Clinical trial NCT02367040
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: 2015-08-03; Completion date: 2024-11-15
Enrollment: 458 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging progression free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab and who either had a treatment-free interval of ≥ 12 months after completion of the last rituximab-containing treatment, or who are unwilling to receive chemotherapy/for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity.

Detailed description:

Arms: arm 1: Combination of the Copanlisib and rituximab arm 2: Combination of Copanlisib placebo and rituximab
Interventions: intervention 1: Copanlisib (Aliqopa, BAY80-6946) intervention 2: Placebo intervention 3: Rituximab
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. Dosing will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered before rituximab. 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 on Days 1, 8 and 15 of each 28-day cycle. Placebo will be administered before rituximab. intervention 3: Rituximab dose 375 mg/m2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 7 and 9.The solution for IV infusions is obtained after reconstitution of a calculated concentration of 1 to 4 mg/ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection or 5% D-Glucose in water.

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol  
Official Title: 
A Phase III, randomized, double-blind, placebo-controlled study 
evaluating the efficacy and safety of copanlisib in combination 
with rituximab in patients with relapsed indolent B-cell non-
Hodgkin’s lymphoma (iNHL) – CHRONOS-3 
NCT Number: 
NCT02367040 
Document Date: 
22-MAY-2020 
 


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Cover page of the integrated protocol
A Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy 
and safety of copanlisib in combination with rituximab in patients with relapsed 
indolent B-cell non-Hodgkin’s lymphoma (iNHL) – CHRONOS-3
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 21 MAY 2014
Amendment 01 (global amendment described in Section 13.1)
forming integrated protocol Version 2.0, dated 23 JAN 2015
Amendment 06 (global amendment described in Section 13.2)
forming integrated protocol Version 3.0, dated 18 FEB 2016
Amendment 07 (global amendment described in Section 13.3)
forming integrated protocol Version 4.0, dated 28 JUL 2016
Amendment 09 (global amendment described in Section 13.4)
forming integrated protocol Version 5.0, dated 02 FEB 2018
Amendment 10 (global amendment described in Section 13.5)
forming integrated protocol Version 6.0, dated 08 OCT 2019
Amendment 11 (global amendment described in Section 13.6)
forming integrated protocol Version 7.0, dated 22 MAY 2020
Amendments not included in the consecutive numbering of amendments are 
local amendments not forming part of this integrated global protocol. This currently 
includes:
Amendment 02, dated 11 MAY 2015
(local amendment valid for Ireland, Germany and Belgium only)
Amendment 03, dated 25 AUG 2015
(local amendment valid for France only)
Amendment 04, dated 01 SEP 2015
(local amendment valid for Denmark only)
Amendment 05, dated 13 OCT 2015
(local amendment valid for Turkey only)
Amendment 08, dated 18 APR 2017
(local amendment valid for Japan only)


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Title page
A Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy 
and safety of copanlisib in combination with rituximab in patients with relapsed 
indolent B-cell non-Hodgkin’s lymphoma (iNHL) – CHRONOS-3
Copanlisib and rituximab in relapsed iNHL
Test drug:
BAY 80-6946 / copanlisib
Clinical study phase:
III
Date:
22 MAY 2020
EudraCT no.:
2013-003893-29
Version no.:
7.0
Study no.:
BAY 80-6946 / 17067
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:
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 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
100 Bayer Boulevard, P.O.box 915
Whippany, NJ, USA
   
Telephone no.: 
PPD


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Signature of principal investigator
The signatory agrees to the content of the final integrated 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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Synopsis
Title
A Phase III, randomized, double-blind, placebo-controlled study evaluating the 
efficacy and safety of copanlisib in combination with rituximab in patients with 
relapsed indolent B-cell non-Hodgkin’s lymphoma (iNHL) – CHRONOS-3
Short title
Copanlisib and rituximab in relapsed iNHL
Clinical study phase
III
Study objective(s)
The primary objective of this study is:
To evaluate whether copanlisib in combination with rituximab is superior to placebo 
in combination with rituximab in prolonging progression-free survival (PFS) in 
patients with relapsed iNHL who have received one or more lines of treatment, 
including rituximab, and who either had a treatment-free interval of ≥12 months 
after completion of the last rituximab-containing treatment, or who are unwilling to 
receive chemotherapy/for whom chemotherapy is contraindicated on reason of age, 
comorbidities, and/or residual toxicity
The secondary objectives of this study are to evaluate:

The following characteristics of disease-related symptoms: “time to 
deterioration” and “time to improvement” 

Other radiological and clinical indicators of treatment efficacy

Safety and tolerability of copanlisib
The other objectives of this study are to evaluate:

Pharmacokinetics

Biomarkers

Quality of life
Test drug(s)
Copanlisib
Name of active 
ingredient
Copanlisib / BAY 80-6946 / phosphatidylinositol-3 kinase (PI3K) inhibitor
Treatment 
administered
Copanlisib in combination with rituximab
Dose(s) 
Copanlisib starting dose: 60 mg. Dose reductions to 45 mg and further to 30 mg are 
possible, should toxicities occur. Dosing will be administered on Days 1, 8 and 15 of 
each 28-day cycle. Copanlisib will be administered before rituximab.
Rituximab: 375 mg/m2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22, 
and then on Day 1 of Cycles 3, 5, 7 and 9.
Route of administration Intravenous (IV) infusions
Duration of treatment
Copanlisib treatment will be continued until disease progression (PD) (per central 
independent blinded radiology review) as defined in the 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]), unacceptable toxicity, or until another
criterion is met for withdrawal from the study treatment.
Rituximab treatment will be continued until the same criteria as defined for 
copanlisib are met, for a maximum of 8 infusions (until Cycle 9).
Reference drug(s)
Placebo


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Name of active 
ingredient
Not applicable
Treatment administered Placebo in combination with rituximab 
Dose(s)
Placebo starting dose: 60 mg. Dummy dose reductions to 45 mg and further to 30 mg 
are possible should toxicities occur. Dosing will be administered on Days 1, 8 and 15 
of each 28-day cycle. Placebo will be administered before rituximab.
Rituximab: 375 mg/m2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22,
and then on Day 1 of Cycles 3, 5, 7 and 9. 
Route of administration IV infusions
Duration of treatment
Placebo treatment will be continued until PD (per central independent blinded 
radiology review), as defined in the Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
Lugano Classification (Owen Criteria for patients with WM), unacceptable toxicity, 
or until another criterion is met for withdrawal from the study treatment. 
Rituximab treatment will be continued until the same criteria as defined for placebo 
are met, for a maximum of 8 infusions (until Cycle 9).
Indication
Relapsed indolent B-cell non-Hodgkin’s lymphoma
Diagnosis and main 
criteria for inclusion
Histologically confirmed diagnosis of iNHL in CD20 positive patients with 
histological subtype limited to:

Follicular lymphoma (FL) G1-2-3a

Small lymphocytic lymphoma (SLL) with absolute monoclonal lymphocyte 
count <5x109/L at study entry

Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)

Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
Patients must have relapsed (recurrence after complete response or presented 
progression after partial response) after the last rituximab-, rituximab biosimilars-, or 
anti-CD20 monoclonal antibody (e.g. obinutuzumab)-containing therapy (other 
previous treatment lines after rituximab are allowed). A previous regimen is defined 
as one of the following: at least 2 months of single-agent therapy (less than 2 months 
of therapy is allowed for patients who responded to single-agent rituximab, 
rituximab biosimilars, or anti-CD20 monoclonal antibody); at least 2 consecutive 
cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Previous 
exposure to PI3K is acceptable (except to copanlisib) provided there is no resistance.
Patients with prior intolerance to PI3K inhibitors other than copanlisib are eligible.
Non-WM patients must have at least one bi-dimensionally measurable lesion (that 
has not been previously irradiated) according to the Recommendations for Initial 
Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma: 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 
≥2x 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 for central pathology 


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(obtained within 5 years of the consent date) at Screening.
Adequate baseline laboratory values as assessed within 7 days before starting study 
treatment.
Left ventricular ejection fraction ≥ 45%.
Patients must either

have had a progression-free and treatment-free interval of ≥12 months after 
completion of the last rituximab-containing treatment
OR

be considered unfit to receive chemotherapy on reason of age, concomitant 
morbidities, and/or residual toxicity from previous treatments, or 
unwillingness to receive chemotherapy. These patients must also have had a 
progression-free and treatment free interval of ≥ 6 months after completion 
of the last rituximab-containing treatment. Patients in whom chemotherapy 
is contraindicated are defined by one of the following features:
o Age ≥80 years
o Age < 80 years and at least 1 of the following conditions:

at least 3 grade 3 CIRS-G comorbidities 
OR

at least 1 grade 4 CIRS-G comorbidity (if considered compatible with 
participation in the study).
Main criteria for 
exclusion
Follicular lymphoma grade 3b or transformed disease, or chronic lymphocytic 
leukemia.
Progression-free interval or treatment-free interval of less than 12 months since the 
last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. 
obinutuzumab)-containing treatment (including maintenance with these drugs). For 
patients considered unwilling/unfit to receive chemotherapy: progression-free interval
or treatment-free interval of less than 6 months since the last rituximab-, rituximab 
biosimilars-, or anti-CD20 monoclonal antibody-containing treatment (including 
maintenance with these drugs), as assessed by the investigator.
History or concurrent condition of interstitial lung disease and/or severely impaired 
lung function.
Known lymphomatous involvement of the central nervous system.
Patients with HbA1c > 8.5% at Screening.
Known history of human immunodeficiency virus (HIV) infection.
Hepatitis B (HBV) or hepatitis C (HCV). Patients positive for HBsAg or HBcAb will 
be eligible if they are negative for HBV-DNA, these patients should receive 
prophylactic antiviral therapy. 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.
Prior treatment with copanlisib.
Study design
A randomized, double-blind, placebo-controlled, 2-arm phase III study to evaluate 
the efficacy and safety of copanlisib in combination with rituximab, in comparison to 
placebo in combination with rituximab in patients with relapsed iNHL.
Approximately 450 FL and other iNHL patients who meet the eligibility criteria will 
be randomly assigned in a 2:1 ratio to the double blinded treatment arms: copanlisib 
plus rituximab or placebo plus rituximab, respectively. 
Patients will be stratified by a combination of NHL histology (FL vs. other iNHL), 


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inclusion criteria (progression-free and treatment-free interval of ≥12 months after 
the last rituximab-containing treatment vs. unwilling/unfit to receive chemotherapy), 
presence of bulky disease (yes vs. no) and previous treatment with PI3K inhibitors 
(yes vs. no). If the patient fulfills both entry criteria, the criterion “unwilling/unfit to 
receive chemotherapy” should be selected.
After the 30th randomized patient has completed the first cycle of treatment, the Data 
Monitoring Committee will review the unblinded safety data accumulated up to that 
time and provide recommendation on whether it is safe to continue in the 
combination arm at the initial dose of copanlisib. The investigators, patients and the 
sponsor will remain blinded.
Methodology
The primary efficacy variable is PFS, defined as the time (in days) from 
randomization to PD as assessed by central review or death from any cause (if no 
progression is documented). 
Secondary efficacy variables are objective tumor response rate (ORR), duration of 
response (DOR), complete response rate (CRR), time to progression (TTP), overall 
survival (OS), time to improvement and the time to deterioration in disease-related 
symptoms - physical (DRS-P) of at least 3 points as measured by the FLymSI-18 
questionnaire (FLymSI = NCCN-FACT Lymphoma Symptom Index).
Other efficacy variables are FLymSI-18 subscale, total score analyses and time to 
onset of physical symptoms of lymphoma based on DRS-P, and ECOG performance 
status.
The study is composed of the following periods: Screening, Treatment, Safety 
follow-up, Active follow-up (if applicable) and Survival follow-up. 
Patients randomized to copanlisib + rituximab arm will receive 60 mg copanlisib IV 
infusion on Days 1, 8 and 15 of each 28-day treatment cycle, and 375 mg/m2
rituximab during Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 
7 and 9. 
Patients randomized to placebo + rituximab arm will receive placebo IV infusion on 
Days 1, 8 and 15 of each 28-day treatment cycle, and 375 mg/m2 rituximab during 
Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 7 and 9. 
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 (window 
of +5 days allowed) after the last administration of study treatment.
Patients who discontinue study treatment because of PD will enter Safety follow-up 
period and patients who 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 follow-up tumor assessments by central independent blinded 
review as outlined in this protocol from the day of randomization 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 intervals 
during the Survival follow-up period (up to 3 years after the last patient started study 
treatment), except for patients who object to follow-up data collection.
Study participants may be offered the option to transition into a roll-over study
(ROS).
Safety evaluations will be done at Screening, on the first day of study treatment 
administration (Cycle 1 Day 1), at each clinic visit during treatment, and at the safety 
follow-up visit.
The first radiological tumor assessments with IV (and oral, if indicated, per Imaging 


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Manual) contrast-enhanced computed tomography / magnetic resonance imaging 
(CT/MRI) scans of neck, chest, abdomen and pelvis 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 the 
screening CT/MRI (if a patient is on chronic corticosteroid therapy, corticosteroids 
should be de-escalated to the maximum allowed dose before the screening). The 
method chosen at baseline 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 period as well as during the Active follow-up period, tumor 
assessments with the same modality will be performed every 8 weeks (7 days) 
during Year 1, every 12 weeks (7 days) during Year 2, and every 24 weeks 
(7 days) during Year 3 and onwards, starting from Cycle 1 Day 1. CT/MRI scans 
are not required at the EOT visit if the patient discontinues because of PD which has 
been radiologically confirmed within the 4 weeks preceding the EOT.
As long as the patient has not experienced PD, investigator’s assessment is sufficient 
for case management. In the event of progression, radiological real-time confirmation 
by central independent blinded evaluation is required before a final decision to stop 
the treatment is made. Radiological real-time confirmation will only be conducted 
until the database cut-off for the primary analysis. The final evaluation of treatment 
response (best response: ORR and CRR) will be done by central blinded review and 
for those not undergoing PD-confirmation in retrospective setting.
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. However, in cases when WM patients will 
develop disease progression confirmed radiologically by presenting with measurable 
lesion(s) without simultaneous increase in IgM, the imaging scans should be 
submitted for 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. Biopsies taken up to 28 days 
prior to first dose are acceptable. If the baseline biopsy is positive for lymphoma 
infiltration at Screening, it will be mandatory to perform it again to confirm the first 
complete response (CR) by sending the sample to central review after local bone 
marrow assessment, and also at the investigator discretion if clinical evaluation leads 
to suspicion of bone marrow infiltration without further radiological findings.
Type of control
Inactive control: placebo
Number of patients
Assuming 30% screening failure rate, 643 patients (including FL and other iNHL) 
need to be enrolled to have 450 randomized patients. Patients will not be replaced. 
Primary variable
The primary variable is PFS, defined as the time (in days) from randomization to PD
as assessed by central review or death from any cause (if no progression is 
documented).
Plan for statistical 
analysis
Efficacy analysis: The primary efficacy variable is PFS, as assessed by central 
review in the full analysis set (FAS), which is defined as all patients who were 
randomized. Patients alive without documented progression at the time of analysis 
will be censored at the date of their last tumor evaluation. Copanlisib in combination 
with rituximab vs. placebo in combination with rituximab will be compared in the 
FAS, using a one-sided log-rank test stratified by the same factors as used for 
randomization: FL vs. other iNHL histologies and progression-free and treatment-
free interval of ≥12 months after completion of the last rituximab-containing
treatment vs. unwilling/unfit to receive chemotherapy.


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Kaplan-Meier estimates and survival curves will also be presented for each treatment 
group, as well as the hazard ratios with their confidence intervals.
Separate statistical test strategies will be conducted for the United States and Europe
For the US, if the null hypothesis in the primary efficacy variable is rejected in the 
FAS, PFS in the combined FL and MZL population, ORR in the combined FL and 
MZL population, time to deterioration and time to improvement in DRS-P in the 
combined FL and MZL population will be tested sequentially. For the EU, if the null 
hypothesis in the primary efficacy variable is rejected in the FAS, ORR in the FAS
population, time to deterioration and time to improvement in DRS-P in the FAS
population will be tested sequentially.
OS, TTP, DOR, time to deterioration and time to improvement in DRS-P of at least
3 points will be analyzed using a stratified log-rank test similar to that for the 
primary endpoint, PFS.
ORR and CRR will be analyzed using the Cochran-Mantel-Haenszel test. The tests 
will be adjusted for the same stratification factors as used for PFS.
Other efficacy endpoints will be analyzed descriptively.
Safety analysis: Safety variables will be summarized by means of descriptive 
statistics and/or frequency tables as appropriate. Summaries will be given by 
treatment group.


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Table of contents
Cover page of the integrated protocol .................................................................................... 1
Title page................................................................................................................................... 2
Signature of principal investigator ......................................................................................... 3
Synopsis..................................................................................................................................... 4
Table of contents..................................................................................................................... 10
Table of tables......................................................................................................................... 16
Table of figures....................................................................................................................... 16
List of abbreviations............................................................................................................... 17
Definitions of terms ................................................................................................................ 20
1.
Introduction ..................................................................................................................... 21
1.1
Background.................................................................................................................... 21
1.1.1
Copanlisib (BAY 80-6946)......................................................................................... 22
1.1.2
Clinical experience ..................................................................................................... 23
1.2
Rationale for the study................................................................................................... 25
1.3
Benefit-risk assessment.................................................................................................. 25
2.
Study objectives............................................................................................................... 26
3.
Investigator and other study personnel......................................................................... 27
4.
Study design..................................................................................................................... 28
5.
Study population ............................................................................................................. 32
5.1
Eligibility ....................................................................................................................... 32
5.1.1
Inclusion criteria......................................................................................................... 32
5.1.2
Exclusion criteria........................................................................................................ 34
5.1.3
Justification of selection criteria................................................................................. 37
5.2
Withdrawal of patients from study ................................................................................ 38
5.2.1
Withdrawal ................................................................................................................. 38
5.2.1.1
Withdrawal of study treatment................................................................................ 38
5.2.1.2
Withdrawal from follow-up period ......................................................................... 40
5.2.2
Replacement ............................................................................................................... 40
5.3
Patient identification ...................................................................................................... 40
6.
Treatments ....................................................................................................................... 41
6.1
Treatments to be administered....................................................................................... 41
6.2
Identity of investigational medicinal products............................................................... 41
6.3
Treatment assignment .................................................................................................... 42
6.4
Dosage and administration............................................................................................. 43
6.4.1
Dose modification....................................................................................................... 45
6.4.1.1
Hematological toxicity ............................................................................................ 46
6.4.1.2
Non-hematological toxicity..................................................................................... 46
6.4.2
Treatment of toxicities................................................................................................ 49


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6.4.2.1
Management of transient post-infusion glucose increases that can occur with 
copanlisib................................................................................................................. 49
6.4.2.2
Management of hyperlipidemia............................................................................... 51
6.4.2.3
Treatment of blood pressure increases associated with copanlisib ......................... 51
6.4.2.4
Treatment of vomiting and diarrhea........................................................................ 51
6.4.2.5
Treatment of dermatologic toxicity......................................................................... 51
6.4.2.6
Special considerations for patients unfit for chemotherapy .................................... 52
6.4.2.7
Guidance for monitoring and prophylaxis of opportunistic infection (OI)............. 53
6.4.2.7.1
Monitoring guidelines for OI............................................................................... 53
6.4.2.7.2
Prophylaxis of OI................................................................................................. 53
6.5
Blinding.......................................................................................................................... 54
6.6
Drug logistics and accountability................................................................................... 55
6.7
Treatment compliance.................................................................................................... 55
6.8
Post-study therapy.......................................................................................................... 55
6.9
Prior and concomitant therapy....................................................................................... 55
6.9.1
Prohibited concomitant therapy.................................................................................. 55
6.9.2
Permitted concomitant therapy................................................................................... 56
7.
Procedures and variables................................................................................................ 57
7.1
Schedule of procedures.................................................................................................. 57
7.1.1
Tabulated overview .................................................................................................... 57
7.1.2
Timing of assessment ................................................................................................. 65
7.1.2.1
Screening period...................................................................................................... 65
7.1.2.2
Treatment period ..................................................................................................... 67
7.1.2.2.1
Treatment – Cycle 1............................................................................................. 67
7.1.2.2.2
Treatment – Cycle 2 and higher........................................................................... 70
7.1.2.3
Tumor assessments.................................................................................................. 73
7.1.2.4
End-of-treatment visit.............................................................................................. 74
7.1.2.5
Follow-up periods.................................................................................................... 75
7.1.2.5.1
Safety follow-up................................................................................................... 75
7.1.2.5.2
Active follow-up .................................................................................................. 76
7.1.2.5.3
Survival follow-up ............................................................................................... 76
7.2
Population characteristics .............................................................................................. 76
7.2.1
Demographics............................................................................................................. 76
7.2.2
Medical history........................................................................................................... 76
7.2.3
Other baseline characteristics ..................................................................................... 77
7.3
Efficacy.......................................................................................................................... 77
7.3.1
Primary efficacy variable............................................................................................ 77
7.3.2
Radiological tumor assessments................................................................................. 77
7.3.3
Tumor assessments in patients with WM................................................................... 79
7.4
Pharmacokinetics / pharmacodynamics......................................................................... 79
7.4.1
Sampling..................................................................................................................... 79
7.4.2
Analysis ...................................................................................................................... 80
7.5
Safety ............................................................................................................................. 80
7.5.1
Adverse events............................................................................................................ 80
7.5.1.1
Definitions............................................................................................................... 80
7.5.1.2
Classifications for adverse event assessment .......................................................... 81
7.5.1.2.1
Seriousness........................................................................................................... 81


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7.5.1.2.2
Intensity................................................................................................................ 81
7.5.1.2.3
Causal relationship............................................................................................... 81
7.5.1.2.4
Action taken with study treatment ....................................................................... 83
7.5.1.2.5
Other specific treatment(s) of adverse events...................................................... 83
7.5.1.2.6
Outcome............................................................................................................... 83
7.5.1.3
Assessments and documentation of adverse events ................................................ 83
7.5.1.4
Reporting of serious adverse events ........................................................................ 84
7.5.1.5
Expected adverse events.......................................................................................... 85
7.5.1.6
Adverse events of special safety interest................................................................. 85
7.5.2
Pregnancies................................................................................................................. 85
7.5.3
Further safety.............................................................................................................. 86
7.5.3.1
Laboratory ............................................................................................................... 86
7.5.3.2
Physical examinations............................................................................................. 87
7.5.3.2.1
Complete physical examination........................................................................... 87
7.5.3.2.2
Brief physical examination .................................................................................. 88
7.5.3.3
Vital signs................................................................................................................ 88
7.5.3.4
12-lead ECG............................................................................................................ 88
7.5.3.5
Cardiac function ...................................................................................................... 89
7.5.3.6
ECOG performance status....................................................................................... 89
7.5.3.7
Glucose measurement on copanlisib/placebo infusion days ................................... 89
7.6
Other procedures and variables...................................................................................... 89
7.6.1
Biomarker investigations............................................................................................ 89
7.6.2
Quality of life questionnaire....................................................................................... 91
7.6.3
Electronic patient-reported outcomes evaluation ....................................................... 92
7.7
Appropriateness of procedures / measurements............................................................. 92
8.
Statistical methods and determination of sample size ................................................. 92
8.1
General considerations................................................................................................... 92
8.2
Analysis sets................................................................................................................... 92
8.3
Variables ........................................................................................................................ 93
8.3.1
Efficacy variables ....................................................................................................... 93
8.3.1.1
Primary efficacy variable ........................................................................................ 93
8.3.1.2
Secondary efficacy variables................................................................................... 93
8.3.1.3
Other efficacy variables........................................................................................... 94
8.3.2
Safety variables........................................................................................................... 94
8.4
Statistical and analytical plans....................................................................................... 94
8.4.1
Population characteristics........................................................................................... 94
8.4.2
Efficacy....................................................................................................................... 95
8.4.2.1
Primary efficacy analysis ........................................................................................ 95
8.4.2.2
Secondary efficacy parameters................................................................................ 96
8.4.2.3
Confirmatory statistical test strategy....................................................................... 96
8.4.2.4
Other efficacy evaluations....................................................................................... 99
8.4.3
Subgroup Analyses..................................................................................................... 99
8.4.4
Safety Analyses ........................................................................................................ 100
8.4.5
Pharmacokinetic Data............................................................................................... 100
8.5
Planned interim analyses.............................................................................................. 100
8.6
Determination of sample size....................................................................................... 100
9.
Data handling and quality assurance .......................................................................... 101


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9.1
Data recording.............................................................................................................. 101
9.2
Monitoring ................................................................................................................... 102
9.3
Data processing............................................................................................................ 102
9.4
Audit and inspection .................................................................................................... 103
9.5
Archiving ..................................................................................................................... 103
10. Premature termination of the study ............................................................................ 103
11. Ethical and legal aspects............................................................................................... 104
11.1
Ethical and legal conduct of the study......................................................................... 104
11.2
Patient information and consent................................................................................... 105
11.3
Publication policy ........................................................................................................ 106
11.4
Compensation for health damage of patients / insurance ............................................ 106
11.5
Confidentiality ............................................................................................................. 106
12. Reference list.................................................................................................................. 106
13. Protocol amendments.................................................................................................... 111
13.1
Amendment 1............................................................................................................... 111
13.1.1
Overview of changes ................................................................................................ 111
13.1.1.1
Modification 1 – inclusion criteria changed.......................................................... 111
13.1.1.2
Modification 2 – exclusion criteria updated.......................................................... 112
13.1.1.3
Modification 3 – target population for efficacy analysis changed ........................ 113
13.1.1.4
Modification 4 – randomization ratio and stratification changed ......................... 113
13.1.1.5
Modification 5 – time to improvement in DRS-P added as secondary efficacy 
variable .................................................................................................................. 113
13.1.1.6
Modification 6 – subgroup analyses added ........................................................... 113
13.1.1.7
Modification 7 – patient enrollment and DMC review of safety data changed .... 114
13.1.1.8
Modification 8 – language on informed consent, re-screening and re-testing 
revised ................................................................................................................... 114
13.1.1.9
Modification 9 – language on study drug reconstitution modified ....................... 114
13.1.1.10 Modification 10 – guidelines on management of hyperglycemia updated ........... 114
13.1.1.11 Modification 11 – laboratory evaluations revised................................................. 115
13.1.1.12 Modification 12 – blood pressure and ECG measurements revised ..................... 115
13.1.1.13 Modification 13 – tumor assessments clarified..................................................... 115
13.1.1.14 Modification 14 – completion of PRO information sheet clarified....................... 115
13.1.1.15 Modification 15 – blinding details removed ......................................................... 115
13.1.1.16 Modification 16 – collection of biomarker and PK samples revised .................... 116
13.1.1.17 Modification 17 – tumor response criteria udpated............................................... 116
13.1.1.18 Modification 18 – copanlisib clinical experience udpated.................................... 116
13.1.1.19 Modification 19 – administrative information udpated......................................... 116
13.1.1.20 Modification 20 – other clarifications and corrections ......................................... 117
13.1.2
Changes to the protocol text ..................................................................................... 117
13.2
Amendment 6............................................................................................................... 117
13.2.1
Overview of changes ................................................................................................ 117
13.2.1.1
Modification 1 – update of clinical experience with copanlisib ........................... 117
13.2.1.2
Modification 2 – previous exposure to alkylating agents removed....................... 117
13.2.1.3
Modification 3 – clarification of inclusion criterion related to WM patients ....... 117
13.2.1.4
Modification 4 – modification of coagulation language ....................................... 118


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13.2.1.5
Modification 5 – modification of contraception and pregnancy testing 
requirements .......................................................................................................... 118
13.2.1.6
Modification 6 – clarification of the requirements for baseline laboratory 
analyses ................................................................................................................. 118
13.2.1.7
Modification 7 – modification of conditions for rituximab use and alignment of 
time frame reference.............................................................................................. 118
13.2.1.8
Modification 8 – modification of exclusion criterion related to arterial 
hypertension .......................................................................................................... 119
13.2.1.9
Modification 9 – exclusion of patients based on plasma glucose levels removed 119
13.2.1.10 Modification 10 – prophylaxis for HBV and monitoring of HBV and HCV 
added ..................................................................................................................... 119
13.2.1.11 Modification 11 – clarification of exclusion criterion related to proteinuria........ 119
13.2.1.12 Modification 12 – language on corticosteroid therapy clarified ........................... 119
13.2.1.13 Modification 13 – modification of exclusion criterion related to evidence of 
resistance to PI3K inhibitors ................................................................................. 120
13.2.1.14 Modification 14 – prior treatment with copanlisib added to the exclusion criteria.120
13.2.1.15 Modification 15 – language regarding reconstitution, dilution and storage of 
copanlisib modified............................................................................................... 120
13.2.1.16 Modification 16 – updated guidance for glucose increase management and 
monitoring ............................................................................................................. 120
13.2.1.17 Modification 17 – updated guidance for management and monitoring of blood 
pressure increases.................................................................................................. 121
13.2.1.18 Modification 18 – minimum exposure to rituximab added................................... 121
13.2.1.19 Modification 19 – fasting requirement for lipid panels revised ............................ 121
13.2.1.20 Modification 20 – central pathology review of bone marrow samples clarified... 121
13.2.1.21 Modification 21 – clarification of tumor response language ................................ 122
13.2.1.22 Modification 22 – usage of verapamil and diltiazem amended............................. 122
13.2.1.23 Modification 23 – PK sampling time modified..................................................... 122
13.2.1.24 Modification 24 – clarification of SAE reporting language.................................. 123
13.2.1.25 Modification 25 – language related to hemoglobin A1c measurements clarified. 123
13.2.1.26 Modification 26 – assessment of hydration status added...................................... 123
13.2.1.27 Modification 27 – paper PRO questionnaire removed.......................................... 123
13.2.1.28 Modification 28 – reference to the Declaration of Objection form removed........ 123
13.2.1.29 Modification 29 – administrative change.............................................................. 123
13.2.1.30 Modification 30 – other clarifications and corrections ......................................... 123
13.2.2
Changes to the protocol text ..................................................................................... 124
13.3
Amendment 7............................................................................................................... 124
13.3.1
Overview of changes ................................................................................................ 124
13.3.1.1
Modification 1 – update of clinical experience with copanlisib ........................... 124
13.3.1.2
Modification 2 – modification of inclusion criteria .............................................. 125
13.3.1.3
Modification 3 – modification of exclusion criteria.............................................. 125
13.3.1.4
Modification 4 – change of extended period for IVRS/IWRS randomization 
transaction ............................................................................................................. 125
13.3.1.5
Modification 5 – modification of absolute neutrophil count (ANC) criteria for 
copanlisib dosing................................................................................................... 126
13.3.1.6
Modification 6 – guidance for management of toxicities added........................... 126
13.3.1.7
Modification 7 – addition of guidance for monitoring and prophylaxis of 
opportunistic infections (OI) ................................................................................. 126


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13.3.1.8
Modification 8 – reference to patient’s paper blood glucose tracking diary was 
added ..................................................................................................................... 127
13.3.1.9
Modification 9 – clarification on procedure schedule........................................... 127
13.3.1.10 Modification 10 – change in agenda of procedures .............................................. 127
13.3.1.11 Modification 11 – clarification of reporting period of adverse events during 
safety follow-up..................................................................................................... 127
13.3.1.12 Modification 12 – clarification of language regarding ePRO devices .................. 127
13.3.1.13 Modification 13 – clarification for prohibited concomitant therapy..................... 127
13.3.1.14 Modification 14 - other clarifications and corrections .......................................... 127
13.3.2
Changes to the protocol text ..................................................................................... 128
13.4
Amendment 9............................................................................................................... 128
13.4.1
Overview of changes ................................................................................................ 128
13.4.1.1
Modification 1 – changes in the statistical analysis and sample size.................... 128
13.4.1.2
Modification 2 – clarifications/modifications of inclusion criteria....................... 128
13.4.1.3
Modification 3 – clarifications/modifications of exclusion criteria ...................... 129
13.4.1.4
Modification 4 – clarification of stratification factors related to entry criteria..... 129
13.4.1.5
Modification 5 – updated guidance for management of glucose increases........... 130
13.4.1.6
Modification 6 – modification of the monitoring guidelines for OI ..................... 130
13.4.1.7
Modification 7 – updated guidance for blood pressure measurements on infusion 
days........................................................................................................................ 131
13.4.1.8
Modification 8 – clarification of bone marrow assessments................................. 131
13.4.1.9
Modification 9 – changes based on drug-drug interaction data ............................ 131
13.4.1.10 Modification 10 – introduction of dose interval for rituximab ............................. 132
13.4.1.11 Modification 11 – clarifications of the tumor assessment/response evaluation.... 132
13.4.1.12 Modification 12 – clarification of PK sampling and analysis............................... 132
13.4.1.13 Modification 13 – clarification of QoL questionnaire schedule............................ 132
13.4.1.14 Modification 14 – administrative changes ............................................................ 132
13.4.1.15 Modification 15 – other clarifications and corrections ......................................... 133
13.4.2
Changes to the protocol text ..................................................................................... 133
13.5
Amendment 10............................................................................................................. 133
13.5.1
Overview of changes ................................................................................................ 133
13.5.2
Changes to the protocol text ..................................................................................... 134
13.6
Amendment 11............................................................................................................. 135
13.6.1
Overview of changes ................................................................................................ 135
13.6.2
Changes to the protocol text ..................................................................................... 136
14. Appendices ..................................................................................................................... 137
14.1
CYP3A4 inhibitors and inducers ................................................................................. 137
14.2
ECOG Performance Status .......................................................................................... 138
14.3
New York Heart Association (NYHA) Functional Classification............................... 138
14.4
Evaluation of tumor response ...................................................................................... 139
14.5
Quality of life questionnaire: FLymSI-18.................................................................... 141
14.6
Glomerular filtration rate ............................................................................................. 142
14.7
Cumulative Illness Rating Scale for Geriatrics (CIRS-G)........................................... 143
14.8
The average glycemic index of common foods derived from multiple studies by 
different laboratories section removed ........................................................................ 144


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Table of tables
Table 6–1 Fasting requirements and pre-dose glucose levels ................................................ 43
Table 6–2 Laboratory test criteria for Day 1 dose of subsequent cycles................................ 44
Table 6–3 Dose levels of copanlisib and placebo................................................................... 45
Table 6–4 Dose modification of copanlisib/placebo for hematological toxicity.................... 46
Table 6–5 Dose modification of copanlisib/placebo for non-hematological toxicity ............ 47
Table 6–6 Dose modification of copanlisib/placebo for dermatologic toxicity..................... 47
Table 6–7 Dose adjustment in cases of non-infectious pneumonitis (NIP) ........................... 48
Table 6–8 Dose modification of copanlisib/placebo for arterial hypertension ...................... 49
Table 6–9 Management of transient post-infusion glucose increases .................................... 50
Table 6–10 Guidance on treatment of skin toxicities............................................................... 52
Table 7–1 Study flow chart .................................................................................................... 58
Table 7–2 PK sampling schedule ........................................................................................... 64
Table 8–1 Assessment of statistical power for PFS test in the overall FAS population and 
combined FL and MZL population ....................................................................... 98
Table 8–2 Required number of PFS events per entry criteria stratum ................................. 101
Table of figures
Figure 4–1 Study periods......................................................................................................... 29
Figure 8–1 Confirmatory test strategy based on five test families for United States .............. 97
Figure 8–2 Confirmatory test strategy based on four test families for Europe........................ 99


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List of abbreviations
AE
Adverse event
Ab
Antibody
Ag
Antigen
AKT
Protein kinase B
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the curve
BfS
Federal Office for Radiation Protection 
BP
Blood pressure
BTK
Bruton’s tyrosine kinase
BUN
Blood urea nitrogen
C
Cycle
CBC
Complete blood count
CD
Cluster of differentiation
c-KIT
Proto-oncogen c-KIT (CD117)
CHGRAO
China Human Genetic Resources Administration Office
CHOP
Cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone
CI
Confidence interval
CIRS-G
Cumulative Illness Rating Scale for Geriatrics 
CLL
Chronic lymphocytic leukemia
Cmax
Maximum drug concentration
CMV
Cytomegalovirus
CR
Complete response
CRF
Case report form
CRO
Contract research organization
CRP
C-reactive protein
CRR
Complete response rate
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CVP
Cyclophosphamide, vincristine, prednisolone
CYP3A4
Cytochrome P450 isoenzyme 3A4
D
Day
dL
Deciliter
DLBCL
Diffuse large B-cell lymphoma
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DOR
Duration of response
DPP4
Dipeptidyl peptidase-4
DRS-E
Disease-related symptoms – emotional (subscale)
DRS-P
Disease-related symptoms – physical (subscale)
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
e.g.
For example (exempli gratia)
EGFR
Epidermal growth factor receptor
EOT
End of treatment


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ePRO
Electronic patient-reported outcome
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin-fixed paraffin-embedded
FL
Follicular lymphoma
FLIPI
Follicular lymphoma International Prognostic Index
FLymSI-18
NCCN-FACT Lymphoma Symptom Index-18
FND
Fludarabine, mitoxantrone, dexamethasone
FSH
Follicle stimulating hormone
FU
Follow-up
FWB
Functional and well-being (subscale)
g
Gram
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GFR
Glomerular filtration rate
GMP
Good Manufacturing Practice
GPV
Global Pharmacovigilance
h
Hour(s)
Hb
Hemoglobin
HbA1c
Glycated hemoglobin
HBcAb
Hepatitis B core antibody
HBeAg
Hepatitis B e antigen
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCG
β-human chorionic gonadotropin 
HCV
Hepatitis C Virus
HCVAb
Anti-HCV antibody
HDL
High-density lipoprotein
HER
Human epidermal growth factor receptor 
HIV
Human immunodeficiency virus
HR
Hazard ratio
IB
Investigator’s Brochure
ICF
Informed Consent Form
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonization
IDMS
Isotope dilution mass spectroscopy
i.e.
That is (id est)
IEC
Independent Ethics Committee
IGF-1R
Insulin-like growth factor 1 receptor
IgM
Immunoglobulin M
IHC
ImmunoHistoChemistry
iNHL
Indolent non-Hodgkin’s lymphoma
INR
International normalized ratio
IRB
Institutional review board
ISO
International Organization for Standardization
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System


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kg
Kilogram
LDH
Lactate dehydrogenase
LDi
Longest diameter
LDL
Low-density lipoprotein
LPL 
Lymphoplasmacytoid lymphoma 
LVEF
Left ventricular ejection fraction
M-1
Metabolite 1
MALT
Marginal-zone lymphoma of mucosa-associated lymphoid tissue
MD
Medical Doctor
MDRD
Modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minutes
mmHg
Millimeter of mercury
mL
Milliliter 
MR
Minor response
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
mTOR
Mammalian target of rapamycin
MUGA
Multiple gated acquisition
MZL
Marginal-zone lymphoma
NaOH
Sodium hydroxide
NCCN
National Comprehensive Cancer Network
NCCN-FACT 
National Comprehensive Cancer Network – Functional Assessment of Cancer 
Therapy
NCI
National Cancer Institute
NHL
Non-Hodgkin’s Lymphoma
NIP
Non-infectious pneumonitis
nM
Nanometer
NMZL
Nodal marginal-zone lymphoma
NYHA
New York Heart Association
OI
Opportunistic infection
ORR
Objective tumor response rate
OS
Overall survival
PCR
Polymerase chain reaction
PD
Disease progression
PDGFR
Platelet-derived growth factor receptor
PDK1
Phosphoinositide-dependent kinase 1
PET 
Positron emission tomography 
PFS
Progression-free survival
pH
Negative log of hydrogen ion concentration
PI-4,5-P2
Phosphatidylinositol-4,5-bisphosphate
PID
Patient identification number
PI3K
Phosphatidylinositol-3-kinase
PIP3
Phosphatidylinositol-3,4,5-trisphosphate
PK
Pharmacokinetic(s)
PPD
Product of perpendicular diameters
PR
Partial response
PRO
Patient-reported outcomes
PT
Prothrombin time
PTEN
Phosphatase and tensin homolog
PTT
Partial thromboplastin time


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QoL
Quality of life
RBC
Red blood cell count
RNA
Ribonucleic acid
ROS
Roll-over study
RR
Response rate
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical analysis system
SCR
Serum creatinine
SDi
Shortest diameter
SFU
Safety follow-up
SGLT-2
Sodium/glucose co-transporter 2
SLL
Small lymphocytic lymphoma
SmPC
Summary of Product Characteristics
SPD
Sum of the product of the diameters
SMZL
Splenic marginal-zone lymphoma
SOC
Standard of care
SUSAR
Suspected, unexpected, serious adverse reaction
TEAE
Treatment-emergent adverse event
TSE
Treatment side effects (subscale)
TTP
Time to progression
ULN
Upper limit normal
UPCR
Urine protein to creatinine ratio
vs.
Versus
VEGF
Vascular endothelial growth factor
VGPR
Very good partial response
WBC
White blood cell count
WHO
World Health Organization
WHO-DD
WHO Drug Dictionary
WM
Waldenström macroglobulinemia
WOCBP
Woman of childbearing potential
Definitions of terms
Throughout this protocol, prior rituximab therapy covers treatment with rituximab, rituximab 
biosimilars, or anti-CD20 monoclonal antibody (e.g. obinutuzumab).
Lugano Classification – criteria for tumor response assessment as defined in the 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma (27).
Owen Criteria – criteria for tumor response assessment applicable for patients with 
Waldenström macroglobulinemia (WM), as defined in the Response Assessment in 
Waldenström macroglobulinemia: update from the VIth International Workshop (35).


