A Phase 2 Study of Response-Adapted Therapy With Copanlisib and Rituximab in Untreated Follicular Lymphoma
Phase: PHASE2
Conditions: Follicular Lymphoma, Non-Hodgkin's Lymphoma, NHL
Sponsor: National Cancer Institute (NCI)



Abbreviated Title:  Copanlisib Window in FL 
  
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PRÉCIS 
Background: 
x Follicular lymphoma (FL) is the most common indolent non-Hodgkin’s lymphoma (NHL) 
with a highly variable clinical course across patients 
x Standard frontline therapy for FL includes a monoclonal anti-CD20 antibody with or 
without chemotherapy that can induce durable remissions but is generally not curable 
x The 20% of patients who relapse within 2 years of frontline chemotherapy have an inferior 
overall survival; molecular profiles and gene-expression signatures can identify patients at 
high-risk of early treatment failure but are incomplete and require further validation 
x The phosphoinositide 3-kinase (PI3K) pathway is critically important in FL; agents that 
target PI3K show good clinical activity in patients who relapse early after chemotherapy  
x Copanlisib is an intravenous therapy targeting both PI3K-D and PI3K-G isoforms and is 
FDA-approved for use in adults with relapsed and refractory FL 
x Induction therapy with copanlisib and rituximab may produce deep and durable remissions 
in patients with FL without the use of cytotoxic agents 
x Circulating tumor DNA (ctDNA) is a promising modality for monitoring therapy   
Objective: 
x To determine the complete response (CR) rate after copanlisib and rituximab as induction 
therapy for patients with untreated follicular lymphoma 
Eligibility: 
x Patients with histologically confirmed stage II-IV follicular lymphoma, grade 1-2 or 3a 
that meet criteria for initiation of systemic therapy 
x No previous systemic therapy; prior local radiation permitted 
x ECOG performance status 0-2 
x Adequate bone marrow and organ function  
Design: 
x Phase 2 study of up to 65 patients with untreated FL who meet standard criteria for 
treatment 
x Patients will first be treated with a “window” of copanlisib monotherapy, followed by  
induction therapy with copanlisib and rituximab for up to 6 cycles 
x Patients who achieve a CR after 6 cycles of induction therapy will stop treatment and be 
monitored with computed tomography (CT) scans and plasma assays for circulating tumor 
DNA (ctDNA). Patients who relapse > 6 months from the end of induction can be re-treated 
with 6 additional cycles of copanlisib and rituximab 
x Patients who achieve a partial response after 6 cycles of induction therapy will receive an 
additional 6 cycles of extended induction therapy with copanlisib and rituximab  
x Patients who do not achieve at least a partial response after 6 cycles of induction therapy 
will stop treatment and be monitored with CT scans and peripheral blood assays for ctDNA 
x Patients who progress or relapse after induction therapy and meet criteria for salvage 
therapy will be treated with standard chemotherapy and a monoclonal anti-CD20 antibody 
 

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TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
STATEMENT OF COMPLIANCE ................................................................................................ 6 
1 
INTRODUCTION .................................................................................................................. 6 
1.1 
Study Objectives and Endpoints ................................................................................... 6 
1.2 
Background and Rationale ............................................................................................ 7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 20 
2.1 
Eligibility Criteria ....................................................................................................... 20 
2.2 
Screening Evaluation .................................................................................................. 23 
2.3 
Participant Registration and Status Update Procedures ............................................. 25 
2.4 
Baseline Evaluation .................................................................................................... 26 
3 
STUDY IMPLEMENTATION ............................................................................................ 26 
3.1 
Study Design............................................................................................................... 26 
3.2 
Drug Administration ................................................................................................... 27 
3.3 
Dose Modifications..................................................................................................... 28 
3.4 
On Study Assessments/Evaluations............................................................................ 37 
3.5 
Treatment Considerations/Exceptions ........................................................................ 38 
3.6 
Post-Treatment Evaluations ........................................................................................ 40 
3.7 
Follow-Up Evaluations ............................................................................................... 40 
3.8 
Study Calendar ........................................................................................................... 42 
3.9 
Cost and Compensation .............................................................................................. 45 
3.10 
Criteria for Removal from Protocol Therapy and Off Study Criteria ........................ 45 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 46 
4.1 
Acceptable/Permitted Medications ............................................................................. 46 
4.2 
Medications to be Used With Caution ........................................................................ 46 
4.3 
Prohibited Medications ............................................................................................... 47 
4.4 
Other Considerations (Copanlisib IB) ........................................................................ 48 
5 
CORRELATIVE STUDIES FOR RESEARCH ................................................................... 48 
5.1 
Summary ..................................................................................................................... 48 
5.2 
Biospecmen Collection ............................................................................................... 51 
5.3 
Biomarker and Research Methods .............................................................................. 54 
5.4 
Sample Storage, Tracking and Disposition ................................................................ 59 
5.5 
Samples for Genetic/Genomic Analysis ..................................................................... 60 
5.6 
Exploratory Analysis of Early [18F]-FDG-PET/CT and CT Scans ............................ 61 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 61 

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6.1 
Data Collection ........................................................................................................... 61 
6.2 
Data Sharing Plans...................................................................................................... 62 
6.3 
Response Criteria ........................................................................................................ 63 
6.4 
Toxicity Criteria ......................................................................................................... 66 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .... 66 
7.1 
Definitions .................................................................................................................. 66 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING ........ 67 
7.3 
NCI Clinical Director Reporting ................................................................................ 67 
7.4 
NIH Required Data and Safety Monitoring Plan........................................................ 67 
8 
SPONSOR PROTOCOL/SAFETY REPORTING ............................................................... 67 
8.1 
Definitions .................................................................................................................. 67 
8.2 
Assessment of Safety Events ...................................................................................... 69 
8.3 
Reporting of Serious Adverse Events ......................................................................... 69 
8.4 
Waiver of expedited reporting to CCR ....................................................................... 69 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ................................. 70 
8.6 
Reporting Pregnancy .................................................................................................. 71 
8.7 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .............. 71 
8.8 
Sponsor Protocol Deviation Reporting ....................................................................... 71 
9 
CLINICAL MONITORING ................................................................................................. 72 
10 STATISTICAL CONSIDERATIONS.................................................................................. 73 
10.1 
Statistical Hypothesis ................................................................................................. 73 
10.2 
Sample Size Determination and Statistical Plan......................................................... 73 
10.3 
Populations for Analyses ............................................................................................ 75 
10.4 
Statistical Analyses ..................................................................................................... 75 
11 COLLABORATIVE AGREEMENTS ................................................................................. 76 
11.1 
Cooperative Research and Development Agreement (CRADA) ............................... 76 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................... 76 
12.1 
Rationale For Subject Selection ................................................................................. 76 
12.2 
Participation of Children ............................................................................................ 76 
12.3 
Evaluation of Benefits and Risks/Discomforts ........................................................... 76 
12.4 
Consent Process and Documentation ......................................................................... 77 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 78 
13.1 
Study Discontinuation and Closure ............................................................................ 78 
13.2 
Quality Assurance and Quality Control ...................................................................... 79 
13.3 
Conflict of Interest Policy........................................................................................... 79 
13.4 
Confidentiality and Privacy ........................................................................................ 79 

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14 PHARMACEUTICAL INFORMATION ............................................................................. 80 
14.1 
Copanlisib (BAY 80-6946, Aliqopa) (IND #141280) .............................................. 80 
14.2 
Rituximab ................................................................................................................... 84 
15 REFERENCES ..................................................................................................................... 87 
16 APPENDICES ...................................................................................................................... 92 
Appendix A:  Performance Status Criteria ............................................................................... 92 
Appendix B:  Guidelines for Pregnancy and Nursing .............................................................. 93 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
x United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES AND ENDPOINTS 
1.1.1 Primary Objective 
To determine the complete response rate after copanlisib + rituximab induction therapy  
1.1.2 Secondary Objectives 
x To determine the safety and tolerability of induction therapy with copanlisib and 
rituximab  
x To determine the clinical activity and depth of response after induction therapy with 
copanlisib and rituximab 
x To determine the durability of responses after induction therapy with copanlisib and 
rituximab 
x To assess time to next treatment, progression-free survival, and overall survival  
1.1.3 Exploratory Objectives 
x To determine if induction therapy with copanlisib and rituximab can achieve deep and 
durable responses in patients with “high-risk” FL as defined by published gene expression 
signatures and mutational profiles  
x To identify a mutational or gene-expression signature that predicts early clinical response 
to copanlisib monotherapy 
x To identify a mutational or gene-expression signature that predicts clinical response to 
induction therapy with copanlisib and rituximab 
x To identify a mutational or gene-expression signature associated with intrinsic resistance 
to induction therapy with copanlisib and rituximab 
x To explore the mechanisms of acquired resistance to copanlisib + rituximab 

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x To determine if ctDNA assays such as clonoSEQ identify molecular relapse prior to 
clinical progression in FL 
x To determine if copanlisib and rituximab induces durable complete responses in patients 
with untreated follicular lymphoma characterized by the CCP-32 assay  
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Trial design summary 
This study will evaluate the safety and efficacy of copanlisib and rituximab when used as frontline 
induction therapy for patients with untreated FL. Patients who achieve CR after the initial 6 
induction cycles of copanlisib and rituximab will be allowed to stop therapy and will undergo 
active surveillance for relapse with periodic CT scans and assays for ctDNA.  Patients who achieve 
a PR after the initial 6 induction cycles of copanlisib and rituximab will be treated with an 
additional 6 cycles of extended induction therapy before stopping therapy and initiating active 
surveillance. Patients who do not achieve at least a PR after the initial 6 induction cycles of 
copanlisib and rituximab will stop therapy and initiate active surveillance.  All patients who relapse 
or progress after copanlisib and rituximab induction therapy and meet clinical criteria for salvage 
therapy will be offered standard treatment with a monoclonal anti-CD20 antibody and 
chemotherapy. An important objective of this study is to determine the molecular correlates of 
response to copanlisib. 
1.2.2 Follicular lymphoma  
Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL), 
accounting for about 20-25% of cases(1). The clinical course is highly variable; many patients 
have indolent disease that is slowly progressive and defined by a perpetually relapsing and 
remitting course, while other patients experience rapid growth of lymph nodes, histologic 
transformation, early recurrences, or refractory disease(2, 3). FL is generally not curable with 
standard frontline systemic chemotherapy, although some patients may achieve durable remissions 
after chemotherapy with rituximab(4).  The overall prognosis for patients with FL has improved 
in recent decades and the median overall survival in the modern rituximab era is over 18 years(5).  
Given the heterogeneity in clinical outcomes, current research focuses on understanding the 
molecular biology of patients with FL at the highest risk of early disease progression after standard 
frontline chemotherapy. Patients who meet this clinical definition of “high-risk” FL could thereby 
be prioritized for treatment with novel agents designed to overcome intrinsic chemotherapy 
resistance.  
The Follicular Lymphoma International Prognostic Index (FLIPI) is a prognostic score that 
incorporates baseline clinical variables for the purpose of identifying subgroups with differences 
in survival(6). The FLIPI scoring system was determined on the basis of a retrospective 
multivariate analysis of over 4000 patients with newly diagnosed FL and separates patients into 
three major risk groups (low, intermediate, high) on the basis of age, stage, serum lactate 
dehydrogenase (LDH), hemoglobin, and the number of nodal sites. The FLIPI scoring system has 
been validated to predict clinical outcomes in FL, but was developed before rituximab, and cannot 
be used as a guide for individual treatment decisions. Another international project was conducted 
on over 1000 patients with newly diagnosed FL treated with rituximab-based regimens termed the 
FLIPI-2 that incorporates measures of tumor bulk and beta-2-microglobulin(7). Both the FLIPI 
and FLIPI-2 are unable to perform at the individual patient level and are not biologic classifiers.(7)  
Another important limitation of the FLIPI scores is the inability to separate age from underlying 

