab and R-B, R-CVP or R-CHOP) was considered as 
too restrictive. There is for example lack of vincristine in some countries and it is being 
replaced with other agents, such as vindesine.  
Treatment allocation language was changed accordingly: patients who never received prior 
treatment with R-B will be randomized to study drug + R-B treatment group. 
Sections affected by this modification: Synopsis, 4.2 Phase III part, 5.1 Design overview, 
5.3 Phase III, 6.1 Inclusion criteria, 7.3.2 Phase III part 
15.3.1.2 
Modification 2 – combination with study drug and R-B allowed for 
patients who have received prior treatment with R-B 
The study design was modified to allow patients who have received R-B as a previous line of 
therapy to be randomized to study drug plus R-B group in case there is ≥ 24 months 
progression-free interval after the last R-B treatment. The change was done because patients 
who relapse within 24 months but more than 6 months would be eligible for copanlisib plus 
R-CHOP. These patients are also more likely to be treated by R-CHOP. Patients who relapse 
≥ 24 months after first R-B treatment respond well to R-B treatment. These patients are more 
likely to be treated with other treatment options rather than R-CHOP. 
The following exclusion criterion was removed as a result of the change: “Patients who 
received R-B and R-CHOP or R-B and R-CVP as previous lines of therapy”. 
Sections affected by this modification: Synopsis, 5.3 Phase III, 6.2 Exclusion criteria, 
7.3.2 Phase III part 
15.3.1.3 
Modification 3 – changes in the statistical analysis and sample size 
There is no regulatory obligation of powering on a specific subtype of iNHL. As a result, the 
total sample size was reduced from 676 patients to 520 patients and primary efficacy analysis 
will be performed in the FAS instead of both FAS and FL subgroup. Additionally, the 
recruitment ramp up period increase from 6 months to 15 months based on more updated site 
information. 
A clarification was added that patients recruited into the safety run-in part will not be 
evaluated as part of the phase III part. 
Sections affected by this modification: Synopsis, 5.2 Safety run-in part, 5.3 Phase III, 
5.3.1 Primary variable, 5.3.3 End of study, 10.3.2.1 Population characteristics, 
10.3.2.5 Primary efficacy analysis, 10.3.2.6 Secondary efficacy analysis, 

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10.3.2.7 Confirmatory statistical test strategy (section removed), 10.3.2.8 Other efficacy 
analysis, 10.3.2.10 Safety variables and analysis, 10.4 Determination of sample size 
15.3.1.4 
Modification 4 – RP3D for copanlisib in combination with R-B 
determined 
The protocol was updated to include new information on the RP3D of copanlisib in 
combination with R-B. The dose was determined as 60 mg in the safety run-in part of the 
protocol in accordance with the DMC. 
It was also further clarified that it is possible to start the phase III part for the treatment 
combination to which RP3D has already been determined even though the safety run-in part 
for the other treatment combination is still ongoing. See also amendment 2, in Section 
15.2.1.29. This change was made to avoid a potential delay of the start of the phase III part. 
Sections affected by this modification: Synopsis, 3.3 Benefit-risk assessment, 5.2 Safety 
run-in part 
15.3.1.5 
Modification 5 – changes in exclusion criteria 
New exclusion criterion was added: patients who have received live vaccination, including 
virus vaccination and yellow fever vaccination, within 6 months before start of study 
treatment will not be eligible. According to the Centers for Disease Control and Prevention 
guidance on the timing of receiving the live vaccines, live vaccines may cause infections in 
patients receiving immunochemotherapy and patients with weak immune system. 
The definition of rituximab resistance was modified for clarification. It was clarified that the 
last course of treatment with a rituximab containing regimen includes rituximab maintenance. 
For other changes in exclusion criteria, see Modification 2.  
Section affected by this modification: Synopsis, 6.2 Exclusion criteria 
15.3.1.6 
Modification 6 – patients experiencing disease progression may 
continue on treatment 
The language was modified to allow patients to continue treatment with copanlisib if, in the 
investigator’s opinion, treatment is providing clinical benefit. 
Sections affected by this modification: Synopsis, 5.1 Design overview, 5.3 Phase III  
15.3.1.7 
Modification 7 – changes to the safety evaluation schedule 
The safety evaluations to be performed on Day 22 were removed for patients in the 
copanlisib/placebo + R-B combination therapy group (from C1 to C6) and for all patients 
during copanlisib/placebo monotherapy (from C7 onwards). The modification was done since 
study treatment is not administered on Day 22 of any treatment cycle, and therefore, there is 
no harm for patient safety.  
Similarly, the safety evaluations to be performed on Day 15 were removed for patients in the 
copanlisib/placebo + R-CHOP combination therapy group (from C1 to C6) since study 
treatment is not administered on those days. 

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Sections affected by this modification: Synopsis, 9.1 Tabular schedule of evaluations, 
9.2.1.2.1 Treatment – Cycle 1, 9.2.1.2.2 Treatment – From Cycle 2 to Cycle 6, 
9.2.1.2.3 Treatment – From Cycle 7 onwards (during copanlisib/placebo monotherapy) 
15.3.1.8 
Modification 8 – clarifications related to bone marrow assessments 
The text was modified to clarify that bone marrow biopsy can be used for histological 
confirmation of WM diagnosis and for biomarker analyses in patients with WM. The IgM 
monoclonal gammopathy and confirmed invasion at bone marrow biopsy are the requirements 
for WM diagnosis and no lymph node biopsies are necessary. In case of lymphadenomegaly, 
the measurable lesions will only contribute for the tumor radiological assessment and will not 
have an impact on WM diagnosis. Therefore there is no need to expose the patient to lymph 
node biopsy. Also, for biomarker analysis in patients with WM, bone marrow biopsy can be 
used as the tumor tissue samples. 
It was also clarified that bone marrow biopsy needs to be assessed locally before providing it 
to central pathology review. 
In addition, the text related to platelet count values for patients with lymphomatous bone 
marrow infiltration was modified to take into account the bone marrow infiltration result 
based on local assessment performed at study entry. This change was also done for 
clarification. 
Sections affected by this modification: Synopsis, 5.1 Design overview, 6.1 Inclusion criteria, 
7.4 Dosage and administration, 9.1 Tabular schedule of evaluations, 9.2.1.1 Screening period, 
9.2.1.3 Tumor assessments, 9.7.1 Biomarker investigations 
15.3.1.9 
Modification 9 – clarifications to the OI guidance 
The blood test schedule for CMV was modified. The tests were aligned with study treatment 
schedule and visits (i.e. cycles) instead of months. It was also clarified that CMV can be 
analyzed retrospectively to avoid study drug interruptions in case the results are not 
immediately available. 
Since all patients have lymphoma at study entry, clarification was added that lymphoma 
should not be considered a risk factor for enhanced monitoring of OI (history of 
immunodeficiency in the last 12 months).  
It was also clarified that additional assessments indicated for patients with identified risk 
factors and those who developed OI on study treatment are not mandatory. 
Sections affected by this modification: 7.4.3.6.1 Monitoring guidelines for OI, 9.1 Tabular 
schedule of evaluations, 9.2.1.2 Treatment period, 9.6.3.1  Laboratory 
15.3.1.10 Modification 10 – clarification to urinalysis examinations (dipstick) 
The modification was done to clarify that bilirubin test is not mandatory at urinalysis 
(dipstick).  
Bilirubin test is not standard test at urinalysis and has no clinical impact since bilirubin is 
already analyzed as part of the complete chemistry panel. 
Section affected by this modification: 9.6.3.1 Laboratory. 

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15.3.1.11 Modification 11 – changes and clarifications to radiological tumor 
assessments 
The requirement that tumor assessments must be performed within 7 days after the last dose 
(previous cycle) of study drug and before Day 1 of the subsequent cycle was removed. The 
change was done to guarantee that tumor assessments will be performed at the same time for 
both copanlisib and placebo treatment groups and to ensure that results are comparable 
irrespective of patient receiving the drug or not. 
Further clarification was added that calculation of tumor assessment time points (e.g. every 
12 weeks) starts from Cycle 1 Day 1. 
Recommendations related to the use of PET-CT imaging were added to the protocol. It was 
recommended to perform a PET-CT, if at a previous imaging visit the tumor response was 
derived from PET-CT and CT/MRI alone shows any change in the response assessment on 
subsequent imaging visits. As PET-CT trumps CT in most cases, the recommendation to 
perform PET-CT in case CT/MRI alone shows any change was added in order to be able to 
upgrade the response.  
The language was clarified to state that all sites of disease selected as target lesions “should 
be preferably” PET positive instead of “must be”. Target lesions can be only selected and 
identified with CT/MRI. If the PET scan is done but is negative, target lesions would be still 
identified with CT/MRI. 
Withdrawal criterion was modified to clarify that disease progression leading to 
discontinuation of study treatment should be based on the assessment of independent central 
review.  
Language in Appendix 16.5 was also modified since conversion of lymphoma from PET 
negative to PET positive would be a valid PD assessment. 
Sections affected by this modification: Synopsis, 9.1 Tabular schedule of evaluations, 
9.2.1.3 Tumor assessments, 9.2.1.4 End-of-treatment visit, 9.2.1.5.2 Active follow-up, 
9.4.2 Radiological tumor assessments, 16.5 Evaluation of tumor response 
15.3.1.12 Modification 12 – reporting of medical device failures of imported and 
non-approved third-party device 
According to a new regulatory requirement in Japan, Bayer Japan has to report medical device 
failures of imported and non-approved third-party device used in Bayer-sponsored clinical 
trials in Japan to the PMDA, IECs/IRBs and investigators. A new section was added to 
include this requirement. 
Section affected by this modification: 9.6.3.9 Reporting of medical device failures (new 
section) 
15.3.1.13 Modification 13 – change in the PK sampling schedule  
The PK samples that were to be collected on Cycle 9 and Cycle 12 were removed from the 
protocol. The number of samples was reduced based on the feedback from the investigators. 