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1.
Introduction
1.1
Background
Non-Hodgkin’s lymphomas (NHLs) are a heterogeneous group of lymphoproliferative 
malignancies arising either from B lymphocytes (85–90%) or from T/NK lymphocytes. These 
malignancies typically originate in the lymph nodes, but can involve almost any organ 
tissue (1).
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 (1).
NHLs can be divided according to their clinical behavior in two main prognostic groups: 
indolent NHL and aggressive NHL. Aggressive lymphomas are characterized by an 
aggressive clinical course and may evolve into a lethal presentation if not immediately treated. 
However, with modern chemo-immunotherapy regimens and stem cell transplant 
consolidation a definitive cure can be reached in 50-60% of patients. 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 be generally 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. The risk of 
transformation has been estimated to be 2-3% per year.
Indolent NHLs encompass the following low-grade histologic subtypes of B-cell NHL
included in the 2008 WHO classification of lymphoid neoplasm: 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) (3). FL is the second most common subtype of NHL (22% of newly 
diagnosed cases) (4), 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.
Optimal treatment of advanced stages of indolent NHL is controversial because of low cure 
rates with the current therapeutic options. The first-line standard therapy includes rituximab, 
usually administered together with cytotoxic combinations (CHOP, CVP) or single agents 
(alkylators, e.g. bendamustine, or purine nucleoside analogs such as fludarabine or 2-
chlorodeoxyadenosine).
There is no acknowledged standard treatment for patients with recurrent disease. As long as 
disease appears to be responsive to rituximab (treatment-free intervals of > 6 months after the 
previous rituximab-containing treatment), a rituximab-based chemoimmunotherapy using 
non-cross-resistant cytotoxic agents would be administered at the next relapse.
While the good tolerability of rituximab makes repeated administration possible, alkylating 
agents and purine nucleoside analogs can progressively reduce the bone marrow reserve (5) 


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and cause secondary malignancies (6, 7). Doxorubicin is associated with dose-dependent 
cardiac toxicity. Cardiac abnormalities can occur in patients treated with doxorubicin for 
lymphoma in the absence of congestive heart failure, even in patients who received moderate 
anthracycline doses (8, 9). More than half of all lymphomas occur in patients older than 
65 years (10). Acute and residual toxicities of chemotherapy are particularly important in an 
elderly patient population because they interfere with the ability of the patient to tolerate 
treatment at optimum dose and schedule, and reduce the number of options for subsequent 
treatments. In addition, these elderly patients will frequently have various comorbidities, 
which further limit their ability to cope with toxicity.
As patients will invariably relapse, further active and well-tolerated agents are needed. 
Copanlisib has a molecular target and mechanism of action different from those of cytotoxic 
agents, a non-overlapping safety profile, and single-agent activity in patients with 
relapsed/refractory iNHL. Therefore, copanlisib could represent an adequate partner for 
rituximab in a cytotoxic-free combination that could be offered to patients expected to derive 
a benefit from rituximab-based treatment.
1.1.1
Copanlisib (BAY 80-6946)
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) 
pathway is one of the prominent pathways that promote cellular survival and constitutively is 
activated in many types of cancers (11, 12). Class I PI3K is downstream of most cancer-
associated tyrosine kinase growth factor receptors (such as epidermal growth factor receptor 
[EGFR]/ human epidermal growth factor receptor [HER], insulin-like growth factor 1 receptor 
[IGF-1R], platelet-derived growth factor receptor [PDGFR], vascular endothelial growth 
factor [VEGF], c-KIT or mesenchymal epithelial transition factor [Met]). Once PI3K is 
activated, it activates Pleckstrin Homology Domain (PH-domain) proteins including 3-
phosphoinositide-dependent protein kinase-1 (PDK-1) and AKT as well as guanine nucleotide 
exchange factor by generation of phosphoinositol-3-phosphate (PIP3). The tumor suppressor 
phosphatase and tensin homolog (PTEN) antagonizes PI3K by dephosphorylating PIP3, and 
its activity is frequently lost in cancer cells (13). In addition to mediating cancer associated 
signals, activation of the PI3K/AKT pathway is also one of the major mechanisms by which 
tumors escape from, and become resistant to, the effects of cytotoxic chemotherapy, targeted 
agents such as trastuzumab (12), and radiation (12, 14). 
Four of these PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ) are categorized as class I 
enzymes because they can use phosphatidylinositol-4,5-bisphosphate (PI-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. The clinical relevance of PI3K inhibition has 
been demonstrated by the activity of idelalisib (PI3Kδ-targeted compound) in patients with 
refractory iNHL (15).
As expected from its pharmacological properties, copanlisib, a small molecule PI3K inhibitor, 
showed excellent anti-tumor activity in pre-clinical models with up-regulated PI3Kα pathway. 
However, copanlisib not only inhibits PI3Kα with IC50 of 0.5 nM, but also PI3Kδ with IC50 of 
0.7 nM. Copanlisib also potently regulates nuclear localization of the forkhead family 
members resulting in the induction of transcriptional programs that lead to rapid cell death by 


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apoptosis. In addition, copanlisib exhibits anti-angiogenesis activity by effectively blocking 
VEG-stimulated endothelial cell proliferation (for details see Investigator’s Brochure [IB]).
1.1.2
Clinical experience
Copanlisib is currently under investigation in various trials enrolling cancer patients.
As of 01 FEB 2016, approximately 627 patients with advanced cancer have been treated with 
copanlisib in Phase I, Phase II and Phase III clinical trials as a single agent or in combination 
with other agents.
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 (MTD) 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. In AUG 2013, the enrollment in study 12871 was 
completed. Dose-limiting toxicity was observed at 1.2 mg/kg with MTD established at 
0.8 mg/kg when administered intravenously (IV) over 1 h, on Days 1, 8 and 15 of every 
28 days as a single agent. The flat dose of 65 mg correlates with 0.8 mg/kg (MTD level) dose 
and was selected in order to control copanlisib exposure in obese patients. 
In the NHL expansion cohort of Study 12871, a total of 6 non-diabetic patients with FL and 
3 patients with diffuse large B-cell lymphoma (DLBCL) were treated, all initially dosed at 
0.8 mg/kg. As of 01 FEB 2014, according to investigator’s assessment, 7 patients (77.8%) with 
NHL experienced partial response (PR) as best overall response and 2 patients (22.2%) had 
progressive disease. Partial responders included 6 patients with FL and 1 patient with DLBCL. 
A retrospective independent review performed in 8 of the 9 NHL patients (excluding the
clinical assessment) concluded that a complete response (CR) was the best overall response in
the 2 FL long-term responders (assessed as partial responders by the investigators).
The most common treatment-emergent adverse events (TEAEs), regardless of seriousness, 
severity, and causality, occurring in ≥20% of the 57 subjects 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%).


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Pharmacokinetic (PK) results indicate nearly dose proportional increase in maximum 
concentration (Cmax) and area under curve (AUC(0-25)) values in the 0.1 to 1.2 mg/kg dose 
range and lack of significant accumulation after once weekly dosing. At the maximum 
tolerated dose of 0.8 mg/kg, the geometric mean half-life, (t1/2) was approximately 36-42 h 
(preliminary data), supporting a once weekly dosage regimen. To date, one metabolite, the 
morpholinone derivate M-1, showing approximately 4 to 16% of the AUC(0-25) of copanlisib 
has been identified and is currently being investigated in clinical studies. Results of a 
preliminary population PK analysis of copanlisib in studies 12871, 15205 (Phase I 
monotherapy study in Japanese subjects) and Phase II study 16349 (part A) showed no 
correlation between body weight and copanlisib clearance, indicating that body weight-based 
dosing does not reduce between-subject variability in copanlisib PK. The use of a fixed dose 
regimen for all patients was therefore considered suitable. Using the available data on 
preliminary safety and efficacy of copanlisib monotherapy, a fixed dose of 60 mg copanlisib 
has been defined as the recommended dose for use in all patients in future clinical studies. 
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%). A t 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.


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1.2
Rationale for the study
Rituximab is approved for the treatment of CD20+ relapsed or refractory iNHL, and is widely 
used as a single drug or in combination regimens (16-20). Retreatment with rituximab alone 
or in combination has been shown to be feasible and active (21, 22) also in a large 
comparative trial involving rituximab retreatment in relapsed patients with FL initially 
responsive to rituximab-containing therapy (23).
To further improve outcomes in relapsed iNHL including augmenting the efficacy of 
rituximab retreatment, additional therapeutic options that incorporate novel active drugs are 
needed.
Considering the pre-clinical profile of copanlisib and the promising preliminary efficacy data 
from the Phase I study 12871 and the ongoing Phase II study 16349, it is expected that in 
comparison to rituximab with placebo, copanlisib in combination with rituximab will lengthen 
progression-free survival (PFS) in patients with relapsed iNHL who have received one or 
more lines of treatment, have been exposed to rituximab and who either had a treatment-free
interval of ≥ 12 months after completion of the last rituximab-containing treatment, or who
are unwilling to receive chemotherapy/for whom chemotherapy is contraindicated.
The prolonged rituximab treatment (4 weekly infusions + 4 bimonthly) has proved to be 
associated with a longer event-free survival and response duration compared to the standard 
4 weekly infusions schedule, without additional clinical toxicity in both relapsed iNHL (24, 
25) and as front line therapy (26), and this is the reason why it was chosen as a reference drug 
in this study.
1.3
Benefit-risk assessment
The proposed indication is a serious and, in the long-term, life-threatening disease. Advanced 
iNHL can be controlled with the current treatments for a relatively long time, but remains an 
incurable disease of which the patient would ultimately die. While at the early stages of 
advanced iNHL effective treatments are available (e.g. rituximab + CHOP and rituximab + 
bendamustine), the efficacy of subsequent lines of treatment tends to diminish, with 
progressively decreasing response rate and PFS. There are no guideline recommendations, or 
widely accepted standards of care for patients beyond first relapse. The treatment given 
depends on patient’s condition, physician’s preference, and availability of drugs not already 
used with other in previous lines of treatment. In patients with limited ability to cope with 
toxicity the number of options is further reduced. There is therefore a need for drugs with new 
targets and mechanisms of action that are effective and have a safety profile different from 
that of drugs used in earlier lines of treatment.
Copanlisib showed activity in patients with relapsed or refractory iNHL (see Section 1.1.2).
Hyperglycemia and hypertension, the most frequently observed and expected toxicities with 
copanlisib, proved to be manageable, without CTCAE Grade 4 events. Toxicities will be 
carefully monitored during the course of the study with a detailed and tailored program of 
management. Rituximab and copanlisib have different targets and mechanisms of action, and 
their safety profiles indicate that no major overlapping toxicities are expected. Furthermore,
the safety and feasibility of combination will be evaluated after the first 30 patients have been 
treated for at least one cycle. A Data Monitoring Committee (DMC) will be instituted to 
ensure the safety of patients participating in the study.


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Considering the existing evidence of the efficacy of copanlisib treatment in patients with 
iNHL and the manageable toxicities, the benefit/risk ratio of the copanlisib treatment is 
assessed as positive.
2.
Study objectives
The primary objective of this study is:

To evaluate whether copanlisib in combination with rituximab is superior to placebo in 
combination with rituximab in prolonging progression-free survival (PFS) in patients 
with relapsed iNHL who have received one or more lines of treatment, including 
rituximab, and who either had a treatment-free interval of ≥12 months after 
completion of the last rituximab-containing treatment, or who are unwilling to receive
chemotherapy/for whom chemotherapy is contraindicated on reason of age, 
comorbidities, and/or residual toxicity
The secondary objectives of this study are to evaluate:

The following characteristics of disease-related symptoms: “time to deterioration” and 
“time to improvement”

Other radiological and clinical indicators of treatment efficacy

Safety and tolerability of copanlisib
The other objectives of this study are to evaluate:

Pharmacokinetics

Biomarkers

Quality of life


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3.
Investigator and other study personnel
Sponsor’s Medical Expert
Name: 
Title: 
Address: 
100 Bayer Boulevard, P.O.box 915
Whippany, NJ, USA 
Telephone no.:
Coordinating Co-Investigators:
Name:
Title:
Address: 
Italy 
Telephone no.
Fax no.:
E-mail:
Name:
Address: 
Telephone no:
Fax no: 
E-mail:
All other study personnel not included in this section 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 sheet before patient
recruitment may start at the respective center. Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the principal investigator before coming into effect at 
the respective center.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor 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 
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 or under supervision of the study 
statistician. 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.
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 computed tomography/magnetic resonance imaging (CT/MRI) 
scans will be performed centrally.
Central pathology review
The retrospective confirmation of histopathological diagnosis will be performed centrally.
4.
Study design
Design overview
This is a randomized, double-blind, placebo-controlled, two-arm, Phase III study to evaluate 
efficacy and safety of copanlisib in combination with rituximab, in comparison to placebo in 
combination with rituximab, in patients with relapsed iNHL. 
Approximately 450 (including FL and other iNHL) patients who meet the eligibility criteria 
will be randomly assigned in a 2:1 ratio to one of the double-blinded treatment arms: 
copanlisib plus rituximab or placebo plus rituximab. Patients will be stratified by a 
combination of NHL histology (FL vs. other iNHL), inclusion criteria (progression-free and 
treatment-free interval of ≥ 12 months after completion of the last rituximab-containing
treatment vs. unwilling/unfit to receive chemotherapy), presence of bulky disease (yes vs. no)
and previous treatment with PI3K inhibitors (yes vs. no). For details see Section 6.3.
After the 30th patient has completed the first cycle of treatment the Data Monitoring 
Committee will review the unblinded safety data of all patients treated up to that timepoint


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and provide recommendation on whether it is safe to continue recruitment into the 
combination arm at the initial dose of copanlisib. The investigators, patients and the sponsor 
will remain blinded.
The overview of study periods is presented in Figure 4–1. 
Figure 4–1
Study periods
On study
Off study
Screening
Treatment
Safety follow-up / 
Active follow-up a
Survival 
follow-up
Cycle 1
(Day 1 to 28)
Cycle 2 etc.
(Day 1 to 28)
EOT 
visit
SFU visit
Tumor 
assessments a
Informed
consent
First dose of 
study 
treatment 
Last dose of study 
treatment/
End of last cycle
Last protocol-
stipulated 
procedure
EOT = End of treatment; SFU = Safety follow-up
a: If applicable
The start of the study period is defined by signing of the informed consent form (ICF). 
Patients who meet the eligibility criteria as defined in Section 5.1 will be randomized to one 
of the two arms and will start treatment (see Section 6.3).
The start of the treatment period is defined by the first administration of study treatment. 
Treatment with copanlisib or placebo will be continued until the occurrence of PD (per central 
independent blinded radiology review) as defined in the Lugano Classification (for patients 
with WM according to the Owen Criteria), unacceptable toxicity, or until another criterion is 
met for withdrawal from the study treatment (see Section 5.2.1.1) For the definitions of 
Lugano Classification and Owen Criteria please refer to the Definitions of terms. Rituximab 
treatment will be continued until the same criteria as defined for copanlisib are met, for a 
maximum of 8 infusions (until Cycle 9).
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 (window of +5 days allowed) after the last 
administration of study treatment. 
Patients who discontinue study treatment because of PD will enter the Safety-follow up period 
and patients who 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 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 from the day of 
randomization 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. During the 
Active follow-up period, serious adverse events (SAEs) and AEs assessed as related to study 
procedures by the investigator will be reported. AE pages of the electronic Case Report Form 
(eCRF) and the SAE Form should be completed in the usual manner and forwarded to the 
sponsor’s GPV department. 


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All patients will be followed off study for overall survival at 3-monthly intervals during the 
Survival follow-up period (up to 3 years after the last patient started study treatment), except 
for patients who object to follow-up data collection. During this period, patients are not 
considered to be “on-study”. 
Safety evaluations will be done at Screening, on the first day of study treatment administration 
(Cycle 1 Day 1), at each clinic visit during the 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, 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 6.4.1).
The first radiological tumor assessments with IV (and oral, if indicated, per Imaging Manual)
contrast-enhanced CT/MRI scans of neck, chest, abdomen and pelvis 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 the 
screening CT/MRI (if a patient is on chronic corticosteroid therapy, corticosteroids should be 
de-escalated to the maximum allowed dose before the screening). The method chosen at 
baseline 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 (for further 
details see Section 7.3.2).
During the treatment period as well as during the Active follow up period tumor assessments 
with the same modality will be performed every 8 weeks (7 days) during Year 1, every 
12 weeks (7 days) during Year 2, and every 24 weeks (7 days) during Year 3 and 
onwards, starting from Cycle 1 Day 1. CT/MRI scans are not required at the EOT visit if the 
patient discontinues due to PD, which has been radiologically confirmed within the 4 weeks
preceding EOT.
The response assessment will be done according to the Lugano Classification, and, for 
patients with WM, according to the Owen Criteria. As long as the patient has not experienced 
PD, investigator’s assessment is sufficient for case management. In the event of progression, 
radiological real-time confirmation by central independent blinded evaluation is required 
before a final decision to stop the treatment is made. Radiological real-time confirmation will 
only be conducted until the database cut-off for the primary analysis. The final evaluation of 
treatment response (best response: objective tumor response rate and complete response rate) 
will be done by central blinded review and for those not undergoing PD-confirmation in
retrospective setting.
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. However, in cases when WM patients will develop disease 
progression confirmed radiologically by presenting with measurable lesion(s) without 
simultaneous increase in IgM, the imaging scans should be submitted for 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. Biopsies taken up to 28 days prior to first dose are 
acceptable. If the baseline biopsy is positive for lymphoma infiltration at Screening, it will be 


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mandatory to perform it again to confirm the first complete response (CR) by sending the 
sample to central review after local bone marrow assessment, and also at the investigator 
discretion if clinical evaluation leads to suspicion of bone marrow infiltration without further 
radiological findings. 
Tumor tissue collection will be mandatory at Screening for central pathology review. 
In addition, additional 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 7.6.1).
Blood samples for PK analysis will be collected from all patients to characterize the PK of 
copanlisib and rituximab (see Section 7.4). Plasma samples for biomarker analyses will be 
collected from every patient, according to the schedule specified in Section 7.1. Blood 
samples for exploratory genetic biomarker analysis will be collected on Cycle 1 Day 1 from 
patients who provide “genetic research” consent (voluntary).
PK and biomarker samplings are not applicable to sites who cannot obtain approval by 
competent Health Authority.
Primary variable
The primary efficacy variable is PFS, defined as the time (in days) from randomization to PD
as assessed by central review or death from any cause (if no progression is documented). The 
main analysis of the study will be performed when at least 190 PFS events (PD by central 
review or death before PD) are observed in the study.
Justification of the design
Single-agent rituximab represents a valid therapy option for patients who had a long response 
following the last rituximab-based treatment, as well as for non-refractory patients with 
responses of shorter duration in whom chemotherapy is contraindicated for medical reasons
(see Section 1.2).
The 2:1 randomization in favor of the treatment arm increases the probability for a study 
participant to receive the study drug.
The use of placebo in this study is justified for the following reasons:

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 two specific AEs, 
hyperglycemia and hypertension, the risk of inadvertent unblinding is low. In the 
majority of the cases, the intensity of both symptoms is low; both symptoms are 
relatively frequently found in the age group to which the majority of iNHL patients 
belong; and most investigators will treat 1-2 patients only due to the rarity of patients 
with the requested profile.
End of study
For each participating European Union (EU) country, the end of the study will be reached 
when the last visit of the last patient for all centers in the respective country has occurred.The 


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end of study 17067 as a whole will be reached as soon as the last visit of the last patient 
(LPLV) has been reached in all centers in all participating countries (EU and non-EU).
Study participants may be offered the option to transition into a roll-over study (ROS). For 
further details on the ROS refer to Section 6.8.
The primary completion date for this study according to the Food and Drug Administration 
(FDA) Amendment Act is specified in a separate document (not part of this protocol).
The end of study notification to Health Authorities will be based on the completion of the 
collection of survival data.
5.
Study population
5.1
Eligibility
5.1.1
Inclusion criteria
1. Ability to understand and willingness to sign written informed consent. Signed 
informed consent must be obtained before any study specific procedure 1.
2. Histologically confirmed diagnosis of iNHL in CD20 positive patients, with 
histological subtype limited to:
Follicular lymphoma (FL) grade 1-2-3a
Small lymphocytic lymphoma (SLL) with absolute monoclonal lymphocyte count 
<5x109/L at study entry
Lymphoplasmacytoid 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) after the last rituximab-, rituximab biosimilars-, or 
anti-CD20 monoclonal antibody (e.g. obinutuzumab)-containing therapy (other 
previous treatment lines after rituximab are allowed). A previous regimen is defined 
as one of the following: at least 2 months of single-agent therapy (less than 2 months 
of therapy is allowed for patients who responded to single-agent rituximab, rituximab 
biosimilars, or anti-CD20 monoclonal antibody); at least 2 consecutive cycles of 
polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to 
PI3K is acceptable (except to copanlisib) provided there is no resistance (see also 
exclusion criterion 40). Patients with prior intolerance to PI3K inhibitors other than 
copanlisib are eligible.
4. Non-WM patients must have at least one bi-dimensionally measurable 2 lesion (which 
has not been previously irradiated) according to the Lugano Classification. For 
                                                
1 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, CT/MRI scans, bone 
marrow sample, MUGA/echocardiogram and hepatitis testing which may be used provided they fall into the 
protocol specified 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. CT/MRI must also meet the quality standards 
of the Imaging Manual.


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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 x 
upper limit of normal (ULN) and positive immunofixation test.
6. Male or female patients ≥18 years of age.
7. ECOG performance status ≤ 2 (ECOG: Eastern Cooperative Oncology Group).
8. Life expectancy of at least 3 months
9. Availability of fresh tissue and/or archival tumor tissue for central pathology
(obtained within 5 years of the consent date) 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 5 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 (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 baseline laboratory values collected no more than 7 days before starting 
study treatment:
Total bilirubin ≤1.5 x ULN (< 3 x ULN for patients with Gilbert-Meulengracht 
syndrome or for patients with cholestasis due to compressive adenopathies of the 
hepatic hilum).
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x 
ULN (≤5 x ULN for patients with liver involvement by lymphoma).
Lipase ≤ 1.5 x ULN.
Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease (MDRD) abbreviated formula. If not on 
                                                                                                                                                        
2 Minimum measurements for measurable disease according to the Lugano Classification: 

nodal lesions > 1.5 cm LDi

extranodal lesions > 1 cm LDi


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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 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 x ULN. PT can be used instead of INR if ≤1.5 x ULN.
Platelet count ≥ 75,000 /mm3. For patients with confirmed lymphomatous bone 
marrow infiltration, platelet count ≥ 50,000 /mm3 .
Platelet transfusion should not be given less than 7 days before the exam collection.
Hemoglobin (Hb) ≥ 8 g/dL.
Packed red blood cell transfusion or erythropoietin should not be given less than 
7 days before the exam collection.
Absolute neutrophil count (ANC) ≥ 1,000/mm3. For patients with confirmed 
lymphomatous bone marrow infiltration, ANC count ≥ 750 /mm3.
Myeloid growth factors should not be given less than 7 days before the exam 
collection.
12. Left ventricular ejection fraction (LVEF) ≥ 45%.
13. Patients must either:

have had a progression-free and treatment-free interval of at least 12 months after 
completion of the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal 
antibody-containing treatment (see exclusion criterion 4)
OR
be considered unfit to receive chemotherapy on reason of age, concomitant 
morbidities, and/or residual toxicity from previous treatments, or unwillingness to 
receive chemotherapy. These patients must also have had a progression-free and 
treatment-free interval of at least 6 months after completion of the last rituximab-, 
rituximab biosimilars-, or anti-CD20 monoclonal antibody-containing treatment 
(see exclusion criterion 4). Patients in whom chemotherapy is contraindicated are 
defined by one of the following features:
o Age ≥80 years
o Age < 80 years and at least 1 of the following conditions:

at least 3 grade 3 CIRS-G comorbidities (see Appendix 14.7)
OR

at least 1 grade 4 CIRS-G comorbidity (if compatible to participation 
in the study - see exclusion criterion no. 26).
5.1.2
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. Close affiliation with the investigational site; e.g. a close relative of the investigator, 
dependent person (e.g. employee or student of the investigational site).


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Excluded medical conditions:
3. FL grade 3b or transformed disease, or chronic lymphocytic leukemia.
4. Progression-free interval or treatment-free interval of less than 12 months since the 
last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal antibody (e.g. 
obinutuzumab)-containing treatment (including maintenance with these drugs). For 
patients considered unwilling/unfit to receive chemotherapy (see inclusion 
criterion 13): progression free-interval or treatment-free interval of less than 6 months 
since the last rituximab-, rituximab biosimilars-, or anti-CD20 monoclonal 
antibody-containing treatment (including maintenance with these drugs), as assessed 
by the investigator.
5. Previous or concurrent cancer that is distinct in primary site or histology from 
indolent B-cell NHL(as described in inclusion criterion 2) within 5 years prior to 
treatment start 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]), and asymptomatic prostate cancer 
without known metastatic disease and with no requirement for therapy or requiring 
only hormonal therapy and with normal prostate-specific antigen for ≥1 year prior to 
randomization.
6. Known lymphomatous involvement of the central nervous system.
7. Congestive heart failure > New York Heart Association (NYHA) class 2.
8. 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.
9. Uncontrolled arterial hypertension despite optimal medical management (per 
investigator’s assessment).
10. Patients with HbA1c > 8.5% at Screening.
11. 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 treatment.
12. Non-healing wound, ulcer, or bone fracture.
13. Active, clinically serious infections > CTCAE Grade 2.
14. Known history of human immunodeficiency virus (HIV) infection.
15. Hepatitis B (HBV) or hepatitis C (HCV). 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 HBsAg or HBcAb will be eligible if they are 
negative for HBV-DNA, these patients should receive prophylactic antiviral therapy.
Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-
RNA.
16. Patients with seizure disorder requiring medication.
17. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding 
event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study treatment.
18. Criterion 18 was removed by amendment 1.


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19. Proteinuria ≥CTCAE Grade 3 as assessed by either a 24 h total urine protein 
quantification or a urine protein to creatinine ratio (UPCR) > 3.5 on a random urine 
sample.
20. History or concurrent condition of interstitial lung disease of any severity and/or 
severely impaired lung function (as judged by the investigator).
21. Concurrent diagnosis of pheochromocytoma.
22. Pregnant or breast-feeding patients. Women of childbearing potential must have a 
serum pregnancy test performed a maximum of 7 days before start of treatment, and a 
negative result must be documented before start of treatment.
23. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior 
therapy/procedure, excluding alopecia, peripheral neuropathy, and bone marrow 
parameters.
24. Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the 
formulation.
25. Substance abuse, medical, psychological or social conditions that may interfere with 
the patient’s participation in the study or evaluation of the study results.
26. Any illness or medical conditions that are unstable or could jeopardize the safety of 
patients and their compliance in the study.
Excluded previous therapies and medications:
27. Criterion 27 removed by amendment 1.
28. Treatment with investigational drugs other than PI3K inhibitors less than 28 days 
before start of treatment, unless evidence of progression since last treatment.
29. Ongoing immunosuppressive therapy.
30. Radiotherapy or immuno-/chemotherapy less than 4 weeks before start of treatment, 
unless evidence of progression since last treatment.
31. Radioimmunotherapy or autologous transplant less than 3 months before start of 
treatment, unless evidence of progression since last treatment.
32. Myeloid growth factors less than 7 days before start of treatment.
33. Blood or platelet transfusion less than 7 days before start of treatment.
34. Ongoing systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone 
or equivalent. Previous corticosteroid therapy must be stopped or reduced to the 
allowed dose at least 7 days before performing the screening CT/MRI. If a patient is 
on chronic corticosteroid therapy, corticosteroids should be de-escalated to the 
maximum allowed dose before the screening. Patients may be using topical or inhaled 
corticosteroids. 
35. History of having received an allogeneic bone marrow or organ transplant.
36. Major surgical procedure or significant traumatic injury (as judged by the 
investigator) less than 28 days before start of treatment, open biopsy less than 7 days 
before start of treatment.


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37. Anti-arrhythmic therapy (beta blockers or digoxin are permitted).
38. Use of strong inhibitors of CYP3A4 is prohibited from Day -14 of Cycle 1 until the 
Safety follow up visit (see Appendix 14.1).
39. Use of strong inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 until the 
Safety follow up visit (see Appendix 14.1).
40. 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.
41. Prior treatment with copanlisib.
Other exclusions:
42. Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at baseline 
will not be eligible.
For prohibited concomitant therapy please see Section 6.9.1.
5.1.3
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-refractory. The
combination of rituximab and copanlisib is expected to be sufficiently well tolerated when 
administered to patients in whom chemotherapy is contraindicated on reason of age and 
comorbidities. These patients will be selected according to the CIRS-G score, which has been 
validated with respect to the clinical outcome in older patients (28) and proved to be useful in 
the assessment of NHL patients as well (29, 30). 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.


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5.2
Withdrawal of patients from study
5.2.1
Withdrawal
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been randomized. A patient who, for any reason (e.g., 
failure to satisfy the selection criteria), terminates the study before randomization is regarded 
a “screening failure”.
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.
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/MRI scans, bone marrow sample, 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 for HbA1c.
5.2.1.1
Withdrawal of study treatment
Patients must be withdrawn from the study treatment for the following reasons:

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 
unless they object to follow-up data collection (see Section 11.2).

If, in the investigator's opinion, continuation of the study would be harmful to the 
patient's well-being.

Disease progression as defined in the Lugano Classification and, for patients with 
WM, according to the Owen Criteria.

Occurrence of unacceptable toxicity.

CTCAE Grade 4 arterial hypertension.


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
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.

CTCAE Grade 4 dermatologic toxicity.

CTCAE Grade ≥3 (or recurrent Grade 2) non-infectious pneumonitis.

Drug-induced pancreatitis.

Development of a malignancy other than indolent B-cell NHL. New malignancy will 
be reported as a SAE.

Start of a new anti-cancer regimen.

The patient does not tolerate copanlisib/placebo dose of 30 mg.

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 test drug (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.

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.
The patient must be withdrawn from the study for the following reasons:

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).
Any patient removed from the study will remain under medical supervision until discharge or 
transfer is medically acceptable.


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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.
In all cases, the reason for discontinuing study treatment and the completion of the follow-up 
periods must be clearly documented in the eCRF and in the patient’s medical records.
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. 
Details for the premature termination of the study are provided in Section 10.
5.2.1.2
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 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 to 
determine survival status (up to 3 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
5.2.2
Replacement
Patients will not be replaced.
5.3
Patient identification
At Screening upon signing the ICF, each patient will be assigned a unique patient 
identification number (PID) by the IVRS/IWRS for unambiguous identification. The PID will 
be constructed as follows:
a.
Digits 1 to 2: Unique country code 
b. Digits 3 to 5: Center code (unique within each country)
c.
Digits 6 to 9: Unique patient code (unique within each center)
Within the unique patient code, the first digit (digit 6) represents the study a patient is 
participating in.
Patients participating in study 17067 (this study) have a “7” as the 6th digit. As an example,
PIDs in this study have the structure “aabbb7ccc”. 
Once allocated, the patient’s PID number will identify the patient throughout the study and 
will be entered into the Site Enrollment Log and in the eCRF.


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6.
Treatments
6.1
Treatments to be administered
The study treatment (=study drugs) will comprise the following:
The combination of the test drug copanlisib (BAY 80-6946) and rituximab, to be 
administered as combination therapy. Copanlisib will be administered before rituximab.
The combination of placebo and rituximab, to be administered as combination therapy. 
Placebo will be administered before rituximab.
For the dosage and administration please see Section 6.4.
6.2
Identity of investigational medicinal products
All 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 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 study treatment as well as the 
labels will be maintained in the sponsor’s study file.
An approved representative at the site will ensure that all received study drugs are stored in a 
secured area on site, under recommended storage conditions and in accordance with 
applicable regulatory requirements.
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 infusions is obtained after reconstitution 
of the lyophilisate with normal saline 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.
Placebo for copanlisib
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 6.5.


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Rituximab
Rituximab will be sourced centrally or locally by the sponsor depending on the local law and 
requirements. For full details on rituximab and instructions for dilution, please refer to the 
current prescribing information / Summary of Product Characteristics (SmPC).
6.3
Treatment assignment
At the end of the screening period, eligible patients will be randomly assigned in a 2:1 ratio to 
the two double-blinded treatment arms: copanlisib + rituximab or placebo + rituximab, 
respectively. 
Treatment will be assigned based on information obtained from IVRS/IWRS.
IVRS/IWRS will stratify patients according to four factors based on baseline characteristics:

NHL histology
o
FL histology
o
Other iNHL histology (SLL, MZL, LPL/WM)

Entry criterion:
o
progression-free and treatment-free interval of ≥12 months after completion 
of the last rituximab-containing treatment
o
considered unwilling/unfit to receive chemotherapy for age or comorbidities
(see inclusion criterion 13 for further details)
If the patient fulfills both entry criteria, please select the criterion “considered 
unwilling/unfit to receive chemotherapy for age or comorbidities”.

Presence of bulky disease (as defined by the presence of a nodal or extranodal mass 
≥7 cm in the longest diameter, with the exception of spleen):
o
yes
o
no

Previous treatment with PI3K inhibitors
o
yes
o
no
Resulting from the combination of these 4 stratification factors, patients will be randomized 
into 16 different strata. The randomization must be performed up to maximum 72 h before the 
first dose of study treatment.
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.


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6.4
Dosage and administration
Copanlisib and placebo
Copanlisib and placebo for copanlisib formulations are administered before rituximab, in a 
normal saline solution, intravenously, over approximately 1 h. See Pharmacy Manual for 
additional details. No intravenous glucose preparations should be administered on the days of
infusion.
Dosing is weekly for the first 3 weeks of a 28-day cycle (on Days 1, 8, and 15), followed by a 
1-week break (i.e., no infusion on Day 22).
The requirements for fasting state and pre-dose glucose levels are presented in Table 6–1.
Table 6–1
Fasting requirements and pre-dose glucose levels
Period
Fasting ≥ 8 h required before first 
glucose measurement
Pre-dose glucose levels
(first glucose measurement)
Cycle 1 Day 1 
Yes a
≤125 mg/dL (non-diabetic patients)
<160 mg/dL (diabetic patients)
Subsequent 
infusions after 
Cycle 1 Day 1
No b
<160 mg/dL (fasting)
< 200 mg/dL (non-fasting) 
a Diabetic patients who take insulin treatment at any cycle visit: Timing and content of meal intake will be 
managed by the investigator. Consultation with treating physician or diabetologist/endocrinologist is advised.
b The decision regarding meal timing and fasting can be made by the investigator based on glucose response 
patterns during prior treatment days.

Fasting refers to a ≥ 8 h fast.

Non-fasting status includes any caloric intake such as meals and also juice, snacks, and 
other caloric intake not consistently called a meal.
From Cycle 1 Day 1 onwards, 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 calorie or 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.
Rituximab
Rituximab will be given IV at 375 mg/m2 body surface weekly during Cycle 1 (on Days 1, 8, 
15 and 22). Although the dose is calculated by the IVRS/IWRS a minor variation (±5%) of the 
recommended dose is allowed due to the local standard of care disbursing requirements. 
However, a +5% variance is only permitted if a new vial is not required. For those patients 
who are still on treatment after evaluation at the end of Cycle 2 (not in PD), rituximab will be 


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administered once in each of Cycles 3, 5, 7 and 9 (on Day 1). It 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.
Dosing criteria
Starting from Cycle 1 Day 8, laboratory tests prior to each infusion may be performed either 
the day before or on the planned date of infusion, with the exception of glucose, which must 
be performed on the day of copanlisib/placebo infusion. All laboratory results must be 
assessed by the investigator and/or appropriate site personnel prior to administration of the 
planned dose.
On Day 1 of each subsequent cycle, the dose of study treatment will be given only if the 
criteria described in Table 6–2 are met.
Table 6–2
Laboratory test criteria for Day 1 dose of subsequent cycles
Laboratory Test
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. For patients with confirmed lymphomatous bone marrow infiltration at 
screening and ANC ≥ 750/mm3 - < 1000/mm3: ANC ≥ 750/mm3. b
Platelets
≥ 50,000/mm3
ALT
≤ 5 X ULN 
AST
≤ 5 X ULN 
Total bilirubin
≤ 3 X ULN
GFR (MDRD) 
≥ 30 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 h 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 For patients with lymphomatous bone marrow infiltration:

If ANC ≥ 1000/mm3 during screening, the limit of ANC ≥ 1000/mm3 should be applied during 
the study.