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biology. Although, patients under 40 years old are a small subset of patients with FL, these patients 
remain largely understudied, and represent an unmet clinical need as they may have more favorable 
features that respond to novel targeted therapies and can avoid the long-term risks associated with 
chemotherapy(8, 9). 
A retrospective analysis of 588 patients with FL in the National LymphoCare database 
demonstrated that approximately 20% of patients experience progression of disease within 2 years 
of diagnosis (POD24) despite therapy with rituximab plus cyclophosphamide, doxorubicin, 
vincristine, and prednisone (R-CHOP).(10) The patients with POD24 had significantly worse 
overall survival including a hazard ratio for early death of 7.17 (95% CI, 4.83 to 10.65) compared 
with the reference group(10). A follow-up analysis known as the Follicular Lymphoma Analysis 
of Surrogacy Hypothesis (FLASH) study performed a pooled analysis of 13 randomized clinical 
trials of patients in both the pre and post rituximab era (total sample size of 5,453) to validate 
POD24 as an early clinical endpoint in FL datasets(11). A landmark analysis confirmed the 
association between POD24 and overall survival (OS) in patients who were alive 24 months after 
trial registration. Patients alive without progression at 24 months were younger and more 
commonly had favorable PS, limited stage, low FLIPI risk score, normal baseline hemoglobin, and 
normal baseline B2M. Taken together, these results indicate that early progression after induction 
chemotherapy is an early clinical indicator of poor survival in FL. However, the biology 
underlying this poor-risk group of FL patients is unknown, and it cannot be applied prospectively 
to identify high-risk patients who have not yet undergone systemic treatment.   
The first biologic-based classifier for FL was established with gene-expression profiling (GEP) 
performed on baseline tumor samples in 191 patients(12). This landmark study represented the 
first evidence that survival outcomes in FL correlate with the molecular features of the 
nonmalignant immune cells (termed the Immune Response survival predictor score; IR-1 and IR-
2) in the baseline biopsy specimen, and was independent of clinical variables(12). These signatures 
have not been translated to the clinic, in part, because the technology used was based on fresh-
frozen tissue samples and a clinically applicable, reproducible assay will need validation on 
paraffin-embedded tissue specimens. Novel GEP signatures have recently been reported that 
identify a subset of high-risk patients that make up 25% of those undergoing first-line therapy(13).   
The prognostic value of combining individual somatic mutations with clinical variables was 
retrospectively assessed in two separate cohorts of patients with FL who underwent first-line 
therapy(14).  A prognostic model was created by combining clinical variables with the result of 
next-generation DNA sequencing panels that tested the mutation status of 74 relevant genes(14). 
Patients were treated uniformly, and biopsies were within 1 year of starting therapy. The resulting 
risk model, termed the m7-FLIPI, combines the ECOG performance status, the FLIPI score, and 
the mutational status of 7 genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and 
CARD11). The m7-FLIPI demonstrated superior predictive power over clinical factors alone and 
identified a subgroup of FL patients (28% of total cohort) who had a 5-year failure-free survival 
of only 38.29% (95% CI 25.31-57.95). These findings were validated in a separate cohort and 
identified a subgroup of FL patients (22% of total cohort) with a 5-year failure-free survival of 
25% (95% CI 12.5-49.99).(14). The m7-FLIPI, was recently analyzed for its ability to predict 
POD24 after initial therapy(15) The study confirmed the poor overall survival of FL patients who 
progress within 2 years after initial therapy, but 39% and 57% of cases with POD24 within the two 
cohorts tested, respectively, were categorized as “low-risk” by the m7-FLIPI(15). Conversely, 
14% and 21% of patients within the two cohorts, respectively, were considered “high-risk” by m7-

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FLIPI, did not progress early after initial therapy.  
Taken together, these findings highlight the need for further refinement of biologic-based risk 
assessments of prognosis from the time of diagnosis. Precise characterization of the molecular 
biology of “high-risk” FL could facilitate the proper selection of patients for novel treatment 
regimens designed to overcome intrinsic chemotherapy resistance (16).  
1.2.3 Non-cytotoxic combination therapy in FL 
The standard approach to frontline treatment of FL is combination chemotherapy with the addition 
of a monoclonal antibody targeting CD20, such as rituximab(17). Although some patients are 
treated with rituximab monotherapy, this approach is most commonly applied to patients with low 
tumor burden and/or with advanced age or co-morbid conditions that preclude the safe use of 
conventional cytotoxic chemotherapy(17, 18). Randomized phase III studies have demonstrated 
that rituximab added to combination chemotherapy platforms improves both PFS and OS 
compared to chemotherapy alone(19-21). Newer chemotherapy platforms and novel anti-CD20 
antibodies have been tested and demonstrate high overall response rates including the ability to 
achieve remission in many patients(22-24). However, no evidence exists that combination 
chemotherapy + anti-CD20 monoclonal antibodies can reliably cure patients with FL(4, 23, 25).  
Further, cytotoxic chemotherapy is associated with significant short-term toxicities and long-term 
complications including secondary malignancies and increased risk of infections(4, 24).  Since 
achieving a prolonged remission duration while maintaining quality of life is important in FL 
therapy, novel combinations are needed(26). The incorporation of novel targeted agents that target 
oncogenic pathways such as B-cell receptor signaling raise the intriguing possibility of 
“chemotherapy-free” combinations that can be tailored to individual subsets of FL patients and 
possibly result in deep and durable remissions. 
Phase II studies have investigated frontline treatment regimens that incorporate non-cytotoxic 
agents such as lenalidomide combined with rituximab (R2) and demonstrated very high overall 
response rates.(27, 28). Lenalidomide-rituximab was tested in a single institution study of 46 
patients with previously untreated FL and demonstrated an overall response rate of 95% including 
87% rate of complete response(27).  A second multi-center study by the Alliance for Clinical Trials 
in Oncology tested the same regimen in 66 patients with previously untreated FL and showed an 
ORR of 95%, a CR rate of 72%, and a 2-year PFS of 86%(28). Based on these promising phase II 
results, lenalidomide plus rituximab was compared to rituximab with combination chemotherapy 
in an ongoing randomized phase III study (RELEVANCE study), that has recently reported no 
difference in CR rates at 30 months (CR30) or progression-free survival (press release).  It is 
unknown if lenalidomide plus rituximab benefits certain subsets of patients or provides benefits 
regarding toxicities or quality of life. 
Recommendations for clinical trial development in FL highlight the importance of identifying 
effective therapies for high-risk FL patients as well as the need for comprehensive molecular 
characterization of the tumors that respond to novel therapies(26). In this way, therapy selection 
may ultimately be determined by individual risk or disease biology (i.e. precision medicine)(16).  
Recognizing that precision medicine focuses on subsets of patients that are most likely to respond 
to targeted therapies, a series of smaller phase II trials with strong translational endpoints are 
required to better understand the correlation between tumor biology and tumor response(26). An 
important objective of this trial is to define the complete response rate as well as the complete 
molecular remission rate, using sensitive markers of minimal residual disease (MRD), after 
therapy with copanlisib plus rituximab. Further, the durability of those remissions will be 

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investigated as complete responses that last at least 30 months (CR30); this endpoint was selected 
as a secondary endpoint of interest since it was recently shown to be a valid surrogate of both PFS 
and OS(29). Finally, a fundamental need in frontline therapy for FL includes regimens that are 
effective without a requirement for indefinite therapy or prolonged maintenance schedules(26).  
For this reason, a defined period of treatment duration was selected for this trial with an option for 
re-treatment in patients who relapse after complete response. 
1.2.4 Phosphoinositide 3-kinase (PI3K) pathway as a therapeutic target  
The phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) pathway, also known as the AKT 
signaling pathway, holds a central role for normal cellular responses to growth factors and cellular 
homeostasis(30, 31). As a consequence, aberrant activation of the PI3K pathway enhances cell 
survival and proliferation, thereby leading to malignant transformation across a variety of cancers. 
Human cells express three classes of PI3K enzymes and mammals express four class I catalytic 
isoforms (p110D, E, J, and G).  Class IA PI3Ks are heterodimeric enzymes consisting of regulatory 
p85 and catalytic p110 subunits and are primarily responsible for phosphorylating the second 
messenger, phosphatidylinositol 4,5-bisphosphate (PIP2) (Figure 1). Redundancy exists since 
each of the catalytic subunits can bind to each of the regulatory subunits and different heterodimers 
are recruited to the same receptors(32).  The p110D and p110E proteins are ubiquitous whereas the 
expression of p110J and p110G are predominantly within immune cells. The PI3K family members 
participate in a broad range of cellular regulatory processes including growth, proliferation, 
metabolism, and motility(33).  Notably, the immune system relies on PI3K signaling and catalytic 
isoforms must be properly balanced for normal immune cell development. 
Figure 1:  Class IA PI3Ks enzymes 
 
P110D is the only PI3K catalytic subunit isoform that is significantly associated with cancer-
associated somatic mutations in its gene, PIK3CA(34), but other mechanisms of PI3K activation 
exist including the loss of the tumor suppressor, phosphatase and tensin homolog gene, PTEN(35).  

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Further, class I PI3Ks are involved in the recruitment of a number of specific proteins to 
membrane-signaling complexes, and PI3K effectors including serine/threonine kinases of the AKT 
family, tyrosine kinases of the TEC family (ITK, BTK, etc.), as well as mTORC1 and 
mTORC2(31). In this way, multiple downstream signaling pathways can be triggered by PI3K 
activation. The pathway also contributes to cancer-promoting aspects of the tumor 
microenvironment including angiogenesis and immune cell crosstalk (Figure 2).  
 