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Sections affected by this modification: 9.1 Tabular schedule of evaluations, 
9.2.1.2.2 Treatment – From Cycle 2 to Cycle 6, 9.2.1.2.3 Treatment – From Cycle 7 onwards 
(during copanlisib/placebo monotherapy), 9.5.1 Sampling 
15.3.1.14 Modification 14 – a minimum length for the screening period added 
A minimum screening period of 7 days was added to the protocol to ensure timely supply of 
the study drug to the sites. 
Sections affected by this modification: 5.1 Design overview, 9.2.1.1 Screening period 
15.3.1.15 Modification 15 – changes based on drug-drug interaction data 
The guidance text regarding the use of drugs that are substrates of P-gp and/or BCRP was 
removed from the protocol since the potential for drug-drug interactions appears to be very 
low based on the observed clinical Cmax (~ 1µM) for copanlisib at the recommended clinical 
dose of 60 mg vs. in vitro IC50 for P-gp (7.0 and 7.6 µM) and BCRP (11µM). As a result of 
this change, Appendix 16.2 was removed from the protocol and all information regarding the 
use of MATE2K substrates was transferred to Section 8.1.2. 
The language stating that non-dihydropyridine calcium channel blockers (verapamil and 
diltiazem) should be used with caution due to a potential CYP3A4 interaction was removed 
from the protocol as there is a low drug-drug interaction liability based on the current clinical 
knowledge with copanlisib. 
It was also further clarified that the use of strong inhibitors of CYP3A4 and strong inducers of 
CYP3A4 is not permitted. 
Sections affected by this modification: 6.2 Exclusion criteria, 7.4.3.3 Treatment of blood 
pressure increases associated with copanlisib, 8.1.1 Prohibited concomitant therapy, 
8.1.2 Permitted concomitant therapy, 16.1 CYP3A4 inhibitors and inducers, 16.2 Pg-p 
substrates, BCRP substrates and MATE2K-substrates 
15.3.1.16 Modification 16 – possibility to use paper QoL questionnaire in case 
ePRO device is not available 
Language regarding the use of the paper version of PRO was added so that sites have the 
option to use this version if and when the ePRO device is not available and only if the 
Sponsor approves. 
Section affected by this modification: 9.7.3 Electronic patient-reported outcomes evaluation 
15.3.1.17 
Modification 17 – other clarifications and corrections 
• It was clarified that dose modifications are allowed during all treatment cycles in the 
phase III part of the study but only starting from Cycle 2 in the safety run-in part. 
• Language was modified to further clarify that in countries where prednisone is not 
available, prednisolone can be administered instead. 
• Since comparators will either be sourced centrally or provided locally by the 
sites/investigators followed by reimbursement, it was clarified that rituximab and 
chemotherapeutic agents will be sourced centrally or locally. 

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• The term “unblinded monitor” was changed to “independent monitor” as monitors are 
only potentially exposed to receive unblinded information from the unblinded 
pharmacist. 
• Glucose monitoring guidance for diabetic patients was clarified to align the protocol 
with other copanlisib studies. “Non-fasting glucose < 200 mg/dL” was removed and 
no specific goal for the blood glucose values after 72 h post-infusion was included.  
Section affected by this modification: Synopsis, 7.2 Identity of study treatment, 7.4 Dosage 
and administration, 7.4.2 Dose modification, 7.4.3.1 Management of transient post-infusion 
glucose increases that can occur with copanlisib, 7.5 Blinding, 7.7 Treatment compliance, 
9.1 Tabular schedule of evaluations, 9.2.1.2.1 Treatment – Cycle 1, 
9.2.1.2.2 Treatment - From Cycle 2 to Cycle 6 
15.3.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 3 are provided in Section 15.3.2 of the 
Amendment 3. 

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15.4 
Amendment 5 
Amendment 5 is a global amendment dated 14 AUG 2017. 
15.4.1 
Overview of changes 
Modification 1 – patients experiencing disease progression not allowed to continue on 
treatment 
The language was modified not to allow patients to continue treatment in CHRONOS-4 
beyond disease progression. This change was made at the request of French Health Authority, 
L’Agence nationale de sécurité du médicament et des produits de santé. 
Sections affected by this modification: Synopsis, 5.1 Design overview, 5.3 Phase III  
15.4.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 5 are provided in Section 15.4.2 of the 
Amendment 5. 

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15.5 
Amendment 6 
Amendment 6 is dated 25 SEP 2018.  
15.5.1 
Overview of changes 
15.5.1.1 
Modification 1 – updated guidance for management of glucose 
increases 
Based on available safety data on copanlisib and to align with copanlisib prescribing 
information, the dose reduction guidance and withdrawal criterion for persistent occurrence of 
post-infusion blood glucose was modified from > 400 mg/dL to > 500 mg/dL.  
Based on available safety data, fasting status has no significant clinical impact on post-
infusion blood glucose. Fasting requirement at C1D1 and on D1 of subsequent cycles was 
removed. On infusion days, the timing of meal intake and additional glucose testing (if 
applicable) is managed and monitored by the investigators. 
Based on available data, post-infusion blood glucose increase related to copanlisib treatment 
is transient and manageable. Home glucose monitoring was modified to allow investigator to 
determine a need for home glucose monitoring based on post-infusion glucose profile and 
clinical status of the patient. 
On infusion days the allowed time window for post-infusion glucose measurements was 
changed from  5 min to  10 min for easier compliance. The time window for glucose 
measurements on D2 was extended from 5 minutes to 30 minutes to allow more flexibility. In 
addition, the language related to glucose measurement time points was clarified. 
The schedule for HbA1C measurements was updated and an additional measurement of 
HbA1C 3 months after the EOT visit was implemented in order to assess HbA1C after 
treatment with copanlisib. 
Sections affected by this modification: 6.4.1.1 Withdrawal criteria, 6.4.1.2 Screening failure, 
7.4 Dosage and administration, 7.4.2.3 Non-hematological toxicity, 7.4.3.1 Management of 
transient post-infusion glucose increases that can occur with copanlisib, 9.1 Tabular schedule 
of evaluations, 9.2.1.1 Screening period, 9.2.1.2.1 Treatment – Cycle 1, 9.2.1.2.2 Treatment – 
From Cycle 2 to Cycle 6, 9.2.1.2.3 Treatment – From Cycle 7 onwards (during 
copanlisib/placebo monotherapy), 9.2.1.4 End-of-treatment visit, 9.2.1.5 Follow-up periods, 
9.6.3.2 Glucose measurement on treatment days, 16.8 The average Glycemic Index of 
common foods derived from multiple studies by different laboratories 
15.5.1.2 
Modification 2 – updated guidance for blood pressure measurements  
The guidance related to blood pressure measurements on infusion days was clarified, 
however, the data points remained unchanged. The time interval for the pre-dose 
measurement was updated to be aligned with copanlisib labeling information. The 
requirement to measure blood pressure on D2 (C1-C6) before and after rituximab 
administration was removed to be aligned with the rituximab label. 
Sections affected by this modification: 9.2.1.2.1 Treatment – Cycle 1, 9.2.1.2.2 Treatment – 
From Cycle 2 to Cycle 6, 9.6.3.5 Blood pressure measurement on treatment days 

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15.5.1.3 
Modification 3 – updated guidance for dermatologic and hematological 
toxicity 
Updated guidance for dose modifications in cases of dermatologic toxicity was added to be 
aligned with the copanlisib label. 
Following the investigator’s feedback guidance text for hematological toxicity was modified 
to clarify that the use of G-CSF is based on local standard of care and that prophylactic 
treatment with G-CSF is allowed. In addition, it was also clarified G-CSF should be 
prescribed when ANC <1000/mm3. 
Section affected by this modification: 7.4.2.2 Hematological toxicity, 7.4.2.3 Non-
hematological toxicity 
15.5.1.4 
Modification 4 – clarifications/modifications of inclusion criteria 
Inclusion criterion 3 was modified to clarify that if prior line of rituximab-based 
immunochemotherapy and alkylating agents have been given concomitantly, they are 
considered one line of therapy. In addition the requirement for the previous regimen was 
clarified; less than 2 months of therapy with single agent rituximab can be considered a 
previous regimen in the case the patient responded to it. 
The requirement for splenic MZL was clarified in inclusion criterion 4 since this group of 
patients presents manifestations which usually include only spleen and bone marrow. Nodal 
and extranodal involvement is rare, and therefore requiring a bi-dimensionally measurable 
lesion for this subtype is unreasonable. 
See Modification 8 for the description of change in inclusion criterion 11.  
Sections affected by the modification: Synopsis, 5.1 Design overview, 6.1 Inclusion criteria 
15.5.1.5 
Modification 5 – clarifications/modifications of exclusion criteria 
Exclusion criterion 3 was removed, patients with close affiliation with the investigational site 
are no longer excluded from the study. This change was made to per site feedback to remove 
study participation restriction for these patients and to harmonize language within copanlisib 
protocols.  
The definition of rituximab resistance was clarified in exclusion criterion 5 to explain that it is 
progression within 6 months of the last date of rituximab administration, including rituximab 
maintenance. 
Please see Modification 8 for the change in exclusion criterion 10, 22 and 41. 
Exclusion criterion 14 on excluding patients with history of current autoimmune disease was 
removed. Ongoing immunosuppressive treatment is already prohibited in exclusion criterion 
30. 
Sections affected by the modification: Synopsis, 5.1 Design overview, 6.2 Exclusion criteria  

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15.5.1.6 
Modification 6 – clarification of the administration of study treatment 
It was clarified that if any of the study treatment (copanlisib/placebo or 
immunochemotherapy) must be permanently discontinued, all other study treatment must be 
discontinued as well (excluding the planned discontinuation of R-B or R-CHOP after Cycle 
6). In addition, it was emphasized, that if any drug administration is delayed, all drug 
combinations must be delayed. 
It was also clarified that rituximab biosimilars cannot be prescribed in this study to avoid 
introducing any more variables to the study. 
Sections affected by the modification: 7.2 Identity of study treatment, 7.4.2 Dose modification 
15.5.1.7 
Modification 7 – clarification of time window for assessments 
It was clarified that the -1 to + 2 days time window for study drug administration in the 
tabular schedule of evaluations does not apply to visits at CxD2.  
It was also clarified that starting from Cycle 1 Day 8 all laboratory tests performed prior to 
infusion including complete blood count with the exception of blood glucose may be done 
and assessed either the day before or on the planned day of infusion. This change was made to 
be aligned with the SOC and to make the test feasible for the sites.  
At screening, an extended window of 14 days for diagnostic tests (if approved by the sponsor) 
was added. This change was made to increase flexibility at the sites and prevent unnecessary 
testing if historic test results are available. 
It was clarified that IVRS/IWRS transactions for medication dispensing at Cycle 2 and above 
will be on Day 1 of each cycle or as described in the Pharmacy Manual. Individual sites may 
be permitted to perform the IVRS/IWRS transactions for medication dispensing up to 48 
hours earlier than Day 1 of each Cycle due to logistics involved in medication being stored at 
main site and transported to a satellite location for dose administration.  
Sections affected by the modification: 7.4 Dosage and administration, 9.1 Tabular schedule of 
evaluations (Tables 9-1, 9-2 and 9-3), 9.2.1.1 Screening period, 9.2.1.2.1 Treatment – Cycle 
1, 9.2.1.2.2 Treatment – From Cycle 2 to Cycle 6, 9.2.1.2.3 Treatment – From Cycle 7 
onwards (during copanlisib/placebo monotherapy) 
15.5.1.8 
Modification 8 – modification of the laboratory assessments 
The requirement for total bilirubin level was changed from normal limit to  < 1.5 × ULN for 
inclusion criterion 11 and for laboratory test criteria for Day 1 dose (in Cycle 2 and higher). 
This change was made because the review of safety data allows more flexibility to enroll 
patients with < 1.5 × ULN and  to be aligned with other Chronos trials. It was also clarified 
that conjugated and unconjugated bilirubin must be calculated only if bilirubin > 1.5 × ULN). 
This change was made to be aligned with clinical practice and local SOC. 
Guidance on how to consider a PCR test positive for CMV was added and a time window 
of -1 day was added. It was also emphasized that treatment of CMV should be initiated based 
on local SOC. The timing of the PCR test for CMV was also clarified. 