If after screening the ANC raises to levels above 1000/mm3, it is recommended to confirm 
the result of the test within 1 day. Unconfirmed single assessment or confirmed double 
assessment of ANC > 1000/mm3 warrants ANC ≥ 1000/mm3 to receive further doses of study 
drugs for this patient for the remainder of the study.
A blood count will be performed and assessed prior to the subsequent doses in each cycle of 
copanlisib/placebo on Days 8 and 15. The study drug will not be administered if, on the day of 
scheduled dosing, any of the following criteria is met:

CTCAE Grade 4 neutrophil count decreased (ANC < 500/mm3)
(G-CSF is mandatory if ANC < 1000/mm3 and should be administered as per label)

CTCAE Grade ≥3 platelets count decreased (platelets < 50,000/mm3)


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
CTCAE Grade ≥3 anemia (hemoglobin < 8 g/dL), see footnote a in Table 6–2
Doses 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 copanlisib/placebo is 5 days.
6.4.1
Dose modification
Dose modifications due to toxicities described below apply to copanlisib and placebo for
copanlisib (“dummy dose modification”).There will be no dose reduction of rituximab. If 
severe (life-threatening) reaction to rituximab infusion occurs despite supportive treatment 
patients should be withdrawn from the study treatment. Patients must have received at least 
4 complete rituximab infusions until Cycle 3 Day 1 (included) to continue the treatment with 
single agent copanlisib/placebo.
It is recognized that attribution of causality of any AE to the test drug specifically may be 
difficult. However, certain toxicities were seen only in relation to copanlisib in Phase I and II 
trials: 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 must be done according to the guidelines in 
Section 6.4.1.1 and 6.4.1.2. The investigator may judge a more conservative dose 
modification 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.
The dose modification levels of copanlisib and placebo are outlined in Table 6–3:
Table 6–3
Dose levels of copanlisib and placebo
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, with the 
exception of non-infectious pneumonitis (NIP).
Patients who do not tolerate the copanlisib/placebo dose of 30 mg must discontinue study 
treatment permanently. 


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6.4.1.1
Hematological toxicity
Neutropenia and febrile neutropenia are listed in the current version of IB as expected adverse 
events. If the guidelines given in Table 6–4 are not followed, the rationale for other measures 
is to be documented in detail in the patient’s medical record.
Table 6–4
Dose modification of copanlisib/placebo for hematological toxicity
Hematological toxicity (any of the following)
Test drug 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 e
CTCAE Grade ≥3 anemia (Hb < 8 g/dL)
Delay infusion until criteria displayed in
Table 6–2 are met.d Patient can be treated at 
one dose level lower at the investigator’s 
discretion.b 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;
G-CSF = Granulocyte colony stimulating factor; Hb = hemoglobin; INR = international normalized ratio, 
PTT = partial thromboplastin time
a For patients who develop CTCAE Grade ≥ 3 neutropenia, a blood count after 3 days is recommended. For 
patients with CTCAE Grade 3 neutropenia and no bone marrow infiltration, consider reducing the dose of 
copanlisib until recovery to Grade 2 and also consider the use of myeloid stimulating factor as long as the 
patient responds or does not progress. G-CSF is mandatory if ANC < 1000/mm3 and should be administered 
as per label).
b 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.
c Footnote c deleted by amendment 7.
d Treatment with transfusion or growth factors is allowed at the investigator’s discretion.
e INR and PTT should have returned to ≤ 1.5 and ≤1.5 x ULN, respectively, with no signs of bleeding.
6.4.1.2
Non-hematological toxicity
Dose modifications for non-hematologic toxicities except glucose increases, dermatologic 
toxicity, non-infectious pneumonitis and arterial hypertension are outlined in Table 6–5.


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Table 6–5
Dose modification of copanlisib/placebo for non-hematological toxicity 
(except glucose increases, dermatologic toxicity, non-infectious pneumonitis and arterial 
hypertension)
Test 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
–
a Toxicities according to CTCAE version 4.03
b Despite maximum supportive therapy
c Not applicable for 30 mg dose level (footnote d deleted by amendment 1)
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 cytomegalovirus (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.
Dermatologic toxicity
The guidelines for dose modifications in cases of dermatologic toxicity are outlined in Table 
6–6. If these guidelines are not followed, the rationale for other measures will be documented 
in detail in the patient’s medical record.
Table 6–6
Dose modification of copanlisib/placebo for dermatologic toxicity
Study Drug Action
Toxicity a
Occurrence
For current course of therapy
For next course of therapy
Grade 1
Any appearance
No change
No change
Grade 2 b
1st appearance
Interruption until Grade ≤1
No change
2nd appearance
Interruption until Grade ≤1
Decrease by one dose level c
3rd appearance
Interruption until Grade ≤1
Decrease by one dose level c
4th appearance
Permanent discontinuation 
–
Grade 3 b
1st appearance
Interruption until Grade ≤1
Decrease by one dose level c
2nd appearance
Interruption until Grade ≤1
Decrease by one dose level c
3rd appearance
Permanent discontinuation
–
Grade 4
1st appearance
Permanent discontinuation
–
a  Toxicities according to CTCAE version 4.03
b  Despite maximum supportive therapy
c  Not applicable for 30 mg dose level (footnote d deleted by amendment 1)
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.


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Non-infectious pneumonitis (NIP)
In the event of suspected NIP of any grade, copanlisib/placebo treatment should be adjusted 
according to the guidance in Table 6–7.
Table 6–7
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.
Pneumonitis is to be reported as such only in the event of NIP. The investigator is requested to 
differentiate between non-infectious pneumonitis (NIP) from infectious pneumonitis (viral, 
bacterial, fungal), aspiration pneumonitis, or other pneumonitis.
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 6.4.2.1.

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 5.2.1.1).
b) Arterial hypertension
The guidelines for dose modifications of copanlisib/placebo in case of arterial hypertension 
are given in Table 6–8.
No dose should be given if blood pressure is ≥ 150/90 mmHg. Instructions for blood pressure 
measurement are given in Section 7.5.3.3. Antihypertensive medication may be given to 


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control the arterial hypertension. Dosing can proceed on the scheduled day if there are at least 
2 consecutive measurements <150/90 mmHg. Otherwise dosing must be delayed. 
If drug-related arterial hypertension (post-dose blood pressure of CTCAE Grade 3 or 
160/100 mmHg) is not manageable with optimal antihypertensive treatment, the dose for the 
subsequent copanlisib/placebo administrations may be reduced by 1 or 2 dose levels at the 
investigator’s discretion. Guidelines for the treatment of blood pressure increases are given in 
Section 6.4.2.3. Patients with a hypertension of CTCAE Grade 4 must permanently 
discontinue the study drug (see Section 5.2.1.1).
Table 6–8
Dose modification of copanlisib/placebo for arterial hypertension
Toxicity (CTCAE)
Study drug action
Recommendation
Pre-dose measurements
BP ≥150/90 mmHg
No dose should be given until 
recovery to < 150/90 mmHg.
Consider 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, delay dosing until 
next visit.
During infusion:
CTCAE hypertension of 
grade 3 
or ≥160/100 mmHg
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 discretion.b
Post-dose:
Drug-related
CTCAE hypertension of 
grade 3
or ≥160/100 mmHg a
–
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 discretion.b
CTCAE hypertension of 
grade 4
Permanent discontinuation
–
CTCAE = Common Terminology Criteria for Adverse Events; BP = Blood pressure
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.
6.4.2
Treatment of toxicities
Recommendations for the treatment of toxicities described below apply to copanlisib and 
placebo. For monitoring and management of adverse reactions following rituximab 
administration please refer to rituximab SmPC.
6.4.2.1
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.


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The guidelines for management of transient post-infusion glucose increases on infusion days 
are given in Table 6–9.
Table 6–9
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 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
On subsequent days:
Max post-infusion glucose 
> 200 mg/dL noted on 
subsequent days
Oral glucose lowering medication 
recommended on subsequent days
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


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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 already monitors his/her blood glucose as part of routine antidiabetic care, the 
routine measurements should not be replaced by the study specific measurements.
6.4.2.2
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 (31). 
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 fasting requirements, the 
evaluation of lipid-panels including triglycerides is considered as not feasible.
6.4.2.3
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 arterial hypertension following copanlisib/placebo will need to be 
individualized for each patient, but the experience in Phase I has suggested the benefit of 
dihydropyridine calcium channel blockers (i.e., amlodipine, felodipine). 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. In the event of the occurrence 
of arterial hypertension ≥150/90 mmHg during infusion of copanlisib/placebo at any cycle
antihypertensive treatment is suggested as indicated above. In the event of the occurrence of 
CTCAE Grade 3 arterial hypertension (≥160/100 mmHg) during infusion of 
copanlisib/placebo, the infusion should be interrupted and antihypertensive treatment as 
suggested above is administered. Infusion can be resumed when blood pressure has returned 
to <150/90 mmHg.
6.4.2.4
Treatment of vomiting and diarrhea
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 or Lomotil, which contains diphenoxylate plus atropin 
might also be used. In the event of CTCAE Grade 3 diarrhea with maximal pharmacological 
support, the administration of the test drug should be delayed.
6.4.2.5
Treatment of dermatologic toxicity
If dermatologic changes occur, the patient should be treated quickly and aggressively. 


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Table 6–10 can be used as guidance.
Table 6–10
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 
a Cross check with short-term corticosteroid administration (see Section 6.9).
Bid = twice daily, CTCAE = Common Terminology Criteria for Adverse Events
Source: Lacouture ME.,2008 (32)
6.4.2.6
Special considerations for patients unfit for chemotherapy
By definition patients unfit for chemotherapy are vulnerable to toxicities. A structure covering 
for adequate support at home should be present. Special consideration has to be paid to:

Quality of outpatient glucose monitoring and management

New onset/worsening of dyspnea or cough
o
Check oxygen saturation
o
Consider further diagnostic steps early

Adequate hydration and electrolyte balance: generally in a population with likely reduced 
sense of thirst and in patients with transient glucose increases, polyuria, nausea, vomiting 
or diarrhea:
o
Consider unscheduled checks of electrolytes
o
Consider parenteral fluids early


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6.4.2.7
Guidance for monitoring and prophylaxis of opportunistic 
infection (OI) 
6.4.2.7.1
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/placebo:

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 or when ANC of CTCAE grade 4, PCR for CMV (every cycle on 
Cycle X Day 1 for the first 6 months of study treatment and every 3 cycles thereafter).
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. 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 myelosupressive cytotoxic therapy)

History of CMV, herpes

History of lower respiratory tract infection, history of immunodeficiency (excluding 
lymphoma) in the last 12 months

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, C-reactive protein (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 or CT scans)
o
Note: Treatment of developed OI should be based on local SOC.
6.4.2.7.2
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.


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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 6.4.2.7.1).
6.5
Blinding
Patients will be randomized to receive copanlisib in combination with rituximab or placebo in 
combination with rituximab, 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. 
The DMC will review the safety data of the first 30 patients after their first cycle in an 
unblinded manner, to assess the safety of the copanlisib + rituximab combination. However, 
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 7.5.1.5), the patient’s treatment code will usually be 
unblinded before reporting to the health authorities, ethic committees and investigators (see 
Section 7.5.1.4) if the SUSAR was related to the blinded treatment.
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.


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6.6
Drug logistics and accountability
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
department of the sponsor (or its affiliate/contract research organization [CRO]), and will be 
inaccessible to unauthorized personnel. Special storage conditions and a complete record of 
batch numbers and expiry dates can be found in the sponsor study file; the site-relevant 
elements of this information will be available in the investigator site file. The responsible site 
personnel will confirm receipt of study drug via IVRS/ IWRS and will use the study drug only 
within the framework of this clinical study and in accordance with this protocol. Receipt, 
distribution, return and destruction (if any) of the study drug must be properly documented 
according to the sponsor’s agreed and specified procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
6.7
Treatment compliance
The administration of intravenous copanlisib/placebo and rituximab will be performed in the 
clinic on a weekly basis and must be recorded in the eCRF.
6.8
Post-study therapy
After the end of this study, further therapy is at the discretion of the investigator.
At the conclusion of the study, patients who demonstrate clinical benefit may be eligible to 
continue to receive study treatment. They may receive further treatment, assessments and/or 
be followed either via a ROS – subject to approval by the competent health authority and 
EC/IRB – or through any other mechanism in accordance with local legal and compliance 
rules. This applies to patients on study treatment and in follow-up.
6.9
Prior and concomitant therapy
For prohibited prior therapy please refer to Section 5.1.2.
6.9.1
Prohibited concomitant therapy

CYP3A4 inhibitors and inducers (see Appendix 14.1): copanlisib is primarily 
metabolized by CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 
(e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir), and 
strong inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, 
St. John’s Wort) is not permitted from Day -14 of Cycle 1 until the Safety follow-up 
visit.

Grapefruit and grapefruit juice (CYP3A4 inhibitor) consumption is not permitted 
during the study treatment until the Safety follow-up visit.

Anti-arrhythmic therapy other than beta blockers or digoxin

Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed 
dose at least 7 days prior to the screening CT/MRI. If a patient is on chronic 
corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed 
dose before the screening. Patients may be using topical or inhaled corticosteroids. 
Short-term systemic corticosteroids above 15 mg prednisolone or equivalent will be 


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allowed for the management of acute conditions and as premedication prior to 
rituximab infusion and for radiological contrast infusion. The use of corticosteroids as 
antiemetics prior to copanlisib/placebo administration will not be allowed. 

Myeloid growth factors removed by amendment 1

Ongoing immunosuppressive therapy 

Concomitant radiotherapy (it is assumed that radiation would be indicated only in case 
of progression, when the patient would come off study medication anyway)

Use of biotin (vitamin B7) produces high levels of the vitamin, which can interfere 
with the result of the immunoassay tests including biomarker analysis, HBcAb, 
HBeAg, HBsAg, HCVAb, HIV-Ag/Ab combo, HIV combo. Therefore, refrain from
the use of biotin for at least 72 hours prior to immunoassay test collection.
6.9.2
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.

Antiemetics: Prophylactic anti-emetics may be administered according to standard 
practice. The routine use of standard antiemetics, including5-HT3 blockers, such as 
granisetron, ondansetron, or an equivalent agent, is allowed as needed. The use of 
corticosteroids as antiemetics prior to copanlisib/placebo administration will be not 
allowed.

Palliative and supportive care for the other disease-related symptoms (with the 
exception of radiotherapy) 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 (with the 
exception of radiotherapy).

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.


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
Calcium channel blockers to control pre-existing hypertension.
7.
Procedures and variables
7.1
Schedule of procedures
7.1.1
Tabulated overview
Schedule of procedures are presented in Table 7–1 and Table 7–2.


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Table 7–1
Study flow chart
Screening 
maximum days 
before C1D1
Treatment
EOT
Safety 
FU
Active 
FU z
Survival 
FU aa
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 x
7
30 + 5
days 
window y
every 3 
months
Acceptable deviation (in days)
-1 to + 2 days
-1 to + 2 days
Decision 
to stop
Last 
dose
14 days
Screening and enrollment
Patient informed consent (including genetic)
Written patient informed consent must be obtained prior to any study-specific procedures ab
Check in- and exclusion criteria
X
X
X
Medical history a
X
IVRS/IWRS transaction b
X
Xb
X
X
HBsAg, HBcAb, anti-HCV antibody ac
X
CMV PCR test ad
X
X ad
X ad
Beta-2-microglobulin (for patients with WM/FL)
X
Serum pregnancy test (if applicable) c
X
X c
X c
UPCR / 24 h total urine protein quantification
X
GFR calculation (MDRD abbreviated formula)
X
X
Safety
Toxicity / AE assessment d
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication d
X
X
X
X
X
X
X
X
X
X
Complete physical examination e
X
X
X
X
Brief physical examination f
X
X
X
X
X
(X)
12-lead ECG g
X
X
X g
X
MUGA scan or echocardiogram h
X
(X)h
X h
X
Hemoglobin A1c i
X
X i
X
Complete blood count j
X
X
X
X
X
C2 only C2 only
X
(X)
Hemoglobin, ANC and platelet counts (from 
Cycle 3 onwards)
X
X
Chemistry panel k
X k
X
X
X
X k
C2 only C2 only
X k
(X)
Coagulation panel: PTT,PT and INR
X
X
X
X
(X)
Urinalysis (dipstick)
X
X
X


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Table 7–1
Study flow chart
Screening 
maximum days 
before C1D1
Treatment
EOT
Safety 
FU
Active 
FU z
Survival 
FU aa
Cycle 1
Cycle 2 and higher
Within (days) after
Days
-28 -14
-7
D1
D4
D8
D15
D22
D1
D8
D15
D22 x
7
30 + 5
days 
window y
every 3 
months
Acceptable deviation (in days)
-1 to + 2 days
-1 to + 2 days
Decision 
to stop
Last 
dose
14 days
CD4 (for patients with signs of infection) and 
cultures if febrile neutropenia ae, af
Glucose l
X
X
X
X
X
X
Blood pressure n
X
X
X
X
X
X
Efficacy
CT / MRI and tumor evaluations o
X
X o
(X)
X o
QoL questionnaire (FLymSI-18) and PRO 
information sheet p
X
X p
X
X
Bone marrow biopsy q
X
X q
For LPL/WM patients only
Serum protein electrophoresis r
Xr
X r
(X) r
X r
Immunofixation r
Xr
X r
(X) r
X r
Serum quantitative IgM test r
Xr
X r
(X) r
X r
Serum or plasma viscosity r
Xr
(X) r
(X) r
Pharmacokinetic sample (see Table 7–2)
X
X
X
Biomarkers
Tumor tissue (central pathology and biomarkers)s
X
(X) s
Plasma for tumor genetics t
X
X
Plasma for non-genetic biomarker analysis u
X
X
X
C2 only C2 only C2 only
X
Whole blood for biomarkers v
X
Drug administration
Copanlisib/placebo IV infusion, before rituximab 
infusion
X
X
X
X
X
X
Rituximab IV infusion w
X
X
X
X
C3,5,7,9
Survival status, new anticancer therapy
X
AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BUN = blood urea nitrogen; C = cycle; 
CBC = complete blood count; CD = cluster of differentiation; CMV = cytomegalovirus; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse 
Events, version 4.03; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FL = follicular lymphoma; FLymSI-


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18 = NCCN-FACT Lymphoma Symptom Index-18; FU = follow-up; GFR = glomerular filtration rate; HBV = Hepatitis B virus; HCV = Hepatitis C virus; HDL = high-density 
lipoprotein; INR = international normalized ratio; IV = intravenous; LDH = lactate dehydrogenase; LDL = low-density lipoprotein; LPL/WM = Lymphoplasmacytoid 
lymphoma/Waldenström macroglobulinemia; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multiple gated acquisition; 
NYHA = New York Heart Association; OI = opportunistic infection; PCR = polymerase chain reaction; PD = disease progression; SOC = standard of care; PT = prothrombin 
time; PTT = partial thromboplastin time, QoL = quality of life; RBC = red blood cell count; SAE = serious adverse event; UPCR = urine protein to creatinine ratio; 
WBC = white blood cell count; WM = Waldenström macroglobulinemia
a
Complete medical and surgical history including demographics, relevant medical history findings, concomitant illnesses, CIRS-G if applicable, 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. Information on patient’s smoking history will also be collected and recorded.
b
IVRS/IWRS transaction to register the patient in the system will be at Screening. IVRS/IWRS randomization transaction will take place maximum 72 h before the first 
dose (Cycle 1 Day 1). IVRS/IWRS transactions for medication dispensing will be on Day 1 of each cycle. IVRS/IWRS transaction to register end of treatment will be at 
the EOT visit.
c
After Cycle 1 serum pregnancy test is mandatory at every cycle and at the EOT visit for countries where it is required by local regulations.
d
After Screening: AE assessment and concomitant medication review must be updated before each dose and 30 days after last dose. 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.
e
Complete physical examination to include: ECOG performance status, NYHA classification, height (only at Screening), weight, vital signs (temperature, pulse and blood 
pressure), and complete review of body systems, including lung examination. After the patient signs the informed consent, any new finding discovered not present in 
the patient’s medical history or a worsening of a prior medical history finding must be recorded as an AE. 
f
Brief physical examination to include: ECOG performance status, vital signs (temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms), including lung examination.
g
12-lead ECG (including QT cB 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 infusion and at the end of infusion (window of up to 2 h prior to and post- infusion is allowed). On the days of rituximab administration, 
ECG will be measured after rituximab infusion. 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), within 7 days prior to dosing on Day 1 of every 3rd cycle (3, 6, 9 
etc.), and at the EOT (if not previously done within 4 weeks). Same modality must be used throughout the study. For patients with LVEF below lower level of normal for 
the institution at Screening: one additional assessment should be made at any time between 5 h after the first dose and before the second dose of copanlisib.
i
Hemoglobin A1c (HbA1c) at Screening, on Day 1 of every 3 cycles (4, 7, 10 etc.) starting from Cycle 4 and at the EOT visit. The testing is not required if the previous 
test was performed within 4 weeks preceding EOT visit. HbA1C testing should also be performed approximately 3 months after the EOT visit whenever possible.
j
CBC: Hemoglobin, hematocrit, RBC, WBC (with differential to include neutrophil, lymphocyte, monocyte, basophil and eosinophil counts), and platelet count. From 
Cycle 3 onwards, only hemoglobin, platelet and ANC will be performed on Day 8 and Day 15 prior to each copanlisib/placebo infusion. Differential blood count in 
percentage can be provided when absolute count is not available per standard of care of the local lab.
k
Complete chemistry panel: calcium, sodium, potassium, chloride, phosphorous, magnesium, bicarbonate (or carbon dioxide, if bicarbonate is not routinely measured at 
the site), total protein, albumin, glucose, BUN (or urea if BUN is not routinely measured at the site), serum creatinine, uric acid, total bilirubin, ALT, AST, LDH, alkaline 
phosphatase, creatine phosphokinase, lipase, amylase (or pancreatic amylase, if total amylase is not routinely measured at the site), cholesterol (total and LDL) and 
triglycerides. Laboratory tests prior to each infusion may be performed either the day before or on the planned date of infusion, with the exception of glucose, which 
must be performed on the day of infusion. Triglycerides, LDL cholesterol and total cholesterol will be tested only at Screening, on Day 1 of every second cycle (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.


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l
On Day 1 of Cycle 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 rituximab infusion
(10 min). 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 infusion; and at the end of the rituximab infusion (if applicable) (10 min). The pre-dose glucose sample on Cycle 1
Day 1 should be after an 8 h fasting. For details on fasting requirements and pre-dose glucose levels see Section 6.4.
m
Home glucose monitoring removed by amendment 9.
n
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/place 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. On copanlisib/placebo 
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 h after the end of
copanlisib/placebo infusion. In addition, on the days of rituximab administration, blood pressure will be measured 30 min after the start of rituximab infusion and at the 
end of rituximab infusion. Time window of ± 10 min is allowed for all post-dose blood pressure measurements.
o
The first IV (and oral, if indicated, per Imaging Manual) contrast enhanced CT/MRI scans of neck, chest, abdomen and pelvis must be performed at Screening (including 
WM patients). Corticosteroids must stopped or reduced to the allowed dose (≤15 mg of prednisone or equivalent) at least 7 days before performing the screening 
CT/MRI (if a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose before the screening). During treatment 
and Active follow-up periods, tumor scans will be done with the same modality every 8 weeks (7 days) during Year 1, every 12 weeks (7 days) during Year 2, and 
every 24 weeks (7 days) during Year 3 and onwards, starting from Cycle 1 Day 1. CT/MRI scans are not required at the EOT visit if the patient discontinued due to PD 
which has been radiologically evaluated within the 4 weeks preceding EOT. Tumor scans will be done until PD is documented or new anti-tumor treatment is 
administered. MRI shall be performed instead of CT when local regulations do not permit the use of CT as requested per protocol schedule (see Section 7.3.2). 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. However, in cases when WM patients will develop disease progression confirmed radiologically by presenting with measurable 
lesion(s) without simultaneous increase in IgM, the imaging scans should be submitted for 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 (see footnote r, and 
Sections 7.1.2.3 and 7.3.3).
p
FLymSI-18 questionnaire is to be completed on Cycle 1 Day 1 and every two cycles thereafter (i.e. on Day 1 of Cycles 3, 5, 7 etc.), at the EOT visit and Safety FU visit. 
Questionnaire should be self-administered by the patient via an ePRO 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.


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q
Bone marrow biopsy is 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 at Screening, it will be mandatory to perform it again to confirm the first CR by sending the sample to central review after local bone marrow 
assessment, and also at the investigator discretion if clinical evaluation leads to suspicion of bone marrow infiltration without further radiological findings.
r
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 tumor evaluation 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.
s
Tumor tissue collection will be mandatory for central pathology review. 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. A tumor biopsy is encouraged at 
the time of progression (optional) to allow investigation of copanlisib resistance. In addition, if a tumor biopsy/excision occurs during the course of the study based on 
medical need, a sample should be submitted (though no biopsy is required during treatment) (see Section 7.6.1).
t
Plasma for tumor genetics: On Cycle 1 Day 1, blood for plasma preparation should be drawn prior to drug administration.
u
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 drug 
administration.
v
Whole blood for biomarkers: On Day 1 of Cycle 1 (prior to drug administration), whole blood will be taken only from patients who have provided genetic consent.
w
Rituximab infusions during Cycle 1 on Days 1, 8, 15 and 22. For those patients who are still on treatment after evaluation at the end of Cycle 2 (not in PD), rituximab 
will be administered once at each of Cycles 3, 5, 7 and 9 (on Day 1). Rituximab is administered after copanlisib/placebo IV infusion.
x
After Cycle 1, there are no mandatory procedures on Day 22 of subsequent cycles. Day 22 from Cycle 2 onwards is the earliest time for procedures due at latest on 
Day 1 of the next cycle.
y
The post-treatment follow-up 30 days (window of +5 days is allowed) after the last dose can be conducted via telephone if the patient is no longer being actively seen 
at the clinic or has started another therapy. Procedures marked with “(X)” are only to be performed, if clinically indicated.
z
Patients who discontinue study drug for reasons other than PD will enter Active follow-up period (except for patients who object to FU data collection). These patients 
should have follow-up tumor assessments as outlined in this protocol from the day of randomization until PD is documented or new anti-tumor treatment is 
administered, whichever occurs first. 
aa
Patients or their health care providers will be contacted either in person or by telephone (except for patients who object to FU data collection). The contacts will be 
made every 3 months (± 14 days), until death or until the end of the trial (up to 3 years after the last patient started study treatment), whichever comes first. Information 
to be recorded: Date of contact, survival status, the first new anti-cancer regiment (if applicable), and date and cause of death (if applicable). 
ab
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, CT/MRI scans, bone marrow sample, MUGA/echocardiogram and hepatitis testing which may be used provided they fall into the protocol 
specified 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. CT/MRI must also meet the quality standards of the 
Imaging Manual. 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 (up to additional 14 days permitted).
ac
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 and should perform HBV DNA test with PCR monthly 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 monthly through treatment and 6 months thereafter. If viral load becomes positive, patient should be withdrawn from the study.
ad
Blood test for CMV. Should be performed in all patients prior to IV infusion of copanlisib/placebo. Every cycle on Cycle X Day 1 for the first 6 months of study treatment 


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and every 3 cycles thereafter. If PCR test is positive for CMV, treatment should be delayed until recovery. 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.
ae
Blood cultures should be performed as per local SOC if the patient develops febrile neutropenia or ANC of CTCAE grade 4. CD4 count should be performed for 
patients with signs of infection.
af
For patients with identified risk factors and those who developed OI, additional assessments will 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. chest X-ray or CT scans) (Note: Treatment of developed OI should be based on local SOC).


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Table 7–2
PK sampling schedule
Time point
Copanlisib (Plasma)
Rituximab (Serum)
Cycle 1 Day 8
pre-infusion copanlisib/placebo
X
---
5 - 15 min
X
---
55 min
X
---
Cycle 1 Day 15
pre-infusion rituximab *
X
X
end of infusion rituximab *
X
X
Cycle 1 Day 22
pre-infusion rituximab
---
X
end of infusion rituximab
---
X
* same time points for both copanlisib and rituximab samples
min = minute; PK = pharmacokinetic
For further details, see Section 7.4. Note: PK samplings are not applicable to sites who cannot obtain 
approval by competent Health Authority.


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7.1.2
Timing of assessment
If not stated otherwise, the measurements listed in the following sections will be performed by 
or under the supervision of an investigator or a delegate.
All procedures during the treatment period should be done according to the relative days 
mentioned in this study protocol. Deviations of -1 day and +2 days are acceptable with the 
exception of glucose and blood pressure measurement before copanlisib/placebo infusion.
7.1.2.1
Screening period
Screening examinations will be performed after the patient has given written informed 
consent. 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, CT/MRI scans, bone marrow sample, MUGA/echocardiogram and 
hepatitis testing which may be used provided they fall into the protocol specified 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. CT/MRI must also meet the 
quality standards of the Imaging Manual. 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 (up to additional 14 days permitted). 
Within 28 days before the first study drug administration:

IVRS/IWRS transaction to register the patient in the system (see Section 5.3)

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 and should perform HBV DNA test with PCR monthly through 
treatment and 12 months thereafter (47). 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 monthly through treatment and 6 months thereafter (47). If viral load 
becomes positive, patient should be withdrawn from the study.

Blood test for CMV infection. Patients who are CMV PCR positive at baseline will not 
be eligible.

12-lead ECG including QTcB and QTcF evaluation (see Section 7.5.3.4).

IV (and oral, if indicated, per Imaging Manual) contrast-enhanced CT/MRI of neck, 
chest, abdomen and pelvis (including WM patients). Only MRI will be performed in 
countries where CT cannot be used according to local regulations. Corticosteroids must 
be stopped or reduced to the allowed dose (≤15 mg of prednisone or equivalent) at 
least 7 days before performing the screening CT/MRI (if a patient is on chronic 
corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed 
dose before the screening) (see Section 7.3.2).


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
Bone marrow biopsy: 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 at Screening, it will be 
mandatory to perform it again to confirm the first CR by sending the sample to central 
review after local bone marrow assessment, and also at the investigator discretion if 
clinical evaluation leads to suspicion of bone marrow infiltration without further 
radiological findings.

Tumor tissue collection will be mandatory at Screening for central pathology review. In 
addition, additional 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 7.6.1).

Only in patients affected by LPL/WM:
o Serum protein electrophoresis
o Immunofixation
o Serum quantitative IgM test 
o Serum or plasma viscosity (if hyperviscosity syndrome is suspected)

Only in patients affected by WM and FL: 
o Beta-2-microglobulin
Within 14 days before the first study drug administration:

ECG removed by amendment 1.

Check inclusion and exclusion criteria (see Section 5.1).

Complete medical and surgical history including demographics, relevant medical 
history findings, concomitant illnesses, CIRS-G if applicable, 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. Information on patient’s 
smoking history will also be collected and recorded.

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 7.5.1).

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 including ECOG performance status (see 
Appendix 14.2, NYHA classification (see Appendix 14.3), height, weight, vital signs 
(temperature, pulse and blood pressure), and a complete review of body systems (see 
Section 7.5.3.2).

MUGA scan or echocardiogram to measure LVEF. The method chosen at baseline 
must be the same throughout the whole study period (see Section 7.5.3.5).


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Within 7 days before the first study drug administration:

Check inclusion and exclusion criteria (see Section 5.1).

Serum pregnancy test (if applicable) (see Section 7.5.3.1).

UPCR/24 h total urine protein quantification (see Section 7.5.3.1).

GFR calculation according to MDRD abbreviated formula (see Section 7.5.3.1 and 
Appendix 14.6).

Blood tests for hemoglobin A1c, complete blood count, complete chemistry and 
coagulation panels (see Section 7.5.3.1). 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 (see Section 
6.4.2.2).

Urinalysis (dipstick). Microscopy as clinically indicated (see Section 7.5.3.1).

Training on glucose self-monitoring removed by amendment 9.
7.1.2.2
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.
The following assessments should be performed at each visit before receiving study 
treatment

Monitoring for OI (see Section 6.4.2.7.1): 
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 low ANC
of CTCAE grade 4 occurs, PCR for CMV (every cycle on Cycle X Day 1 for first 
6 months of treatment and every 3 cycles thereafter). CMV can be analyzed 
retrospectively in case the results are not immediately available.
Note: If PCR test is positive for CMV, treatment should be delayed until recovery. 
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.
7.1.2.2.1
Treatment – Cycle 1
Cycle 1, Day 1
On Cycle 1 Day 1 patients should be fasting for at least 8 h prior to the pre-dose glucose 
measurement. For details on fasting requirements and pre-dose glucose levels, see Section 6.4.
Patients can stay overnight at the site, if needed, based on the investigator’s decision.

Quality of life (QoL) questionnaire (FLymSI-18): at the start of the infusion day, 
before the patient sees the physician, to be completed by electronic patient-reported 
outcome (ePRO) device (see Section 7.6.2).


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
Check inclusion and exclusion criteria. No patient may receive treatment unless 
adherence to all selection criteria as given in Section 5.1 is established.

IVRS/IWRS randomization transaction. The randomization must be performed up to 
maximum 72 h before the first dose of study treatment (see Sections 6.3 and 6.5).

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 7.5.1).

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 including ECOG performance status, NYHA 
classification, weight, vital signs (temperature, pulse and blood pressure), and 
complete review of body systems (see Section 7.5.3.2).

12-lead ECG including QTcB and QTcF evaluation prior to infusion and at the end of 
infusion (window of up to 2 h prior to and post-infusion is allowed) (see 
Section 7.5.3.4).

Monitoring for OI (see Section 6.4.2.7.1).

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 rituximab infusion (window of 10 min
is allowed except for the pre-dose measurement). See Section 7.5.3.7. Additional 
measurements to be performed at the clinic as clinically indicated.
Note: If patient needs to take a meal, then glucose test should be taken prior to meal 
intake.

Blood pressure measurements according to guidance provided in Section 7.5.3.3.

Collection of blood for biomarker analyses prior to infusion (see Section 7.6.1):
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)

Copanlisib/placebo IV infusion, before rituximab IV infusion.

Rituximab IV infusion.

Home blood glucose monitoring removed by amendment 9.

MUGA scan/echocardiogram for patients with LVEF below lower level of normal for 
the institution at Screening: one additional LVEF assessment should be made at any 
time between 5 h after the first dose and before the second dose of copanlisib (between 
Day 1 and Day 8 of Cycle 1).
Cycle 1, Day 4

Review of blood glucose measurements, meal timing, oral glucose lowering 
medication and/or insulin administration, if applicable. Patients who might need 
treatment with glucose lowering medications not only on the day of infusion, may be 


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referred to the local diabetes center/endocrinologist for glucose management if 
appropriate e.g. to be trained to self- administer insulin or oral glucose lowering 
medication, and to be provided with glucose lowering medication prescription and an 
insulin sliding scale regimen, if applicable. Investigators will be free to manage 
patients in the same way as described in Section 6.4.2.1. If indicated, domiciliary 
support will be arranged.
Cycle 1, Day 8

Toxicity/ AE assessment (see Section 7.5.1.3).

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, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Blood tests for complete blood count and chemistry panel (excluding triglycerides, 
LDL cholesterol and total cholesterol) (see Section 7.5.3.1).

Monitoring for OI (see Section 6.4.2.7.1).

Glucose test prior to copanlisib/placebo infusion and 1 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). See Section 7.5.3.7. 
Patients are not required to be fasting prior to pre-dose glucose measurement (see 
Section 6.4).

Blood pressure measurements according to guidance provided in Section 7.5.3.3.

PK sampling (see Table 7–2).

Collection of plasma for non-genetic biomarker analyses prior to copanlisib/placebo 
infusion (see Section 7.6.1).

Copanlisib/placebo IV infusion, before rituximab IV infusion.

Rituximab IV infusion.

Home blood glucose monitoring removed by amendment 9.
Cycle 1, Day 15

Toxicity/ AE assessment (see Section 7.5.1.3).

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, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Blood tests for complete blood count, chemistry (excluding triglycerides, LDL 
cholesterol and total cholesterol) and coagulation panels (see Section 7.5.3.1).


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
Monitoring for OI (see Section 6.4.2.7.1).

Glucose test prior to copanlisib/placebo infusion and 1 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). See Section 7.5.3.7. 
Patients are not required to be fasting prior to pre-dose glucose measurement (see 
Section 6.4).

Blood pressure measurements according to guidance provided in Section 7.5.3.3.

PK sampling (see Table 7–2).

Collection of plasma for non-genetic biomarker analyses prior to copanlisib/placebo 
infusion (see Section 7.6.1). 

Copanlisib/placebo IV infusion, before rituximab IV infusion.

Rituximab IV infusion.

Home blood glucose monitoring removed by amendment 9.
Cycle 1, Day 22

Toxicity/ AE assessment (see Section 7.5.1.3).

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, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Blood tests for complete blood count and chemistry panel (excluding triglycerides, 
LDL cholesterol and total cholesterol) (see Section 7.5.3.1).

PK sampling (see Table 7–2). 

Rituximab IV infusion.
After Cycle 1, there are no mandatory procedures on Day 22 of subsequent cycles. Day 22 
from Cycle 2 onwards is the earliest time for procedures due at latest on Day 1 of the next 
cycle.
7.1.2.2.2
Treatment – Cycle 2 and higher
Cycle 2 and higher, Day 1

QoL questionnaire (FLymSI-18): on Day 1 of every two cycles, starting from Cycle 3 
(i.e. Cycles 3, 5, 7 etc.), to be completed by ePRO device at the start of the infusion 
day, before the patient sees the physician (see Section 7.6.2).

IVRS/IWRS transaction for medication dispensing.

Serum pregnancy test (if applicable): after Cycle 1 serum pregnancy test is mandatory 
at every cycle for countries where it is required by local regulations.

Toxicity/ AE assessment (see Section 7.5.1.3).