Figure 2:  PI3K activation pathway 
 
Due to its central role in multiple malignancies, a number of agents have been developed that target 
the various PI3K isoforms.  However, since the PI3K pathway is important for the regulation of a 
variety of physiological processes in virtually all tissues types, the clinical development of targeted 
PI3K inhibitors has been slowed by the emergence of dose-limiting toxicities and on-target adverse 
events. Idelalisib (Zydelig) is a highly selective, orally bioavailable inhibitor of the PI3K-G 
isoform, and is FDA-approved for use as monotherapy in relapsed FL in patients who have 
received at least two prior systemic therapies(36).  Idelalisib was approved on the basis of its ability 
to achieve clinical responses in patients who were “double-refractory” to both rituximab and 
alkylating agents.  The overall response rate to idelalisib in this refractory population was 57% 
including a 6% rate of complete responses. Potentially more intriguing, however, is the ability of 
idelalisib to remain effective in patients who relapse within two years of chemotherapy 
(POD24)(37). In 37 patients with relapsed FL who had experienced early progression after 
chemotherapy, idelalisib demonstrated an ORR of 59.4% and the median duration of response in 
these patients was 11.8 months (95% CI, 3.8, not reached).  The PI3K pathway serves to attenuate 
the inflammatory response, however, and the resulting pro-inflammatory effect of targeted 
inhibition with idelalisib resulted in severe toxicities of autoimmune colitis, mucositis, and 
pneumonitis in some patients. These toxicities resulted in a black box warning in the FDA label 
warning of fatal and serious toxicities associated with idelalisib including hepatic, severe diarrhea, 
colitis, pneumonitis, and intestinal perforation.  Taken together, these results establish the PI3K 
pathway as an attractive target for patients with high-risk FL, but with important caveats regarding 
potential toxicities. 
1.2.5 Copanlisib (BAY-80-6946, Aliqopa) 
Copanlisib is an intraveneous pan-class I PI3K inhibitor with predominant activity against the 
PI3K-D and PI3K-G isoforms. Copanlisib uses an intermittent dosing schedule designed to achieve 
optimal target inhibition within the tumor while sparing normal tissue.  Indeed, the strategy of 
intermittent dosing was more effective in mice bearing breast cancer xenografts than continuous 

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dosing(38). Another potential benefit of simultaneous targeting of the PI3K-D isoform is that 
upregulation of alternative isoforms over time may be a mechanism of resistance to selective PI3K-
G inhibitors(39, 40). Studies in mantle cell lymphoma cell lines and from patient samples have 
shown that p110D expression increased significantly upon relapse after treatment with idelalisib, 
suggesting p100D plays a mechanistic role in relapse. In addition, combined inhibition of both 
p110-D and p110-G isoforms was a more effective strategy for inhibiting constitutive PI3K 
activation in cell lines(39). 
Pre-clinical studies of copanlisib
A set of primary PD studies was performed to characterize and assess the efficacy and 
specificity of copanlisib as a single agent and in combination with investigational or established 
therapeutic agents in various models in vitro and in vivo. Secondary PD was addressed in the 
frame of the primary PD and safety pharmacology. The safety pharmacology studies addressed 
the impact of copanlisib on vital organ functions (CNS, cardiovascular system [including ECG], 
respiratory system) as well as on supplemental organ systems and functions. Pharmacodynamic 
interaction studies with various antidiabetics have been performed. Results of the program are 
summarized below.
Metabolism of copanlisib
In vitro investigations revealed oxidation and/or dealkylation reactions at the alkylmorpholine 
side chain as the most important biotransformation reactions in liver microsomes and 
hepatocytes of various animal species and man. No major species differences were observed. 
Based on the in vitro data, oxidative metabolism of copanlisib was predominantly catalyzed by 
CYP3A4 (>90%) and to a minor extent by CYP1A1 (<10%). In vitro investigations revealed 

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that enzymatic activities of major CYP and UGT isoforms as well as DPD were not affected in 
the presence of copanlisib (IC50 >50 μM) or metabolite M-1 (IC50 > 20 μM). Copanlisib and 
its metabolite M-1 showed no induction of CYP1A2 and CYP3A4 in the in vitro test system up 
to concentrations of 1111 μg/L. Therefore, clinically relevant PK DDI through 
inhibition/induction of major CYP and UGT isoforms or DPD (IC50 > 20 μM) caused by 
copanlisib and metabolite M-1 are unlikely.
Absorption of copanlisib
The pharmacokinetics of copanlisib were very similar in rats, dogs and Cynomolgus monkeys. 
The low to moderate clearance and a high volume of distribution resulted in moderate to long 
elimination half-lives of parent compound between 4 and 17 hours. The pharmacokinetic in 
mice was different and showed a very high CL. Thus, elimination occurred with a very short 
t1/2 of about 1 hour. The pharmacokinetics of copanlisib were almost linear in rats and dogs 
after administration of the lower dose levels. With increasing doses, a slight tendency to an 
over-proportional increase of the AUC was observed in rats and dogs. This trend was not 
reflected by the Cmax Pharmacokinetics was not dependent on sex and no relevant drug 
accumulation was observed in the rat and dog 1 Cycle, repeat-dose toxicity studies.
The extent of plasma protein binding of copanlisib was low in various species with free fractions 
between 10% and 42% (15.8% in human plasma). With the exception of Cynomolgus monkeys, 
free fractions of copanlisib were 2 to 3 times higher in the various animal species in comparison 
with man. There was no saturation of plasma protein binding of copanlisib within the 
investigated pharmacological and toxicological relevant concentration range (100-10000 μg/L). 
The plasma protein binding of the metabolite M-1 was similar to the unchanged copanlisib. The 
free fractions ranged between 20% and 56% (20.0% in human plasma).
Excretion of copanlisib
In rats, dogs, and man, radioactivity was excreted mainly via the biliary/fecal route after i.v. 
administration of [14C]copanlisib. About 10% of the administered radioactivity was excreted 
by the renal route in rats and dogs. In man, 22% of the administered radioactivity were excreted 
via urine. In rats, considerable direct radioactivity excretion into the gastrointestinal contents 
was observed.
Pharmacokinetics of copanlisib
The pharmacokinetics of copanlisib (BAY 80-6946) were studied in vivo in CD-1 mice, Wistar 
rats, Beagle dogs, and Cynomolgus monkeys after i.v. administration copanlisib or 
[14C]copanlisib. The free base, BAY 80-6946, was formulated in a mannitol solution after 
addition of hydrochloric acid, so that the hydrochloride/dihydrochloride salt was formed in the 
administration solution. The dihydrochloride salt of BAY 80-6946 (BAY 84-1236) was used in 
some of the in vitro studies. All doses and equivalent concentrations refer to BAY 80-6946 (i.e., 
the pharmacologically active component). Data on PK after repeated administration were 
derived from the exposure determination performed as part of the toxicity studies in Wistar rats 
and Beagle dogs. Distribution studies in rats were performed by means of autoradiography. 
Additionally, in vitro studies were performed to investigate plasma protein binding, blood 
cell/plasma partitioning, drug metabolism in several species including humans and drug 
transporter characteristics as well as pharmacokinetic drug-drug interaction potential towards 
metabolizing enzymes and transporters.

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14 
Results of the program are briefly summarized as: 
x Almost linear pharmacokinetics in rats and dogs after i.v. administration, tendency to over-
proportional increase in the AUC after higher doses. 
x Low extent of plasma protein binding of copanlisib in various species with free fractions 
between approximately 10% and 42% (15.8% in human plasma). Protein binding of 
metabolite M-1 was observed with free fractions between 20% and 56% (20.0% in human 
plasma). 
x Significant distribution of radioactivity (copanlisib and radioactive metabolites) from 
blood into the organs and tissues of rats, with higher concentrations in organs and tissues 
in comparison with blood. Moderate penetration of the blood-brain barrier; high affinity to 
melanin-bearing tissues. 
x Penetration of the placental barrier in rats to a low to moderate extent, lower fetal organ 
and tissue radioactivity concentrations than in maternal organs and tissues, with the 
exception of brain (higher radioactivity concentrations in fetuses than in dams). 
x Oxidation and/or dealkylation at the alkylmorpholine side chain are major 
biotransformation pathways in liver microsomes and hepatocytes of various animal species 
and man; with no major species differences. CYP3A4 is major metabolizing enzyme in 
man (>90%), while CYP1A1 (<10%) contributes to a minor extent based on the in vitro 
data. 
x Copanlisib was the predominating component in plasma of mouse, rat, dog, and man 
(>84% of total radioactivity AUC). Metabolite M-1 was the only relevant circulating 
metabolite in plasma of rat and man (about 10% and 5% of total radioactivity AUC in rat 
and man, respectively). Metabolites M-1 and M-3 were occasionally found in mouse 
plasma. 
x In man and rat, balanced excretion via unchanged copanlisib and oxidative 
biotransformation products. In dogs, mainly oxidative biotransformation and less excretion 
of unchanged copanlisib. Metabolites almost solely formed by dealkylation and/or 
oxidation at the alkylmorpholine side chain. Biotransformation of copanlisib is mediated 
by CYP3A4 (>90% of metabolism) and to a minor extent by CYP1A1 (<10% of 
metabolism). Radioactivity excreted mainly via the biliary/fecal route in rat (85%), dog 
(75%) and man (64%) after i.v. administration of [14C] copanlisib. About 10% of the 
administered radioactivity excreted by the renal route in rats and dogs. In man, 22% of the 
administered radioactivity excreted via urine. 
x Unchanged copanlisib represented approximately 30% of the administered dose in feces 
and 15% in urine, respectively. 
x [14C]Copanlisib-related radioactivity was secreted into the milk of lactating rats only to a 
low extent (1.7% of dose). 
x Based on in vitro studies with different cell lines, copanlisib is a substrate of P-gp and of 
BCRP. Copanlisib is not a substrate of OCT, OAT or OATP. Copanlisib is not a substrate 
of MATE1 or MATE2K 
x Low risk for clinically relevant PK DDI through inhibition (IC50 > 50 μM) or induction 
(assessable up to 1111 mg/L in vitro) of major CYP isoforms, inhibition of major UGT 