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The timing for HBV DNA PCR and HCV RNA test was clarified, these tests should be 
performed every cycle (±7 days) through treatment, not monthly. For consistency, these tests 
were added also to Day 1 of Cycle 2 - Cycle 6, Day 1 of C7 onwards and to the Active FU. In 
addition, it was clarified that patients positive for HBsAg or HBcAb and negative for HBV-
DNA should receive prophylactic antiviral therapy as per rituximab label to be eligible.  
The criterion to perform blood cultures when ANC CTCAE grade 4 occurs was removed to 
align the protocol language with the current SOC, since ANC grade 4 alone is not usually a 
mandatory criterion to perform blood cultures. 
It was clarified that UPCR > 3.5 is equivalent to > 396 mg / mmol. This change was made to 
avoid unit conversion by the site when checking the excluded medical condition. In addition, 
the units of total urine protein and urine creatinine were removed as it should not be specified 
which unit the site will enter.  
Sections affected by the modification: 6.1 Inclusion criteria, 6.2 Exclusion criteria 7.4 Dosage 
and administration, 7.4.3.6.1 Monitoring guidelines for OI, 9.1 Tabular schedule of 
evaluations, 9.2.1.1 Screening period, 9.2.1.2 Treatment period, 9.2.1.2.2 Treatment – From 
Cycle 2 to Cycle 6, 9.2.1.2.3 Treatment – From Cycle 7 onwards (during copanlisib/placebo 
monotherapy), 9.2.1.5.2 Active follow-up, 9.6.3.1 Laboratory 
15.5.1.9 
Modification 9 – clarification of tumor assessments 
It was clarified that bone marrow biopsy should be provided  to central pathology review also 
at the investigator discretion if clinical evaluation leads to suspicion of bone marrow 
infiltration without further radiological findings. Protocol was also modified to remind about 
the need for bone marrow evaluation for those patients who had previous lymphoma in the 
bone marrow. The text was aligned with other copanlisib protocols. 
It was clarified that PET functional imaging is preferred modality and should be done based 
on institutional standards. 
It was also clarified that CT/MRI scans are starting from Cycle 1 Day each year, not only in 
Year 1. 
Language on CT/MRI scans at EOT visit was modified;  these scans are not required, if the 
patient has been radiologically evaluated within the 4 weeks preceding EOT. This change was 
made to avoid unnecessary radiological exposure in all patients despite of the reason for drug 
withdrawal. 
Sections affected by the modification: Synopsis, 5.1 Design overview,  9.2.1.3 Tumor 
assessments, 9.2.1.4 End-of-treatment visit,  9.2.1.5.2 Active follow-up, 9.4.2 Radiological 
tumor assessments, 9.8 Appropriateness of procedures / measurements 
15.5.1.10 Modification 10 – clarification of stratification factor related to 
treatment-free interval 
Due to feedback from sites and to be aligned with the exclusion criterion 5, it was clarified 
that patients will be stratified by the duration of progression-free interval from the last 
rituximab containing regimen. 

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Given the recognition that some sites are using progression-free interval for stratification, the 
change of stratification factor is considered beneficial for correct stratification of future 
patients. 
Sections affected by this modification: Synopsis, 5.3 Phase III, 7.3.2 Phase III part 
15.5.1.11 Modification 11 – administrative change 
The contact information of sponsor’s medical expert was changed. One of the co-ordinating 
investigators was changed. In addition, the sponsor’s medically responsible person was 
changed. 
Sections affected by this modification: Title page, 13.1 Investigator(s) and other study 
personnel, and Signature of the sponsor’s medically responsible person 
15.5.1.12 Modification 12 – changes to prohibited concomitant therapy 
The use of Biotin is prohibited for at least 72 hours prior to immunoassay test collection as 
requested in the FDA Safety communication/recommendations on the use of Biotin. Since the 
use of Biotin produce high levels of the vitamin, these can interfere  with the result of the 
immunoassay test. 
Section affected by this modification: 8.1.1 Prohibited concomitant therapy 
15.5.1.13 Modification 13 – other clarifications and corrections 
• HBV DNA and HCV RNA test was added also to tabular schedule of evaluations 
(Tables 9-1 and 9-2) for consistency. 
• For this protocol, it was clarified in Section 5 (Study design) that one month is 
considered to have 30 days. 
• The reference to the version number of the NCCN-FACT Lymphoma Symptom 
Index-18 (FLymSI-18) questionnaire was corrected in Section 9.7.2, it should be 
version 4 instead of 2. The actual FLymSI-18 questionnaire was removed from the 
Appendix 16.6 to be consistent with protocol guidelines and to avoid potential 
amendments in the future. 
• It was clarified that the EOT visit must take place also when the patient completes 12 
months of treatment (maximum duration of therapy) if the patient has not discontinued 
treatment due to other reasons. 
• It was explained in the study flow chart footnote “o” that Active follow-up period 
includes all patients who discontinued treatment due to any other reason than PD. 
• “Evaluation of any new onset or worsening of pulmonary symptoms” was removed 
from the study flow charts Table 9-1, Table 9-2 and Table 9-3 to avoid overlap as brief 
and complete physical examinations already include lung examination. 
• A reference to DMC charter was added instead of mentioning a specific timepoint for 
the DMC review to avoid protocol deviations. 
• It was clarified that the enrollment period of 33 months and follow-up of 19 months 
are approximations. The terminology for progression was clarified for better 
readability. 
 

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In addition, minor editorial corrections to language were done throughout for consistency 
and to improve readability  
15.5.2 
Changes to the protocol text 
Changes to the protocol text are provided in a separate track changes version. 
15.6 
Amendment 8 
Amendment 8 is a global amendment dated 14 AUG 2019. 
15.6.1 
Protocol amendment summary of changes table 
Section # and name 
Description of changes 
Brief rationale 
Section 2 Synopsis, 
Section 4.2 Phase III part, 
Section 5.1 Design overview, 
Section 5.3 Phase III, 
Section 6.1 Inclusion criteria, 
Section 6.2 Exclusion criteria, 
Section 6.3 Justification of 
selection criteria, 
Section 7.3.2 Phase III part 
Addition of prior anticancer 
therapies with rituximab 
biosimilars, and/or anti-CD20 
monoclonal antibody 
Considering the current 
iNHL treatment landscape 
and following the 
investigator’s feedback, the 
eligibility criteria was 
modified to allow prior 
anticancer therapies with 
rituximab biosimiliars, 
and/or anti-CD20 
monoclonal antibody. 
Section 7.2 Identity of study 
treatment, 
Section 7.6 Drug logistics and 
accountability 
Clarification of the local and 
central drug supply batch 
number tracking requirements 
for sites 
 
 
In order to maintain 
consistency throughout the 
protocol, the requirement 
on how to handle 
background treatments was 
added. 
Section 9.1 Tabular schedule of 
evaluations, 
Section 9.2.1.2.1 Treatment – 
Cycle 1, 
Section 9.2.1.2.2 Treatment – 
From Cycle 2 to Cycle 6, 
Section 9.2.1.2.3 Treatment – 
From Cycle 7 onwards (during 
copanlisib/placebo 
monotherapy), 
Section 9.2.1.4 End-of-treatment 
visit, 
Section 9.2.1.5.1 Safety follow-
up, 
Section 9.7.2 Quality of life 
questionnaire – Phase III part 
only, 
Section 9.7.3 Electronic patient 
reported outcomes evaluation, 
Section 11.3 Data processing 
Removal of PRO electronic 
device, Correction of version 
number of FLymSI-18 
Due to technical issues with 
the devices at the start of 
the study, paper PRO is 
being used instead of 
ePRO. 
Section 9.2.1.2.1 Treatment – 
Cycle 1 
Deletion of descriptive text of 
excluding blood count test at 
CxD8 
Correction of error 

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15.6.2 
Changes to the protocol text 
Changes to the protocol text are provided in a separate tracked-changes version. 
15.7 
Amendment 9 
Amendment 9 is a global amendment dated 21 MAR 2023. 
15.7.1 
Protocol amendment summary of changes table 
Section 9.1 Tabular schedule of 
evaluations 
Deletion of BP measurement at 
D2 (C1-C6) 
Correction of error 
Section 1 Title page, 
Signature of the sponsor’s 
medically responsible person, 
Section 13.1 Investigator(s) and 
other study personnel 
Update contact information of 
sponsor’s medical expert 
Administrative changes 
Section # and name 
Description of changes 
Brief rationale 
2. Synopsis 
5.3.1. Primary variable 
5.3.3. End of study 
10.3.2.5. Primary efficacy 
analysis 
10.3.2.6. Secondary efficacy 
analysis 
10.3.2.7. Confirmatory statistical 
test strategy 
10.4. Determination of sample 
size 
Changed the number of PFS 
events for primary completion 
from approximately 256 events 
to approximately 280 events  
 
Provided that confirmatory 
statistical testing strategies will 
be provided in the SAP. 
To address the US FDA 
comment for the primary 
endpoint to include the FL 
subpopulation  
9.1. Tabular schedule of 
evaluations 
9.2.1.5.2. Active follow-up 
Changed the end of the active 
follow up period to extend up to 
2 years after study primary 
completion 
To clarify the end of the 
active follow up period after 
study primary completion 
 
2. Synopsis 
5.1. Design overview 
6.4.1.1. Withdrawal criteria 
9.1. Tabular schedule of 
evaluations 
9.2.1.5.3. Survival follow-up 
Changed the time for collecting 
survival follow up data from 5 to 
10 years after the last patient 
started study treatment 
The extension of survival 
follow-up period from 5 
years up to 10 years would 
allow long-term assessment 
of OS as both a safety and 
efficacy endpoint. 
2. Synopsis 
Section 4.2. Study Objectives – 
Phase III Part 
10.3.2.3 Secondary efficacy 
variables 
10.3.2.6. Secondary efficacy 
analysis 
Added disease control rate as a 
secondary objective and defined 
its respective analyses 
Considered to be an 
informative secondary 
endpoint. 
9.1. Tabular schedule of 
evaluations 
Section 9.2.1.5.2 Active follow-
up 
Section 9.7.2 Quality of life 
questionnaire 
Provided that FLyMSi 
questionnaire will be completed 
during the active follow up 
period for up to at least 1 year 
after study primary completion 
or until the sponsor advises 
termination of its collection 
To extend a QOL 
assessment beyond the 
study primary completion 
allowing more data 
collection for the treatment 
evaluation. 