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
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 including ECOG performance status (see 
Appendix 14.2, NYHA classification (see Appendix 14.3), weight, vital signs 
(temperature, pulse and blood pressure), and a complete review of body systems (see 
Section 7.5.3.2).

12-lead ECG 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 infusion (window of up to 
2 h prior to and post-infusion is allowed) (see Section 7.5.3.4).

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 7.5.3.5).

Blood tests for complete blood count, chemistry and coagulation panels (see 
Section 7.5.3.1). Blood test for hemoglobin A1c will be done on Day 1 of every 
3 cycles (4, 7, 10 etc.), starting from Cycle 4. Blood tests for triglycerides, LDL 
cholesterol and total cholesterol will be done 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 (see Section 6.4.2.2).

Urinalysis (dipstick). Microscopy as clinically indicated (see Section 7.5.3.1).

GFR measurement (see Section 7.5.3.1 and Appendix 14.6).

Monitoring for OI (see Section 6.4.2.7.1).

Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo infusion, and at the end of rituximab infusion (if applicable)
(window of 10 min is allowed except for the pre-dose measurement). See 
Section 7.5.3.7. Patients are not required to be fasting prior to pre-glucose 
measurement (see Section 6.4).

Blood pressure measurements according to guidance provided in Section 7.5.3.3.

Only in Cycle 2: collection of plasma for non-genetic biomarker analyses prior to 
copanlisib/placebo infusion (see Section 7.6.1).

Copanlisib/placebo IV infusion, before rituximab infusion (if applicable).

Rituximab IV infusion (only at Cycles 3, 5, 7 and 9).

Home blood glucose monitoring removed by amendment 9.

Only in patients affected by WM:
o
Serum or plasma viscosity: if abnormal at baseline then every 3rd cycle, starting 
from Day 1 of Cycle 3


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Cycle 2 and higher, Day 8

Toxicity/ AE assessment (see Section 7.5.1.3).

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, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2).

Blood tests for complete blood count and complete chemistry panel (excluding 
triglycerides, LDL cholesterol and total cholesterol) (Cycle 2 only). From Cycle 3 
onwards, only hemoglobin, platelet and absolute neutrophil count will be performed 
prior to each copanlisib/placebo infusion (see Section 7.5.3.1).

Monitoring for OI (see Section 6.4.2.7.1).

Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo infusion (window of 10 min is allowed except for the pre-dose 
measurement). See Section 7.5.3.7. Patients are not required to be fasting prior to pre-
dose glucose measurement (see Section 6.4).

Blood pressure measurements according to guidance provided in Section 7.5.3.3.

Only in Cycle 2: collection of plasma for non-genetic biomarker analyses prior to
copanlisib/placebo infusion (see Section 7.6.1).

Copanlisib/placebo IV infusion.

Home blood glucose monitoring removed by amendment 9.
Cycle 2 and higher, Day 15

Toxicity/ AE assessment (see Section 7.5.1.3).

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, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2)

12-lead ECG and subsequent PK sampling were removed by amendment 1.

Blood tests for complete blood count and chemistry panel (excluding triglycerides, 
LDL cholesterol and total cholesterol) (Cycle 2 only). From Cycle 3 onwards, only 
hemoglobin, platelet and absolute neutrophil count will be performed prior to each 
copanlisib/placebo infusion (see Section 7.5.3.1).

Monitoring for OI (see Section 6.4.2.7.1).

Glucose test prior to copanlisib/placebo infusion and 1 h after the end of 
copanlisib/placebo infusion (window of 10 min is allowed except for the pre-dose 


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measurement). See Section 7.5.3.7. Patients are not required to be fasting prior to pre-
dose glucose measurement (see Section 6.4).

Blood pressure measurements according to guidance provided in Section 7.5.3.3.

PK sampling was removed by amendment 1.

Only in Cycle 2: collection of plasma for non-genetic biomarker analyses prior to 
copanlisib/placebo infusion (see Section 7.6.1).

Copanlisib/placebo IV infusion.

Home blood glucose monitoring removed by amendment 9.
7.1.2.3
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 treatment period as well as during the active follow up period at the following 
intervals (see also Section 7.3.2):

Year 1: Every 8 weeks (7 days), starting from Cycle 1 Day 1

Year 2: Every 12 weeks (7 days)

Year 3 and onwards: Every 24 weeks (7 days) 
MRI shall be performed instead of CT when local regulations do not permit the use of CT as 
requested per protocol schedule.
Bone marrow biopsy will be mandatory at baseline and will be sent to central pathology 
review after local bone marrow assessment. If the baseline biopsy is positive for lymphoma 
infiltration at Screening, it will be mandatory to perform it again to confirm the first CR by 
sending the sample to central review after local bone marrow assessment, and also at the 
investigator discretion if clinical evaluation leads to suspicion of bone marrow infiltration 
without further radiological findings.
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 7.3.3). 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):
o
Serum protein electrophoresis
o
Immunofixation
o
Serum quantitative IgM test


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7.1.2.4
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. They will comprise the following:

QoL questionnaire (FLymSI-18): at the start of a visit, before the patient sees the 
physician, to be completed by ePRO device (see Section 7.6.2).

IVRS/IWRS transaction to register end of treatment.

Serum pregnancy test (if applicable): mandatory for countries where it is required by 
local regulations (see Section 7.5.3.1).

Toxicity/AE assessment (see Section 7.5.1.3).

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).

Review of the blood glucose measurements/meal timing/oral glucose lowering 
medication/insulin doses, if applicable (see Section 6.4.2.1).

Complete physical examination including ECOG performance status (see 
Appendix 14.2, NYHA classification (see Appendix 14.3), weight, vital signs 
(temperature, pulse and blood pressure), and a complete review of body systems, see 
Section 7.5.3.2).

12-lead ECG including QTcB and QTcF evaluation (if not previously done within four 
weeks) (see Section 7.5.3.4).

MUGA scan or echocardiogram to measure LVEF (if not previously done within four 
weeks) (see Section 7.5.3.5). The method must be the same as used at baseline and 
throughout the whole study.

Blood tests for hemoglobin A1c, complete blood count, complete chemistry and 
coagulation panels (see Section 7.5.3.1). 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 (see 
Section 6.4.2.2).
The testing for HbA1c is not required if the previous test was performed within 
4 weeks preceding EOT visit.

Urinalysis (dipstick). Microscopy as clinically indicated (see Section 7.5.3.1).

Collection of plasma for tumor genetics and non-genetic biomarker analyses (see 
Section 7.6.1).

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 discontinues 
due to PD which has been radiologically evaluated within the 4 weeks preceding EOT 
(see Section 7.3.2).


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
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). 
o
Serum or plasma viscosity if abnormal at baseline

A tumor biopsy is encouraged at the time of progression (optional) to allow 
investigation of copanlisib resistance. In addition, if a tumor biopsy/excision occurs 
during the course of the study based on medical need, a sample should be submitted 
(though no biopsy is required during treatment).
7.1.2.5
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). 
HbA1C testing should be performed approximately 3 months after the EOT visit whenever 
possible.
7.1.2.5.1
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.
This visit includes:

QoL questionnaire (FLymSI-18): at the start of a visit, before the patient sees the 
physician, to be completed by ePRO device (see Section 7.6.2)

Toxicity/AE assessment (see Section 7.5.1.3)

Concomitant medication review
If clinically indicated:

Brief physical examination, including ECOG performance status, vital signs 
(temperature, pulse and blood pressure), examination of pertinent organ systems, and 
brief interim history (change of symptoms) (see Section 7.5.3.2)

Complete blood count (see Section 7.5.3.1)

Complete chemistry and coagulation panels (see Section 7.5.3.1)
If a patient has begun treatment with another anti-cancer agent and 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.


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7.1.2.5.2
Active follow-up 
Patients who 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. The patients in the Active follow-up will have follow-up 
tumor assessments (also by central independent blinded review), including bone marrow 
analysis to confirm the first CR in patients with previous bone marrow infiltration during 
Screening, as outlined in this protocol from the day of randomization until disease progression 
is documented or new anti-tumor treatment is administered. For further details see 
Section 7.3.2.
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 GPV department.
The end of Active follow-up period is defined as (i) when disease progression is documented 
or (ii) when a new anti-tumor treatment is administered, whichever occurs first. 
7.1.2.5.3
Survival follow-up
All patients will be followed off study for overall survival at 3-monthly intervals during the 
survival follow-up period (up to 3 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
7.2
Population characteristics
7.2.1
Demographics
Baseline patient data pertaining to demographic information should be documented on the 
eCRFs including the following:

Year of birth and age

Sex

Race

Ethnicity
7.2.2
Medical history
Relevant medical history findings (i.e., relevant previous diagnoses, diseases or surgeries) 
meeting all criteria listed below will be collected:

Not pertaining to the study indication


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
Start before signing of the informed consent 
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 7.5.1.1.
The CIRS-G scoring sheet will be completed and recorded, if applicable (see Appendix 14.7).
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, 
peripheral neuropathy, and bone marrow parameters 

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 
7.2.3
Other baseline characteristics
Information on patient’s history of smoking will be collected and recorded.
7.3
Efficacy
7.3.1
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 central review or death from any 
cause (if no progression is documented).
For secondary and other efficacy variables please refer to Section 8.3.1. 
7.3.2
Radiological tumor assessments
Radiologic tumor assessments will include neck, chest, abdomen and pelvis, and will be 
evaluated locally at the study site and by the central review.
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 CT/MRI (if a patient is on chronic 
corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose 
before the screening). Scans done up to 28 days prior to first dose can be used as baseline 
studies. The method chosen at baseline 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. 


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During the treatment phase as well as during the active follow up period, radiological (IV [and
oral, if indicated, per Imaging Manual] contrast-enhanced CT/MRI) tumor assessment will be 
performed every 8 weeks (7 days) during Year 1, every 12 weeks (7 days) during Year 2, 
and every 24 weeks (7 days) during Year 3 and onwards. CT/MRI scans are not required at 
the EOT visit if the patient discontinues due to PD which has been radiologically confirmed 
within the 4 weeks preceding EOT.
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 progression, radiological real-time confirmation by central 
blinded review is required before a final decision to stop treatment is made. Radiological 
real-time confirmation will only be conducted until the database cut-off for the primary 
analysis. In case of uncertain radiological disease progression the patient may stay on 
treatment at the investigator’s discretion until progression is definitely confirmed on the 
subsequent tumor assessment. The final evaluation of treatment response (best response: ORR 
and CRR) will be done by central blinded review and for those not undergoing PD-
confirmation in retrospective setting. 
The response assessment will be done according to the Lugano Classification. For patients 
with WM, additional criteria apply (see Section 7.3.3). Detailed instructions on tumor 
assessment are provided in Appendix 14.4.
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 (and oral, if indicated, per Imaging Manual) 
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 treatment phase of the study, the case examinations 
should be continued without contrast. In certain countries MRI should be used based on local 
regulations.
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 central review.
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, 
e.g. for bone marrow biopsy. The primary efficacy variable will be analyzed based on the 
assessment of the central image evaluation.


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7.3.3
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, in 
cases when WM patients will develop disease progression confirmed radiologically by 
presenting with measurable lesion(s) without simultaneous increase in IgM, the imaging scans
should be submitted for 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 7.1.2.3). 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 14.4.
7.4
Pharmacokinetics / pharmacodynamics
7.4.1 Sampling
PK sampling will be performed in all patients as follows (see also Table 7–2):
For copanlisib + 
metabolite (M-1), and 
other metabolites, if 
needed:
on Cycle 1 Day 8: pre-infusion copanlisib/placebo, 5-15 min and 
55 min (within 5 min prior to end of infusion)
on Cycle 1 Day 15: pre-infusion and end of rituximab infusion 
(within 5 min prior to the end of infusion)
For rituximab:
on Cycle 1 Day 15: pre-infusion and end of rituximab infusion 
(within 5 min prior to the end of infusion)
on Cycle 1 Day 22: pre-infusion and end of rituximab infusion 
(within 5 min prior to the end of infusion)
If sampling for copanlisib/placebo and/or rituximab is not feasible at Cycle 1, samples may be 
collected at Cycle 3 (on the corresponding days with the matched medication). A separate IV 
line should be used for PK draws.
Additional PK sampling on Day 15 of every third cycle removed by amendment 1.
Deviations from the specified time points will be documented and taken into account when 
calculating the PK parameters. Those deviations do not qualify as protocol violation. All 
blood samples should be collected, processed, stored, and shipped according to procedures 
outlined in the Laboratory Manual.
PK samplings are not applicable to sites who cannot obtain approval by competent Health 
Authority.


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7.4.2 Analysis
PK samples will be analyzed for copanlisib, M-1, and other metabolites, if needed, and 
rituximab. 
Concentration data of copanlisib, its metabolite M-1, and other metabolites, if 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, if needed, in this Phase III population. A population 
pharmacokinetic approach will be used for the analysis and reported in a standalone report.
7.5
Safety
7.5.1
Adverse events
7.5.1.1
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 
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 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.
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.


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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:
- The admission results in a hospital stay of less than 12 hours
- The admission is pre-planned 
(i.e. elective or scheduled surgery arranged prior to the start of the study)
- 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.
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 medically important serious event as judged by the investigator
7.5.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
7.5.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 7.5.1.1.
7.5.1.2.2
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
7.5.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a clinical decision based on all available information at the time of the completion of the 
CRF.
The causality assessment should be done separately for each study treatment as detailed on the 
CRF.


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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”
An assessment of “no” would include:
1. The existence of a clear 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 there is a reasonable suspicion that the AE is 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 patients response after re-challenge should be 
considered in the 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 may be suspected to cause the event in 
question.
- 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.
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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7.5.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.
- Drug withdrawn
- Drug interrupted
- Dose reduced
- Dose not changed
- Not applicable
- Unknown
The study treatment action should be recorded separately for each study treatment as detailed 
on the CRF.
7.5.1.2.5
Other specific treatment(s) of adverse events
- None
- Remedial drug therapy
- Other
7.5.1.2.6
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
7.5.1.3
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. AEs will be documented in an 
event-based manner, using NCI-CTCAE v.4.03 guidelines. 
The observation phase for AEs will start with signing the ICF and shall end 30 days after the 
last dose of study drug. The safety follow-up visit shall occur 30 days (window of +5 days 
allowed) after the last dose of study medication. AEs still present at the end of the observation
phase should be followed until resolution or stabilization unless, in the investigator’s opinion, 
the condition is unlikely to resolve due to the patient’s underlying disease.
AEs to be documented include all AEs that were ongoing at the end of treatment as well as 
new AEs that, in the opinion of the investigator, could be related to study treatment 
(information may be obtained via phone call). Documentation must be supported by an entry 
in the patient’s file.
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 GPV department. 


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The investigator is responsible for the grading of each category mentioned in Section 7.5.1.2.
For all SAEs the sponsor is to carry out a separate assessment for expectedness, seriousness 
and causal relationship to the test drug.
If any patient dies in the safety follow-up period 30 days (window of +5 days allowed) after 
last dose of study medication, the investigator will inform the sponsor and record the cause of 
death in detail within 24 hours on an SAE form.
A laboratory test abnormality considered clinically relevant, e.g., causing the patient to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, or 
judged relevant 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. 
7.5.1.4
Reporting of serious adverse events
The definition of SAEs is given in Section 7.5.1.1.
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.
All SAEs occurring during the observation period defined in Section 7.5.1.3 must 
immediately (within 24 hours of the investigator’s awareness) be reported to the recipient 
detailed in the manual. An SAE form must also be completed within 24 hours of the 
investigator awareness and forwarded to the designated recipient. Each SAE must be followed 
up until resolution or stabilization by submission of updated reports to the designated 
recipient.
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 7.5.1.1), 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”.
In the event of a fatal or life-threatening reaction, the investigator must seek relevant follow-
up information and must complete a follow-up report to be faxed 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.
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 
International Conference on Harmonization (ICH) criteria for an SAE (see SAE definition in 
Section 7.5.1.1).
Once data regarding survival and remission status are no longer required by the protocol, only 
additional primary tumors regarded as related to study treatment should be reported.
Progressive disease should not be reported.


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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.
7.5.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the IB for 
copanlisib and prescribing information / SmPC for rituximab.
Overview listings of frequent events that have occurred so far in the clinical development 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.
7.5.1.6
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 
unexpected AEs, including hypersensitivity reactions.
Based on data from Phase I studies with copanlisib, as soon as there is reasonable suspicion of 
the following AE, the investigator should immediately notify the sponsor as outlined in 
section 7.5.1.4, regardless of whether the investigator assessed the AE as serious or non-
serious:

Non-infectious pneumonitis
7.5.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a study patient during 
the patient’s participation in this study. The report should be submitted within the same 
timelines as an SAE, although a pregnancy per se is not considered an SAE.
For a study patient, the outcome of the pregnancy should be followed up carefully, and any 
outcome of the mother or the child should be reported.
The sponsor usually does not gather information of drug exposure via the father, however, if 
such cases are reported, all efforts should be made to obtain similar information on course and 
outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used.


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7.5.3
Further safety
7.5.3.1
Laboratory
All laboratory analyses will be performed locally according to the schedule summarized in the 
flow chart of Section 7.1.1. Dipsticks should be available for urinalysis.

Complete blood count: hemoglobin, hematocrit, RBC, and WBC (with differential to 
include neutrophil, lymphocyte, monocyte, basophils and eosinophil counts), and 
platelet count. Differential blood count in percentage can be provided when absolute 
count is not available per standard of care of the local lab.

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, BUN (or urea if BUN is not routinely 
measured at the site), creatinine, uric acid, total bilirubin, creatine kinase, ALT, AST, 
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 according 
to local standards prior to sampling. For patients who cannot adhere to these fasting 
requirements the evaluation of lipid-panels including triglycerides is considered not 
feasible.

Coagulation panel: INR or PT, and PTT.

Urinalysis: blood cells (RBC and leukocytes), glucose, ketones, bilirubin, protein, and 
pH (dipstick).
Additional microscopic examinations will be performed if clinically indicated.

Serum pregnancy test in women of childbearing potential. 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).

Quantification of proteinuria by either a 24 h 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 on the same sample. Dipstick analysis is not 
acceptable to assess proteinuria.

Measurement of GFR according to the MDRD abbreviated formula.

Blood test for HBV and HCV (HBsAg, HBcAb and anti-HCV antibody; if HBsAg or 
HBcAb positive also HBV DNA; if anti-HCV antibody positive also HCV RNA).

Hemoglobin A1c.

CD4 (for patients with signs of infection), blood cultures if febrile neutropenia occurs 
or when ANC of CTCAE grade 4, PCR for CMV.

For patients with identified risk factors and those who developed OI, additional 
laboratory assessments will include (see Section 6.4.2.7.1):
o
CD4 and CD8 count and ratio, CRP, blood cultures
o
Any additional laboratory assessments according to local SOC reported as 
unscheduled laboratory assessments.


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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 7.5.1.1). 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.
7.5.3.2
Physical examinations
Physical examinations will be performed according to the schedule summarized in the flow 
chart of Section 7.1.
7.5.3.2.1 Complete physical examination
Complete physical examination includes ECOG performance status assessment, NYHA 
classification (see Appendix 14.3), height (only at Screening), weight, vital signs (see 
Section 7.5.3.3), and 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 (paleness, jaundice, redness/rash, acneiform changes) including clinical 
assessment of hydration status via hand extensor surface skin turgor

Hand and feet (signs of hand-foot-skin-syndrome/ hand-foot skin reaction)

Eyes (accommodation, double images, abnormal sensitivity to light, jaundice)

Ears, nose, throat (presence of petechial bleeding, gingival bleeding) including 
inspection of oral mucosa for hydration status

Head and neck

Lungs: evaluation of new onset or worsening of pulmonary symptoms, and lung 
examination

Heart

Abdomen (pain, tenderness, peristaltism, ascites, organomegaly)

Lymph nodes

Musculoskeletal system and spine

Lower legs (petechial bleedings, ulcer, signs of thrombosis)

Neurologic findings


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7.5.3.2.2 Brief physical examination
Brief physical examination includes ECOG performance status, vital signs (see 
Section 7.5.3.3), examination of pertinent organ systems, and brief interim history (change of 
symptoms).
The examination of pertinent organ systems should investigate at minimum:

Skin (paleness, jaundice, redness/rash, acneiforme changes) including clinical 
assessment of hydration status via hand extensor surface skin turgor

Hand and feet (signs of hand-foot-skin-syndrome)

Throat (presence of petechial bleeding, gingival bleeding) including inspection of oral 
mucosa for hydration status

Lungs: evaluation of new onset or worsening of pulmonary symptoms, and lung 
examination 

Abdomen (pain, tenderness, peristaltic, ascites, organomegaly)

Neurologic findings
Other clinical signs and regions might be investigated as well, if clinically indicated.
7.5.3.3
Vital signs
Pulse, blood pressure and temperature will be assessed according to the schedule summarized 
in the flow chart of Section 7.1. If clinically indicated, it is at the investigator’s discretion to 
perform these measurements more frequently.
Blood pressure measurement on infusion 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 min before blood pressure is recorded.

On copanlisib/placebo 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 h after 
the end of copanlisib/placebo infusion. 

In addition, on the days of rituximab administration, blood pressure will be measured
30 min after the start of rituximab infusion and at the end of rituximab infusion.

Note: time window of ± 10 min is allowed for all post-dose blood pressure 
measurements.
For details on the management of arterial hypertension, see also Sections 6.4.1 (dose 
modification) and 6.4.2.3 (treatment of blood pressure increases).
7.5.3.4
12-lead ECG
12-lead ECGs will be performed according to the schedule summarized in the flow chart in 
Section 7.1. The study number, patient number, visit and the date of the ECG will be noted on 
every ECG.


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The patient should rest for 5-10 min 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.
7.5.3.5
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.
7.5.3.6
ECOG performance status
Grading definitions are given in Appendix 14.2.
7.5.3.7
Glucose measurement on copanlisib/placebo infusion days

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 rituximab infusion. 
Additional measurements to be performed at the clinic as clinically indicated.

On subsequent copanlisib/placebo infusion days: 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 (if applicable). Additional measurements to be 
performed at the clinic as clinically indicated.

On all copanlisib/placebo infusion days: time window of ± 10 min is allowed for 
glucose measurements (except for the pre-dose measurement).
7.6
Other procedures and variables
7.6.1
Biomarker investigations
Overview
There will be several parts to biomarker testing in this study:
1) tumor-genetic testing of fresh (preferred) or archival tumor tissue, and possibly of 
circulating tumor DNA isolated from plasma 
2) non-genetic biomarker testing
3) genetic biomarker research
Genetic biomarker research of the whole blood requires separate ‘genetic’ research consent 
(optional testing for research). All other analyses are covered by the main ICF.


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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
Biomarker samplings are not applicable to sites who cannot obtain approval by competent 
Health Authority.
Optional Tumor Tissue
One or more of the following pre-treatment tumor tissue samples should 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 study enrollment) is mandatory when 
available.
A tumor biopsy is also encouraged at the time of progression (optional) to allow investigation 
of copanlisib resistance. In addition, if a tumor biopsy/excision occurs during the course of the 
study based on medical need, a sample should be submitted (though no biopsy is required 
during treatment)
Archival 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 in addition 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 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 Table 7–1). 
Plasma may be used to quantify the circulating levels of various proteins. 


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Plasma for tumor genetics: Blood samples will be obtained and used for plasma preparation 
at the time points as indicated in the study flow chart (see Table 7–1). Plasma may be used as 
a source of circulating tumor DNA for the evaluation of mutations in tumor-related genes of 
interest.
Whole blood (only applicable for patients who provided ‘genetic’ research consent): At
Screening, 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, if the 
evaluations are performed.
In addition to the proteins and genes 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.
7.6.2
Quality of life questionnaire
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.
In this study physical symptoms of lymphoma will be assessed using the NCCN-FACT
Lymphoma Symptom Index-18 (FLymSI-18), version 2 (see Appendix 14.5) (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 
instrument was developed in accordance with recent Food and Drug administration (FDA)
guidance for the development of instruments for patient-reported outcomes (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 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 (33, 34).
The FLymSI-18 will be administered according to the schedule specified in the study flow 
chart (see Table 7–1).


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At the visits where it is scheduled to be completed, 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.
7.6.3
Electronic patient-reported outcomes evaluation
Electronic PRO (ePRO) device will be implemented in this study. It will be used to complete 
the FlymSI-18 questionnaire. A Site Manual will be provided to sites and each patient will be 
trained how the ePRO device works and how to use it correctly. If, for any reason, a device is 
not available at the site, or technical problems prevent it from working properly, the FLymSI-
18 questionnaire will not be completed at that visit.
7.7
Appropriateness of procedures / measurements
The efficacy assessments used in this study include those considered standard of care to 
evaluate objective tumor response rate in patients with iNHL. Although the recently published 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification (27) strongly support the use of PET-
CT for staging and response assessment of routinely FDG-avid histologies, especially in 
clinical trials, it was decided to use in this study only a CT-based response. CT/MRI-based 
response remains in fact preferred for histologies with low or variable FDG avidity and in 
regions of the world where PET-CT is unavailable. Moreover, in trials exploring new agents
in multiply relapsed disease where data are lacking regarding PET-CT and where assessment 
of disease control is more important than likelihood of cure, CT/MRI-based response may 
also be more relevant. 
The safety assessments are appropriate and standard to monitor safety and assess toxicity.
8.
Statistical methods and determination of sample size
8.1
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). 
Further details on the statistical analyses including handling of missing data will be provided 
in the SAP that will be approved before database release.
8.2
Analysis sets
The statistical analysis sets are defined as follows:


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Full analysis set (FAS): all patients randomized.
Safety analysis set (SAF): all FAS patients with at least one intake of copanlisib/placebo or 
rituximab. 
All patients with valid PK data will be included in the evaluation of PK concentrations and 
parameters. 
The efficacy variables will be analyzed in the FAS.
The SAF will be used for the analyses of the safety variables. The FAS will be used for the 
display of all other variables.
8.3
Variables
8.3.1
Efficacy variables
Disease progression (PD) in the context of statistical efficacy evaluation is considered to be 
radiological progression, as assessed by central review. For WM patients without radiologically 
measureable disease, clinical progression will be used. 
8.3.1.1
Primary efficacy variable 

Progression-free survival (PFS), defined as the time (in days) from randomization to 
PD or death from any cause (if no progression is documented). The actual date of 
tumor assessments will be used for this calculation. PFS for patients without PD or 
death at the time of analysis will be censored at the date of their last tumor evaluation. 
PFS for patients who have neither tumor assessments nor death after baseline will be 
censored at Day 1.
8.3.1.2
Secondary efficacy variables

Objective tumor response rate (ORR) assessed in all patients up to the time of analysis
of PFS. ORR is defined as the proportion of patients who have a best response rating 
over the whole duration of the study (i.e. until time of analysis of PFS) of complete 
response (CR) or partial response (PR) according to the Lugano Classification and for 
patients with WM a response rating of CR, very good partial response (VGPR), PR, or 
minor response (MR) according to the Owen Criteria. Detailed instructions on tumor 
assessment are provided in Appendix 14.4.

Duration of response (DOR), 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. DOR will only be defined for patients with at least one CR, VGPR, PR, or MR. 
Patients without PD or death at the time of analysis will be censored at the date of their 
last tumor evaluation.

Complete response rate (CRR), assessed in all patients up to the time of analysis of PFS.

Time to progression (TTP), defined as the time from randomization to PD or death 
related to PD, whichever is earlier. The actual dates of tumor assessments will be used 
for this calculation. 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 evaluation. TTP 
for patients who have neither tumor assessments nor death related to PD after baseline 
will be censored at Day 1. Death related to PD is considered to be any death except 
for:


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o
Death due to an AE unrelated to progression
o
Death with a specification of “other” as reason (which excludes PD)

Overall survival (OS), 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 the last 
date they were known to be alive. 

Time to deterioration in DRS-P of at least 3 points, as measured by the FLymSI-18 
questionnaire. Patients will be considered as “censored” at the date of their last tumor 
evaluation, if the reason for stopping treatment is not related to PD. Patients dropping 
out due to progression-related reason or experiencing a PD event or death due to any 
reason will be considered as having had their decline in DRS-P at the date of their last 
tumor evaluation. 

Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 
questionnaire, 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). Patients will 
be considered as "censored" at the date of their last tumor evaluation, if the reason for 
stopping treatment is not related to PD. Patients dropping out due to progression-
related reason or experiencing a PD event or deaths due to any reason will be 
considered censored at the largest observation time (of events and censoring in all 
patients evaluated for improvement), plus 1 day.
Further sensitivity analyses for the DRS-P analyses will be described in the SAP (e.g. might 
involve different handling of the last response status for that patient or considering PD and 
death as censored). 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.
8.3.1.3
Other efficacy variables

AUC across all data of FLymSI-18 DRS-P subscale score

FLymSI-18 total and subscale scores (DRS-P, DRS-E, TSE, FWB), and time to onset 
of physical symptoms of lymphoma based on the DRS-P subscale

Performance status (ECOG)
8.3.2
Safety variables 
Safety variables will include treatment-emergent AEs, SAEs, laboratory parameters, and vital 
signs. The severity of AEs will be graded using the CTCAE v 4.03 dictionary. AEs will be 
classified by the investigator as related or not related to test drug. 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 (end of safety follow-up).
8.4
Statistical and analytical plans
8.4.1
Population characteristics
Demographics and baseline characteristics will be summarized by treatment group in the FAS.


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8.4.2
Efficacy
All efficacy analyses will be performed when at least 190 PFS events (PD by central review 
or death before PD) are observed in the study. Also see minimum number of PFS events that 
has to be observed in each of the two strata defined by the inclusion criterion (progression-
free and treatment-free interval of ≥12 months after completion of the last rituximab-
containing treatment vs. unwilling/unfit to receive chemotherapy). See Section 8.6.
Evaluations from central blinded review will be used for the primary efficacy analyses of 
primary and secondary endpoints containing radiological tumor assessments.
8.4.2.1
Primary efficacy analysis
All randomized patients (FAS) will be included in the primary analysis.
In order to evaluate whether copanlisib in combination with rituximab is superior to placebo 
in combination with rituximab in prolonging PFS in patients with relapsed iNHL who have 
received one or more lines of treatment, including rituximab, the following null hypothesis 
will be tested in the FAS:
H0, PFS: SCopanlisib+Rituximab(t) = SPlacebo+Rituximab (t) for all time points t ≥ 0
The alternative hypothesis will be:
H1,PFS: SCopanlisib+Rituximab (t) > SPlacebo+Rituximab (t) for at least one time point t ≥ 0, and
SCopanlisib+Rituximab (t) ≥SPlacebo+Rituximab (t) for all time points t ≥ 0,
where SCopanlisib+Rituximab denotes the survival function of the copanlisib + rituximab group and 
SPlacebo+Rituximab denotes the survival function of the placebo + rituximab group in the total 
study population.
The following decision rule to test the null hypothesis will be applied:
According to the size of this study it is justified to assume under H0, PFS the one-sided log-rank 
test (36) is a sufficiently close approximation to the normal distribution. If the z-value from 
the one-sided log-rank test (for the difference SCopanlisib+Rituximab - SPlacebo+Rituximab, stratified by 
the factors used for randomization: FL vs. other iNHL histologies, and progression-free and 
treatment-free interval of ≥ 12 months after completion of the last rituximab-containing
treatment vs. unwilling/unfit to receive chemotherapy) is larger than the critical quantile from 
the normal distribution (z0.975 = 1.96), the null hypothesis will be rejected in favor of the 
alternative hypothesis.
The PFS will be tested in the hierarchy test (see Section 8.4.2.3).
Additional analyses of the primary efficacy variable
Kaplan-Meier estimates of median times to PFS (including 95% confidence interval) and 
Kaplan-Meier curves will be presented for each treatment group.
The hazard ratios (including 95% confidence interval) will be derived from Cox proportional 
hazards models that are stratified by the same factors as used for the primary efficacy 
analysis.
The censoring mechanism of subjects without PFS event 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 subjects. These will include 


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the use of different rules for considering subjects without PFS events as having an event or 
being censored and will be further outlined in the SAP.
8.4.2.2
Secondary efficacy parameters
All secondary efficacy variables will be analyzed in the FAS at the time of the analysis of the 
primary variable.
The ORR will be analyzed using the Cochran-Mantel-Haenszel test (37), stratified for the 
same stratification factors as used for PFS. The null hypothesis is defined as:
H0, ORR: ORRCopanlisib+Rituximab ≤ ORRPlacebo+Rituximab
The alternative hypothesis is:
H1, ORR: ORRCopanlisib+Rituximab > ORRPlacebo+Rituximab
The following decision rule to test the null hypothesis will be applied:
If the p-value for the two-sided Cochran-Mantel-Haenszel test is smaller than the 0.05
significance level and the estimated difference ORRCopanlisib+Rituximab - ORRPlacebo+Rituximab
(comparing copanlisib + rituximab vs. placebo + rituximab) is greater than 0.0, the null 
hypothesis will be rejected in favor of the alternative hypothesis.
The time to deterioration and time to improvement in DRS-P subscale of FLymSI-18 will be 
analyzed analogously to the PFS, using similar hypotheses, decision rules, and significance 
level.
OS, CRR, TTP as well as DOR will be analyzed supportively only.
OS, TTP, and DOR will be analyzed using stratified log-rank tests analogue to the analysis for 
the primary endpoint, PFS. 
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 PFS. 
The first analysis of OS will be performed at the time of analysis of the primary endpoint,
PFS. The survival status will further be collected quarterly during the survival follow-up 
period up to 3 years after the last patient started study treatment.
A follow-up analysis of OS will be performed. Details will be described in the SAP.
8.4.2.3
Confirmatory statistical test strategy
Separate statistical test strategies will be conducted for the United States and Europe 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 shown in Figure 8–1.
The primary efficacy variable 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,


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a)
a second test on the PFS will be performed (tested at one-sided alpha=0.025), 
evaluating the subpopulation of combined FL and MZL population, if this is successful
b)
a test on the ORR in the combined FL and MZL population will be performed (tested at 
one-sided alpha=0.025), if this is successful
c)
a test on the time to deterioration in DRS-P in the combined FL and MZL population
will be performed (tested at one-sided alpha=0.025), if this is successful
d)
a test on the time to improvement in DRS-P in the combined FL and MZL population
will be performed (tested at one-sided alpha=0.025), it would conclude the 
confirmatory test procedure.
Figure 8–1
Confirmatory test strategy based on five test families for United States
PFS in the iNHL population (FAS)
Alpha: 2.5%
PFS in the combined FL and MZL population
Tested, if success in F1
Alpha: 2.5%
ORR in the combined FL and MZL population
Tested if success in F2
Alpha: 2.5%
Family 3 (F3)
Family 2 (F2)
Family 1 (F1)
DRS-P deterioration in the combined FL and 
MZL population
Tested, if success in F3
Alpha: 2.5%
Family 4 (F4)
DRS-P improvement in the combined FL and MZL 
population
Tested, if success in F4
Alpha: 2.5%
Family 5 (F5)


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For testing Families 1 to 2 of this confirmatory test strategy, an assessment of power based on 
Schoenfeld’s formula (52) was performed for two scenarios as listed in Table 8–1:

Scenario 1: HR=0.61 in the FAS population (according to the re-planned sample size 
planning)

Scenario 2: HR=0.53 in the FAS population (less conservative assumption)
Table 8–1
Assessment of statistical power for PFS test in the overall FAS 
population and combined FL and MZL population
Total 
patients
Dropout 
rate
Events to be 
expected (E)
Hazard
ratio
Power
Scenario 1:
Family 1: overall FAS 
population
458
30%
190
0.61
89.5%
Family 2: combined FL and MZL 
population
370
30%
140
0.61
78.7%
Scenario 2:
Family 1: overall FAS 
population
458
30%
190
0.53
98.5%
Family 2: combined FL and MZL 
population
370
30%
140
0.53
94.3%
The number of total patients in Table 8–1 is the number of patients having been randomized 
in the study.
Europe
For Europe, 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 showing Figure 8–2:
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 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 test on the DSR-P improvement in the FAS population will be performed (tested at 
one-sided alpha=0.025), it would conclude the confirmatory test procedure.


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Figure 8–2
Confirmatory test strategy based on four test families for Europe
Note: EU refers to Europe 
8.4.2.4
Other efficacy evaluations
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. Total FLymSI-18 and subscales will be evaluated descriptively.
Further details on PRO data analysis will be provided in the SAP.
Performance status (ECOG) will be summarized for the original score, as well as for the
change from baseline score by treatment group.
8.4.3
Subgroup Analyses
Countries will be combined into regions US vs. Europe vs. rest of the world in order to define 
regional subgroups.
Subgroup analyses will include forest plots as well as treatment-interaction analyses, both for 
the region subgroups as well as further subgroups (e.g. based on stratification factors and/or 
baseline characteristics) and will be provided both for the primary efficacy endpoint as well as 
other relevant efficacy and/or safety endpoints. The treatment-interaction analysis will be 
conducted for the primary efficacy endpoint (PFS), and the secondary efficacy endpoints time 
to worsening of DRS-P and time to improvement in DRS-P.
Family 4 EU (F4EU)
Family 2 EU (F2EU)
DRS-P deterioration in iNHL population (FAS)
Tested, if success in F2EU
Alpha: 2.5%
Family 3 EU (F3EU)
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 F3EU
Alpha: 2.5%
Family 1 (F1)


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8.4.4
Safety Analyses
Safety variables will be summarized by means of descriptive statistics and/or frequency tables 
as appropriate. Summaries will be given by treatment group.
All AEs, treatment-emergent and hematological/biochemical toxicities based on laboratory 
measurements, as well as drug related AEs and SAEs, will be summarized by CTCAE version 
4.03 category and worst grade.
In addition, results of physical examination, vital signs, and ECG will be summarized.
8.4.5
Pharmacokinetic Data 
Individual concentration-time data will be provided in a clinical study report appendix.
A population pharmacokinetic approach will be used for the analysis, and the results will be 
reported separately in a modeling and simulation report. Rituximab concentrations will be 
listed and the pharmacokinetics compared to the published rituximab PK data in the modeling 
and simulation report. All patients who provide valid PK samples are valid for population PK.
8.5
Planned interim analyses
No interim efficacy analyses are planned for this study. A DMC meeting will take place after 
the 30th randomized patient has completed the first cycle of treatment and provide 
recommendation on whether it is safe to continue recruitment into the combination arm.
8.6
Determination of sample size
EAST 6.4 is used to calculate sample size. Sample size estimation is based on the evaluation 
of the primary efficacy endpoint, PFS, in the FAS.
The two treatment arms copanlisib in combination with rituximab and placebo in combination 
with rituximab will be compared. Superiority of the copanlisib + rituximab arm over the 
placebo + rituximab arm will be tested for the FAS.
Sample size justification for primary efficacy test on PFS in the total study population
A recent study (AUGMENT, 51) reported a hazard ratio of 0.46 (95% CI 0.34-0.62) for the
PFS, and a median PFS of 14.1 months in the rituximab + placebo arm in the indication of 
second line iNHL. Based on the results from this study, Bayer has decided to update the 
sample size justification.
With at least 190 PFS events (progression based on central review or death if death occurs 
before progression), a randomization ratio of 2:1 between the experimental and control arms, 
a 1-sided alpha of 0.025, a hazard ratio of 0.61 (i.e., median PFS of 23 months for copanlisib 
+ rituximab arm and 14 months for placebo + rituximab arm) can be detected with a power of 
at least 89%.
Based on the planned 450 patients for this study and the observed and projected recruitment as 
well as blinded monitoring of event times, the expected study duration to reach at least 190 
events is 59 months, (with maximum accrual rate being approximately 10 patients per month). 
The percentage of dropouts (ie. lost to survival follow-up or withdrawal of consent before 
their PFS event) rate is assumed to be 135 (30%) dropout patients over the duration of the 
study through the primary PFS analysis.