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15
isoforms (IC50 > 50 μM) and inhibition of DPD (IC50 > 20 μM) caused by copanlisib 
(clinically relevant Cmax: about 1 μM in patients).
x
P-gp (IC50: 7 μM and 7.6 μM for digoxin and dipyridamol, respectively) and BCRP (IC50: 
11.5 μM for topotecan) mediated transport was inhibited by copanlisib in vitro. Metabolite 
M-1 showed only a marginal inhibitory effect on P-gp and BCRP-mediated transport 
(IC50: > 40 μM). Copanlisib was a potent inhibitor of MATE2K (IC50: 0.09 μM for 
metformin, 0.58 μM for MPP+) and an inhibitor of MATE1 (IC50: 10.8 μM for 
metformin). The uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and 
OCT2 were not inhibited by copanlisib. No inhibition of BSEP and MRP2 by copanlisib 
was observed. Clinically relevant PK DDI with P-gp, BCRP, MATE1, BSEP and MRP2 
substrates as well as substrates of hepatic and renal uptake transporters are unlikely. 
Copanlisib plasma concentrations in patients exceed the IC50 for MATE2K-inhibition (up 
to 6 hours after copanlisib infusion at the 60 mg dose). The clinical relevance of this 
observation is unknown.
x
According to the copanlisib package insert, itraconazole (CYP3A and BCRP inhibitor) is 
associated with a 53% increase in copanlisib AUC and rifampin (induces CYP3A and P-
gp) causes a 63% decrease in AUC. So deactivating variants in CYP3As would plausibly 
be associated with PK as well. There are several SNPs in CYP3A4 and CYP3A5 with 
robust levels of clinical evidence for association with PK of some medications. Copanlisib 
is also a known substrate of P-gp and BCRP. The PharmacoScan platform (Thermo) is able
to test 4,627 variants in 1191 different pharmacogenes, including all of those involved in 
copanlisib metabolism and transport, and will be utilized to understand copanlisib 
pharmacogenetics.
Pharmacodynamics of copanlisib
The pharmacodynamic effects on glucose and plasma insulin levels as well as [18F]FDG-
CT/PET have been investigated in the first-in-man Study 12871 using copanlisib monotherapy 
at different doses. All 47 non-diabetic patients treated at ≥0.4 mg/kg copanlisib experienced a 
PD effect as well as all 6 diabetic patients treated at 0.4 mg/kg copanlisib. Peak plasma glucose 
values were seen 5 to 8 hours after the start of the copanlisib infusion. Hyperglycaemia was 
reversible, i.e., not observed after copanlisib treatment had been permanently discontinued. 
Dose-related increases in glucose and insulin as well as copanlisib exposure-related increases 
in plasma glucose were observed. Treatment with copanlisib resulted in a reduction in the 
pharmacodynamic marker pAKT in surrogate tissue platelet rich plasma (PRP) with a median 
decrease up to 81.5% at the 0.4 mg/kg dose level and up to 77.8% at the 0.8 mg/kg dose level 
compared with baseline, indicative of a potent inhibition of the PI3K pathway in surrogate tissue 
at both tested dosages of copanlisib (Study 16790). Treatment with copanlisib was associated 
with modulation of blood glucose with corresponding changes in C-peptide and insulin, 
showing a trend towards a dose dependency (0.8 mg/kg >0.4 mg/kg). Copanlisib has been 
shown to prolong the QT/QTc interval, which may lead to an increased risk for ventricular 
arrhythmias. For this reason, it is recommended to use copanlisib with caution in patients who 
have, or may develop prolongation of QT, such as patients with a congenital long QT syndrome, 
patients taking certain anti-arrhythmic medicines or other medicinal products that lead to QT 
prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or 
hypomagnesemia.

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16 
Clinical studies of copanlisib 
A phase I study of copanlisib was done in patients with advanced solid tumors and various 
subsets of NHL demonstrated to determine the safety, tolerability, pharmacokinetics, and 
maximum tolerated dose (MTD) of copanlisib(41). This study included a cohort of patients with 
type 2 diabetes mellitus.  Patients received three weekly intravenous infusions of copanlisib per 
28-day cycle over the dose range 0.1–1.2 mg/kg and plasma copanlisib levels were analyzed 
for pharmacokinetics.  Fifty-seven patients were treated and the MTD of copanlisib was 
established at 0.8 mg/kg. Copanlisib typically reached maximum plasma concentration (Cmax) 
between 0.5 and 1 h. The terminal half-life was 38.2 h (coefficient of variation 43%), and no 
accumulation was observed after once-weekly administration. Patients received a median of 
two treatment cycles (range, 1–49) of copanlisib, and the median duration of treatment was 6 
weeks (range, 0.1–2051). Peak exposure of copanlisib correlated with transient hyperglycemia 
post-infusion. Blood glucose values typically peaked 5–8 h after the start of copanlisib infusion 
and declined to pre-diabetic levels 24–48 h after infusion and to normal levels before the start 
of the next infusion. The most common drug-related adverse events (AEs) were metabolic 
(hyperglycemia), gastrointestinal (nausea and diarrhea), and cardiovascular (hypertension). The 
overall incidence of drug-related all-grade and grade 3 hypertension was 21% and 14%, 
respectively. The incidence and severity of gastrointestinal toxicities due to copanlisib were 
low; nausea was the most common drug-related gastrointestinal toxicity (37%; all events grade 
≤2) and diarrhea was less common (all-grade: 16%; grade ≥3: 2%). Elevated aminotransferase 
was primarily an incidental laboratory toxicity finding and was mostly grade 1; grade ≥3 in five 
patients. Drug-related pneumonitis was reported in two cases. Most AEs were managed with 
dose modifications, and there was only one drug-related AE leading to permanent 
discontinuation [left ventricular systolic dysfunction], which resolved after discontinuation.  In 
this phase 1 study, all patients (n=6) with FL responded (one CR and five PRs)(41). One patient 
with FL was treated for 47 months, and another went off study after having been treated for a 
total of 43 months.  
Copanlisib was further evaluated in a multicenter phase II study for patients with indolent 
lymphoma that was relapsed or refractory after two previous lines of therapy(42). In this study, 
142 patients (n=104 with FL) were enrolled and treated with copanlisib 60mg IV on days 1, 8, 
15 of a 28-day cycle until disease progression or unacceptable toxicity.  The primary end point 
of the study was objective response rate (ORR).  The ORR was 59% and 12% of patients 
achieved a complete response.  The median time to response was 53 days and the median 
duration was 22.6 months.  The toxicity profile of copanlisib was manageable with the most 
frequent treatment-related adverse events of grade 3 or higher were transient hyperglycemia 
(41%), transient hypertension (24%), neutropenia (24%), and lung infection (15%)(42). The 
median duration of treatment was 22 weeks and patients received 96% of the planned dosing.  
Dose delays occurred in 74% of patients and most of these were due to adverse events.  In 25% 
of patients, adverse events led to discontinuation of copanlisib.  An adverse event of special 
interest was noninfectious pneumonitis which occurred in 8% of patients. Three opportunistic 
infections occurred on this study: two P. jirovecii infections and one asperillosis infection. Six 
patients (4%) died during treatment or within 35 days of treatment discontinuation.  Of these 6 
deaths, three were considered treatment-related: lung infection, respiratory failure, and a 
cerebral thromoembolic event. Since p110D mediates most tissue responses to insulin and 
maintains glucose homeostasis, hyperglycemia was an expected on-target effect of copanlisib 
but successfully managed in most cases with the use of intravenous fluids and only occasional 

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17
use of insulin was required.  Gene set enrichment analysis (GSEA) was performed in all patients 
with available gene expression data, and patients with high PI3K/BCR gene expression scores 
were the likeliest to respond to copanlisib.  These data led to the FDA to approve the use of 
copanlisib for patients with relapsed or refractory FL after treatment with at least two lines of 
prior therapy. 
Copanlisib in Combination with Rituximab
Study 17067 (CHRONOS 3) is a randomized, double-blind, placebo-controlled, two-arm, phase 
III study to evaluate the efficacy and safety of copanlisib in combination with rituximab in 
patients with relapsed indolent NHL (iNHL). Approximately 567 (435 FL and 132 other iNHL) 
patients will be randomly assigned in a 2:1 ratio to one of the double blinded treatment arms: 
copanlisib plus rituximab or placebo plus rituximab.  To date, more than 270 patients have been 
enrolled on this study since February 2015 with close monitoring of safety by the study’s data 
monitoring committee.  No interruption or suspension of enrollment has been noted on the 
study.  When more detailed toxicity data is available, and if there is a safety signal of concern, 
a revision to this protocol to include stopping rules may be considered.
1.2.6
Circulating tumor DNA (ctDNA)
Small fragments of DNA from normal and diseased tissue is constantly shed into the bloodstream 
as cell-free DNA (cfDNA) through processes of apoptosis, necrosis, and secretion.(43, 44) A very 
small fraction of the cell-free DNA in patients with FL will originate from malignant cells, and 
can be captured as circulating tumor DNA (ctDNA)(45-47).  Modern next-generation sequencing 
(NGS)-based assays have enabled the detection and quantification of ctDNA in the majority of 
patients with FL(48).  We will use a modern ctDNA platform that combines universal PCR primers 
for the variable-dense-joining (VDJ) region of the immunoglobulin receptor with NGS
technologies (i.e. clonoSEQ)(49).  This ctDNA assay is highly tumor-specific and can be used 
as a method for disease detection at the molecular level in a variety of B-cell lymphomas(48, 50, 
51).  
Assessment of ctDNA along critical clinical landmark timelines, including use as an active 
surveillance monitoring tool for patients who are in remission, offers the promise to overcome
fundamental limitations of our current definitions of disease response.  Namely, radiographic 
imaging scans are unable to measure minimal residual disease (MRD).  Many patients who achieve 
a complete response to therapy based on imaging scans will have the persistence of MRD, 
highlighting the need for more sensitive methods for disease detection(52, 53).  Since the goal of 
our study is to determine patients who are uniquely sensitive to copanlisib, assays for ctDNA will 
be used to determine early signs of biologic activity during the copanlisib window, during 
induction therapy, and at the end of induction therapy to determine the rate of complete molecular 
remission (defined as patients who achieve complete response and are MRD-negative).   After the 
completion of induction therapy, patients will stop treatment and will be active monitored with 
both imaging scans as well as assays for ctDNA.  In this way, ctDNA can be used as a non-invasive 
method to monitor tumor response kinetics during therapy, define the depth of response to 
induction therapy, and be used as a surveillance tool for early disease detection after therapy 
cessation. Although clinical decisions regarding response to induction therapy and timing of 
salvage therapy will not be made based on the results of ctDNA in this study, we hypothesize that 
these assays may outperform conventional methods of determining prognosis prior to starting 
therapy, response to induction therapy, and early detection of disease relapse.  The data generated 