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Section 9.7.2 Quality of life 
questionnaire 
Corrected the version of the 
FLyMSi-18 form from version 4 
to version 2. 
The paper version number 
of the FLyMSi-18 form was 
down-versioned from 
version 4 to version 2 
2. Synopsis 
5.1. Design overview 
9.1. Tabular schedule of 
evaluations 
9.2.1.3. Tumor assessments 
9.4.2. Radiological tumor 
assessments 
Provided guidance to specify the 
tumor assessments beyond 
Year 5 study period. Increased 
the time window to ±14 days for 
performing radiological tumor 
assessments beyond Year 5. 
To provide guidance for 
tumor assessments beyond 
Year 5 of the study period. 
2. Synopsis 
3.3. Benefit-risk assessment 
5.2 Safety run-in part 
Added text confirming the 
completion of the safety run-in 
part of the study for copanlisib in 
combination with R-CHOP 
The safety run-in part of the 
study was completed and 
the DMC determined that 
copanlisib in combination 
with R-CHOP  is a 
recommended and 
approved dose used in the 
phase III part of the study 
9.1. Tabular schedule of 
evaluations 
9.2.1.4 End-of-treatment visit 
9.7.1. Biomarker investigations 
Removed text that required 
submission of a tumor sample 
from a biopsy or excision 
occurring during the study 
based on medical need 
The text is removed due to 
completion of the biomarker 
analysis.  
9. Procedures and Variables 
Added text for participant visits, 
assessments, and monitoring in 
the event of study continuity 
issues 
To provide general 
mitigation strategies in the 
event of a pandemic or 
other major study disruption 
2. Synopsis 
5.1 Design overview 
9.1. Tabular schedule of 
evaluations 
9.2.1.1. Screening period 
9.7.1. Biomarker investigations 
13.1 Investigator(s) and other 
study personnel 
Added text to clarify that central 
pathology will be analyzed only 
as an exploratory analysis 
For the study eligibility 
evaluation, a histologically 
confirmed diagnosis per 
local assessment was 
used. A clarification is 
added that central 
pathology will be analyzed 
only as an exploratory 
analysis. 
2. Synopsis 
5.1 Design overview 
9.2.1.3. Tumor assessments 
9.2.1.5.2 Active follow-up 
Changed the post-baseline bone 
marrow biopsy assessment 
central review to local 
assessment to confirm the first 
complete response. 
Having the study treatment 
period completed in April 
2021, the likelihood of the 
first complete response is 
decreasing significantly in 
time. Therefore, a local 
bone marrow biopsy 
assessment will be allowed 
for the first CR 
confirmation. 
13.5. Publication policy 
Text regarding disclosure of 
study results added 
Clarification to comply with 
the requirement of the  
European Union Clinical 
Trials Regulation (EU-CTR) 
536/2014. 

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15.7.2 
Changes to the protocol text 
Changes to the protocol text are provided in a separate track changes version. 
15.8 
Country-specific requirements 
Amendment 9 is a global amendment dated 21 MAR 2023. 
7.2. Identity of study treatment 
Added guidance for study drug 
storage, accountability, 
reconciliation, and record 
maintenance 
Clarification to comply with 
the requirement of the EU-
CTR 536/2014. 
2. Synopsis 
Included the study rationale in 
the synopsis. 
Clarification to comply with 
the requirement of the EU-
CTR 536/2014. 
2. Synopsis 
5.1 Design overview 
5.3.1. Primary variable 
5.3.3. End of study 
6.4.4.1 Withdrawal criteria 
9.4.1 Primary efficacy variable 
9.4.3 Tumor assessments in 
patients with WM 
10.3.2.2 Primary efficacy 
variable 
10.3.2.5 Primary efficacy 
analysis 
10.4 Determination of sample 
size 
11.4 Missing data 
Aligned text throughout to state 
that disease progression is 
assessed by blinded 
independent central review. 
Clarification to ensure 
consistency throughout. 
13.1. Investigator(s) and other 
study personnel 
Names of sponsor’s medical 
expert and coordinating 
investigators removed. 
This information is identified 
in a separate personnel list 
that is not part of this 
clinical study protocol. 
Title Page 
Sponsor Signatory 
Removed Sponsor Signatory 
page from the protocol 
The signature of the 
Sponsor’s medically 
responsible person is 
generated separately from 
the protocol as a 
standalone document filed 
with the protocol in the Trial 
Master File. 
Throughout 
Minor and editorial changes, 
corrections, and clarifications. 
In addition to the 
modifications described 
above, protocol text was 
revised to address changes 
of editorial nature, 
clarifications for existing 
content, corrections based 
on inconsistencies, and 
typos or updates according 
to external guidance. 

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15.8.1 
Japan 
Local Amendment 4 dated 11 MAY 2017 is specific to Japan. 
15.8.1.1 
Overview of Changes 
15.8.1.1.1 Modification 1 – Japanese safety run-in (J-SRI) cohort added  
According to the administrative notice by Ministry of Health, Labour and Welfare (MHLW)*, 
Japanese safety run-in (J-SRI) cohort is necessary because the increase safety risk associated 
with copanlisib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, 
and prednisone (R-CHOP) / rituximab and bendamustine (R-B) cannot be ruled out.  
The J-SRI cohort was added to confirm that the recommended phase III dose (RP3D) of 
copanlisib in combination with R-B and R-CHOP is safe and tolerable in Japanese subjects. 
The J-SRI is to be performed instead of the safety run-in part of main study (original protocol), 
and started after the RP3D of each combination (copanlisib+R-B or copanlisib+R-CHOP) is 
determined. Once the safety and tolerability of the RP3D of copanlisib in either combination 
with R-CHOP or R-B has been confirmed in Japanese subjects, the enrollment of Japanese 
subjects with the combination in the phase III part will start. The J-SRI of the other 
combination will continue until the safety and tolerability of the RP3D is confirmed. 
*: “Basic Principles on Global Clinical Trials (Reference Cases)” issued by MHLW on 5 Sep. 2012 
Clinical study protocol sections affected by this modification:  
2. Synopsis, List of abbreviations, 3.3 Benefit-risk assessment, 4.1 Safety run-in part (New 
section added: 4.1.1 Japanese safety run-in cohort), 5.1 Design overview, 5.2 Safety run-in 
part (New section added: 5.2.1 Japanese safety run-in cohort), 5.3 Phase III, 5.3.1 Primary 
variable, 5.3.2 Justification of the design, 6. Study population, 6.4.1.1 Withdrawal criteria, 
6.4.1.3 Drop out, 6.4.2 Replacement, 7.1 Treatments to be administered, 7.3.1 Safety run-in 
part (Section title changed), 7.4 Dosage and administration, 7.4.1 Definition of dose-limiting 
toxicities (DLTs), 7.4.2 Dose modification, 7.4.2.1 Safety run-in part and phase III part 
(Section title changed), 7.4.2.2 Hematological toxicity, 7.5 Blinding, 9.1 Tabular schedule of 
evaluations, 9.2.1 Visit descriptions in safety run-in part and phase III part (Section title 
changed), 9.5.1 Sampling, 9.5.2 Analysis, 10.1 General considerations, 10.2 Analysis sets, 
10.3.1 Safety run-in part (Section title changed), 10.3.2.11 Further variables and their analysis, 
10.4 Determination of sample size 
15.8.1.2 
Changes to the protocol text 
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version.  
In the display of modifications, the “old text” refers to the protocol version preceding this 
amendment. Deletions are crossed out in the “old text”. Additions are underlined in the “new 
text”. Corrections of typos or omissions are not highlighted. 

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15.8.1.2.1 
Section 2. Synopsis 
Old text: 
[…] 
[…] 
Study objective(s)  
 
[…] 
• Biomarkers of efficacy, mode-of-action-related effect, safety, and / or the 
pathomechanism of the disease 
Phase III part (randomized, controlled trial)  
Primary objective is: 
[…] 
[…] 
[…] 
Dose(s) 
 
[…] 
After Cycle 1, dose reductions to 45 mg (if starting dose is 60 mg) and further to 
30 mg are possible, should toxicities occur. 
Phase III part: 
Dosing of copanlisib: 
[…] 
[…] 
[…] 
Duration of treatment 
[…] 
The maximum duration of treatment with copanlisib/placebo is 12 months (including 
combination therapy and monotherapy). The duration of treatment in the safety run-
in part will be the same as in the phase III part. 
[…] 
[…] 
Dose(s) 
Safety run-in part: Not applicable 
[…] 
[…] 
[…] 
Study design 
The study has two parts: safety run-in / dose finding part and double-blind, 
controlled, two-arm phase III part. 
Safety run-in part: 
[…] 
Patients recruited into the safety run-in part are treated in an unblinded fashion and 
will thus not be evaluated as part of the phase III part. 
Phase III part: 
[…] 
The study (applicable to safety run-in part and phase III part) is composed of the 
following periods: 

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[…] 
Methodology 
The primary safety variable in the safety run-in part is occurrence of dose-limiting 
toxicities in Cycle 1. The primary efficacy variable in the phase III part is PFS (for 
the definition, see below). 
[…] 
[…] 
[…] 
Number of patients 
Safety run-in part: maximum 2 x 6 patients per combination evaluable for the 
primary endpoint. 
Phase III part: approximately 520 (including FL and other iNHL).  
Patients recruited into the safety run-in part will not be evaluated as part of the phase 
III part. 
Primary variable(s) 
Safety run-in part: The primary safety variable is the occurrence of DLTs in Cycle 
1. 
[…] 
Time point/frame of 
measurement for 
primary variable(s) 
Safety run-in part: Approximately 6-8 months 
[…] 
Plan for statistical 
analysis 
Safety run-in part: Safety data will be summarized or listed per dose level. 
[…] 
 
New text: 
[…] 
[…] 
Study objective(s)  
 
[…] 
• 
Biomarkers of efficacy, mode-of-action-related effect, safety, and / or the 
pathomechanism of the disease 
Japanese safety run-in (J-SRI) cohort 
For Japanese subjects, the Japanese safety run-in (J-SRI) cohort is to be performed 
instead of the safety run-in part. It will start after the RP3D of copanlisib with each 
combination (R-B and R-CHOP) has been determined by the safety run-in part. Once 
the safety and tolerability of the RP3D of copanlisib in either combination 
(copanlisib+R-CHOP or copanlisib+R-B) has been confirmed, the enrollment of 
Japanese subjects with the combination in the phase III part will start. The J-SRI of 
the other combination will continue until the safety and tolerability of the RP3D is 
confirmed. 
Primary objective is to confirm: 
• 
Safety and tolerability of the RP3D of copanlisib determined by the safety run-
in part in each combination (R-B and R-CHOP) in Japanese subjects 
Further objectives are to evaluate: 
• 
Radiological and clinical indicators of treatment efficacy in Japanese subjects 

