Clinical trial NCT02626455
Conditions: Lymphoma, Non-Hodgkin
Keywords: Clinical trial, Phase III Phosphatidylinositol-3-kinase Non-Hodgkin's lymphoma Indolent B-cell non-Hodgkin's lymphoma
Sponsor: Bayer
Start date: 2016-01-06; Completion date: 2023-11-10
Enrollment: 551 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess whether copanlisib in combination with standard immunochemotherapy (rituximab in combination with bendamustine \[R-B\] and rituximab in combination with a 4 drug combination of cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone \[R-CHOP\]) is effective and safe, compared with placebo in combination with standard immunochemotherapy (R-B or R-CHOP) in patients with relapsed iNHL who have received at least one, but at most three, lines of treatment, including rituximab-based immunochemotherapy and alkylating agents.

Detailed description:
Patients should be in need of and fit for immunochemotherapy and should not be resistant to rituximab (resistance defined as lack of response or progression within 6 months of the last date of rituximab administration, including rituximab, and/or rituximab biosimilars, and/or anti-CD20 monoclonal antibody).

This study will be composed of two parts: Safety run-in and phase III part. The purpose of the safety run-in part of this study is to assess whether the drug being tested (copanlisib) in combination with standard immunochemotherapy (R-B or R-CHOP) is safe and at what dose level of the study drug (copanlisib - 45mg or 60 mg) patients are able to tolerate the study treatment combination. In addition to finding a safe and tolerable dose level for the phase III part of the study, efficacy will also be evaluated for patients that stay on the study treatment during the safety run-in. The phase III part of the study started with the determined recommended dose of copanlisib of 60 mg in combination with R-B. Combination treatment of copanlisib at the recommended/approved dose of 60 mg with R-B or R-CHOP was completed in April 2021.

A maximum of 24 patients will take part in the safety run-in part of this study. In the phase III part approximately 520 patients will be randomly assigned to blinded treatment arms of copanlisib plus R-B or R-CHOP or placebo plus R-B or R-CHOP. 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.

Arms: arm 1: Combination of copanlisib with standard immunochemotherapy (rituximab and bendamustine) \[R-B\] or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone \[R-CHOP\] (safety run-in and phase III) arm 2: Combination of placebo and R-B or R-CHOP (phase III only)
Interventions: intervention 1: Copanlisib (BAY80-6946) intervention 2: Placebo intervention 3: Rituximab intervention 4: Cyclophosphamide intervention 5: Doxorubicin intervention 6: Vincristine intervention 7: Bendamustine intervention 8: Prednisone
Intervention descriptions: intervention 1: Copanlisib is supplied as lyophilized preparation in a 6 mL injection vial. The total amount of copanlisib per vial is 60 mg. The solution for IV infusions is obtained after reconstitution with normal saline solution. For patients on R-B dosing of copanlisib will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered and then rituximab followed by bendamustine. For patients on R-CHOP dosing of copanlisib will be administered on Days 1 and 8 of each 21-day cycle. Treatment with copanlisib/placebo will be continued up to 12 months.

Copanlisib will be administered before rituximab followed by cyclophosphamide, doxorubicin and vincristine infusions. Prednisone/prednisolone tablets to be taken for 5 days. intervention 2: Placebo is supplied as lyophilized preparation in a 6 mL injection vial. 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. Placebo dosing will be administered as per copanlisib described above. Applies to the phase III part of the study only. intervention 3: Rituximab is administered as an infusion at a dose of 375 mg/m2 body surface on Day 1 of each 28-day cycle for patients assigned to R-B and on Day 2 of each 21-day cycle for patients assigned to R-CHOP. intervention 4: Cyclophosphamide is administered as an infusion at a dose of 750 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP intervention 5: Doxorubicin is administered as an infusion at a dose of 50 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP intervention 6: Vincristine is administered as an infusion at a dose of 1.4 mg/m2 body surface (maximum dose 2.0 mg) on Day 2 of each 21-day cycle for patients assigned to R-CHOP intervention 7: Bendamustine is administered as an infusion at a dose of 90 mg/m2 body surface on Day 1 and Day 2 for patients assigned to R-B intervention 8: Prednisone is given as 100 mg tablets daily from Day 2 to Day 6 for patients assigned to R-CHOP

Protocol documents:
Prot_000.pdf: 
 
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. 


Integrated Clinical Study Protocol 
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Page:  134 of 193 
 
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 
be confirmed by HbA1c testing at Screening. HbA1c testing at Screening provides an 


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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 
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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 
insufficient treatment exposure due to voluntary withdrawal in Cycle 1 will be replaced. The 


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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 
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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 
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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. 
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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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New text: 
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. 
 
 


Integrated Clinical Study Protocol 
No. BAY 80-6946 / 17833 
 
21 MAR 2023 
Version 8.0 
  
   Page:  193 of 193 
 
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) 
 
 
 

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
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: 
22 SEP 2023 
 


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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 
(Safety run-in) 
Copanlisib and standard immunochemotherapy in relapsed iNHL 
Bayer study drug: 
BAY 80-6946 / Copanlisib 
 
Study purpose: 
Dose-finding, efficacy and safety of copanlisib 
Clinical study 
phase: 
III 
Date: 
22 SEP 2023 
Study No.: 
 
17833 
Version: 
3.0 
Author: 
 
 
 
 
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) are not displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
PPD


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Table of Contents 
Title page .................................................................................................................................... 1 
Table of Contents ....................................................................................................................... 2 
Table of Tables ........................................................................................................................... 3 
Table of Figures .......................................................................................................................... 3 
List of Abbreviations .................................................................................................................. 4 
1. 
Introduction ......................................................................................................................... 6 
2. 
Study Objectives ................................................................................................................. 7 
3. 
Study Design ....................................................................................................................... 7 
3.1 
Definition of dose-limiting toxicities ......................................................................... 11 
4. 
General statistical considerations ...................................................................................... 12 
4.1 
General principles ...................................................................................................... 12 
4.2 
Handling of Dropouts ................................................................................................ 13 
4.3 
Handling of Missing Data .......................................................................................... 13 
4.4 
Handling of investigator assessments when PD is not confirmed by independent 
central review ........................................................................................................................ 15 
4.5 
Handling of clinical laboratory values with qualifiers .............................................. 15 
4.6 
Interim Analyses and Data Monitoring ..................................................................... 15 
4.7 
Data Rules .................................................................................................................. 15 
4.7.1 
Time intervals ................................................................................................. 15 
4.7.2 
Baseline ........................................................................................................... 16 
4.7.3 
Repeated measures .......................................................................................... 16 
4.7.4 
Overall extent of exposure .............................................................................. 17 
4.8 
Validity Review ......................................................................................................... 17 
5. 
Analysis Sets ..................................................................................................................... 18 
6. 
Statistical Methodology .................................................................................................... 18 
6.1 
Population Characteristics ......................................................................................... 18 
6.1.1 
Disposition ...................................................................................................... 18 
6.1.2 
Demographic and other baseline characteristics ............................................. 19 
6.1.3 
Medical history ............................................................................................... 20 
6.1.4 
Prior and concomitant medication .................................................................. 20 
6.1.5 
Treatment duration and exposure ................................................................... 21 
6.2 
Efficacy ...................................................................................................................... 24 
6.3 
Safety ......................................................................................................................... 26 
6.3.1 
Adverse Events ............................................................................................... 26 
6.3.2 
Safety Parameters ........................................................................................... 29 
6.4 
Pharmacokinetics ....................................................................................................... 31 
6.5 
Additional Analyses Planned to Be Reported Outside the Main Report ................... 31 
7. 
Document history and changes in the planned statistical analysis ................................... 31 
7.1 
Document history ....................................................................................................... 31 
7.2 
Changes in the planned statistical analysis ................................................................ 32 
8. 
References ......................................................................................................................... 32 
9. 
Appendix ........................................................................................................................... 32 
9.1 
Imputation rules for partial dates ............................................................................... 32 
9.1.1 
Algorithm for handling partial initial diagnosis date and progression date .... 32 
9.1.2 
Imputation rules for partial/missing Adverse Event (AE)/Concomitant 
medication (CM) dates ...................................................................................................... 34 


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9.1.3 
: Imputation rules for partial/missing anti-cancer treatment start date ........... 35 
 
 
Table of Tables 
Table 9-1: Imputation rules for partial/missing dates .............................................................. 34 
Table 9-2: Imputation rules for partial/missing anti-cancer treatment start dates .................... 35 
 
Table of Figures 
Figure 3–1: Study periods .......................................................................................................... 8 
Figure 3–2: Overall study design of the Safety run-in part ...................................................... 11 
 
 
 


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List of Abbreviations 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
BMI 
Body mass index 
BOR 
Best overall response 
BRM 
Blind review meeting 
CD20 
B lymphocyte antigen CD20 
CHOP 
Cyclophosphamide, hydroxydoxorubicin, vincristine, prednisone 
CMR 
Complete metabolic response 
CR 
Complete response 
CRR 
Complete response rate 
CS 
Clinically significant 
CSP 
Clinical study protocol 
CT 
Computed tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
d 
Days 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
e.g. 
For example (exempli gratia) 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of treatment 
FAS 
Full analysis set 
FL 
Follicular lymphoma 
FU 
Follow-up 
HbA1c 
Glycated hemoglobin 
ID 
Identifier 
i.e. 
That is (id est) 
IgM 
Immunoglobulin M 
iNHL 
Indolent non-Hodgkin’s lymphoma 
kg 
Kilogram 
LKAD 
Last known alive date 
LPL 
Lymphoplasmacytic lymphoma 
MCL 
Mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter  
mmHg 
Millimeter of mercury 
MR 
Minor response 
MRI 
Magnetic resonance imaging 
MUGA 
Multiple gated acquisition 
MZL 
Marginal-zone lymphoma 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin’s lymphoma 
OEE 
Overall extent of exposure 
ORR 
Objective response rate 
OS 
Overall survival 
PBMQ 
Product specific Bayer MedDRA queries 
PD 
Progressive disease 
PET-CT 
Positron emission tomography-computed tomography 
PFS 
Progression-free survival 
PI3K 
Phosphatidylinositol-3-kinase 
PK 
Pharmacokinetic(s) 


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PR 
Partial response 
PT 
Preferred term 
R 
Rituximab  
R-B 
Rituximab and bendamustine 
R-CHOP 
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
RP3D 
Recommended phase III dose 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SD 
Stable disease 
SFU 
Safety follow-up 
SLL 
Small lymphocytic lymphoma 
SMQ 
Standardized MedDRA query 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
US 
United States (of America) 
VGPR 
Very Good Partial Response 
WM 
Waldenström macroglobulinemia 


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1. Introduction 
Rationale of the study  
The usual front-line treatment for indolent non-Hodgkin’s lymphoma (iNHL) consists of the 
anti-CD20-Monoclonal antibody rituximab (R) given together with an alkylating agent 
(bendamustine; R-B), or a chemotherapy combination containing an alkylating agent 
(cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone; R-CHOP]). While the 
R-B combination is preferred in the United States (US), R-CHOP remains the first option in 
the European Union. 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-B/R-CHOP) 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. 
For further information regarding the background and rationale of the study, refer to the study 
protocol and Phase III statistical analysis plan (SAP), version 4.0, 22SEP 2023. 
Protocol Version and Amendments 
This analysis plan is based on an integration of the following protocol versions and integrated 
global amendments: 
• Original protocol, Version 1.0, dated 23 JUN 2015 
• Amendment 01 forming integrated protocol Version 2.0, dated 01 SEP 2015 
• Amendment 02 forming integrated protocol Version 3.0, dated 18 JUL 2016  
• Amendment 03 forming integrated protocol Version 4.0, dated 30 MAR 2017  
• Amendment 05 forming integrated protocol Version 5.0, dated 14 AUG 2017  
• Amendment 06 forming integrated protocol Version 6.0, dated 25 SEP 2018  
• Amendment 08 forming integrated protocol Version 7.0, dated 14 AUG 2019  
• Amendment 09 forming integrated protocol Version 8.0, dated 21 MAR 2023 
and also on local amendments, not forming part of the integrated global protocol:  
• 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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2. Study Objectives 
The primary objective of the Safety run-in part 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 of the Safety run-in part are to evaluate:  
• 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.  
3. Study Design 
The study includes two parts. The Safety run-in part determined the RP3D of copanlisib, in 
combination with standard immunochemotherapy (R-B or R-CHOP), to be used in the 
subsequent Phase III part, treating 21 global patients (excluding Japan) and 6 patients from 
Japan. The Japan cohort was added to confirm that the RP3D of copanlisib in combination 
with R-B or R-CHOP is safe and tolerable in Japanese patients (Amendment 04, dated 11 
MAY 2017). 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 PFS in patients with relapsed, rituximab-sensitive iNHL. 
The study will accrue patients with follicular lymphoma (FL), marginal-zone lymphoma 
(MZL), small lymphocytic lymphoma (SLL), and lymphoplasmacytic lymphoma (LPL) / 
Waldenström macroglobulinemia (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 3–1. 
 


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Figure 3–1: 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.  
Screening period 
The start of the screening period is defined by signing of the informed consent form. After the 
screening period of up to 28 days with a minimum of 7 days, 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. 
Re-screening of patients who have failed screening will only be allowed once, following 
discussion with the sponsor’s designated medical representative and after approval by the 
sponsor. Re-screened patients must re-sign the informed consent form, even if it was not 
changed after the patient’s previous screening. 
Treatment period 
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 (Cycle 1- Cycle 6). Copanlisib/placebo (study drug) monotherapy will 
be administered from Cycle 7 onwards. Tumor assessments with the same modality will be 
performed every 12 weeks (± 7 days) from Cycle 1 Day 1.  
All patients will be treated until the occurrence of progressive disease (PD) (per central 
independent blinded radiology review) as defined by the Lugano Classification [1] (or Owen 
criteria for patients with LPL/WM [2]) or clinical progression (e.g., Eastern Cooperative 
Oncology Group [ECOG] performance status of ≥ 3), unacceptable toxicity occurs, until 
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).  


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An end-of -treatment (EOT) visit will be performed no later than 7 days after the decision is 
made to discontinue study treatment. 
Safety follow-up period 
All patients with the exception of those who died, withdrew consent or were lost to follow-up 
will have a Safety follow-up visit that will take place 30 days (a time window of +5 days is 
allowed) after the last administration of study treatment. 
Active follow-up period 
Only patients who complete 12 months of study treatment without PD or discontinue study 
drug for reasons other than PD will enter the Active follow-up period (which also serves as a 
Safety follow-up), except for patients who specifically object to entering the Active follow-up 
and patients who object to all further data collection after study drug discontinuation. Patients 
in the Active follow-up are to have tumor assessments by central independent blinded review 
as outlined in the protocol (every 12 weeks [± 7 days] from Cycle 1 Day 1 during Years 1 and 
2; every 24 weeks [± 7 days] during Years 3, 4, and 5; and every 24 weeks [± 14 days] 
beyond Year 5, until either PD is centrally evaluated and documented, up to 2 years after 
primary completion date, end of study or a new anti-tumor treatment is administered, 
whichever occurs first). 
Date of last visit 
A patient’s last visit date is defined as their last visit/contact prior to any Survival follow-up 
visits/contact.  
Survival follow-up period 
Except for patients who object to follow-up data collection in the Survival follow-up period, 
all patients are to be followed off-study for overall survival (OS) at 3-month (± 14 days) 
intervals, until death or until the end of study, whichever occurs first.  
End of Study 
The study will end when one of the following conditions is met: 
- final contact with the last remaining patient has occurred,  
- 10 years after the last patient started study treatment. 
Safety run-in part 
The Safety run-in part is 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 for safety and 
tolerability (first dose level of 45 mg and, second dose level of 60 mg). Assignment of R-B or 
R-CHOP will be made according to the following rules. 


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• Patients who received R-CHOP or Rituximab, cyclophosphamide, vincristine, and 
prednisone as a previous line of therapy will be assigned to the copanlisib + R-B 
treatment group 
• Patients who received R-B as a previous line of therapy will be assigned to the 
copanlisib + R-CHOP treatment group. 
The two dose levels will have a minimum of 3 and maximum of 6 patients evaluable for dose-
limiting toxicity (DLT). See Section 4 for the definition of a DLT. 
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 
The dose-finding steps are presented in Figure 3–2.  
Three patients will initially receive 45 mg of copanlisib. If 2 or more of the first 3 patients 
experience a DLT 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 a 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 a DLT at the 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 a DLT, 60 mg will be the recommended dose. If 2 or more out of 6 patients 
experience a 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 a DLT at this dose, then 45 mg will be the recommended dose. If 2 or more of 6 
patients experience a DLT at 45 mg, then the Safety run-in would be closed and the 
combination considered to be not feasible with the tested schedule. 
All patients in the Japan cohort were assigned to 60 mg of copanlisib, in order to confirm that 
the RP3D of copanlisib in combination with R-B or R-CHOP is safe and tolerable in Japanese 
patients (Protocol Amendment 04, dated 11 MAY 2017). Although planned in Protocol 
Amendment 04, all Japanese patients received the RP3D of copanlisib in combination with R-
B. 
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). 
 


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Figure 3–2: 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 (replacement criteria 
are detailed in Section 6.4.2 of the study protocol). Any patient who experiences a DLT 
should not receive further administration of copanlisib or any other study treatment. The 
investigator must notify the sponsor immediately of any Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 3 or 4 AEs or clinically relevant laboratory abnormalities.  
3.1 
Definition of dose-limiting toxicities 
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. National 
Cancer Institute (NCI)-CTCAE Version 4.03 will be used to assess toxicities/adverse events 
(AEs). The data monitoring committee (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: 


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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 (< 500/mm3) lasting >7 days 
• Grade 4 febrile neutropenia (ANC < 1000/mm3 with fever >38.5°C)  
• Grade 4 platelet count decreased (platelet count <25,000/mm3) or Grade 3 platelet 
count decreased (platelet count 25,000/mm3 to > 50,000/mm3) with serious bleeding 
• Signs of serious bleeding and/or international normalized ratio increased or partial 
thromboplastin time prolonged of Grade 3 (> 2.5 upper limit of normal) 
4. General statistical considerations 
4.1 
General principles 
The statistical evaluation will be performed using the Statistical Analysis System (SAS) 
software package release 9.2 or higher (SAS Institute Inc., Cary, NC, US). The version used 
in analyses will be presented in the clinical study report. All data will be listed and all 
variables will be summarized according to their type. Variables measured on metrical scales 
will be summarized by use of descriptive statistics (number of patients, mean, standard 
deviation, median, minimum and maximum). Variables measured on ordinal or nominal 
scales will be summarized by use of frequency tables showing the number and percentage of 
patients falling within a particular category.  
Definition of efficacy and safety endpoints, analysis strategies, structure of analysis datasets 
and layout of analysis data displays are following Bayer standards as documented in the Bayer 
standard system: Oncology Therapeutic Area Standards, Global Medical Standards and will 
comply with the Oncology Common Statistical Language document. The given ordering 
reflects the priority of the different standards, where specifications of the latter standards are 
to be followed only if not specified in the earlier standards. Study-specific specifications may 
be included in addition to the project standards, if needed. 
The Blind Review Report (BRR) may contain decisions which are relevant for statistical 
evaluation, for details see Section 4.8. 


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4.2 
Handling of Dropouts 
A patient who discontinues study participation prematurely (i.e., prior to disease progression 
confirmed by independent central review or death) for any reason is defined as a “dropout” if 
the patient has already been assigned to treatment (Safety run-in part), even if no study drug 
has been taken. 
Patients who discontinue during the first cycle due to reasons other than toxicity will be 
replaced in order to ensure that an adequate number of patients are evaluable for safety.  
A patient who signed the informed consent but for any reason terminated the study before 
treatment is assigned is regarded a “screening failure”. 
Patients who discontinue study drug due to reasons other than death, PD confirmed by 
independent central review, or biomedical progression in patients with LPL/WM without 
measurable lesion in the baseline radiological assessment, will enter the Active follow-up 
period and will not be defined as a “dropout”, except for those who specifically object to 
entering the Active follow-up or object to all further data collection after study drug 
discontinuation. The patients in the Active follow-up will have follow-up tumor assessments 
until disease progression is documented or new anti-tumor treatment is administered, 
whichever occurs first. 
4.3 
Handling of Missing Data 
In order to achieve a well conducted clinical trial in accordance with Good Clinical Practice, 
every effort will be made to collect all data. However, despite best efforts, it may be inevitable 
that missing or incomplete data are reported. If a patient indicates 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 patient for 
tumor assessment until patients develop radiological progression by independent central 
review, or biomedical progression in patients with LPL/WM without baseline lesions 
evaluable by imaging. Survival information including survival status, death date and/or 
contact date should be determined for all patients during the Survival follow-up. All missing 
or partial data will be presented in the patient data listing as they are recorded on the 
electronic Case Report Form. Unless specified, missing data will not be carried forward or 
otherwise imputed in any statistical analysis.  
Missing or non-evaluable tumor observations (including a scheduled assessment that was not 
done and an incomplete assessment that does not result in an unambiguous tumor response or 
detection of new lesions) will not be imputed or used in the calculation of derived efficacy 
variables related to tumor assessments, e.g., response. For example, if a patient misses a scan 
visit and PD is documented at the next available scan visit, the actual visit date of the first 
documented PD will be used to calculate PD-related endpoints. For complete definitions of 
efficacy parameters refer to Section 6.2  


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Partial dates may occur. To impute values, available data from other sources should be 
utilized. The last known alive date (LKAD) is derived from the main data sources and may be 
used in statistical analyses to impute death or tumor assessment dates which are partially or 
completely missing. Except for death, with a date of death on or prior to the data cut-off, data 
reported during cleaning, after the data cut-off date, will not be considered in the derivation of 
LKAD. For such cases the data cut-off date will be used as the LKAD. The last available date 
across all key data panels (laboratory [LB], tumor response [RS], demography [DM], subject 
visits [SV], exposure [EX], disposition [DS], procedures [XP], bone marrow assessments 
[BM], ECG assessments [EG], microbiology [MB], pharmacokinetics [PC], tumor lesion 
measurements [TR] and tumor/lesion identification[TU]) will be used to determine survival 
status and the LKAD for each patient.. If the day of the LKAD is missing, then the earliest 
plausible day of the month should be imputed. If both the day and month of the LKAD are 
missing, then the earliest plausible day of the year should be imputed. 
When appropriate, the following rules will be implemented to avoid excluding patients from 
statistical analyses due to missing or incomplete data: 
Date of death 
If a death date is partially or completely missing, it will be imputed following the 
imputation rules below: 
1. If there is an AE with “Fatal” outcome, the date of death will be imputed by the 
stop date of the AE. 
2. If there is no AE with outcome “Fatal” and only the day of death is missing, it will 
be imputed by the first day of the month unless the LKAD is later than this date; in 
which case the LKAD will be used for imputation. If both day and month and/or 
year are missing, then the LKAD will be used for imputation. 
Date of tumor scan  
If a tumor assessment date is partially missing, it will be imputed following the imputation 
rules below: 
1. If only the day is missing, it will be imputed by the first day of the month. 
2. If day and month are missing, it will be imputed by the date of the last previous 
tumor assessment plus 28 days unless the LKAD is earlier than this date; in which 
case the LKAD will be used for imputation1. 
Response rates 
If a patient has no post-baseline tumor assessment available (or no post-baseline 
laboratory/clinical tests available for LPL/WM patients without radiologically measurable 
lesion[s]), i.e., the overall best response assessment is missing, the patient will be non-
                                                 
1 All tumor assessments, with complete and partial dates, will be ordered sequentially by visit number. If both 
day and month are missing from the final tumor assessment and the penultimate tumor assessment is the patients 
LKAD then the date of the penultimate assessment plus 28 days will be imputed for the final tumor assessment. 


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evaluable, but will be included into denominator for calculation of objective response rate 
(ORR), disease control rate (DCR) and complete response rate (CRR). 
Missing or partially missing start or end dates for AEs and concomitant medications will be 
imputed based on the conventions described in Appendix 9. The purpose of the imputation for 
AEs is to determine whether the event is treatment-emergent, as defined in Section 6.3.1. 
Similarly, the purpose of the imputation for concomitant medications is to determine if the 
medication was given concomitantly with study drug and, in the case of new anti-lymphoma 
therapies, to avoid excluding patients with partial anti-lymphoma therapy start dates from 
statistical analyses due to missing or incomplete data. 
4.4 
Handling of investigator assessments when PD is not confirmed by 
independent central review 
The analysis of efficacy, based on investigator assessments, will exclude response 
assessments collected after the first investigator reported PD, regardless of whether or not the 
PD was confirmed by independent central review. 
4.5 
Handling of clinical laboratory values with qualifiers 
Clinical laboratory values which have qualifiers (for example, > or <) will be included in 
clinical safety analyses and summaries with the qualifier removed. 
4.6 
Interim Analyses and Data Monitoring 
No interim analysis is planned for this study. 
When the required number of events are reached for the Phase III primary completion 
analysis, the combined database of Safety run-in and Phase III patients will be cut and cleaned 
for analysis. This will take place when approximately 280 centrally evaluated PFS events are 
observed in Phase III. 
A DMC was established for an independent review of ongoing data from this trial in 
accordance with a separate DMC Charter. The DMC operated independently of the sponsor 
and investigators. 
4.7 
Data Rules 
4.7.1 
Time intervals 
If time intervals are to be displayed other than days in statistical evaluations, then one year is 
considered to have 365.25 days (average length of a year, including leap years), one month is 
considered to have 30.44 days (average length of a month, including leap years), one week is 
considered to have 7 days, and one cycle is considered to have 28 days (i.e., 4 weeks). All 
time conversions from days will be displayed to 1 decimal place. 


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4.7.2 
Baseline 
Baseline is defined as the last measurements performed prior to the first study drug 
administration in Cycle 1. If the actual time is not available but date is available for certain 
measurements, the baseline value is defined as the last non-missing value collected on or 
before the date of the first dose of study treatment. For patients who have been assigned 
treatment but not treated with any dose, treatment assignment date will be used as the 
reference date for baseline value calculation. 
Also consider: 
• The time part for baseline flagging. Study data tabulation model/analysis data model 
datasets for exposure and laboratory data both capture times. If the time in either one 
is missing, use the dates in that case. 
• Baseline can be either a scheduled or unscheduled visit. 
• If the patient has a measurement on Cycle 1 Day 1 (scheduled), then this measurement 
will be considered as the baseline. 
• If the patient has no measurements on Cycle 1 Day 1, but has a measurement at 
screening visit (scheduled or unscheduled), then the screening visit measurement will 
be considered as the baseline. 
• If multiple measurements were taken at the same Cycle 1 Day 1 visit or same 
screening visit and all with non-missing assessment dates, then the measurement with 
the latest assessment date/time will be considered as baseline, whether scheduled or 
unscheduled. 
• If both scheduled and unscheduled measurements exist for the same visit and cannot 
be decided by the above rules, then the measurement taken at scheduled visit will be 
considered as the baseline. 
4.7.3 
Repeated measures 
If there are repeated measurements per time point [e.g., laboratory values, vital signs, 
electrocardiogram (ECG)], the following rules will be used (unless otherwise specified): 
• Before the start of the study drug administration (i.e., for screening and baseline 
value), the latest non-missing measurement at scheduled visits will be used. 
Unscheduled visits will be used if there are no measurements at scheduled visits. If the 
latter is the case, the last unscheduled visit will be used. 
• In case of repeated measurements at any post baseline time point, the first 
measurement at scheduled visits will be used. 
• When two records have the same patient identifier (ID), results, date, time and 
visit/cycle number, with the exception of page number or record ID, the two records 


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will be considered duplicates and only one record will appear in the corresponding 
analysis dataset. 
4.7.4 
Overall extent of exposure 
As a general rule, and in accordance with the Oncology Therapeutic Area Standard, leading 
“0 mg” (prior to the first positive amount of drug) and trailing “0 mg” records (not followed 
by any positive amount of drug), will not be included in the calculation of any drug duration 
or amount. Similarly, trailing “drug interruptions” will not be used in statistical tables. A 
footnote will be included, stating that “Interruption becoming permanent study treatment 
discontinuation before resumption of study treatment is not counted as an interruption”. 
Overall extent of exposure (OEE) for copanlisib, is defined as the time from first respective 
study drug intake (dayfirst) until last study drug intake (daylast), including 7 additional days in 
order to consider the weekly dosing regimen, and is calculated as: 
OEE = daylast - dayfirst + 7 
OEE for R-CHOP, is defined as the time from first respective study drug intake (dayfirst) until 
last study drug intake (daylast), including 21 additional days to consider the every 3 weeks 
(Q3W) dosing regimen and prednisone/prednisolone dosing up to Day 6, and is calculated as: 
OEE = daylast - dayfirst + 21 – [day(last) – day(first) of last cycle of R-CHOP]  
OEE for R-B, is defined as the time from first respective study drug intake (dayfirst) until last 
study drug intake (daylast), including 28 additional days to consider the Q4W dosing regimen 
and Bendamustine dosing up to Day 2, and is calculated as: 
OEE = daylast - dayfirst +28 – [day(last) – day(first) of last cycle of R-B] 
If the respective treatment ends with dose interruptions, the day of the last actual dose will be 
considered to be daylast. 
4.8 Validity Review 
During study conduct, important protocol deviations and major findings affecting the 
assignment of patients to analysis sets will be identified through ongoing data reviews based 
on the Safety run-in protocol deviation document. A Blind Review Meeting (BRM) will be 
scheduled, just prior to unblinding of Phase III and data release, in which the study team will 
review and finalize the list of minor/major and important/other deviations. Patient validity 
(based on the presence or absence of major deviations) and details relevant to the statistical 
evaluation will be discussed and agreed upon during the BRM and documented in the Blind 
Review Report (BRR). Important deviations and major findings which may affect the 
assignment of patients to analysis sets, data integrity or patient safety will be listed in the 
BRR. Any changes to the statistical analysis prompted by the results of the BRM will be 
documented in an amendment and, if applicable, in a supplement to this SAP. 