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18 
from this study is expected to inform future clinical trials that test the hypothesis of making clinical 
decisions based, in part, on the results of ctDNA assays. 
1.2.7 CCP-32 Gene Expression Profiling Assay in FL  
Follicular lymphoma (FL) is a clinically and biologically heterogeneous B-cell lymphoma and 
survival is improving with modern therapy. Yet patients who progress within 2 years of frontline 
therapy (POD24) have a 5-year overall survival of only 50%. The CCP-32 is a gene-expression 
profiling assay performed on FFPE tissue to identify FL patients who are high-risk for early 
progression (POD24) when treated with standard chemoimmunotherapy. We hypothesize that 
copanlisib and rituximab will induce durable complete responses in patients with untreated 
follicular lymphoma including those characterized as high-risk by the CCP-32 assay. 
1.2.8 Scientific correlates during the copanlisib window   
A critical component of this trial will be the comprehensive assessment of molecular and/or 
immunologic correlates that predict response to copanlisib in both tissue and peripheral blood(16).  
As with most targeted therapies, the accurate identification of patients most likely to respond to 
treatment will be paramount for the success of precision medicine(54).  Similarly, the identification 
of resistance mechanisms will be critical since both intrinsic and acquired resistance to PI3K 
inhibitors is commonly associated with mutations or copy number alterations of regulatory genes 
within the pathway or parallel oncogenic pathways(39). To reach these goals, our study design 
will utilize a “window of opportunity” in which patients will first receive copanlisib as a single 
agent in order to characterize predictive biomarkers including the potential molecular correlates of 
response. The Center for Cancer Research is uniquely positioned to overlay the strong translational 
endpoints within this trial. The Staudt lab will perform comprehensive molecular characterization 
of the tumors at baseline on FFPE blocks, and this evaluation will include whole-exome 
sequencing of tumor DNA, RNA-sequencing, and methylation arrays for copy number 
abnormalities. Further, the study will allow for an optional tissue biopsy after the window of 
copanlisib monotherapy to better assess early predictors of response, drug penetrance into tissue, 
and potential insights into the mechanisms of intrinsic resistance to copanlisib.  We aim to study 
the molecular correlates of response both in pre-treatment tumor tissue as well as through “liquid 
biopsies” obtained via ctDNA(49). 
The tumor microenvironment (TME) within FL may also influence response or resistance to 
targeted therapy since FL is a proliferation of malignant germinal center B-cells admixed with a 
varying proportion of nonmalignant immune cells such as T-cells, follicular dendritic cells, 
macrophages and stromal cells(55). The malignant cells in FL nodes retain a substantial inter-
dependence with the nonmalignant cells and other stromal elements that constitute the tumor 
microenvironment in a pattern recently described as “re-education”(56).  The spatial arrangement 
of the TME in FL varies across patients, however, and depends on genetic aberrations within the 
tumor cells as well as dependence on external stimuli for survival, proliferation, and immune 
escape(56). Early in the disease course, the lymph node architecture resembles that of normal 
reactive germinal centers, but the organization and dependence of the tumor cells on the TME is 
hypothesized to wane over the course of disease. We plan to explore the three-dimensional 
relationship of immune cells and stromal cells of interest in FL using a unique three-dimensional 
histo-cytometry method in collaboration with the Center for Advanced Tissue Imaging here at 
NIH.  The novel imaging technology will enable highly multiplexed, quantitative image analysis 
of tissues samples and can be performed serially. 

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19 
1.2.9 Rationale for response-adapted therapy design  
In order to develop a precision approach to therapy in FL, it is important to identify patients who 
are most sensitive to copanlisib and rituximab therapy.  The primary endpoint of our study is the 
CR rate after induction therapy since these are the patients who are likely to benefit most from this 
novel combination.  Other trials testing the use of novel agents in upfront treatment of FL have 
used treatment durations of 1 year, 2 years, or indefinite therapy(27, 57). These extended durations 
of treatment lead to exorbitant costs of treatment as well as longer periods of exposure to agents 
that may impair immune function.  Extended schedules of treatment may not be justified in patients 
with FL who have an indolent disease course and regimens that offer an option to discontinue 
therapy are justified.   
In our study, we plan to stop therapy in patients who achieve CR after the first 6 cycles of therapy.  
These patients will have received 9 doses of rituximab which is a standard treatment option for 
low tumor burden FL and will serve as a rational comparison to this combination(18). Further, 
discontinuing therapy in patients who achieve deep remissions allows for the testing of novel 
surveillance strategies including monitoring with non-invasive tests such as ctDNA(49).  If such a 
monitoring schedule proves itself to be feasible and effective, it could be further tested and 
developed as a method for rationally deciding treatment durations instead of empiric decision-
making that currently guides maintenance therapy in FL(58). 
It is also possible that treatment duration longer than 6 months is required to achieve a CR to 
induction therapy.  For this reason, patients who achieve at least a PR to therapy, but do not meet 
criteria for CR will be treated with an additional 6 cycle of copanlisib and rituximab at a reduced 
dose schedule of copanlisib of twice per cycle. The modified dosing schedule of copanlisib is 
hypothesized to decrease the number of adverse events associated with treatment, should improve 
patient adherence to long treatment durations, and will provide an opportunity to test if some 
patients require more than 6 cycles of copanlisib and rituximab to achieve a remission. 
Patients that do not respond to copanlisib and rituximab after 6 cycles of induction therapy will 
not be given further cycles of induction, since the likelihood of achieving a first response beyond 
6 cycles would be unlikely. In some situations, however, these patients may have derived clinical 
benefit and do not necessarily need to initiate immediate salvage therapy.  For this reason, these 
patients will stop therapy with copanlisib and rituximab, but will undergo active surveillance with 
ctDNA to further understand the correlations between quantitative results on ctDNA and the 
clinical criteria governing the need for initiation of salvage chemotherapy.  
1.2.10 Rationale for salvage chemotherapy  
The current standard of care for frontline treatment of patients with advanced-stage and high tumor 
burden FL remains combination chemotherapy with the addition of an anti-CD20 monoclonal 
antibody(26, 59). Select patients are treated with rituximab monotherapy, but this approach is 
typically reserved for patients with low tumor burden or with co-morbidities that prevent the safe 
administration of chemotherapy(26). The most commonly used frontline regimens consist of R-
CHOP, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), and rituximab, 
bendamustine (BR). A recent randomized study demonstrated that the use of an alternative anti-
CD20 monoclonal antibody, obinutuzumab, prolonged the PFS of FL patients when used as 
frontline therapy, but since no overall survival benefit has yet to be determined we consider 
rituximab-based therapy as the current standard of care(24).   

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In this protocol, we plan to treat all patients who relapse or progress after induction therapy with 
copanlisib and rituximab with either BR or R-CHOP as standard salvage chemotherapy.  The 
rationale for providing treatment with standard chemotherapy on this protocol is to ensure that 
patients willing to participate in our study of experimental treatment can be assured of an 
opportunity to get standard chemotherapy. Although standard salvage chemotherapy is not 
considered curative, it can induce long durations of remission in some patients.  Further, it is of 
scientific interest to determine if patients who are not sensitive to copanlisib-based therapy can 
achieve quality depths and duration of response to standard therapy.
1.2.11 Study Summary and Hypotheses
We hypothesize that induction therapy with copanlisib and rituximab will result in complete 
responses and durable remissions for most patients with untreated follicular lymphoma. We also 
anticipate that induction therapy with copanlisib and rituximab will be effective in patients with 
high-risk follicular lymphoma as defined by published gene expression and molecular signatures.
In addition, we anticipate that circulating tumor DNA via the clonoSEQ assay will appear in 
plasma months prior to clinical or radiographic relapse, and that progressive rises in ctDNA via 
clonoSEQ will predict the timing of second-line therapy. Finally, we hypothesize that patients 
who achieve a complete response to induction with copanlisib and rituximab lasting at least 6 
months will remain sensitive to re-treatment with copanlisib and rituximab. 
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
Patients must have a confirmed histologic diagnosis of FL, grade 1-2 or 3a, according to 
the criteria established by the most recent version of the World Health Organization
(WHO) classification system.  Pathologic diagnosis must be confirmed by Laboratory of 
Pathology, NCI  
Stage II-IV disease.  NOTE:  Patients with stage I FL who have been treated with 
radiation therapy and have subsequently relapsed are eligible.
No prior systemic treatment for FL with chemotherapy, targeted small molecule therapy, 
or monoclonal antibody therapy prior to the first dose of copanlisib treatment.  Patients 
may have received prior radiation therapy only; radiation therapy must have been 
completed >12 weeks prior to the first dose of copanlisib.  NOTE:  Prior short-term (d7 
days) use of corticosteroids for acute medical complications related to sites of FL 
involvement is permitted.
Patients must meet standard criteria for initiation of systemic therapy as evidenced by 
presence of one of the following:
x
Development of symptomatic enlarged lymph nodes or spleen
x
Development of B symptoms (fever, night sweats, weight loss) or severe pruritus
x
Development of significant serous pleural or pericardial effusions (small effusions 
seen only on CT scans are not indications for systemic therapy)

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x
Development of bone marrow failure as a result of involvement by FL and not 
attributable to other causes; this would be manifest as a Hgb < 9 g/dl, absolute 
neutrophil count < 1 x 109/L, or platelet count < 75 x 109/L
x
Critical organ involvement, organ compression (e.g., ureteric obstruction or 
epidural compression), or significant risk of future organ compressions
x
Increase in the size of lymph nodes on CT scans indicating progression of disease 
from previous CT scans
Adequate tissue from diagnostic biopsy; formalin fixed tissue block or 20 slides of tumor 
sample (archival or fresh) must be available for performance of correlative studies
Be t18 years of age on day of signing informed consent
NOTE:  Because no dosing or adverse event data are currently available on the use of 
(copanlisib) in patients <18 years of age, children are excluded from this study
ECOG performance status 0-2 (see Appendix A)
Adequate organ function as evidenced by the following laboratory parameters:  
x Absolute neutrophil count 
(ANC)
≥1,500 /mm3 (unless due to involvement by 
lymphoma or benign ethnic neutropenia)
x Platelets
≥75,000 / mcL (unless due to involvement by 
lymphoma; transfusions not permitted)
x Hemoglobin
≥8 g/dL (transfusions permitted)
x Renal function
Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 
m2 as estimated by the Modification of Diet in Renal 
Disease (MDRD) abbreviated formula. If not on 
target, a 24-hour urine creatinine clearance can be 
used to directly measure.
x Serum total bilirubin
≤ 1.5 X ULN OR
(< 3 x ULN for patients with Gilbert syndrome,   
patients with cholestasis due to compressive 
adenopathies of the hepatic hilum or documented 
liver involvement or with biliary obstruction due to 
lymphoma)
x AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver 
involvement by lymphoma)
x Lipase
≤ 1.5 x ULN
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 for at least 1 month  after the last dose of copanlisib and 
12 months after the last dose of rituximab, whichever is later, for WOCBP and for men 
after the last administration of study treatment. 
NOTE:  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 