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(for subjects that stay on treatment after Cycle 1) 
• 
Safety and tolerability of copanlisib in combination with R-B/R-CHOP in 
Japanese subjects (for subjects that stay on treatment after Cycle 1) 
• PK of copanlisib in Japanese subjects 
• Biomarkers of efficacy, mode-of-action-related effect, safety, and/or the 
pathomechanism of the disease 
Phase III part (randomized, controlled trial) 
Primary objective is: 
[…] 
[…] 
[…] 
Dose(s) 
 
[…] 
After Cycle 1, dose reductions to 45 mg (if starting dose is 60 mg) and further to 
30 mg are possible, should toxicities occur. 
J-SRIcohort: 
Dosing of copanlisib in this cohort: 
• in combination with R-B: RP3D of copanlisib (60 mg) determined by the safety 
run-in part, on Days 1, 8 and 15 of each 28-day cycle or  
• in combination with R-CHOP: RP3D of copanlisib (60 mg or 45 mg) determined 
by the safety run-in part, on Days 1 and 8 of each 21-day cycle. 
After Cycle 1, dose reductions to 45 mg (if starting dose is 60 mg) and further to 
30 mg are possible, should toxicities occur. 
Phase III part: 
Dosing of copanlisib: 
[…] 
[…] 
[…] 
Duration of treatment 
[…] 
The maximum duration of treatment with copanlisib/placebo is 12 months (including 
combination therapy and monotherapy). The duration of treatment in the safety run-
in part and the J-SRI cohort will be the same as in the phase III part. 
[…] 
[…] 
Dose(s) 
Safety run-in part and J-SRI cohort: Not applicable 
[…] 
[…] 
[…] 
Study design 
The study has two parts: safety run-in (For Japanese subjects, J-SRI cohort will be 
used instead) / dose finding part and double-blind, controlled, two-arm phase III part. 
Safety run-in part: 

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[…] 
Patients recruited into the safety run-in part are treated in an unblinded fashion and 
will thus not be evaluated as part of the phase III part. 
J-SRI cohort: 
The study for Japanese subjects will start with a J-SRI cohort, where the RP3D of 
copanlisib determined by the safety run-in part in combination with each regimen 
(R-B or R-CHOP) will be confirmed safe and tolerable in Japanese subjects.  
During the J-SRI cohort, two treatment combinations (copanlisib with R-B and 
copanlisib with R-CHOP) will be tested at the RP3D for safety and tolerability in 
Japanese subjects. All data available from J-SRI cohort will be reviewed in 
accordance with the predefined DLT evaluation procedures for J-SRI cohort attached 
to DMC charter and evaluated whether protocol specified treatment combinations are 
safe and tolerable. The outcome of the assessment will be reported to DMC. Once 
the safety and tolerability of the RP3D of copanlisib in either combination (R-B and 
R-CHOP) in Japanese subjects has been confirmed by investigators and sponsor in 
parallel with reporting outcome to the DMC, the enrollment of Japanese subjects 
with the combination in the phase III part will start. The J-SRI of the other 
combination will continue until the safety and tolerability of the RP3D is confirmed. 
Subjects recruited into the J-SRI cohort are treated in an unblinded fashion and will 
thus not be evaluated as part of the phase III part. 
Phase III part: 
[…] 
The study (applicable to safety run-in part, J-SRI cohort and phase III part) is 
composed of the following periods: 
[…] 
Methodology 
The primary safety variable in the safety run-in part and the J-SRI cohort is 
occurrence of dose-limiting toxicities in Cycle 1. The primary efficacy variable in 
the phase III part is PFS (for the definition, see below). 
[…] 
[…] 
[…] 
Number of patients 
Safety run-in part: maximum 2 x 6 patients per combination evaluable for the 
primary endpoint. 
J-SRI cohort: 3 or 6 subjects per combination evaluable for the primary endpoint (2 
combinations). 
Phase III part: approximately 520 (including FL and other iNHL).  
Patients recruited into the safety run-in part and J-SRI cohort will not be evaluated as 
part of the phase III part. 
Primary variable(s) 
Safety run-in part and J-SRI cohort: The primary safety variable is the occurrence 
of DLTs in Cycle 1. 
[…] 
Time point/frame of 
measurement for 
primary variable(s) 
Safety run-in part: Approximately 6-8 months 
J-SRI cohort: This cohort runs after the RP3D determined in the safety run-in part 

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of each combination (R-B and R-CHOP) to early phase III part. 
[…] 
Plan for statistical 
analysis 
Safety run-in part: Safety data will be summarized or listed per dose level. 
J-SRI cohort: Safety data will be summarized or listed per dose level, which are 
independent from the safety run-in part.  
[…] 
15.8.1.2.2 
List of abbreviations 
New text: 
J-SRI 
Japanese safety run-in 
15.8.1.2.3 
Section 3.3 Benefit-risk assessment 
Old text: 
[…] 
Safety run-in part for copanlisib in combination with R-B has been completed. DMC has 
reviewed the safety data and decided that copanlisib dose of 60 mg plus R-B is safe to be 
used in the phase III part. Safety run-in for copanlisib in combination with R-CHOP remains 
open for enrollment, and DMC will review the safety data upon completion. 
New text: 
[…] 
Safety run-in part for copanlisib in combination with R-B has been completed. DMC has 
reviewed the safety data and decided that copanlisib dose of 60 mg plus R-B is safe to be 
used in the phase III part. Safety run-in for copanlisib in combination with R-CHOP remains 
open for enrollment, and DMC will review the safety data upon completion.  
For Japanese subjects, the Japanese safety run-in (J-SRI) cohort is to be performed instead of 
the safety run-in part. 
15.8.1.2.4 
Section 4.1.1 Japanese safety run-in (J-SRI) cohort 
Old text: 
Not applicable (this is a new section) 
New text: 
4.1.1 Japanese safety run-in (J-SRI) cohort 
For Japanese subjects, the J-SRI cohort is to be performed instead of the safety run-in part. 
The J-SRI will start after the RP3D of copanlisib with each combination (R-B and R-CHOP) 
has been determined by the safety run-in part. Once the safety and tolerability of the RP3D 
with either combination in Japanese subjects has been confirmed by investigators and sponsor 
in parallel with reporting the outcome to DMC, the enrolment of Japanese subjects with the 
combination in the phase III part will start. The J-SRI of the other combination will continue 
until the safety and tolerability of the RP3D is confirmed. 

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The primary objective is to confirm: 
• 
Safety and tolerability of the RP3D of copanlisib determined by the safety run-in part in 
each combination (R-B and R-CHOP) in Japanese subjects. 
Further objectives are to evaluate: 
• 
Radiological and clinical indicators of treatment efficacy in Japanese subjects (for 
subjects that stay on treatment after Cycle 1). 
• 
Safety and tolerability of copanlisib in combination with R-B/R-CHOP in Japanese 
subjects (for subjects that stay on treatment after Cycle 1). 
• 
PK of copanlisib in Japanese subjects. 
• 
Biomarkers of efficacy, mode-of-action-related effect, safety, and/or the pathomechanism 
of the disease. 
15.8.1.2.5 
Section 5.1 Design overview 
Old text: 
[…] 
The study includes two parts. The safety run-in part will determine the RP3D of copanlisib in 
combination with standard immunochemotherapy (R-B or R-CHOP) to be used in the 
subsequent phase III part. The primary objective of the phase III part is to evaluate whether 
copanlisib in combination with standard immunochemotherapy, is superior to standard 
immunochemotherapy in prolonging progression-free survival (PFS) in patients with relapsed, 
rituximab-sensitive iNHL. The study will accrue patients with FL, MZL, SLL, and LPL/WM. 
In view of the prevalence of various histological types, it is expected that the large majority of 
study participants will be patients with FL. 
[…] 
The following design applies to both safety run-in part and the phase III part unless 
otherwise specified. 
[…] 
New text: 
[…] 
The study includes two parts. The safety run-in part will determine the RP3D of copanlisib in 
combination with standard immunochemotherapy (R-B or R-CHOP) to be used in the 
subsequent phase III part. For Japanese subjects, the J-SRI cohort is to be performed instead 
of the safety run-in part to confirm the safety and tolerability of the RP3D of copanlisib 
determined by the safety run-in part in each combination (R-B and R-CHOP) in Japanese 
subjects. The primary objective of the phase III part is to evaluate whether copanlisib in 
combination with standard immunochemotherapy, is superior to standard 
immunochemotherapy in prolonging progression-free survival (PFS) in patients with relapsed, 
rituximab-sensitive iNHL. The study will accrue patients with FL, MZL, SLL, and LPL/WM. 

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In view of the prevalence of various histological types, it is expected that the large majority of 
study participants will be patients with FL. 
[…] 
The following design applies to safety run-in part, J-SRI cohort and the phase III part 
unless otherwise specified. 
[…] 
15.8.1.2.6 
Section 5.2.1 Japanese safety run-in (J-SRI) cohort 
Old text: 
Not applicable (this is a new section) 
New text: 
5.2.1 Japanese safety run-in (J-SRI) cohort 
The study for Japanese subjects will start with a J-SRI cohort, which is based on an open-
label, one dose level, 3+3 design.  
During the J-SRI cohort, two treatment combinations (copanlisib with R-B and copanlisib 
with R-CHOP) will be tested at the RP3D determined in the safety run-in part for safety and 
tolerability in Japanese subjects. Each treatment combination with one dose level will have a 
minimum of 3 and maximum of 6 patients evaluable for DLT during Cycle 1.  
The dose level of copanlisib in the Japanese safety run-in cohort will be tested as follows: 
Dose level: 
The RP3D of copanlisib determined by the safety run-in part in 
combination with either R-B or R-CHOP 
  
For the dosing of R-B and R-CHOP, please see Section 7.4. For the treatment assignment, 
please see Section 7.3.1. 
The dose-finding steps are presented in Figure 5–2J.  
Three subjects will receive the RP3D of copanlisib. 
• 
If 2 or more of the first 3 subjects experience DLT (see Section 7.4.1 for DLT definitions) 
at the RP3D, the J-SRI cohort would be closed and the participation of Japanese subjects 
in the phase III part considered to be not feasible.  
• 
If 1 out of the first 3 subjects experiences a DLT at the RP3D, 3 additional subjects will 
need to be enrolled at this dose level.  
➢ If 1 or more of the additional 3 subjects experience DLT at the RP3D, then the J-SRI 
cohort would be closed and the participation of Japanese subjects in the phase III part 
considered to be not feasible.  
➢ If none of the additional 3 subjects experiences DLT at the RP3D, the RP3D will be 
the recommended dose for Japanese subjects. 

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• 
If none of the first 3 subjects experience DLT at the RP3D, the RP3D will be the 
recommended dose for Japanese subjects. 
Subjects treated within the J-SRI cohort and who in the investigator’s opinion benefit from 
treatment can continue combination therapy (copanlisib plus R-B or R-CHOP) for a 
maximum of 6 cycles followed by copanlisib monotherapy with the same dose of copanlisib 
administered with immunochemotherapy. The maximum duration of treatment with 
copanlisib is 12 months (including combination therapy and monotherapy). 
 