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5. Analysis Sets 
The following analysis sets will be used in the 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: All patients in the Safety run-in part with at least one valid PK 
measurement (i.e., patients who took at least one dose of study drug and had at least one PK 
sample collected and measured) will be included in the evaluation of PK concentration and 
parameters. 
6. Statistical Methodology 
6.1 
Population Characteristics 
Analyses will be performed on the SAF. Population characteristics will be summarized for 
global patients by background therapy (R-B vs R-CHOP) and dose levels of copanlisib (45mg 
and 60mg). As all patients in the Japan cohort received 60 mg of copanlisib in combination 
with R-B, the summaries of R-B background therapy will include a standalone summary for 
the Japan 60 mg cohort. A requirement of the SAS macro, used to create summaries by 
background therapy, is that the layout of the treatment groups, Copa 45mg, Copa 60 mg and 
Japan (Copa 60 mg), is the same for both background therapies. As a consequence, R-CHOP 
background therapy summaries will display the Japan (Copa 60 mg) treatment cohort with 
zero patients.  
The summaries will not include overall totals as the Phase III part will provide a 
comprehensive review of safety. 
6.1.1 
Disposition 
Sample sizes by background therapy and country/region will be presented and will include the 
number of centers enrolling patients per country/region. The number of patients enrolled, 
assigned to treatment, and valid for the different analysis sets FAS and SAF will be 
summarized by dose level, and country/region. 
The number of screening failures (patients discontinuing the screening period) together with 
primary reasons for discontinuation will be presented overall. The number of patients assigned 
to treatment, in addition to the number of patients discontinuing the treatment, Safety follow-
up, Active follow-up and Survival follow-up periods together with the primary reason for 
discontinuation will be presented by background therapy and dose level/Japan cohort. 
In addition, the number of patients assigned to treatment with important protocol deviations 
will be presented by background therapy and by country/region for each dose level. The 


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frequency of major deviations and number of patients valid for each analysis set will be 
presented by background therapy and dose level/Japan cohort. 
A separate patient listing of protocol deviations related to COVID-19 pandemic (e.g., delay of 
tumor assessments, delay, interruption or discontinuation of the treatment due to the impact of 
COVID-19 pandemic) will be provided by background therapy. These protocol deviations 
will be entered in RAVE as Manual protocol deviations and identified from the specification 
of “COVID”.  
Similarly, if any Safety run-in patients are affected by the Ukraine-Russia conflict, a separate 
patient listing of protocol deviations related to the Ukraine-Russia conflict (e.g., delay of 
tumor assessments, delay, interruption or discontinuation of the treatment due to the impact of 
the conflict) will be provided. These protocol deviations will be entered in RAVE as Manual 
protocol deviations and identified from the specification of “Regional Crisis”.  
6.1.2 
Demographic and other baseline characteristics  
The following demographics and baseline characteristics will be summarized by background 
therapy (R-B vs R-CHOP) and dose level/Japan cohort: age, sex, ethnicity, race, weight, 
height, body mass index (BMI), systolic and diastolic blood pressure, heart rate, temperature, 
New York Heart Association classification, estimated Glomerular Filtration Rate (eGFR), 
glycated hemoglobin (HbA1c), medical history of diabetes and medical history of 
hypertension. Age, BMI, eGFR and HbA1c will be analyzed as continuous variables and in 
addition categorized with the following categories: 
• Age group 1 (years): <65, ≥65 
• Age group 2 (years): <80, ≥80 
• Age group 3 (years): <65, 65-74, 75-84, ≥85 
• BMI group (kg/m²): <18.5, ≥18.5- <30, ≥30 
• eGFR group (mL/min/1.73 m2): Normal: ≥90 vs. Mild impairment: 60 - <90 vs. 
Moderate impairment: 30- <60 vs. Severe impairment: 15 - <30) 
• HbA1c group: <5.7% vs ≥5.7% – <6.5% vs ≥6.5% – ≤8.5% vs >8.5% 
Medical history of diabetes and hypertension, identified by Product specific Bayer MedDRA 
Queries (PBMQ), will be summarized as follows: 
• Diabetic History: [PBMQ] Medical history of diabetes (no/yes) 
• Hypertension History: [PBMQ] Medical history of hypertension (no/yes) 


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The following additional baseline characteristics will be summarized: 
• Histology of tumor per investigator’s assessment (FL, MZL, SLL, and LPL/WM) 
• Staging and size (sum of products of diameters) of tumor at study entry 
• FL grade (for patients with FL) at study entry 
• ECOG performance status at baseline 
• Time from date of initial diagnosis to the date of first study treatment (months) 
• Time from most recent progression to the date of first study treatment (weeks) 
• Time from first progression to the date of first study treatment (months) 
• Number of lesions (number of target and number of non-target lesions) at baseline 
• Serum Immunoglobulin M (IgM) level (for LPL/WM patients) at baseline 
The retrospective evaluation of histopathological diagnosis at baseline will be performed 
centrally. These data are exploratory and will be listed for the Clinical Study Report appendix. 
Quantitative data will be summarized by arithmetic mean, standard deviation, median, 
minimum and maximum. Frequency tables will be provided for qualitative data. 
6.1.3 
Medical history 
Medical history findings (as defined in protocol Section 9.3.2) will be coded by Medical 
Dictionary for Regulatory Activities (MedDRA) codes. Medical history will be presented for 
each MedDRA Primary System Organ Class (SOC) and Preferred Term (PT) by background 
therapy (R-B vs R-CHOP) and dose level/Japan cohort. Ongoing conditions will be presented 
in a similar way. 
6.1.4 
 Prior and concomitant medication 
Prior and concomitant medications will be coded by the Anatomical Therapeutic Chemical 
(ATC) classification system according to the World Health Organization Drug Dictionary. 
Summaries will be provided by ATC class and subclass. The number of patients taking at 
least one prior medication will be reported in addition to the number of patients who have 
taken medication relating to each relevant ATC class and subclass. The same will be reported 
for concomitant medications. Note that the same medication can appear multiple times in the 
table as it can have several ATC codes. 
A medication that has been stopped after first administration of study treatment is considered 
as concomitant, while those that have been stopped before first administration are considered 
as prior. Medications with missing start and stop date but flagged as being ongoing at end of 
study will be considered to have started prior to start of study treatment and ended after stop 


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of study treatment. Medications starting more than 30 days after the last day of study 
treatment will be excluded from the summary of concomitant medications.  
Prior and concurrent anti-cancer therapy 
The mean, minimum, median, standard deviation and maximum number of prior systemic 
anti-cancer therapy lines as well as number of patients with 1, 2, ≥3 lines of prior therapy will 
be summarized by background therapy (R-B vs R-CHOP) and dose level/Japan cohort for 
SAF. Time since last systemic anti-cancer therapy2 will be summarized using descriptive 
statistics by background therapy (R-B vs R-CHOP) and dose level/Japan cohort for SAF. The 
time between the last day of the last course of systemic anti-cancer therapy and the day of 
confirmation of the most recent progression will also be displayed as a classification table, 
showing proportions of patients with ≤ 6 months vs. > 6 to <12 months vs. ≥ 12 months, by 
background therapy (R-B vs R-CHOP) and dose level/Japan cohort.  
In addition, the following frequency tables will be provided by background therapy (R-B vs 
R-CHOP) and dose level/Japan cohort for the SAF: 
• Prior radiotherapies 
• Prior systemic anti-cancer therapies (displayed by 1. ATC classes, 2. drug names)  
• Type of prior systemic anti-cancer therapy 
• Prior treatment with PI3K inhibitors (refer to the Tables, Listings and Figures (TLF) 
specification document for details of how prior PI3K inhibitors are identified).  
• Prior diagnostic and/or therapeutic procedures 
• Concurrent diagnostic and/or therapeutic procedures  
• Radiotherapies during Survival follow-up 
• Systemic anti-cancer therapies during Survival follow-up (displayed by 1. ATC 
classes, 2. Drug names)  
• Type of systemic anti-cancer therapy during Survival follow-up 
6.1.5 
Treatment duration and exposure 
Investigator-recorded cycles for study drug exposure will be mapped to a calculated cycle. 
The analysis of treatment duration and exposure will use the mapped, calculated cycle. A 
description of how investigator defined cycles are mapped to analysis cycles can be found in 
the study document “Analysis Data Reviewer’s Guide”. 
                                                 
2 Time between last day of last systemic anti-cancer therapy and date of first treatment. 


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Descriptive statistical summaries will be provided separately for copanlisib, R-B and R-
CHOP by background therapy (R-B vs R-CHOP) and dose level/Japan cohort for the 
following variables:  
• Overall extent of exposure (OEE, as defined in section 4.7.4) for FL, MZL, SLL, 
LPL/WM and all SAF patients 
• Overall extent of exposure for FL, MZL, SLL, LPL/WM and all SAF patients, by 
categories: 
o 0-90 days 
o 91-180 days 
o 181-270 days 
o 271-365 days 
o >365 days  
• Number of cycles for FL, MZL, SLL, LPL/WM and all SAF patients (statistical 
summaries in addition to number of patients with each number of cycles) 
o For copanlisib: OEE divided by 28 days 
o For R-B: OEE divided by 28 days. 
o For R-CHOP: OEE divided by 21 days 
• Number of infusions during treatment period for FL, MZL, SLL, LPL/WM and all 
SAF patients. For R-CHOP, the number of infusions will be based on rituximab, 
cyclophosphamide, doxorubicin, and vincristine infusions as prednisone is taken 
orally. 
In addition, the following analyses will be provided for the SAF, by background therapy (R-B 
vs R-CHOP) and dose level/Japan cohort, over all cycles and by calculated cycle: 
• Total amount of dose actually administered: sum of actual dose (mg) per calculated 
cycle for each patient 
o For copanlisib, prednisone/prednisolone, the actual dose per timepoint is 
defined as  
Prescribed dose [mg] × (Total amount of dose administered [mg OR mL] / 
Total amount of dose prior to administration [mg OR mL])  
o For rituximab, cyclophosphamide, doxorubicin, vincristine and bendamustine, 
the actual dose per timepoint is defined as  


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Prescribed dose [mg] / Body surface Area (BSA) [m2] × (Total amount of dose 
administered [mL] / Total amount of dose prior to administration [mL]) 
• Percent of planned dose received = Actual dose [mg] / Planned dose [mg] × 100%. 
o For copanlisib, a standard dose of either 45mg or 60 mg is set for all cycles, 
i.e., infusion days (Day 1, Day 8 and Day 15 of each cycle), and for planned 
dose (might however be modified by individual dose interruptions). Completed 
cycles therefore have a planned dose of either 135 mg or 180 mg. For 
incomplete cycles, the planned dose depends on the number of days (d) in that 
calculated cycle: 
▪ 45 mg at dose level 1 or 60 mg at dose level 2 if 0< d <7 
▪ 90 mg at dose level 1 or 120 mg at dose level 2 if 7≤ d <14 
▪ 135 mg at dose level 1 or 180 mg at dose level 2 if 14≤ d ≤28 
o For rituximab, a standard of 375 mg/m² body surface is set for all cycles for 
planned dose. 
o For cyclophosphamide, a standard of 750 mg/m² body surface is set for all 
cycles for planned dose. 
o For doxorubicin, a standard of 50 mg/m² body surface is set for all cycles for 
planned dose. 
o For vincristine, a standard of 1.4 mg/m² body surface is set for all cycles for 
planned dose and a maximum of 2.0 mg/m² is also previewed. 
o For bendamustine, a standard of 90 mg/m² body surface is set for all cycles for 
planned dose (might however be modified by individual dose-reductions or 
interruptions), i.e., infusion days (Day 1 and Day 2 of each cycle). For 
incomplete cycles, the planned dose depends on the number of days (d) in that 
calculated cycle: 
▪ 90 [mg/ m2] ×BSA [m2] if 0< d <2 
▪ 90 [mg/ m2] ×BSA [m2] ×2 if 2≤ d ≤28 
o For prednisone/prednisolone, a standard of 100 mg is set for all cycles, i.e., 
orally (PO) days (Day 2 to Day 6 of each cycle), and for planned dose (might 
however be modified by individual dose-reductions or interruptions). 
Completed cycles therefore have a planned dose of 500 mg. For incomplete 


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cycles, the planned dose depends on the number of days (d) in that calculated 
cycle: 
▪ 0 mg if 0< d <2 
▪ 100 mg if 2≤ d <7 and increase 100 mg per day 
▪ 500 mg if 7≤ d ≤21 
For patients with dose reduction3, interruption or delay, the number of dose reductions, 
interruptions (dose administered is non-zero), or delays (zero dose is administered) per patient 
and their reasons will be summarized separately for copanlisib, rituximab4, 
cyclophosphamide, doxorubicin, vincristine, prednisone/ prednisolone and bendamustine, by 
background therapy (R-B vs R-CHOP) and dose level/Japan cohort in the SAF. Interruptions 
with the same start date will be counted as one interruption. 
The duration of dose delays in days will be summarized for copanlisib by background therapy 
(R-B vs R-CHOP) and dose level/Japan cohort in the SAF. The duration is defined as the 
difference between the date of delay and the date of next exposure information (infusion, 
interruption or delay). Due to the treatment regimen with one week break at the end of each 
cycle, delays on day 15 of R-CHOP combination therapy, or on day 22 of R-B combination 
therapy, are capped at 7 days, in case the calculated duration is greater than 7.  
Patient listings will be provided for dose modifications. 
6.2 
Efficacy  
The analysis of efficacy will be summarized with descriptive statistics for the FAS, by 
background therapy and dose level/Japan cohort. Summaries of tumor response by 
independent central review and investigator’s assessment will be provided. 
Tumor response 
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 
optional imaging modality. Scans will be performed at Screening, during Treatment as well as 
during the Active follow-up period (every 12 weeks [± 7 days] from Cycle 1 Day 1 during 
Years 1 and 2; every 24 weeks [± 7 days] during Years 3, 4, and 5; and every 24 weeks [± 14 
days] beyond Year 5). Response assessment will be based on the Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: 
The Lugano Classification and for patients with LPL/WM according to the Owen Criteria 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 
                                                 
3 Per the clinical study protocol (CSP), there will be no dose reductions of copanlisib, CHOP or bendamustine 
during the first cycle of study treatment. 
4 Per the CSP, there will be no dose reductions for rituximab in any cycle. 


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before a final decision is made by the investigator. Evaluations from independent central 
blinded review will also be used for response endpoints containing radiological tumor 
assessments.  
LPL/WM patients who do not have radiologically measurable lesions 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 central review and PD confirmation. 
LPL/WM patients who have radiologically measurable lesions at Screening will continue to 
have radiological assessments and, in addition, will have laboratory tests performed on the 
same days. 
Bone marrow biopsy will be mandatory at Screening. If the baseline biopsy is positive for 
lymphoma infiltration, it will be mandatory to perform it again to confirm the first complete 
response (CR). 
The CT-based response status consists of complete response (CR), unconfirmed CR, partial 
response (PR), stable disease (SD), and progressive disease (PD). The PET-CT response 
status consists of complete metabolic response (CMR), partial metabolic response, no 
metabolic response, equivalent with stable disease, and progressive metabolic disease, 
equivalent with progressive disease. 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. 
The response status for LPL/WM patients being assessed according to the Owen Criteria 
consists of CR, Very Good Partial Response (VGPR), PR, Minor Response (MR), SD, and 
PD.  
Definition of exploratory efficacy variables 
Objective response rate (ORR) 
Assessed in all patients, ORR is defined as the proportion of patients who have a best 
response rating, while on treatment or in Active follow-up (i.e., until the time of the Phase III 
primary completion analysis), of complete response (CR) or partial response (PR) according 
to the Lugano Classification and for patients with LPL/WM a response rating of CR, VGPR, 
PR, or MR according to the Owen Criteria. As initiation of new anti-tumor therapy ends the 
Active follow-up, any tumor assessments taking place after the initiation of new anti-cancer 
therapy will not be included in the calculation of ORR. 
Disease control rate (DCR) 
DCR is defined as the proportion of patients who have a BOR of CR, unconfirmed CR, 
VGPR, PR, unconfirmed PR, MR, or confirmed stable disease (SD). Unconfirmed SD is 


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defined as SD on or before Study Day 76, which is not confirmed by an additional tumor 
assessment of SD, or better, on Study Day 77 or later.Complete response rate (CRR)  
Assessed in all patients, CRR is defined as the proportion of patients who have a best response 
rating of CR while on treatment or in Active follow-up (i.e., until the time of the Phase III 
primary completion analysis) according to Lugano classification and for patients with 
LPL/WM, a response rating of CR according to the Owen criteria.  
Overall survival (OS)  
OS is defined as the time (in days) from start of study treatment until death from any cause. 
OS of patients alive at the time of the Phase III primary completion analysis will be censored 
at the last date they were known to be alive (last known alive date; LKAD). Death after the 
data cut-off, reported during data cleaning, will be considered for establishing LKAD at data 
cut-off.  
See Section 4.3 for details regarding derivation of LKAD and imputation methods for 
partial/missing death dates. 
Frequency tables of best overall response (BOR), ORR, DCR and CRR by background 
therapy (R-B vs R-CHOP) and dose level/Japan cohort will be presented. 
Due to the small number of patients a descriptive summary of survival will be provided by 
dose level/Japan cohort, for each background therapy and overall. It will include the number 
of patients with an event (death), number of patients censored, median OS, OS interquartile 
range and OS range with and without censored values. Survival rates, and corresponding 
confidence intervals, at 6 monthly time intervals from start of study treatment will also be 
provided. There will be no inferential analysis of OS treatment differences. 
In addition the following patient listing of exploratory efficacy variables will be provided by 
background therapy (R-B vs R-CHOP) and dose level/Japan cohort: patient ID, histology, 
start and stop dates of study treatment, BOR, first response date, time from start of study 
treatment to PD or death from any cause, PFS, date of death, primary cause of death and OS. 
6.3 
Safety 
Analyses will be performed on the SAF by background therapy (R-B vs R-CHOP) and dose 
level/Japan cohort. 
6.3.1 
Adverse Events 
Adverse events (AEs) will be coded according to MedDRA Version 25.1 or later and using 
NCI-CTCAE Version 4.03 (or higher) dictionary. The final versions used will be stored in the 
clinical database and provided in a footnote to the respective tables. Severity of AEs and 
hematological/biochemical toxicities based on laboratory measurements will be graded using 
NCI-CTCAE dictionary. AEs will be classified as related or not related to study drug, as 
determined by the investigator. 


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A treatment-emergent AE (TEAE) is defined as any event occurring or worsening after start 
of study drug administration until 30 days after the last study drug intake.  
Descriptive summary tables (frequency and percentage of patients, not of events) will be 
presented by background therapy (R-B vs R-CHOP) and dose level/Japan cohort, by 
MedDRA SOC/PT and by worst NCI CTCAE grade for the following: 
• Overview of TEAEs 
• TEAEs 
• Drug-related TEAEs (copanlisib or R-B/R-CHOP) 
• Treatment-emergent serious AEs (TESAEs) 
• Drug-related TESAEs 
• DLTs (see Section 3.1 for the definition of DLTs) 
• TEAEs leading to drug interruption 
• TEAEs leading to dose reduction 
• TEAEs leading to permanent treatment discontinuation 
As relationship to study drug is assessed separately for copanlisib, R-B, R-CHOP, drug-
related adverse events will be summarized separately for each study treatment. Deaths 
(including all grade 5 TEAEs) will be summarized by background therapy (R-B vs R-CHOP) 
and dose level/Japan cohort. As “AE” is not captured as a primary cause of death in the 
Survival follow-up, for the overall summary of deaths, deaths with “AE” or “other” as the 
primary cause will be pooled together under the primary cause “other”. 
AEs occurring prior to starting treatment and AEs occurring at least 30 days after the last dose 
of study treatment (i.e., post-treatment AEs) will also be summarized by background therapy 
(R-B vs R-CHOP) and dose level/Japan cohort. 
The categories of TEAEs, Treatment-emergent copanlisib-related AEs, and TESAEs will be 
presented according to time-of-onset (new onset or worsening).  


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The following categories will be presented: 
• Day 1 – Day 90: to include all copanlisib-treated patients 
• Day 91 – Day 180: to include all copanlisib-treated patients treated for at least 3 
months 
• Day 181 – Day 270: to include all copanlisib-treated patients treated for at least 6 
months 
• Day 271 – Day 360: to include all copanlisib-treated patients treated for at least 9 
months 
• Day 361 or greater: to include all copanlisib-treated patients treated for at least 12 
months  
In addition, patient listings will be provided by background therapy (R-B vs R-CHOP) and 
dose level/Japan cohort, for the following AEs: 
• Patients who died during study treatment up to 30 days after last dose of study 
treatment: patient ID, sex, age, race, histology, sponsor AE identifier, start and stop 
dates of study treatment, date of death, days within first and last dose date, cause of 
death, MedDRA SOC and PT and relationship to study drug (related to copanlisib, 
related to R-B/R-CHOP, related to both, and no). 
• Patients who died later than 30 days after last dose of study treatment: patient ID, sex, 
age, race, histology, sponsor AE identifier, start and stop dates of study treatment, date 
of death, days within first and last dose date, cause of death, MedDRA SOC and PT, 
and relationship to study drug (related to copanlisib, related to R-B/R-CHOP, related 
to both, and no). 
• Treatment-emergent SAEs: patient ID, sex, age, histology, race, sponsor AE identifier, 
MedDRA SOC and PT, CTCAE toxicity grade, start and stop dates of study treatment, 
reason for seriousness, start and stop date of AE, relationship to study drug (related to 
copanlisib, related to R-B/R-CHOP, related to both, and no), protocol required 
procedure related (yes/no), outcome, actions taken with each study drug. 
• Listing of study treatment-related SAEs will be provided separately for each 
copanlisib dose level, the Japan cohort (all patients in this cohort received 60 mg of 
copanlisib), R-B (excluding the Japan cohort), R-B (Japan cohort only) and R-CHOP, 
with similar information. 
• TEAEs leading to permanent discontinuation of study treatment, a dose reduction 
(only after cycle 1) or interruption will be listed separately for each copanlisib dose 
level, the Japan cohort (all patients in this cohort received 60 mg of copanlisib), R-B 
(excluding the Japan cohort), R-B (Japan cohort only) and R-CHOP: patient ID, sex, 
age, histology, race, sponsor AE identifier, MedDRA SOC and PT, CTCAE toxicity 
grade, start and stop dates of study treatment, start and stop dates of AE, relationship 
to study drug (related to copanlisib, related to R-B/R-CHOP, related to both, and no), 


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protocol required procedure related (yes/no), serious (yes/no), reason for seriousness, 
outcome, actions taken with each study drug. 
• DLTs: patient ID, sex, age, histology, race, sponsor AE identifier, MedDRA SOC and 
PT, CTCAE toxicity grade, start and stop dates of study treatment, reason for 
seriousness, start and stop date of AE, relationship to study drug (related to copanlisib, 
related to R-B/R-CHOP, related to both, and no), serious (yes/no), reason for 
seriousness, protocol required procedure related (yes/no), outcome, actions taken with 
each study drug. 
• TEAEs of pneumonitis (The standardized MedDRA query (SMQ); 'Interstitial lung 
disease' with narrow search (i.e., category 2A) will be used to select these AEs): 
patient ID, sex, age, race, histology, sponsor AE identifier, MedDRA SOC and PT, 
CTCAE toxicity grade, start and stop dates of study treatment, serious (yes/no), reason 
for seriousness, start and stop date of AE, relationship to study treatment (related to 
copanlisib, related to R-B/R-CHOP, related to both, and no), protocol required 
procedure related (yes/no), serious (yes/no), reason for seriousness, outcome, actions 
taken with each study drug. 
• TEAEs of hyperglycemia (Bayer MedDRA labeling grouping; 'Hyperglycemia' will be 
used to select these AEs): patient ID, sex, age, race, histology, sponsor AE identifier, 
MedDRA SOC and PT, CTCAE toxicity grade, start and stop dates of study treatment, 
serious (yes/no), reason for seriousness, start and stop date of AE, relationship to study 
treatment (related to copanlisib, related to R-B/R-CHOP, related to both, and no), 
protocol required procedure related (yes/no), serious (yes/no), reason for seriousness, 
outcome, actions taken with each study drug 
• TEAEs of arterial hypertension (Bayer MedDRA labeling grouping; 'Hypertension' 
will be used to select these AEs): patient ID, sex, age, race, histology, sponsor AE 
identifier, MedDRA SOC and PT, CTCAE toxicity grade, start and stop dates of study 
treatment, serious (yes/no), reason for seriousness, start and stop date of AE, 
relationship to study treatment (related to copanlisib, related to R-B/R-CHOP, related 
to both, and no), protocol required procedure related (yes/no), serious (yes/no), reason 
for seriousness, outcome, actions taken with each study drug 
COVID-19 pandemic-relevant adverse events 
The COVID-19 pandemic-relevant AEs will be identified using the SMQ “Covid-19” with a 
broad search. A patient listing of these AEs will be provided. The serious AEs and those 
leading to treatment discontinuation and/or deaths will be flagged in the listing. 
6.3.2 
Safety Parameters 
Quantitative data [hematology, blood chemistry, coagulation, urinalysis, vital signs ECG and 
multiple gated acquisition (MUGA)] will summarized by background therapy and dose 
level/Japan cohort and will be described by the following summary statistics: arithmetic mean, 
standard deviation, median, minimum and maximum. These summary statistics will be 
presented at each post-baseline visit for the original data as well as for the change from 
baseline. Frequency tables will be provided for qualitative data.  


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Data from unscheduled visits will not be included in summary analyses over time (by time 
point), ; unless they are the last measurement prior to first study drug intake, but will be 
included in other analyses not summarized by time point, such as shift tables, incidence of 
abnormalities, etc. When summarizing worst-case or best-case data, data from unscheduled 
visits will be considered. Unscheduled laboratory assessments will be included in the patient 
listings of clinical laboratory parameters. 
Changes in worst grade of laboratory toxicities at last pre-treatment value compared to worst 
grade post-baseline value and changes in worst grade of laboratory toxicities under treatment 
will be provided by background therapy and dose level/Japan cohort. For the change in worst 
grade of laboratory toxicities under treatment, observations up until the last on treatment visit 
will be considered. In case there is more than one observation for the same timepoint, the 
worst grade will be taken. In addition, treatment-emergent abnormal laboratory values (above 
and below the normal range) will be summarized by background therapy, dose level/Japan 
cohort and timepoint. For the summary of high treatment-emergent laboratory abnormalities, 
the denominator represents the number of distinct patients at baseline with a normal or lower 
than normal laboratory assessment who also had at least one valid laboratory value (including 
unscheduled visits) after start of study treatment but ≤ 30 days after end of study treatment. 
Patients with missing or high abnormal values at baseline are not included in the denominator. 
The numerator represents the number of distinct patients with at least one high laboratory 
assessment (including unscheduled visits) after the start of treatment who had a normal or 
lower than normal laboratory assessment at baseline. A similar approach is used for low 
treatment-emergent abnormalities except that patients with missing or low abnormal values at 
baseline are not included in the denominator. Urinalysis data will be summarized by 
frequency tables.  
ECOG performance status values and change from baseline values will be summarized by 
background therapy, dose level/Japan cohort and visit as well as to the end of treatment. 
Results of the 12-lead ECGs, including change from baseline, will be summarized with 
descriptive statistics by background therapy, dose level/Japan cohort, visit and timepoint. The 
overall interpretation of the 12-lead ECG and the ECG diagnosis will also be summarized by 
background therapy, dose level/Japan cohort and visit. Frequency and shift tables for the 
number of patients by interpretation of ECG as normal or abnormal will be performed by 
background therapy, dose level/Japan cohort at all visits and analysis time points. A listing of 
clinically significant abnormal 12-lead ECG findings will be provided. 
Results of MUGA/echocardiogram will be summarized with descriptive statistics by 
background therapy, dose level/Japan cohort and visit, including change from baseline where 
appropriate. 
The overall interpretation of the echocardiogram and the corresponding diagnosis will be 
summarized by background therapy, dose level/Japan cohort and visit. 
Frequency and shift tables for number of patients by interpretation of echocardiogram as 
normal, abnormal clinically significant (CS) or abnormal not CS will be performed at all 
visits. A listing of clinically significant abnormal cardiological findings will be provided. 


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Vital sign values and change from baseline values will be summarized descriptively by 
background therapy, dose level/Japan cohort and visit.  
The number of patients with abnormal post-dose blood pressure will be displayed by visit and 
post-dose hypertension grade.  
6.4 
Pharmacokinetics 
The data from the Safety run-in part and Phase III part will be pooled for PK analysis. 
Individual concentration-time data of copanlisib and its metabolite 1 as well as rituximab will 
be listed only. 
6.5 
Additional Analyses Planned to Be Reported Outside the Main Report 
All biomarker analyses will be considered exploratory. There will be no overall or sensitivity 
analysis of central pathology data. Biomarker data collected in the clinical database will be 
listed. Retrospective exploratory biomarker analyses including evaluation of relationship 
between biomarker data and clinical outcomes will be performed by or under the supervision 
of the sponsor's biomarker statistical expert. Results of these analyses will be reported 
separately, under a separate cover.  
7. Document history and changes in the planned statistical analysis 
7.1 Document history 
Version 
Date 
Action 
Comment 
Version 0.1 draft 
28 Jan 2016 
Review 
Safety run-in only 
Version 0.2 draft 
21 Jul 2016 
Update and Review 
Safety run-in only 
Version 1.0 final 
28 Aug 2016 
Signed initial version 
Safety run-in only 
Version 1.01 draft 
14 Jul 2022 
Update and Review 
Safety run-in only 
Version 2.0 final 
22 Jul 2022 
Signed second version Safety run-in only 
Version 2.1 draft 
13 Sep 2023 
Update and review 
Safety run-in only 
Version 2.2 draft 
15 Sep 2023 
Updated with 
comments from review 
of draft version 2.1 
Section 7.2 added 
Safety run-in only 
Version 3.0 final 
22 Sep 2023 
Signed third version 
Safety run-in only 


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7.2 Changes in the planned statistical analysis 
The definition of the secondary efficacy variable DCR has been amended in the SAP to 
remove references to “within 35 days after termination of study treatment” and “within the 
following 25 weeks”. This change has been made to be consistent with the ORR and CRR 
assessment period, by including in the DCR analysis, radiological assessments performed 
during the Active follow-up. 
Definition of DCR as defined in current CSP, Amendment 09, protocol Version 
8.0, dated 21 MAR 2023 
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. 
SAP definition of DCR as specified in Section 6.2 of this SAP 
DCR is defined as the proportion of patients who have a BOR of CR, unconfirmed 
CR, VGPR, PR, unconfirmed PR, MR, or confirmed stable disease (SD). Unconfirmed 
SD is defined as SD on or before Study Day 76, which is not confirmed by an 
additional tumor assessment of SD, or better, on Study Day 77 or later. 
8. References 
1. Cheson, BD, Fisher, RI, Barrington, SF, Cavalli, F, Schwartz, LH, 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):3059-67.  
2. Owen, RG, Kyle, RA, Stone, MJ, Rawstron, AC, Leblond, V, et al. Response 
assessment in Waldenstrom macroglobulinaemia: update from the VIth International 
Workshop. British journal of haematology. 2013; 160(2):171-6. 
9. Appendix 
9.1 
Imputation rules for partial dates 
9.1.1 Algorithm for handling partial initial diagnosis date and progression date 
The following rules are used to impute partial initial diagnosis date and progression date,  
A. If partial date has day and month missing, then January 01 will be assigned to the 
missing fields. 


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B. If partial date has missing day only, then the first day of the month will be assigned to 
the missing day. 
C. If imputed progression date from A or B above is before the Randomization date, then 
Randomization date will be assigned to overwrite the imputed date from A or B. If the 
date is completely missing, no imputation will be applied for initial diagnosis date. 
Use day 1 for progression date. 
 
 


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9.1.2 
Imputation rules for partial/missing Adverse Event (AE)/Concomitant 
medication (CM) dates 
Table 9-1: Imputation rules for partial/missing dates 
Partial Dates 
Imputation 
Rule 
Impute partial AE/CM Start Date 
Impute partial 
AE/CM Stop 
Date 
#1. The day 
missing only 
IF AESTDT year and months is same as TRTSDT year and 
months, then impute AESTDT= TRTSDT 
IF AEENDT year 
and months is 
same as LKAD 
year and months,  
then impute 
AEENDT= LKAD 
ELSE IF AESTDT year and month is before TRTSDT year and 
months, then AESTDT= last date of the months 
ELSE impute 
AEENDT= last 
date of the 
months 
ELSE IF AESTDT year and month is after TRTSDT year and 
months, then AESTDT= first date of the months 
#2. Both day 
and months 
missing 
IF AESTDT year is same as TRTSDT year, then impute 
AESTDT=TRTSDT 
IF AEENDT year 
is same as LKAD 
year,  
then impute 
AEENDT= LKAD 
ELSE IF AESTDT year is before TRTSDT year, then impute 
AESTDT=31DECYYYY 
ELSE impute 
AEENDT=31DEC
YYYY 
ELSE IF AESTDT year is after TRTSDT year, then impute 
AESTDT=01JANYYYY 
#3. Completely 
missing 
No need to impute, try to query the sites by DM 
No need to 
impute, try to 
query the sites by 
DM 
#4 Additional 
criteria to meet 
1. AE/CM start date <= AE/CM stop date 
################################################# 
After the imputation of start/stop date per above rules #1~#3, 
further action is needed if the (imputed) AE/CM start date > the 
(imputed) AE/CM stop date. We will update the (imputed) 
AE/CM start date = the (imputed) AE/CM stop date since the 
imputed stop date is more reliable. 
 