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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.  See 
Appendix B for complete details of acceptable contraceptive methods.
Ability of patient to understand and the willingness to sign a written informed consent 
document
2.1.2
Exclusion Criteria
Known lymphomatous involvement of the central nervous system
History of any known primary or acquired immunodeficiency syndrome (e.g., HIV)
CMV PCR positive at baseline
Hepatitis B surface antigen (HbsAg) or core antibody (HbcAb) positive with a positive  
Hep B DNA Quantitative, HBV Viral Load result.
NOTE: Subjects with positive hepatitis B serology (HbsAg or HbcAb) may be enrolled 
onto the study but they must have a negative Hep B DNA Quantitative, HBV Viral Load 
result before enrollment. See Section 3.4.2 for more information.
Uncontrolled intercurrent illness including, but not limited to the following that may limit 
interpretation of results or that could increase risk to the patient at the discretion of the 
investigator:
x
Active autoimmune disease that has required systemic treatment in the past 12 
months (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs).  NOTE:  Replacement therapy (e.g., thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.
x
History of (non-infectious) pneumonitis that required steroids, evidence of 
interstitial lung disease or active, non-infectious pneumonitis.
x
Active hepatitis C infection.  NOTE:  Subjects who are hepatitis C antibody 
positive will need to have a negative HCV PCR result before enrollment.  Those 
with a positive PCR for hepatitis C are excluded.
x
Congestive heart failure > New York Heart Association (NYHA) class 2
x
Unstable angina
x
Myocardial infarction in the past 6 months
x
Uncontrolled hypertension despite optimal medical management
x
Arterial thromboembolic events such as cerebrovascular accident (including 
transient ischemic attacks), in prior 3 months 
x
Uncontrolled Type I or II diabetes despite optimal medical management
x
Any second malignancy that requires active systemic therapy

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x
Known mental or physical illness that would interfere with cooperation with the 
requirements of the trial or confound the results or interpretation of the results of 
the trial and, in the opinion of the treating investigator, would make the patient 
inappropriate for entry into the study.
x
Severe hepatic impairment (Child-Pugh C) 
Requirement to continue on any of the medications that are excluded (see Section 4.3)
Organ compromise that, in the opinion of the PI, necessitates immediate cytoreductive 
therapy
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
Major surgical procedure or significant traumatic injury (as judged by the investigator) 
within 28 days before start of treatment, or have not recovered from major side effects,  
open biopsy within 7 days before start of treatment
2.1.3
Recruitment Strategies
Study participants will be recruited from the population of patients screened in the lymphoid 
malignancies clinic of the National Institutes of Health.  Our research team currently has an active 
protocol to study the clonal evolution in FL that enrolls patients with untreated FL who are 
appropriate for observation as well as those who require immediate treatment.  In addition, we 
participate in a locoregional consortium of eight academic institutions within the Mid-Atlantic
region (Mid-Atlantic Lymphoma Research Consortium) that shares information regarding active 
clinical protocols and aims to enhance patient recruitment across the region.  Our patients for this 
study will therefore consist of those from the FL clonal evolution study, referrals from outside
physicians, and patient self-referrals. In addition, this study will be posted on NIH websites and 
NIH social media forums. 
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
x
Email, written, in person or telephone communications with prospective subjects 
x
Review of existing medical records to include H&P, laboratory studies, etc. 
x
Review of existing MRI, x-ray, or CT images
x
Review of existing photographs or videos
x
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
A waiver of consent for these activities has been requested in Section 12.4.1.
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the study consent. 
Assessments performed at outside facilities or on another NIH protocol within the timeframes 
below may also be used to determine eligibility once a patient has signed the consent (unless 
otherwise noted).

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NOTE:  Assessments and procedures to confirm study eligibility should be completed within 28
days prior to registration (unless otherwise noted).  See also the Study Calendar (Section 3.8).  
Clinical Evaluations
x
Disease history, including:  diagnosis, prior radiation treatment (if applicable), and 
significant prior/ongoing side effects and symptoms
x
Complete medical history, including: all active conditions considered to be clinically 
significant by the treating investigator
x
Physical examination, including: height (screening only), weight, vital signs (i.e., 
temperature, pulse, respiratory rate, and blood pressure); review of concomitant 
medications and symptoms/side effects; and, assessment of performance status using 
the ECOG scale
Laboratory Evaluations 
x
CBC with differential
x
Chemistry panels (as noted) or specific analyte required for eligibility, including:  
Creatinine (i.e., or Acute Care Panel); Albumin (i.e., or Mineral Panel), ALT, AST, 
total and direct (if required) bilirubin (i.e., or Hepatic Panel); serum lipase, and 24-hour 
urine creatinine clearance (if needed to measure CrCl)
x
Coagulation panel:  PT/INR and aPTT
x
LDH
x
Urinalysis (with microscopic examination if abnormal)
x
Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HbcAb), Hepatitis C 
antibody (HCV) [qualitative]) (within 3 months allowed)
o
Hep B DNA Quantitative, HBV Viral Load for subjects who are HBsAg or 
HbcAb positive.
x
CMV PCR and  CMV IgM and IgG
x
HIV antibody (within 3 months allowed)
x
Hemoglobin A1C
x
Urine and/or serum HCG in women of childbearing potential (within 7 days prior to 
initiation of study therapy)
Imaging Studies 
NOTE:  Results from NIH only.
x
CT chest, abdomen and pelvis or MRI
x
18F-FDG PET/CT
2.2.3
Other Procedures
x
Pathologic review/confirmation of diagnosis by Laboratory of Pathology, NCI (no time 
limit). A tissue sample is required for this evaluation; if archival sample is not available, 
a fresh tumor biopsy will be obtained.
x
Flow cytometry will be performed on peripheral blood for both diagnostic and staging 
purposes (only NIH results accepted; NCI Laboratory of Pathology)

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x
Bone marrow aspiration with flow cytometry (optional at screening at PI discretion) 
and biopsy (results from outside NIH accepted; within 12 months)
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at:
https://nih.sharepoint.com/sites/NCI-CCR-OCD-Communications/SitePages/OEC-
Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit.
2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) because of an
eligibility criterion (e.g., laboratory factor) may be rescreened if other eligibility are still met (e.g., 
prior treatment requirements, etc.). 
2.3.2
Treatment Assignment Procedures
NOTE:  For NCI CCR registration purposes only.   
Cohorts
Number
Name
Description
1
Untreated FL
Untreated FL Stage II-IV or stage I FL who have been 
treated with radiation therapy and have subsequently 
relapsed (up to 65 patients)
Arms
Number
Name
Description
1
Experimental treatment
Window of treatment with Copanlisib 60mg via IV for a 
single 28-day cycle, once weekly for the first 3 weeks and 
then a 1-week break followed by induction therapy with
copanlisib and rituximab. Induction therapy will be 6 cycles 
(28 days) of: copanlisib dose and administration same as 
window, rituximab 375mg/m2 via IV, once weekly for the 
first 4 weeks during cycle 1, subsequent cycles (cycles 2-6), 
rituximab will be dosed only once on day 1 of the cycle.
Further treatment with additional cycles of copanlisib + 
rituximab will be response adapted.
Arm Assignment
This is a single arm , non-randomized study (i.e., patients in Cohort 1 are directly assigned to 
Arm 1).

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27 
3.2 
DRUG ADMINISTRATION 
3.2.1 Drug Administration – Window and Induction Therapy 
The treatment cycle (i.e., “Cycle 0”) for the window of copanlisib monotherapy will be 28 days.  
Each cycle of treatment during induction therapy is 28 days. Patients will be treated for up to 6 
cycles of induction therapy with copanlisib and rituximab (i.e., Cycles 1-6).  A window between 
cycles of -3/+7 due to scheduling or other administrative reasons is allowed; additional delays may 
apply based on toxicities.   
Treatment will generally be given on an outpatient basis; however, may be given as an inpatient 
for matters of convenience or investigator preference in case of additional monitoring.   
3.2.2 Copanlisib 
All patients will receive copanlisib at a fixed dose of 60mg administered via IV in Cycle 0 and for 
Cycles 1-6.  Dosing is not based upon subject weight. Infusions may be done peripherally or via 
central venous access device.  
Copanlisib will be administered as a 60-minute infusion. Every effort should be made to target the 
infusion timing as close to 60 minutes as possible; however, a preferred window of -5/+10 minutes 
to account for variability of infusion pumps is permitted.  On infusion days, patient’s blood 
pressure will be monitored at 0 h (pre-dose), 30 (±10) min (mid-infusion), 60 (±10) min (end of 
infusion) (See Section 3.3.6). 
No premedications are required for copanlisib.   
Copanlisib dosing is weekly for the first 3 weeks of each cycle (i.e., Days 1, 8, and 15) followed 
by a 1-week break (i.e., no infusion on Day 22).  
3.2.3 Rituximab 
Patients will receive rituximab at 375mg/m2 administered via IV in Cycles 1-6. Infusions may be 
done peripherally or via central venous access device.  Rituximab will be administered per current 
standard of practice, including premedications (see Section 14.2.5). 
Rituximab dosing is weekly for the first 4 weeks (i.e., Days 1, 8, 15, and 22) during Cycle 1.  With 
subsequent cycles (i.e., Cycles 2-6), rituximab will be dosed only once on Day 1.   
3.2.4 Drug Administration – Maintenance Therapy 
Patients who achieve a PR to the first 6 cycles of induction therapy with copanlisib and rituximab, 
but do not meet criteria for CR, can be treated with an additional 6 cycles of copanlisib and 
rituximab with a modified schedule of maintenance therapy (i.e., Cycles 7-12).  
Patients will receive copanlisib at the same dose as during induction therapy; however, dosing is 
every other week during each 28-day cycle (i.e., Days 1 and 15) with each dose followed by a 1-
week break (i.e., no infusion on Day 8 or 22). 
Patients will also receive rituximab at the same dose as during induction therapy; however, dosing 
is only on Day 1 of each maintenance therapy cycle.   
3.2.5 Drug Administration – Salvage Chemotherapy Regimens 
Patients who relapse or progress after completing study therapy with copanlisib and rituximab (i.e., 
patients who do not achieve at least a PR to induction therapy, those who relapse after CR within 
6 months from initial induction therapy, and those patients who progress or relapse after 