Figure 5-2J Overall study design of the J-SRI cohort  
 
 
All subjects enrolled in the J-SRI cohort need to be evaluated for occurrence of DLTs during 
the first cycle. Subjects not fully evaluable for occurrence of DLTs during the first cycle of 
therapy will be replaced unless the reason for dropout is a DLT (see Section 6.4.2). Any 
subjects who experiences a DLT during the first cycle of therapy should not receive further 
administration of copanlisib or any other study treatment. The investigator must notify the 
sponsor immediately of any CTCAE Grade 3 or 4 AEs or clinically relevant laboratory 
abnormalities.  
Transition from J-SRI cohort to phase III part  
All data available from the J-SRI cohort will be reviewed in accordance with the predefined 
DLT evaluation process for J-SRI cohort attached to DMC and evaluated whether protocol 
specified treatment combinations are safe and tolerable in Japanese subjects. Outcome of the 
review of each combination (R-B and R-CHOP) will be reported to the DMC, respectively. 
Once the safety and tolerability of the RP3D of copanlisib in either combination in Japanese 
subjects has been confirmed by investigators and sponsor in parallel with reporting outcome 
to the DMC, the enrolment of Japanese subjects with the combination in the phase III part 
will start. The J-SRI of the other combination will continue until the safety and tolerability of 
the RP3D is confirmed.  

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Subjects recruited into the J-SRI cohort are treated in an unblinded fashion and will thus not 
be evaluated as part of the phase III part. 
15.8.1.2.7 
Section 5.3 Phase III 
Old text: 
[…] 
Patients will be stratified by: prior to base treatment regimen (R-chemotherapy to R-B, R-B to 
R-CHOP, and R-B to R-B), NHL histology (FL vs. other iNHL) and duration of treatment-
free interval (6-12 months vs. >12 months). If the copanlisib immunochemotherapy 
combinations are deemed safe in the safety run-in part of the trial, approximately 
520 (including FL and other iNHL) patients who meet the eligibility criteria will be randomly 
assigned in a 1:1 ratio to one of the double-blinded treatment arms (approx. 260 patients per 
arm) in the phase III part: Arm 1: copanlisib plus R-CHOP or R-B and Arm 2: placebo plus 
R-CHOP or R-B, see Figure 5–3. 
[…] 
New text: 
[…] 
Patients will be stratified by: prior to base treatment regimen (R-chemotherapy to R-B, R-B to 
R-CHOP, and R-B to R-B), NHL histology (FL vs. other iNHL) and duration of treatment-
free interval (6-12 months vs. >12 months). If the copanlisib immunochemotherapy 
combinations are deemed safe in the safety run-in part of the trial (for Japanese subjects, the 
J-SRI cohort will be used instead), approximately 520 (including FL and other iNHL) patients 
who meet the eligibility criteria will be randomly assigned in a 1:1 ratio to one of the double-
blinded treatment arms (approx. 260 patients per arm) in the phase III part: Arm 1: copanlisib 
plus R-CHOP or R-B and Arm 2: placebo plus R-CHOP or R-B, see Figure 5–3. 
[…] 
15.8.1.2.8 
Section 5.3.1 Primary variable 
Old text: 
• The primary variable for the safety run-in part is the occurrence of DLTs in Cycle 1. 
[…] 
New text:  
• The primary variable for the safety run-in part and the J-SRI cohort is the occurrence 
of DLTs in Cycle 1. 
[…] 
 

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15.8.1.2.9 
Section 5.3.2 Justification of the design 
Old text: 
[…] 
The safety run-in part uses the standard design of dose-finding study, with 3-6 patients per 
dose level, and occurrence of dose-limiting toxicity as primary endpoint. The intensity and 
frequency of AEs as well as the occurrence of new and unexpected AEs will be carefully 
monitored. Those patients who have benefit and will stay on treatment after the 1st Cycle will 
be also evaluated for treatment efficacy, safety and tolerability of copanlisib in combination 
with R-CHOP/R-B, pharmacokinetics and biomarkers. All these information will be taken 
into account when assessing the performance of the study in the phase III part. 
The phase III part will start after RP3D of copanlisib is defined. The use of placebo can 
minimize investigator bias in assessing treatment effects beyond tumor shrinkage. This is 
particularly important when assessing duration endpoints and patient-reported outcomes. 
Although treatment with copanlisib is associated with infusion-related increases in blood 
glucose and increases in blood pressure, the risk of inadvertent unblinding is low. In the 
majority of the cases, the intensity of both symptoms is low, and both symptoms are not 
infrequent in the age group to which the majority of patients with indolent NHL belong. 
New text: 
[…] 
The safety run-in part uses the standard design of dose-finding study, with 3-6 patients per 
dose level, and occurrence of dose-limiting toxicity as primary endpoint. The intensity and 
frequency of AEs as well as the occurrence of new and unexpected AEs will be carefully 
monitored. Those patients who have benefit and will stay on treatment after the 1st Cycle will 
be also evaluated for treatment efficacy, safety and tolerability of copanlisib in combination 
with R-CHOP/R-B, pharmacokinetics and biomarkers. All these information will be taken 
into account when assessing the performance of the study in the phase III part. 
For Japanese subjects, the J-SRI cohort is to be performed instead of the safety run-in part to 
confirm that the RP3D of copanlisib in each combination determined by the safety run-in part 
is safe and tolerable in Japanese subjects. 
The phase III part will start after RP3D of copanlisib is defined. The use of placebo can 
minimize investigator bias in assessing treatment effects beyond tumor shrinkage. This is 
particularly important when assessing duration endpoints and patient-reported outcomes. 
Although treatment with copanlisib is associated with infusion-related increases in blood 
glucose and increases in blood pressure, the risk of inadvertent unblinding is low. In the 
majority of the cases, the intensity of both symptoms is low, and both symptoms are not 
infrequent in the age group to which the majority of patients with indolent NHL belong. 
 

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15.8.1.2.10 Section 6 Study population 
Old text: 
Criteria for patients’ eligibility, withdrawal and, as well as patients’ identification apply to 
both safety run-in part and phase III part, unless otherwise specified. 
New text: 
Criteria for patients’ eligibility, withdrawal and, as well as patients’ identification apply to 
safety run-in part, J-SRI cohort and phase III part, unless otherwise specified. 
15.8.1.2.11 Section 6.4.1.1 Withdrawal criteria 
Old text: 
[…] 
• Phase III part: The patient does not tolerate copanlisib/placebo dose of 30 mg.  
Safety run-in part: The patient does not tolerate copanlisib dose of 30 mg after 
Cycle 1.  
[…] 
New text: 
[…] 
• Phase III part: The patient does not tolerate copanlisib/placebo dose of 30 mg.  
Safety run-in part and J-SRI cohort: The patient does not tolerate copanlisib dose of 
30 mg after Cycle 1. 
[…] 
15.8.1.2.12 Section 6.4.1.3 Drop out 
Old text: 
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been randomized (phase III part) /assigned to treatment 
(safety run-in part). 
New text: 
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been randomized (phase III part) /assigned to treatment 
(safety run-in part, J-SRI cohort). 
15.8.1.2.13 Section 6.4.2 Replacement 
Old text: 
Safety run-in part 
[…] 

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Safety run-in part and J-SRI cohort 
[…] 
15.8.1.2.14 Section 7.1 Treatments to be administered 
Old text: 
[…] 
The maximum duration of treatment with copanlisib/placebo is 12 months (including 
combination therapy and monotherapy). The duration of treatment in the safety run-in part 
will be the same as in the phase III part. For the dosage and administration please see 
Section 7.4. 
New text: 
[…] 
The maximum duration of treatment with copanlisib/placebo is 12 months (including 
combination therapy and monotherapy). The duration of treatment in the safety run-in part 
and the J-SRI cohort will be the same as in the phase III part. For the dosage and 
administration please see Section 7.4. 
15.8.1.2.15 Section 7.3.1 Safety run-in part 
Old text: 
7.3.1 Safety run-in part 
During the open-label safety run-in part patients who have given written informed consent 
and who satisfy the entry criteria will be assigned to the combination therapy (copanlisib + 
R-B or copanlisib + R-CHOP): 
[…] 
New text: 
7.3.1 Safety run-in part and J-SRI cohort 
During the open-label safety run-in part patients and J-SRI cohort subjects who have given 
written informed consent and who satisfy the entry criteria will be assigned to the 
combination therapy (copanlisib + R-B or copanlisib + R-CHOP): 
[…] 
15.8.1.2.16 Section 7.4 Dosage and administration 
Old text: 
Copanlisib and placebo 
Copanlisib and placebo for copanlisib (only in phase III part) administration described below 
applies to all patients in the safety run-in part and patients in the phase III part, for as long as 
patients are on treatment with copanlisib or placebo. 

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[…] 
New text: 
Copanlisib and placebo 
Copanlisib and placebo for copanlisib (only in phase III part) administration described below 
applies to all patients in the safety run-in part, subjects in the J-SRI cohort and patients in the 
phase III part, for as long as patients are on treatment with copanlisib or placebo. 
[…] 
15.8.1.2.17 Section 7.4.1 Definition of dose-limiting toxicities (DLTs) 
Old text: 
Dose-limiting toxicity – safety run-in part 
[…] 
New text: 
Dose-limiting toxicity – safety run-in part and the J-SRI cohort 
[…] 
15.8.1.2.18 Section 7.4.2 Dose modification 
Old text: 
Dose modifications due to toxicities described below apply to copanlisib and placebo for 
copanlisib (“dummy dose modification”). There will be no dose reductions for rituximab in 
any cycle. For the safety run-in part, there will be no dose reductions of any components of 
CHOP or bendamustine in the first cycle. Modifications for CHOP and bendamustine (safety 
run-in part: Cycle 2 and subsequent cycles, phase III part: all cycles) will be performed 
according to the measures of precaution and toxicity management per local standards of care, 
local prescribing information, and according to investigator’s experience. 
[…] 
New text: 
Dose modifications due to toxicities described below apply to copanlisib and placebo for 
copanlisib (“dummy dose modification”). There will be no dose reductions for rituximab in 
any cycle. For the safety run-in part and the J-SRI cohort, there will be no dose reductions of 
any components of CHOP or bendamustine in the first cycle. Modifications for CHOP and 
bendamustine (safety run-in part and the J-SRI cohort: Cycle 2 and subsequent cycles, phase 
III part: all cycles) will be performed according to the measures of precaution and toxicity 
management per local standards of care, local prescribing information, and according to 
investigator’s experience. 
[…] 
 

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15.8.1.2.19 Section 7.4.2.1 Safety run-in part and phase III part 
Old text: 
7.4.2.1 Safety run-in part and phase III part 
Dose modification levels are outlined in Table 7–4. In the safety run-in part, dose 
modification rules of copanlisib will apply to patients who stay on treatment beyond 1st cycle 
and present toxicities that will need dose adjustments. Dose modification of placebo applies 
only to phase III part.  
Table 7–4 Dose levels of copanlisib and placebo  
If RP3D dose is 45 mg: 
Dose level 1 (starting dose): 
45 mg of copanlisib or placebo 
Dose level -1: 
30 mg of copanlisib or placebo 
 