Because per imputation partial stop date rules #1~#3, the 
(imputed) AE/CM stop date will be the maximum date based 
on the available data unless there’s data issue. If it’s a data 
issue, we can leave the imputation as it is and report the data 
issue to the DM. 
################################################## 
2. The imputed dates <= LKAD 
3. If TRTSDT is missing, use RANDDT as reference date 


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9.1.3 : Imputation rules for partial/missing anti-cancer treatment start date 
Table 9-2: Imputation rules for partial/missing anti-cancer treatment start dates 
Partial Dates 
Imputation 
Rule 
Impute partial anti-cancer treatment start date 
#1. The day 
missing only 
IF *CMSTDTC year is after the year of the last visit, then impute DD to be ‘01’ 
 
ELSE IF *CMSTDTC year is the same as the year of the last visit and *CMSTDTC 
month is after the month of the last visit, then impute DD to be ‘01’  
 
ELSE IF *CMSTDTC year and month is the same as the year and month of the last 
visit, then impute day of the last visit 
 
#2. Both day 
and months 
missing (MM-
DD) 
IF *CMSTDTC year is the same as the year of the last visit, then impute MM-DD to 
be the month and day of the last visit’ 
 
ELSE IF *CMSTDTC year is after the year of the last visit, then impute MM-DD to 
be ‘01-01’ 
 
#3. Completely 
missing 
(YYYY-MM-
DD) 
IF the last visit date is known, then impute the last visit date 
 
*CMSTDTC is the start date/time of the anti-cancer treatment start date 


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          Page: 1 of 85 
 
 
 
 
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 B-cell non-Hodgkin’s lymphoma (iNHL) – 
CHRONOS-4 
Copanlisib and standard immunochemotherapy in relapsed iNHL 
Bayer study drug: 
BAY 80-6946 / Copanlisib 
 
Study purpose: 
Dose-finding, efficacy, and safety of copanlisib 
Clinical study 
phase: 
III 
Date: 
22 SEP 2023 
Study No.: 
 
17833 
Version: 
4.0 
Author: 
 
 
 
 
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) are not displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate Signature Document. 
 
 
 
PPD


Statistical Analysis Plan 
BAY 80-6946/17833 
         Page: 2 of 85 
 
 
 
Table of Contents 
Title page ................................................................................................................................... 1 
Table of Contents ...................................................................................................................... 2 
Table of Tables .......................................................................................................................... 3 
Table of Figures ........................................................................................................................ 4 
List of Abbreviations ................................................................................................................ 5 
1. 
Introduction ....................................................................................................................... 7 
2. 
Study objectives ................................................................................................................. 8 
3. 
Study design ....................................................................................................................... 9 
4. 
General statistical considerations .................................................................................. 13 
4.1 
General principles .......................................................................................................... 13 
4.2 
Handling of dropouts ..................................................................................................... 14 
4.3 
Handling of missing data ............................................................................................... 14 
4.4 
Handling of differing cycle lengths ............................................................................... 16 
4.5 
Handling of investigator assessments when PD is not confirmed by independent 
central review ................................................................................................................. 16 
4.6 
Handling of clinical laboratory values with qualifiers ................................................... 16 
4.7 
Multiple testing .............................................................................................................. 17 
4.8 
Interim analyses and data monitoring ............................................................................ 17 
4.9 
Data Rules ...................................................................................................................... 17 
4.9.1 
Time intervals ............................................................................................................. 17 
4.9.2 
Baseline....................................................................................................................... 18 
4.9.3 
Repeated measures...................................................................................................... 18 
4.9.4 
Overall extent of exposure .......................................................................................... 18 
4.9.5 
FLymSI-18 questionnaire ........................................................................................... 19 
4.9.6 
Stratification ............................................................................................................... 19 
4.9.7 
Region ......................................................................................................................... 20 
4.9.8 
As treated .................................................................................................................... 21 
4.10 Validity Review ............................................................................................................. 21 
5. 
Analysis Sets ..................................................................................................................... 21 
5.1 
Assignment of analysis sets ........................................................................................... 21 
6. 
Statistical Methodology ................................................................................................... 22 
6.1 
Population characteristics .............................................................................................. 22 
6.1.1 
Disposition .................................................................................................................. 22 
6.1.2 
Demographics and other baseline characteristics ....................................................... 24 
6.1.3 
Medical history ........................................................................................................... 26 
6.1.4 
Prior and concomitant medication .............................................................................. 26 
6.1.5 
Treatment duration and exposure ............................................................................... 27 
6.2 
Efficacy .......................................................................................................................... 29 
6.2.1 
Primary efficacy variable ............................................................................................ 29 
6.2.2 
Secondary efficacy variables ...................................................................................... 39 
6.2.3 
Confirmatory statistical test strategy .......................................................................... 45 


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6.2.4 
Other efficacy variables .............................................................................................. 49 
6.2.5 
Subgroup analyses ...................................................................................................... 50 
6.3 
Safety ............................................................................................................................. 52 
6.3.1 
Adverse events (AEs) ................................................................................................. 52 
6.3.2 
Adverse events by time-interval ................................................................................. 54 
6.3.3 
Adverse events of special interest............................................................................... 55 
6.3.4 
Adverse event groupings ............................................................................................ 56 
6.3.5 
Safety OS analysis ...................................................................................................... 58 
6.3.6 
COVID-19 pandemic-relevant adverse events ........................................................... 58 
6.3.7 
Pregnancies ................................................................................................................. 58 
6.3.8 
Clinical laboratory parameters .................................................................................... 58 
6.3.9 
Further safety parameters ........................................................................................... 59 
6.4 
Pharmacokinetics/pharmacodynamics ........................................................................... 62 
6.5 
Biomarker evaluation ..................................................................................................... 63 
6.6 
Determination of sample size ......................................................................................... 63 
7. 
Document history and changes in the planned statistical analysis ............................. 64 
7.1 
Document history ........................................................................................................... 64 
7.2 
Changes in the planned statistical analysis .................................................................... 71 
8. 
References ........................................................................................................................ 73 
9. 
Appendix .......................................................................................................................... 75 
9.1 
Principles for combination of PET and CT/MRI responses .......................................... 75 
9.2 
Scoring instruction for FLymSI-18 ................................................................................ 75 
9.3 
Patient-reported outcomes ............................................................................................. 76 
9.4 
PFS rules ........................................................................................................................ 76 
9.4.1 
Progression and PD after two or more consecutive missed tumor assessments ......... 76 
9.4.2 
Death ........................................................................................................................... 77 
9.4.3 
Patients with new anti-cancer therapy ........................................................................ 77 
9.4.4 
Patients who discontinue or withdraw ........................................................................ 78 
9.5 
Imputation rules for partial dates ................................................................................... 78 
9.5.1 
Algorithm for handling partial initial diagnosis date and progression date................ 78 
9.5.2 
Imputation rules for partial/missing Adverse Event (AE)/Concomitant medication 
(CM) dates .................................................................................................................. 79 
9.5.3 
Imputation rules for partial/missing anti-cancer treatment start date ......................... 80 
9.6 
Hypothetical OS events needed to detect a difference in OS (answering an HA 
request) ........................................................................................................................... 80 
9.7 
Details of OS event analyses for varying primary PFS time points and OS hazard 
ratios (answering an HA request)................................................................................... 82 
9.8 
Likelihood to rule out a harmful effect in OS (answering an HA request) .................... 83 
 
Table of Tables 
Table 2-1: Overview of efficacy objectives and variables ......................................................... 9 
Table 3-1: Dosing of copanlisib/placebo during the study ....................................................... 12 
Table 4-1: Stratum per patient ID/randomization number ....................................................... 19 
Table 6-1: Progression-free survival (PFS) censoring rules .................................................... 30 
Table 6-2: PFS censoring rules for sensitivity analysis 6 (any change or premature 
discontinuation from treatment considered as a progression event) ..................... 36 


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Table 6-3: PFS censoring rules for sensitivity analysis 7 (any change or premature 
discontinuation from treatment or Active follow-up considered as a progression 
event) ..................................................................................................................... 37 
Table 6-4 TTNT censoring rules .............................................................................................. 40 
Table 6-5: DRS-P deterioration censoring rules ...................................................................... 42 
Table 6-6: DRS-P improvement censoring rules ..................................................................... 43 
Table 6-7: Worsening of DRS-P alone sensitivity analysis censoring rules ............................ 45 
Table 6-8 Assessment of Statistical Power for ORR in the Overall FAS ................................ 48 
Table 6-9 Scenarios for formal OS evaluations for efficacy .................................................... 49 
Table 6-10 Overview of Histology Specific Subgroup Analyses ............................................ 50 
Table 6-11: Adverse Event Groupings ..................................................................................... 56 
Table 9-1: Imputation rules for partial/missing dates .............................................................. 79 
Table 9-2 Imputation rules for partial/missing anti-cancer treatment start dates ..................... 80 
Table 9-3: Crude median assumptions and resulting HR displayed with events and study 
duration needed to achieve specific statistical power values ................................ 82 
Table 9-4: Overview of interim and final evaluation conditional power ................................. 83 
Table 9-5: Resulting probability of HR point estimate / upper bound exceeding 1 ................. 84 
 
Table of Figures 
Figure 3-1: Overall study design of Phase III part ................................................................... 10 
Figure 3-2: Study periods ......................................................................................................... 11 
Figure 6-1 Confirmatory test strategy based on four test families for United States ............... 46 
Figure 6-2: Confirmatory Test Strategy Based on Five Test Families for “Europe and the rest 
of the world” .......................................................................................................... 47 
 
 
 


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List of Abbreviations 
ADRG 
Analysis Data Reviewer’s Guide 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the curve 
B 
Bendamustine hydrochloride  
BMI 
Body mass index 
BRM 
Blind review meeting 
BRR 
Blind review report 
BSA 
Body surface area 
CI 
Confidence interval 
CIL 
Confidence interval limit 
CMV 
Cytomegalovirus 
COVID-19 
Corona virus disease 2019 
CSP 
Clinical study protocol 
CR 
Complete response 
CRR 
Complete tumor response rate 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria adverse event 
DCR 
Disease control rate 
DM 
Demography 
DMC 
Data monitoring committee 
DOR 
Duration of response 
DRS-E 
Disease-related symptoms - emotional 
DRS-P 
Disease-related symptoms – physical 
DS 
Disposition 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
e.g. 
For example (exempli gratia) 
eGFR 
Estimated glomerular filtration rate 
EOT 
End-of-treatment 
EX 
Exposure 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FL 
Follicular lymphoma 
FLymSI-18 
National Comprehensive Cancer Network-Functional Assessment of Cancer, Lymphoma 
Symptom Index-18 Questionnaire 
FWB 
Function and well-being 
H0 
Null hypothesis 
H1 
Alternative hypothesis 
HA 
Health authority 
HbA1c 
Glycated hemoglobin 
HLGT 
High level group term  
HLT 
High level term 
HR 
Hazard ratio 
IA-SAP 
Integrated Analysis-Statistical Analysis Plan 
ID 
Identifier 
i.e. 
That is (id est) 
IgM 
Immunoglobulin M 
iNHL 
indolent non-Hodgkin’s lymphoma 
ITT 
Intent-to-treat 
IxRS 
Interactive voice/web response system 
kg 
Kilogram 
LB 
Laboratory 
LKAD 
Last known alive date 


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LPL 
Lymphoplasmacytoid lymphoma 
m 
Meter 
M-1 
Metabolite 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minutes 
MLG 
Bayer MedDRA labeling groupings 
MR 
Minor response 
MUGA 
Multiple gated acquisition 
MZL 
Marginal zone lymphoma 
M&S 
Modeling and Simulation 
NCI 
National Cancer Institute 
NE 
Non-evaluable 
NHL 
Non-Hodgkin's lymphoma 
NYHA 
New York Heart Association 
ODAC 
Oncologic Drugs Advisory Committee 
OEE 
Overall extent of exposure 
ORR 
Objective response rate 
OS 
Overall survival 
PBMQ 
Product  specific Bayer MedDRA Query 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI3K 
Phosphatidylinositol 3-kinase 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetics analysis set 
PT 
Preferred term 
PR 
Partial response 
QoL 
Quality of life 
R 
Rituximab 
R-B 
Rituximab and bendamustine 
R-CHOP 
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
RS 
Tumor response 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
Stable disease 
SLL 
Small lymphocytic lymphoma 
SMQ 
Standardized MedDRA query 
SOC 
Primary system organ class 
SV 
Subject visits 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
TLF 
Tables, listings, and figures 
TSE 
Treatment side-effect 
TTNT 
Time to next anti-lymphoma treatment 
TTP 
Time to progression 
US, USA 
United States (of America) 
VGPR 
Very good partial response 
vs. 
As opposed to (versus) 
WHO-DD 
World Health Organization - Drug Dictionary 
WM 
Waldenström macroglobulinemia 
 
 
 
 


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1. 
Introduction 
Non-Hodgkin’s lymphomas (NHLs) are a heterogeneous group of lymphoproliferative 
malignancies typically originating in the lymph nodes but can involve almost any organ tissue 
[1]. NHLs can be divided according to their clinical behavior in two main prognostic groups: 
indolent NHL (iNHL) and aggressive NHL. Aggressive lymphomas are characterized by an 
aggressive clinical course and may evolve into a lethal presentation if not immediately treated. 
Indolent NHLs have a relatively good prognosis with a median survival longer than 10 years, 
but they are incurable with current available therapeutic options, especially in advanced 
stages. While they are highly responsive to standard chemotherapy regimens and to 
radiotherapy, their natural history is characterized by a continuous pattern of relapses, which 
can generally be treated with success. But the time to next relapse progressively decreases 
each time, finally evolving into a refractory disease or in a transformation into an aggressive 
histologic type. 
Optimal treatment of advanced stages of iNHL is controversial because of low cure rates with 
the current therapeutic options. 
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 [cyclophosphamide, doxorubicin, vincristine, and prednisone 
(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.  
Rituximab is a CD20-directed cytolytic antibody indicated for the treatment of patients with 
NHL and widely used as a single drug or in combination regimens [2-6]. Retreatment with 
rituximab alone or in combination has been shown to be feasible and active [7,8]. 
For patients with relapsed disease, the same regimen (rituximab in combination with an 
alternative chemotherapy) can be used. The safety and efficacy of R-B and R-CHOP in this 
setting were evaluated, showing satisfactory rates of complete response (CR) and overall 
survival (OS) [9,10]. 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. 
Copanlisib is a small molecule phosphatidylinositol 3-kinase (PI3K) inhibitor and showed 
excellent anti-tumor activity in pre-clinical models with up-regulated PI3Kα pathway. The 
PI3K/ Protein kinase B / mammalian target of rapamycin pathway is one of the prominent 
pathways that promote cellular survival and is constitutively activated in many types of 
cancers [11,12]. 
Copanlisib has activity as monotherapy in patients with relapsed or refractory iNHL (shown 
in the results of studies 12781- and 16349-Part A). Results from the Phase II pivotal study 
16349 Part B were compelling enough for the Food and Drug Administration (FDA) to grant 
copanlisib (Aliqopa) accelerated approval in the treatment of adult patients with relapsed 
follicular lymphoma (FL) who have received at least two prior therapies. 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-
B/R-CHOP) 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 
symptom control in comparison to the standard immunochemotherapy. In study 17833, the 


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Safety run-in part for copanlisib in combination with R-B/R-CHOP has been completed. The 
Data Monitoring Committee (DMC) reviewed the safety data and approved that a copanlisib 
dose of 60 mg is safe to be used in combination with both R-B and R-CHOP in the Phase III 
part.  
This Statistical Analysis Plan (SAP) is based on the integrated clinical study protocol (CSP, 
Amendment 09, protocol Version 8.0, dated 21 MAR 2023) and describes the primary 
analysis of the study 17833 Phase III part to be included in the clinical study report (CSR). 
The final analysis of the study 17833 Safety run-in part is described in a separate SAP 
(version 3.0, 22 SEP 2023). 
2. 
Study objectives 
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 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 (B) 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), disease control 
rate (DCR), time to progression (TTP), time to next anti-lymphoma treatment (TTNT), 
overall survival (OS, 5-year survival rate), time to improvement and the time to 
deterioration in disease-related symptoms – physical (DRS-P)).  
• Safety and tolerability of copanlisib in combination with R-B/R-CHOP.  
The further objectives of the Phase III part are to evaluate: 
• Pharmacokinetics (PK) of copanlisib 
• Biomarkers of efficacy, mode-of-action-related effect, safety, and / or the 
pathomechanism of the disease.  
Table 2–1 gives an overview of the primary and secondary efficacy objectives and the 
relevant variables to be analyzed. 
 
 


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Table 2–1: Overview of efficacy objectives and variables 
Objective 
Variable 
Primary objective 
Progression-free survival (PFS)*, described in Section 6.2.1. 
Secondary objective:  
Response rate 
Objective response rate (ORR)*, 
described in Section 6.2.2. 
Secondary objective: 
Characteristics of 
disease-related 
symptoms 
Time to deterioration in DRS-P of at least 3.0 points**, 
Time to improvement in DRS-P of at least 3.0 points**, 
described in Section 6.2.2 
Secondary objective:  
Other radiological and 
clinical indicators 
Duration of response (DOR), 
Disease control rate (DCR), 
Complete response rate (CRR), 
Time to progression (TTP), 
Time to next anti-lymphoma treatment (TTNT), 
Overall survival* (OS, 5-year survival rate), 
described in Section 6.2.2. 
Other efficacy 
variables 
National Comprehensive Cancer Network-Functional Assessment 
of Cancer, Lymphoma Symptom Index-18 (FLymSI-18) total and 
subscale scores (DRS-P, DRS-E, TSE, F/WB), described in 
Section 6.2.4 
*Variable is part of the United States as well as Europe and rest of world confirmatory testing strategy (see 
Section 6.2.3) 
**Variable is only part of the Europe and rest of world confirmatory testing strategy (see Section 6.2.3) 
3. 
Study design 
This is a randomized 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 given concomitantly; and patients must not 
have had a lack of response, or progression within 6 months of the last date of treatment with 
a rituximab containing regimen. 


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Patient randomization was to be stratified by:  
• Prior to base treatment regimen1: R-chemotherapy to R-B, R-B to R-CHOP, and R-B 
to R-B2 
• NHL histology: FL histology and other iNHL histology (Small lymphocytic 
lymphoma [SLL], Marginal zone lymphoma [MZL], lymphoplasmacytoid lymphoma 
[LPL] / Waldenström macroglobulinemia [WM]) 
• Duration of progression-free interval on the last rituximab, or rituximab biosimilars, or 
anti-CD20 monoclonal antibody containing regimen: 6-12 months and >12 months  
After the copanlisib immunochemotherapy combinations were deemed safe in the Safety run-
in part of the trial, approximately 520 (including FL and other iNHL) patients who met the 
eligibility criteria were to be randomly assigned in a 1:1 ratio to one of the double-blinded 
treatment arms (approximately 260 patients per arm) in the Phase III part:  
Arm 1: copanlisib plus R-B or R-CHOP and  
Arm 2: placebo plus R-B or R-CHOP.  
• Patients who never received R-B as a previous line of therapy were to be randomized 
to copanlisib/placebo + R-B treatment group. 
• Patients who received R-B as a previous line of therapy were to 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  
 
Figure 3–1: Overall study design of Phase III part  
 
FL = follicular lymphoma; FU = follow-up; iNHL = indolent non-Hodgkin’s lymphoma; N = total number of 
patients; 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 
 
1 Where prior treatment regimen refers to treatment received prior to entering the trial, and base treatment 
regimen refers to the base treatment received on the trial. 
2 If ≥ 24 months progression-free interval after the last R-B treatment. 


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monotherapy). Study treatment will be continued until occurrence of PD (per central independent blinded 
radiological review), clinical progression, unacceptable toxicity, 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). 
 
An overview of the study periods is presented in Figure 3–2. The study is comprised of the 
following periods: Screening, Treatment, Safety follow-up, Active follow-up (if applicable) 
and Survival follow-up. 
Figure 3–2: 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). 
 
Screening period 
The start of the screening period is defined by signing of the informed consent form. After a 
screening period of up to 28 days with a minimum of 7 days, patients who met the entry 
criteria were to 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. 
Re-screening of patients who failed screening was only to be allowed once, following 
discussion with the sponsor’s designated medical representative and after approval by the 
sponsor. Re-screened patients had to re-sign the informed consent form, even if it had not 
changed since the patient’s previous screening. 
Treatment period 
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) was to be administered for a 
maximum of 6 cycles (C1-C6). Copanlisib/placebo (study drug) monotherapy was to be 
administered from C7 onwards. Tumor assessments with the same modality were to be 
performed every 12 weeks (± 7 days) from Cycle 1 Day 1.  
For a detailed description of study treatment dosage and administration refer to Section 7.4 of 
the study protocol. An overview is presented in Table 3–1. 


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Table 3–1: 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 
All patients were to be treated until the occurrence of progressive disease (PD) (per central 
independent blinded radiology review) as defined by the Lugano Classification [13] (or Owen 
criteria for patients with LPL/WM [14]) or clinical progression (e.g., Eastern Cooperative 
Oncology Group [ECOG] performance status of ≥ 3), unacceptable toxicity occurred, until 
another criterion was met for withdrawal from study or until completion of monotherapy, 
whichever came first. The maximum duration of treatment with copanlisib/placebo was to be 
12 months (including combination therapy and monotherapy).  
An end-of -treatment (EOT) visit was to be performed no later than 7 days after the decision 
was made to discontinue study treatment or when the patient completes 12 months of 
treatment (maximum duration of therapy).  
Safety follow-up period 
All patients except for those who died, withdrew consent, or were lost to follow-up were to 
have a Safety follow-up visit that would take place 30 days (a time window of +5 days is 
allowed) after the last administration of study treatment. 
Active follow-up period 
Only patients who completed 12 months of study treatment without PD or discontinuing study 
drug for reasons other than PD were to enter the Active follow-up period (which also served 
as a Safety follow-up), except for patients who specifically objected to entering the Active 
follow-up and patients who objected to all further data collection after study drug 
discontinuation. Patients in the Active follow-up are to have tumor assessments by central 
independent blinded review as outlined in the protocol (every 12 weeks [± 7 days] from Cycle 
1 Day 1 during Years 1 and 2; every 24 weeks [± 7 days] during Years 3, 4, and 5; and every 
24 weeks [±14 days] beyond Year 5, until either PD is centrally evaluated and documented, 
up to 2 years after primary completion date, end of study or a new anti-tumor treatment is 
administered, whichever occurs first). 
Date of last visit 
A patient’s last visit date is defined as their last visit/contact prior to any Survival follow-up 
visits/contact.  
Occasionally FLymSI-18 quality of life (QoL) questionnaires were completed by patients 
after their final radiological assessment in the Active follow-up. In such cases, if the patient 
ended AFU for reasons other than PD or new anti-lymphoma therapy, and the questionnaire’s 
completion date was prior to entering the Survival follow-up, then the patient’s last visit date 
will be the completion date of the QoL questionnaire. 


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Survival follow-up period 
Except for patients who objected to follow-up data collection in the Survival follow-up 
period, all patients are to be followed off-study for overall survival at 3-monthly (± 14 days) 
intervals, until death or until the end of study, whichever occurs first.  
End of Study 
The study will end when one of the following conditions is met: 
- final contact with the last remaining patient has occurred,  
- 10 years after the last patient started study treatment. 
Efficacy analyses will be performed when approximately 280 centrally evaluated PFS events 
are observed in the study. Evaluations from central independent blinded review will be used 
for the primary efficacy analyses of primary and secondary endpoints containing radiological 
tumor assessments. For patients who withdraw prematurely from the treatment period due to 
reasons other than PD or death, tumor assessments from the Active follow-up will be included 
in the primary and secondary analyses. For details of radiological tumor assessment and 
schedule see Section 9.4.2 of the study protocol.  
4. 
General statistical considerations 
4.1 
General principles 
Statistical analyses will be conducted by or under the supervision of the sponsor’s Study 
Statistician, except for the analysis of biomarker data and 
pharmacokinetics/pharmacodynamics data, which will be performed by or under the direction 
of the sponsor’s Biomarker Statistical Expert and PK experts.  
The statistical evaluation will be performed by using the software package “Statistical 
Analysis System” (SAS), release 9.2 or higher (SAS Institute Inc., Cary, NC, USA). All 
variables will be summarized by descriptive statistical methods. The number of data available 
and missing data, mean, standard deviation, minimum, quartiles, median, and maximum will 
be calculated for numeric data. Frequency tables will be generated for categorical data. 
A statistical evaluation of this study will be performed when approximately 280 PFS events 
(radiological progressive disease confirmed by independent central review, or biomedical 
progression in patients with LPL/WM without measurable lesion in the baseline investigator 
radiological assessment or death if death is before progressive disease) are observed. 
Definition of efficacy and safety endpoints, analysis strategies, structure of analysis datasets 
and layout of analysis data displays are following Bayer standards as documented in the Bayer 
standard system: Oncology Therapeutic Area Standards, Global Medical Standards and will 
comply with the Oncology Common Statistical Language document. The given ordering 
reflects the priority of the different standards, where specifications of the latter standards are 
to be followed only if not specified in the earlier standards. Study-specific specifications may 
be included in addition to the project standards, if needed. 
The Blind Review Report (BRR) may contain decisions which are relevant for statistical 
evaluation, for details see Section 4.10. 


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4.2 
Handling of dropouts 
A patient who discontinues study participation prematurely (i.e., prior to disease progression 
confirmed by independent central review or death) for any reason is defined as a “dropout” if 
the patient has already been randomized, even if no study drug has been taken. Patients who 
drop out will not be replaced. Refer to Section 6.4 of the study protocol for details regarding 
the withdrawal of patients from the study. 
A patient who signed the informed consent but for any reason terminated the study before 
randomization is regarded a “screening failure”. 
Patients who discontinue study drug due to reasons other than death, PD confirmed by 
independent central review or biomedical progression in patients with LPL/WM without 
measurable lesion in the baseline investigator radiological assessment, will enter the Active 
follow-up period and will not be defined as a “dropout”, except for those who specifically 
object to entering the Active follow-up or object to all further data collection after study drug 
discontinuation. The patients in the Active follow-up will have follow-up tumor assessments 
until disease progression is documented or new anti-tumor treatment is administered, 
whichever occurs first.  
4.3 
Handling of missing data 
To achieve a well conducted clinical trial in accordance with Good Clinical Practice, every 
effort will be made to collect all data. However, despite best efforts, it may be inevitable that 
missing or incomplete data are reported. If a patient indicates 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 patient for tumor 
assessment until patients develop radiological progression by independent central review or 
biomedical progression in patients with LPL/WM without investigator assessed baseline 
lesions evaluable by imaging. Survival information including survival status, death date 
and/or contact date should be determined for all patients during the Survival follow-up. All 
missing or partial data will be presented in the patient data listing as they are recorded on the 
electronic Case Report Form (eCRF). Unless specified, missing data will not be carried 
forward or otherwise imputed in any statistical analysis.  
Missing or non-evaluable tumor observations (including a scheduled assessment that was not 
done and an incomplete assessment that does not result in an unambiguous tumor response or 
detection of new lesions) will not be imputed or used in the calculation of derived efficacy 
variables related to tumor assessments, e.g., response. No imputation will be performed for 
missing tumor assessment and response. For example, if a patient misses a scan visit and PD 
is documented at the next available scan visit, the actual visit date of the first documented PD 
will be used to calculate PD-related endpoints. For complete definitions of efficacy 
parameters refer to Section 6.2. 
Partial dates may occur. To impute values, available data from other sources should be 
utilized. The last known alive date (LKAD) is derived from the main data sources and may be 
used in statistical analyses to impute death or tumor assessment dates which are partially or 
completely missing. Except for death (with a date of death on or prior to the data cut-off) data 
reported during cleaning, after the data cut-off date, will not be considered in the derivation of 
LKAD. For such cases the data cut-off date will be used as the LKAD. The last available date 


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across all key data panels (laboratory [LB], tumor response [RS], demography [DM], subject 
visits [SV], exposure [EX], disposition [DS], procedures [XP], bone marrow assessments 
[BM], ECG assessments [EG], microbiology [MB], pharmacokinetics [PC], tumor lesion 
measurements [TR] and tumor/lesion identification[TU]) will be used to determine survival 
status and the LKAD for each patient. If the day of the LKAD is missing, then the earliest 
plausible day of the month should be imputed. If both the day and month of the LKAD are 
missing, then the earliest plausible day of the year should be imputed. 
When appropriate, the following rules will be implemented to avoid excluding patients from 
statistical analyses due to missing or incomplete data: 
Date of death 
If a death date is partially or completely missing, it will be imputed following the 
imputation rules below: 
1. If there is an adverse event (AE) with “Fatal” outcome, the date of death will be 
imputed by the stop date of the AE. 
2. If there is no AE with outcome “Fatal” and only the day of death is missing, it will 
be imputed by the first day of the month unless the LKAD is later than this date; in 
which case the LKAD will be used for imputation. If both day and month and/or 
year are missing, then the LKAD will be used for imputation. 
Date of tumor scan  
If a tumor assessment date is partially missing, it will be imputed following the imputation 
rules below: 
1. If only the day is missing, it will be imputed by the first day of the month. 
2. If day and month are missing, it will be imputed by the date of the last previous 
tumor assessment plus 28 days unless the LKAD is earlier than this date; in which 
case the LKAD will be used for imputation3 . 
Response rates 
If a patient has no post-baseline tumor assessment available (or no post-baseline 
laboratory/clinical tests available for LPL/WM patients without investigator assessed 
radiologically measurable lesion[s]), i.e., the overall best response assessment is missing, the 
patient will be non-evaluable (NE), but will be included into denominator for calculation of 
ORR, DCR and CRR. 
Patient-reported outcomes  
Physical symptoms of lymphoma are assessed by the FLymSI-18 questionnaire. Missing 
responses will not be replaced. Missing individual items will be handled in accordance with 
the scoring instructions for the FLymSI-18 questionnaire (Appendix 9.2). Specifically, if there 
are missing items, subscale scores are prorated. This is done by multiplying the sum of the 
subscale by the number of items in the subscale, then dividing by the number of items 
answered. 
 
3 All tumor assessments, with complete and partial dates, will be ordered sequentially by visit number. If both 
day and month are missing from the final tumor assessment and the penultimate tumor assessment is the patients 
LKAD then the date of the penultimate assessment plus 28 days will be imputed for the final tumor assessment. 


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When there are missing data, prorating by subscale in this way is acceptable if at least 50% of 
the items were answered (e.g., a minimum of 5 of 9 items, 2 of 4 items, etc.). The total score 
is considered to be an acceptable indicator of patient quality of life as long as overall item 
response rate is greater than 80%. This is not to be confused with individual subscale item 
response rate, which allows a subscale score to be prorated for missing items if greater than 
50% of items are answered. In addition, a total score should only be calculated if all of the 
component subscales have valid scores. 
Time to deterioration in DRS-P of at least 3 points (see Appendix 9.3): Patients without 
deterioration will be censored at the date of their last tumor evaluation, if the reason for 
stopping treatment is not related to PD or deaths. 
Time to improvement in DRS-P of at least 3 points (see Appendix 9.3): Patients will be 
censored at the date of their last tumor evaluation, if the reason for stopping the study (i.e., not 
being in treatment or Active follow-up) is not related to PD. Patients dropping out due to 
progression-related reasons (e.g., an AE related to PD) or experiencing a PD event (as defined 
for the primary analysis of PFS) or death due to any reason will be censored at the largest 
observation time (of events and censoring in all patients evaluated for improvement), plus 1 
day.  
Missing or partially missing start or end dates for AEs and concomitant medications will be 
imputed based on the conventions described in Appendix 9.5. The purpose of the imputation 
for AEs is to determine whether the event is treatment-emergent, as defined in Section 6.3.1. 
Similarly, the purpose of the imputation for concomitant medications is to determine if the 
medication was given concomitantly with study drug and, in the case of new anti-lymphoma 
therapies, to avoid excluding patients with partial anti-lymphoma therapy start dates from 
statistical analyses due to missing or incomplete data. 
4.4 
Handling of differing cycle lengths 
Due to the differing cycle lengths of copanlisib/placebo+R-B compared to 
copanlisib/placebo+R-CHOP, by visit summaries will only be tabulated by background 
therapy if 5 or more patients are randomized to receive the background therapy. If a 
background therapy has less than 5 patients assigned the equivalent data will be listed in 
Section 10 of the CSR. In Section 10 of the CSR patients assigned to the non-tabulated 
background therapy will be listed first. 
4.5 
 Handling of investigator assessments when PD is not confirmed by 
independent central review 
The analysis of efficacy, based on investigator assessments, will exclude response 
assessments collected after the first investigator reported PD, regardless of whether or not the 
PD was confirmed by independent central review. 
4.6 
Handling of clinical laboratory values with qualifiers 
Clinical laboratory values which have qualifiers (for example, > or <) will be included in 
clinical safety analyses and summaries with the qualifier removed. 