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The primary analysis will be performed when at least 190 centrally evaluated PFS events are 
observed in the study.
As an additional criterion, a sufficient number of PFS events has to be observed in each of the 
two strata defined by the inclusion criterion (progression-free and treatment-free interval of 
≥12 months after completion of the last rituximab-containing treatment vs. unwilling/unfit to 
receive chemotherapy) before the study is unblinded for primary evaluation. This especially 
ensures the contribution of events also from patients who have previously shown a good 
response to rituximab.
The required minimum number of PFS events in these strata will depend on the relative 
proportion of patients recruited into the respective cohorts and can be seen from Table 8–2
The observed proportions and event numbers will be determined during blind data review 
after the end of recruitment.
Table 8–2
Required number of PFS events per entry criteria stratum 
Proportion of patients 
randomized in one 
strata
Required number of 
PFS events
Proportion of patients 
randomized in the 
other strata
Required number of 
PFS events
0% - 5%
no required numbers
(in both strata)
95% - 100%
no required numbers
(in both strata)
>5% - 10%
10
90% - <95%
122
>10% - 20%
20
80% - <90%
112
>20% - 30%
33
70% - <80%
99
>30% - 40%
46
60% - <70%
86
>40% - 50%
59
>50% - <60%
73
As an example: In case 32% of patients would be recruited in the “progression-free and 
treatment-free interval of ≥12 months after completion of the last rituximab-containing 
treatment” stratum, then at least 46 PFS events are required in this stratum. In addition, at 
least 86 PFS events from the complement stratum “considered unwilling/unfit to receive 
chemotherapy by the CIRS-G” are required. To fulfill the overall criterion of at least 190 PFS 
events, approximately 58 additional events from any of the two strata are required.
In case of an extreme proportion of censored/discontinued patients in a stratum that severely 
impacts the relation of "Proportion of recruited patients" ≈ "Proportion of PFS events", the 
study team might decide to deviate from the above rule during blind data review.
Sample size assumptions for the first DMC meeting.
When the first 30 patients are recruited in this blinded study, the probability to have at least 15
patients in the copanlisib+rituximab arm is greater than 95%. These 15 patients are considered 
to be adequate for initial assessment of safety of the combination drug by DMC.
9.
Data handling and quality assurance
9.1
Data recording
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site. The site must implement processes to ensure this happens.
A source document checklist will be used at the site to identify the source data for all data 
points collected and the monitor will work with the site to complete this.


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Data recorded from “only screened patients (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, data to be recorded on the CRF are 
demographic information (patient number, year of birth/age, sex, race and ethnicity), the 
reason for premature discontinuation and date of last visit. These data will be transferred to 
the respective database.
For screening failures with an SAE, the following additional data should be collected on the 
CRF, in addition to demographic information, primary reason for discontinuation and date of 
last visit: 
All information about the SAE
All information related to the SAE such as: 

Concomitant medication

Medical history

Other information needed for SAE complementary page
9.2
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 
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
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.
9.3
Data processing
The data collection tool for this study will be a validated electronic system called RAVE.
Patient data necessary for analysis and reporting will be entered/ transmitted into a validated 
database or data system (e.g. TOSCA; SAS). Clinical data management will be performed in 
accordance with applicable sponsor’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, ePRO).
For data coding internationally recognized and accepted dictionaries will be used, Medical 
Dictionary for Regulatory Activities (MedDRA) and the CTCAE version 4.03 for AEs and 
medical history, and WHO-Drug Dictionary (WHO-DD) for concomitant medications. 


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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.
9.4
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.
9.5
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.
10.
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,
- Safety findings from this study (e.g. SAEs)
Results of any interim analysis removed by amendment 1
- Results of parallel clinical studies
- Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).


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
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.
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 given by the sponsor for destruction.

In case 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 5.2.1.
11.
Ethical and legal aspects
11.1 Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
GCP guidelines and under the guiding principles detailed in the Declaration of Helsinki. The 
study will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/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.
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 10.


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11.2 Patient information and consent
All relevant information on the study will be summarized in an integrated patient information 
sheet ICF provided by the sponsor or the study center. A sample patient information and ICF
is provided as a document separate to this protocol. Separate patient information sheets/ ICFs 
will be provided to the patients on a voluntary basis for the following:

Pharmacogenetic ICF

ICF for collection of data on pregnancy and birth

ICF on study updates
Based on the patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient, 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 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 data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the SAP.

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 SAP. The patient has the right to object to the generation and 
processing of this post-withdrawal data. The patient’s oral objection may be 
documented in the patient’s source data.
Each patient will have ample time and opportunity to ask questions.
Only if the patient voluntarily agrees to sign the informed consent form and has done so, may 
he/she enter the study. Additionally, the investigator and other information provider (if any) 
will personally sign and date the form. The patient 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.
The informed consent form and any other written information provided to patients 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 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 


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written informed consent form and written information must receive the IEC/IRB`s approval / 
favorable opinion in advance of use.
11.3 Publication policy
The sponsor is interested in the publication of the results of every study it performs.
All relevant aspects regarding publication will be part of the contract between the sponsor and 
the investigator/institution.
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.
11.4 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.
11.5 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 on
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.
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.
12.
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Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. 
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Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, et al. Poor 
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Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, et al. 
Frontline therapy with rituximab added to the combination of cyclophosphamide, 
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CHOP alone: results of a prospective randomized study of the German Low-Grade 
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Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, Raposo JC, et al. 
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J Clin Oncol. 2008;26(28):4579-86.
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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).


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19.
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.
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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.
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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.
22.
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.
23.
Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, Offner F, et al. Bortezomib 
plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or 
rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. The lancet 
oncology. 2011;12(8):773-84.
24.
Ghielmini M, Rufibach K, Salles G, Leoncini-Franscini L, Leger-Falandry C, Cogliatti 
S, et al. Single agent rituximab in patients with follicular or mantle cell lymphoma: 
clinical and biological factors that are predictive of response and event-free survival as 
well as the effect of rituximab on the immune system: a study of the Swiss Group for 
Clinical Cancer Research (SAKK). Annals of oncology : official journal of the 
European Society for Medical Oncology / ESMO. 2005;16(10):1675-82.
25.
Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, et al. 
Prolonged treatment with rituximab in patients with follicular lymphoma significantly 
increases event-free survival and response duration compared with the standard 
weekly x 4 schedule. Blood. 2004;103(12):4416-23.
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Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, et al. Long-term 
follow-up of patients with follicular lymphoma receiving single-agent rituximab at two 
different schedules in trial SAKK 35/98. J Clin Oncol. 2010;28(29):4480-4.
27.
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.
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Miller MD, Towers A. A Manual of Guidelines for Scoring the Cumulative Illness 
Rating Scale for Geriatrics (CIRSG). Pittsburg, PA: University of Pittsburg; 1991.
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Visani G, Ferrara F, Alesiani F, Ronconi S, Catarini M, D'Adamo F, et al. R-COMP 21 
for frail elderly patients with aggressive B-cell non-Hodgkin lymphoma: a pilot study. 
Leuk Lymphoma. 2008;49(6):1081-6.
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Tucci A, Ferrari S, Bottelli C, Borlenghi E, Drera M, Rossi G. A comprehensive 
geriatric assessment is more effective than clinical judgment to identify elderly diffuse 


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large cell lymphoma patients who benefit from aggressive therapy. Cancer. 
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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(23):2919-28.
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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(9):1001-11.
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Hlubocky FJ, Webster K, Beaumont J, Cashy J, Paul D, Abernethy A, et al. A 
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advanced lymphoma: the National Comprehensive Cancer Network-Functional 
Assessment of Cancer Therapy - Lymphoma Symptom Index. Leuk Lymphoma. 
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Cella D, Rosenbloom SK, Beaumont JL, Yount SE, Paul D, Hampton D, et al. 
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Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. 'Categorical Data Analysis' in
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Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method 
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Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine 
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13.
Protocol amendments
13.1
Amendment 1
Amendment 1 is dated 23 JAN 2015.
13.1.1
Overview of changes
13.1.1.1
Modification 1 – inclusion criteria changed
Inclusion criteria were supplemented with the following condition: patients must either have 
had a treatment-free interval of 12 months or longer after completion of the last rituximab-
containing treatment, or be considered unfit to receive chemotherapy for reasons of age, 
concomitant morbidities and/or residual toxicity from previous treatments. Contraindications 
to chemotherapy were added, as well as an appendix on Cumulative Illness Rating Scale for 
Geriatrics (CIRS-G). Based on this criterion the stratification factors were also updated (see 
Section 13.1.1.4). Rationale: patients considered unfit for chemotherapy for reasons of 
comorbidities, residual toxicity, or advanced age may respond less well to study treatment.
To adjust to the new patient profile the following changes were made to inclusion criteria:

Laboratory entry criteria were changed: amylase and serum creatinine were removed 
from the inclusion criteria, and entry values for hemoglobin and ANC were decreased 
(hemoglobin from 9 g/dL to 8 g/dL, ANC from 1,500 mm3 to 1,000 mm3). 

Criterion for left ventricular ejection fraction was specified to be no less than 45%. 
Consequently, the following changes were made in other protocol sections:

Dose modification in the event of NIP was adjusted, as well as text related to NIP in 
prohibited medications section, and a separate chapter was added, for patients who are 
unfit to receive chemotherapy.

One more MUGA/echocardiogram test was added for patients with LVEF below lower 
level of normal for the institution, with flexibility regarding the time point (any time 
between 5 hours after the first dose and before the next administration).
In addition, the inclusion criteria were changed as follows:

The possibility for the second evaluation of GFR was added, if it is not on target at the 
first screening, and either MDRD or 24-hour sampling can be used to fulfill the 
inclusion criterion. This was added because GFR can be more accurately calculated by 
comparative measurements of creatinine in blood and urine than by using a formula
and to give a chance for reevaluation of the patient.

Eligibility threshold of platelet and neutrophil counts was reduced for patients with 
confirmed lymphomatous bone marrow infiltration (≥ 50,000 /mm3 and ≥ 750/mm3 for 
platelet and neutrophil counts, respectively). Therefore, laboratory test criteria for 
Days 1, 8 and 15 of subsequent cycles were updated. This change was made because 
in patients whose cytopenias are due to lymphomatous bone marrow infiltration as 
histologically proven during screening, the benefit from treatment is expected to 
exceed the risk of drug-induced marrow depletion.


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Sections affected by this modification: Synopsis, 1.1 Background, 1.2 Rationale for the 
study, 1.3 Benefit-risk assessment, 2 Study objectives, 4 Study design, 5.1.1 Inclusion 
criteria, 5.1.3 Justification of selection criteria, 6.4 Dosage and administration, 6.4.1.1
Hematological toxicity, 6.4.1.2 Non-hematological toxicity, 6.4.2.6 Special considerations 
for patients unfit for chemotherapy, 6.9.1 Prohibited concomitant therapy, 7.1.1 Tabulated 
overview, 7.1.2.1 Screening period, 7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 – Treatment –
Cycle 2 and higher, 7.1.2.4 End-of-treatment visit, 7.2.2 Medical history, 8.6
Determination of sample size, 12 Reference list, 14.6 Glomerular filtration rate and
Appendix 14.7 (appendix added).
13.1.1.2
Modification 2 – exclusion criteria updated
To adjust to the new patient profile the following changes were made to the exclusion criteria:

Criterion “renal failure requiring hemo- or peritoneal dialysis” was removed. 

More exceptions were added to the following exclusion criteria: previous or 
concurrent cancer (asymptomatic prostate cancer without known metastatic disease) 
and unresolved toxicity higher than CTCAE Grade 1 (peripheral neuropathy and bone 
marrow parameters). 

Cut-off time period for excluded myeloid growth factors and blood or platelet 
transfusion was changed from 14 days to 7 days before the start of treatment 
After consultation with regulatory authorities prior exposure to PI3K inhibitors was removed 
as an exclusion criterion, and documented progression to PI3K inhibitors was added instead
(patients pre-exposed, but not resistant, to PI3K inhibitors, can be accrued to the study). 
Consequently, prior treatment with PI3K inhibitor was added as a new stratification factor 
(see Section 13.1.1.4).
Definition of rituximab refractoriness was replaced by a condition excluding patients whose 
last rituximab infusion was within 12 months of the start of the next treatment, and, for 
patients unfit to receive chemotherapy – within 6 months after the last rituximab-containing 
regimen. This change was done because many patients are most often referred after relapse, 
and regional centers do not have access to the imaging examinations checking the progression 
within 6 months of the last course of rituximab-containing regimen. A long-term response 
with rituximab is used instead, verifying that rituximab is an active agent against the selected 
disease.
Patients who show evidence of progression since last treatment were exempt of the required 
minimum time for the following criteria:

Treatment with investigational drugs other than PI3K inhibitors less than 28 days 
before start of treatment

Radiotherapy or immuno-/chemotherapy less than 4 weeks before start of treatment

Radioimmunotherapy or autologous transplant less than 3 months before start of 
treatment
This was done to allow accrual of patients in whom the effect of previous treatment can safely 
be excluded and because evidence of progression brings urgency to the treatment of this 
elderly population.
Sections affected by this modification: Synopsis, 5.1.1 Inclusion criteria, 5.1.2 Exclusion 
criteria and 7.2.2 Medical history.


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13.1.1.3
Modification 3 – target population for efficacy analysis changed
Following advice received by regulatory authorities, the study target population for efficacy 
analysis was changed from iNHL patients to FL patients, with a possibility to also recruit 
other iNHL patients. However, the study will be powered for FL patients. Consequently, the 
number of PFS events and the number of patients were re-calculated, with patients divided 
into FL subgroup and other iNHL group. 
Likewise, the confirmatory statistical test strategy was revised to include separate tests in the 
FL subgroup and total population, respectively. In accordance with the target population of FL 
patients, the study-wise alpha is initially split with 80% to the primary analysis in the FL 
subgroup. Furthermore, any potential alpha propagation is initially done within the FL 
subgroup or from the total population to the FL subgroup as well. 
Sections affected by this modification: Synopsis, 4 Study design, 8.4.1 Population 
characteristics, 8.4.2 Efficacy, 8.6 Determination of sample size and 12 Reference list.
13.1.1.4
Modification 4 – randomization ratio and stratification changed
Randomization ratio was changed from 1:1 to 2:1. Stratification factors were changed to 
comprise iNHL histology (FL histology vs. other iNHL histology), newly added inclusion 
criterion (treatment-free interval after rituximab treatment vs. contraindication for 
chemotherapy), presence of bulky disease (yes vs. no) and prior exposure to PI3K inhibitors.
FLIPI score and time between the last therapy and the most frequent progression were
removed as stratification factors. Rationale: randomization was changed to 2:1 in order to 
increase the patients’ odds of being randomized to the study treatment arm, and to increase the 
level of experience with the study drug. Stratification was changed because histology, 
patient’s profile as defined by the entry criteria and bulky disease could influence the 
magnitude of the effect of treatment. The FLIPI prognostic score was deleted at the suggestion 
of FDA because the usefulness of the FLIPI score in patients who have had multiple relapses 
to balance randomization is not known. 
Sections affected by this modification: Synopsis, 4 Study design, 6.3 Treatment assignment,
7.2.2 Medical history, 8.4.2 Efficacy and 8.6 Determination of sample size.
13.1.1.5
Modification 5 – time to improvement in DRS-P added as secondary 
efficacy variable
Because of a change in the patient population, time to improvement in disease-related 
symptoms - physical (DRS-P) was added as an additional secondary efficacy variable, to be 
measured for patients with a baseline DRS-P score of 30 points or less (i.e. patients who still 
have room for improvement in symptoms). Consequently, study objectives and fixed sequence 
test hierarchy were updated.
Sections affected by this modification: Synopsis, 2 Study objectives, 7.6.2 Quality of life 
questionnaire, 8.3.1.2 Secondary efficacy variables and 8.4.2 Efficacy.
13.1.1.6
Modification 6 – subgroup analyses added
In accordance with the EMA draft guideline on the investigation of subgroups in confirmatory 
clinical trials, a section describing a pre-defined region definition, as well as briefly describing 
subgroup analyses for regions and other subgroups (e.g. based on stratification factors and 
other baseline characteristics), was added to the protocol. 


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Section affected by this modification: 8.4.3 Subgroup analyses.
13.1.1.7
Modification 7 – patient enrollment and DMC review of safety data
changed
After the 30th randomized patient has completed the first cycle treatment, enrollment will not 
be stopped. Data Monitoring Committee will review the safety data of all patients treated up 
to that time point. 
Rationale: If no safety-relevant events occur in the first 30 patients treated, there will not be 
any need to stop accrual. If such an event occurs, accrual will be stopped anyway.
Sections affected by this modification: Synopsis, 4 Study design.
13.1.1.8
Modification 8 – language on informed consent, re-screening and re-
testing revised
Wording related to the re-consent of the re-screened patients was corrected. Text about 
screening was updated to clarify which test results can be accepted even if performed as part 
of routine practice provided that they fall into the protocol-specified time window and the 
patient has given informed consent to use them.
Sections affected by this modification: Synopsis, 4 Study design, 5.1.1 Inclusion criteria, 5.2.1
Withdrawal, 7.1.1 Tabulated overview and 7.1.2.1 Screening period.
13.1.1.9
Modification 9 – language on study drug reconstitution modified
The volume of copanlisib and placebo solution was removed and reference to the Pharmacy 
manual was added instead, to avoid discrepancies between the protocol and the Pharmacy 
Manual.
Sections affected by this modification: 6.4 Dosage and administration.
13.1.1.10
Modification 10 – guidelines on management of hyperglycemia
updated
Recommendations regarding management of hyperglycemia were changed in order to 
simplify and harmonize guidance between planned clinical studies. Modifications are based 
on review of the latest data on Phase I studies and Phase II study 16349 (part A). These 
modifications include changes in patient’s fasting requirements and subsequent modifications 
on glucose measurement time points on Cycle 1 Day 1 as these time points are tailored based 
on fasting. It is considered safe and beneficial to shorten the time-interval of both fasting 
requirements and blood glucose assessments.
Guidance for home blood glucose monitoring for non-diabetic patients on Cycle 1 Day 1 was 
harmonized with guidance in place for days of infusion from Cycle 1 Day 8 onwards. 
Therefore only those non-diabetic patients will be required to monitor their blood glucose at 
home who develop hyperglycemia > 250 mg/dL or require insulin administration. 
In addition, diary was added to record home glucose measurement and insulin administration, 
if applicable.
Sections affected by this modification: 5.2.1.1 Withdrawal of study treatment, 6.4 Dosage and 
administration, 6.4.2.1 Management of hyperglycemia that can occur with copanlisib, 7.1.1
Tabulated overview, 7.1.2.2.1 Treatment – Cycle 1 and 7.1.2.2.2 Cycle 2 and higher.


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13.1.1.11
Modification 11 – laboratory evaluations revised
HDL measurement was removed from the complete chemistry panel; only total cholesterol 
and LDL cholesterol will be checked following recommendations of Busaidy et al.(31).
Turbidity was removed from urinalysis, GFR calculation was added to Day 1 of Cycle 2 and 
higher.
Sections affected by this modification: 7.1.1 Tabulated overview, 7.1.2.1 Screening period
and 7.5.3.1 Laboratory.
13.1.1.12
Modification 12 – blood pressure and ECG measurements revised
Number of blood pressure measurements on Cycle 1 Day 1 was reduced, because safety data 
from part A of study 16349 showed that there was no substantial amount of patients with new 
onset of Grade 3 hypertension after 3 hours of monitoring on Cycle 1 Day 1. Therefore, 
monitoring at 30 minutes, 1 hour, 2 hours and 3 hours after the start of copanlisib infusion on 
Cycle 1 Day 1 is comparable to 6 hours monitoring to detect at least one Grade 3 event.
ECG measurement timing was changed to be performed within 28 days of Cycle 1 Day 1 
(instead of 14 days) and on Cycle 1 Day 1. Measurement on Day 15 of every third cycle was 
removed (tests on Day 1 of every third cycle and EOT remained unchanged). This was done 
to monitor patients’ ECG parameters.
The required position for the patient before blood pressure and ECG measurement was 
changed from “lying down” to “rest” as being more common in clinical practice. 
Sections affected by this modification: 7.1.1 Tabulated overview, 7.1.2.1 Screening period, 
7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and higher, 7.5.3.3 Vital signs 
and 7.5.3.4 12-lead ECG.
13.1.1.13
Modification 13 – tumor assessments clarified
Starting time point for tumor assessment was added for clarity (Cycle 1 Day 1), as well as 
tumor assessments guidance for WM patients. Oral contrast agent for radiological tumor 
assessment was added to IV contrast for consistency with the Imaging Manual. Footnote 
explaining the reason for performing MRI instead of CT in Germany was deleted as being too 
specific to be described in a protocol.
Sections affected by this modification: Synopsis, 4 Study design, 7.1.1 Tabulated overview,
7.1.2.1 Screening period, 7.1.2.3 Tumor assessments, 7.1.2.4 End-of-treatment visit, 7.3.2
Radiological tumor assessments, 7.3.3 Tumor assessments in patients with WM (added) and 
8.3.1 Efficacy variables.
13.1.1.14
Modification 14 – completion of PRO information sheet clarified
Responsible persons for completing the PRO information sheet (nurse/investigator) were 
replaced by “study personnel” to allow more flexibility.
Section affected by this modification: 7.6.2 Quality of Life questionnaire.
13.1.1.15
Modification 15 – blinding details removed
Detailed information about the measures to preserve the blinding was removed because it will 
be described in the Pharmacy Manual.
Section affected by this modification: 6.5 Blinding.


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13.1.1.16
Modification 16 – collection of biomarker and PK samples revised
Requirements about collection of tumor tissue were specified further to make sure the best 
material is received if available but at the same time not to restrict patients from participating 
in the study if sufficient sample is not available for biomarkers (tumor tissue for central 
pathology review is still mandatory). Timing of plasma collection for tumor genetics and non-
genetic biomarker analysis was changed to only be performed at Cycles 1, 2 (non-genetic 
sample only), and end-of-treatment visit, i.e. sampling on Day 1 of subsequent cycles was 
removed. 
PK sampling on Day 15 of Cycle 2 and higher was removed. The number of required samples 
on Day 8 of Cycle 1 was decreased to three samples.
This was done to reduce the burden on the patients and the sites, and to reduce the overall 
number of samples to be shipped and processed.
Sections affected by this modification: 4 Study design, 7.1.1 Tabulated overview, 7.1.2.2.2
Treatment – Cycle 2 and higher,7.1.2.4 End-of-treatment visit, 7.4.1 Sampling and 7.6.1
Biomarker investigations
13.1.1.17 Modification 17 – tumor response criteria udpated
Criteria for assessing tumor response were updated following the most recent publication by 
Cheson (27); assessment of response and disease progression will be done according to the 
Lugano Classification. According to the new criteria organomegaly is only defined by CT 
imaging therefore splenomegaly/hepatomegaly will no longer be checked at physical 
examinations. Ann Arbor terminology will no longer use suffixes A and B for symptoms 
related to NHL (they will only be included for Hodgkin Lymphomas), therefore B symptoms 
will not be collected. The change in CT-based criteria resulted in an updated table for tumor 
response definitions (Appendix 14.4). However, even though PET CT was formally 
incorporated into standard staging for FDG-avid lymphomas, the current study will only use 
CT scan for response assessment (see Section 7.7). Criteria for assessing tumor response in 
WM patients were also updated.
Sections affected by this modification: Synopsis, List of abbreviations, Definition of terms, 4
Study design, 5.1.1 Inclusion criteria, 5.2.1.1 Withdrawal of study treatment, 7.1.1 Tabulated 
overview, 7.1.2.1 Screening period, 7.1.2.2.2 Treatment – Cycle 2 and higher, 7.1.2.3 Tumor 
assessments, 7.1.2.4 End-of-treatment visit, 7.3.2 Radiological tumor assessments, 7.5.3.2
Physical examinations, 7.7 Appropriateness of procedures / measurements, 8.3.1.2 Secondary 
efficacy variables, 12 Reference list and 14.4 Evaluation of tumor response.
13.1.1.18 Modification 18 – copanlisib clinical experience udpated
Data related to study 16349 (part A) were updated based on the most recent clinical study 
report. Wording regarding population PK analysis was updated accordingly.
Section affected by this modification: 1.1.2 Clinical experience.
13.1.1.19
Modification 19 – administrative information udpated
Study medical expert changed therefore the contact details were updated. Contact details of 
another coordinating co-investigator were added. The study received an abbreviated name 
CHRONOS-3 that was added to the study title.
Sections affected by this modification: Title page, 3 Investigator and other study personnel


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13.1.1.20 Modification 20 – other clarifications and corrections
In addition to the modifications specified above there have been minor corrections for better 
clarity and consistency.
Sections affected by this modification: Synopsis, 1.1 Background, 1.3 Benefit-risk 
assessment, 2 Study objectives, 3 Investigator and other study personnel, 4 Study design, 
5.2.1.1 Withdrawal of study treatment, 5.3 Patient identification, 6.1 Treatments to be 
administered, 6.2 Identity of investigational medicinal products, 6.4.1 Dose modification, 
6.4.1.1 Hematological toxicity, 6.4.1.2 Non-hematological toxicity, 6.4.2.1 Management of 
hyperglycemia that can occur with copanlisib, 6.4.2.5 Treatment of dermatologic toxicity,
6.9.1 Prohibited concomitant therapy, 7.1.1 Tabulated overview, 7.1.2.2.1 Treatment –
Cycle 1, 7.1.2.5 Follow-up periods (added), 7.1.2.5.1 Safety follow-up, 7.1.2.5.3 Survival 
follow-up, 7.3.2 Radiological tumor assessments, 7.4.1 Sampling, 7.4.2 Analysis, 7.5.1.1
Definitions, 7.5.3.1 Laboratory, 7.6.3 Electronic patient-reported outcomes evaluation, 8.1
General considerations, 8.3.1.2 Secondary efficacy variables, 10 Premature termination of the 
study and 14.6 Glomerular filtration rate.
13.1.2
Changes to the protocol text 
Changes to the protocol text done in Amendment 1 are provided in Section 13.1.2 of 
Amendment 1.
13.2
Amendment 6
Amendment 6 is dated 18 FEB 2016.
13.2.1
Overview of changes
13.2.1.1
Modification 1 – update of clinical experience with copanlisib
Introductory information on patients treated with copanlisib was updated based on most recent 
data. In addition, the results from copanlisib studies 12871 and 16349 part A were updated.
Section affected by this modification: 1.1.2 Clinical experience
13.2.1.2
Modification 2 – previous exposure to alkylating agents removed
Mandatory exposure to alkylating agents was removed since only the assessment of rituximab 
effectiveness is evaluated by the inclusion/exclusion criteria of this protocol and the 
mandatory use of alkylating agents could potentially exclude part of the population who is 
considered unfit for chemotherapy.
Sections affected by this modification: Synopsis, 1.2 Rationale for the study, 2 Study 
objectives, 5.1.1 Inclusion criteria, 8.4.2.1 Primary efficacy analysis
13.2.1.3
Modification 3 – clarification of inclusion criterion related to WM 
patients
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 x 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.
Sections affected by this modification: Synopsis, 5.1.1 Inclusion criteria


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13.2.1.4
Modification 4 – 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 ≤ 1.5 x ULN. The modification was done because previous language 
(INR ≤ 1.5 x 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: 5.1.1 Inclusion criteria and 7.5.3.1 Laboratory
13.2.1.5
Modification 5 – modification of contraception and pregnancy testing
requirements
Text was added in the inclusion criteria to clarify the required time period of contraceptive 
use, to provide a detailed description of effective contraception and to provide definition of a 
woman of childbearing potential (WOCBP) and a post-menopausal state. 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. 
Serum pregnancy test was added to be performed at the EOT visit in countries where it is 
required by local regulations. The list of specific countries where pregnancy test is mandatory 
after Cycle 1 was removed to avoid confusion and to present a general statement applicable to 
all countries with such a requirement.
These changes were made according to recommendations related to contraception and 
pregnancy testing in clinical trials by the Clinical Trial Facilitating Group.
Sections affected by this modification: 5.1.1 Inclusion criteria, 7.1.1 Tabulated overview, 
7.1.2.2.2 Treatment – Cycle 2 and higher, 7.1.2.4 End-of-treatment visit.
13.2.1.6
Modification 6 – clarification of the requirements for baseline 
laboratory analyses
Inclusion criteria related to adequate baseline laboratory values were modified to clarify that 
platelet transfusion, packed red blood cells or erythropoietin; and myeloid growth factors 
should not be given less than 7 days before the exam collection for platelet count, hemoglobin 
and ANC, respectively. The use of these treatments could act as confounding factors in order 
to establish evidence of minimal bone marrow function, hence the limitation of treatment 
period providing an improved assessment.
Section affected by this modification: 5.1.1 Inclusion criteria
13.2.1.7
Modification 7 – modification of conditions for rituximab use and 
alignment of time frame reference
Progression of disease after the last rituximab infusion within defined time period before next 
treatment was added as an exclusion condition to ensure that rituximab had been previously 
proven to be beneficial to the target population. For patients considered unfit to receive 
chemotherapy the timeframe reference was also realigned to match that of the overall 
population.


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Sections affected by this modification: Synopsis, 5.1.2 Exclusion criteria
13.2.1.8
Modification 8 – modification of exclusion criterion related to arterial 
hypertension 
The conservative requirement for blood pressure levels during the evaluation of patient’s 
eligibility was removed due to feedback from the investigators and lymphoma specialists. 
Appropriate blood pressure levels prior to study treatment and available prophylactic 
treatments are considered to be the most important safety points.
Section affected by this modification: 5.1.2 Exclusion criteria
13.2.1.9
Modification 9 – exclusion of patients based on plasma glucose levels 
removed
Exclusion of patients with fasting plasma glucose > 160 mg/dL at Screening was removed to 
implement the advisory board recommendations. 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.
Sections affected by this modification: Synopsis, 5.1.2 Exclusion criteria
13.2.1.10 Modification 10 – prophylaxis for HBV and monitoring of HBV and 
HCV added
Requirement was added that prophylactic antiviral therapy should be given 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, 5.1.2 Exclusion criteria, 5.2.1.1 Withdrawal 
of study treatment, 7.1.1 Tabulated overview, 7.1.2.1, Screening period, 7.5.3.1 Laboratory, 
12 Reference list
13.2.1.11 Modification 11 – 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. 
Following the investigator’s feedback on the study feasibility, the criterion was amended to 
make the patient evaluation more flexible and feasible.
Section affected by this modification: 5.1.2 Exclusion criteria,7.1.1 Tabulated 
overview,7.1.2.1 Screening period,7.5.3.1 Laboratory
13.2.1.12 Modification 12 – 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. 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.


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Sections affected by this modification: 5.1.2 Exclusion criteria and 6.9.1 Prohibited 
concomitant therapy
13.2.1.13 Modification 13 – modification of exclusion criterion related to 
evidence of resistance to PI3K inhibitors
The exclusion criterion was modified since the definition of resistance should be progression
within 6 months starting from the treatment with PI3K inhibitors instead of within 6 months 
from the end of therapy.
Sections affected by this modification: Synopsis, 5.1.2 Exclusion criteria
13.2.1.14 Modification 14 – prior treatment with copanlisib added to the 
exclusion criteria.
Copanlisib was included to the list of prohibited previous therapies and medications. 
Modification was done because prior treatment with copanlisib could jeopardize the clinical 
assessment of the study drug.
Sections affected by this modification: Synopsis, 5.1.2 Exclusion criteria
13.2.1.15 Modification 15 – 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.
Section affected by this modification: 6.2 Identity of investigational medicinal products
13.2.1.16 Modification 16 – updated guidance for glucose increase management 
and monitoring
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 4 symptomatic hyperglycemia or glucose 
intolerance” was revised to align with a new guidance for the transient glucose 
increases management.Appendix 14.8 was added based on the new guidance for the 
transient glucose increases management and to clarify average glycemic index of 
common foods derived from multiple studies by different laboratories.


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Sections affected by this modification: 5.2.1.1 Withdrawal of study treatment, 6.4 Dosage and 
administration, 6.4.1 Dose modification, 6.4.1.2 Non-hematological toxicity, 
6.4.2.1 Management of transient post-infusion glucose increases that can occur with
copanlisib, 6.4.2.6 Special considerations for patients unfit for chemotherapy, 7.1.1 Tabulated 
overview, 7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and higher, 
7.1.2.4 End-of-treatment visit, 7.5.3.7 Glucose measurements on copanlisib/placebo infusion
days, Appendix 14.8 The average glycemic index of common foods derived from multiple 
studies by different laboratories
13.2.1.17 Modification 17 – 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: 6.4.1 Dose modification, 6.4.1.2 Non-hematological 
toxicity, 6.4.2.3 Treatment of blood pressure increases associated with copanlisib, 
7.1.1 Tabulated overview, 7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and 
higher, 7.5.3.3 Vital signs
13.2.1.18 Modification 18 – minimum exposure to rituximab added
The only proven medication to establish an effect on the cancer is rituximab. For ethical 
reasons, it was required that a minimum exposure of 4 doses until Cycle 3 Day 1 (included) is 
mandatory for patients to be able to continue on the study.
Section affected by this modification: 6.4.1 Dose modification
13.2.1.19
Modification 19 – fasting requirement for lipid panels revised
The 11 h fasting requirement before evaluation of 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: 6.4.2.2 Management of hyperlipidemia, 
7.1.1 Tabulated overview, 7.1.2.1 Screening period, 7.1.2.2.2 Treatment – Cycle 2 and higher, 
7.1.2.4 End-of-treatment visit, 7.5.3.1 Laboratory
13.2.1.20 Modification 20 – 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, after the first complete response if the baseline sample was 
positive, and for suspicion of progressive disease restricted to bone marrow infiltration 
without radiological findings; assuring that central pathology review confirms the disease
response status.
Sections affected by this modification: Synopsis, 4 Study design, 7.1.1 Tabulated overview, 
7.1.2.1 Screening period, 7.1.2.3 Tumor assessments


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13.2.1.21 Modification 21 – clarification of tumor response language
The language related to radiological tumor assessments was modified to clarify the process for 
central review that the evaluation of tumor response will be done retrospectively only for 
those patients who did not experience PD.
Modifications were also done to harmonize the language across the protocol and with other 
copanlisib protocols, e.g. language regarding tumor assessment in patients with WM was 
clarified. 
In general, CT/MRI needs to be performed with IV 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.
Table for the CT and/or MRI response assessment criteria was also clarified:

Original wording from the Lugano Classification 2014 (27) was inserted to the column 
“bone marrow” for PD.

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 (27). The total value of increase is also 
in line with the total increase required for the bigger lesions, i.e. lesions > 2 cm.

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.

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.
Sections affected by this modification: Synopsis, 4 Study design, 7.1.1 Tabulated overview,
7.3.2 Radiological tumor assessments,7.3.3 Tumor assessments in patients with WM,
14.4 Evaluation of tumor response
Modification 22 – 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 
itraconazole (a strong CYP 3A4 inhibitor) only increased copanlisib exposure by 1.42 fold.
Sections affected by this modification: 6.4.2.3 Treatment of blood pressure increases 
associated with copanlisib
13.2.1.23 Modification 23 – PK sampling time modified
The possible PK sampling time for copanlisib/placebo was changed from Cycle 2 to Cycle 3 
in case the sampling is not feasible on Cycle 1. The wording was added that also sampling for 
rituximab can be done on Cycle 3 if not feasible at Cycle 1.
The modification was done to be able to characterize the PK of copanlisib when 
coadministered with rituximab and there is no rituximab administration on Cycle 2.
Section affected by this modification: 7.4.1 Sampling


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13.2.1.24 Modification 24 – clarification of SAE reporting language
The language regarding reporting of SAEs that occur after the protocol-defined observation 
was modified to meet the current regulations.
Section affected by this modification: 7.5.1.4 Reporting of serious adverse events
13.2.1.25
Modification 25 – language related to hemoglobin A1c measurements 
clarified
It was clarified in the protocol that test for HbA1c is not required at the EOT visit if the 
previous test was performed within 4 weeks preceding EOT visit. The rationale for this 
change was to implement the consideration of erythrocyte lifecycle. 
HbA1c was added to the list of laboratory evaluations in further safety section for consistency.
Sections affected by this modification: 7.1.1 Tabulated overview, 7.1.2.4 End-of-treatment 
visit, 7.5.3.1 Laboratory
13.2.1.26 Modification 26 – assessment of hydration status added
Language on clinical assessment of hydration status was included to be part of complete and 
brief physical examinations. This change was made to emphasize the importance to check a 
hydration status during patient physical examination.
Sections affected by this modification: 7.5.3.2.1 Complete physical examination and 
7.5.3.2.2 Brief physical examination
13.2.1.27 Modification 27 – paper PRO questionnaire removed
The possibility to use paper PRO surveys was removed since only electronic devices will be 
used in this study. If electronic device is not available at the site, or technical problems 
prevent it from working properly, the PRO questionnaire will not be completed at that visit.
Section affected by this modification: 7.6.3 Electronic patient-reported outcomes evaluation
13.2.1.28 Modification 28 – 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. Patient information and 
content section was updated based on current protocol template text.
Sections affected by this modification: 5.2.1.1 Withdrawal of study treatment, 11.2 Patient 
information and consent
13.2.1.29 Modification 29 – administrative change
The sponsor’s medically responsible person was changed.
Section affected by this modification: Signature of the sponsor’s medically responsible 
person.
13.2.1.30 Modification 30 – other clarifications and corrections
In addition to the modifications specified above there have been minor corrections for better 
clarity and consistency.