If RP3D dose is 60 mg: 
Dose level 1 (starting dose): 
60 mg of copanlisib or placebo 
Dose level -1: 
45 mg of copanlisib or placebo 
Dose level -2: 
30 mg of copanlisib or placebo 
[…] 
New text: 
7.4.2.1 Safety run-in part, J-SRI cohort and phase III part 
Dose modification levels are outlined in Table 7–4. In the safety run-in part and the J-SRI 
cohort, dose modification rules of copanlisib will apply to patients who stay on treatment 
beyond 1st cycle and present toxicities that will need dose adjustments. Dose modification of 
placebo applies only to phase III part.  
Table 7–4 Dose levels of copanlisib and placebo  
If RP3D dose* is 45 mg: 
Dose level 1 (starting dose): 
45 mg of copanlisib or placebo 
Dose level -1: 
30 mg of copanlisib or placebo 
 
If RP3D dose* is 60 mg: 
Dose level 1 (starting dose): 
60 mg of copanlisib or placebo 
Dose level -1: 
45 mg of copanlisib or placebo 
Dose level -2: 
30 mg of copanlisib or placebo 
*: Copanlisib dose of the J-SRI cohort is equal to the RP3D dose defined in the safety run-in part of the main study 
[…] 

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15.8.1.2.20 Section 7.4.2.2 Hematological toxicity 
Old text: 
Neutropenia and febrile neutropenia are listed in the current version of IB as expected adverse 
events. If the guidelines given in Table 7–5 are not followed, the rationale for other measures 
is to be documented in detail in the patient’s medical record. The use of myeloid growth 
factors in the therapeutic setting is allowed during study treatment at investigator’s discretion 
for safety run-in part and phase III part. 
[…] 
New text: 
Neutropenia and febrile neutropenia are listed in the current version of IB as expected adverse 
events. If the guidelines given in Table 7–5 are not followed, the rationale for other measures 
is to be documented in detail in the patient’s medical record. The use of myeloid growth 
factors in the therapeutic setting is allowed during study treatment at investigator’s discretion 
for safety run-in part, J-SRI cohort and phase III part. 
[…] 
15.8.1.2.21 Section 7.5 Blinding 
Old text: 
Blinding measures are only applicable for the phase III part which follows double-blind 
design. The safety run-in part is open-label. 
[…] 
New text: 
Blinding measures are only applicable for the phase III part which follows double-blind 
design. The safety run-in part and the J-SRI cohort are open-label. 
[…] 
15.8.1.2.22 Section 9.1 Tabular schedule of evaluations 
Old text: 
This section contains three tabular schedule of evaluations which are valid to both safety run-
in part and phase III part of the study (unless otherwise specified): 
[…] 
New text: 
This section contains three tabular schedule of evaluations which are valid to safety run-in 
part, J-SRI cohort and phase III part of the study (unless otherwise specified): 
[…] 

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15.8.1.2.23 Section 9.2.1 Visit descriptions in safety run-in part and phase III 
part 
Old text: 
9.2.1 Visit descriptions in safety run-in part and phase III part 
[…] 
New text: 
9.2.1 Visit descriptions in safety run-in part, J-SRI cohort and phase III part 
[…] 
15.8.1.2.24 Section 9.5.1 Sampling 
Old text: 
[…] 
Table 9–4 PK assessments in the safety run-in part and phase III part 
[…] 
New text: 
[…] 
Table 9–4 PK assessments in the safety run-in part, J-SRI cohort and phase III part 
[…] 
15.8.1.2.25 Section 9.5.2 Analysis 
Old text: 
[…] 
Concentration data of copanlisib, its metabolite M-1, and other metabolites, as needed, from 
this study will be analyzed to estimate the individual maximum drug concentration (Cmax) and 
area under the curve (AUC), and to measure the variability of the PK of copanlisib, its 
metabolite M-1 and other metabolites, as needed, in the safety run-in part and phase III 
population. A population pharmacokinetic approach will be used for the analysis. 
[…] 
New text: 
[…] 
Concentration data of copanlisib, its metabolite M-1, and other metabolites, as needed, from 
this study will be analyzed to estimate the individual maximum drug concentration (Cmax) and 
area under the curve (AUC), and to measure the variability of the PK of copanlisib, its 
metabolite M-1 and other metabolites, as needed, in the safety run-in part, J-SRI cohort and 
phase III population. A population pharmacokinetic approach will be used for the analysis. 
[…] 

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15.8.1.2.26 Section 10.1 General considerations 
Old text: 
[…] 
Statistical analyses will be performed using Statistical Analysis System (SAS); the version 
used will be specified in the statistical analysis plan (SAP). As a general principle, the safety 
run-in part and phase III part will be analyzed separately. 
[…] 
New text: 
[…] 
Statistical analyses will be performed using Statistical Analysis System (SAS); the version 
used will be specified in the statistical analysis plan (SAP). As a general principle, the safety 
run-in part, J-SRI cohort and phase III part will be analyzed separately. 
[…] 
15.8.1.2.27 Section 10.2 Analysis sets 
Old text: 
[…] 
Pharmacokinetic analysis set (PKAS): All patients in the safety run-in part with a valid PK 
profile will be included in the analysis of PK data. 
Phase III part: 
[…] 
New text: 
[…] 
Pharmacokinetic analysis set (PKAS): All patients in the safety run-in part with a valid PK 
profile will be included in the analysis of PK data. 
J-SRI cohort:  
Full analysis set (FAS): All patients in the J-SRI cohort who receive at least one dose of 
study drug. 
Safety analysis set (SAF): All patients in the J-SRI cohort who receive at least one dose of 
study drug.  
Pharmacokinetic analysis set (PKAS): All patients in the J-SRI cohort with a valid PK 
profile will be included in the analysis of PK data. 
Phase III part: 
[…] 
 

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15.8.1.2.28 Section 10.3.1 Safety run-in part 
Old text: 
10.3.1 Safety run-in part 
The recommended dose of copanlisib in combination with standard immunochemotherapy 
will be determined based on a 3+3 design. The primary safety variable is the occurrence of 
DLTs during Cycle 1. Safety variables will include also treatment-emergent AEs, SAEs, 
laboratory parameters, and vital signs. The safety data will be listed by dose level. The best 
overall response will be summarized. For further details on PK and biomarker variables and 
analysis, see Section 10.3.2.11. 
New text: 
10.3.1 Safety run-in part and J-SRI cohort 
The recommended dose of copanlisib in combination with standard immunochemotherapy 
will be determined based on a 3+3 design. The primary safety variable is the occurrence of 
DLTs during Cycle 1. Safety variables will include also treatment-emergent AEs, SAEs, 
laboratory parameters, and vital signs. The safety data will be listed by dose level. The safety 
data of J-SRI cohort will be summarized, which are independent from the safety run-in part. 
The best overall response will be summarized. For further details on PK and biomarker 
variables and analysis, see Section 10.3.2.11. 
15.8.1.2.29 Section 10.3.2.11 Further variables and their analysis 
Old text: 
[…] 
The data from the safety run-in part and phase III part will be pooled for PK analysis. 
[…] 
New text: 
[…] 
The data from the safety run-in part, the J-SRI cohort and phase III part will be pooled for PK 
analysis. 
[…] 
15.8.1.2.30 Section 10.4 Determination of sample size 
Old text: 
Safety run-in part 
Maximum 2 x 6 evaluable patients per combination (dependent on visibility of DLT) will be 
included into two dose levels to identify the RP3D.  
Phase III part 
[…] 

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New text: 
Safety run-in part 
Maximum 2 x 6 evaluable patients per combination (dependent on visibility of DLT) will be 
included into two dose levels to identify the RP3D.  
J-SRI cohort 
Three or 6 evaluable subjects per combination will be included into the RP3D (one dose level) 
determined by the safety run-in part. 
Phase III part 
[…] 
15.8.2 
Germany 
Local Amendment 7 dated 12 MAR 2019 is specific to Germany. 
15.8.2.1 
Overview of Changes 
15.8.2.1.1 Modification 1 – Revised blood glucose withdrawal criterion 
The withdrawal criterion for persistent occurrence of post-infusion blood glucose was revised 
from >500 mg/dL to >400 mg/dL. 
Supporting the 17833 global protocol amendment 6, a local protocol amendment has been 
generated to satisfy the German Ethics Committee (EC) request not to modify the withdrawal 
criterion for persistent occurrence of post-infusion blood glucose.  However, the EC has 
acknowledged that the withdrawal criterion for post-infusion blood glucose increases in the 
17833 global CSP 6 was modified following the glucose increase management guidance in 
the copanlisib program, which was updated based on the available copanlisib integrated safety 
data, to address investigators’ feedback, and to be aligned with the Aliqopa label. 
Clinical study protocol sections affected by this modification:  
6.4.1.1 Withdrawal criteria, and 7.4.2.3 Non-hematological toxicity / Glucose increases 
15.8.2.1.2 Modification 2 – New Sponsor Personnel 
Sponsor’s medically responsible person and sponsor’s medical expert were changed. 
Clinical study protocol sections affected by this modification:  
1. Title page, Signature of the sponsor’s medically responsible person, 13.1 Investigator(s) 
and other study personnel 
15.8.2.2 
Changes to the protocol text 
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version.  