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4.7 
Multiple testing 
Except for the analysis of the primary efficacy endpoint and confirmatory statistical testing 
strategy, all other analyses will be descriptive. Any resulting p-values from these descriptive 
analyses will be nominal as there will be no multiplicity adjustments for multiple testing. 
4.8 
Interim analyses and data monitoring 
No interim analyses are planned for this study’s primary endpoint of PFS. The primary PFS 
analysis will be performed when approximately 280 centrally evaluated PFS events are 
observed in the study. Further details on the primary PFS analysis are included in Section 
6.2.1 and details on the confirmatory statistical testing strategy are provided in Section 6.2.3. 
The number of PFS events will be monitored in the blinded database throughout the study. 
When the required numbers of events are reached, the database will be cut and cleaned for 
analysis. Data reported during cleaning after the data cut-off will not be considered in the 
primary analysis except for any death reported during data cleaning with a date of death on or 
prior to the data cut-off. 
An interim analysis of OS will also be performed at the time of the primary PFS analysis. The 
survival status will further be collected quarterly during the Survival follow-up period up to 
10 years after the last patient started study treatment, at which point the final descriptive 
analysis of OS at study end will take place.  
Twelve months after the primary analysis of the primary and secondary efficacy variables, 
and at yearly intervals thereafter until the final descriptive analysis of OS at study end, further 
descriptive analyses of OS (each a “follow-up OS analysis”) will be performed. These 
analyses will be updates of the analysis of OS performed on data available at the time of 
analysis of the primary endpoint, PFS. 
A DMC was established to ensure that patients were not exposed to undue risk during this 
study and regularly reviewed study data, as outlined in the DMC charter [15], to provide an 
independent recommendation on the advisability of continuing this study. Investigators, 
patients, and the sponsor remain blinded to treatment. 
Until all patients discontinued study treatment, the report for the DMC included tables, 
listings, and figures, and was generated by an independent statistician from a Statistical 
Analysis Center. The format and content of these data summaries have been specified 
separately from this study SAP.  
Decisions on trial termination, amendment, or cessation of patient recruitment based on 
risk/benefit assessment, were made after recommendations from the DMC were assessed by 
the sponsor. 
4.9 
Data Rules 
4.9.1 
Time intervals 
If time intervals are to be displayed other than days in statistical evaluations, then one year is 
considered to have 365.25 days (average length of a year, including leap years), one month is 
considered to have 30.44 days (average length of a month, including leap years), one week is 
considered to have 7 days, and one cycle is considered to have 28 days (i.e., 4 weeks). In 
terms of data display, this generally also applies for patients treated with CHOP as base 
regimen. All time conversions from days will be displayed to 1 decimal place. 


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4.9.2 
Baseline 
Baseline is defined as the last measurements performed prior to the first study drug 
administration in Cycle 1. If the actual time is not available but date is available for certain 
measurements, the baseline value is defined as the last non-missing value collected on or 
before the date of the first dose of study treatment. For patients who have been randomized 
but not treated with any dose, randomization date will be used as the reference date for 
baseline value calculation. 
Also consider: 
• The time part for baseline flagging. Study data tabulation model/analysis data model 
datasets for exposure and laboratory data both capture times. If the time in either one 
is missing, use the dates in that case. 
• Baseline can be either a scheduled or unscheduled visit. 
• If the patient has a measurement on Cycle 1 Day 1 (scheduled), then this measurement 
will be considered as the baseline. 
• If the patient has no measurements on Cycle 1 Day 1 but has a measurement at 
screening visit (scheduled or unscheduled), then the screening visit measurement will 
be considered as the baseline. 
• If multiple measurements were taken at the same Cycle 1 Day 1 visit or same 
screening visit and all with non-missing assessment dates, then the measurement with 
the latest assessment date/time will be considered as baseline, whether scheduled or 
unscheduled. 
• If both scheduled and unscheduled measurements exist for the same visit and cannot 
be decided by the above rules, then the measurement taken at scheduled visit will be 
considered as the baseline. 
4.9.3 
Repeated measures 
If there are repeated measurements per time point (e.g., laboratory values, vital signs, etc.), the 
following rules will be used (unless otherwise specified): 
• Before the start of the study drug administration (i.e., for screening and baseline 
value), the latest non-missing measurement at scheduled visits will be used. 
Unscheduled visits will be used if there are no measurements at scheduled visits. If the 
latter is the case, the last unscheduled visit will be used. 
• In case of repeated measurements at any post baseline time point, the first 
measurement at scheduled visits will be used.  
• When two records have the same patient identifier (ID), results, date, time, and 
visit/cycle number, except for page number or record ID, the two records will be 
considered duplicates and only one record will appear in the corresponding analysis 
dataset. 
4.9.4 
Overall extent of exposure 
As a rule, and in accordance with the Oncology Therapeutic Area Standard, leading “0 mg” 
(prior to the first positive amount of drug) and trailing “0 mg” records (not followed by any 
positive amount of drug), will not be included in the calculation of any drug duration or 
amount. Similarly, trailing “drug interruptions” will not be used in statistical tables. A 


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footnote will be included, stating that “Interruption becoming permanent study treatment 
discontinuation before resumption of study treatment is not counted as an interruption”. 
Overall extent of exposure (OEE) for copanlisib/placebo, is defined as the time from first 
respective study drug intake (dayfirst) until last study drug intake (daylast), including 7 
additional days to account for the weekly dosing regimen, and is calculated as: 
OEE = daylast - dayfirst + 7 
OEE for R-CHOP, is defined as the time from first respective study drug intake (dayfirst) until 
last study drug intake (daylast), including 21 additional days to account for the “every 3 
weeks” (Q3W) dosing regimen and prednisone/prednisolone dosing up to Day 6, and is 
calculated as: 
OEE = daylast - dayfirst + 21 – [day(last) – day(first) of last cycle of R-CHOP]  
OEE for R-B, is defined as the time from first respective study drug intake (dayfirst) until last 
study drug intake (daylast), including 28 additional days to consider the Q4W dosing regimen 
and B dosing up to Day 2, and is calculated as: 
OEE = daylast - dayfirst +28 – [day(last) – day(first) of last cycle of R-B] 
If the respective treatment ends with dose interruptions, the day of the last actual dose will be 
assumed to be daylast. 
4.9.5 
FLymSI-18 questionnaire 
FLymSI-18 QoL questionnaires are patient-administered and should be completed by the 
patient as scheduled in the CSP, at the start of the study visit prior to any contact with the 
investigator or site personnel. If the completion date of a questionnaire is not within ± 7 days 
of the corresponding scheduled visit, it will be excluded from the analysis of efficacy. If a 
patient withdraws consent for radiological assessments but consents to completing QoL 
questionnaires, the questionnaires will be included in the analysis of efficacy if they were 
completed within ± 7 days of the scheduled visit and were not completed during the patient’s 
Survival follow-up. 
4.9.6 
Stratification 
In case of discrepancies between stratification factors entered in the interactive voice/web 
response system (IxRS) and information entered in eCRF, the information from IxRS will be 
used for analysis. This especially includes analyses that are performed separately for the 
subgroup of FL patients, which is based on one of the stratification factors. 
The stratification that was assigned in IxRS will be reflected in the patient’s ID number. The 
mapping of patient ID/randomization numbers to assigned IxRS strata is summarized in Table 
4–1. 
Table 4–1: Stratum per patient ID/randomization number 
Randomization 
Start Number 
Description of strata1,2 
 – 
  
01: R-chemotherapy to R-B, FL, treatment-free / progression-free interval on 
the last rituximab, or rituximab biosimilars, or anti-CD20 monoclonal 
antibody containing regimen 6-12 months  
 – 
 
 
02: R-chemotherapy to R-B, FL, treatment-free / progression-free interval on 
the last rituximab, or rituximab biosimilars, or anti-CD20 monoclonal 
PPD
PPD
PPD
PPD


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Randomization 
Start Number 
Description of strata1,2 
antibody containing regimen >12 months 
 
 
  
 
03: R-chemotherapy to R-B, other iNHL, treatment-free / progression-free 
interval on the last rituximab, or rituximab biosimilars, or anti-CD20 
monoclonal antibody containing regimen 6-12 months  
 
 – 
 
 
04: R-chemotherapy to R-B; other iNHL, treatment-free / progression-free 
interval >12 months  
 
 – 
 
 
05: R-B to R-CHOP, FL, treatment-free / progression-free interval 6-12 
months  
 
 – 
 
 
06: R-B to R-CHOP, FL, treatment-free / progression-free interval >12 
months  
 
 – 
 
07: R-B to R-CHOP, other iNHL, treatment-free / progression-free interval 
=6-12 months  
 – 
 
 
08: R-B to R-CHOP, other iNHL, treatment-free / progression-free interval 
> 12 months  
 
 – 
 
09: R-B to R-B, FL, treatment-free / progression-free interval 6-12 months  
 
 – 
 
10: R-B to R-B, FL, treatment-free / progression-free interval >12 months  
 
 – 
 
11: R-B to R-B, other iNHL, treatment-free / progression-free interval 6-12 
months  
 
 – 
 
12: R-B to R-B, other iNHL, treatment-free / progression-free interval >12 
months  
 
iNHL: indolent non-Hodgkin's Lymphoma; FL: Follicular Lymphoma; R = Rituximab; R-B = Rituximab and 
bendamustine; R-CHOP = Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
treatment-free / progression-free interval: duration of treatment-free / progression-free interval on the last 
rituximab, or rituximab biosimilars, or anti-CD20 monoclonal antibody containing regimen.  
1Stratification factor “duration of treatment-free interval (6-12 months vs. >12 months)” was amended with CSP 
Amendment 06, Version 6.0, dated 25 SEP 2018 to “duration of progression-free interval on the last 
rituximab containing regimen (6-12 months vs. >12 months) 
2Stratification category “other iNHL” includes SLL, MZL and LPL/WM. 
This study is using 12 strata (defined by 3 stratification variables of which 2 are binary 
stratification variables) with 524 patients randomized in a 1:1 ratio.  
4.9.7 
Region 
For demographics overview and subgroup by region efficacy analyses, patients will be 
grouped together, summarized, and analyzed for two separately defined groupings of 
geographic regions: Geographic Regions 1 and Geographic Regions 2. These groupings are 
defined as follows: 
Geographic Regions 1: 
• US 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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• Europe (Belgium, Bulgaria, Czech Republic, Denmark, Finland, France, Germany, 
Greece, Hungary, Ireland, Israel, Italy, Poland, Portugal, Romania, Slovakia, Spain, 
Ukraine, and United Kingdom)  
• Rest of the world (All other countries/regions) 
Geographic Regions 2: 
• 
North America (Canada, Mexico, and United States)  
• Asia Pacific, excluding Australia, (China, Japan, Korea, Taiwan, Hong Kong, 
Singapore, and Thailand),  
• Rest of the world (All other countries/regions) 
4.9.8 
As treated 
An IxRS will be used for drug distribution. Despite the obligatory use of the IxRS, patients 
may erroneously receive the wrong study treatment (i.e., copanlisib instead of placebo or vice 
versa). For the “as treated” safety analyses, using a conservative approach, patients that have 
received at least one dose of copanlisib will be considered for the copanlisib treatment group. 
Patients who have exclusively received placebo (and R-B or R-CHOP) and no copanlisib will 
be considered for the placebo treatment group. 
4.10 
Validity Review 
During study conduct, important protocol deviations and validity findings affecting the 
assignment of patients to analysis sets will be identified through ongoing data reviews. A 
Blind Review Meeting (BRM) will be scheduled, just prior to unblinding and data release, in 
which the study team will review and finalize the list of important deviations and validity 
findings. Patient validity and details relevant to the statistical evaluation will be discussed and 
agreed upon during the BRM and documented in the BRR. Validity findings which will affect 
the assignment of a patient’s data to analysis sets, and important deviations which may 
significantly affect patient safety, patient rights or may affect study data completeness, 
accuracy, and/or reliability, will be listed in the BRR and Protocol Deviation Document. Any 
changes to the statistical analysis prompted by the results of the BRM will be documented in 
an amendment and, if applicable, in a supplement to this SAP. 
5. 
Analysis Sets 
5.1 
Assignment of analysis sets 
Final decisions regarding the assignment of patients to analysis sets will be made during the 
BRM based on the validity findings in the final list of important deviations and other findings 
and documented in the BRR (see Section 4.10). 
Patients who signed the informed consent but for any reason terminate the study before 
randomization will be considered screening failures. These patients will be listed separately. 
Full analysis set (FAS)  
The primary population for all efficacy analyses is the FAS (considering the Intent-to-treat 
[ITT] principle) population, which is defined as all randomized patients in the Phase III part. 
The FAS will be used for the display of efficacy variables and for the display of 
demographics, baseline characteristics and exposure. Following the ITT principle, patients 


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will be analyzed as randomized, meaning, even if a patient was randomized and received no 
study drug or if randomized and received incorrect drug, these patients will still be analyzed 
for efficacy under FAS, 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). The SAF will be used for the analyses of safety 
variables. Patients will be analyzed as treated. 
In case the SAF and FAS differ, depending on the degree of difference it will be considered 
whether displays for baseline characteristics, demographics and exposure will be repeated in 
the SAF. 
Pharmacokinetic analysis set (PKS)  
All patients in the Phase III part with at least one valid PK measurement (i.e., patients who 
took at least one dose of study drug and had at least one PK sample collected and measured) 
will be included in the evaluation of PK concentration and parameters. 
6. 
Statistical Methodology 
6.1 
Population characteristics 
Population characteristics will be summarized overall and by randomized treatment group 
(copanlisib in combination with R-B or R-CHOP versus placebo in combination with R-B or 
R-CHOP). Unless otherwise specified, analyses will be performed in the FAS. In case the 
FAS and SAF differ, depending on the degree of difference it will be considered whether 
displays for baseline characteristics, demographics and exposure will be repeated in the SAF. 
Patients will be analyzed as randomized for the FAS and as treated for the SAF. 
6.1.1 
Disposition 
The number of countries/regions and centers enrolling patients will be presented and will 
include the number of centers enrolling patients by country/region and pooled country/region. 
The number of patients enrolled, randomized, and valid for the different analysis sets FAS, 
SAF and PKS will be summarized overall, by treatment groups, by country/region and by 
pooled countries/regions. Individual countries/regions will be pooled into regions and these 
regions will be pooled into geographic regions as defined in Section 4.9.7. 
The number of screening failures (patients discontinuing the screening period) together with 
primary reasons for discontinuation will be presented overall. Re-screened patients will not be 
counted as screening failures unless they failed re-screening. A listing of re-screened patients, 
which will include all patient IDs associated with the patient, all dates of informed consent, 
screening visits and last visits, and reasons for failing initial screening, will be provided. If 
patients are screen failures, the failed inclusion/exclusion criteria will also be included. 
“Other” reasons for premature discontinuation from screening will be listed by treatment 
group and patient ID. 
The number of patients assigned to treatment, in addition to the number of patients 
discontinuing the treatment, Safety follow-up, Active follow-up and Survival follow-up 
periods, together with the primary reason for discontinuation will be presented by treatment 
group and overall. Discontinuations due to death after the data cut-off date, reported during 


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data cleaning, will be included in the disposition summaries. “Other” reasons for premature 
discontinuations from these study epochs will be listed by treatment group and patient ID. 
Time to end of study treatment and time to cause specific treatment discontinuation are 
calculated as time from first study drug intake to the last day of study drug intake (i.e., the last 
non 0 mg dose). A Kaplan-Meier plot for “Time to end of study treatment” will be provided 
by treatment group. Cumulative incidence function curves will be provided for “Time to cause 
specific treatment discontinuation” by treatment group and reason for discontinuing 
treatment4.  
For time to end of study treatment all patients permanently discontinuing treatment, including 
those that complete 12 months of treatment per protocol, will be treated as events.  
For time to cause specific treatment discontinuation, patients who complete 12 months of 
treatment per protocol will be considered as events, while patients that permanently 
discontinue treatment prior to 12 months will be considered as competing risk events.  
Time to treatment discontinuation due to AEs not associated with clinical disease progression 
will additionally be reported separately by AE severity5 and treatment group, using 
cumulative incidence function curves. Only patients who discontinue treatment permanently 
due to AEs not associated with clinical disease progression will be included in this analysis. 
Following the inverse event indicator method [16], PFS and OS events censor the true but 
unknown observation time of an individual and censoring in these cases are classified as 
events. The unobservable follow-up time of a patient that has progressed or died is interpreted 
as the follow-up time that potentially would have been obtained had that patient not 
progressed or died.  
PFS follow-up time and rate, as assessed by investigator and independent central review, will 
be determined by treatment group using the inverse event indicator method. Patients who have 
progressed or died (where no progression is documented) during treatment or active follow-
up, will be classified as censored and follow-up time for PFS will be calculated as time from 
date of randomization until date of progression or date of death. Otherwise, patients will be 
classified as having had events and follow-up time for PFS will be calculated as time from 
date of randomization until date of last evaluable tumor assessment (or last biochemical 
assessment for patients with LPL/WM). 
OS follow-up time and rate will be determined by treatment group using the inverse event 
indicator method. Follow-up time for OS will be calculated as time from date of 
randomization until date of death or LKAD (see Section 4.3) if there is no date of death. 
Patients who have died will be classified as censored, and patients who have not died will be 
classified as events. 
The frequency and percentage of patients: 
• Not completing follow-up on the primary endpoint PFS: 
 
4 Reasons for treatment discontinuation will be grouped as follows: completed 12 months of treatment, 
progressed or died during treatment period (including clinical progression and AEs related to clinical 
progression), discontinued treatment due to AEs (not related to progression, including additional primary 
malignancies), discontinued treatment due to patient or physician decision, lost to follow-up (including logistical 
reason), or discontinued treatment due to other reasons (including protocol violations and non-compliance with 
study drug). 
5AE severity will be grouped as follows: CTCAE grade 1 or 2, CTCAE grade 3 or 4 and CTCAE grade 5. 


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o censored for PFS prior to primary cut-off date. 
• Completing follow-up on the primary endpoint PFS until either:  
o having a PFS event 
o still ongoing in Active follow-up without a PFS event at the data cut-off date. 
will be tabulated by treatment group and overall, for both blinded independent central review 
and investigator assessments of PFS. 
A similar table will summarize the frequency and percentage of patients: 
• Not completing follow-up on the secondary efficacy/safety endpoint OS: 
o censored for OS prior to primary cut-off date. 
• Completing follow-up on the secondary efficacy/safety endpoint OS: 
o having an OS event (i.e., death) 
o still ongoing in either Active or Survival follow-up without an OS event at the 
data cut-off date. 
In addition, the number of randomized patients with important protocol deviations will be 
presented overall and by country/region for treatment group. The frequency of important 
deviations, validity findings and number of patients valid for each analysis set will be 
presented by treatment group and overall. 
A separate patient listing of protocol deviations related to the coronavirus disease 2019 
(COVID-19) pandemic (e.g., delay of tumor assessments, delay, interruption, or 
discontinuation of the treatment due to the impact of COVID-19 pandemic) will be provided.  
The number of patients with protocol deviations associated with COVID-19 pandemic will be 
summarized overall and by protocol deviation category (important vs. other). The number of 
patients affected by COVID-19 pandemic related study disruptions (protocol deviations, 
premature discontinuations, and AEs) will also be summarized in a separate table. These 
protocol deviations will be entered in the Rave Electronic Data Capture (EDC) system as 
Manual protocol deviations and identified from the specification of “COVID”.  
Similarly, a separate patient listing of protocol deviations related to the Ukraine-Russia 
conflict (e.g., delay of tumor assessments, delay, interruption, or discontinuation of the 
treatment due to the impact of the conflict) will be provided. These protocol deviations will be 
entered in the Rave EDC system as Manual protocol deviations and identified from the 
specification of “Regional Crisis”.  
6.1.2 
Demographics and other baseline characteristics 
Demographic variables and other baseline characteristics will be summarized by treatment 
group and overall. In addition, summary statistics will be presented for continuous variables. 
Frequency tables will be presented for categorical variables.  
These will include, but may not be limited to, demographic variables (age, sex, race, ethnicity, 
body mass index (BMI), systolic and diastolic blood pressure, height, weight, heart rate, 
temperature, New York Heart Association (NYHA) classification, estimated Glomerular 
Filtration Rate (eGFR), glycated hemoglobin (HbA1c), medical history of diabetes and 
medical history of hypertension). Age, BMI, eGFR and HbA1c will be analyzed as continuous 
variables and in addition categorized with the following categories: 


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• Age group 1 (years): <65, ≥65 
• Age group 2 (years): <80, ≥80 
• Age group 3 (years): <65, 65-74, 75-84, ≥85 
• BMI group (kg/m²): <18.5, ≥18.5- <30, ≥30 
• eGFR group (mL/min/1.73 m2): Normal: ≥ 90 vs. Mild impairment: 60 - <90 vs. 
Moderate impairment: 30 - <60 vs. Severe impairment: 15 - <30) 
• HbA1c group at baseline: <5.7% vs ≥5.7% – <6.5% vs ≥6.5% – ≤8.5% vs >8.5% 
Medical history of diabetes and hypertension, identified by Product specific Bayer MedDRA 
Queries (PBMQ), will be summarized as follows:  
• Diabetic History: [PBMQ] Medical history of diabetes (no/yes) 
• Hypertension History: [PBMQ] Medical history of hypertension (no/yes) 
In addition, the three stratification factors as reported on the randomization page in the eCRF 
will be summarized. 
The following additional baseline characteristics will be summarized: 
• Histology of tumor per investigator’s assessment (FL, MZL overall and including 
subtype of MZL, SLL, and LPL/WM) 
• Staging and size (sum of products of diameters) of tumor at study entry 
• FL grade (for patients with FL) at study entry 
• ECOG performance status at baseline 
• Time from date of initial diagnosis to the date of randomization (months) 
• Time from most recent progression to the date of randomization (weeks) 
• Time from first progression to the date of randomization (months) 
• Number of lesions (number of target and number of non-target lesions) at baseline 
• Number of LPL/WM patients with and without measurable disease at baseline 
• Serum Immunoglobulin M (IgM) level (for LPL/WM patients) at baseline 
• Reason for treatment allocation 
o Prior to base treatment regimen 
• R-chemotherapy to R-B  
• R-B to R-CHOP 
• R-B to R-B 
o Duration of treatment-free/progression-free interval  
• 6-12 months 
• >12 months 


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In addition, demographic and other baseline characteristics will be summarized for each 
histology (FL, MZL, SLL, and LPL/WM) in the FAS. 
The retrospective evaluation of histopathological diagnosis at baseline will be performed 
centrally. These data are exploratory and will be listed for the CSR appendix. 
6.1.3 
Medical history 
Medical history findings (as defined in protocol Section 9.3.2) will be coded by Medical 
Dictionary for Regulatory Activities (MedDRA) codes, v25.1 or higher. Medical history will 
be presented for each MedDRA Primary System Organ Class (SOC) and Preferred Term (PT) 
by treatment group and overall. Ongoing conditions will be presented in a similar way but will 
also include National Cancer Institute (NCI) Common Terminology Criteria Adverse Event 
(CTCAE) grade at baseline. Version 4.03 (or higher) of the NCI-CTCAE dictionary will be 
used. 
6.1.4 
Prior and concomitant medication 
Prior and concomitant medications will be coded by the Anatomical Therapeutic Chemical 
(ATC) classification system according to the World Health Organization Drug Dictionary 
(WHO-DD). Summaries will be provided by ATC class and subclass. The number of patients 
taking at least one prior medication will be reported in addition to the number of patients who 
have taken medication relating to each relevant ATC class and subclass. The same will be 
reported for concomitant medications. Note that the same medication can appear multiple 
times in the table as it can have several ATC codes. 
A medication that has been stopped after first administration of study treatment is considered 
as concomitant, while those that have been stopped before first administration are considered 
as prior. Medications with missing start and stop date but flagged as being ongoing at end of 
study will be considered to have started prior to start of study treatment and ended after stop 
of study treatment. Medications starting more than 30 days after the last day of study 
treatment will be excluded from the summary of concomitant medications.  
Prior and concurrent anti-cancer therapy 
The mean, minimum, median, standard deviation, and maximum number of prior systemic 
anti-cancer therapy lines as well as number of patients with 1, 2, ≥3 lines of prior therapy will 
be summarized by treatment group and overall, for FAS. Time since last systemic anti-cancer 
therapy6 will be summarized using descriptive statistics by treatment group and overall, for 
FAS. The time between the last day of the last course of systemic anti-cancer therapy and the 
day of confirmation of the most recent progression will also be displayed as a classification 
table, showing proportions of patients with ≤ 6 months vs. > 6 to <12 months vs. ≥ 12 months, 
by treatment group.  
In addition, the following frequency tables will be provided by treatment group and overall, 
for the FAS: 
• Prior anti-cancer therapy and therapeutic procedures 
• Prior radiotherapies 
• Prior systemic anti-cancer therapies (displayed by 1. ATC classes, 2. Drug names)  
 
6 Time between last day of last systemic anti-cancer therapy and randomization date. 


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• Type of prior systemic anti-cancer therapy 
• Prior treatment with PI3K inhibitors (refer to the Tables, Listings and Figures (TLF) 
specification document for details of how prior PI3K inhibitors are identified)  
• Prior diagnostic and/or therapeutic procedures for iNHL 
• Concurrent diagnostic and/or therapeutic procedures  
• Radiotherapies during Survival follow-up 
• Systemic anti-cancer therapies during Survival follow-up (displayed by 1. ATC 
classes, 2. Drug names)  
• Type of systemic anti-cancer therapy during Survival follow-up 
6.1.5 
Treatment duration and exposure 
Investigator-recorded cycles for study drug exposure will be mapped to a calculated cycle. 
The analysis of treatment duration and exposure will use the mapped, calculated cycle. A 
description of how investigator defined cycles are mapped to analysis cycles can be found in 
the study document “Analysis Data Reviewer’s Guide (ADRG)”. 
Descriptive statistical summaries will be provided separately for copanlisib/placebo, R-B and 
R-CHOP by treatment group for the following variables:  
• Overall extent of exposure (OEE, as defined in section 4.9.4) for FL, MZL, SLL, 
LPL/WM and all SAF patients 
• Overall extent of exposure, for FL, MZL, SLL, LPL/WM and all SAF patients, by 
categories: 
o 0-90 days 
o 91-180 days 
o 181-270 days 
o 271-365 days 
o >365 days  
• Number of cycles for FL, MZL, SLL, LPL/WM and all SAF patients (statistical 
summaries in addition to number of patients with each number of cycles), determined 
by patients’ last calculated cycle. 
• Number of infusions during treatment period for FL, MZL, SLL, LPL/WM and all 
SAF patients. For patients in the R-CHOP combination arm, the number of infusions 
will be based on rituximab, cyclophosphamide, doxorubicin, and vincristine infusions 
as prednisone is taken orally. 
In addition, the following analyses will be provided over all cycles and by calculated cycle for 
FL, MZL, SLL, LPL/WM and all SAF patients: 


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• Total amount of dose actually administered: sum of actual dose (mg) per calculated 
cycle for each patient 
o For copanlisib/placebo, prednisone/prednisolone, the actual dose per timepoint is 
defined as  
Prescribed dose [mg] × (Total amount of dose administered [mg OR mL] / 
Total amount of dose prior to administration [mg OR mL])  
o For rituximab, cyclophosphamide, doxorubicin, vincristine and B, the actual dose 
per timepoint is defined as  
Prescribed dose [mg] / Body surface Area (BSA) [m2] × (Total amount of dose 
administered [mL] / Total amount of dose prior to administration [mL])  
• Percent of planned dose received = Actual dose [mg] / Planned dose [mg] × 100%.  
o For copanlisib/placebo, a standard of 60 mg is set for all cycles, i.e., infusion days 
(D1, D8 and D15 of each cycle), and for planned dose (might however be 
modified by individual dose-reductions or interruptions). Completed cycles 
therefore have a planned dose of 180 mg. For incomplete cycles, the planned dose 
depends on the number of days (d) in that calculated cycle: 
▪ 60 mg if 0< d <7 
▪ 120 mg if 7≤ d <14 
▪ 180 mg if 14≤ d ≤28 
o For rituximab, a standard of 375 mg/m² body surface is set for all cycles for 
planned dose. 
o For cyclophosphamide, a standard of 750 mg/m² body surface is set for all cycles 
for planned dose. 
o For doxorubicin, a standard of 50 mg/m² body surface is set for all cycles for 
planned dose. 
o For vincristine, a standard of 1.4 mg/m² body surface is set for all cycles for 
planned dose and a maximum of 2.0 mg/m² is also previewed. 
o For B, a standard of 90 mg/m² body surface is set for all cycles for planned dose 
(might however be modified by individual dose-reductions or interruptions), i.e., 
infusion days (D1 and D2 of each cycle). For incomplete cycles, the planned dose 
depends on the number of days (d) in that calculated cycle: 
▪ 90 [mg/ m2] ×BSA [m2] if 0< d <2 
▪ 90 [mg/ m2] ×BSA [m2] ×2 if 2≤ d ≤28 
o For prednisone/prednisolone, a standard of 100 mg is set for all cycles, i.e., oral 
days (D2 to D6 of each cycle), and for planned dose (might however be modified 
by individual dose-reductions or interruptions). Completed cycles therefore have 
a planned dose of 500 mg. For incomplete cycles, the planned dose depends on 
the number of days (d) in that calculated cycle: 
▪ 0 mg if 0< d <2 
▪ 100 mg if 2≤ d <7 and increase 100 mg per day 


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▪ 500 mg if 7≤ d ≤21 
For patients in the SAF population with dose reduction and re-escalation (only for 
copanlisib/placebo), interruption (dose administered is non-zero), or delay (zero dose is 
reported), the number of dose reductions, interruptions, or delays per patient and their reasons 
will be summarized separately for copanlisib/placebo, rituximab7, cyclophosphamide, 
doxorubicin, vincristine, prednisone/prednisolone and B. Interruptions with the same start 
date will be counted as one interruption. 
The duration of dose delays in days will be summarized for copanlisib/placebo. The duration 
is defined as the difference between the date of delay and the date of next exposure 
information (infusion, interruption, or delay). Due to the treatment regimen with one week 
break at the end of each cycle, delays on day 15 of R-CHOP combination therapy, or on day 
22 of R-B combination therapy, are capped at 7 days, in case the calculated duration is greater 
than 7.  
Patient listings will be provided for dose modifications. 
6.2 
Efficacy 
Descriptive evaluations of all efficacy variables will be performed. Summaries of tumor 
response by independent central review and investigator’s assessment will be provided. 
Disease progression in the context of statistical efficacy evaluation is radiological progression, 
as assessed by independent central review. For LPL/WM patients without investigator 
assessed radiologically measurable disease at baseline, progression per Owen criteria 
(assessed locally) will be used. 
Efficacy analyses will be performed when approximately 280 centrally evaluated PFS events 
(PD by independent central review, progression per Owen criteria or death from any cause 
before PD) are observed in the study, see Section 6.6.  
Evaluations from independent central blinded review (defined by Lugano Classification [13]), 
and Owen criteria (assessed locally) for LPL/WM patients, will be used for the efficacy 
analyses of primary and secondary endpoints containing radiological tumor assessments. 
Efficacy analyses will be performed using the FAS, i.e., patients will be analyzed as 
randomized, as described in Section 5.1. For time-to-event analyses the censoring mechanism 
is assumed to be non-informative. Patients will be handled as right-censored in time-to-event 
analyses, if applicable. Censoring of efficacy variables will be handled according to Sections 
6.2.1, 6.2.2, 6.2.1.4.5, 6.2.1.4.6 and 6.2.1.4.7. Missing or non-evaluable tumor observations 
and missing overall best response assessment will be managed as described in Section 4.3. 
6.2.1 
Primary efficacy variable  
Definition of progression-free survival (PFS) 
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), whichever occurs earlier. The 
primary PFS analysis will be based on independent central review. Radiological progression 
will be confirmed in real-time by independent central review. Biochemical progression in 
patients with LPL/WM without measurable lesions evaluable by imaging at baseline 
according to investigator assessment will be assessed locally, and the confirmation of PD by 
 
7 Per the CSP, there will be no dose reductions for rituximab in any cycle. 


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independent central review is not needed8. However, because on progression these patients 
may have developed measurable disease by imaging without simultaneous increase in IgM, 
the imaging material will be submitted for independent central review and PD confirmation. 
LPL/WM patients with a radiologically measurable lesion at Screening will continue to have 
radiological assessments and, in addition, have laboratory tests performed on the same days. 
PFS for patients without PD or death at the time of analysis will be censored at the date of last 
evaluable tumor assessment or last biochemical assessment for patients with LPL/WM 
without measurable lesions evaluable by imaging. 
For ease of reading, tumor assessment in the following context refers to either 1) tumor 
imaging assessment or 2) biochemical assessment for patients with LPL/WM without 
measurable lesions evaluable by imaging. 
The actual date of tumor assessments or date of death will be used for this calculation. If no 
assessment was done at all or the assessment was incomplete at a particular time point, in 
general, the patient is non-evaluable (NE) for this time point. If the examination was 
incomplete and only a subset of measurements could be made but fulfill the criteria for 
progression and/or new lesions are detected, this patient would be considered evaluable with 
assessment of PD. If a tumor assessment is performed over more than one day (e.g., scans for 
chest and abdomen done on different days for a same evaluation) and the response is 
progression (PD), the earliest date /occurrence of the observed progression (i.e., as an event) 
will be used for the calculation of the PFS.  
PFS for patients who have neither tumor assessments nor death after baseline will be censored 
at Day 1. PFS for patients without baseline tumor assessments (e.g., non-existence of a 
measurable lesion at baseline confirmed by independent central review) will be censored at 
Day 1. 
If a tumor assessment date is partially missing, it will be imputed following the imputation 
rules detailed in Section 4.3. 
Table 6–1 lists the censoring rules for PFS events.  
Table 6–1: Progression-free survival (PFS) censoring rules 
Situation 
End Date/Day  Censored Reason for 
Censoring 
Detailed 
Reference  
No baseline tumor assessment 
and no death, or death more 
than 25 (12+12+1) weeks after 
randomization   
Reference 
Date/Day 1 
Yes 
No baseline tumor 
assessment 
 
No baseline tumor assessment 
and death within first 25 
(12+12+1) weeks after 
randomization 
Date of death 
No 
N/A 
 
No post-baseline tumor 
assessment and no death 
Reference 
Date/Day 1 
Yes 
No post-baseline 
tumor assessment 
and no death 
 
 
8 If independent and local assessments are both available for these patients, both will be used to determine 
efficacy endpoints. The patient’s last available tumour assessment in this case will be their last assessment, 
regardless of whether this was assessed locally or by independent central review. 