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
The clarification was made that the study drug is to be administered in an approximate 
timeframe of 1 h to allow for a little time window. The change was done following the 
feedback from the investigators.

It was clarified that the laboratory test results can be assessed by the investigator 
and/or appropriate site personnel before administration of study drug.

The symbol “≥” was added to dosing criteria section to clarify that dosing criteria 
apply to neutrophil count decreased, platelet count decreased and anemia of CTCAE 
grade ≥3, not only for events of CTCAE grade 3.

A footnote was added to Table 6–4 clarifying that treatment with transfusion or growth 
factors is allowed at the investigator’s discretion.

Table 6–5 was clarified to harmonize the language with other dose modification tables.

Cyclosporin was removed from the list of permitted concomitant medications since the 
protocol prohibits concomitant therapy with immunosuppressive agents.

PRO information sheet was added to Table 7–1 for clarification.

Brief physical examination was removed from tabulated overview (Day 22 of Cycle 2 
and higher) for consistency.

Reference to PK section was added to Table 7–2.

Clarification was made in the screening period section that procedures need to be 
performed within x days before start of study treatment instead of less than x days.
Sections affected by this modification: 6.4 Dosage and administration, 6.4.1.1 Hematological 
toxicity, 6.4.1.2 Non-hematological toxicity, 6.9.2 Permitted concomitant therapy, 
7.1.1 Tabulated overview, 7.1.2.1 Screening period
13.2.2
Changes to the protocol text
Changes to the protocol text done in Amendment 6 are provided in Section 13.2.2 of 
Amendment 6.
13.3
Amendment 7
Amendment 7 is dated 28 JUL 2016. 
13.3.1
Overview of changes
13.3.1.1
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.


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Section affected by this modification: 1.1.2 Clinical experience
13.3.1.2
Modification 2 – modification of inclusion criteria

Definition of relapse was clarified. In addition a clarification was added that patients 
with prior intolerance to PI3K inhibitors are eligible although patients with resistance 
to PI3K inhibitors are not.

It was clarified that chemotherapy is contraindicated also in patients who are unwilling 
to be treated with chemotherapy.
Section affected by these modifications: Synopsis, 5.1.1 Inclusion criteria
13.3.1.3
Modification 3 – modification of exclusion criteria

Language on exclusion after rituximab therapy was modified to ensure that the last 
assessment of rituximab therapy was proven to be beneficial for the subjects; this 
change also clarifies the timeframe for the conditions to be verified.

Exclusion criterion regarding HbA1c levels in patients with diabetes mellitus was 
changed. It was clarified that the HbA1c >8.5% level concerns all patients at 
screening, not only patients with diabetes mellitus.

The exclusion criterion related to evidence of resistance to PI3K inhibitors was 
corrected. The proposed definition is a more appropriate definition of resistance to 
PI3K inhibitors and aligned with the program language

See Modification 7 for exclusion of patients with cytomegalovirus (CMV) infection.
Sections affected by these modifications: Synopsis, 5.1.2 Exclusion criteria
13.3.1.4
Modification 4 – change of extended period for 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: 6.3 Treatment assignment, 7.1.1 Tabulated overview, 
7.1.2.2.1 Treatment – Cycle 1


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13.3.1.5
Modification 5 – 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 ≥500/mm3 for Day 8 and 15. 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 6–4 “Dose 
modification of copanlisib/placebo for hematological toxicity” was also modified accordingly.
Sections affected by this modification: 6.4 Dosage and administration, 6.4.1.1 Hematological 
toxicity
13.3.1.6
Modification 6 – guidance for management of toxicities added
Guidance in Table 6–4 “Dose modification of copanlisib/placebo for hematological toxicity” 
was updated: reference to patients with lymphomatous bone marrow infiltration was removed 
due to the new lowered ANC threshold (500 from 1000). INR and PTT ranges are clarified 
since they are not mentioned in Table 6–2.
Sections affected by this modification: 6.4 Dosage and administration, 6.4.1.1 Hematological 
toxicity
13.3.1.7
Modification 7 – addition of guidance for monitoring and prophylaxis 
of opportunistic infections (OI)
Following Health Authority alerts related to safety issues with Zydelig (idelalisib, a PI3K 
inhibitor) treatment in clinical trials, Section 6.4.2.7 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.
The guidance includes additional CD4, CD8, CMV and blood culture laboratory tests, and 
lung examinations to be monitored during study treatment in patients who are at risk of 
development of infections. Schedule of procedures were modified to be consistent with the OI 
guidance.
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. Reactivation means 
that acute infection needs treatment. Patients with chronic infection could be eligible as long 
as they do not exhibit symptoms of acute infection which should be confirmed by negative 
CMV PCR test at baseline.
These criteria were modified to avoid worsening of CMV infection in patients with active 
CMV and to harmonize the protocol with other copanlisib studies.
Sections affected by this modification: Synopsis, 5.1.2 Exclusion criteria, 5.2.1.1 Withdrawal 
of study treatment, 6.4.1.2 Non-hematological toxicity, 6.4.2.7 Guidance for monitoring and 
prophylaxis of opportunistic infection, 7.1.1 Tabulated overview, 7.1.2.1 Screening period, 
7.1.2.2 Treatment period, 7.1.2.2.1 Treatment Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and 
higher, 7.5.3.1 Laboratory, 7.5.3.2.1 Complete physical examination, 7.5.3.2.2 Brief physical 
examination


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13.3.1.8
Modification 8 – reference to patient’s paper blood glucose tracking 
diary was added
Reference to patient’s paper blood glucose tracking diary instructions was added to give 
guidance for glucose monitoring at home. The definition of glucose goal values was deleted 
since it is disclosed in the aforementioned document.
Section affected by this modification: 6.4.2.1 Management of transient post-infusion glucose 
increases that can occur with copanlisib
13.3.1.9
Modification 9 – clarification on procedure schedule
This modification clarifies when the ECG shall be measured on the days of rituximab 
infusion.
Section affected by this modification: 7.1.1 Tabulated overview
13.3.1.10 Modification 10 – change in agenda of procedures
The time for diagnostic procedure was increased to allow more flexibility for the sites and 
patients to collect diagnostic exams for patients with LPL/WM or WM and FL.
Sections affected by this modification: 7.1.1 Tabulated overview, 7.1.2.1 Screening period
13.3.1.11 Modification 11 – 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. A safety follow-up visit may occur 30 days 
(window of +5 days is allowed) after last treatment.
Sections affected by this modification: 4 Study design, 7.1.1 Tabulated overview, 7.1.2.5.1
Safety Follow-up, 7.5.1.3 Assessments and documentation of adverse events, 8.3.2 Safety 
variables
13.3.1.12 Modification 12 – clarification of language regarding ePRO devices
Language regarding the ePRO devices was modified for clarification.
Sections affected by this modification: 7.6.3 Electronic patient-reported outcomes evaluation
13.3.1.13 Modification 13 – clarification for prohibited concomitant therapy
The clarification for use of short-term systemic corticosteroids above 15 mg prednisolone or 
equivalent will be allowed prior to for radiological contrast infusion.
Section affected by this modification: 6.9.1 Prohibited concomitant therapy
13.3.1.14 Modification 14 - other clarifications and corrections

Due to sponsor name change, sponsor information and sponsor logo were changed.

Text was modified in Section 7.5.3.1 “Laboratory” and in Table 7–1 footnote “j” to 
allow site to provide differential blood count in percentage when absolute count is not 
available per standard of care of the local lab.

It was clarified in Section 5.2.1.1 “Withdrawal of study treatment” that patients must 
(not may) be withdrawn from the study at the specific request of the sponsor and in 
liaison with the investigator.


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
The dose modification guidance for the management of Hypertension of grade 3 was 
clarified in Table 6–8. If subjects developed grade 3 hypertension during infusion, it 
was clarified that study drug infusion may be resumed immediately when blood 
pressure has returned to < 150/90 mmHg, otherwise this dose will be skipped.

Minor modifications regarding verapamil and diltiazem use were added to Section 
6.9.2“Permitted concomitant therapy” to be consistent with Section 6.4.2.3 “Treatment 
of blood pressure increases associated with copanlisib”
Sections affected: Title page, 5.2.1.1 Withdrawal of study treatment, 6.4.1.2 Non-
hematological toxicity, 6.9.2Permitted concomitant therapy, 7.1.1Tabulated overview, 
7.5.3.1 Laboratory
13.3.2
Changes to the protocol text
Changes to the protocol text done in Amendment 7 are provided in Section 13.3.2 of 
Amendment 7.
13.4
Amendment 9
Amendment 9 is dated 02 FEB 2018. 
13.4.1
Overview of changes
13.4.1.1
Modification 1 – 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 567 patients to 450 patients and primary efficacy analysis 
will be performed in the FAS instead of both FAS and FL subgroup. 
Based on more updated site information, the recruitment ramp up period was increased from 
6 months to 29 months and the dropout rate was increased from 20% to 30%.
In addition, minor clarifications were done in the statistical sections. The language regarding 
deaths that are related to PD was transferred from Section 8.3.1 to Section 8.3.1.2 since it is 
only applicable for the secondary efficacy variable “time to progression”. Also, the definition 
of PFS was further clarified and the reference related to minimum number of PFS events was 
included in Section 8.4.2.
Sections affected by this modification: Synopsis, 4 Study design , 8.3.1 Efficacy variables, 
8.3.1.2 Secondary efficacy variables, 8.4.1 Population characteristics, 8.4.2 Efficacy, 
8.4.2.1 Primary efficacy analysis, 8.4.2.2 Secondary efficacy analysis, 8.4.2.3 Confirmatory 
statistical test strategy (section removed), 8.4.2.4 Other efficacy evaluations, 8.4.3 Subgroup 
analyses, 8.4.4 Safety analyses, 8.6 Determination of sample size, 12 Reference list
13.4.1.2
Modification 2 – clarifications/modifications of inclusion criteria
Although introduced changes do not alter the essence of the protocol, some modifications 
were considered necessary to improve clarity of the protocol procedures. 
Inclusion criterion 2 was clarified to provide less chance for misinterpretation. The definition 
of SLL was also adjusted to utilize more updated diagnostic definition of the pathology as 
well defining the requirements only for study entry. 


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Inclusion criterion 3 was modified to clarify that the requirement is applied for the last line of 
rituximab-containing therapy ensuring that the treatment was effective. Regarding the 
definition of a previous regimen, the specific requirement for rituximab monotherapy was 
included to ensure the alignment with the current clinical practice.
Inclusion criterion 4 was clarified. A footnote describing the minimum values for measurable 
disease according to the Lugano Classification was added. The requirement for splenic MZL 
was also clarified 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.
It was added that archival tumor tissue was to be obtained within 5 years of the consent date 
in inclusion criterion 9. The modification was done for further clarification.
Inclusion criterion 13 was adjusted to be consistent with exclusion criterion 4. In addition, 
following wording was harmonized throughout the protocol since there were minor variations 
although the meaning was the same: progression-free and treatment-free interval of 
≥12 months after completion of the last rituximab containing treatment.
Sections affected by the modification: Synopsis, 1.2 Rationale for the study, 4 Study design, 
5.1.1 Inclusion criteria, 6.3 Treatment assignment, 8.4.2.1 Primary efficacy analysis, 
8.6 Determination of sample size
13.4.1.3
Modification 3 – clarifications/modifications of exclusion criteria
The requirement of “histologically confirmed diagnosis” was removed from exclusion 
criterion 3. A suspicion of FL grade 3b or transformed disease, or chronic lymphocytic 
leukemia should preclude the enrolment to the study. If confirmation is required, there is a 
potential risk of enrolling this unwarranted population.
For exclusion criterion 4, see Modification 13.4.1.4.
A reference to inclusion criterion 2 was added to exclusion criterion 5 to further clarify 
indolent B-cell NHL histologies that are allowed in the study.
Based on drug-drug interaction data, it was clarified that the use of strong inducers of 
CYP3A4 is prohibited (exclusion criterion 39). See also Modification 13.4.1.9.
Sections affected by the modification: Synopsis, 5.1.2 Exclusion criteria 
13.4.1.4
Modification 4 – clarification of stratification factors related to entry 
criteria
The definition of stratification factor related to entry criteria was adjusted according to the 
clarification of inclusion criterion 13 (see Modification 13.4.1.2). Since inclusion criterion 13 
was modified to be consistent with exclusion criterion 4, following wording was also 
harmonized in the definition of the entry criteria stratification factor: progression-free and 
treatment-free interval of ≥ 12 months after completion of the last rituximab containing 
treatment.
The patients considered unwilling/unfit to receive chemotherapy were bundled to differentiate 
them in a subgroup different from the long-term responders (i.e. progression-free and 


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treatment-free interval of ≥ 12 months after completion of the last rituximab containing 
treatment). In case a patient fulfills both entry criteria the preferential assignment should be 
for the group labeled as “unwilling/unfit to receive chemotherapy” providing a resolution to a 
possible impasse.
In addition, all applicable protocol sections were updated to clarify that patients may be 
unwilling or unfit to receive chemotherapy. 
Sections affected by the modification: Synopsis, 1.2 Rationale for the study, 2 Study 
objectives, 4 Study design, 5.1.2 Exclusion criteria, 6.3 Treatment assignment, 
8.4.2.1 Primary efficacy analysis, 8.6 Determination of sample size
13.4.1.5
Modification 5 – 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 (at the lowest study drug 
dose level) for persistent occurrence of post-infusion blood glucose was modified from 
> 400 mg/dL to > 500 mg/dL. 
The language related to meal timing on infusion days was revised. Based on available safety 
data, fasting status has no significant clinical impact on post-infusion blood glucose. 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 language was changed to allow 
investigator to determine if home glucose monitoring is needed 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 site compliance. 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/demonstrate that 
HbA1C elevations revert to baseline after stopping copanlisib.
Sections affected by this modification: 5.2.1 Withdrawal, 5.2.1.1 Withdrawal of study 
treatment, 6.4 Dosage and administration, 6.4.1.2 Non-hematological toxicity, 
6.4.2.1 Management of transient post-infusion glucose increases that can occur with 
copanlisib, 7.1.1 Tabulated overview, 7.1.2.1 Screening period, 7.1.2.2.1 Treatment – Cycle 1, 
7.1.2.2.2 Treatment –  Cycle 2 and higher, 7.1.2.5 Follow-up periods, 7.5.3.7 Glucose 
measurement on copanlisib/placebo infusion days, 12 Reference list, 14.8 The average 
glycemic index of common foods derived from multiple studies by different laboratories 
(section removed)
13.4.1.6
Modification 6 – modification of the monitoring guidelines for OI
To facilitate the patient adherence to the protocol requirements, the blood test schedule for 
CMV was modified. The tests were aligned with study treatment schedule and visits (i.e. 


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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 a suggestion and should be 
addressed by the standard of care followed by the institution.
Sections affected by the modification: 6.4.2.7.1 Monitoring guidelines for OI, 7.1.1 Tabulated 
overview, 7.1.2.2 Treatment period
13.4.1.7
Modification 7 – updated guidance for blood pressure measurements 
on infusion days
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.
Sections affected by this modification: 7.1.1 Tabulated overview, 7.1.2.2.1 Treatment –
Cycle 1, 7.1.2.2.2 Treatment – Cycle 2 and higher, 7.5.3.3 Vital signs
13.4.1.8
Modification 8 – clarification of bone marrow assessments
It was clarified that bone marrow biopsy should be evaluated first locally and the surplus 
material, if available, should be provided to central pathology review. The text was aligned 
with other copanlisib protocols.
Protocol was also modified to remind about the need for bone marrow evaluation for those 
patients who had previous lymphoma in the bone marrow.
Sections affected by the modification: Synopsis, 4 Study design, 7.1.1 Tabulated overview, 
7.1.2.1 Screening period, 7.1.2.3 Tumor assessments, 7.1.2.5.2 Active follow-up
13.4.1.9
Modification 9 – changes based on drug-drug interaction data
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.
The list of strong CYP3A4 inhibitors and inducers was updated and it was further clarified 
that the use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 is not permitted.
To be aligned at the project-level, the guidance text for the use of substrates of the renal drug 
transporter MATE2K was included to the protocol.
Sections affected by this modification: 5.1.2 Exclusion criteria, 6.4.2.3 Treatment of blood 
pressure increases associated with copanlisib, 6.9.1 Prohibited concomitant therapy, 
6.9.2 Permitted concomitant therapy, 12 Reference list, 14.1 CYP3A4 inhibitors and inducers


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13.4.1.10 Modification 10 – introduction of dose interval for rituximab 
Due to differences between different body surface area calculation methods the final 
rituximab dose may present variation. To acknowledge these differences, which are not 
medically significant, an interval was granted.
Sections affected by the modification: 6.4 Dosage and administration
13.4.1.11
Modification 11 – clarifications of the tumor assessment/response 
evaluation
The response criteria in patients affected by WM were clarified: “lowest nadir” was changed 
to “nadir confirmed by a repeat assessment” since nadir is already the definition of the lowest 
point and the assessment must be confirmed.
Sections affected by the modification: 14.4 Evaluation of tumor response
13.4.1.12 Modification 12 – clarification of PK sampling and analysis
It was clarified that PK sampling should be done on the corresponding days with the matched 
medication if samples are collected at Cycle 3 (rituximab infusion is performed on Day 1 of 
Cycle 3).
It was also clarified that a population pharmacokinetic analysis will be reported in a 
standalone report.
Sections affected by the modification: 7.4.1 Sampling, 7.4.2 Analysis 
13.4.1.13 Modification 13 – clarification of QoL questionnaire schedule
The timing of the completion of FLymSI-18 questionnaire was further clarified. The 
questionnaire should be completed at the visits where it is scheduled to be completed i.e. 
during the treatment period, the questionnaire is completed at the start of the infusion day and 
not during visits on previous days.
Sections affected by the modification: 7.1.2.2.1 Treatment – Cycle 1, 7.1.2.2.2 Treatment –
Cycle 2 and higher, 7.6.2 Quality of life questionnaire
13.4.1.14 Modification 14 – administrative changes
The sponsor’s medically responsible person was changed as a result of study personnel 
change.
The Coordinating Co-Investigator was changed. 
Sections affected by this modification: Signature of the sponsor’s medically responsible 
person, 3 Investigator and other study personnel


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13.4.1.15 Modification 15 – other clarifications and corrections

The term “unblinded monitor” was changed to “independent monitor” in Section 6.5
Blinding

Oudated recommendation (a fresh biopsy is recommended in patients with clinical 
suspicion of transformed disease) was deleted from Synopsis since this 
recommendation had been removed from the main protocol already in Amendment 1.

The way changes are indicated throughout the protocol body was updated for better 
readability. Instead of indicating all changes separately in the protocol text, a general 
statement and a cross-reference to the respective amendment section was included to 
each amended section.
13.4.2
Changes to the protocol text
Changes to the protocol text done in Amendment 9 are provided in a separate track changes 
version.
13.5
Amendment 10
13.5.1
Overview of changes
Amendment 10 is dated 08 OCT 2019. 
Section(s)
Description of change
Rationale
4 Study design
8.4.2 Efficacy
8.6 Determination of sample size
12 Reference list
The statistical assumptions for 
the primary efficacy analysis of 
PFS were modified. The 
required number of PFS events 
was changed from 288 to 190.
A recent study (AUGMENT, 51) 
has reported a hazard ratio of 
0.46 (95% CI 0.34-0.62) for 
PFS and median PFS of 14.1 
months in Rituximab + Placebo 
arm in the indication of second 
line iNHL. Based on the results 
from this study, it was decided 
to update the sample size 
justification
Synopsis
8.4.2.1 Primary efficacy analysis
8.4.2.2 Secondary efficacy 
parameters
8.4.2.3 Confirmatory statistical 
test strategy 
The confirmatory testing 
hierarchy was modified to 
include a sequential test of PFS 
in the overall iNHL population, 
PFS in the combined FL and 
MZL population, ORR in the 
combined FL and MZL 
population, PFS in the SLL 
population, DRS-P 
deterioration and DRS-P 
improvement in the combined 
FL and MZL population.

FL + MZL are the most 
common types of indolent 
non-Hodgkins lymphomas.

Rituximab-based treatment 
is standard for both FL and 
MZL lymphomas.

FL + MZL are responsive to 
PI3K inhibition.
Combination of both 
lymphomas into one 
analysis cohort would 
increase the statistical 
power of the result.
Synopsis
Definitions of terms
5.1.1 Inclusion criteria
The protocol was modified to 
allow prior anticancer therapies 
with rituximab biosimilars, 
and/or anti-CD20 monoclonal 
The change was done 
considering the current iNHL 
treatment landscape and 
following the investigator’s 


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5.1.2 Exclusion criteria
antibody (e.g. obinutuzumab).
feedback.
Synopsis
4 Study design
7.1.1 Tabulated overview
7.1.2.3 Tumor assessments  
7.3.2 Radiological tumor 
assessments
The language related to the 
schedule of radiological tumor 
assessments was modified.
To allow the collection of tumor 
imaging data for beyond 3 
years since patients may 
continue in the study for more 
than 3 years.
Synopsis
4 Study design
7.3.2 Radiological tumor 
assessments
It was clarified that radiological 
real-time confirmation of 
disease progression will only 
be performed until the 
database cut-off for the primary 
analysis. 
To allow retrospective reading 
of the scans after the primary 
completion.
6.9.1 Prohibited concomitant 
therapy
The use of biotin was 
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 
produces high levels of the 
vitamin, these can interfere with 
the result of the immunoassay 
test.
Synopsis
4 Study design
5.1.1 Inclusion criteria
7.1.1 Tabulated overview
7.4.1 Sampling
7.6.1 Biomarker investigations
It was clarified that PK and 
biomarker samplings are not 
applicable to sites who cannot 
obtain approval by competent 
Health Authority.
To add flexibility for the sample 
availability from China due to 
the limitation from CHGRAO.
5.2.1.1 Withdrawal of study 
treatment
6.4.1.2 Non-hematological toxicity
NIP of any grade is no longer a 
withdrawal criterion, only 
grade ≥3 (or recurrent grade 2).
Actions to be taken regarding 
the AESI NIP were updated to 
reflect the approved label and 
to align with other program 
protocols.
Title page
Signature of the sponsor’s 
medically responsible person
3 Investigator and other study 
personnel
Sponsor’s medical expert and 
medically responsible person 
were changed.
Administrative change.
13.1.2, 13.2.2 and 13.3.2
Changes to the protocol text
The detailed old vs. new text 
comparisons for protocol 
amendments 1, 6 and 7 were 
replaced with a reference to the 
respective protocol 
amendment.
To improve readability, and to 
reduce complexity of the 
protocol.
13.5.2
Changes to the protocol text
Changes to the protocol text done in Amendment 10 are provided in a separate track changes 
version.


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13.6
Amendment 11
13.6.1
Overview of changes
Amendment 11 is dated 22 MAY 2020.
Section(s)
Description of change
Rationale
4. Study design
8.4.2 Efficacy
8.6 Determination of 
sample size
Text for time point of primary analyses 
was slightly revised for more flexibility.
A minimum of 190 events in 
iNHL population is needed. 
However, by the time of 
database lock, there will be 
more than 190 events 
expected. The study power of 
the results increases with the 
number of events. If the study
is closed with at least 190 PFS 
events, there is no negative 
impact on study outcome.
2. Synopsis
8.4.2.1 Primary efficacy 
analysis
Stratification factors “bulky disease 
[yes vs. no]” and “previous treatment 
with PI3K inhibitors [yes vs. no]” are
removed in the statistical analysis 
In order to avoid a too low 
number of events, only 
stratification factors “NHL 
history” and “entry criterion” 
will be adjusted at the same 
time in the statistical analyses.
2. Synopsis
8.4.2.2 Secondary 
efficacy parameters
8.4.2.3 Confirmatory 
statistical test strategy
The testing of PFS in SLL population is 
removed from the confirmatory 
statistical test strategy for the United 
States.
The treatment effect may not 
be detected due to the small 
sample size in SLL.
2. Synopsis
8.4.2.3 Confirmatory 
statistical test strategy
A separate confirmatory statistical test 
strategy for Europe is added.
To maximize the study power, 
all statistical tests will be 
conducted in the FAS 
population. 
8.4.2.3 Confirmatory 
statistical test strategy
8.6 Determination of 
sample size
Power estimation is updated based on 
blinded study information using 
Schoenfeld’s formula
To confirm the study has 
enough power to reject null 
hypothesis for the testing of 
primary efficacy endpoint and 
key secondary efficacy 
endpoints. 
2. Synopsis
4. Study design
6.8 Post-study therapy
The option for patients currently 
receiving treatment in this study to 
continue treatment in a roll-over study 
was added.
To enable patients receiving 
copanlisib treatment in the 
current study to continue to 
receive copanlisib treatment 
when the study is completed.
Title page
Signature of the 
sponsor’s medically 
responsible person
The signature of the Sponsor’s 
medically responsible person was 
removed from the clinical study 
protocol.
Administrative change of 
Bayer process
Editorial changes and clarifications


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13.6.2
Changes to the protocol text
Changes to the protocol text done in Amendment 11 are provided in a separate track changes 
version.


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14.
Appendices
14.1
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, troleoandomycin, 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: 41, 48, 49 and 50.


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14.2
ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-diseases performance without restriction. 
(Karnofsky 90-100)
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). 
(Karnofsky 70-80)
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. (Karnofsky 50-60)
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. (Karnofsky 30-40)
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. (Karnofsky 10-20)
14.3
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 (42)


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14.4
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 (27).
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 not 
assessable:
IHC negative
PR
Decrease ≥ 50% in the SPD 
from baseline
All normal
or stable
Spleen must have 
regressed by 50% in extent 
beyond normal at baseline 
(=value over 13 cm)
No
Not relevant
Stable 
disease
• Decrease < 50% in the 
SPD from baseline
• No criteria for PD
All normal 
or stable
Normal size or
stable size
No
Not relevant
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 = disease progression; PPD = 
product of perpendicular diameters; PR = partial response; SDi = shortest diameter; SPD = sum of the product of the 
diameters
* If LDi ≤ 2 cm 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. 


Clinical Study Protocol Global Amendment 11
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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 sings/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 sings/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 sings/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 sings/symptoms of active disease
Progressive 
Disease
≥ 25% increase in serum IgM level from nadir confirmed by a repeat assessment (an 
absolute value increase 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
Source: Adapted from Owen RG et al, 2013 (35)


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14.5 Quality of life questionnaire: FLymSI-18
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days.
Not 
at all
A 
little 
bit
Some-
what
Quite
a bit
Very 
much
GP1
I have a lack of energy
0
1
2
3
4
GP4
I have pain
0
1
2
3
4
C2
I am losing weight
0
1
2
3
4
Leu1
I am bothered by lumps or swelling in certain 
parts of my body (e.g., neck, armpits, or groin)
0
1
2
3
4
BMT6
I get tired easily
0
1
2
3
4
BP1
I have bone pain
0
1
2
3
4
HI8
I have trouble concentrating
0
1
2
3
4
GF5
I am sleeping well
0
1
2
3
4
C6
I have a good appetite
0
1
2
3
4
GE6
I worry that my condition will get worse
0
1
2
3
4
BR
M9
I have emotional ups and downs
0
1
2
3
4
Leu4
Because of my illness, I have difficulty planning 
for the future
0
1
2
3
4
Leu5
I feel uncertain about my future health
0
1
2
3
4
GP2
I have nausea
0
1
2
3
4
N3
I worry about getting infections
0
1
2
3
4
GP5
I am bothered by side effects of treatment
0
1
2
3
4
GF3
I am able to enjoy life
0
1
2
3
4
GF7
I am content with the quality of my life right now
0
1
2
3
4
DRS-P = disease-related symptoms subscale – physical; DRS-E = disease-related symptoms 
subscale – Emotional; TSE = treatment side effects subscale; FWB = function and well-being subscale
D
R
S-
P
T
S
E
F
W
B
D
R
S-
E


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14.6
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, 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 x 186 x SCR-1.154 x 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 < 30 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 acceptable range, it may be used to fulfill the inclusion criteria instead.
For further information on assessing renal function using GFR estimates, see references 43, 44
and 45.


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14.7
Cumulative Illness Rating Scale for Geriatrics (CIRS-G)
Scoring Sheet
CUMULATIVE ILLNESS RATING SCALE FOR GERIATRICS (CIRS-G)
Miller, Paradis, and Reynolds 1991
PATIENT______________________________________________________AGE_________
RATER________________________________________________________AGE_________
Instructions: Please refer to the CIRS-G Manual. Write brief descriptions of the medical problem(s)
that justified the endorsed score on the line following each item. (Use the reverse side for more
writing space).
RATING STRATEGY
0 - No Problem
1 - Current mild problem or past significant problem
2 - Moderate disability or morbidity/requires "first line" therapy
3 – Severe/constant significant disability / “Uncontrollable” chronic problems
4 - Extremely Severe/immediate treatment required/end organ failure/severe impairment in function
SCORE
HEART....................................................................................................................
VASCULAR........................................................................................................... 
HEMATOPOIETIC............................................................................................... 
RESPIRATORY...................................................................................................... 
EYES, EARS, NOSE AND THROAT AND LARYNX........................................
UPPER GI................................................................................................................. 
LOWER GI.............................................................................................................. 
LIVER....................................................................................................................... 
RENAL..................................................................................................................... 
GENITOURINARY................................................................................................. 
MUSCULOSKELETAL/INTEGUMENT............................................................. 
NEUROLOGICAL................................................................................................... 
ENDOCRINE/METABOLIC AND BREAST....................................................... 
PSYCHIATRIC ILLNESS.......................................................................................
TOTAL NUMBER CATEGORIES ENDORSED………………………………._______
TOTAL SCORE........................................................................................................_______ 
Severity Index: (total score/total number of categories endorsed)......................_______
Number of categories at level 3 severity.................................................................._______ 
Number of categories at level 4 severity.................................................................._______
Source: (28), GI = Gastrointestinal


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Page: 144 of 144
14.8
The average glycemic index of common foods derived from multiple studies 
by different laboratories section removed
Appendix removed by amendment 9.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan  
Official Title: 
A Phase III, randomized, double-blind, placebo-controlled study 
evaluating the efficacy and safety of copanlisib in combination 
with rituximab in patients with relapsed indolent B-cell non-
Hodgkin’s lymphoma (iNHL) – CHRONOS-3 
NCT Number: 
NCT02367040 
Document Date: 
26-AUG-2020 
 
 
 


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 17067
Page: 1 of 55
Title page
A Phase III, randomized, double-blind, placebo-controlled study 
evaluating the efficacy and safety of copanlisib in combination with 
rituximab in patients with relapsed indolent B-cell non-Hodgkin’s 
lymphoma (iNHL) – CHRONOS -3
Copanlisib and rituximab in relapsed iNHL
Bayer study drug
BAY 80-6946 / Copanlisib
Study purpose:
Efficacy and safety (Quality of Life and biomarker)
Clinical study 
phase:
III
Date:
26 AUG 2020
Study No.:
17067
Version:
6.0
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
Protocol No.: BAY 80-6946 / 17067
Page: 2 of 55
Table of Contents
Title page....................................................................................................................................1
Table of Contents......................................................................................................................2
List of Abbreviations ................................................................................................................5
1.
Introduction........................................................................................................................7
2.
Study Objectives ................................................................................................................8
3.
Study Design.......................................................................................................................9
4.
General Statistical Considerations.................................................................................11
4.1
General Principles ..........................................................................................................11
4.2
Handling of Dropouts.....................................................................................................11
4.3
Handling of Missing Data ..............................................................................................12
4.3.1
Time-to-event variables ..............................................................................................12
4.3.2
Response rates.............................................................................................................12
4.3.3
Patient-Reported Outcomes Questionnaire.................................................................12
4.4
Interim Analyses and Data Monitoring ..........................................................................13
4.5
Sample size justification for primary efficacy test on PFS in the total study population14
4.6
Data Rules ......................................................................................................................15
4.6.1
Time intervals..............................................................................................................15
4.6.2
Baseline.......................................................................................................................15
4.6.3
Repeated measures......................................................................................................16
4.6.4
Overall extent of exposure ..........................................................................................16
4.6.5
Stratification................................................................................................................16
4.6.6
Region .........................................................................................................................17
4.6.7
As treated ....................................................................................................................18
4.7
Validity Review..............................................................................................................18
5.
Analysis Sets.....................................................................................................................18
5.1
Assignment of analysis sets............................................................................................18
6.
Statistical Methodology ...................................................................................................18
6.1
Population characteristics...............................................................................................18
6.1.1
Disposition ..................................................................................................................19
6.1.2
Demographics and other baseline characteristics .......................................................19
6.1.3
Medical history............................................................................................................20
6.1.4
Prior and concomitant medication ..............................................................................21
6.1.5
Treatment duration and exposure................................................................................21
6.2
Efficacy...........................................................................................................................22
6.2.1
Primary Efficacy Variable Progression-Free Survival................................................23
6.2.2
Secondary Efficacy Variables .....................................................................................28
6.2.3
Confirmatory statistical test strategy...........................................................................33
6.2.4
Other Efficacy Variables.............................................................................................35
6.2.5
Subgroup Analyses......................................................................................................36
6.2.5.1
Histology specific subgroup analysis.......................................................................36
6.2.5.2
Other subgroup analyses..........................................................................................37
6.3
Safety..............................................................................................................................38
6.3.1
Adverse Events (AEs).................................................................................................38


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 17067
Page: 3 of 55
6.3.2
Adverse events by time-interval..................................................................................40
6.3.3
Non-infectious Pneumonitis/Interstitial lung disease..................................................40
6.3.4
COVID-19 relevant adverse events ............................................................................41
6.3.5
Pregnancies .................................................................................................................41
6.3.6
Clinical Laboratory Parameters...................................................................................41
6.3.7
Further Safety Parameters...........................................................................................42
6.3.7.1
Hyperglycemia.........................................................................................................42
6.3.7.2
Electrocardiogram (ECG) ........................................................................................43
6.3.7.3
Vital Signs................................................................................................................43
6.3.7.4
Echocardiogram .......................................................................................................43
6.3.7.5
Hypertension............................................................................................................43
6.4
Pharmacokinetics/pharmacodynamics ...........................................................................43
6.5
Biomarker evaluation .....................................................................................................44
7.
Document history and changes in the planned statistical analysis..............................44
7.1
Document history ...........................................................................................................44
7.2
Changes in the planned statistical analysis.....................................................................44
7.2.1
Changes from the SAP V1.0 .......................................................................................44
7.2.2
Changes from the SAP V2.0 .......................................................................................46
7.2.3
Changes from the SAP V3.0 .......................................................................................46
7.2.4
Changes from the SAP V4.0 .......................................................................................47
7.2.5
Changes from the SAP V5.0 .......................................................................................48
8.
References.........................................................................................................................48
9.
Appendix...........................................................................................................................50
9.1
Scoring Instruction for FLymSI-18................................................................................50
9.2
Patient Reported Outcomes ............................................................................................53
9.3
PFS Rules .......................................................................................................................53
9.3.1
Progression and PD after Two or More Consecutive Missed tumor assessments ......53
9.3.2
Death ...........................................................................................................................54
9.3.3
Subjects with New Anti-Cancer Therapy ...................................................................54
9.3.4
Subjects Discontinued or Withdrew............................................................................54
9.4
Imputation rule for Initial Diagnosis Date and Progression Date ..................................55
Table of Tables
Table 2–1: Overview of Efficacy Objectives and Variables ......................................................8
Table 4–1: Required number of PFS events per entry criteria stratum.....................................14
Table 4–2: Stratum per randomization number ........................................................................17
Table 6–1: Progression-free survival (PFS) censoring rules ....................................................24
Table 6–2: Entry Criteria Stratum and Exclusions ...................................................................27
Table 6–3: Progression-free survival (PFS) censoring rules for sensitivity analysis (any 
change considered as a progression event) ............................................................28
Table 6–4: DRS-P deterioration censoring rules ......................................................................30
Table 6–5: DRS-P improvement censoring rules .....................................................................31
Table 6–6: Assessment of Statistical Power for PFS Test in the Overall FAS Population and 
Combined FL and MZL Population.......................................................................33
Table 6–7: Overview of Histology Specific Subgroup Analyses .............................................36


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 17067
Page: 4 of 55
Table of Figures
Figure 6–1: Confirmatory Test Strategy Based on Five Test Families for United States ........34
Figure 6–2: Confirmatory Test Strategy Based on Four Test Families for Europe..................35


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 17067
Page: 5 of 55
List of Abbreviations
AE
Adverse event
AKT
Protein kinase B
ATC
Anatomical Therapeutic Chemical
AUC
Area under the curve
BMI
Body mass index
BSA
Body Surface Area
CHOP
Cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone
CI
Confidence interval
CSP
Clinical study protocol
CR
Complete response
CRF
Case Report Form
CRR
Complete tumor response rate
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria Adverse Event
CVP
Cyclophosphamide, vincristine, prednisolone
DMC
Data Monitoring Committee
DOR
Duration of response
DRS-E
Disease-related symptoms - emotional
DRS-P
Disease-related symptoms – physical
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
FLymSI-18
NCCN-FACT Lymphoma Symptom Index-18 Questionnaire
FWB
Function and well-being
GCP
Good Clinical Practice
h
Hour(s)
H0
Null hypothesis
H1
Alternative hypothesis
HbA1c
Glycated hemoglobin
ID
Identifier
i.e.
That is (id est)
IgM
Immunoglobulin M
ImpDRSP
Improvement in disease-related symptoms - physical
iNHL
indolent non-Hodgkin’s lymphoma
IRC
Independent review committee
ITT
Intention-to-treat
IV
Intravenous
IxRS
Interactive Voice/Web Response System
kg
Kilogram
LKAD
Last known alive date
LPL
Lymphoplasmacytic lymphoma
m
Meter
M-1
Metabolite 1
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minutes
MR
Minor response
MRI
Magnetic resonance imaging
mTOR
Mammalian target of rapamycin
MUGA
Multiple gated acquisition


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 17067
Page: 6 of 55
MZL
Marginal-zone lymphoma
NCCN-FACT
National Comprehensive Cancer Network – Functional Assessment of Cancer
NCI
National Cancer Institute
NE
Non-evaluable
NHL
Non-Hodgkin's lymphoma
NYHA
New York Heart Association
OEE
Overall extent of exposure
ORR
Objective tumor response rate
OS
Overall survival
PBMQ
Product-specific Bayer Medical Queries
PD
Progressive disease
PFS
Progression-free survival
PI3K
Phosphatidylinositol 3-kinase
PK
Pharmacokinetics
PT
Preferred Term
PR
Partial response
SAC
Statistical Analysis Center
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SLL
Small lymphocytic lymphoma
SOC
Primary System Organ Class
TEAE
Treatment-emergent adverse event
TSE
Treatment side-effect
TTP
Time to progression
US, USA
United States (of America)
VGPR
Very good partial response
VRM
Validity Review Meeting
VRR
Validity Review Report
vs.
As opposed to (versus)
WHO-DD
World Health Organization - Drug Dictionary
WM
Waldenström macroglobulinemia


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 17067
Page: 7 of 55
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 be generally 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 indolent NHL is controversial because of low cure 
rates with the current therapeutic options.  The first-line standard therapy includes rituximab, 
usually administered together with cytotoxic combinations (CHOP, CVP) or single agents 
(alkylators, e.g. bendamustine, or purine nucleoside analogs such as fludarabine or 2-
chlorodeoxyadenosine). 
There is no acknowledged standard treatment for patients with recurrent disease. As long as 
disease appears to be responsive to rituximab (treatment-free intervals of > 6 months after the 
previous rituximab-containing treatment), a rituximab-based chemoimmunotherapy using 
non-cross resistant cytotoxic agents would be administered at the next relapse.
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].
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/AKT/mTOR pathway is one of the prominent pathways that promote cellular survival 
and constitutively is activated in many types of cancers [9,10].
Considering the pre-clinical profile of copanlisib and the promising preliminary efficacy data 
from the Phase I study 12871 and the ongoing Phase II study 16349, it is expected that in 
comparison to rituximab with placebo, copanlisib in combination with rituximab will 
lengthen progression-free survival (PFS) in patients with relapsed iNHL who have received 
one or more lines of treatment, including rituximab and who either had a treatment-free 
interval of ≥ 12 months after completion of the last rituximab-containing treatment, or are 
considered unwilling to receive chemotherapy/for whom chemotherapy is contraindicated. 
This Statistical Analysis Plan (SAP) is based on the integrated clinical study protocol (CSP
Amendment 11, version 7.0, dated 22 MAY 2020) and describes the primary analysis of 
study 17067 to be included in the clinical study report (CSR).