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In the display of modifications, the “old text” refers to the protocol version preceding this 
amendment. Deletions are crossed out in the “old text”. Additions are underlined in the “new 
text”. Corrections of typos or omissions are not highlighted. 
15.8.2.2.1 
Section  1. Title page 
[...] 
Sponsor’s medical expert: 
 
 
Rua Cancioneiro de Évora, 255, Prédio E1, 1º andar 
04708-904, São Paulo, Brazil 
Phone: 
 
Mobile
Fax: 
 
 
 
Address: 100 Bayer Boulevard P.O. Box 915 
Phone: 
 
Mobile: 
 
Fax: 
 
 (Contact information changed in amendment 6) 
 
15.8.2.2.2 
Section  Signature of the sponsor’s medically responsible person 
Name: 
 
 
 
 
Role:   
 
 
 
Date: 
 
 
Signature:  
15.8.2.2.3 
Section 6.4.1.1 
Withdrawal criteria 
[…] 
• Persistent occurrence of post-infusion blood glucose > 500 400 mg/dL based on 
laboratory analysis which occurred at the lowest copanlisib/placebo dose level despite 
optimal glucose lowering therapy (after at least one cycle of treatment).  
Definition of persistent occurrence is based on repeated post-infusion blood glucose 
laboratory analysis taken at different time during the whole cycle of treatment. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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[…] 
15.8.2.2.4 
Section 7.4.2.3 
Non-hematological toxicity 
[…] 
• Persistent occurrence of post-infusion blood glucose > 500 400 mg/dL based on 
laboratory analysis which occurred at the lowest copanlisib/placebo dose level despite 
optimal glucose lowering therapy (after at least one cycle of treatment) requires 
permanent discontinuation of the study treatment (see Section 6.4.1.1). 
[…] 
15.8.2.2.5 
Section 13 Investigator(s) and other study personnel 
Sponsor’s medical expert: (changed by amendment 2 and 6) 
Name:  
 
 
 
Address:  
Rua Cancioneiro de Évora, 255 | prédio E1 | 1º andar  
04708-904 
São Paulo, Brazil100 Bayer Boulevard P.O. Box 915 
Telephone: 
 
 
Mobile: 
 
Fax: 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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16. 
Appendices 
16.1 
CYP3A4 inhibitors and inducers  
A list of strong inhibitors and strong inducers of CYP3A4 (excluded drugs) is shown below. 
Strong CYP3A4 inhibitors 
Boceprevir, clarithromycin, conivaptan, grapefruit juice, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, voriconazole, atazanavir, 
tipranavir, troleandomycin, elvitegravir, danoprevir, conivaptan, 
boceprevir, suboxone and cobicistat 
Strong CYP3A4 inducers 
 
Avasimibe, carbamazepine, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin), St. John's wort 
(hypericum perforatum) and enzalutamide 
CYP3A4 = Cytochrome P450 isoenzyme 3A4 
Source: 23, 24, 25 and 26. 
16.2 
Section removed by amendment 3. 
See Section 15.3.1.15. 
16.3 
ECOG Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-diseases performance without restriction.  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g. light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.  
 
 

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16.4 
New York Heart Association (NYHA) Functional Classification 
NYHA Class 
Symptoms 
Not applicable 
No cardiac disease 
I 
No symptoms and no limitation in ordinary physical activity, e.g., shortness of 
breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
Source: Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels (19) 
 

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16.5 
Evaluation of tumor response 
Tumor response will be evaluated according to Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification (14). 
Criteria for CT - based response assessment  
Target lesions 
(nodal) 
Target lesions 
(extranodal) 
Non-target 
lesions 
Spleen 
New lesion 
Bone marrow 
CR 
All normal 
(LDi ≤ 1.5 cm) 
All 
disappeared 
All normal 
Normal size 
No 
Normal by 
morphology; if 
indeterminate, 
IHC and/or 
PCR negative  
PR 
Decrease ≥ 50% in the SPD of 
up to 6 target measurable 
nodes and extranodal sites 
All normal or 
stable 
Spleen must have 
regressed by >50% in 
extent beyond normal 
at baseline (=value 
over 13 cm) 
No 
Not applicable 
SD 
Decrease < 50% from baseline 
in SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
PD are met 
All normal or 
stable 
Normal size or  
stable size 
No 
Not applicable 
PD 
Individual node/lesion: 
LDi > 1.5 cm  
AND 
Increase ≥ 50% in the PPD 
from nadir  
AND 
Increase in LDi or SDi from 
nadir* ≥ 0.5 cm for lesions 
≤ 2 cm  
≥ 1.0 cm for lesions > 2 cm 
New or 
increased 
New splenomegaly:  
the splenic length 
must increase ≥ 2 cm 
from baseline length 
and be > 13 cm  
Recurrent 
splenomegaly: 
the splenic length 
must increase ≥ 2 cm 
from nadir length and 
be > 13 cm  
Progressive 
splenomegaly: 
the splenic length 
must increase by 
> 50% of the extent 
beyond normal at 
baseline (=value over 
13 cm) and must 
increase ≥ 1 cm in 
total vertical length 
Yes: 
New node > 1.5 cm 
in any axis 
New extranodal site 
> 1.0 cm in any 
axis  
(if < 1.0 cm in any 
axis its presence 
must be 
unequivocal and 
must be attributable 
to lymphoma) 
 
New or 
recurrent 
involvement 
CR = complete response; IHC = Immunohistochemistry; LDi = longest diameter; PD = progressive disease; 
PPD=product of perpendicular diameters; PR = partial response; SD =stable disease; SDi = shortest 
diameter; SPD = sum of the product of the diameters 
* If LDi ≤ 2cm at nadir, absolute increase required for any diameter (LDi or SDi) will be 0.5 cm; if LDi > 2 cm at 
nadir, absolute increase required for any diameter (LDi or SDi) will be 1.0 cm 
Note: In case the patient has only diffuse spleen involvement with splenomegaly careful evaluation of the spleen 
should be performed as the overall response will be driven by the response for splenomegaly, unless any 
non-target lesion(s) or a target lesion shows progression or a new lesion/new or recurrent involvement of 
bone marrow is present.  

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Criteria for PET-CT response assessment 
Target 
Lesions  
(Nodal) 
Target 
lesions  
(Extranodal) 
Non target 
lesions 
Spleen 
New lesions 
Bone marrow 
CMR 
Score 1, 2, or 3 with or 
without a residual mass on 
5PS*  
N/A 
N/A 
None 
No evidence of 
FDG-avid 
disease in 
marrow 
PMR 
Score 4 or 5 with reduced 
uptake compared with 
baseline and residual 
mass(es) of any size 
At interim, these findings 
suggest responding disease; 
at end of treatment, these 
findings indicate residual 
disease 
N/A 
N/A 
None 
Residual uptake 
higher than 
uptake in normal 
marrow but 
reduced 
compared with 
baseline (diffuse 
uptake 
compatible with 
reactive changes 
from 
chemotherapy 
allowed) 
NMR  
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment 
N/A 
N/A 
None 
No change from 
baseline 
PMD 
Individual target nodes/nodal 
masses  
Score 4 or 5 with an increase 
in intensity of uptake from 
baseline  
and/or  
Extranodal lesions 
new FDG-avid foci consistent 
with lymphoma at interim or 
end-of-treatment assessment  
None 
N/A 
New FDG-avid foci 
consistent with 
lymphoma rather than 
another etiology (e.g. 
infection, inflammation). 
If uncertain regarding 
etiology of new lesions, 
biopsy or interval scan 
may be considered 
New or recurrent 
FDG-avid foci 
CMR= complete metabolic response; FDG = Fluorodeoxyglucose; N/A = not applicable; PMR= partial 
metabolic response; NMR= no metabolic response, equivalent with stable disease; PMD= progressive 
metabolic disease, equivalent with progressive disease 
Note:  
• Most avid lesion will determine final score whereas volume/overall uptake and/or intensity of uptake of lesions 
should also be considered for response assessments. 
• PET-avid lesions must have a minimum score of 4 at baseline in order to be called “PET positive”. 
• Only lesions with a score ≥ 4 can be considered a valid measurable target lesion if CT scan is available.  
• Lesions with score 1, 2 or 3 are considered “PET negative” and do not qualify for target lesion at baseline 
• PET negative patients at BL with a positive histology can be followed-up with CT scan only. 
For further details refer to the Imaging Manual. 
* 5PS= 5 point score for the visual assessment of PET-CT: 
Score 1 = no uptake above background 
Score 2=uptake ≤ mediastinum 
Score 3 =uptake > mediastinum but ≤ liver 
Score 4 = uptake moderately > liver 
Score 5=uptake markedly higher than liver and/or new lesions  
Score X= new areas of uptake unlikely to be related to NHL 

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Response assessment based on PET-CT and CT/MRI scans. 
Note: a PET-CT response overrides in most cases the response by CT and/or MRI alone: e.g. 
if PET-CT response = CMR and CT/MRI response = PR, overall response is CR (for further 
details refer to the Imaging Manual). 
Response criteria in patients affected by Waldenström macroglobulinemia (WM): 
Complete 
Response 
• 
Absence of serum monoclonal IgM by immunofixation AND normal serum IgM level  
• 
Complete resolution of extramedullary disease 
• 
Normal bone marrow 
Very Good 
Partial 
Response 
• 
IgM M protein still detectable by immunofixation BUT ≥ 90% reduction in serum IgM level 
from baseline 
• 
Complete resolution of extramedullary disease 
• 
No new signs/symptoms of active disease 
Partial 
Response 
• 
IgM M protein still detectable by immunofixation BUT ≥ 50% and < 90% reduction in serum 
IgM level from baseline 
• 
Reduction in extramedullary disease 
• 
No new signs/symptoms of active disease 
Minor 
Response 
• 
IgM M protein still detectable by immunofixation BUT ≥ 25% and < 50% reduction in serum 
IgM level from baseline 
• 
No new signs/symptoms of active disease 
Stable 
Disease 
• 
IgM M protein still detectable by immunofixation BUT < 25% reduction and < 25% increase 
in serum IgM level from baseline 
• 
No new signs/symptoms of active disease 
Progressive 
Disease 
After Partial Response: 
• ≥ 25% increase in serum IgM level from lowest nadir (an absolute value of 5 g/L is required 
if IgM level is the only criterion) 
• OR 
• Progression in clinical features (signs/symptoms) attributable to disease 
After Complete Response: 
• Reappearance of IgM M protein 
OR 
• Recurrence of bone marrow involvement, extramedullary disease, symptoms attributable to 
disease 
 
IgM = immunoglobulin M 
Source: Adapted from Owen RG et al, 2013 (13) 
 

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16.6 
Quality of life questionnaire: FLymSI-18 section removed 
Appendix removed by amendment 6 (Section 15.5.1.13). 

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16.7 
Glomerular filtration rate 
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated glomerular filtration rate 
(GFR), calculated using the Modification of Diet in Renal Disease (MDRD) study 
abbreviated formula. 
This equation of 4 variables (serum creatinine level [SCR], age, sex, and ethnicity) is 
recommended by the National Kidney Foundation for use in individuals 18 years or older. 
The formula is as follows: 
GFR (mL/min/1.73m2) = k × 186 × SCR-1.154 × age-0.203 
where k = 1 (men) or 0.742 (women), GFR indicates glomerular filtration rate, and serum 
creatinine level is measured in mg/dL. 
NOTE: This equation should be used only with those creatinine methods that have not been 
recalibrated to be traceable to isotope dilution mass spectroscopy (IDMS). 
If standardized IDMS-traceable creatinine assay is used, please use the calculator provided in 
the following link: http://www.kidney.org/professionals/kdoqi/gfr_calculator. 
The above result should be multiplied by 1.212 for African-Americans. 
Patients with a baseline GFR < 40 mL/min calculated by this method will not be allowed to 
participate in the study. If not on target, this evaluation may be repeated once after at least 
24 hours either according to the MDRD abbreviated formula or by 24-hour sampling. If the 
later result is within an acceptable range, it may be used to fulfill the inclusion criteria instead. 
For further information on assessing renal function using GFR estimates, see references 20, 
21, 22. 
 
 

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16.8 
The average Glycemic Index of common foods derived from multiple studies by different laboratories 
section removed 
Appendix removed by amendment 6 (Section 15.5.1.1)