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Table 6–1: Progression-free survival (PFS) censoring rules 
Situation 
End Date/Day  Censored Reason for 
Censoring 
Detailed 
Reference  
No post-baseline tumor 
assessment and died after the 
first 25 (12+12+1) weeks after 
randomization  
Reference 
Date/Day 1 
Yes 
Death happened after 
time window specified 
in Appendix 9.4.2 
Appendix 9.4.2 
Death after randomization 
during treatment, Active follow-
up period or early enough in 
Survival follow-up to be within 
the time window for a PFS 
event 
Date of death 
No 
N/A 
Appendix 9.4.2 
Death too late in the Survival 
follow-up to be within the time 
window for a PFS event 
Last Tumor 
assessment 
date  
Yes 
Death happened after 
time window specified 
in Appendix 9.4.2 
Appendix 9.4.2 
Death occurs after two or more 
consecutive missed tumor 
assessments  
Last tumor 
assessment 
date 
Yes 
Two or more 
consecutive missed 
tumor assessments 
immediately prior to 
death  
 
New anti-cancer treatment 
other than the study treatment 
prior to observing 
progression1,2  
Last evaluable 
tumor 
assessment 
date prior to the 
initiation of anti- 
cancer 
treatment 
Yes 
New anti-cancer 
treatment 
Appendix 9.4.3 
The progression occurs at the 
next tumor assessment after 
two or more consecutive 
missing or non-evaluable 
assessments  
Last tumor 
assessment 
date before the 
missing tumor 
assessments 
Yes 
Two or more 
consecutive missed 
tumor assessments 
immediately prior to 
progression  
Appendix 9.4.1 
Post-baseline tumor 
assessments but discontinued 
or withdrew early from study 
without documented disease 
progression 
Last tumor 
assessment 
date 
Yes 
Discontinued 
treatment or Active 
follow-up. Given 
Active follow-up may 
be continued despite 
premature EOT, 
patients will be 
censored at last 
tumor assessment 
date (which might be 
in Active follow-up). 
Appendix 9.4.4 
Progression without two or 
more consecutive missed 
tumor assessments 
immediately prior to 
progression 
Date of 
progression  
No  
N/A 
 
Neither PD nor death and no 
other criteria fulfilled 
Last tumor 
assessment 
date 
Yes 
Patient continuing in 
treatment period or 
Active follow-up in the 
absence of 
experiencing a PFS 
event  
 


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1Or surgery affecting target/non-target lesions prior to observing progression.  
2If progression occurs on the same date as start of new anti-cancer treatment it will be assumed that progression 
was prior to the start of new anti-cancer treatment and PFS will not be censored.  
6.2.1.1 
Primary analysis of PFS 
All randomized patients (FAS) will be included in the primary efficacy analysis. 
The analysis will be performed when approximately 280 PFS events (PD by independent 
central review, biochemical progression in patients with LPL/WM without measurable lesions 
evaluable by imaging at baseline, or death if death is before PD) in the FAS are observed.  
The primary efficacy analyses will evaluate whether PFS in the copanlisib in combination 
with R-B or R-CHOP group is longer compared with PFS in the placebo in combination with 
R-B or R-CHOP group in the FAS. 
Descriptive summaries (frequency and percentage of patients) will be provided by treatment 
group for PFS event types and PFS censoring reasons. 
The two treatment groups will be compared using a stratified log-rank test with one-sided 
alpha of 0.025 for the FAS. The primary analysis will include all three stratification factors, 
unless the smallest group within a stratification factor is less than 5% of the total number of 
randomized patients. If this occurs the stratification factor subgroup will not be included in 
the stratified log-rank test but suitably combined into another subgroup. This will also 
counteract the small possibility of exclusive randomization to placebo or copanlisib in groups 
of a small size. If after combining subgroups a stratification factor has no subgroups, then the 
stratification factor will not be included in the stratified log-rank test. A sensitivity log-rank 
test analysis including all groups of the three stratification factors will be performed, see 
Section 6.2.1.4 (Sensitivity Analysis 1). Details of the stratification factors used in 
randomization can be found in Section 4.9.6 
The following test procedure will be applied: 
According to the size of this study it is justified to assume that under H0, PFS, the one-sided 
log-rank test [17] is a sufficiently close approximation to the normal distribution. The actual 
normal distributed one-sided log-rank test will be developed by dividing the test statistic with 
the standard error and comparing the resulting p-value against the study-wise alpha of 2.5%. 
The SAS code to generate the required test statistic will be comparable to the following 
pseudo code, with variable names taking their obvious meaning: 
PROC LIFETEST DATA=dataset; 
  TIME event_time*censorny(cens_value); 
  STRATA {strata variables}/ group=treatmgr test=(logrank); 
  ODS OUTPUT homtests=loguni; 
RUN; 
Technically, the binary treatment variable will be designed with “1” representing copanlisib 
treatment, to allow the correct direction of the one-sided log-rank test (and “0” representing 
the placebo group). 
For the purpose of the analysis, patients who before Protocol amendment 6 were stratified as 
“duration of treatment-free interval ≥6-12 months after completion of the last rituximab 
containing treatment” will be combined with those who after Protocol amendment 6 were 
stratified as “duration of progression-free ≥6-12 months after completion of the last rituximab, 


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or rituximab biosimilars, or anti-CD20 monoclonal antibody containing treatment”; and 
patients who before Protocol amendment 6 were stratified as “duration of treatment-free 
interval >12 months after completion of the last rituximab containing treatment” will be 
combined with those who after amendment 6 were stratified as “duration of progression-free 
>12 months after completion of the last rituximab, or rituximab biosimilars, or anti-CD20 
monoclonal antibody containing treatment”.  
PFS will be tested based on hierarchy test, see Section 6.2.3. 
6.2.1.2 
Additional analyses of PFS 
The hazard ratio (HR), (including 95% confidence interval), will be derived for the total study 
population from the Cox proportional hazards models that are stratified by the same factors as 
used for the primary efficacy analysis. SAS code comparable to the following pseudo code 
will be used: 
PROC PHREG DATA=dataset; 
  MODEL event_time*censorny(cens_value) = treatmgr; 
  STRATA {strata variables}; 
RUN; 
Kaplan-Meier estimates of median PFS (including 95% two-sided confidence intervals) and 
Kaplan-Meier curves will be presented for each treatment group using the following pseudo 
code: 
PROC LIFETEST DATA=dataset; 
 
  TIME event_time*censorny(cens_value); 
 
  STRATA treatmgr; 
 
RUN; 
Subgroup analysis for PFS will be performed by histology (FL, MZL, SLL, and LPL/WM), 
see Section 6.2.5.  
6.2.1.3 
Exploratory analyses of PFS 
Analysis of concordance and discordance between radiological progression evaluation by 
independent central blinded review and by investigator assessment during the blinded study 
phase will be performed via cross tabulations in FAS for overall and for each treatment group.  
To assess the impact of the stratification variables, Kaplan-Meier curves and median PFS 
times by treatment groups will be estimated for each of the 3 stratification variables (if the 
smallest group within one stratification factor is less than 5% of the total number of 
randomized patients then groups of the stratification factor will be suitably combined), 
comparable to the following SAS pseudo-code: 
PROC LIFETEST DATA=dataset; 
BY {strata variable}; 
 
  TIME event_time*censorny(cens_value); 
 
  STRATA treatmgr; 
 
RUN; 
To assess the potential impact of clinical progression, the investigator-based evaluation of 
PFS will also be performed including clinical progression (either direct “clinical progression” 


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or “AE related to clinical progression”) as a progression event9. The first PD assigned by the 
investigator will be used as event. 
Exploratory follow-up analyses of PFS and other efficacy endpoints may be repeated at 
timepoints for follow-up OS analyses (see Section 6.2.2 for details of OS follow-up 
timepoints). 
6.2.1.4 
Sensitivity analyses of PFS 
The following sensitivity analyses for the primary PFS analysis will be performed using 
similar methodology as the primary analysis by independent central review unless otherwise 
specified: 
6.2.1.4.1 Sensitivity Analysis 1 (only if all groups within the 3 stratification 
factors are not used in the primary PFS analysis) 
If the smallest group within one stratification factor is less than 5% of the total number of 
randomized patients a sensitivity analysis for PFS will be conducted using stratified log-rank 
test with all three stratification factors at randomization. The three stratification factors are: 
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).  
6.2.1.4.2 Sensitivity Analysis 2 
PFS will be evaluated with the unstratified log-rank test and Cox model. 
6.2.1.4.3 Sensitivity Analysis 3  
PFS will be evaluated by log-rank test and Cox model and stratified by the following regions:  
o North America (Canada, Mexico, and United States),  
o Asia Pacific, excluding Australia (China, Taiwan, Hong Kong, Japan, Korea, 
Singapore, and Thailand) 
o Rest of the world (All other countries/regions). 
 
9 If the clinical progression is at end of treatment, the last date of treatment, or if there is an AE related to clinical 
progression, the earlier date of either is used. If the clinical progression is at end of active follow-up, the last visit 
date (as provided on the eCRF), or if there is an AE related to clinical progression, the earlier date of either is 
used. If both radiological and clinical progression are documented, the earlier date of radiological progression or 
the derived date of clinical progression is used. In case of death without prior progression, the date of death is 
used, and the patient is considered to have an event. 


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6.2.1.4.4 Sensitivity Analysis 4 
In case of many discrepancies between stratification factors entered in the IxRS and 
information entered in eCRF, PFS will be evaluated with the stratified log-rank test and Cox 
model based on stratification information entered in eCRF. In the case that this is not 
evaluable the prior to base treatment regimen categories R-B to R-CHOP and R-B to R-B, 
will be combined in the analysis. In the case that a patient has an eCRF entry for both 
“progression-free survival >12 months” and for “treatment-free survival >12 months”, 
progression-free survival >12 months will be used. Patients with the important protocol 
deviation rituximab resistance (defined as lack of response, or progression within 6 months of 
the last course of treatment with a rituximab containing regimen, including rituximab 
maintenance) will be excluded from the sensitivity analysis as their stratification factor, 
duration of progression-free interval on the last rituximab, or rituximab biosimilars, or anti-
CD20 monoclonal, is entered incorrectly in both IxRS and the eCRF.  
The censoring mechanism of patients without PFS events at the time of analysis is assumed to 
be non-informative for the primary efficacy analysis. Sensitivity analyses will be performed, 
assessing the impact of a potential informative censoring of such patients.  
6.2.1.4.5 Sensitivity Analysis 5 
PFS will be evaluated considering all patients that are censored, and not at risk, to have events 
in both arms (Kaplan-Meier curves and Cox model for HR). This excludes patients ongoing in 
Active follow up at the time of analysis, as these patients will still be “administratively 
censored” for this sensitivity analysis. 
6.2.1.4.6 Sensitivity Analysis 6 
PFS will be evaluated considering any change as a progression event, e.g., treating initiation 
of a new anti-cancer agent10 as an event at the date of start of new anti-cancer agent, disease 
progression as an event at the date of progression ignoring scheduled missing assessments, 
premature treatment discontinuation as an event at the date of discontinuation [18]. Table 6–2 
lists the censoring order and rules for this sensitivity analysis. If a patient satisfies multiple 
criteria in Table 6–2, then the earliest criterion will be considered. 
 
 
10 Or surgery affecting target/non-target lesions prior to observing progression 


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Table 6–2: PFS censoring rules for sensitivity analysis 6 (any change or premature 
discontinuation from treatment considered as a progression event) 
Situation and censoring order 
End Date/Day  Censored Reason for 
Censoring 
Detailed 
Reference  
All patients regardless of whether they have a baseline or post-baseline tumor assessment 
New anti- cancer treatment prior to 
observing progression1,2 
Date of start of 
new anti-cancer 
treatment3 
No 
N/A 
 
Discontinued or withdrew early 
from treatment without 
documented disease progression 
Date of 
treatment 
discontinuation 
(i.e., date of last 
non 0mg dose) 
No 
N/A 
 
Patients with neither baseline nor post-baseline tumor assessment 
Death within 25 (12+12+1) weeks 
after randomization 
Date of death 
No 
N/A 
 
Death more than 25 (12+12+1) 
weeks after randomization 
Reference 
Date/Day 1 
Yes 
Death happened after 
time window specified 
in Appendix 9.4.2 
Appendix 
9.4.2 
Patients without a baseline tumor assessment 
No baseline tumor assessment 
and no death  
Reference 
Date/Day 1 
Yes 
No baseline tumor 
assessment and no 
death 
 
No baseline tumor assessment 
and death within 25 (12+12+1) 
weeks after randomization 
Date of death 
No 
N/A 
 
No baseline tumor assessment 
and death during treatment period 
or Active follow-up 
Date of death 
No 
N/A 
 
Death early enough in Survival 
follow-up to be within the time 
window for a PFS event. 
Date of death 
No 
N/A 
 
Death too late in the Survival 
follow-up to be within the time 
window for a PFS event 
Last Tumor 
assessment  
Yes 
Death happened after 
time window specified 
in Appendix 9.4.2 
Appendix 
9.4.2 
Patients without a post-baseline tumor assessment 
No post-baseline tumor 
assessment and no death 
Reference 
Date/Day 1 
Yes 
No post-baseline 
tumor assessment and 
no death 
 
No post-baseline tumor 
assessment and death during 
treatment period or Active follow-
up 
Date of death 
No 
N/A 
 
No post-baseline tumor 
assessment and death during 
Survival follow-up, within 25 
(12+12+1) weeks after 
randomization 
Date of death 
No 
N/A 
 
No post-baseline tumor 
assessment and death during 
Survival follow-up, but more than 
25 (12+12+1) weeks after 
randomization 
Reference 
Date/Day 1 
Yes 
Death happened after 
time window specified 
in Appendix 9.4.2 
Appendix 
9.4.2 


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Table 6–2: PFS censoring rules for sensitivity analysis 6 (any change or premature 
discontinuation from treatment considered as a progression event) 
Situation and censoring order 
End Date/Day  Censored Reason for 
Censoring 
Detailed 
Reference  
Patients with both baseline and post-baseline tumor assessment 
Death or progression occurred 
during treatment, Active follow-up 
or early enough in Survival follow-
up to be within the time window for 
a PFS event, regardless of missed 
tumor assessments 
Earliest of: 
• 
Death date 
or 
• 
Date of 
progression 
 
No 
N/A 
 
Death too late in the Survival 
follow-up to be within the time 
window for a PFS event 
Last Tumor 
assessment  
Yes 
Death happened after 
time window specified 
in Appendix 9.4.2 
Appendix 
9.4.2 
Neither PD nor death and no other 
criteria fulfilled 
Last tumor 
assessment  
Yes 
Patient continuing in 
treatment period or 
Active follow-up in the 
absence of 
experiencing a PFS 
event  
 
1 Or surgery affecting target/non-target lesions prior to observing progression. 
2If progression occurs on the same date as start of new anti-cancer treatment it will be assumed that progression 
was prior to the start of new anti-cancer treatment and PFS will not be censored. 
3Or date of surgery. 
6.2.1.4.7 Sensitivity Analysis 7 
PFS will be evaluated more conservatively than in Sensitivity analysis 6 by additionally 
treating premature discontinuations from the Safety follow-up or Active-follow-up as PFS 
events on the date of discontinuation [18]. Table Table 6–3 lists the rules for this sensitivity 
analysis. 
 
Table 6–3: PFS censoring rules for sensitivity analysis 7 (any change or premature 
discontinuation from treatment or Active follow-up considered as a progression 
event) 
Situation and censoring order 
End Date/Day  Censored Reason for 
Censoring 
Detailed 
Reference  
All patients regardless of whether they have a baseline or post-baseline tumor assessment 
New anti- cancer treatment prior to 
observing progression1,2 
Date of start of 
new anti-cancer 
treatment3 
No 
N/A 
 
Discontinued or withdrew early 
from treatment, Safety follow-up or 
Active follow-up without 
documented disease progression 
Date of 
discontinuation 
(i.e., date of last 
non 0mg dose) 
No 
N/A 
 
Patients with neither baseline nor post-baseline tumor assessment 
Death within 25 (12+12+1) weeks 
after randomization 
Date of death 
No 
N/A 
 
Death more than 25 (12+12+1) 
weeks after randomization 
Reference 
Date/Day 1 
Yes 
Death happened after 
time window specified 
in Appendix 9.4.2 
Appendix 
9.4.2 


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Table 6–3: PFS censoring rules for sensitivity analysis 7 (any change or premature 
discontinuation from treatment or Active follow-up considered as a progression 
event) 
Situation and censoring order 
End Date/Day  Censored Reason for 
Censoring 
Detailed 
Reference  
Patients without a baseline tumor assessment 
No baseline tumor assessment 
and no death  
Reference 
Date/Day 1 
Yes 
No baseline tumor 
assessment and no 
death 
 
No baseline tumor assessment 
and death within 25 (12+12+1) 
weeks after randomization 
Date of death 
No 
N/A 
 
No baseline tumor assessment 
and death during treatment period 
or Active follow-up 
Date of death 
No 
N/A 
 
Death early enough in Survival 
follow-up to be within the time 
window for a PFS event. 
Date of death 
No 
N/A 
 
Death too late in the Survival 
follow-up to be within the time 
window for a PFS event 
Last Tumor 
assessment  
Yes 
Death happened after 
time window specified 
in Appendix 9.4.2 
Appendix 
9.4.2 
Patients without a post-baseline tumor assessment 
No post-baseline tumor 
assessment and no death 
Reference 
Date/Day 1 
Yes 
No post-baseline 
tumor assessment and 
no death 
 
No post-baseline tumor 
assessment and death during 
treatment period or Active follow-
up 
Date of death 
No 
N/A 
 
No post-baseline tumor 
assessment and death during 
Survival follow-up, within 25 
(12+12+1) weeks after 
randomization 
Date of death 
No 
N/A 
 
No post-baseline tumor 
assessment and death during 
Survival follow-up, but more than 
25 (12+12+1) weeks after 
randomization 
Reference 
Date/Day 1 
Yes 
Death happened after 
time window specified 
in Appendix 9.4.2 
Appendix 
9.4.2 
Patients with both baseline and post-baseline tumor assessment 
Death or progression occurred 
during treatment, Active follow-up 
or early enough in Survival follow-
up to be within the time window for 
a PFS event, regardless of missed 
tumor assessments 
Earliest of: 
• 
Death date 
or 
• 
Date of 
progression 
 
No 
N/A 
 
Death too late in the Survival 
follow-up to be within the time 
window for a PFS event 
Last Tumor 
assessment  
Yes 
Death happened after 
time window specified 
in Appendix 9.4.2 
Appendix 
9.4.2 
Neither PD nor death and no other 
criteria fulfilled 
Last tumor 
assessment  
Yes 
Patient continuing in 
treatment period or 
Active follow-up in the 
absence of 
experiencing a PFS 
event  
 


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1 Or surgery affecting target/non-target lesions prior to observing progression. 
2 If progression occurs on the same date as start of new anti-cancer treatment it will be assumed that progression 
was prior to the start of new anti-cancer treatment and PFS will not be censored. 
3Or date of surgery. 
6.2.1.4.8 Sensitivity Analysis 8 
A listing of dose delays ≥ 60 days due to COVID-19 or the Ukraine-Russia conflict will be 
presented. Additional sensitivity analyses of PFS related to COVID-19 and/or the Ukraine-
Russia conflict will be performed if treatment delays due to either are observed and PFS 
evaluations are thought to be at risk of being affected. If further analyses are deemed 
necessary, these will be detailed in a supplement to the SAP.  
6.2.2 
Secondary efficacy variables 
Definition of secondary efficacy variables 
ORR 
Assessed in all patients, ORR is defined as the proportion of patients who have a best 
response rating while on treatment or in Active follow-up (i.e., until time of analysis of PFS) 
of CR or partial response (PR) according to the Lugano Classification and for patients with 
LPL/WM a response rating of CR, very good partial response (VGPR), PR, or minor response 
(MR) according to the Owen Criteria. As initiation of new anti-tumor therapy ends the Active 
follow-up, any tumor assessments taking place after the initiation of new anti-cancer therapy 
will not be included in the calculation of ORR. 
DOR 
Assessed in responders only, 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 if available or at day 1 of response, otherwise. DOR will only be 
defined for patients with at least one CR, VGPR, PR, or MR. The conventions for defining 
progressive disease after 2 missing assessments are the same as for PFS (see Table 6–1).  
DCR 
DCR is defined as the proportion of patients who have a BOR of CR, unconfirmed CR, 
VGPR, PR, unconfirmed PR, MR, or confirmed stable disease (SD). Unconfirmed SD is 
defined as SD on or before Study Day 76, which is not confirmed by an additional tumor 
assessment of SD, or better, on Study Day 77 or later. 
CRR 
Assessed in all patients, CRR is defined as the proportion of patients who have a best 
response rating of CR while on treatment or in Active follow-up (i.e., until the time of 
analysis of PFS) according to Lugano classification and for patients with LPL/WM, a 
response rating of CR according to the Owen criteria.  


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TTP 
TTP is defined as the time (in days) from randomization to PD or death related to PD, 
whichever is earlier. Death related to PD is any death except for: 
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 with death not related to progression 
will be censored at the date of their last tumor evaluation. TTP for patients who have neither 
tumor assessments nor death related to PD after baseline will be censored at Day 1. TTP for 
patients without baseline tumor assessments, and no death related to PD within the first 25 
weeks after randomization, will be censored at Day 1. The conventions for calculation of TTP 
are the same as for PFS (Section 6.2.1) with the exception that death not related to PD will not 
be considered as an event. 
The actual dates of tumor assessments will be used for this calculation.  
TTNT 
TTNT is defined as the time from date of randomization to start of new anti-lymphoma 
therapy, where date of randomization is day 1. Start of new anti-lymphoma therapy is a 
component of the Survival follow-up assessments, and it is assumed that, unless documented, 
patients did not receive concomitant anti-lymphoma therapy during treatment/Active follow-
up (as this would trigger the EOT/end of Active follow-up period), or in Safety follow-up (if a 
patient who stopped treatment did not enter the Active follow-up). New anti-lymphoma 
therapy is any new systemic anti-cancer treatment, or radiotherapy for lymphoma with a 
consolidation intent. The start date of the first new anti-lymphoma therapy (systemic or 
radiotherapy) will be used as the start date of new anti-lymphoma therapy.  
Table 6–4 lists the censoring rules for TTNT. 
Table 6–4 TTNT censoring rules 
End Date/Day 
Censored  Situation 
Reason for Censoring 
Start date of new anti- 
cancer treatment 
No 
New anti-cancer treatment 
received by patient 
N/A 
Last visit date 
Yes 
Patient randomized but did not 
take study medication, did not 
enter active follow-up and no 
Survival follow-up assessment 
of new anti-cancer treatment 
No survival assessment of 
new anti-cancer treatment 
 
 
Alive at EOT, did not enter 
Active follow-up and no Survival 
follow-up assessment of new 
anti-cancer treatment 
No survival assessment of 
new anti-cancer 
treatment.  
 
 
Discontinued Active follow-up 
for reasons other than death, 
did not enter Survival follow-up 
No survival assessment of 
new anti-cancer 
treatment. 
 
 
Still ongoing in Survival follow-
up, never entered Active follow-
up and has no assessments of 
new anti-cancer treatment 
recorded 
No survival assessment of 
new anti-cancer 
treatment. 
 
 
Still ongoing in Survival follow-
up, entered Active follow-up 
No survival assessment of 
new anti-cancer treatment 


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Table 6–4 TTNT censoring rules 
End Date/Day 
Censored  Situation 
Reason for Censoring 
and no assessment of new anti- 
cancer treatment recorded 
 
 
Discontinued from Survival 
follow-up for reasons other than 
death, never entered Active 
follow-up and no assessment of 
new anti-cancer treatment 
recorded 
No survival assessment of 
new anti-cancer 
treatment. 
 
 
Discontinued from Survival 
follow-up for reasons other than 
death, entered Active follow-up 
and no assessment of new anti- 
cancer treatment recorded 
No survival assessment of 
new anti-cancer treatment 
 
 
Died during Survival follow-up, 
never entered Active follow-up 
and no assessment of new anti- 
cancer treatment recorded 
No survival assessment of 
new anti-cancer 
treatment. 
 
 
Died during Survival follow-up, 
entered Active follow-up and no 
assessment of new anti-cancer 
treatment recorded 
No survival assessment of 
new anti-cancer treatment 
Data cut-off date 
Yes 
Still ongoing in Active follow-up 
Still on study so 
assumption is they have 
not started a new anti-
cancer treatment. 
Date of death 
Yes 
Died during treatment, Safety 
follow-up or Active follow-up 
Died before endpoint 
reached. 
 
 
 
 
Date of last survival 
assessment of new 
anti- cancer treatment 
Yes 
Still ongoing in Survival follow-
up with survival assessments of 
new anti-cancer treatment but 
no new therapy reported 
Endpoint not reached yet. 
 
 
Discontinued from Survival 
follow-up for reasons other than 
death, was assessed for new 
anti- cancer treatment but no 
new therapy reported 
Discontinued before 
endpoint reached. 
 
 
Died during Survival follow-up, 
was assessed for new anti- 
cancer treatment but no new 
therapy reported and date of 
death after the date of the last 
survival assessment of new 
anti- cancer treatment. 
Died before endpoint 
reached. 
OS 
OS is defined as the time (in days) from randomization until death from any cause. OS of 
patients alive at the time of analysis will be censored at their LKAD. Death after the data cut-
off, reported during cleaning, will be considered for establishing LKAD at data cut-off.  


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See Section 4.3 for details regarding derivation of LKAD and imputation methods for 
partial/missing death dates. 
Time to deterioration in DRS-P of at least 3 points 
Time to deterioration in DRS-P of at least 3 points, as measured by the FLymSI-18 
questionnaire, will be evaluated for all patients. It is defined as the time (in days) from 
randomization to DRS-P decline, PD (as defined for the primary analysis of PFS), or death 
due to any reason, whichever is earlier. DRS-P deterioration censoring rules are listed in 
Table 6–5. 
Table 6–5: DRS-P deterioration censoring rules 
Situation 
End Date/Day  
Censored 
Reason for Censoring 
No baseline DRS-P assessment 
Reference 
Date/Day 1 
Yes 
No baseline or post-baseline 
DRS-P assessment 
No post-baseline DRS-P 
assessment and no PD or death 
within time window 
Reference 
Date/Day 1 
Yes 
No post-baseline DRS-P 
assessment and no PD/death 
within time window 
Patient has DRS-P deterioration 
and has PD  
Min (DRS-P 
deterioration date, 
PD)  
No 
N/A 
Patient has DRS-P deterioration 
and no PD 
DRS-P 
deterioration date 
No 
N/A 
Patient has no DRS-P 
deterioration but has PD before 
the last DRS-P assessment 
PD date 
No 
Has event, as PD occurred 
(even if no deterioration) 
Patient has no DRS-P 
deterioration but has PD or death 
within the time window 
PD date or death 
date 
No 
 
Patient has no DRS-P 
deterioration, no PD, or no death 
within time window 
Last DRS-P 
assessment date 
Yes 
Patient no longer “on study” and 
event for DRS-P deterioration 
not reached. 
New anti-cancer treatment other 
than the study treatment prior to 
observing DRS-P deterioration 
(and no PD before switch to new 
anti-cancer treatment) 
Last evaluable 
DRS-P 
assessment date 
prior to the 
initiation of anti-
cancer treatment 
Yes 
New anti-cancer treatment 
Discontinued or withdraw early 
from the study without 
documented DRS-P deterioration 
or PD or Death within time window 
Last DRS-P 
assessment date 
Yes 
Discontinued 
Neither DRS-P deterioration, nor 
PD/death and no other criteria 
fulfilled 
Last DRS-P 
assessment date 
Yes 
Patient regularly ongoing in trial 
without DRS-P event occurred 
PD as defined for the primary analysis of PFS. 
Similar time window for PFS will be used for the derivation. 
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, will be evaluated for all patients. It is defined as the time (in months) from 
randomization to DRS-P improvement of at least 3 points. The patient will generally be 
censored at the last non-missing post-baseline DRS-P score, if no DRS-P improvement, PD 


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(as defined for the primary analysis of PFS), or death occurs. If a PD or death occurs before a 
potential DRS-P improvement (or no DRS-P improvement is documented at all), the patient 
will be censored at the largest observation time (of events and censoring in all patients 
evaluated for improvement), plus 1 day. Regular censoring rules, apart from the special rule 
for PD/Death will be comparable to the censoring for deterioration of DRS-P. The DRS-P 
improvement censoring rules are listed in Table 6–6. 
Table 6–6: DRS-P improvement censoring rules 
Situation 
End Date/Day  
Censored 
Reason for Censoring 
Patient has DRS-P improvement 
before PD or death 
DRS-P improvement 
date  
No 
N/A 
Patient has PD or death (including 
drop out due to PD) before DRS-P 
improvement  
Largest observation 
time (of events and 
censoring in all 
patients evaluated 
for improvement), 
plus 1 day 
Yes 
PD / death occurs before 
improvement and thus 
improvement becomes 
impossible for these patients 
Patient has PD or death (including 
drop out due to PD) after DRS-P 
improvement 
DRS-P improvement 
date 
No 
Same rule as Line 1, as PD / 
death after DRS-P 
improvement has no impact  
No baseline or post-baseline 
DRS-P assessment 
Reference Date/Day 
1 
Yes 
No baseline or post-baseline 
DRS-P assessment 
Patient has no DRS-P 
improvement, no PD, and no 
death  
Last DRS-P 
assessment 
Yes 
Event for DRS-P improvement 
not reached 
New anti-cancer treatment other 
than the study treatment prior to 
observing DRS-P improvement 
(and no PD before last DRS-P 
assessment before switch to other 
than study treatment) 
Largest observation 
time (of events and 
censoring in all 
patients evaluated 
for improvement), 
plus 1 day 
Yes 
New anti-cancer treatment 
Discontinued or withdraw early 
from the study without 
documented DRS-P improvement 
or PD/Death  
Last DRS-P 
assessment date 
Yes 
Discontinued 
Neither DRS-P improvement, nor 
PD/death and no other criteria 
fulfilled 
Last DRS-P 
assessment 
Yes 
Patient regularly ongoing in 
trial without DRS-P event 
occurred 
PD (as defined for the primary analysis of PFS) 
FLymSI-18 questionnaire 
The FLymSI-18 questionnaire 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 the 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 function and 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. A summary of 
the scoring guideline is included in Appendix 9.2. 