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 17067
Page: 8 of 55
2.
Study Objectives
The primary objective of this study is:

To evaluate whether copanlisib in combination with rituximab is superior to placebo 
in combination with rituximab in prolonging PFS in patients with relapsed iNHL who 
have received one or more lines of treatment, including rituximab, and who either had 
a treatment-free interval of ≥ 12 months after completion of the last rituximab-
containing treatment, or who are unwilling to receive chemotherapy/ for whom 
chemotherapy is contraindicated on reason of age, comorbidities, and/or residual 
toxicity
The secondary objectives of this study are to evaluate:

The following characteristics of disease-related physical symptoms (DRS-P): 'time to 
deterioration' and 'time to improvement'

Other radiological and clinical indicators of treatment efficacy (ORR, DOR, CRR, 
TTP, and OS)

Safety and tolerability of copanlisib
The other objectives of this study are to evaluate:

Pharmacokinetics

Biomarkers

Quality of life
Table 2–1 gives an overview of the primary and secondary efficacy objectives and the 
relevant variables to be analyzed.
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 tumor response rate (ORR)*,
described in Section 6.2.2
Secondary objective:
Characteristics of disease-related 
physical symptoms
Time to deterioration in DRS-P of at least 3 points*,
Time to improvement in DRS-P of at least 3 points*,
described in Section 6.2.2


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Table 2–1: Overview of Efficacy Objectives and Variables
Objective
Variable
Secondary objective: 
Other radiological and clinical indicators
Duration of response (DOR),
Disease control rate (DCR),
Complete response rate (CRR),
Time to progression (TTP),
Overall survival (OS),
described in Section 6.2.2
*Variable is part of the confirmatory testing strategy (see Section 6.2.3)
For the analyses of primary efficacy endpoint and key secondary efficacy endpoints, separate 
test strategies will be used for the United States and Europe (see Section 6.2.3). 
3.
Study Design
This is a randomized, double-blind, placebo-controlled, two-arm, Phase III study to evaluate 
efficacy and safety of copanlisib in combination with rituximab, in comparison to placebo in 
combination with rituximab, in patients with relapsed iNHL.
Approximately 450 (including follicular lymphoma (FL) and other iNHL) patients who meet 
the eligibility criteria will be randomly assigned in a 2:1 ratio to one of the double blinded 
treatment arms: copanlisib plus rituximab or placebo plus rituximab.  Patients will be 
stratified according to four factors based on baseline characteristics:
iNHL histology:

FL histology

Other iNHL histology (Small lymphocytic lymphoma (SLL), Marginal-zone 
lymphoma (MZL), Lymphoplasmacytic lymphoma (LPL)/Waldenström 
macroglobulinemia (WM)) 
Entry criterion:

progression-free and treatment-free interval of ≥ 12 months following completion of 
the last rituximab- containing treatment 

considered unwilling/unfit to receive chemotherapy 
Presence of bulky disease (as defined by the presence of a nodal or extranodal mass ≥ 7 cm in 
the longest diameter, with the exception of spleen):

yes

no
Previous treatment with PI3K inhibitors:

yes

no


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Resulting from the combination of these four stratification factors, patients will be 
randomized into 16 different strata (see Table 4–2).  The stratification factor 'entry criterion' 
is an abbreviation of the inclusion criterion 13 from the integrated CSP Amendment 10. The 
exact definition from the inclusion criterion should be used to assess which entry criterion is 
fulfilled.  If the patient fulfills both entry criteria, patients will be stratified into the criterion 
“considered unwilling/unfit to receive chemotherapy for age or comorbidities”.
The study is composed of the following periods:

Screening

Treatment

Safety follow-up / Active follow-up

Survival follow-up
The start of the screening period is defined by signing of the informed consent form.  The 
maximum interval allowed between signature of informed consent and start of treatment is 
28 days. The start of the treatment period is defined by the first administration of study 
treatment.
Copanlisib and placebo for copanlisib formulations are administered before rituximab, in a 
normal saline solution, intravenous (IV), over 1 hour.  Dosing is weekly for the first 3 weeks 
of a 28-day cycle (on Days 1, 8, and 15), followed by a 1-week break (i.e., no infusion on 
Day 22).
Rituximab will be given IV at 375 mg/m2 body surface weekly during Cycle 1 (on Days 1, 8, 
15 and 22). For those patients who are still on treatment after evaluation at the end of 
Cycle 2, rituximab will be administered once in each of Cycles 3, 5, 7 and 9 (on Day 1).
Treatment with copanlisib or placebo will be continued until the occurrence of progressive 
disease (PD; per central independent blinded radiology review) as defined in the Lugano 
Classification [11] (for patients with WM according to the Owen Criteria [12]), unacceptable 
toxicity, or until another criterion is met for withdrawal from the study treatment (as 
described in protocol Section 5.2.1.1).  Rituximab treatment will be continued until the same 
criteria as defined for copanlisib are met, for a maximum of 8 infusions (until Cycle 9).
An end-of-treatment (EOT) visit will be performed no later than 7 days after the decision is 
made to discontinue study treatment.  Patients who discontinue study treatment because of 
PD will enter the Safety-follow up period and patients who 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 object to follow-up data collection.  The patients in the 
Active follow-up will have tumor assessments by central independent blinded review 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-monthly intervals during the 
Survival follow-up period (up to 3 years after the last patient started study treatment), except 
for patients who object to follow-up data collection.  During this period, patients are not 
considered to be 'on-study'.
The first radiological tumor assessments with IV contrast-enhanced computed 
tomography/magnetic resonance imaging (CT/MRI) scans of neck, chest, abdomen and pelvis 


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will be performed at Screening (including WM patients).  During the treatment period as well 
as during the Active follow up period tumor assessments with the same modality will be 
performed every 8 weeks (± 7 days) during Year 1, every 12 weeks (± 7 days) during Year 2, 
and every 24 weeks (± 7 days) during Year 3 and onwards, starting from Cycle 1 Day 1. 
CT/MRI scans are not required at the EOT visit if the patient discontinues due to PD, which 
has been radiologically confirmed within the 4 weeks preceding EOT. 
The response assessment will be done according to the Lugano Classification, and, for 
patients with WM, according to the Owen Criteria.  In the event of progression, radiological 
real-time confirmation by central independent blinded evaluation is required before a final 
decision to stop the treatment is made. Radiological real-time confirmation will only be 
conducted until the database cut-off for the primary analysis. The final evaluation of 
treatment response (best response: objective tumor response rate and complete response rate) 
will be done by central blinded review retrospectively.
All efficacy analyses will be performed when at least 190 centrally evaluated PFS events are 
observed in the study.  Evaluations from central blinded review will be used for the primary 
efficacy analyses of primary and secondary endpoints containing radiological tumor 
assessments.
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 Genomics and Biomarker Statistical Expert and PK experts. 
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA).  All variables will be analyzed by descriptive 
statistical methods.  The number of data available and missing data, mean, standard 
deviation, minimum, quartiles, median, and maximum will be calculated for metric data.  
Frequency tables will be generated for categorical data.
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:  Clinical Copanlisib Project Standards, Oncology Therapeutic Area 
Standards, and Global Medical Standards, respectively.  The order reflects the priority of the 
different standards, where specifications of the latter ones have to be followed only if not 
specified in standards mentioned before.  Study-specific specifications may be included in 
addition to the project standards, if needed.
4.2
Handling of Dropouts
A patient who discontinues study participation prematurely (i.e. prior to disease progression 
confirmed by 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. 
A subject who for any reason terminates the study before randomization is regarded a 
'screening failure'.


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Patients who discontinue study drug due to reasons other than death or PD confirmed by 
central review shall enter the Active follow-up period, except for those who object to follow-
up data collection.  The patients in the Active follow-up shall have follow-up tumor 
assessments until disease progression is documented or new anti-tumor treatment is 
administered, whichever occurs first.  Tumor assessments from the Active follow-up will also 
be used for primary and secondary analyses.
4.3
Handling of Missing Data
In order to achieve a well conducted clinical trial in accordance with Good Clinical Practice 
(GCP), every effort will be made to collect all data.  However, despite best efforts, it may be 
inevitable that missing or incomplete data are reported.  All missing or partial data will be 
presented in the subject data listing as they are recorded on the Case Report Form (CRF).  
Unless specifically specified, missing data will not be carried forward or otherwise imputed 
in any statistical analysis.
The following rules will be implemented where appropriate so as not to exclude patients from 
statistical analyses due to missing or incomplete data.
4.3.1
Time-to-event variables
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.
Missing or non-evaluable tumor observations (including scheduled assessment that was not 
done and incomplete assessment that does not result in an unambiguous tumor response) will 
not be 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 subject 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 such as PFS, OS and TTP, and specific 
handling of missing data for time to event variables refer to Section 6.2.
4.3.2
Response rates
If a patient has no post-baseline tumor assessment available (or no post-baseline 
laboratory/clinical tests available for WM patients without 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 objective tumor 
response rate (ORR) and complete response rate (CRR).
4.3.3
Patient-Reported Outcomes Questionnaire
Physical symptoms of lymphoma are assessed by the NCCN-FACT Lymphoma Symptom 
Index-18 (FLymSI-18) questionnaire. Missing individual items will be handled in accordance 
with the scoring instructions for the FLymSI-18 questionnaire (Appendix 9.1). 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 
actually answered.
When there are missing data, prorating by subscale in this way is acceptable as long as at 
least 50% of the items were answered (e.g., a minimum of 5 of 9 items, 2 of 4 items, etc.). 


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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 
at least 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 disease-related symptoms – physical (DRS-P) of at least 3 points
(See Appendix 9.2): 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 9.2): 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 PD event 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.  
4.4
Interim Analyses and Data Monitoring
No interim analysis is planned for this study before the primary evaluation. However, a Data 
Monitoring Committee (DMC) will be monitoring the safety of the drug combination while 
keeping the sponsor blinded. For more details see DMC discussion below.  
The first analysis of overall survival (OS) will also be performed at the time of primary PFS 
analysis.  The survival status will further be collected quarterly during the survival follow-up 
period up to 3 years after the last patient started study treatment.  Twelve months after 
analysis of the primary and secondary efficacy variables, a further analysis of OS ('follow-up 
OS analysis') will be performed.  This analysis will be an update of the analysis of OS 
performed on data available at the time of analysis of the primary endpoint, PFS.
After the follow-up analysis of OS, it will be determined whether a subsequent final OS
analysis will be required, and the study duration will be adjusted accordingly.  A subsequent 
final OS analysis will be required, if OS data are not yet mature at the time of the follow-up 
analysis.  Mature OS data is available if the estimated median of the time-to OS will not 
change in further follow-up which is the case if no administrative censoring (i.e. no patients 
under risk are censored by the cut-off date) occurs before the estimated median.
A DMC is established for this study that is reviewing study data and providing an 
independent recommendation on the advisability of continuing the study as planned. 
The report for the DMC, including tables, listings, and figures, is generated by an 
independent statistician from a Statistical Analysis Center (SAC).  The format and content of 
these data summaries have been specified separately from this study SAP.
When the first 30 patients were recruited in the blinded study, the probability to have at least 
15 patients in the copanlisib + rituximab arm was greater than 95%.  Based on these 30 
patients, a protocol pre-specified initial assessment of safety of the drug combination was 
performed by the DMC in these patients. The DMC agreed to proceed with the continued 
enrollment. The investigators, patients, and the sponsor remain blinded during the study.  
Further DMC reviews will take place as outlined in the DMC charter.


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Decisions on trial termination, amendment, or cessation of patient recruitment based on the 
risk/benefit assessment will be made after recommendations from the DMC have been 
assessed by the sponsor.
4.5
Sample size justification for primary efficacy test on PFS in the total 
study population
Study AUGMENT [13] reported a hazard ratio of 0.46 (95% CI 0.34-0.62) for PFS and 
median PFS of 14.1 months in the rituximab + placebo arm in the indication of second line 
iNHL. Based on the results from this study, Bayer has decided to update the sample size 
justification.
With at least 190 PFS events (progression based on central review or death if death occurs 
before progression), a randomization ratio of 2:1 between the experimental and control arms, 
a 1-sided alpha of 0.025, a hazard ratio of 0.61 (i.e., median PFS of 23 months for copanlisib
+ rituximab arm and 14 months for placebo + rituximab arm) can be detected with a power of
at least 89%. Based on the planned 450 patients for this study and the observed and projected
recruitment as well as blinded monitoring of event times, the expected study duration to reach 
190 events is 59 months, (with maximum accrual rate being approximately 10 patients per 
month). The rate of dropouts (i.e. lost to survival follow-up or withdrawal of consent before 
their PFS event) is assumed to be 135 (30%) patients over the duration of the study through 
the primary PFS analysis. 
The primary analysis will be performed when at least 190 centrally evaluated PFS events are 
observed in the study.
As an additional criterion, a sufficient number of PFS events has to be observed in each of the 
two strata defined by the inclusion criterion (progression-free and treatment-free interval of 
≥12 months after completion of the last rituximab-containing treatment vs. unwilling/unfit to 
receive chemotherapy) before the study is unblinded for primary evaluation. This especially 
ensures the contribution of events also from patients who have previously shown a good 
response to rituximab.
The required minimum number of PFS events in these strata will depend on the relative 
proportion of patients recruited into the respective cohorts and can be seen from Table 4–1. 
The observed proportions and event numbers will be determined during blind data review 
after the end of recruitment.
Table 4–1: Required number of PFS events per entry criteria stratum
Proportion of patients 
randomized in one 
strata
Required number of 
PFS events
Proportion of patients 
randomized in the 
other strata
Required number of 
PFS events
0% - 5%
no required numbers 
(in both strata)
95% - 100%
no required numbers 
(in both strata)
>5% - 10%
10
90% - <95%
122
>10% - 20%
20
80% - <90%
112
>20% - 30%
33
70% - <80%
99
>30% - 40%
46
60% - <70%
86
>40% - 50%
59
>50% - <60%
73


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As an example: In case 32% of patients would be recruited in the “progression-free and 
treatment-free interval of ≥ 12 months after completion of the last rituximab-containing 
treatment” stratum, then at least 46 PFS events are required in this stratum. In addition, at 
least 86 PFS events from the complement stratum “considered unwilling/unfit to receive 
chemotherapy” are required. To fulfill the overall criterion of at least 190 PFS events, 
approximately 58 additional events from any of the two strata are required.
In case of an extreme proportion of censored/discontinued patients in a stratum that severely 
impacts the relation of "Proportion of recruited patients" ≈ "Proportion of PFS events", the 
study team might decide to deviate from the above rule during blind data review.
The number of PFS events will be monitored in the blinded database throughout the study.  
When the required numbers of events are reached in the FAS population and each of the two 
strata defined by the inclusion criterion (treatment-free interval after rituximab treatment vs. 
contraindication for chemotherapy) the database will be cut and cleaned for analysis.  Data 
reported during cleaning for the time after the data cut will not be considered in the final 
analysis with the exception of any death reported during that time.
4.6
Data Rules
4.6.1
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).
4.6.2
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 medication. 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:

Consider the time part for baseline flagging. EX and LB 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 can’t be 
decided by the above rules, then the measurement taken at scheduled visit will be 
considered as the baseline.


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4.6.3
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 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.  Unscheduled visits will be used, if 
there are no measurements at scheduled visits.  If the latter is the case, the first 
unscheduled visit will be used.
4.6.4
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, the according 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 accounted as an 
interruption'.
Overall extent of exposure (OEE) for copanlisib/placebo or rituximab, respectively, 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
If the respective treatment ends with dose interruptions, the day of the last actual dose will be 
considered to be daylast.
4.6.5
Stratification
In case of discrepancies between stratification factors entered in the interactive voice/web 
response system (IxRS) and information entered in the CRF, the information from IxRS will 
be used for analysis. This especially includes analyses that are performed separately for the 
subgroup of FL subjects, which is based on one of the stratification factors.
The stratification from IxRS will be derived from the subjects' randomization number.  The 
mapping of randomization numbers to strata is summarized in Table 4–2.


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Table 4–2: Stratum per randomization number
Randomization 
Numbers
Stratum
iNHL 
Histology
Entry 
Criterion
Presence of 
bulky disease
Previous treatment 
with PI3Ki
FL 
treatment-free interval
yes
yes
FL
treatment-free interval
yes
no
FL
treatment-free interval
no
yes
FL
treatment-free interval
no
no
FL
unfit for chemotherapy
yes
yes
FL
unfit for chemotherapy
yes
no
FL
unfit for chemotherapy
no
yes
FL
unfit for chemotherapy
no
no
other iNHL
treatment-free interval
yes
yes
other iNHL
treatment-free interval
yes
no
other iNHL
treatment-free interval
no
yes
other iNHL
treatment-free interval
no
no
other iNHL
unfit for chemotherapy
yes
yes
other iNHL
unfit for chemotherapy
yes
no
other iNHL
unfit for chemotherapy
no
yes
other iNHL
unfit for chemotherapy
no
no
iNHL: indolent non-Hodgkin's Lymphoma; FL: Follicular Lymphoma; PI3Ki: Phosphatidylinositol 3-
Kinase Inhibitor; 
treatment-free interval: progression and treatment-free interval following the last rituximab-containing 
treatment ≥ 12 months unfit for chemotherapy: considered unwilling/unfit to receive chemotherapy 
This study is using 16 strata (defined by 4 binary stratification variables) with 450 patients to 
be recruited and including a 2:1 randomization. In order to avoid a too low number of events,
only stratification factors “iNHL histology” and “entry criterion” will be adjusted 
simultaneously in the statistical analyses, e.g., stratified log-rank test, and Cox proportional 
hazard model. 
4.6.6
Region
For demographics overview and subgroup analyses, subjects are grouped together into 
regions. The following regions are defined:
Geographic Regions 1 (as of protocol):

US

Europe (Austria, Belgium, Bulgaria, Germany, Spain, France, Greece, Hungary,
Ireland, Italy, Lithuania, Poland, Portugal, Romania, Slovakia, and Ukraine)

Rest of the world (All other countries)
Geographic Regions 2:

North America (Canada and United States),

Asia Pacific (China, Japan, Korea, Taiwan, Hongkong, Malaysia, Singapore,
Thailand, Vietnam, and Philippines), excluding Australia,
PPD


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
Rest of the world (All other countries).
4.6.7
As treated
An IxRS will be used for drug distribution.  Despite the obligatory use of the IxRS, patients 
may erroneously receive the wrong study medication (i.e. copanlisib instead of placebo or 
vice versa).  For the 'as treated' analyses, using a conservative approach, subjects that have 
received at least one dose of copanlisib will be considered for the copanlisib treatment group.  
Subjects that have received exclusively placebo (and rituximab) and no copanlisib will be 
considered for the placebo treatment group.
4.7
Validity Review
The results of the validity review meeting (VRM) will be documented in the Validity Review 
Report (VRR) and may comprise decisions and details relevant for statistical evaluation.  Any 
changes to the statistical analysis prompted by the results of the validity review meeting 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 subjects to analysis sets will be made during the 
VRM and documented in the VRR (see Section 4.7).
Full analysis set (FAS):  All subjects randomized.
Safety analysis set (SAF):  All FAS subjects with at least one intake of copanlisib/placebo or 
rituximab.
Pharmacokinetics analysis set (PKS):  All subjects with at least one valid pharmacokinetics 
(PK) measurement (i.e. subjects 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.
The FAS will be used for the display of efficacy variables.  Following the intention-to-treat 
(ITT) principle, the analyses will be performed as randomized.  The FAS will also be used to 
display demographics and baseline characteristics.
The SAF will be used for the analyses of safety variables.  The analyses will be performed as 
treated.
In case the SAF and FAS are differing, displays for baseline characteristics and demographics
will be repeated in the SAF.
Patients who signed the informed consent but were not assigned to treatment will be 
considered screening failures.  They will be listed separately.
6.
Statistical Methodology
6.1
Population characteristics
Population characteristics will be summarized by randomized treatment group and overall.  
Unless otherwise specified, analyses will be performed in the FAS and, in case it is differing, 
in the SAF. Patients will be analyzed as randomized for the FAS and as treated for the SAF.


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6.1.1
Disposition
The number of subjects enrolled, randomized, and valid for the different analysis sets FAS, 
SAF will be summarized overall and by treatment group, country.  
The number of subjects discontinuing the screening phase together with the primary reason 
for discontinuation will be presented overall.  The number of subjects discontinuing the 
treatment, safety, active and survival follow-up phases together with the primary reason for 
discontinuation will be presented by treatment group and overall.  
Kaplan-Meier plot for 'Time to end of study treatment' will be provided by treatment group.
In addition, the number of subjects with major, minor, and important protocol deviations will 
be presented overall and by country for treatment group and overall. 
A separate subject listing of protocol deviations related to COVID-19 (e.g., delay of tumor 
assessments, interruption or discontinuation of the treatment due to the impact of COVID-19) 
will be provided. These protocol deviations will be identified from the investigators’ 
specification with “COVID”. 
6.1.2
Demographics and other baseline characteristics
Demographics variables and baseline characteristics will be summarized by treatment group 
and overall.  In addition, summary statistics will be presented for metric variables. Frequency 
tables will be presented for categorical variables.  
Demographic variables include age, gender, race, ethnicity, body weight, body height, body 
mass index (BMI), systolic and diastolic blood pressure, heart rate and temperature.  Age and 
BMI will each be summarized as continuous variable and categorized with the following 
categories:

Age group (years): <80, ≥80

Age group (years): < 65, >=65

Age group (years): < 65, 65-74, 75-84, >=85

BMI group (kg/m²): <18.5, ≥18.5- <30, ≥30
In addition, the four stratification factors as reported on the randomization page in the CRF 
will be summarized.
The following additional baseline characteristics will be analyzed:

Most recent histology of tumor

Most recent staging of tumor at study entry

FL grade (for patients with FL) at study entry

Eastern Cooperative Oncology Group (ECOG) performance status at baseline

Time from initial diagnosis to the date of randomization (months)

Time from most recent progression to the date of randomization (weeks)

Time since first progression to the date of randomization (months)

New York Heart Association (NYHA) classification


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
Baseline tumor size (evaluated as sum of the product of the perpendicular diameters 
of up to 6 target measurable nodes and extranodal sites)

Number of lesions (number of target and non-target lesions) at baseline

Serum IgM level (for WM patients only) at baseline

Estimated Glomerular Filtration Rate (eGFR) at baseline (continuous and 
categorization: eGFR Normal: ≥ 90 vs. Mild: 60 - <90 vs. Moderate: 30 - <60)

HbA1c at baseline (< 5.7% vs. ≥ 5.7% – < 6.5% vs. ≥ 6.5%)

Diabetic History: [PBMQ] Medical history of diabetes (no/yes)

Hypertension History: [PBMQ] Medical history of hypertension (no/yes)

Hepatic function at baseline
o
Normal: Total bilirubin and AST ≤ ULN
o
Mild impairment: Total bilirubin > ULN to 1.5 x ULN and AST any value; or 
Total bilirubin ≤ ULN and AST> ULN 
o
Moderate impairment: Total bilirubin > 1.5 to 3 x ULN and AST any value 

Bilirubin at baseline

Histology group by investigator at baseline (FL, MZL, SLL and LPL/WM)

Reason for treatment allocation
○Progression-free interval of at least 12 months after completion of the last
rituximab-containing treatment
○patients unfit or unwilling to receive chemotherapy

>= 80 years old

< 80 years with at least 3 G3 CIRS-G comorbidities

< 80 years with at least 1 G4 CIRS-G comorbidity

Unwilling to receive chemotherapy

Smoking history
In addition, demographic and other baseline characteristics will be summarized for each 
Histology (FL, MZL, SLL and LPL/WM).
The retrospective evaluation of histopathological diagnosis at baseline will be performed 
centrally. These data are exploratory and will be listed for the CSR addendum.
6.1.3
Medical history
Medical history findings (as defined in protocol Section 7.2.2) 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 treatment 
group and overall.


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6.1.4
Prior and concomitant medication
Prior and concomitant medications will be coded by 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.  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 and otherwise 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 medication and end after stop of study medication.
Prior and concurrent anti-cancer therapy
The minimum, median, and maximum number of prior systemic anti-cancer therapy lines as 
well as number of patients with 1, 2, 3, ≥4 lines of therapy will be summarized by treatment 
group and overall for FAS.  Time since last systemic anti-cancer therapy will be summarized 
using descriptive statistics by treatment group and overall for FAS.  The time between the 
start day of 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 FAS:

Prior radiotherapies

Prior systemic anti-cancer therapies 

Type of prior systemic anti-cancer therapy

Prior diagnostic and/or therapeutic procedures for iNHL

Prior treatment with PI3K inhibitors

Concurrent diagnostic and/or therapeutic procedures for iNHL

Radiotherapies during follow-up

Systemic anti-cancer therapies during follow-up 

Type of systemic anti-cancer therapy during follow-up
6.1.5
Treatment duration and exposure
Descriptive statistical summaries will be provided separately for copanlisib/placebo and 
rituximab by treatment group for the following variables: 

Overall extent of exposure (OEE, as defined in Section 4.6.4) for FL, MZL and all 
patients

Overall extent of exposure by categories:
o
0-180 days
o
181-360 days
o
361-540 days


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o
541-720 days
o
>720 days

Number of cycles  

Number of infusions during treatment phase
In addition, the following analyses will be provided 

Total amount actually administered: sum of actual dose (mg) for each patient
o
For rituximab, the actual dose is defined as Prescribed dose [mg/m2] × (Total 
amount administered [ml] / Total amount prior to administration [ml]) / Body 
surface Area (BSA) [m2]

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 time points, i.e. 
infusion days (D1, D8 and D15 of each cycle), 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 cycle:

60 mg if 0 < d < 8

120 mg if 8 ≤ d < 15

180 mg if 15 ≤ d < 28
o
For rituximab, a standard of 375 mg/m² BSA is set for all time points for 
planned dose.
Evaluations of this section will be done in SAF by treatment group.
For patients with dose reduction and re-escalation (only for copanlisib/placebo), interruption, 
or delay, the number of dose reductions, interruptions, or delays per patient and their reasons 
will be summarized separately for copanlisib/placebo and rituximab. 
The duration of dose interruptions or delays in days will be summarized for 
copanlisib/placebo.  The duration is defined as the difference between the date of interruption 
or delay and the date of next infusion. Due to the treatment regimen with one week break at 
the end of each cycle, interruptions or delays on day 15 are reduced by 7 days, if the next 
infusion is given in a subsequent cycle. 
Subject listings will be provided for dose modification. 
6.2
Efficacy
Descriptive evaluations of efficacy variables will be performed.  Especially, summaries of 
tumor response by central review and investigator’s assessment will be provided.
Disease progression in the context of statistical efficacy evaluation is considered to be
radiological progression, as assessed by central review.  For WM patients without 
radiologically measurable disease, clinical progression will be used. 
All efficacy analyses will be performed when at least 190 PFS events are observed in the 
study. See Section 4.4.


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Evaluations from central blinded review and Owen criteria for WM patients will be used for 
the primary efficacy analyses of primary and secondary endpoints containing radiological 
tumor assessments.
Efficacy analyses will be performed as randomized in the FAS. Censoring of efficacy 
variables will be handled according to Sections 4.3.1, 4.3.2, 6.2.1 and 6.2.2.
6.2.1
Primary Efficacy Variable Progression-Free Survival
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 central review. Radiological progression will be 
confirmed in real-time by 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. Progression-free survival (PFS) for patients without PD or death 
at the time of analysis will be censored at the last actual date of tumor assessment or last 
biochemical assessment for patients with WM without 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 WM without 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 fulfilling the criteria for 
progression and/or new lesions were detected, this patient would be considered evaluable 
with assessment of PD. 
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 central review) will be censored at Day 1.  
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 Last known active date (LKAD) is earlier than this 
date; in which case the LKAD will be used for imputation.
Table 6–1 lists the censoring rules for PFS events.


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Table 6–1: Progression-free survival (PFS) censoring rules
Situation
End Date/Day 
Censored
Reason for 
Censoring
Detailed 
Reference 
No baseline tumor assessment Reference 
Date/Day 1
Yes
No baseline tumor 
assessment
No post-baseline tumor 
assessment and no death
Reference
Date/Day 1
Yes
No post-baseline 
tumor assessment 
and no death
Appendix 9.3.1
Death during treatment and 
active follow-up period or early 
enough in survival follow-up to 
be within the time window
Death date 
No
N/A
Appendix 9.3.2
Death after the time window
Last Tumor 
assessment 
Yes
Death happened 
after time window
specified in 
Appendix 9.3.2
Appendix 9.3.2
No post-baseline tumor 
assessment and died after the 
first 17 (16+1) weeks after 
randomization during survival 
follow-up period
Reference 
Date/Day 1
Yes
N/A
Death occurs after two or more 
consecutive missed tumor 
assessments immediately 
during survival follow-up period 
Last tumor 
assessment 
Yes
Two or more 
consecutive missed 
tumor assessments 
immediately prior to 
death
New anti-cancer therapy other 
than the study medication prior 
to observing progression
Last evaluable 
tumor assessment 
prior to the 
initiation of anti-
cancer therapy
Yes
New anti-cancer 
therapy
Appendix 9.3.3
The progression occurs at the 
next tumor assessment after 
two or more consecutive 
missing or non-evaluable 
assessments  
Last tumor 
assessment before 
the missing tumor 
assessments
Yes
Two or more 
consecutive missed 
tumor assessments 
immediately prior to 
progression 
Appendix 9.3.1
Discontinued or withdraw early 
from the study without 
documented disease 
progression
Last tumor 
assessment date
Yes
Discontinued
Appendix 9.3.4
Progression without two or 
more consecutive missed 
tumor assessments 
immediately prior to death
Date of 
progression 
No 
N/A
Neither PD nor death and no 
other criteria fulfilled
Last tumor 
assessment 
Yes
Patient regularly 
ongoing in trial 
without PFS event 
occurred
Primary analysis of PFS
The primary efficacy analyses will evaluate whether PFS in the copanlisib group is longer 
compared to PFS in the placebo group for FAS for the total study population, by means of a 
stratified log-rank test.


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Stratification factors for this test will be “iNHL histology” and “entry criterion” used for 
randomization (see Section 4.6.5).
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 [14] 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 similar 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 7 were stratified as 
unfit will be combined with those who after protocol amendment 7 were stratified as unfit 
and unwilling; and patients who before protocol amendment 9 were stratified as “treatment-
free ≥ 12 months after completion of the last rituximab containing treatment” will be 
combined with those who after protocol amendment 9 were stratified as “progression-free 
and treatment-free ≥ 12 months after completion of the last rituximab containing treatment”.
The PFS will be tested based on hierarchy test, refer to section 6.2.3.
Additional analyses of PFS
The hazard ratio (including 95% two-sided 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 similar 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 times to 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;


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RUN;
Subgroup analysis for PFS will be done by histology (FL, MZL SLL, and LPL/WM), see 
section 6.2.5.
Exploratory analyses of PFS
Analysis of concordance and discordance between radiological progression evaluation by 
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 four binary stratification variables, similar 
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” 
or “AE related to clinical progression”) as a progression event1. The first PD assigned by the 
investigator will be used as event. It is acknowledged that due to a substantial amount of “PD 
non-confirmation” that might occur in the study, the investigator PFS times might be 
generally shorter, in both study arms. This will be attributable to the above effect and needs 
to be considered in the statistical interpretation of results.
Sensitivity analyses of PFS
To align with US health authority, a sensitivity analysis for PFS will be conducted using 
stratified log-rank test with all four stratification factors at randomization. The four 
stratification factors are iNHL histology, entry criterion, presence of bulky disease, and 
previous treatment with PI3Ki.
The censoring mechanism of subjects without PFS event at the time of analysis is assumed to 
be non-informative for the primary efficacy analysis. Therefore, additional sensitivity 
analyses will be performed, assessing the impact of a potential informative censoring of such 
patients.  The following sensitivity analyses for the primary PFS analysis will be performed 
using similar methodology as the primary analysis by central review unless otherwise 
specified: 

Consider all patients that are censored to be events in both arms (Kaplan-Meier curves 
and Cox model for hazard ratio).
                                                
1 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 CRF) or, if there is an AE related to clinical progression, the earlier date of 
either is used.  


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Further sensitivity analyses will be

PFS will be evaluated with the unstratified log-rank test and Cox model.

In case of many discrepancies between stratification factors entered in the interactive 
voice/web response system (IxRS) and information entered in CRF, PFS will be 
evaluated with the stratified log-rank test and Cox model based on stratification 
information entered in CRF. Note that some subjects will be excluded from this 
analysis (see Table 6–2) since these patients should not have been enrolled.
Table 6–2: Entry Criteria Stratum and Exclusions  
Treatment- and 
progression-free 
interval ≥ 12 months
Treatment- and 
progression-free interval 
between 6 and 12  
months
Treatment- and 
progression-free 
interval < 6 months
Willing/Fit to receive 
chemotherapy (none of 
the unfit criteria is 
fulfilled)
Treatment and 
progression-free 
interval ≥ 12
Excluded
Excluded
Unwilling/Unfit to 
receive chemotherapy 
(at least one of the unfit 
criteria is fulfilled)
Unwilling/Unfit for 
chemotherapy
Unwilling/Unfit for 
chemotherapy
Excluded

PFS will be evaluated considering any change as a progression event, e.g., treating 
initiation of a new anticancer agent as an event at the date of start of new anticancer 
agent, treating disease progression as an event at the date of progression ignoring 
scheduled missing assessments, treating treatment discontinuation as an event at the 
date of discontinuation [15]. Table 6–3 lists the rules for sensitivity analysis. 


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Table 6–3: Progression-free survival (PFS) censoring rules for sensitivity analysis 
(any change considered as a progression event) 
Situation
End Date/Day 
Censored
Reason for 
Censoring
Detailed 
Reference 
No baseline tumor assessment
Reference 
Date/Day 1
Yes
No baseline tumor 
assessment
No post-baseline tumor 
assessment and no death
Reference 
Date/Day 1
Yes
No post-baseline 
tumor assessment 
and no death
Appendix 
9.3.1
Death or progression occurred 
during treatment period
Earliest of:

Death date
or

Date of 
progression
No
N/A
New anti-cancer therapy other 
than the study medication prior to 
observing progression
Date of start of 
new anticancer 
treatment
No
N/A
Discontinued or withdraw early 
from the treatment without 
documented disease progression
Date of treatment 
discontinuation
No
N/A
Neither PD nor death and no other 
criteria fulfilled
Last tumor 
assessment 
Yes
Patient regularly 
ongoing in trial 
without PFS event 
occurred

PFS will be evaluated by log-rank test and Cox model and stratified by the following 
regions:
○
North America (Canada and United States), 
○
Asia Pacific, excluding Australia (China, Japan, Korea, Taiwan, Hongkong, Malaysia, 
Singapore, Thailand, Vietnam, and Philippines)
○
Rest of the world (All other countries).

Additional sensitivity analysis of PFS related to COVID-19 will be performed if 
treatment interruptions due to COVID-19 are observed and PFS evaluations are 
considered being affected.    
6.2.2
Secondary Efficacy Variables
Definition of secondary efficacy variables
Objective tumor response rate (ORR), assessed in all patients up to the time of analysis of 
PFS.  ORR is defined as the proportion of patients who have a best response rating over the 
whole duration of the study (i.e. until time of analysis of PFS) of complete response (CR) or 
partial response (PR) according to the Lugano Classification and for patients with WM a 
response rating of CR, very good partial response (VGPR), PR, or minor response (MR) 
according to the Owen Criteria. 
Duration of response (DOR), 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.  DOR will 
only be defined for patients with at least one CR, VGPR, PR, or MR.