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28
maintenance or re-induction therapy) will be offered treatment at the NCI with standard salvage 
chemotherapy regimens as deemed most appropriate per the most recent National Comprehensive 
Cancer Network (NCCN) guidelines. These patients will be considered to have completed protocol 
therapy and will be followed for PFS and OS. During treatment with salvage chemotherapy, 
adverse events will not be collected and recorded, unless considered at least possibly related to the 
copanlisib and/or rituximab.  Patients must meet conventional definitions of disease relapse or 
progression as per the investigator and reappearance of ctDNA alone is not considered disease 
relapse.
Standard chemotherapy regimens for FL include rituximab, cyclophosphamide, doxorubicin, 
vincristine, prednisone (R-CHOP) or bendamustine and rituximab (BR) for up to 6 cycles.  R-
CHOP is typically administered every 21 days while BR is typically administered every 28 days.
After salvage chemotherapy, follow-up for overall survival will continue as per the Study Calendar 
(Section 3.8).  
3.2.6
Supportive Medications
Pneumocystis Jiroveci Prophylaxis
All subjects should receive prophylaxis for Pneumocystis Jiroveci during study therapy 
administration. Trimethoprim/sulfamethoxazole 1 DS tablet by mouth on Monday, Wednesday, 
and Friday is the preferred schedule. 
Prophylaxis will begin Cycle 0, Day 1 (Day 1 of the copanlisib window; +1/-1 day) and will be 
stopped upon completion of study therapy. Continued administration of prophylaxis beyond 
completion of study therapy will only be performed if deemed clinically necessary (e.g., based 
on inadequate immune reconstitution).  
Subjects allergic to either component may receive inhaled pentamidine 300 mg once a month 
or other standard treatments. 
Antiemetics
Prophylactic anti-emetics may be administered according to standard practice. The routine use 
of standard antiemetics, including 5-HT3 blockers, such as granisetron, ondansetron, or an 
equivalent agent, is allowed as needed. The use of corticosteroids as antiemetics prior to 
copanlisib administration will be not allowed.
Hepatitis B Reactivation Treatment
In the event that patients develop reactivation of Hepatitis B without any evidence of active 
Hepatitis B infection, then medications such as entecavir will be administered according to local 
medical standards. 
3.3
DOSE MODIFICATIONS 
Adverse events may occur shortly after the first dose or several months after the last dose of 
treatment.  Copanlisib must be withheld for all drug-related toxicities considered severe or life-
threatening AEs as per below.  For all AEs/SAEs, the treating investigator may use discretion with 
regards to dose holds, modifications, and supportive care.  It is recognized that attribution of 
causality of any AE to the test drug specifically may be difficult. However, in previous trials, 
certain toxicities were seen only in relation to copanlisib,  e.g., transient increases in glucose and 

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29 
blood pressure. Based on this knowledge the investigator may decide on the necessary dose 
modifications as per Table 1. 
Table 1:  Dose levels of copanlisib 
Dose level 1 (starting dose): 
60 mg of copanlisib  
Dose level -1: 
45 mg of copanlisib  
Dose level -2: 
30 mg of copanlisib  
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 copanlisib dose of 30 mg must 
discontinue study treatment permanently. 
Dosing interruptions are permitted in the case of medical and/or surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays).  Patients should be placed back on study therapy within 3 weeks of the 
scheduled interruption, whenever possible.  The reason for interruption should be documented in 
the medical/research records.  These interruptions will not be considered protocol deviations. 
3.3.1 Unacceptable Toxicity – Withdrawal Criteria 
x CTCAE Grade 4 hypertension 
x CTCAE Grade 4 dermatologic toxicity 
x CTCAE Grade ≥ 3 non-infectious pneumonitis  
x Persistent post-infusion hyperglycemia despite optimal glucose lowering therapy in 
consultation with a diabetologist or endocrinologist 
x Drug-induced pancreatitis 
x Development of a new malignancy. New malignancy will be reported as an SAE. 
x Severe allergic reaction to study drug (such as CTCAE Grade 3 or 4 hypersensitivity 
reaction). 
3.3.2 Hematologic toxicity 
Dose modifications and treatment interruptions for copanlisib must be done according to the 
guidelines in Table 2. The investigator may judge a more conservative dose modification 
appropriate. Therefore, if these guidelines are not followed, the rationale for other measures is to 
be documented in detail in the patient’s medical record. 
Table 2:  Dose modification of copanlisib/for hematological toxicity 

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NOTE: Caloric intake and timing recommendations for diabetic patients who require insulin 
treatment prior to the infusion at any cycle visit should be managed by the investigator based on 
consultation with treating physician or diabetes/endocrinologist physician.
Glucose measurements
Cycle 0 Day 1:  
Fasting is required (8-hour minimum) only on Cycle 0 Day 1 before the first glucose 
measurement on date of infusion. A low glycemic index meal may be taken 2 hours post-
infusion unless the patient needs to have a low glycemic meal and is unable to fast for this 
period of time, then glucose test should be taken prior to meal intake.
All subsequent infusions after Cycle 0 Day 1:
The decision regarding meal timing can be made by the investigator based on glucose response 
patterns during prior treatment days.
NOTE: If patient needs to have a low glycemic meal prior to the infusion, then glucose test 
should be taken prior to the meal and/or at 1-2 hours after the meal. 
After Cycle 0 Day 1, a low glycemic index meal may be taken at least 4 h before the start of the 
study drug infusion for patients who have their infusions scheduled at a later treatment time or 
due to their age or medical condition when fasting prior to infusion is not viable.
Glucose monitoring
Treatment Cycle 0, Day 1
The following assessments should be performed on Cycle 0, Day 1 before receiving study 
treatment unless otherwise specified.
x
On Cycle 0 Day 1, patients should be fasting for at least 8 hours prior to the pre-dose 
glucose measurement. For details on fasting requirements and glucose measurement during 
Cycle 0 Day 1 please refer to Table 7.
x
Blood glucose will be measured prior to infusion either with serum chemistry on the day 
of infusion or an immediate fingerstick glucose check within 30 minutes pre-dose and 
subsequently, if clinically indicated at the discretion of the investigator. Patients should be 
educated on the signs and symptoms of hyperglycemia, such as frequent urination, 
increased thirst, blurred vision, headaches and difficulty concentrating and must report 
these to the investigator or their physician immediately. It is recommended for all patients 
on Cycle 0 Day 1 to measure glucose levels post-infusion at  3, 5, 6 and 8 hours  (study 
specific measurements). 
All subsequent infusions after Cycle 0 Day 1
If hyperglycemia noted less than 250 mg/dL on Cycle 0 Day 1, at the discretion of the 
investigator, post-infusion glucose monitoring may or may not be performed. Pre-infusion 
glucose test prior to each subsequent infusion either with serum chemistry or an immediate 
fingerstick glucose check within 30 minutes pre-dose is required to ensure fasting levels less 
than 160 mg/dL or random/non-fasting glucose levels less than 200 mg/dL. 
Glucose monitoring at home 
x
For all patients (who experienced persistent glucose >250 mg/dL (13.9 mmol/L) or 
received anti-diabetic treatment on the day of infusion), fasting glucose should be measured 

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38 
3.4.2 Hepatitis B Reactivation Monitoring and Considerations 
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death can 
occur in patients treated with anti-CD20 antibodies including rituximab.  HBV screening will be 
performed in all patients before study enrollment.  At a minimum this will include HBsAg and 
HBcAb status.  These can be complemented with other appropriate markers as per local guidelines.  
Patients with active Hepatitis B disease will not be enrolled onto the study per exclusion criteria 
(Section 2.1.2.4).  Patients with positive Hepatitis B serology, such as HbsAg or HBcAb, but 
without evidence of active Hepatitis B disease, may be enrolled and will be monitored and 
managed following local medical standards to prevent hepatitis reactivation; including prophylaxis 
with medications such as entecavir as well as periodic monitoring of hepatitis DNA. 
If HBV reactivation occurs without any evidence on active Hepatitis B infection and normal liver 
associated enzymes, patients may continue on study treatment if, at the discretion of the 
investigator, they are receiving clinical benefit.  These patients will be treated with medications 
such as entecavir to prevent liver injury.  
Patients with a positive Hepatitis B serology, but without evidence of active Hepatitis B disease, 
will be monitored for Hepatitis B DNA via a Hep B DNA Quantitative, HBV Viral Load before 
every new cycle. Please see Study Calendar (Section 3.8). 
3.5 
TREATMENT CONSIDERATIONS/EXCEPTIONS   
3.5.1 Laboratory Criteria For Initiating A Cycle of Copanlisib 
In order to initiate a subsequent cycle of treatment with copanlisib, patients must meet minimum 
requirements for laboratory criteria as indicated below:   
x Glucose  
< 200 mg/dL (non-fasting) 
x Hemoglobin  
≥ 8 g/dL a 
x ANC 
≥ 1,000/mm3 
x Platelets 
≥ 75,000/mm3 
x ALT 
<2.5 x ULN b  
x AST 
<2.5 x ULN c 
x Total bilirubin 
within normal limits d 
x GFR (MDRD) 
≥ 40 mL/min/1.73 m2 
a. 
If hemoglobin is < 8 g/dL but ≥ 6 g/dL on the day of planned study drug administration it is permissible to 
give the study drug dose as scheduled and transfuse within 48 hours after the dose, if the patient is 
hemodynamically stable and in opinion of investigator benefits outweigh risks.  
b. < 5 x ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to 
lymphoma. 
c. 
< 5 x ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to 
lymphoma. 
d. <3 x ULN in patients with Gilbert syndrome, patients with cholestasis due to compressive adenopathies of the 
hepatic hilum or documented liver involvement by lymphoma. 
A blood count will be performed and assessed prior to study drug infusion on Day 8 and 15 of 
each cycle. On Days 8 and 15, the dose of copanlisib will be administered if, on the day of 
scheduled dosing, the laboratory test criteria for hemoglobin, ANC and platelets are met. 
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 study drug is 5 days. 