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Analyses of secondary efficacy variables 
All secondary efficacy endpoints will be analyzed in the FAS at the time of the analysis of the 
primary efficacy variable. Image based secondary efficacy endpoints will be analyzed based 
on blinded independent central review data, except for patients with LPL/WM without 
measurable lesions evaluable by imaging at baseline investigator assessment, whose local 
assessments will be used in place of centrally reviewed data. Image based secondary efficacy 
endpoints analyses will also be analyzed and presented based on investigator assessments. 
PET-CT combined investigator assessment will be derived following the principles detailed in 
Appendix 9.1. 
The ORR will be analyzed using the Cochran-Mantel-Haenszel test stratified by the same 
stratification factors used in the PFS analysis. The null hypothesis is defined as: 
H0, ORR: ORRCopanlisib+R-B/R-CHOP ≤ ORRPlacebo+R-B/R-CHOP 
The alternative hypothesis is: 
H1, ORR: ORRCopanlisib+R-B/R-CHOP > ORRPlacebo+R-B/R-CHOP 
In addition, the point estimate as well as 95% two-sided confidence intervals for the Mantel-
Haenszel weighted treatment difference [19] will be calculated. 
The time to deterioration and time to improvement in DRS-P subscale of FLymSI-18 will be 
analyzed analogously to PFS, using similar hypotheses, decision rules, and significance level, 
but will only be included in the confirmatory testing for “Europe and the rest of the world” 
(Section 6.2.3). 
Analysis of OS 
OS will be analyzed in terms of safety and efficacy. Further details with regards to the OS 
safety analysis are included in Section 6.3.5, while OS efficacy analyses are detailed in this 
section. 
For efficacy, the analysis of OS will be performed initially as an interim analysis at the time 
of primary completion of the primary endpoint, PFS. The final formal statistical analysis of 
OS will take place 5 years after the last patient started study treatment, when it is predicted 
that approximately 176 OS events will have occurred. In both instances, OS will be analyzed 
using stratified log-rank tests analogue to the analysis for the primary analysis of the primary 
endpoint. Further details regarding the division of study-wise alpha are included in Section 
6.2.3. The final descriptive analysis of OS will take place at the end of the study, up to 10 
years after the last patient started study treatment.  
The survival status of each patient will be collected quarterly during the Survival follow-up 
period, up to 10 years after the last patient started study treatment. At this point the final 
descriptive analysis of OS at study end will take place.  
Approximately 12 months after analysis of the primary and secondary efficacy variables, and 
at yearly intervals thereafter, further descriptive analyses of OS (each a “follow-up OS 
analysis”) will be performed. These analyses will be updates of the analysis of OS performed 
on data available at the time of analysis of the primary endpoint, PFS. 
Analysis of other secondary efficacy variables 
TTP, DOR, TTNT as well as CRR will not be included into the confirmatory testing strategy 
but analyzed supportively only.  


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TTP, DOR and TTNT will be analyzed using stratified log-rank tests analogue to the analysis 
for the primary analysis of the primary endpoint. CRR will be analyzed using the Cochran-
Mantel-Haenszel test and estimated difference analogous to the analysis of ORR. The test will 
be adjusted for the same stratification factors as used for the primary analysis of PFS. 
Additional analyses of secondary efficacy variables 
ORR 
Exploratory analysis will be performed to summarize the concordance and discordance 
between best overall response results by independent central review and investigator’s 
assessment.  
Subgroup analysis for ORR will be performed by histology (FL, MZL, SLL, and LPL/WM), 
see Section 6.2.5. 
DRS-P 
As a sensitivity analysis, an analysis of “worsening of DRS-P alone”, considering patients as 
“censored” at the date of their last DRS-P measurement, ignoring PD or death (that is, not 
considering PD or death as events), will be performed. The sensitivity analysis censoring 
rules, for the worsening of DRS-P alone, are listed in Table 6–7. 
Table 6–7: Worsening of DRS-P alone sensitivity analysis censoring rules 
Situation 
End Date/Day  
Censored 
Reason for Censoring 
No baseline DRS-P assessment 
Reference 
Date/Day 1 
Yes 
No baseline or post-baseline 
DRS-P assessment 
Patient has DRS-P deterioration  
DRS-P 
deterioration date 
No 
N/A 
Patient has no DRS-P 
deterioration  
Last DRS-P 
assessment 
Yes 
New anti-cancer treatment other 
than the study treatment prior to 
observing DRS-P deterioration  
Last evaluable 
DRS-P 
assessment prior 
to the initiation of 
anti-cancer 
treatment 
Yes 
New anti-cancer treatment 
Discontinued or withdraw early 
from the study without 
documented DRS-P deterioration  
Last DRS-P 
assessment date 
Yes 
Discontinued 
No DRS-P deterioration and no 
other criteria fulfilled 
Last DRS-P 
assessment 
Yes 
Patient regularly ongoing in trial 
without DRS-P event having 
occurred 
6.2.3 
Confirmatory statistical test strategy 
Separate statistical testing strategies will be conducted for (1) the United States and (2) 
Europe and the rest of the world, as outlined below. 
United States 
For the United States, to control the study-wise alpha, a fixed-sequence multiple testing 
strategy will be implemented. The sequence of the testing of primary and secondary endpoints 
will be as follows and as shown in Figure 6–1: 


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The primary endpoint PFS will be tested in the FAS population (tested at one-sided 
alpha=0.025). 
If the PFS test in the FAS population is successful, 
a) a second test on PFS in the FL histology population will be performed (tested at one-sided 
alpha=0.025); if this is successful, 
b) a third test on the ORR in the FAS population will be performed (tested at one-sided 
alpha=0.025); if this is successful, 
c) a fourth test on the OS in the FAS population will be performed. An interim OS analysis 
(tested at one-sided alpha=0.002) and a final formal OS analysis (tested at one-sided 
alpha=0.023) will be performed. This would conclude the confirmatory test procedure. 
Figure 6–1 Confirmatory test strategy based on four test families for United States 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Europe and the rest of the world 
For Europe and the rest of the world, to control the study-wise alpha, a fixed-sequence 
multiple testing strategy will be implemented. In this strategy, the sequence of the testing of 
primary and secondary endpoints is as follows and as shown in Figure 6–2: 
Family 3 (F3) 
Family 2 (F2) 
PFS in iNHL population (FAS) 
Alpha: 2.5% 
PFS in FL population   
Tested, if success in F1 
Alpha: 2.5% 
ORR in iNHL population (FAS)  
Tested, if success in F2 
Alpha: 2.5% 
Family 1 (F1) 
Family 4a (F4a) 
Interim OS for efficacy in 
iNHL population (at 
primary PFS evaluation) 
(FAS) 
Tested, if success in F3 
Alpha: 0.2% 
 
Final formal OS for 
efficacy in iNHL 
population (at 
approximately 176 OS 
events) (FAS) 
Tested, if success in F3 
Alpha: 2.3% 
Family 4b (F4b) 
Alpha=0.002 Alpha=0.023 


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The primary endpoint PFS will be tested in the FAS population (tested at one-sided 
alpha=0.025). 
If the PFS test in the FAS population is successful,  
a) a second test on the ORR in the FAS population will be performed (tested at one-sided 
alpha=0.025); if this is successful, 
b) a third test on the DRS-P deterioration in the FAS population will be performed (tested at 
one-sided alpha=0.025); if this is successful, 
c) a fourth test on the DSR-P improvement in the FAS population will be performed (tested 
at one-sided alpha=0.025); if this is successful, 
d) a fifth test on the OS in the FAS population will be performed. An interim OS analysis 
(tested at one-sided alpha=0.002) and a final formal OS analysis (tested at one-sided 
alpha=0.023) will be performed. This would conclude the confirmatory test procedure. 
Figure 6–2: Confirmatory Test Strategy Based on Five Test Families for “Europe and 
the rest of the world” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family 4 (F4) 
Family 2 (F2) 
DRS-P deterioration in iNHL population (FAS) 
Tested, if success in F2 
Alpha: 2.5% 
Family 3 (F3) 
PFS in iNHL population (FAS) 
Alpha: 2.5% 
ORR in iNHL population (FAS)  
Tested, if success in F1 
Alpha: 2.5% 
DRS-P improvement in iNHL population (FAS) 
Tested, if success in F3 
Alpha: 2.5% 
Family 1 (F1) 
Family 5a (F5a) 
Interim OS for efficacy in 
iNHL population (at 
primary PFS evaluation) 
(FAS) 
Tested, if success in F4 
Alpha: 0.2% 
 
Final formal OS for 
efficacy in iNHL 
population (at 
approximately 176 OS 
events) (FAS) 
Tested, if success in F4 
Alpha: 2.3% 
Family 5b (F5b) 
Alpha=0.002 Alpha=0.023 


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Conditional power with respect to PFS and ORR in the full study population, and PFS in the 
FL subpopulation, is determined based on published studies that evaluate 2nd line immuno-
chemotherapy combinations in iNHL populations: Rummel, 2005 [10], Rummel, 2016 [24] 
and Rueda, 2018 [25], which are also described in Section 9.6. 
Conditional statistical power assessments for the test in ORR, under different scenarios, is 
provided in Table 6–8. 
Table 6–8 Assessment of Statistical Power for ORR in the Overall FAS 
Assumed ORR 
Assumed risk 
difference 
Resulting conditional power 
Placebo 
Copanlisib 
0.80 
0.90 
0.1 
87.7% 
0.85 
0.90 
0.05 
36.0% 
0.85 
0.95 
0.1 
96.7% 
0.90 
0.95 
0.05 
53.5% 
ORR = objective response rate. 
Note: Calculated using binomial enumeration, for Fisher’s exact test, using PASS, 2022. 
Table 6–8  shows that the conditional statistical power for the test in ORR is expected to 
range between 36% and 97%. 
As iNHL is an indolent condition, there may not be a meaningful number of OS events at the 
time of the primary analysis of PFS. Therefore, the study-wise alpha, assigned for the analysis 
of OS, will be divided between an interim and a final formal OS analysis, as detailed in 
Section 4.8. 
The formal interim analysis of OS for efficacy is planned at the time of primary analysis for 
PFS (F4a in the United States and F5a in “Europe and the rest of the world”), if all other key 
secondary endpoints are significant, using a small portion of the study-wise alpha (0.002). At 
the time point of primary analysis, it is assumed that approximately 151 OS events have 
occurred. In that case, the considered scenarios would detect a significant OS effect with 
statistical (conditional) power ranging from 6.6% (if true OS HR=0.8) to 60.3% (if true OS 
HR=0.6). 
A final formal analysis of OS for efficacy (F4b in the United States and F5b in “Europe and 
the rest of the world”) is planned to be performed after all patients have been followed up for 
at least 5 years, when approximately 176 OS events are expected to have occurred and will 
use the remaining portion of the study-wise alpha (0.023). At this analysis the considered 
scenarios would detect a significant OS effect with statistical conditional power ranging from 
30.3% (if true OS HR=0.8) to 91.8% (if true OS HR=0.6). 
If the formal interim analysis of OS is significant, this final formal analysis of OS for efficacy 
will be for descriptive purposes only. 


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Beyond the final formal analysis of OS, there might be additional follow-up analyses not 
formally applying alpha control.  
Power results for all scenarios and formal analyses are presented in Table 6–9 
Table 6–9 Scenarios for formal OS evaluations for efficacy 
True underlying 
HR for OS  
Power to detect significant treatment effect in OS vs. HR=1 
 
With 151 events and alpha of 
0.002 
With 176 events and alpha of 
0.023 
0.60 
60.3% 
91.8% 
0.65 
40.9% 
80.6% 
0.70 
24.6% 
64.5% 
0.75 
13.3% 
46.5% 
0.80 
  6.6% 
30.3% 
Given current information, the analysis considering a Hazard Ratio for OS of 0.75 is 
considered the most appropriate. To power a hypothetical new study with 80% at the final 
formal analysis of OS with HR=0.75 as true hazard ratio, 380 OS events would be needed.  
Additional assessments of OS data and scenarios for OS (answering an HA request) 
In Appendix 9.6, an assessment of OS events needed to detect a difference in OS compared 
with the placebo group, for plausible HR assumptions, over a range of power levels from 60% 
to 90% is described.  
In Appendix 9.7, details of the formal OS event analyses for varying primary PFS time points 
and OS hazard ratios are described. 
In Appendix 9.8, the likelihood to rule out a harmful effect in OS with additional OS follow-
up beyond the final formal (at approximately 176 OS events) analysis is simulated. 
6.2.4 
Other efficacy variables 
Due to differing cycle lengths, by visit summaries will be reported for those assigned to R-B 
treatment (copanlisib+R-B and placebo+R-B) only. Equivalent data for those assigned to R-
CHOP treatment will be listed. 
FLymSI-18 total and subscale scores (DRS-P, DRS-E, TSE, FWB) are other efficacy 
variables. 
1. Area under the curve (AUC) across all data of FLymSI-18 DRS-P subscale score 
An additional analysis of the physical symptoms of lymphoma (as measured using the 
FLymSI-18 DRS-P subscale) will be performed to assess differences between treatment arms 
in the FAS based on AUC. AUC will be derived using the linear trapezoidal rule: 
 
𝐴𝑈𝐶0−𝑡𝑛≈
1
2 ∑
(𝑡𝑖+1 −𝑡𝑖)(𝐶𝑖+ 𝐶𝑖+1)
𝑛−1
𝑖=1
 
where Ci denotes the non-missing DRS-P score at timepoint ti. Missing DRS-P scores will not 
be replaced. If a patient has only the baseline value, the AUC will not be calculated.  
Summary statistics will be provided for AUC and for the AUC normalized over the 
observation time.  


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2. FLymSI-18 total and subscale scores (DRS-P, DRS-E, TSE, FWB), and time to 
meaningful worsening of physical symptoms of lymphoma based on the DRS-P subscale. 
Total FLymSI-18 and subscales will be evaluated descriptively. The number and percentage 
of patients with a meaningful worsening of physical symptoms, defined as a decrease in DRS-
P score ≥3 points, will be presented by visit and overall. The time to meaningful worsening of 
physical symptoms will be described. 
3. ECOG performance status 
ECOG performance status will be summarized by visit using descriptive statistics for the 
original score, as well as for the change from baseline score by treatment group in the FAS. 
6.2.5 
Subgroup analyses 
6.2.5.1 
Histology specific subgroup analysis 
For selected subgroups of patients in the FAS, as defined by cancer histology, separate 
analyses of treatment effect for the primary and various secondary endpoints will be 
performed. Diagnosis of cancer histology from investigator’s assessment will be used in 
statistical analyses.  
The respective endpoints and histology can be seen from Table 6–10, which describes the 
planned output format. 
In addition, for the time to event endpoints, histology-specific Kaplan Meier evaluations 
comparing treatment groups will be provided (i.e., KM plot and descriptive statistics 
including log-rank test). 
Table 6–10 Overview of Histology Specific Subgroup Analyses 
  
Variable 
Histology 
Subgroup 
PFS ORR  CRR  DCR  
Time to 
deterioration*  
DRS-P 
Time to 
improvement*  
DRS-P 
OS 
 FL 
c) 
b) 
b) 
b) 
a) 
a) 
a) 
MZL 
a) 
b) 
b) 
b) 
a) 
a) 
a) 
   
Extranodal 
MZL 
a) 
b) 
b) 
b) 
a) 
a) 
a) 
    Nodal 
MZL 
a) 
b)  
b)  
b)  
a) 
a) 
a) 
    Splenic 
MZL  
a) 
b) 
b) 
b) 
a) 
a) 
a) 
SLL 
a) 
b) 
b) 
b) 
a) 
a) 
a) 
LPL/WM 
a) 
b) 
b) 
b) 
a) 
a) 
a) 


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* of at least 3 points 
FL: follicular lymphoma; MZL: marginal-zone lymphoma; SLL: small lymphocytic lymphoma; 
LPL: lymphoplasmacytic lymphoma; WM: Waldenström macroglobulinemia 
a) Evaluated by use of a non-stratified Cox-PH model.  
Results displayed in table: Number of events per treatment group, HR, 95% CI. 
b) Evaluated by use of a chi-square test. Results displayed in table: Number patients per treatment group, 
estimated treatment difference and 95% CI. 
c) Evaluated by use of stratified Cox-PH model (stratified by prior to base treatment regimen and duration of 
progression free interval) and also a non-stratified Cox-PH model. Results displayed in table: Number of 
events per treatment group, HR, 95% CI. 
The same subgroup analyses will be conducted for the secondary endpoints DOR, TTP and 
TTNT by histology subgroups FL and MZL, separately.  
6.2.5.2 
Other subgroup analyses 
Subgroup analyses will include forest plots of response/HRs as well as treatment-interaction 
analyses. The forest plots of response/HRs will be provided for the primary efficacy endpoint 
(PFS) as well as the secondary efficacy endpoints ORR, time to deterioration in DRS-P and 
time to improvement in DRS-P. The treatment-interaction analysis will be conducted for the 
primary efficacy endpoint (PFS), and the secondary efficacy endpoints time to deterioration in 
DRS-P and time to improvement in DRS-P. Kaplan-Meier estimates of median times to PFS 
(including 95% CI) and Kaplan-Meier curves will be provided for each subgroup level for 
each treatment group. Subgroup levels without a sufficient number of events observed will be 
excluded from corresponding subgroup analysis. All subgroup analyses will be done on non-
stratified Cox model and log-rank test. For efficacy endpoint ORR, chi-square test will be 
used. 
For the primary efficacy endpoint (PFS), subgroup levels to be analyzed are: 
• iNHL histology (FL vs. other iNHL histology)  
• iNHL histology (FL vs. MZL vs. SLL vs. LPL/WM) treatment interaction test only 
will be performed; for subpopulation analysis see Section 6.2.5.1 
• Prior to base treatment regimen (R-chemotherapy to R-B vs. R-B to R-CHOP vs. R-B 
to R-B). Prior to base treatment regimen categories R-B to R-CHOP and R-B to R-B 
may be combined due to small patient numbers. 
• 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) 
• Prior lines of systemic anti-cancer therapy (1 vs. 2 vs. ≥3) 
• Geographic regions 1 (US, Europe, Rest of world) 
• Geographic regions 2 (North America, Asia Pacific, Rest of the world) 
• Age group (years) (<65 vs. ≥65) 
• ECOG performance status (0 vs. 1 vs. 2) 
• Sex (Male vs. Female) 
• Race 
• Ethnicity (Hispanic or Latino vs. non-Hispanic and non-Latino) 


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For secondary efficacy endpoints ORR, DCR, CRR, time to deterioration of DRS-P, and time 
to improvement in DRS-P, the same subgroup levels will be analyzed excluding sex.  
Subgroup analyses may be performed for OS at the time of the final formal OS analysis 
(approximately 5 years after the last patient started study treatment). 
6.3 
Safety 
6.3.1 
Adverse events (AEs) 
AEs will be coded by MedDRA codes and NCI-CTCAE version 4.03 (or higher) dictionary. 
The final versions used will be stored in the clinical database and provided in a footnote to the 
respective tables. Severity of AEs and hematological/biochemical toxicities based on 
laboratory measurements will be graded using NCI-CTCAE dictionary. AEs will be classified 
as related or not related to study drug, as determined by the investigator. 
A treatment-emergent AE (TEAE) is defined as any event occurring or worsening after start 
of study drug administration until 30 days after the last study drug intake.  
Descriptive summary tables (frequency and percentage of patients, not of events) will be 
presented by treatment group and overall, by MedDRA SOC/PT and by worst NCI CTCAE 
grade for the following: 
• Overview of TEAEs  
• TEAEs  
• TEAEs of infusion related reaction 
• Drug-related TEAEs (copanlisib/placebo or R-B/R-CHOP)  
• Treatment-emergent serious AEs (TESAEs) 
• Drug-related TESAEs 
• TEAEs of special interest (as detailed in Section 6.3.3).  
Exposure adjusted TEAEs will be summarized by treatment group and by MedDRA SOC/PT. 
The exposure adjusted incidence rate per 100 patient years is defined as 100 times the number 
of patients with at least one TEAE divided by the sum of exposure times in years, where 
exposure time is the time to first occurrence if a TEAE occurs, or the treatment duration plus 
time at risk after treatment ends if no TEAE occurs. The time at risk after treatment is the 
minimum of 30 days or the days of death relative to the last treatment. 
Incidences of patients’ TEAEs, drug-related (copanlisib/placebo or R-B/R-CHOP, 
respectively) and/or TESAEs by MedDRA SOC/PT and worst NCI-CTCAE grade will be 
repeated by the following criteria:  
• age group (Years): (<65 vs. ≥65) 
• sex (Male vs. Female) 
• history of hypertension: [PBMQ = Standardized MedDRA Query (SMQ)_90001275 in 
MedDRA v25.1 or higher] Medical history of hypertension (yes vs. no) and 
• history of diabetes: [PBMQ = SMQ_90001276 in MedDRA v25.1 or higher] Medical 
history of diabetes (yes vs. no).  


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Furthermore, all TEAEs and drug-related TEAEs with incidence of at least 10% will be 
summarized by MedDRA SOC/PT and worst NCI-CTCAE grade. In addition, all TEAEs and 
drug-related TEAEs with incidence of at least 5% will be summarized by MedDRA for worst 
NCI-CTCAE grade and for NCI-CTCAE grade 3-4. All TEAEs will be summarized by 
MedDRA SOC/PT for NCI-CTCAE grade 5. 
The number and percentage of patients who discontinued study treatment due to a 
TEAE/TESAE (discontinued all study treatments) or required a dose reduction 
(copanlisib/placebo/R-B/R-CHOP) due to a TEAE or interruption caused by a TEAE will be 
summarized separately for copanlisib/placebo and R-B/R-CHOP by MedDRA SOC/PT and 
worst NCI-CTCAE grade. The incidences of these TEAEs will be presented also separately 
by drug relatedness (copanlisib/placebo or R-B/R-CHOP) and by MedDRA SOC/PT and 
worst NCI-CTCAE grade.  
In addition, the following AE summaries by cancer histology (according to investigator 
pathology) will be provided: 
• 
Overview of TEAEs 
• TEAEs  
• Drug-related TEAEs (copanlisib/placebo or R-B/R-CHOP) 
• TESAEs  
• Drug-related TESAEs  
Deaths (including all grade 5 TEAEs) will be summarized by treatment group and overall. As 
“AE” is not captured as a primary cause of death in the Survival follow-up, for the overall 
summary of deaths, deaths with “AE” or “other” as the primary cause will be pooled together 
under the primary cause “other”. 
AEs occurring prior to starting treatment and AEs occurring at least 30 days after the last dose 
of study treatment (i.e., post-treatment AEs) will also be summarized by treatment group and 
overall. 
In addition, patient listings will be provided by treatment group for the following AEs: 
• Patients who died during study treatment up to 30 days after last dose of study 
treatment: patient ID, sex, age, race, histology, sponsor AE identifier, start and stop 
dates of study drug, combination therapy (R-B/R-CHOP), date of death, days within 
first and last dose date, cause of death, MedDRA SOC and PT and relationship to 
study drug (related to copanlisib/placebo, related to R-B/R-CHOP, related to both, and 
no). 
• Patients who died later than 30 days after last dose of study treatment (including 
patients with a death date after the data cut-off date, reported during data cleaning): 
patient ID, sex, age, race, histology, sponsor AE identifier, start and stop dates of 
study drug, combination therapy (R-B/R-CHOP), date of death, days within first and 
last dose date, cause of death, MedDRA SOC and PT, and relationship to study drug 
(related to copanlisib/placebo, related to R-B/R-CHOP, related to both, and no). 
• Treatment-emergent serious adverse events (TESAEs): patient ID, sex, age, histology, 
race, sponsor AE identifier, reported term, MedDRA SOC and PT, CTCAE toxicity 
grade, reason for seriousness, combination therapy (R-B/R-CHOP), days within first 


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and last dose date, start and stop dates of AE, relationship to study drug (related to 
copanlisib/placebo, related to R-B/R-CHOP, related to both, and no), protocol required 
procedure related (yes/no), outcome, actions taken with each study drug.  
• Study drug-related SAEs will be provided separately for copanlisib/placebo and R-
B/R-CHOP, respectively, with similar information. 
• TEAEs of special interest: patient ID, sex, age, histology, race, sponsor AE identifier, 
reported term, MedDRA SOC and PT, CTCAE toxicity grade, days within first and 
last dose date, combination therapy (R-B/R-CHOP), start and stop dates of AE, 
relationship to study drug (related to copanlisib/placebo, related to R-B/R-CHOP, 
related to both, and no), protocol required procedure related (yes/no), serious (yes/no), 
reason for seriousness, outcome, actions taken with each study drug. 
• TEAEs leading to permanent discontinuation of study treatment, a dose reduction 
(copanlisib/placebo/R-B/R-CHOP) or interruption/delay will be listed separately for 
copanlisib/placebo and R-B/R-CHOP, respectively: patient ID, sex, age, histology, 
race, sponsor AE identifier, reported term, MedDRA SOC and PT, CTCAE toxicity 
grade, days within first and last dose date, start and stop dates of AE, relationship to 
study drug (related to copanlisib/placebo, related to R-B/R-CHOP, related to both, and 
no), protocol required procedure related (yes/no), serious (yes/no), reason for 
seriousness, outcome, actions taken with each study drug. 
6.3.2 
Adverse events by time-interval 
TEAEs, drug-related TEAEs, and TESAEs will be presented for each study drug according to 
time-of-onset (new onset or worsening).  
The following time intervals will be presented for copanlisib and placebo: 
• Day 1 – Day 90: to include all copanlisib/placebo-treated patients 
• Day 91 – Day 180: to include all copanlisib/placebo-treated patients, treated for at 
least 3 months 
• Day 181 – Day 270: to include all copanlisib/placebo-treated patients, treated for at 
least 6 months 
• Day 271 – Day 360: to include all copanlisib/placebo-treated patients, treated for at 
least 9 months 
• Day 361 or greater: to include all copanlisib/placebo-treated patients, treated for at 
least 12 months. 
The following time intervals will be presented for R-B and R-CHOP: 
• Day 1 – Day 90: to include all R-B/R-CHOP-treated patients 
• Day 91 – Day 180: to include all R-B/R-CHOP-treated patients, treated for at least 3 
months 
• Day 181 or greater: to include all R-B/R-CHOP-treated patients, treated for at least 6 
months. 


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6.3.3 
Adverse events of special interest 
Non-infectious pneumonitis/interstitial lung disease 
Non-infectious pneumonitis is defined as AE of special safety interest (protocol Section 
6.4.1). The SMQ 'Interstitial lung disease' with narrow search (i.e., category 2A) will be used 
to select these AEs of special interest. 
Patient listings will be provided by treatment group for TEAEs of pneumonitis leading to 
copanlisib/placebo treatment discontinuation: patient ID, sex, age, histology, race, sponsor AE 
identifier, MedDRA SOC and PT, reported term, CTCAE toxicity grade, days within first and 
last dose date, reason for seriousness, combination therapy (R-B/R-CHOP), start and stop 
dates of AE, relationship to study drug (related to copanlisib/placebo, related to R-B/R-
CHOP, related to both, and no), protocol required procedure related (yes/no), outcome, 
actions taken with each study drug. 
A descriptive summary of treatment-emergent and copanlisib/placebo-related treatment-
emergent MedDRA PTs within the SMQ “Interstitial lung disease” (frequency and percentage 
of patients, not of events) will be presented by treatment group and cancer histology (total 
iNHL and histological subpopulations according to investigator pathology). 
For treatment emergent events under the SMQ “Interstitial lung disease”, the incidence 
proportions of worst CTCAE grades, seriousness, outcomes, and actions taken will be 
presented for the total iNHL and histological subpopulations (according to investigator 
pathology). This table will also be provided for the subgroups of patients with and without 
history of respiratory disorders (as defined in Section 6.3.4.1).  
For copanlisib/placebo-related treatment emergent events under the SMQ “Interstitial lung 
disease”, the incidence proportions of worst CTCAE grade, seriousness, outcome, and action 
taken will be presented for the total iNHL and histological subpopulations (according to 
investigator pathology). This table will also be provided for the subgroups of patients with 
and without history of respiratory disorders (as defined in Section 6.3.4.1).  
Tabular and graphical displays of time-of-onset (treatment emergent new onset or worsening 
of non-infectious pneumonitis) using the time intervals: 
• Day 1 – Day 90: to include all copanlisib/placebo-treated patients 
• Day 91 – Day 180: to include all copanlisib/placebo-treated patients treated for at least 
3 months 
• Day 181 – Day 270: to include all copanlisib/placebo-treated patients treated for at 
least 6 months 
• Day 271 – Day 360: to include all copanlisib/placebo-treated patients treated for at 
least 9 months 
• Day 361 or greater: to include all copanlisib/placebo-treated patients treated for at 
least 12 months  
will be presented by treatment group and cancer histology (total iNHL and histological 
subpopulations according to investigator pathology). 
Tabular and graphical displays of time-of-onset of copanlisib/placebo related non-infectious 
pneumonitis TEAEs (treatment emergent new onset or worsening of non-infectious 


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pneumonitis consider related to copanlisib/placebo), applying the same time intervals above, 
will be presented by treatment group for total iNHL. 
Summary of patients with treatment-emergent non-infectious pneumonitis/Interstitial lung 
disease requiring corticosteroids, antibiotics, or both will be displayed descriptively. Refer to 
the TLF specification document for details of how corticosteroids and antibiotics are 
identified. 
6.3.4 
Adverse event groupings  
Table 6–11 resents definitions for AE groupings. The overall strategy for the MedDRA 
searches is aimed at achieving high specificity. When considered to be appropriate, narrow 
versions of SMQs will be used. Additional Bayer-specific MedDRA groupings will be used 
for searches when SMQs would not adequately cover the targeted search. The Bayer-specific 
MedDRA groupings include MedDRA Labeling Groupings (MLG). These groupings are 
created and centrally maintained by a dedicated coding group, according to requests by end-
users from the medical and statistical functions. They are therefore potentially subject to 
change, e.g., through MedDRA up-versioning. 
A table of AE groupings, their definition (MLG/SMQ/MedDRA high level group term 
(HLGT)/ MedDRA high level term (HLT)) and the observed PTs under this grouping will be 
provided. 
Table 6–11: Adverse Event Groupings 
Adverse Event Grouping 
MedDRA Search criteria  
 
Arterial hypertension 
MLG: Hypertension 
Hyperglycemia 
MLG: Hyperglycemia 
Lymphopenia 
MLG: Lymphopenia plus PT: CD4 lymphocytes 
decreased.  
Myocardial ischemia 
MLG: Myocardial ischemia and angina pectoris  
Neutropenia (incl. Febrile 
neutropenia) 
MLG: Neutropenia plus PT: Febrile neutropenia 
Opportunistic Infections 
SMQ: Opportunistic infections (narrow, i.e., 
category 2A) 
Respiratory tract infections 
HLGT: Respiratory tract infections plus HLT 
Lower respiratory tract and lung infections, plus 
HLT: Upper respiratory tract infections 
Thrombocytopenia 
MLG: Thrombocytopenia 
Colitis (excl. infective) 
HLT: Colitis (excl infective) 
Diarrhoea (excl. infective) 
HLT: Diarrhoea (excl infective) 
Cytomegalovirus (CMV) 
infections 
HLT: Cytomegaloviral infections plus PT: 
Cytomegalovirus test positive 
Descriptive summary tables (frequency and percentage of patients, not of events) of MedDRA 
PTs (within each AE grouping) will be presented by treatment group and cancer histology 
(total iNHL and histological subpopulations) for TEAEs and copanlisib/placebo related 
TEAEs. 
An additional table will be provided for the AE grouping “Opportunistic infections” which 
will present the incidence of TEAEs within the grouping by HLGT and MedDRA PT, by 
treatment group and cancer histology (total iNHL and histological subpopulations).  
For each of the AE groupings in Table 6–11, descriptive summaries (frequency and 
percentage of patients, not of events) for treatment-emergent events within the grouping will 


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be presented by treatment group and cancer histology (total iNHL and histological 
subpopulations) and will include: 
• Incidence proportions of worst CTCAE grades, of seriousness, of outcomes, and of 
actions taken, 95% Clopper Pearson (exact) confidence interval (CI) for the overall 
incidence proportion and for the category of serious AEs.  
• Incidence proportions of time-of-onset (new onset or worsening), including tabular 
and graphical displays; with time intervals as follows: 
o Day 1 – Day 90: to include all copanlisib/placebo-treated patients 
o Day 91 – Day 180: to include all copanlisib/placebo-treated patients treated 
for at least 3 months 
o Day 181 – Day 270: to include all copanlisib/placebo-treated patients 
treated for at least 6 months 
o Day 271 – Day 360: to include all copanlisib/placebo-treated patients 
treated for at least 9 months 
o Day 361 or greater: to include all copanlisib/placebo-treated patients 
treated for at least 12 months  
For each of the AE groupings in Table 6–11, descriptive summaries (incidence and percentage 
of patients, not of events) for copanlisib/placebo-related treatment-emergent events within the 
grouping will be presented by treatment group and cancer histology (total iNHL and 
histological subpopulations) and will include: 
• Incidence proportions of worst CTCAE grade, of seriousness, of outcomes, and of 
actions taken, 95% Clopper Pearson (exact) CI for the overall incidence proportion 
and for the category of serious AEs. 
• Incidence proportions of worst CTCAE grade, of seriousness, of outcomes, and of 
actions taken for the following AE groupings and subgroups: 
o respiratory tract infections by history of respiratory disorders [MedDRA 
System Organ Class] (no/yes)  
o arterial hypertension by history of hypertension [PBMQ=SMQ] 
o hyperglycemia by history of diabetes, 
as defined above and in Section 6.3.4.1. 
6.3.4.1 
Subgroups 
The following subgroups will be presented, for the AE groupings described in Section 6.3.4: 
• sex (Male and Female) 
• age group (<65 years and ≥65 years) 
• BMI group (<18.5 kg/m², 18.5 - <30 kg/m² and ≥30 kg/m²) 
• Duration of progression-free interval on the last rituximab, or rituximab biosimilars, or 
anti-CD20 monoclonal antibody containing regimen (6-12 months and >12 months)  
• Prior to base treatment regimen (R-chemotherapy to R-B vs. R-B to R-CHOP vs. R-B 
to R-B). Prior to base treatment regimen categories R-B to R-CHOP and R-B to R-B 
may be combined due to small patient numbers. 