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Disease control rate (DCR), DCR is defined as the proportion of patients who have a best 
response rating of CR, VGPR, PR, MR or SD (excluding unconfirmed early SD) that is 
achieved during treatment or within 35 days after termination of study treatment. The 
unconfirmed early SD is defined as SD on or before Study Day 48.
Complete response rate (CRR), assessed in all patients up to the time of analysis of PFS.  
CRR is defined as the proportion of patients who have a best response rating over the whole 
duration of the study (i.e. until the time of analysis of PFS) of CR according to the Lugano 
Classification and for patients with WM a response rating of CR according to the Owen 
criteria.
Time to progression (TTP), defined as the time (in days) from randomization to PD or death 
related to PD, whichever is earlier. Death related to PD is considered to be 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) 
Time to progression (TTP) for patients without PD or with death not related to PD at the time 
of analysis 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 will be censored at Day 1. The 
conventions for calculation of TTP are the same as for PFS (See Section 6.2.1) except 
without considering death not related to PD as an event. 
The actual dates of tumor assessments will be used for this calculation. 
Overall survival (OS), defined as the time (in days) from randomization until death from any 
cause. Overall survival (OS) of patients alive at the time of analysis will be censored at the 
last date they were known to be alive (last known alive date; LKAD).  Death after the data
cut reported during cleaning will be considered for the OS analysis and will be censored at 
the date of cutoff.
The LKAD is derived from the main data sources. Except for death, data reported during 
cleaning for the time after the data cut will not be considered in the derivation of LKAD.  The 
last available date across all key data panels will be picked as the LKAD by patient.  
Information from key data, e.g., visit dates, exposure information, laboratory measurements, 
tumor assessment dates and disposition events or follow up assessments will be used to 
determine survival status.
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 outcome 'Death', the date of death will be 
imputed by the end date of the AE.
2. If there is no AE with outcome 'Death' 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 are 
missing, then the LKAD will be used for imputation.
If a tumor assessment date is partially missing, it will be imputed following the imputation 
rules below:


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3. If only the day is missing, it will be imputed by the first day of the month.
4. 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 imputation.
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 or death due to any reason, whichever is earlier.  DRS-P 
deterioration censoring rules are listed in the Table 6–4.
Table 6–4: 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 also 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
Yes
New anti-cancer therapy other 
than the study medication prior to 
observing DRS-P deterioration 
(and no PD before switch to new 
anti-cancer therapy)
Last evaluable 
DRS-P 
assessment prior 
to the initiation of 
anti-cancer 
therapy
Yes
New anti-cancer therapy
Discontinued or withdraw early 
from the study without 
documented DRS-P or PD or, 
Death within time window
Last DRS-P 
assessment date
Yes
Discontinued
Neither DRS-P, nor PD/death 
and no other criteria fulfilled
Last DRS-P 
assessment
Yes
Patient regularly ongoing in trial 
without DRS-P event occurred
Similar time window for PFS will be used for the derivation.
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 days) 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 
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 


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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 similar to the censoring for 
deterioration of DRS-P. The DRS-P improvement censoring rules censoring rules are listed in
Table 6–5:
Table 6–5: 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 therapy other 
than the study medication prior to 
observing DRS-P improvement 
(and no PD before last DRS-P 
assessment before switch to other 
than study medication)
largest observation 
time (of events and 
censoring in all 
patients evaluated 
for improvement), 
plus 1 day
Yes
New anti-cancer therapy
Discontinued or withdraw early 
from the study without 
documented DRS-P or PD/Death 
Last DRS-P 
assessment date
Yes
Discontinued
Neither DRS-P, nor PD/death and 
no other criteria fulfilled
Last DRS-P 
assessment
Yes
Patient regularly ongoing in 
trial without DRS-P event 
occurred
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 an 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 9.1.


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Analyses of secondary efficacy variables
Analysis of ORR, Time to deterioration and Time to improvement in DRS-P
All secondary efficacy variables will be analyzed in the FAS at the time of the analysis of the 
primary variable.
The ORR will be analyzed using the Cochran-Mantel-Haenszel test, stratified for the same 
stratification factors as used for PFS. The null hypothesis is defined as:
H0, ORR: ORRCopanlisib+Rituximab ≤ ORRPlacebo+Rituximab
The alternative hypothesis is:
H1, ORR: ORRCopanlisib+Rituximab > ORRPlacebo+Rituximab
In addition, the point estimate as well as 95% two-sided confidence intervals for the Mantel-
Haenszel weighted treatment difference [16] 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.
Analysis of other secondary efficacy variables
OS, TTP, DOR as well as CRR will not be included into the confirmatory testing strategy but 
analyzed supportively only.  
OS, TTP, and DOR will be analyzed using stratified log-rank tests analogue to the analysis 
for the primary analysis of the primary endpoint, PFS.  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.
The first analysis of OS will be performed at the time of analysis of the primary endpoint, 
PFS. The survival status will further be collected quarterly during the survival follow-up 
period up to 3 years after the last patient started study treatment. 
Twelve months after analysis of the primary and secondary efficacy variables, a further 
analysis of OS ('follow-up OS analysis') will be performed. This analysis will be an update of 
the analysis of OS performed on data available at the time of analysis of the primary 
endpoint, PFS.
After the follow-up analysis of OS, it will be determined whether a subsequent final OS 
analysis will be required, and the study duration will be adjusted accordingly.
Additional analyses of secondary efficacy variables
ORR
Subgroup analysis for ORR will be done by histology (FL, MZL SLL, and LPL/WM), see 
section 6.2.5.
DRS-P deterioration 
As 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.


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6.2.3
Confirmatory statistical test strategy
Separate statistical test strategies will be conducted for the United States and Europe 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 is as follows and shown in Figure 6–1:
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 PFS will be performed (tested at one-sided alpha=0.025), evaluating 
the subpopulation of combined FL and MZL population, if this is successful
b) a test on the ORR in the combined FL and MZL population will be performed (tested at 
one-sided alpha=0.025), if this is successful,
c) a test on the DRS-P deterioration in the combined FL and MLZ population will be 
performed (tested at one-sided alpha=0.025), if this is successful. 
d) a test on the DSR-P improvement in the combined FL and MZL population will be 
performed (tested at one-sided alpha=0.025), it would conclude the confirmatory test 
procedure.
For the testing Families 1 to 2 of this confirmatory test strategy, an assessment of power 
based on Schoenfeld’s formula [17] was performed for two scenarios as listed in Table 6–6:

Scenario 1: HR=0.61 in the study (according to the re-planned sample size planning)

Scenario 2: HR=0.53 in the study (less conservative assumption)
Table 6–6: Assessment of Statistical Power for PFS Test in the Overall FAS 
Population and Combined FL and MZL Population
Total 
Patients
Dropout 
rate
Events to be 
expected (E)
Hazard
ratio
Power
Scenario 1:
Family 1: overall FAS 
population
458
30%
190
0.61
89.5%
Family 2: combined FL 
and MZL population
370
30%
140
0.61
78.7%
Scenario 2:
Family 1: overall FAS 
population
458
30%
190
0.53
98.5%
Family 2: combined FL 
and MZL population
370
30%
140
0.53
94.3%
The number of total patients in Table 6–6 is the number of patients having been randomized 
in the study. 


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Figure 6–1: Confirmatory Test Strategy Based on Five Test Families for United States
Europe
For Europe, 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 shown in Figure 6–2:
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,
ORR (combined FL and MZL population)
Tested if success in F2
Alpha: 2.5%
Family 4 (F4)
Family 5 (F5)
Family 2 (F2)
DRS-P deterioration (combined FL and MZL 
population)
Tested, if success in F3
Alpha: 2.5%
Family 3 (F3)
PFS in iNHL population (FAS)
Alpha: 2.5%
PFS (combined FL and MZL population)
Tested, if success in F1
Alpha: 2.5%
DRS-P improvement (combined FL and MZL 
population)
Tested, if success in F4
Alpha: 2.5%
Family 1 (F1)


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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 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 test on the DSR-P improvement in the FAS population will be performed (tested at one-
sided alpha=0.025), it would conclude the confirmatory test procedure.
Figure 6–2: Confirmatory Test Strategy Based on Four Test Families for Europe
Note: EU refers to Europe 
6.2.4
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:
	
 ≈

 ∑
( −)( + )


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. 
Family 4EU (F4EU)
Family 2EU (F2EU)
DRS-P deterioration in iNHL population (FAS)
Tested, if success in F2EU
Alpha: 2.5%
Family 3EU (F3EU)
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 F3EU
Alpha: 2.5%
Family 1 (F1)


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Summary statistics will be provided for AUC and for the AUC normalized over the 
observation time.  
2. FLymSI-18 total and subscale scores (DRS-P, DRS-E, TSE, FWB), and time to onset 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 onset of physical symptoms defined as a decrease in DRS-P score ≥ 3 points 
will be presented by visit and overall. The time to onset of physical symptoms will be 
described.
3. Performance status (ECOG)
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 subgroups can be seen from Table 6–7, 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, descriptive statistics including 
log-rank test).
Table 6–7: 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
a)
b)
b)
b)
a)
a)
a)
MZL
a)
b)
b)
b)
a)
a)
a)
    Extranodal
a)
b)
b)
b)
a)
a)
a)
    Nodal
a)
b) 
b)
b)
a)
a)
a)
    Splenic 
a)
b)
b)
b)
a)
a)
a)
SLL
a)
b)
b)
b)
a)
a)
a)
LPL/WM
a)
b)
b)
b)
a)
a)
a)
* of at least 3 points
FL: follicular lymphoma; MZL: marginal-zone lymphoma; SLL: small lymphocytic lymphoma; LPL: 


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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.
Same subgroup analyses will be conducted for the secondary endpoints DOR, and TTP by 
histology subgroups FL and MZL separately.
6.2.5.2
Other subgroup analyses
Subgroup analyses will include forest plots of response/hazard ratios as well as treatment-
interaction analyses. The forest plots of response/hazard ratios will be provided for the 
primary efficacy endpoint (PFS) as well as the secondary efficacy endpoints ORR, time to 
deterioration in DRS-P, 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 
sufficient number of events 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

Entry criterion (progression-free and treatment-free interval following the last 
rituximab-containing treatment ≥12 months vs. considered unwilling/unfit to receive 
chemotherapy for age or comorbidities)

Presence of bulky disease (yes vs. no)

Previous treatment with PI3K inhibitors (yes vs. no)

Prior lines of systemic anti-cancer therapy (1 vs. 2 vs. 3 vs. ≥4)

Geographic regions 1 (US, Europe, Rest of world)

Geographic regions 2 (North America, Asia Pacific, Rest of the world)

Age (<65 vs. ≥ 65)

ECOG performance status (0 vs. 1 vs. 2)

Gender (male vs. female)

Race

Ethnicity (Hispanic or Latino vs. non-Hispanic and non-Latino)

BMI group (<18.5 vs. 18.5 - <30 vs. ≥30 kg/m²)

Renal function at baseline (eGFR Normal: ≥ 90 vs. Mild: 60 - < 90 vs. Moderate: 30 -
<60 vs Severe:15- <30 mL/min/1.73m²)


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For secondary efficacy endpoints ORR, time to deterioration of DRS-P, and time to 
improvement in DRS-P, the same subgroup levels will be analyzed excluding gender, BMI 
group, and renal function at baseline.  
The descriptive statistics on ORR and DOR by treatment will also be provided for subjects 
with at least 2 prior therapies in the MZL subgroup.
6.3
Safety
6.3.1
Adverse Events (AEs)
Adverse events will be coded by Medical Dictionary for Regulatory Activities (MedDRA) 
codes and National Cancer Institute (NCI) Common Terminology Criteria Adverse Event 
(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 by the investigator as related or not related to 
study drug.
A treatment-emergent AE (TEAE) is defined as any event arising or worsening after the start 
of study drug administration until 30 days after the last study drug administration (end of 
safety follow-up).
Descriptive summary tables (frequency and percentage of subjects, not of events) will be
presented by treatment group, MedDRA SOC/PT and by NCI CTCAE worst grade for the 
following:

An overall summary of TEAEs  

TEAEs 

Drug-related TEAEs

Treatment-emergent serious AEs (TESAEs)

Drug-related TESAEs

TEAEs of special safety interest.  
Exposure adjusted TEAEs will be summarized by treatment group and MedDRA SOC/PT.
The exposure adjusted incidence rate per 100 subject years is defined as 100 times the 
number of subjects with at least one TEAE divided by the sum of exposure times in years, 
where exposure time is the time to first occurrence if an 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.
Incidence rates of TEAEs, drug-related TEAEs (copanlisib/placebo or rituximab-related) 
and/or TESAEs will be repeated by the following criteria:

entry criterion strata (progression-free and treatment-free interval following the last 
rituximab-containing treatment ≥ 12 months vs. considered unwilling/unfit to receive 
chemotherapy for age or comorbidities) 

renal function at baseline (GFR Normal: ≥ 90 vs. Mild: 60 - < 90 vs. Moderate: 30 -
<60 vs. Severe: 15- < 30 mL/min/1.73m²)


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
hepatic function at baseline (Normal: Total bilirubin and AST ≤ ULN vs. Mild hepatic 
impairment: Total bilirubin > ULN to 1.5 x ULN and AST any value; or Total 
bilirubin ≤ ULN and AST > ULN vs. Moderate impairment: Total bilirubin > 1.5 to 3 
x ULN and AST Any value vs. Severe impairment: Total bilirubin > 3-10 x ULN, 
AST Any value)

age (<65 vs. ≥ 65)

gender

history of hypertension: [PBMQ] Medical history of hypertension (n/y)

history of diabetes: [PBMQ] Medical history of diabetes mellitus (n/y), and

BMI group (<18.5 vs. 18.5 - <30 vs. ≥30 kg/m²).
Furthermore, all TEAEs and drug-related TEAEs with incidence of at least 10% will be 
summarized by MedDRA and by 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, for NCI-CTCAE grade 3-4.  All TEAEs will be summarized by 
MedDRA for NCI-CTCAE grade 5.
The number and percentage of patients who discontinued study treatment due to TEAE or 
required a dose reduction (copanlisib/placebo only) or interruption caused by a TEAE will be 
summarized.  The incidences of these TEAEs will be presented also separately by drug 
relatedness (copanlisib/placebo and/or rituximab).
In addition, the following AE summary according to investigator pathology for FL and MZL 
patients will be provided:

Overview of TEAEs (i.e. includes deaths, discontinuations and dose modifications)

TEAEs 

drug-related TEAEs 

TESAEs 

drug-related TESAEs 

The Standardized MedDRA Query (SMQ) with narrow search (i.e. category 2A):
Interstitial lung disease 
Deaths will be summarized by treatment group and overall.
In addition, subject listings will be provided for the following AEs by treatment group:

Subjects who died during study treatment or up to 30 days after the last dose of study 
medication:  subject ID, histology, sponsor AE identifier, start and stop date of study 
medication, date of death, cause of death, MedDRA SOC and PT term and CTCAE 
toxicity grade.

Subjects who died later than 30 days after the last dose of study medication:  subject 
ID, histology, sponsor AE identifier, start and stop date of study medication, date of 
death, cause of death, MedDRA SOC and PT term and CTCAE toxicity grade.

Subjects with treatment-emergent SAEs:  subject ID, histology, sponsor AE identifier, 
investigator AE term, MedDRA SOC and PT term and toxicity grade, start and stop 


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dates of study drug administration, start and stop date of AE, drug related (yes/no), 
protocol required procedure related (yes/no), outcome, action taken.  Listing of study
drug-related SAEs will be provided separately for copanlisib/placebo and rituximab, 
respectively, with similar information.

Subjects with TEAEs of special interest: subject ID, histology, sponsor AE identifier, 
investigator AE term, MedDRA SOC and PT term and toxicity grade, start and stop 
dates of study drug administration, start and stop date of AE, drug related (yes/no), 
protocol required procedure related (yes/no), outcome, action taken.

Subjects who discontinued study treatment, required a dose reduction 
(copanlisib/placebo only), or interruption caused by a TEAE will be listed separately 
for copanlisib/placebo and rituximab, respectively:  subject ID, histology, sponsor AE 
identifier, investigator AE term, MedDRA SOC and PT term and toxicity grade, start 
and stop dates of study drug administration, start and stop date of AE, drug related 
(yes/no), protocol required procedure related (yes/no), outcome.
6.3.2
Adverse events by time-interval
The categories of TEAEs, TE copanlisib-related AEs, and TE serious AEs will be presented 
according to time-of-onset (new onset or worsening). 
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 91 
days

Day 181 – Day 270: to include all copanlisib-treated patients treated for at least 181 
days

Day 271 – Day 360: to include all copanlisib-treated patients treated for at least 271 
days

Day 361 – Day 450: to include all copanlisib-treated patients treated for at least 361 
days

Day 451 – Day 540: to include all copanlisib-treated patients treated for at least 451 
days

Day 541 – Day 630: to include all copanlisib-treated patients treated for at least 541 
days

Day 631 and greater: to include all copanlisib-treated patients treated for at least 631 
days
6.3.3
Non-infectious Pneumonitis/Interstitial lung disease
Non-infectious Pneumonitis is defined as AE of special safety interest (protocol Section 
6.4.1). The Standardized MedDRA Query (SMQ) 'Interstitial lung disease' with narrow 
search (i.e. category 2A) will be used to select these AEs of special interest.
Summary of patients with Non- infectious pneumonitis/Interstitial lung disease requiring 
corticosteroids, antibiotics, or both will be displayed descriptively. 


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6.3.4
COVID-19 relevant adverse events
The COVID-19 relevant adverse events will be identified using a high-level term (HLT) of
coronavirus infection via latest MedDRA version. A subject listing of these AEs will be 
provided. The serious AEs will be flagged in the listing.
6.3.5
Pregnancies
The results of pregnancy tests will be listed.  Any pregnancy will be documented.
6.3.6
Clinical Laboratory Parameters
Laboratory toxicities by worst CTCAE grade post-baseline will be summarized. Summary 
statistics on the values and changes from baseline will also be presented for each quantitative 
clinical laboratory variable, at each post-baseline visit. 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
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 is also provided. For the change in worst grade of laboratory toxicities under 
treatment the latest observation will be taken. In case there is more than one observation for 
the same latest time, the worst grade will be taken.
In addition, for renal function (eGFR and CLcr) and hepatic function, worst grade during 
study will be summarized. 
The eGFR, CLcr and hepatic function grade are defined as the following:

eGFR, as defined per draft FDA guidance [18]
Normal: eGFR ≥90 ml/min/1.73m²
Mildly impaired: 60 ≤ eGFR < 90 ml/min
Moderately impaired: 30 ≤ eGFR < 60 ml/min/1.73m²
Severly impaired: 15 ≤ eGFR < 30 ml/min/1.73m²
End stage renal disease: eGFR < 15 ml/min/1.73m²

Creatinine Clearance (CLcr), as defined per draft FDA guidance [18]:
Normal: CLcr ≥90 ml/min
Mildly impaired: 60 ≤ CLcr < 90 ml/min
Moderately impaired: 30 ≤ CLcr < 60 ml/min
Severly impaired: 15 ≤ CLcr <30 ml/min
End stage renal disease: CLcr < 15 
CLcr will be calculated according to the Cockcroft-Gault formula:


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
Hepatic impairment [19] [20]: 
Normal: Total bilirubin and AST ≤ upper limit of normal (ULN)
Mild impairment: Total bilirubin > ULN to 1.5 x ULN or (Total bilirubin ≤ ULN and 
AST > ULN)
Moderate impairment: Total bilirubin > 1.5 to 3 x ULN, any AST
Severe impairment: Total bilirubin > 3 x ULN, any AST
In addition to the above summary, specific glucose evaluation will be described in the next 
section.
6.3.7
Further Safety Parameters
6.3.7.1
Hyperglycemia
Hyperglycemia adverse events using specific MedDRA PT grouping ‘MLG Hyperglycemia’ 
will be summarized by treatment group and by NCI CTCAE worst grade for the following:

TEAEs

Drug-related TEAEs

TESAE

Drug-related TESAE
Glucose measurements will be displayed by CTCAE grade of pre copanilisib/placebo 
infusion and post-dose 1 h and 2 h after the end of copanlisib/placebo infusion, and at the end 
of rituximab infusion on Cycle 1 Day 1, and by CTCAE grade of pre copanlisib/placebo 
infusion and post-dose 1 h after the end of copanlisib/placebo infusion, and at the end of 
rituximab infusion on subsequent visits. 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. 
Patients will be categorized according to their HbA1c baseline values as

< 5.7%

≥ 5.7% – < 6.5%

≥ 6.5%.
Within each group, the maximum HbA1c values by cycle and end of treatment visit, as well 
as 3 months after last dose (if available) will be summarized by descriptive statistics. Shift 
table from baseline to end of treatment visit, and 3 months after last dose for each category of 
HbA1c will be presented.
For patients who required home glucose monitoring, home blood glucose information will be 
listed in Appendix 16 of the CSR.
For patients with hyperglycemia adverse events, the number of patients using
antihyperglycemic treatment with drug start date on or after their first treatment-emergent 


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adverse event will be summarized in overall, and separately for the WHO-DD ATC classes 
for a) insulin and analogues and b) Blood glucose lowering drugs, excluding insulins.  In 
addition, these summaries will be presented separately for the subgroups of patients with vs 
without history of diabetes (as defined in Section 6.3.1).
6.3.7.2
Electrocardiogram (ECG)
Results of electrocardiogram (ECG) will be summarized with descriptive statistics and/or 
frequency tables.  ECG data will be summarized by visit and timepoint, including change 
from baseline where appropriate.
The overall interpretation of the 12-lead ECG and the ECG diagnosis, as well as 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 electrocardiogram 
(ECG) as abnormal will be performed at all-time points. 
6.3.7.3
Vital Signs
Results of vital signs will be summarized with descriptive statistics and/or frequency tables.  
Vital signs will be summarized by visit and timepoint, including change from baseline where 
appropriate.
6.3.7.4
Echocardiogram
The number of patients with abnormal cardiac function will be displayed for echocardiogram 
and multiple gated acquisition (MUGA) by visit.
6.3.7.5
Hypertension
Hypertension adverse events will be presented using MLG grouping of MLG 
Hypertension for the following:

TEAEs

Drug-related TEAEs

TESAE

Drug-related TESAE
For patients with hypertension adverse events, the number of patients using antihypertensive 
treatment with drug start date on or after their first treatment-emergent adverse event will be 
summarized descriptively.  In addition, the number of patients requiring new antihypertensive 
treatment will be presented separately for the subgroups of patients with vs without 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.
6.4
Pharmacokinetics/pharmacodynamics
Individual concentration-time data of copanlisib and its metabolite M-1 as well as rituximab 
will be listed.  Further analyses will be performed and reported under separate cover by PK 
experts (pharmacometrics) and include population pharmacokinetics, and exposure response 
analysis. 


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6.5
Biomarker evaluation
Biomarker data, if 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 genomics and 
biomarker statistical expert and/or pharmacometrics 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

SAP final version 1.0, dated 13 FEB 2017

SAP final version 2.0, dated 12 DEC 2018

SAP final version 3.0, dated 15 JAN 2020

SAP final version 4.0, dated 03 MAR 2020

SAP final version 5.0, dated 28 JUL 2020 

SAP final version 6.0, dated 26 AUG 2020
7.2
Changes in the planned statistical analysis
7.2.1
Changes from the SAP V1.0
SAP version 2.0 was done to reflect Amendment 9 of the protocol.
Study objective
Wording of the study objective was adapted in order to be fully consistent with updates in the 
protocol Amendment 9 (in which changes in the inclusion criterion 13 and exclusion criterion 
4 were aligned with the study objectives). 
Sample size
The sample size estimation was updated to be based on the FAS instead of the follicular 
lymphoma subgroup (also changed in the protocol Amendment 9).
Handling of Missing Data
Reorganized the rules for handling of missing data for time to event variables under the 
definitions of individual time to event variables in Section 6.2.
Stratification
The assessment and handling of stratification factor 'entry criterion' is further clarified.
The definition entry criteria stratification factor was adjusted according to the clarification of 
inclusion criterion 13 in the protocol Amendment 9.  Since the inclusion criterion 13 was 
modified to be consistent with exclusion criterion 4, the following wording was also 
harmonized in the definition of the entry criteria stratification factor: progression-free and 
treatment-free interval of ≥ 12 months after completion of the last rituximab-containing 
treatment.


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For the purpose of the analysis, patients who were stratified before protocol Amendment 7 as 
unfit will be combined with those who were stratified after protocol Amendment 7 as unfit 
and unwilling; and patients who were stratified before protocol Amendment 9 as “treatment-
free ≥ 12 months after completion of the last rituximab-containing treatment” will be 
combined with those who were stratified after protocol Amendment 9 as “progression-free 
and treatment-free ≥ 12 months after completion of the last rituximab-containing treatment”.  
Which stratum patients should be randomized to if a they fulfill both entry criteria was 
changed to match IxRS instructions and protocol Amendment 9.
Demography and baseline characteristics
Demographic and other baseline characteristics will be summarized for each Histology (FL, 
MZL, SLL and LPL/WM).
HbA1c, Diabetic and Hypertension history and Hepatic function at baseline were added to the 
baseline characteristics to be summarized.
Efficacy
There is no regulatory obligation of powering on a specific subtype of iNHL. As a result, the 
total sample size was reduced from 567 patients to 450 patients and the primary efficacy 
analysis will be performed in the FAS instead of both FAS and FL subgroup. The 
confirmatory statistical testing section was modified to reflect this change in strategy.
Based on more updated site information, the recruitment ramps up period was increased from 
6 months to 29 months and the dropout rate was increased to 30%.
All analysis by FL and total study population will be done for the FAS population. 
Additional conditions related to the minimum number of PFS events was included.
A potential pooling of strata strategy has been added.
Additional PFS sensitivity analysis were added.
Additional rules were added for censoring or calculating PFS in special case such as, if 
progression occurs at the next tumor assessment after 2 or more consecutive missing or non-
evaluable assessments.
For the purpose of the analysis, patients who were stratified before protocol Amendment 7 as 
unfit will be combined with those who were stratified after protocol Amendment 7 as unfit 
and unwilling; and patients who were stratified before protocol Amendment 9 as treatment-
free ≥ 12 months after completion of the last rituximab-containing treatment will be 
combined with those who were stratified after protocol amendment 8 as progression- and 
treatment-free ≥ 12 months after completion of the last rituximab-containing treatment.  
The Time to deterioration in DRS-P of at least 3 points was changed to Time to deterioration 
in DRS-P of at least 3.5 points.
The Time to improvement in DRS-P of at least 3 points was changed to Time to deterioration 
in DRS-P of at least 3.5 points.
Efficacy Subgroup Analysis
Histology Specific Subgroup Analysis were added.
Safety 


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Page: 46 of 55
Adverse Events
Clarification that incidences of TEAE, drug-related and/or Serious TEAEs and TEAEs of 
special interest will be summarize by subgroup as specified in section 6.3.1.
The categories of TEAEs, drug-related TEAEs, and TESAEs will be presented according to 
time-of-onset (new onset or worsening)
Clinical Laboratory 
Clinical laboratory use updated to reflect the current best practices.
7.2.2
Changes from the SAP V2.0
SAP version 3.0 was done to reflect Amendment 10 of the protocol.

The statistical assumptions for the primary efficacy analysis of PFS were modified. 
The required number of PFS events was changed from 288 to 190

The confirmatory testing hierarchy was modified to include a test for the PFS in the 
combined FL and MZL population after testing the overall iNHL population and a test 
for the ORR in the combined FL and MZL population after the testing on PFS.

Added TEAE by histology (FL, MZL) analysis.

Added ORR by histology analysis.
7.2.3
Changes from the SAP V3.0
The following updates are made:

Subgroup analysis by history of safety and exposure analysis were updated to be done 
for FL/MZL and all patients.

The Pooling strategy in Appendix 9.3 is updated.


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
Removed concurrent procedures from the list of ‘Prior and concurrent anti-cancer 
therapy’ (Section 6.1.4).

Added eGFR, CLcr, and hepatic function calculation and grade definition (Section 
6.3.5).

Updated censoring rules for DRS-P endpoints (Section 6.2.2).

Remove PKS (pharmacokinetics analysis set) definition (Section 5.1).

Updated disposition section by removing the analysis ‘by investigator’ (Section 
6.1.1).

Added age group/renal function/bilirubin/histology by investigator/histology by 
independent assessor in demographic and baseline characteristics section (Section 
6.1.2).

Removed concurrent procedure in ‘prior and concurrent anti-cancer therapy’ (Section 
6.1.4).

Removed ‘by hepatic function at baseline’ from other subgroup analysis (Section 
6.2.5.2).
7.2.4
Changes from the SAP V4.0
SAP version 5.0 was done to reflect Amendment 11 of the protocol.

Power estimation is updated based on blinded study information using Schoenfeld’s 
formula. (Section 4.5 & Section 6.2.3)

Removed potential pooling of strata. In order to avoid a too low number of events,
only stratification factors “iNHL histology” and “entry criterion” will be adjusted 
simultaneously in the statistical analyses. (Section 4.6.5) 

Added a separate subject listing of protocol deviations related to COVID-19. (Section 
6.1.1)

Added PKS (pharmacokinetics analysis set) definition because listings will be 
provided for PK data. (Section 5.1)

Removed the Kaplan-Meier plot for ‘time to the end of study’. (Section 6.1.1)

Removed histology group from independent assessor at baseline from the baseline 
summary tables because all the subgroup analyses are based on the histology group by 
investigator at baseline. (Section 6.1.2)

Removed ‘Concurrent radiotherapies’ from the list of ‘Prior and concurrent anti-
cancer therapy’. (Section 6.1.4).

Removed evaluations for treatment duration and exposure in FAS. (Section 5.1 & 
Section 6.1.5)

Modified one of the sensitivity analyses for PFS based on the stratification 
information entered in IxRS to be based on the stratification information entered in 
CRF. (Section 6.2.1)


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Protocol No.: BAY 80-6946 / 17067
Page: 48 of 55

Added additional sensitivity analysis for the primary efficacy endpoint PFS
considering any change as a progression event. (Section 6.2.1)

Added possible sensitivity analysis for the primary efficacy endpoint PFS if the 
impact of COVID-19 on the study treatment was observed. (Section 6.2.1)

Added DCR and its definition as one of the secondary efficacy variables. (Section 
6.2.2)

Removed a test of the PFS in SLL population from the confirmatory statistical test 
strategy for the United States. (Section 6.2.3)

Added a separate confirmatory statistical test strategy for Europe. (Section 6.2.3).

Added subgroup analyses for the secondary endpoints DOR, and TTP by histology 
subgroups FL and MZL. (Section 6.2.5.1)

Added subgroup analyses on ORR and DOR for subjects with at least 2 prior 
therapies in the MZL subgroup. (Section 6.2.5.2)

Added Section 6.3.4 for COVID-19 relevant adverse events.

Modifications were made on the summary of hyperglycemia adverse events and 
laboratory hyperglycemia glucose measurements. (Section 6.3.7.1)

Modifications were made on the summary of hypertension adverse events. (Section 
6.3.7.5)
7.2.5
Changes from the SAP V5.0

Added a statement to indicate the evaluation of histopathological diagnosis from 
central reviewer at baseline is retrospective. Data will be presented in the CSR 
addendum and are considered as exploratory. (Section 6.1.2) 

Added a sensitivity analysis of PFS to align with US health authority feedback 
received on August 3, 2020. (Section 6.2.1) 

Removed stratification factors from the subgroup analyses. Subgroup analyses will be 
conducted using unstratified log-rank test or unstratified Cox regression model for 
time to event outcome. For binary efficacy endpoints, e.g. ORR, chi-square test will 
be used. (Section 6.2.5)
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 


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 17067
Page: 49 of 55
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. 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.
10. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. 
Oncogene. 2008;27(41):5497-510.
11. 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. 
12. Owen, RG, Kyle, RA, Stone, MJ, Rawstron, AC, Leblond, V, et al. Response assessment 
in Waldenstrom macroglobulinaemia: update from the VIth International Workshop. 
Britisch journal of haematology. 2013; 160(2):171-6.
13. Leonard JP, Trneny M, Izutsu K, Fowler NH, Hong X, Zhu J, Zhang H, Offner F, 
Scheliga A, Nowakowski GS, Pinto A. AUGMENT: a phase III study of lenalidomide 
plus rituximab versus placebo plus rituximab in relapsed or refractory indolent 
lymphoma. Journal of Clinical Oncology. 2019;37(14):1188-+.
14. Collett D. Modelling Survival Data in Medical Research: Chapman and Hall; 2003.
15. 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)


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16. 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.
17. Schoenfeld D. The asymptotic properties of nonparametric tests for comparing survival 
distributions. Biometrika. 1981;68(1): 316–319.
18. FDA. Guidance for Industry Pharmacokinetics in Patients with Impaired Renal Function 
– Study Design, Data Analysis, and Impact on Dosing and Labeling, Draft guidance, 
March 2010
19. FDA. Guidance for Industry Pharmacokinetics in Patients with Impaired Hepatic
Function: Study Design, Data Analysis, and Impact on Dosing and Labeling, May 2003
20. CTEP Simplified Disease Classification v1.0 (MedDRA v10.0), Available from:  
https://ctep.cancer.gov/protocolDevelopment/codes_values.htm (accessed date: 21 MAY 
2020) 
9.
Appendix
9.1
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
BMT6: I get tired easily
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.


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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.
NCCN/FACT Lymphoma Symptom Index-18 (FLymSI-18) 
Scoring Guidelines (Version 2) 
Instructions:*
1. Record answers in "item response" column. If missing, mark with an X
   
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by 
the  
    number of items answered.  This produces the symptom index score.
4. As with all FACIT questionnaires, a high score is good. Therefore, a score of “0” is a 
severely symptomatic patient and the highest possible score is an asymptomatic patient.
Scale
         Item Code       Reverse item?            Item response        
Item Score
FLymSI-18
GP1
4
-
________
=________
Total
GP4
4
-
________
=________
C2
4
-
________
=________
    
LEU1
4
-
________
=________
      
BMT6
4
-
________
=________
      
BP1
4
-
________
=________
      
HI8
4
-
________
=________
      
GF5
0
+
________
=________
      
Ca6
0
+
________
=________
      
GE6
4
-
________
=________
      
BRM9
4
-
________
=________
      
LEU4
4
-
________
=________
      
LEU5
4
-
________
=________
      
GP2
4
-
________
=________
      
N3
4
-
________
=________
Score range: 0-72
Score range: 0-72


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Page: 52 of 55
      
GP5
4
-
________
=________
      
GF3
0
+
________
=________
      
GF7
0
+
________
=________
      
              Sum individual item scores:  ________  
                   Multiply by 18:  ________
         Divide by number of items answered:  ________
                                                            =FLymSI-18 score
Subscale
         Item Code       Reverse item?            Item response        
Item Score
FLymSI-DRS-P
GP1
4
-
________
=________
(Disease Related
GP4
4
-
________
=________
Symptoms-Physical)
C2
4
-
________
=________
    
LEU1
4
-
________
=________
      
BMT6
4
-
________
=________
      
BP1
4
-
________
=________
      
HI8
4
-
________
=________
      
GF5
0
+
________
=________
      
Ca6
0
+
________
=________
      
              Sum individual item scores:  ________  
              
                                Multiply by 9:    ________
            Divide by number of items answered:  ________
                                                     =FLymSI-DRS-P score
Subscale
         Item Code       Reverse item?            Item response        
Item Score
FLymSI-DRS-E
GE6
4
-
________
=________
(Disease Related
BRM9
4
-
________
=________
Symptoms-Emotional)
LEU4
4
-
________
=________
    
LEU5
4
-
________
=________
      
              Sum individual item scores:  ________  
              
                                Multiply by 4:    ________
            Divide by number of items answered:  ________
                                                    =FLymSI-DRS-E score
FLymSI-TSE
GP2
4
-
________
=________
(Treatment
N3
4
-
________
=________
Side Effects)
GP5
4
-
________
=________
    
      
              Sum individual item scores:  ________  
                   Multiply by 3:  ________
            Divide by number of items answered:  ________
                                                         =FLymSI-TSE score
Score range: 0-36
Score range: 0-12
Score range: 0-16
Score range: 0-36
Score range: 0-16
Score range: 0-12


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FLymSI-F/WB
(Function/
GF3
0
+
________
=________
Well-Being)
GF7
0
+
________
=________
    
              Sum individual item scores:  ________  
                   Multiply by 2:    ________
            Divide by number of items answered:  ________
                                                      =FLymSI-F/WB score
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring 
Guidelines in the manual or on-line at www.facit.org.
9.2
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)
9.3
PFS Rules
9.3.1
Progression and PD after Two or More Consecutive Missed tumor 
assessments
If the progression occurs at the next tumor assessment after 2 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 every 8 
weeks (± 7 days) during Year 1, every 12 weeks (± 7 days) during Year 2, and every 24 
weeks (± 7 days) during Year 3 and onwards), the following conditions will apply to account 
for the tumor assessment schedule change starting at year 2 and year 3:
For subjects with progression observed before death with an evaluable post-baseline 
evaluation before two missing assessments. 

if date of progression is ≤ 64 weeks (56 weeks+8 weeks) after randomization and > 
last evaluable assessment + 2*8 + 1 weeks, PFS will be censored at the date of the last 
evaluable scan. 

if date of progression is > 64 (56+8 weeks) and ≤ 76 (64+12 weeks) weeks after 
randomization and > last evaluable tumor assessment + 8+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 > 76 and ≤ 120 weeks (108+12 weeks) after randomization 
and > last evaluable tumor 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 > 120 and ≤ 144 weeks (120+24 weeks) 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.
Score range: 0-8
Score range: 0-8


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
if date of progression is > 144 weeks after randomization and > last evaluable tumor 
assessment + 2*24 + 1 weeks, 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. 
For subjects with progression observed before death without any evaluable post-baseline 
tumor evaluation before disease progression, 

if progression occurs within the 17 (16+1) weeks after randomization, PFS time will 
not be censored and will be calculated as the date of progression minus the date of 
randomization

if progression occurs later than 17 (16+1) weeks after randomization, PFS will be 
censored at Day 1. 
9.3.2
Death 
Considering tumor assessments are scheduled at every 8 weeks (± 7 days) during Year 1, 
every 12 weeks (± 7 days) during Year 2, and every 24 weeks (± 7 days) during Year 3 and 
onwards), the following conditions will apply: 
For subjects 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 ≤ 64 weeks after randomization, and within the 16+1 weeks of the 
last evaluable tumor assessment, 

if date of death is > 64 and ≤ 76 weeks after randomization, and within the 20+1 
weeks of the last evaluable tumor assessment,

if date of death is > 76 and ≤ 120 weeks after randomization, and within the 24 +1 
weeks of the last evaluable tumor assessment,

if date of death is > 120 and ≤ 144 weeks after randomization, and within the 36 +1 
weeks of the last evaluable tumor assessment, 

if date of death is > 144 weeks after randomization, and within the 48 +1 weeks of the 
last evaluable tumor assessment.
9.3.3
Subjects with New Anti-Cancer Therapy
For subjects who change anti-cancer therapy to something other than the study medication 
prior to observing progression, PFS will be censored at the date of the last evaluable tumor 
assessment prior to the initiation of anti-cancer therapy. 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 anticancer therapy. For Waldenström’s 
macroglobulinemia (WM) patients, if PD was assessed by an investigator based on laboratory 
parameters alone, no independent confirmation of PD by independent blinded review is 
necessary.
9.3.4
Subjects Discontinued or Withdrew
For subjects 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 


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the subject dies and death is considered as a PFS event mentioned above. Note that this 
applies to subjects without progression based on blinded central radiological review but who 
discontinued because according to the investigator assessment he/she had progresses (if such 
a subject exists).
9.4
Imputation rule for 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. 
D. If the date is completely missing, no imputation will be applied for initial diagnosis 
date. Use day 1 for progression date.