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6.3.5 
Safety OS analysis  
In the briefing document for the 21 APR 2022 Oncologic Drugs Advisory Committee 
(ODAC) meeting [23], the FDA indicates the need for future randomized studies of PI3K 
inhibitors in hematologic malignancies to assess “the impact [of study drug] on [overall] 
survival as both a safety and efficacy metric” in order to have a “high likelihood that when a 
study is completed it can indicate an acceptable benefit-risk profile”. 
While this CHRONOS-4 study had been planned prior to the 21 APR 2022 ODAC meeting, 
an OS safety analysis is planned to be performed at the time of primary completion for the 
primary endpoint of PFS.  
The analysis planned is to be considered descriptive/exploratory in nature and is to be used as 
a pre-specified measure to identify whether caution is warranted regarding the risk of a 
substantial detrimental OS treatment effect. 
This analysis will also be independent of OS as assessed as an efficacy measure and thus is 
considered to not affect the study alpha. 
The analysis performed will analyze OS until 6 months after the end of study treatment. Thus, 
only OS events until 6 months (i.e., 183 days) after the end of the respective study treatment 
of patients will be considered. Patients with no OS event at this time will be censored at either 
their LKAD (if they are lost to follow-up before 183 days after EOT) or at 183 days after the 
end of study treatment. 
Analogous to the efficacy analysis of OS, the stratified cox regression model will be 
considered. In contrast to the efficacy analysis of OS, the safety analysis of OS will be 
performed on the SAF. 
The CHRONOS-4 study is not powered to detect an OS statistical difference and the 
restriction to consider only OS events until 6 months after the end of study treatment further 
restricts statistical power. Thus, 80% CIs will be provided for the HR and the model will be 
considered as descriptive/exploratory in nature. 
In addition to the results of the Cox regression, Kaplan-Meier plots and statistics will be 
provided for this analysis. 
6.3.6 COVID-19 pandemic-relevant adverse events 
The COVID-19 pandemic-relevant AEs will be identified using the SMQ “Covid-19” with a 
broad search. A patient listing of these AEs will be provided. The serious AEs and those 
leading to treatment discontinuation and/or deaths will be flagged in the listing.  
6.3.7 
Pregnancies 
The results of pregnancy tests will be listed. Any pregnancy and pregnancy outcome will be 
documented. 
6.3.8 
Clinical laboratory parameters 
Due to differing cycle lengths, by visit summaries will be reported for those assigned to R-B 
treatment (copanlisib+R-B and placebo+R-B) only. Equivalent data for those assigned to R-
CHOP treatment will be listed. 
Results of the clinical laboratory evaluations (coagulation, hematology, chemistry and 
urinalysis) will be summarized by visit, treatment group and overall, with worst CTCAE 
grade post-baseline. For tables displaying treatment-emergent laboratory abnormalities, 


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patient specimens collected between the start of treatment and 30 days after EOT (i.e., the 
date of last study drug) will be included.  
Summary statistics on the values and changes from baseline will also be presented for each 
quantitative clinical laboratory variable by treatment group and overall, at each post-baseline 
visit. Unscheduled laboratory assessments will not be included in summary analyses over time 
(by time point), unless they are the last measurement prior to first study drug intake, but will 
be included in other analyses not summarized by time point, such as shift tables, incidence of 
abnormalities, etc. For these variables, the number and percentage of patients with transitions 
from worst grade at baseline to worst grade at post-baseline visits relative to the respective 
laboratory’s reference ranges will be presented by study visit.  
Changes in worst grade of laboratory toxicities at last pre-treatment value compared to worst 
grade post-baseline value and changes in worst grade of laboratory toxicities under treatment 
will also be provided. For the change in worst grade of laboratory toxicities under treatment, 
observations until the last on treatment visit will be considered. In case there is more than one 
observation for the same timepoint, the worst grade will be taken. Unscheduled laboratory 
assessments will be included in the patient listings of clinical laboratory parameters.  
In addition to the above summary, specific glucose evaluations will be described in the next 
section. 
6.3.9 Further safety parameters 
Due to differing cycle lengths, by visit summaries will be reported for those assigned to R-B 
treatment (copanlisib+R-B and placebo+R-B) only. Equivalent data for those assigned to R-
CHOP treatment will be listed. 
6.3.9.1 
Hyperglycemia 
Hyperglycemia AEs using specific MedDRA PT grouping “MLG Hyperglycemia” will be 
summarized by treatment group and overall, by worst NCI CTCAE grade for the following: 
• TEAEs 
• Drug-related TEAEs 
• TESAEs 
• Drug-related TESAEs 
Glucose measurements on Day 1 of Cycle 1 will be displayed by CTCAE grade of pre 
copanlisib/placebo infusion and post-dose, 1 hour and 2 hours after the end of 
copanlisib/placebo infusion, at the end of rituximab infusion and at the end of B infusion11.  
For all other Day 1, Day 8 and Day 15 infusions, glucose measurements will be displayed by 
CTCAE grade of pre-copanlisib/placebo infusion and post-dose 1 hour after the end of 
copanlisib/placebo infusion, at the end of rituximab infusion (Day 1), and at the end of B 
infusion if the patient has received corticosteroid premedication prior to the B infusion11. 
Glucose measurements on Day 2 of Cycles 1 to 6 will be displayed by CTCAE grade prior to 
B infusion and at the end of the B infusion (within 30 min) if a patient has received 
corticosteroid premedication prior to B infusion11; and for the R-CHOP group prior to 
 
11 If patient is in the R-B group and receives corticosteroid premedication prior to the bendamustine infusion 


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rituximab infusion and at the end of rituximab infusion (within 30 min) if the patient has 
received corticosteroid premedication prior to the rituximab infusion. 
Changes from respective pre-dose (defined as the last pre-dose glucose measurement in each 
visit) in glucose will be summarized using descriptive statistics at each visit and analysis time 
point by pre-dose fasting status and overall. Unspecified glucose values will not be 
summarized.  
The following plots will be provided overall and for fasting12 and non-fasting status: 
• mean pre-dose glucose values by visits and treatment group 
• mean glucose values 1 hour post end of copanlisib/placebo infusion by visits and 
treatment group 
• mean change, 1 hour post end of copanlisib/placebo infusion, from respective pre-dose 
glucose value, by visits and treatment group 
Patients will be categorized according to their HbA1c baseline values as: 
• <5.7% 
• ≥5.7% – <6.5% 
• ≥6.5% – ≤8.5% 
• >8.5%. 
Within each group, the maximum HbA1c values by cycle and EOT visit13, as well as 3 
months after last dose (if available) will be summarized by descriptive statistics. A plot of 
mean change from baseline HbA1c value, by visits and treatment group, will be provided for 
each HbA1c baseline category. Shift tables from baseline to the EOT visit (or last test if this is 
within 4 weeks preceding the EOT visit), and 3 months after last dose (where available) for 
each category of HbA1c will be presented.  
For patients with hyperglycemia AEs, the number of patients using antihyperglycemic 
treatment with a drug start date on or after their first TEAE will be summarized overall and 
separately for the WHO-DD ATC classes for: a) insulin and analogues and b) blood glucose-
lowering medications, excluding insulins. In addition, these summaries will be presented 
separately for the subgroups of patients with versus without a history of diabetes (as defined 
in Section 6.3.1). 
6.3.9.2 
Electrocardiogram (ECG) 
Results of ECGs will be summarized with descriptive statistics by visit and timepoint, 
including change from baseline when appropriate. 
12-lead ECG evaluation (including QT interval corrected for heart rate – Bazett and QT 
interval corrected for heart rate – Fridericia) will be performed at screening and at each visit. 
 
12 Fasting status was collected prior to the infusion so “Pre-dose” refers to fasting status. 
13 HbA1c test should be performed at EOT if not performed within 4 weeks preceding the EOT visit. If no value 
is given at EOT visit, but their last value is within the allowed 4 weeks prior to the EOT visit, their last value will 
be used here. 


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Summary of ECG absolute QTc interval prolongation or QTc increase from baseline will be 
presented by treatment groups. The criteria are:  
QTc prolongation: QTc interval ≤ 450 msec, QTc interval 451-480 msec, QTc interval 481- 
500 msec and QTc interval > 500 msec.  
Increase from baseline in QTc interval increases from baseline < 20 msec, increases from 
baseline ≥ 20 - < 30 msec, increases from baseline ≥ 30 - < 60 msec and increases from 
baseline ≥ 60 msec. 
The overall interpretation of the 12-lead ECG and the ECG diagnosis will be summarized by 
visit. 
Frequency and shift tables for the number of patients by interpretation of ECG as normal or 
abnormal will be performed at all visits and analysis time points. A listing of clinically 
significant abnormal 12-lead ECG findings will be provided. 
6.3.9.3 
Vital signs 
Blood pressure on treatment days will be measured at pre-dose, 30 min (after the start of 
infusion), right after the end of infusion, and 1 hour and 2 hours after the end of infusion, on 
infusion days. 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 
allowed14) from Cycle 1-6 in the R-B treatment groups. 
Results of vital signs will be summarized with descriptive statistics by visit, including change 
from baseline when appropriate. The number of patients with abnormal post-dose blood 
pressure will be displayed by visit and post-dose hypertension grade. 
Changes from respective pre-dose in blood pressure will be summarized using descriptive 
statistics at each visit and analysis time point by diastolic and systolic blood pressures 
(mmHg) and overall. 
The following descriptive analysis box plots will be provided for diastolic blood pressure and 
systolic blood pressure: 
• mean pre-dose values by cycle and treatment group 
• mean values 30 minutes after start of copanlisib/placebo infusion by cycle and 
treatment group 
• mean values at end of copanlisib/placebo infusion by cycle and treatment group 
• mean values 1 hour post end of copanlisib/placebo infusion by cycle and treatment 
group 
• mean values 2 hours post end of copanlisib/placebo infusion by cycle and treatment 
group 
• mean change, 30 minutes after start of copanlisib/placebo infusion, from respective 
pre-dose value, by cycle and treatment group 
• mean change, at end of copanlisib/placebo infusion, from respective pre-dose value, 
by cycle and treatment group 
 
14 A time window of ±10 min is allowed for all post-dose blood pressure measurements. 


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• mean change, 1 hour post end of copanlisib/placebo infusion, from respective pre-dose 
value, by cycle and treatment group 
• mean change, 2 hours post end of copanlisib/placebo infusion, from respective pre-
dose value, by cycle and treatment group 
6.3.9.4 
Echocardiogram 
Results of multiple gated acquisition (MUGA)/echocardiogram will be summarized with 
descriptive statistics by visit, including change from baseline where appropriate. 
The overall interpretation of the echocardiogram and the corresponding diagnosis will be 
summarized by visit. 
Frequency and shift tables for number of patients by interpretation of echocardiogram as 
normal, abnormal CS or abnormal not CS will be performed at all visits. A listing of clinically 
significant abnormal cardiological findings will be provided. 
6.3.9.5 
Hypertension 
Hypertension AEs will be presented using MLG grouping of MLG Hypertension for the 
following: 
• TEAEs 
• Drug-related TEAEs 
• TESAEs 
• Drug-related TESAEs 
For patients with hypertension AEs, the number of patients using antihypertensive treatment 
with a drug start date on or after their first TEAE of hypertension will be summarized 
descriptively. In addition, the number of patients requiring new antihypertensive treatment 
will be presented separately for the subgroups of patients with versus without a history of 
hypertension (as defined as Section 6.3.1). The number of patients with abnormal blood 
pressure (according to CTCAE grading) will be displayed by visit and worst post-infusion 
hypertension grade. 
6.3.9.6 
Integrated analysis 
Details of the pooling strategy will be described in an Integrated Analysis - Statistical 
Analysis Plan (IA-SAP). Results of these analyses will be presented in a separate report.  
6.4 
Pharmacokinetics/pharmacodynamics 
The data from the Safety run-in part and Phase III part will be pooled for PK analysis. 
Individual concentration-time data of copanlisib and its metabolite M-1 as well as rituximab 
will be listed only. Further analyses will be described in a separate Modeling & Simulation 
(M&S) Plan and performed by a PK expert (pharmacometrics) and will include population 
pharmacokinetics, and exposure-response analysis.  
The pharmacokinetic serum exposure of rituximab will be compared to predictions from a 
published population PK model of rituximab [20]. The results will be reported together with 
the population PK and exposure-response of copanlisib in the M&S Report. 


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6.5 
Biomarker evaluation 
All biomarker analyses will be considered exploratory. There will not be an overall or 
sensitivity analysis of central pathology data. Biomarker data collected in the clinical database 
will be listed. Retrospective exploratory biomarker analyses including evaluation of 
relationship between biomarker data and clinical outcomes will be performed by or under the 
supervision of the sponsor's biomarker statistical expert. Results of these analyses will be 
reported separately, under a separate cover.  
6.6 
Determination of sample size 
EAST 6.4 was used to calculate sample size. The sample size calculation is based on the 
primary efficacy endpoint, PFS, in the FAS and was performed exclusively for the Phase III 
part.  
The sample size calculation assumes that the median PFS in the control arm (base regimen 
either R-B or R-CHOP) is 24 months. With regard to R-B, a Phase 2 study in relapsed 
indolent B-cell (82% of patients) and mantle cell (18% of patients) lymphoma was considered 
for median PFS [21]. This study had, for the full population, a median PFS of 22.9 months, 
but the median PFS was not reported per indication. As the study population was a mixture of 
B-cell and mantle cell lymphoma, a more conservative median PFS of 24 months was 
assumed for R-B treatment. With regard to R-CHOP, a study in 16 relapsed FL patients was 
considered for the median PFS assumption due to the limited data available for R-CHOP in 
iNHL patients at the time of this assessment. The median PFS in the 13 FL patients not 
receiving autologous stem cell transplant was extrapolated based on the disease survival curve 
of patients who achieved a CR. Based on this extrapolation, a median PFS of around 20 
months was assumed for R-CHOP in FL patients [22]. Building on these studies and 
considering that majority of the patients in this study are on R-B, a combined median PFS of 
24 months was considered as a reasonable assumption for the control arm.  
The HR was developed by considering copanlisib monotherapy data and publicly available 
information as of JAN 2016 (study inception), in studies in which treatments had been 
evaluated in similar indications. Sample size planning for CHRONOS-4 targeted an increase 
of 50% in median PFS time in the copanlisib + R-B/R-CHOP combination arms. This equates 
to a targeted median PFS time of 36 months and results in a targeted HR of 0.667. 
Assuming a median PFS of 24 months under the control treatment, a 1-sided alpha of 0.025, a 
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 if death occurs 
before progression) are required to detect a 50% increase in PFS. The monthly dropout (loss 
to follow-up and unevaluable for tumor assessment) rate is assumed to be 0.48%, which 
corresponds to a total number of 52 (10%) unevaluable/dropout patients over the duration of 
the study through to 256 PFS events.  
A total of approximately 520 patients were to be accrued and randomized in the two treatment 
groups combined. The actual total number of patients enrolled and randomized was 524. 
Due to health authority (HA) interest in a powered result for PFS in the FL population that 
was received after all randomized patients had completed study treatment, primary completion 
has been extended to when approximately 280 PFS events are reached in the iNHL 
population. At this point it is expected that there will be sufficient PFS events to achieve an 


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adequately powered comparison between the experimental and control arms, with an expected 
number of approximately 192 PFS events in the FL population. 
The expected study duration to reach approximately 280 PFS events is at least 52 months, and 
the expected accrual duration was 33 months with a 15-month linear ramp-up (maximum 
accrual rate being approximately 20 patients per month). 
 
7. 
Document history and changes in the planned statistical analysis 
7.1 
Document history 
• SAP final version 1.0, dated 24 FEB 2021  
• SAP final version 2.0, dated 08 AUG 2022 
- Section 1, deletion of unnecessary information regarding R-B and R-CHOP 
completion times. 
- Section 3, amended to past tense and to include definitions of prior to base 
treatment regimen, start of the treatment period and patient’s last visit date. 
Reordered study periods section and added clarification that re-screened patients 
must re-sign the informed consent form. Detail on tumor assessments from Active 
follow-up being included in the primary and secondary analyses has also been 
moved from Section 4.2. The text “the estimated median OS time will not change 
in further follow-ups, i.e., all patients censored by the cut-off date have a censored 
OS time greater than the estimated median OS time in both arms” has been 
removed as an of “End of Study” condition. 
- Section 4.1, addition of reference to Oncology Common Statistical Language 
document. Clinical Copanlisib Project Standards removed as they do not exist. 
- Section 4.2, clarification added that those entering Active follow-up will not be 
defined as a “dropout”. 
- Section 4.4 and throughout, wording “approximately 256 centrally evaluated PFS 
events’ updated to ‘at least 256 centrally evaluated PFS events”. 
- Section 4.5.3, amended to include decision on how to handle duplicate records in 
analysis datasets. 
- Section 4.5.4, amended to include option of prednisolone. 
- Section 4.5.5, rules added for including QoL questionnaires in analysis of efficacy 
- Section 4.5.6, stratification factors expanded in Table 4-1 for clarity and 
consistency with Section 3. 
- Section 4.5.7, amended to include the term “regions” in addition to rest of world 
countries. 
- Section 5.1, reordered final two paragraphs to include these under “Assignment of 
analysis sets’ and “Safety analysis set (SAF)” headings. 
- Section 6.1, moved specification of treatment groups from Section 6.1.2.  


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- Section 6.1.1, clarified that the number of patients assigned to treatment will be 
presented. Additional text added regarding how the number of countries/regions 
and centers enrolling patients will be presented. Tables added for duration of 
follow-up and summarizing number of patients completing endpoint follow-up, 
having an event, and being censored. Amended section to include definitions for 
time to end of study treatment and time to cause specific treatment discontinuation, 
and cumulative incidence function curves of time to cause specific treatment 
discontinuations and time to treatment discontinuation due to AEs. Additionally, 
further details have been provided for the COVID-19 pandemic related protocol 
deviations listing and a listing of protocol deviations related to the Ukraine-Russia 
conflict added. 
- Section 6.1.2, amended age group ordering, numbered each age group, and 
removed duplication of “Histology group by investigator at baseline”. Hepatic 
function at baseline added to demography. NYHA classification, HbA1c group, 
eGFR group, medical history of diabetes and medical history of hypertension 
moved from baseline cancer characteristics to demography.  
- Section 6.1.3, on-going medical history conditions added. 
- Section 6.1.4, amended to include mean number of prior systemic anti-cancer 
therapy lines, the definition of time since last systemic anti-cancer therapy and 
further detail on what will be reported for prior and concomitant medications. Last 
category of prior lines has also been amended from ‘≥4 lines of prior therapy’ to 
“≥3 lines of prior therapy”. Prior and concurrent therapies bullet points have been 
reordered for clarity, with “Radiotherapies during long term follow-up” changed to 
‘Radiotherapies during Survival follow-up’ as palliative radiotherapies only 
collected during Survival follow-up. The following text was added for clarity 
“Medications starting more than 30 days after the last day of study treatment will 
be excluded from the summary of concomitant medications”. 
- Section 6.1.5, amended to state that number of patients with each number of cycles 
will also be summarized, summaries by histology added and OEE categories have 
been amended from “271-360 days” and “361-390 days” to “271-365 days” and 
“>365 days” respectively. By cycle summaries changed to by calculated cycle (see 
ADRG).  
- Section 6.2.1, amended to include footnote detailing how independent and local 
assessments for patients with LPL/WM will be used, and text split and assigned to 
subsections 6.2.1.1, 6.2.1.2, 6.2.1.3 and 6.2.1.4. 
-  Table 6-1, Table 6-2 and Table 6-3, censoring rules updated. 
- Section 6.2.1.1, amended to include descriptive summary of PFS event types and 
PFS censoring reasons and to clarify how stratification factors will be included in 
the analysis of PFS. 
- Section 6.2.1.4, Sensitivity Analysis 6 amended to specify that only patients not at 
risk will be considered as events, Table 6-2 has been amended to add more 
scenarios and Sensitivity Analysis 8 has been added. 
- Section 6.2.2, TTNT updated, and table of censoring rules added. 


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- Section 6.2.2, time to improvement in DRS-P definition changed from days to 
months and OS follow-up analysis timing changed from 24 months after analysis 
of the primary and secondary efficacy variables, to 12 months after. 
- Section 6.2.2 and 6.2.3, amended to include OS in confirmatory hierarchical 
testing. 
- Section 6.2.4, “time to onset of physical symptoms on the DRS-P subscale” 
changed to “time to onset of meaningful worsening of physical symptoms on the 
DRS-P subscale” as this is a more precise definition. The content of the variable 
has not changed. 
- Section 6.2.5.2, prior lines of therapy categories updated to “1 vs. 2 vs. ≥3” from 
“1 vs. 2 vs. 3 vs. ≥4”. 
- Section 6.3.1, summaries of non-infectious pneumonitis/interstitial lung disease 
removed as pneumonitis/interstitial lung disease are now in Section 6.3.3, AEs of 
special interest. Clarification added that all grade 5 TEAEs will be included when 
summarizing deaths, and AEs occurring prior to starting treatment will also be 
summarized. Table of deaths updated as deaths with “AE” or “other” as the 
primary cause will be pooled together under the primary cause “other”. Additional 
detail on what will be reported in each patient listing has also been added. History 
of hypertension and history of diabetes mellitus PBMQs updated from MedDRA 
21.1 to MedDRA v25.0. Drug-related listings of death added. 
- Section 6.3.2, amended to include footnote specifying study procedure related AEs 
and SAEs occurring during Active follow-up will also be included in each time-
interval. Typo of ‘Day 181 or greater’ has also been corrected to ‘Day 181 – Day 
270’. Interval summaries and for R-B and R-CHOP related TEAEs and SAEs 
added. 
- Section 6.3.3, new section on adverse events of special interest added. 
- Section 6.3.4, new section on AE groupings added. 
- Section 6.3.5, Safety OS analysis added. 
- Section 6.3.6, amended details on how COVID-19 relevant AEs will be identified 
and reported. 
- Section 6.3.7, amended to add pregnancy outcomes will also be reported. 
- Section 6.3.8, clarified that EOT is defined as the date of last study drug.  
- Section 6.3.9.1, added footnote and details within text to clarify which HbA1c test 
values should be used for the EOT time point. Additional summary plots added. 
- Section 6.3.9.3, summary of the number of patients with abnormal post-dose blood 
pressure by visit and post-dose hypertension grade added. 
- Section 6.3.9.2, moved echocardiogram related summaries to Section 6.3.9.4. 
- Section 6.3.9.2, 6.3.9.3 and 6.3.9.4, amended to align text with what will be 
presented. 
- Section 6.3.9.3, additional summary plots added. 
- Section 6.3.9.6, “Integrated analysis” added. 
- Section 6.6, amended to include additional detail on sample size assumptions for 
the median time on control arm and the targeted HR. 
- Section 8, amended to include 2 references added to Section 6.6,1 reference moved 
from Section 6.4 and 1 reference added to Section 6.3.5. 


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- Section 9.3.2 The following text was added “A death event is a PFS event if the 
date of death is ≤ 25 (12+12+1) weeks after randomization.”. 
• SAP final version 3.0, dated 04 APR 2023 
- Section 1, version of integrated clinical study protocol updated to Amendment 09, 
protocol Version 8.0, dated 21 MAR 2023. 
- Section 2, Table 2-1 updated to reflect two testing hierarchies, one for United 
States, and one for Europe and rest of world. 
- Section 3, details of schedule of tumor assessment in active follow-up, end of 
study definition and the number of PFS events required for primary completion 
analysis, updated based on integrated clinical study protocol (CSP, Amendment 
09, protocol Version 8.0, dated 21 MAR 2023), to reflect tumor assessments 
beyond year 5, the potential for patients to be followed off-study for up to 10 years 
(previously 5 years) and that approximately 280 centrally evaluated PFS events 
(previously 256) are required for the primary completion analysis. 
- Section 4.1, updated based on integrated clinical study protocol (CSP, Amendment 
09, protocol Version 8.0, dated 21 MAR 2023), to reflect statistical evaluation of 
this study will be performed when approximately 280 centrally evaluated PFS 
events are observed (previously 256). 
- Section 4.3, updated to list all key panels used to determine survival status and 
LKAD. Text added to the explain the method and purpose of imputing missing or 
partially missing start or end dates for adverse events and concomitant 
medications. 
- Section 4.4, updated, based on integrated clinical study protocol (CSP, 
Amendment 09, protocol Version 8.0, dated 21 MAR 2023), to reflect the potential 
for patients to be followed off-study for up to 10 years (previously 5 years) and the 
amended number of PFS events required for the primary completion analysis. Text 
relating to DMC updated to past tense. 
- Section 4.5.6 text detailing relationship between strata and patient ID updated for 
clarity, after FDA review comment. 
- Section 4.5.7, further detail added to describe groupings of geographic regions and 
how these will be analyzed. 
- Section 6.1, text regarding differing FAS and SAF updated to align with Section 
5.1. 
- Section 6.1.1, text describing number of patient summaries updated for clarity. 
Text added to avoid double counting patients, who passed re-screening, in number 
of screening failures and number of randomized patients.  
Additional listings of re-screened patients and “Other” reasons for premature 
discontinuations from epochs added.  
Summary of “time to treatment discontinuation due to AEs” amended to “time to 
treatment discontinuation due to AEs not associated with clinical disease 
progression”. 


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Duration of study participation to last visit and to LKAD replaced with summary 
of PFS follow-up and OS follow-up by treatment group using the inverse event 
indicator method. 
Tables added summarizing number of patients with protocol deviations associated 
with COVID-19 pandemic, overall and by protocol deviation category number, 
and number of patients affected by COVID-19 pandemic related study disruptions. 
- Section 6.1.2, “other” added to “baseline characteristics”, and definition of 
moderate impairment changed from “40- <60” to “30- <60”. 
Description of diabetes and hypertension medical history identification updated for 
clarity. 
Number of LPL/WM patients with and without measurable disease at baseline 
added to summary of other baseline characteristics. 
Analysis population defined (FAS) for by histology (FL, MZL, SLL, and 
LPL/WM) summaries of demographic and other baseline characteristics. 
- Section 6.1.4, text amended to clarify the definition of prior medication. 
Frequency table added for prior anti-cancer therapy and therapeutic procedures. 
- Section 6.1.5, added text to describe patients in the R-CHOP arm will have number 
of infusions calculated based on rituximab, cyclophosphamide, doxorubicin, and 
vincristine. 
- Section 6.2, updated, based on integrated clinical study protocol (CSP, 
Amendment 09, protocol Version 8.0, dated 21 MAR 2023), to amend number of 
PFS events required for the primary completion analysis. 
- Section 6.2.1, removal of “progression-free survival” from heading, removal of 
text describing imputation method when tumor assessment date is partially missing 
and replaced with a reference to Section 4.3, as this is repeated text. 
First censoring scenario updated to include “or death more than 25 (12+12+1) 
weeks after randomization”. 
Censoring scenario updated from “discontinued or withdrew early from treatment” 
to “discontinued or withdrew early from study”. 
Explanatory footnote added to Table 6-1 for the scenario where progression occurs 
on the same date as start of new anti-cancer treatment. 
- Section 6.2.1.1, updated, based on integrated clinical study protocol (CSP, 
Amendment 09, protocol Version 8.0, dated 21 MAR 2023), to amend number of 
PFS events required for the primary completion analysis. 
- Section 6.2.1.3, text added to detail follow-up analyses of PFS and other efficacy 
endpoints at timepoints for follow-up OS. 
- Section 6.2.1.4.7, 6.2.1.4.8, Explanatory footnote added to Table 6-2 and Table 6-3 
for the scenario where progression occurs on the same date as start of new anti-
cancer treatment. 
- Section 6.2.2, added a clarification that new anti-cancer therapy ends the Active 
follow-up period. 


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Added text “and no death related to PD within the first 25 weeks after 
randomization” under TTP heading. 
Added the word “study” to “treatment” under TTNT heading. 
Reason for censoring added to scenario in Table 6-5, to distinguish row from 
“Neither DRS-P, nor PD/death and no other criteria fulfilled”. 
Removed repetition of “censoring rules” from time to improvement section. 
Removed subheading “Analysis of ORR, time to deterioration, time to 
improvement in DRS-P” and wording updated to reflect image based secondary 
efficacy endpoints. 
Added clarification that local assessments will be used in place of centrally 
reviewed data for LPL/WM patients without measurable disease at baseline. 
Added reference to Appendix 9.1, detailing how PET-CT investigator assessments 
will be combined. 
Updates to analysis of OS section, to include a final descriptive analysis of OS at 
end of study. 
Added censoring rules for DRS-P sensitivity analysis to Table 6-7. 
- Section 6.2.2 and 6.2.3, amended to include two testing hierarchies: one for US 
and one for Europe and rest of world. US hierarchy updated to include PFS in FL 
population and to remove time to deterioration and time to improvement in DRS-
P. 
- Section 6.2.3, added reference to Appendices 9.6, 9.7 and 9.8, which describe 
further assessments of OS data and scenarios for OS (answering an HA request). 
- Section 6.2.4, 6.3.8 and 6.3.9, clarified that by visit summaries will be reported for 
those assigned to R-B only. 
- Section 6.2.5.2, updated in include a stratified Cox-PH model for the FL histology 
subgroup. 
- Section 6.3.1, all references to MedDRA v25.0 updated to v25.1. 
The number and percentage of patients who discontinued study treatment due to a 
TESAE (discontinued all study treatments) was added. 
- Section 6.3.2, updated text to add treatment emergent AEs, as well as treatment 
emergent drug-related AEs and TESAEs. 
Removal of footnote 12, as all treatment emergent AEs will be summarized. 
- Section 6.3.4, addition of CMV infections to AE Groupings. 
- Section 6.3.4.1, definition of “Prior to base treatment regimen” updated to reflect 
same definition as in Section 6.2.5. 
- Section 6.3.9.1, text relating to blood pressure removed and added to Section 
6.3.9.3. 
- Section 6.6, sample size text updated to reflect changes to primary completion 
definition in integrated CSP amendment 09, version 8.0, dated 21 MAR 2023. 


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Text added to specify 192 events in the FL population are expected at the time of 
primary completion. 
- Appendix 9.1, principles for combination of PET and CT/MRI responses, added. 
- Appendices 9.4.1 and 9.4.2, details of schedule of tumor assessment in active 
follow-up updated based on integrated clinical study protocol (CSP, Amendment 
09, protocol Version 8.0, dated 21 MAR 2023), to reflect tumor assessments 
beyond year 5. 
- Appendix 9.5.1, algorithm added for handling partial initial diagnosis date and 
progression date.  
- Appendix 9.5.2, imputation rules added for partial/missing Adverse 
Event/Concomitant medication dates. 
- Appendix 9.5.3, imputation rules added for partial/missing anti-cancer treatment 
start dates. 
- Appendix 9.6, added to provide reassurance, regarding OS safety, following an 
HA request. 
- Appendix 9.7, added to provide reassurance, regarding OS safety, following an 
HA request. 
- Appendix 9.8, added to provide reassurance, regarding OS safety, following an 
HA request.  
• SAP draft version 4.0, dated 22 SEP 2023 
- MedDRA v25.1 updated to “v25.1 or higher” as v25.1 has been superseded. 
- Specified throughout that measurable lesions assessed by investigator are required 
for LPL/WM patients. 
- Section 4.3, additional datasets added to determine survival status and the LKAD. 
- Section 4.4, added in case a background therapy has less than 5 randomized 
patients assigned. 
- Section 4.5, added in case further investigator assessments are taken following 
investigator reported PD. 
- Section 4.6, added to clarify how clinical laboratory values with qualifiers will be 
included in analyses and summaries. 
- Section 4.7, added to clarify that p-values are nominal, except for the primary 
efficacy endpoint and confirmatory statistical testing strategy.  
- Section 4.9.4, R-B and R-CHOP overall extent of exposure updated to handle 
study drug combinations with differing start and end dates in the final cycle. 
- Section 6.1.5, amended to clarify interruptions are distinguished from delays by 
non-zero dose administered, and delays from interruptions by zero dose 
administered. Text added to explain that interruptions with the same start date will 
be counted as one interruption. Duration of interruption has been removed from 
the summaries, only duration of delay will be summarized. 


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The number of days used to calculate the planned dose for incomplete cycles has 
been amended to take in to account the ‘-1 to +2 days’ time window for study drug 
administration. 
- Section 6.2.1.3, footnote (9) amended to use a corrected derivation for the date of 
clinical progression. 
- Section 6.2.1.4, Sensitivity Analysis 5 moved to end of section and re-numbered as 
Sensitivity Analysis 8. Dose delays due to the Ukraine-Russia conflict and related 
analyses added to re-numbered Sensitivity Analysis 8. Previous Sensitivity 
Analyses 6, 7 and 8 updated and re-numbered accordingly. 
Table 6–2 and Table 6–3 updated to correct Appendix references. 
- Section 6.2.2, definition of DCR amended to remove references to “within 35 days 
after termination of study treatment” and “within the following 25 weeks”. Also 
refer to Section 7.2 (“Changes in the planned statistical analysis”). 
Definition of TTNT amended from “stop of study treatment to start of new anti-
lymphoma therapy” to “date of randomization to start of new anti-lymphoma 
therapy” and censoring rules updated. This change was made because the 
definition of TTNT in Section 10.3.2.3 of CSP, Amendment 09, protocol Version 
8.0, dated 21 MAR 2023 is incorrect. Also refer to Section 7.2 (“Changes in the 
planned statistical analysis”). Table 6–4 also updated to remove “LKAD” when 
patient died during treatment, Safety follow-up or Active follow-up. 
- Section 6.2.3, additional information on conditional power added. 
- Section 6.3.3, tabular and graphical displays added for time-of-onset of 
copanlisib/placebo related non-infectious pneumonitis TEAEs. 
- Section 9.5.3, Table 9–2, updated and footnote added. 
- Section 9.7, updated to use a benchmark number of OS events under 80% power to 
calculate the information fractions instead of a target number of events. 
- Section 9.8, Table 9–5, probability of point estimate / upper bound exceeding 1 
added for final formal OS analysis, projected number of events as a percentage is 
recalculated relative to benchmark number of events (380) instead of expected 
number of events at final formal OS analysis (176), results from additional 
simulations with a true HR=0.75 added. 
7.2 
Changes in the planned statistical analysis 
• The secondary efficacy variable TTNT is incorrectly defined in Section 10.3.2.3 of 
CSP, Amendment 09, protocol Version 8.0, dated 21 MAR 2023. 
Incorrect definition of TTNT as defined in current CSP, Amendment 09, protocol 
Version 8.0, dated 21 MAR 2023 
TTNT is defined as the time from stop of study medication to start of new anti-
lymphoma therapy.  
Corrected definition of TTNT as specified in Section 6.2.2 of this SAP 
TTNT is defined as the time from date of randomization to start of new anti-
lymphoma therapy, where date of randomization is day 1.  


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The intention is to correct the TTNT definition in the next CSP amendment. However, 
if primary completion occurs prior to the next CSP amendment the correct definition 
will be specified in the SAP and used in the analysis, with the divergence from the 
CSP definition also documented in the SAP and CSR as “changes in the planned 
statistical analysis”.  
• The definition of the secondary efficacy variable DCR has been amended in the SAP 
to remove references to “within 35 days after termination of study treatment” and 
“within the following 25 weeks”. This change has been made to be consistent with the 
ORR and CRR assessment period, by including in the DCR analysis, radiological 
assessments performed during the Active follow-up. 
Definition of DCR as defined in current CSP, Amendment 09, protocol Version 
8.0, dated 21 MAR 2023 
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. 
SAP definition of DCR as specified in Section 6.2.2 of this SAP 
DCR is defined as the proportion of patients who have a BOR of CR, unconfirmed 
CR, VGPR, PR, unconfirmed PR, MR, or confirmed stable disease (SD). Unconfirmed 
SD is defined as SD on or before Study Day 76, which is not confirmed by an 
additional tumor assessment of SD, or better, on Study Day 77 or later. 


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8. 
References 
1. Shankland KR, Armitage JO, Hancock BW. Non-Hodgkin lymphoma. Lancet. 2012; 
380(9844):848-57. 
2. 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. 
3. Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, Raposo JC, et al. 
Phase III study of R-CVP compared with cyclophosphamide, vincristine, and 
prednisone alone in patients with previously untreated advanced follicular lymphoma. 
J Clin Oncol. 2008;26(28):4579-86. 
4. Rummel M, Kaiser U, Balser C. Bendamustine plus rituximab versus fludarabine plus 
rituximab in patients with relapsed follicular, indolent and mantle cell lymphomas - 
final results of the randomized phase III study NHL 2-2003 on behalf of the StiL 
(Study Group Indolent Lymphomas, Germany) Blood. 2010(116). 
5. Hainsworth JD, Litchy S, Burris HA, 3rd, Scullin DC, Jr., Corso SW, Yardley DA, et 
al. Rituximab as first-line and maintenance therapy for patients with indolent non-
Hodgkin’s lymphoma. J Clin Oncol. 2002;20(20):4261-7. 
6. McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, et 
al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent 
lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 
1998;16(8):2825-33. 
7. Johnston A, Bouafia-Sauvy F, Broussais-Guillaumot F, Michallet AS, Traulle C, 
Salles G, et al. Retreatment with rituximab in 178 patients with relapsed and refractory 
B-cell lymphomas: a single institution case control study. Leuk Lymphoma. 
2010;51(3):399-405. 
8. Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi M, Greco FA. 
Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment 
at progression in patients with indolent non-Hodgkin's lymphoma--a randomized 
phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 
2005;23(6):1088-95. 
9. 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. 
10. 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. 


Statistical Analysis Plan 
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11. Ihle NT, Powis G. Take your PIK: phosphatidylinositol 3-kinase inhibitors race 
through the clinic and toward cancer therapy. Molecular cancer therapeutics. 
2009;8(1):1-9. 
12. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. 
Oncogene. 2008;27(41):5497-510. 
13. Cheson, BD, Fisher, RI, Barrington, SF, Cavalli, F, Schwartz, LH, 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):3059-67.  
14. Owen, RG, Kyle, RA, Stone, MJ, Rawstron, AC, Leblond, V, et al. Response 
assessment in Waldenstrom macroglobulinaemia: update from the VIth International 
Workshop. British journal of haematology. 2013; 160(2):171-6. 
15. Data monitoring committee charter. version 1.0, 24 March 2017  
16. Schemper M and Smith TL. A note on quantifying follow-up in studies of failure time. 
Controlled Clinical Trials. 1996; 17(4):343-346. 
17. Collett D. Modelling Survival Data in Medical Research: Chapman and Hall; 2003. 
18. FDA. Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer 
Drugs and Biologics Guidance for Industry, April 2015. Available from: 
https://www.fda.gov/downloads/drugs/guidances/ucm259421.pdf (accessed date: 18 
MAY 2020) 
19. Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. 'Categorical Data Analysis' in 
Statistical methodology in the pharmaceutical sciences /edited by Berry DA, Marcel 
Dekker; 1990.  
20. Rozman S et al. Population pharmacokinetics of rituximab in patients with diffuse 
large B-cell lymphoma and association with clinical outcome. Br J Clin Pharmacol 
2017; 83: 1782-1790. DOI:10.1111/bcp.13271 
21. Robinson KS, Williams ME, van der Jagt RH, Cohn P, Herst JA, Tulpule A, et al. 
Phase II multicenter study of bendimustine plus rituximab in patients with relapsed 
indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol. 2008 Sep 
20;26(27):4473-9. 
22. Domingo-Domenech E, Gonzalez-Barca E, Estany C, Sureda A. Besalduch J, 
Fernandez de Sevilla A. Combined treatment with anti-CD20 (rituximab) and CHOP 
in relapsed advanced-stage follicular lymphomas, Haematologica. 2002 
Nov;87(110);1229-30. 
23. FDA. Phosphatidylinositol 3-kinase (PI3K) inhibitors in hematologic malignancies. 
Briefing document, Oncologic Drugs Advisory Committee Meeting, 21 APR 2022. 
24. Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, et al. 
Bendamustine plus rituximab versus fludarabine plus rituximab for patients with 
relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, 
non-inferiority phase 3 trial. Lancet Oncology. 2016 January; 17(1):57-66. 


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25. Rueda A, Calvo V, Casanova M, Rodriguez-Abreu D, Aguiar D, et al. Efficacy of the 
combination of rituximab-bendamustine as a second-line treatment in patients with 
follicular lymphoma who progress after immunochemotherapy: a phase II trial of the 
Spanish Lymphoma Oncology Group. Leuk Lymphoma. 2019 Jun; 60(6):1576-1579. 
Epub 2018 Dec 5. 
9. 
Appendix 
9.1 
Principles for combination of PET and CT/MRI responses 
• FDG-PET response overrides, in most cases, CT/MRI response  
e.g. If CT response = PD and PET response = CMR → Overall response is CR  
• If an FDG-PET assessment is not within a ±7 day time window of a CT/MRI 
assessment, then the FDG-PET assessment will be considered as a standalone 
assessment.  
• After a combined response of FDG-PET and CT/MRI is derived for a particular FU 
time point it is highly recommended that subsequently any change of overall response 
that is derived from CT or MRI alone is confirmed with PET.  
• Any following time points assessed with CT or MRI alone are affected by a prior 
FDG-PET result, with no time limit for carrying forward an FDG-PET result, i.e.  
1. Prior PET response will determine further FU overall responses, as long as CT 
response does not get worse compared to previous CT responses  
e.g. FU 3: PET (NMR), CT (SD) → overall response SD;  
FU 4: No PET, CT (PR) → overall response SD;  
FU 5: PET (CMR), CT (PR) → overall response CR  
2. A worse CT response will determine FU overall response  
e.g. FU 3: PET (CMR), CT (PR) → overall response CR;  
FU 4: No PET, CT (SD) → overall response SD;  
FU 5: PET (PMD), CT (SD) → overall response PD  
After a combined response of FDG-PET and CT/MRI is derived for a particular FU time point 
PET should be performed to confirm CR and/or disease progression. 
9.2 
Scoring instruction for FLymSI-18 
Record answers of each item response (0 = 'Not at all' to 4 = 'Very much'). In order to have a 
common order for the scores with 0 reflecting worst outcome and 4 reflecting best outcome, 
reverse the coding for the following items by subtracting the response from '4': 
GP1: I have lack of energy 
GP4: I have pain 
C2: I am losing weight 
Leu1: I am bothered by lumps or swelling in certain parts of my body 
MBT6: I get tired easily 


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BP1: I have bone pain 
HI8: I have trouble concentrating 
GE6: I worry that my condition will get worse 
BRM9: I have emotional ups and downs 
Leu4: Because of my illness, I have difficulty planning for the future 
Leu5: I feel uncertain about my future health 
GP2: I have nausea 
N3: I worry about getting infections 
GP5: I am bothered by side effects of treatment 
FLymSI-18 Total score (range 0-72) 
Sum the (reversed, if applicable) responses of all items. Multiply by 18 (number of items in 
the FLymSI-18) and divide by the number of items answered. 
FLymSI-18 DRS-P score (range 0-36) 
Sum the (reversed, if applicable) responses of the items GP1, GP4, C2, Leu1, BMT6, BP1, 
HI8, GF5, C6. Multiply by 9 (number of items in the FLymSI-18 DRS-P score) and divide by 
the number of items answered. 
FLymSI-18 DRS-E score (range 0-16) 
Sum the reversed responses of the items GE6, BRM9, Leu4, Leu5. Multiply by 4 (number of 
items in the FLymSI-18 DRS-E score) and divide by the number of items answered. 
FLymSI-18 TSE score (range 0-12) 
Sum the reversed responses of the items GP2, N3, GP5. Multiply by 3 (number of items in the 
FLymSI-18 TSE score) and divide by the number of items answered. 
FLymSI-18 FWB score (range 0-8) 
Sum the responses of the items GF3, GF7. Multiply by 2 (number of items in the FLymSI-18 
FWB score) and divide by the number of items answered. 
9.3 
Patient-reported outcomes 
Please refer to Patient-Reported Outcomes Dossier in Support of the National Comprehensive 
Cancer Network—Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 
(NFLymSI-18) in Indolent B-Cell Non-Hodgkin’s Lymphoma (iNHL) Patients by 
(Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern 
University). 
9.4 
PFS rules 
9.4.1 
Progression and PD after two or more consecutive missed tumor 
assessments 
If the progression occurs at the next tumor assessment after two or more consecutive missing 
or non-evaluable assessments, PFS will be censored at the date of the last evaluable scan 
before the consecutive missing assessments. Considering tumor assessment are scheduled at 


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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, the following 
conditions will apply to account for the tumor assessment schedule change starting at year 2 
and year 3. 
For patients with progression observed before death with an evaluable post-baseline 
evaluation before two missing assessments:  
• if date of progression is ≤ 117 weeks (104 weeks+12 weeks + 1 week) after 
randomization and > last evaluable assessment + 2*12 + 1 weeks, PFS will be 
censored at the date of the last evaluable scan BEFORE the two missing assessments.  
• if date of progression is > 117 weeks (104 weeks +12 weeks + 1 week) and ≤ 141 
weeks (116 weeks +24 weeks + 1 week) after randomization and > last evaluable 
tumor assessment + 12+24 + 1 weeks, PFS will be censored at the date of the last 
evaluable scan BEFORE the two missing assessments.  
• if date of progression is > 141 weeks after randomization and > last evaluable tumor 
assessment + 2*24 + 1 weeks during Year 3, 4 and 5; or > last evaluable tumor 
assessment + 2*24 + 2 weeks beyond Year 5, PFS will be censored at the date of the 
last evaluable scan BEFORE the two missing assessments. 
• otherwise, the PFS time will not be censored and be calculated as the date of 
progression minus the date of randomization.  
9.4.2 
Death 
Considering tumor assessments are scheduled at 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, the following conditions will apply: 
A death event is a PFS event if the date of death is ≤ 25 (12+12+1) weeks after 
randomization. 
For patients who die after the last evaluable tumor assessment, in the absence of progression, 
the death event is a PFS event in the following conditions: 
• if date of death is ≤ 117 weeks (104 weeks+12 weeks+1 week) after randomization, 
and within the 24+1 week of the last evaluable tumor assessment,  
• if date of death is > 117 and ≤ 141 weeks (116 weeks+24 weeks+1 week) after 
randomization, and within the 36+1 weeks of the last evaluable tumor assessment, 
• if date of death is > 141 weeks after randomization, and within the 48 +1 weeks of the 
last evaluable tumor assessment during Year 3, 4 and 5, or within the 48 +2 weeks of 
the last evaluable tumor assessment beyond Year 5. 
9.4.3 
Patients with new anti-cancer therapy 
For patients who change anti-cancer treatment15 to something other than the study treatment 
prior to observing progression, PFS will be censored at the date of the last evaluable tumor 
assessment prior to the initiation of anti-cancer treatment. Independent review committee 
(IRC) assessments will be used in the event of IRC and investigator disagreement on the last 
response assessment prior to a switch to a new anti-cancer treatment. For LPL/WM patients, if 
 
15 Or have surgery affecting target/non-target lesions prior to observing progression 


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PD was assessed by an investigator based on laboratory parameters alone, no independent 
confirmation of PD by independent blinded review is necessary. 
9.4.4 
Patients who discontinue or withdraw 
For patients who discontinue or withdraw early from the study without documented disease 
progression, PFS will be censored at the date of the last evaluable tumor assessment unless the 
patient dies, and death is considered as a PFS event mentioned above. Note that this applies to 
patients without progression based on blinded independent central radiological review but 
who discontinued because according to the investigator assessment he/she had progressed (if 
such a patient exists). 
9.5 
Imputation rules for partial dates 
9.5.1 
Algorithm for handling partial initial diagnosis date and progression 
date 
The following rules are used to impute partial initial diagnosis date and progression date:  
A. If partial date has day and month missing, then January 01 will be assigned to the 
missing fields. 
B. If partial date has missing day only, then the first day of the month will be assigned to 
the missing day. 
C. If imputed progression date from A or B above is before the Randomization date, then 
Randomization date will be assigned to overwrite the imputed date from A or B. If the 
date is completely missing, no imputation will be applied for initial diagnosis date. 
Use day 1 for progression date. 


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9.5.2 
Imputation rules for partial/missing Adverse Event (AE)/Concomitant 
medication (CM) dates 
Table 9–1: Imputation rules for partial/missing dates 
Partial Dates 
Imputation 
Rule 
Impute partial AE/CM Start Date 
Impute partial 
AE/CM Stop 
Date 
#1. The day 
missing only 
IF AESTDT year and months is same as TRTSDT year and 
months, then impute AESTDT= TRTSDT 
IF AEENDT year 
and months is 
same as LKAD 
year and months,  
then impute 
AEENDT= LKAD 
 
ELSE IF AESTDT year and month is before TRTSDT year and 
months, then AESTDT= last date of the months 
ELSE impute 
AEENDT= last 
date of the 
months 
ELSE IF AESTDT year and month is after TRTSDT year and 
months, then AESTDT= first date of the months 
#2. Both day 
and months 
missing 
IF AESTDT year is same as TRTSDT year, then impute 
AESTDT=TRTSDT 
IF AEENDT year 
is same as LKAD 
year,  
then impute 
AEENDT= LKAD 
ELSE IF AESTDT year is before TRTSDT year, then impute 
AESTDT=31DECYYYY 
ELSE impute 
AEENDT=31DEC
YYYY 
ELSE IF AESTDT year is after TRTSDT year, then impute 
AESTDT=01JANYYYY 
#3. Completely 
missing 
No need to impute, try to query the sites by DM 
No need to 
impute, try to 
query the sites by 
DM 
#4 Additional 
criteria to meet 
1. AE/CM start date <= AE/CM stop date 
################################################# 
After the imputation of start/stop date per above rules #1~#3, 
further action is needed if the (imputed) AE/CM start date > the 
(imputed) AE/CM stop date. We will update the (imputed) 
AE/CM start date = the (imputed) AE/CM stop date since the 
imputed stop date is more reliable. 
 
Because per imputation partial stop date rules #1~#3, the 
(imputed) AE/CM stop date will be the maximum date based 
on the available data unless there’s data issue. If it’s a data 
issue, we can leave the imputation as it is and report the data 
issue to the DM. 
################################################## 
2. The imputed dates <= LKAD 
3. If TRTSDT is missing, use RANDDT as reference date 


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9.5.3 
Imputation rules for partial/missing anti-cancer treatment start date 
Table 9–2 Imputation rules for partial/missing anti-cancer treatment start dates 
Partial Dates 
Imputation 
Rule 
Impute partial anti-cancer treatment start date 
#1. The day 
missing only 
IF *CMSTDTC year is after the year of the last visit, then impute DD to be ‘01’ 
 
ELSE IF *CMSTDTC year is the same as the year of the last visit and *CMSTDTC 
month is after the month of the last visit, then impute DD to be ‘01’  
 
ELSE IF *CMSTDTC year and month is the same as the year and month of the last 
visit, then impute day of the last visit 
 
#2. Both day 
and months 
missing (MM-
DD) 
IF *CMSTDTC year is the same as the year of the last visit, then impute MM-DD to 
be the month and day of the last visit’ 
 
ELSE IF *CMSTDTC year is after the year of the last visit, then impute MM-DD to 
be ‘01-01’ 
 
#3. Completely 
missing 
(YYYY-MM-
DD) 
IF last visit date is known, then impute the last visit date 
 
*CMSTDTC is the start date/time of the anti-cancer treatment. 
9.6 
Hypothetical OS events needed to detect a difference in OS (answering 
an HA request) 
Modelling of plausible range of median OS estimates for control arm 
Three publications studying patients with Rituximab-Bendamustine (R-B) in second line have 
been identified that are describing results for OS: 
a) Rummel, 2005 [10] (N=63): With a schedule of R-B for four cycles, one dose of R 7 
days before first cycle and 28 days after last cycle 
b) Rummel, 2016 [24] (N=116, in R-B arm): R-B for 6 cycles (R Day 1, RB Day 1,2), 
followed by R maintenance (every 12 weeks, for 2 years), introduced per amendment 
c) Rueda, 2018 [25] (N=40): R-B for 6 cycles (R Day 1, RB Day 1,2), followed by R 
maintenance (every 12 weeks, for 2 years) 
The studies express some variability regarding composition of proportion of Rituximab 
sensitive patients, NHL histologies included (FL only for c), iNHL including mantle cell 
lymphoma for Rummel, 2005 and Rummel, 2016) 
Beside variations mentioned above, the main difference between the studies is regarding the 
use of R maintenance therapy: 
For studies b) and c), the results can be considered confounded because of using Rituximab 
maintenance, as compared to how R-B is applied in the C-4 study. 


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As median OS was generally not reached for most studies and because Rituximab-
maintenance has been applied, the OS curves were:  
a) modelled using accelerated failure time models and  
b) restricted data (i.e., first 12/24/36 months in separate models) was used in studies that 
applied maintenance 
This approach indicated that it is plausible to assume that median OS is within a range of 75-
85 months for RB therapy in 2-line NHL, if no maintenance therapy is applied (data on file).  
Modelling of median OS estimates for blinded C-4 study data (as of 27/03/2023)  
Using blinded C-4 study data, a model was fitted to ongoing OS data, which resulted in a 
plausible estimate of 115 months (or 9.6 years) for the median of OS in the total (blinded) 
population. It is considered that 100 months is a conservative and plausible estimate to use in 
the crude calculation of median OS for the C-R treatment arm. 
Crude modelling of potential HR for OS of C-4 
To generate the plausible range of median OS estimates for the C-R treatment arm (in a crude 
fashion), the above results are then considered to be from an exponential distribution with 
constant hazard, where the (crude) median for copanlisib is calculated as:  
Crude median(copanlisib) = 2*median(pooled C-4) – median(control arm). 
This crude median is then used to calculate a range of crude potential HRs that might be seen 
in C-4. 
The resulting crude medians and hazard ratios are displayed in Table 9–3, together with the 
corresponding number of events required, for a range of power values from 60-90% and a 
two-sided test with alpha of 5%. The expected study duration to obtain the respective number 
of OS events, was determined using a simulation approach.  
While acceptable HR/power combinations seem possible, the timing until sufficient events are 
accumulated in many cases would stretch beyond feasible calendar dates (i.e., beyond the year 
2029). 


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Table 9–3: Crude median assumptions and resulting HR displayed with events and 
study duration needed to achieve specific statistical power values 
 
 
Crude Median OS [months] 
Events# 
needed 
Date at which 
number of 
events is 
reached## 
Power 
Crude HR 
Placebo 
Copanlisib 
 
 
60% 
0.600 
75 
125 
76 
N/A 
 
0.667 
80 
120 
120 
24.04.2023 
 
0.702 
82.5 
117.5 
157 
18.09.2024 
 
0.739 
85 
115 
215 
20.03.2027 
70% 
0.600  
75 
125 
95 
N/A 
 
0.667  
80 
120 
151 
25.06.2024 
 
0.702 
82.5 
117.5 
198 
08.06.2026 
 
0.739  
85 
115 
270 
>2029 
80% 
 
0.600  
75 
125 
121 
08.05.2023 
 
0.667  
80 
120 
192 
02.03.2026 
 
0.702 
82.5 
117.5 
251 
05.01.2029 
 
0.739  
85 
115 
344 
>2029 
90% 
 
0.600  
75 
125 
162 
30.11.2024 
 
0.667  
80 
120 
257 
05.05.2029 
 
0.702 
82.5 
117.5 
336 
>2029 
 
0.739  
85 
115 
460¹ 
>2029 
N/A: Number of events already reached. ¹Number of events not reached before remaining patients dropped out in 
~4% of cases. 
# Schoenfeld formula applied. 
## Median of simulations reported 
9.7 
Details of OS event analyses for varying primary PFS time points and 
OS hazard ratios (answering an HA request)  
The information fraction compared to a benchmark number of 380 events16, expected number 
of OS events and conditional power for various assumed HRs, at interim and final formal 
analysis, are shown in Table 9–4 below. 
Note that no alpha spending function is used, but instead a weighted Bonferroni approach 
(0.002 at initial interim evaluation, 0.023 at final formal analysis) is applied. 
The number of OS events is dependent on the timing of the primary evaluation of PFS. The 
results presented in Table 9–4 are based on the earliest and best guess estimates of the primary 
completion date, using the current blinded study data. 
 
16 Following the strategy proposed by the FDA in an information request, 380 events are needed for a successful 
final OS analysis, if true HR=0.75 and power is to be 80% 


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Table 9–4: Overview of interim and final evaluation conditional power 
 
If primary PFS event target reached in June 2024: 
 
 
 
 
 
Bonferroni 
Planned 
OS time 
point 
Expected 
OS 
events at 
time 
point 
Benchm
ark 
number 
of OS 
events3  
 
Information
fraction 
compared 
to bench-
mark3 
split 
of 
alpha 
(for 
1-
sided 
test) 
 
 
 
 
 
Conditional power, if true HR= 
0.6 
0.65 
0.70 
0.75 
0.80 
Interim1 
151 
380 
  39.7% 
0.002 
60.3% 
40.9% 
24.6% 
13.3% 
  6.6% 
Final2 
176 
380 
  46.3% 
0.023 
91.8% 
80.6% 
64.5% 
46.5% 
30.3% 
 
If primary PFS event target reached in Feb 2024: 
 
 
 
 
 
Bonferroni 
Planned 
OS time 
point 
Expected 
OS 
events at 
time 
point 
Benchm
ark 
number 
of  
OS 
events3 
 
Information
fraction 
compared 
to bench-
mark3 
split 
of 
alpha 
(for 
1-
sided 
test) 
 
 
 
 
 
Conditional power, if true HR= 
0.6 
0.65 
0.70 
0.75 
0.80 
Interim1 
141 
380 
  37.1% 
0.002 
56.1% 
37.4% 
22,3% 
12.1% 
  6.0% 
Final2 
176 
380 
  46.3% 
0.023 
91.8% 
80.6% 
64.5% 
46.5% 
30.3% 
 
 
 
 
 
 
 
 
 
 
1Interim OS analysis at PFS primary completion. 
²Final formal OS analysis (at approximately 176 OS events). 
3Using benchmark of 380 events, following the strategy proposed by the FDA in an information request. 
9.8 
Likelihood to rule out a harmful effect in OS (answering an HA request) 
The likelihood that a sufficient number of OS events will be observed, to rule out any 
potential harmful effect in OS, given 3 and 5 years of additional OS follow-up beyond the 
planned, final, formal OS analysis (at approximately 176 OS events), was assessed using the 
following simulation approach: 
a) The original (blinded) study data was used as source data for the simulations. 
b) A random treatment group assignment was simulated. 
c) For patients at risk, future OS events and censoring times were predicted (using a 
model based on (a) above, where predictions were independent of the simulated 
treatment group). 


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d) For each HR assumption, shown in Table 9–5, individual survival times were scaled 
according to the patient’s random treatment assignment17 . 
e) The simulated data was then administratively censored at the respective dates, 3 and 5 
years after the predicted date for the final formal OS analysis, (i.e., after 3 years of 
additional FUP and after 5 years of additional FUP). 
f) A Cox PH model was fitted to the simulated data, and a point estimate for HR as well 
as an upper 95% confidence interval limit (CIL) was saved. 
g) This was repeated 10000 times, and the proportion of saved point estimates > 1, as 
well as the proportion of saved upper 95% CILs > 1, were determined.  
The above steps were repeated for all HR assumptions and additional FUP combinations and 
reported in Table 9–5. 
Table 9–5: Resulting probability of HR point estimate / upper bound exceeding 1 
Time points of evaluation  
Final formal OS 
analysis 
3 years additional FUP 
after final formal OS 
analysis  
5 years 
additional FUP 
after final formal 
OS analysis  
Expected date 
25-Jun-2025 
25-Jun-2028 
25-Jun-2030 
Projected number of 
events 
(in % compared to 
benchmark number of 380 
events1)  
 
176 (46.3%) 
 
240 (63.2%) 
 
276 (72.6%) 
True HR for OS 
Probability of Point Estimate / Upper Bound Exceeding 1 
HR=0.600  
<0.1% /   7.6% 
<0.1% / 3.3% 
  0.0% / 2.1% 
HR=0.667  
  0.5% / 26.0% 
  0.1% / 14.7% 
  0.1% / 11.3% 
HR=0.702 
  0.9% / 36.8% 
  0.3% / 25.8% 
  0.3% / 20.8% 
HR=0.739  
  2.3% / 49.6% 
  1.3% / 40.1% 
  0.8% / 34.1% 
HR=0.75 
  3.0% / 54.7% 
  1.5% / 43.5% 
  1.2% / 38.4% 
HR=0.8 
  7.3% / 70.2% 
  4.9% / 62.2% 
  4.3% / 58.8% 
HR=0.9 
24.9% / 90.8% 
22.5% / 88.2% 
20.4% / 86.8% 
HR=1.0 
49.3% / 97.4% 
48.5% / 97.5% 
49.7% / 97.3% 
1Following the strategy proposed by the FDA in an information request, a benchmark of 380 events is required 
for a successful final OS analysis, if true HR=0.75 and power is to be 80%. 
At the final formal OS analysis, a harmful effect (considered as HR for OS > 1.0) can be ruled 
out: 
a) For the point estimate with a high probability of 97% (=100%-3.0%) or higher for 
a true HR of 0.75 or lower, while  
b) For the upper bound of the confidence interval, high probability of 92.4% (=100%-
7.6%) can only be achieved for a true HR of 0.60 or lower. 
 
 
17 Assuming a constant hazard, predicted OS event times will be calculated using,  
• 
Simulated survival time × 2 × HR/(1+HR), for patients in the simulated placebo group 
• 
Simulated survival time × 2 × 1/(1+HR), for patients in the simulated copanlisib group 


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These simulations indicate that with an additional follow-up of 5 years, a harmful effect 
(considered as HR for OS > 1.0) can be ruled out  
c) For the point estimate with a high probability of 98.8% (=100%-1.2%) or higher 
for a true HR of 0.75 or lower, while  
d) For the upper bound of the confidence interval,  high probability of 97.9% 
(=100%-2.1%) can only be achieved for a true HR of 0.60 or lower. 
This result is considered indicative of this trial 
a) having been designed for a primary endpoint of PFS, and  
b) studying a patient population with anticipated long survival time leading to a long time 
until sufficient OS events can be collected.  
The result is also considered to reinforce the result of Table 9–3, where many scenarios would 
result in evaluations in 2030 or beyond.