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3.5.2
Discontinuation of Study Therapy
For details regarding formal stopping rules for futility and unacceptable toxicities see Section 
10.2.
Post 6 Cycles of Induction Therapy and Achieve a Complete Response
Patients who complete 6 cycles of induction therapy with copanlisib and rituximab and achieve 
a CR as defined by conventional Lugano response criteria will stop therapy and initiate active 
surveillance with CT scans and assays for ctDNA for up to 5 years as per Section 3.1. These 
patients will not be treated with maintenance therapy as per Section 3.2.4.  Patients who achieve 
CR and relapse during active surveillance at least 6 months after induction therapy may be 
eligible for re-induction therapy as per Section 3.5.3.  If disease relapses within 6 months of 
finishing induction therapy, these patients may be treated with salvage chemotherapy as per 
Section 3.2.5.
Post 12 Cycles of Induction Therapy 
Patients who complete 6 cycles of induction therapy with copanlisib and rituximab as well as 6 
cycles of maintenance therapy with copanlisib and rituximab will stop therapy and initiate active 
surveillance with CT scans and assays for ctDNA for up to 5 years as per Section 3.1. At the 
time of disease progression, these patients may be treated with salvage chemotherapy as per 
Section 3.2.5.
Post 6 Cycles of Induction Therapy and Do Not Achieve a Partial Response
Patients who complete 6 cycles of induction therapy with copanlisib and rituximab and do not 
achieve at least a PR (best response stable disease or progressive disease) as defined by 
conventional Lugano response criteria will stop therapy and initiate active surveillance with CT 
scans and assays for ctDNA for up to 5 years as per Section 3.1. These patients will not be 
treated with maintenance therapy. At the time of disease progression, these patients may be 
treated with salvage chemotherapy as per Section 3.2.5.
3.5.3
Criteria For Therapy With A Second (Re-) Induction Therapy
Patients who stop therapy with copanlisib and rituximab after achievement of CR may be eligible 
for a second course of induction therapy (re-induction) with the same drug administration schedule 
as outlined in Section 3.2 (Induction Therapy schedule) if they relapse after stopping study 
treatment. This retreatment is termed the Second Induction Phase of this study and is only available 
if the study remains open and the subject meets the following conditions:
x
Stopped initial treatment with copanlisib and rituximab after attaining an investigator-
determined confirmed CR after 6 cycles of induction
x
At least 6 months have passed since the last dose of copanlisib
x
Did not receive any anti-cancer treatment since the last dose of copanlisib
x
No evidence of histologic transformation to diffuse large B-cell lymphoma
x
Has a performance status of 0-2 on the ECOG Performance Scale
x
Demonstrates adequate organ function as detailed in Section 2.1.1.8
x
Female subject of childbearing potential should have a negative serum or urine pregnancy 
test within 72 hours prior to receiving retreatment with study medication.  

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40 
x Female subject of childbearing potential, as defined in Section 2.1.1.9, should be willing 
to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual 
activity. This applies for the time period between signing of the informed consent form and 
for at least 1 month after the last dose of copanlisib and 12 months after the last dose of 
rituximab, whichever is later, after the last dose of study medication (Appendix B).    
x Male subject should agree to use an adequate method of contraception. This applies for 
the time period between signing of the informed consent form and for at least 1 month 
after the last dose of copanlisib and 12 months after the last dose of rituximab, whichever 
is later, after the last dose of study therapy.   
x Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of the 
trial or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator. 
Patients who restart treatment will be retreated at the same dose and dose interval as when they 
last received copanlisib and rituximab. Treatment will be administered for an additional 6 cycles. 
After discontinuing the Second Course/Retreatment Phase, patients should return to the site for a 
Safety Follow-up Visit (Section 3.7.1) and then proceed to the Follow-Up Period of the study 
(Sections 3.7.2 and 3.7.3). 
3.6 
POST-TREATMENT EVALUATIONS 
Patients will be evaluated at the end of study treatment (+/-2 weeks), about 30 days following the 
last dose of treatment (+/-7 days), and post-treatment prior to (or at) disease progression.  See 
Study Calendar (Section 3.8) for additional information.  If a subject initiates a new anti-cancer 
therapy within 30 days after the last dose of trial treatment, the 30-day safety follow-up visit must 
occur before the first dose of the new therapy.   
Unless otherwise noted, follow-up will occur at the following time points:  every 3 months (+/- 2 
weeks) for two years after completion of induction therapy, every 6 months for years 2-5 (+/- 4 
weeks), and then annually thereafter (+/- 6 weeks) at the discretion of the investigator.  Any other 
evaluations and tests should be performed as clinically indicated.   
Upon disease progression or initiation of other anti-cancer therapy, contact will be for survival 
only until the subject is off study (i.e., every 3 months [+/-4 weeks]); unless otherwise clinically 
indicated.  See Study Calendar (Section 3.8) for additional information.  Any adverse events which 
are present at the time of discontinuation should be followed in accordance with the safety 
requirements.   
3.7 
FOLLOW-UP EVALUATIONS 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days after 
the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the first dose 
of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move into 
survival follow-up. 
3.7.1 30-Day Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 

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41 
first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Patients with an 
AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning 
of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 30 days of the 
end of treatment or before initiation of a new anti-cancer treatment should also be followed and 
recorded.  Patients who are eligible for retreatment with copanlisib and rituximab (as described in 
Section 3.5.3) may have up to two safety follow-up visits, one after the Treatment Period and one 
after the Second Course Phase. 
3.7.2 Follow-Up Visits – Prior to Disease Progression 
Patients who discontinue trial treatment for a reason other than disease progression will move into 
the Follow-Up Phase and should be assessed as detailed in Section 3.6  Scans will be done at least 
every 6 months to monitor disease status.  Every effort should be made to collect information 
regarding disease status until the start of new anti-neoplastic therapy, disease progression, death, 
end of the study or if the subject begins retreatment with copanlisib and rituximab as detailed in 
Section 3.5.3.  Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated. 
Patients who are eligible to receive retreatment with copanlisib and rituximab according to the 
criteria in Section 3.5.3 will move from the follow-up phase to the Second Course Phase when 
they experience disease progression.   
3.7.3 Follow-Up Visits – Survival/Post-Disease Progression 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted at least every 3 months 
(+/-4 weeks)  to assess for survival status until death, withdrawal of consent, or the end of the 
study, whichever occurs first (see Section 3.8, Study Calendar). 

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13 
Bone marrow aspiration with flow cytometry and biopsy (within 12 months prior to starting treatment) if clinically indicated; repeat in follow-up to confirm response or progression.   
14 
CT scans (preferred) of chest, abdomen and pelvis at baseline; may be adjusted to assess additional known sites of disease, as needed.  Scans performed after cycles 3 and 6 (last 7 days of 
each cycle) of both induction and maintenance, as applicable.  Repeat also within last 7 days of copanlisib window. MRIs may be used instead of CT scans as necessary.  
15 
PET scans to be performed after cycles 6 and 12 (last 7 days of each cycle) of both induction and maintenance, as applicable.  Repeat also within last 7 days of copanlisib window. 
16 
Induction therapy consists of up to 6 cycles of copanlisib and rituximab.  For patients who achieve PR to Induction Therapy, but not CR, treat with up to an additional 6 cycles of 
Copanlisib+Rituximab at  reduced schedule.  Please refer to Section 3.2 for all treatment days/cycles for copanlisib and rituximab. 
17 
If adequate archival tissue at baseline, fresh tumor biopsy is optional.  Optional “on-treatment” tumor biopsies will be performed at disease progression in all subjects (see Section 5). 
18 
Samples for correlative research blood and saliva (preferred)/buccal swab samples to be collected as indicated in Section 5. 
19 
All participants will undergo ECG at baseline. Participants with prolonged QTc at baseline, participants with congenital prolonged QT syndrome, and participants chronically on medications 
listed in Section 4.2 will have ECG monitoring after copanlisib window, and every 3 cycles thereafter.  
 
 

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3.9 
COST AND COMPENSATION  
3.9.1 Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they are 
not covered by their insurance company. Medicines that are not part of the study treatment will 
not be provided or paid for by the NIH Clinical Center.   
3.9.2 Compensation 
No compensation is provided for participants on this study. 
3.9.3 Reimbursement  
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy. 
3.10 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all patients complete a safety visit 
approximately 30 days following the last dose of study therapy.  Additional safety visits and 
follow-up will continue as per Section 3.6. 
Criteria for Removal from Protocol Therapy 
x Confirmed radiographic disease progression 
x Unacceptable toxicity as listed in Section 3.3.1 
x Intercurrent illness that prevents further administration of treatment 
x Requirement for use of prohibited therapies as listed in Section 4.3 
x Pregnancy 
x Subject’s requests to be withdrawn from protocol therapy 
x Noncompliance with trial treatment or procedure requirements such as a delay in test 
drug administration due to toxicities for > 28 days 
x Investigator’s decision to withdraw the subject 
x Study is cancelled for any reason 
 
3.10.1 Off-Study Criteria 
x Completion of study follow-up period 
x Subject requests to be withdrawn from study 
x Subject is lost to follow-up 
x Death 
x Study is cancelled for any reason 
x Screen failure 

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3.10.2 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for three (3) 
consecutive scheduled visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
x The site will attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
x Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, an IRB approved certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file.  
x Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.   
4.1 
ACCEPTABLE/PERMITTED MEDICATIONS 
All treatments that the investigator considers necessary for a subject’s welfare, including the use 
of growth factors support (e.g., filgastrim injections) may be administered at the discretion of the 
investigator in keeping with the community standards of medical care.  Palliative and supportive 
care for the other disease-related symptoms and for toxicity associated with treatment will be 
offered to all patients in this trial. 
All concomitant medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids.  If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and date 
may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  
4.2 
MEDICATIONS TO BE USED WITH CAUTION  
Patients who are chronically on the following medications that can prolong QT interval will have 
ECG performed after copanlisib window treatment (C0) and every 3 cycles thereafter until the 
end of treatment.  
x Antiarrhythmics: Amiodarone, Dofetilide, Disopyramide, Flecainide, Procainamide, 
Quinidine, Sotalol. 
x Antibiotics: Erythromycin, Gatifloxacin, Grepafloxacin, Levofloxacin, Pentamidine, 
Moxifloxacin, Sparfloxacin  

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x Anticonvulsants: Fosphenytoin, Felbamate 
x Antidepressants: Venlafaxine 
x Antidiarrheals: Octreotide  
x Antiemetics: Dolasetron, Droperidol, Domperidone, Palonosetron  
x Antipsychotics: Chlorpromazine, Haloperidol, Mesoridazine, Pimozide, Quetiapine, 
Risperidone, Thioridazine, Ziprasidone  
x Antivirals: Foscarnet, Amantadine  
x Anti-asthmatics: Salmeterol 
x Calcium Channel Blockers: Nicardipine, Bepridil, Isradipine  
x Migraine medications: Naratriptan, Sumatriptan, Zolmitriptan  
x Narcotics: Methadone   
4.3 
PROHIBITED MEDICATIONS 
Patients are prohibited from receiving the following therapies during treatment on this trial.  
Patients who, in the assessment by the investigator, require the use of any of the following 
treatments for clinical management should be removed from the trial.  Patients may receive other 
medications that the investigator deems to be medically necessary. 
x Other therapy for the disease under study not specified in this protocol, unless specifically 
noted as permitted 
x Investigational agents other than copanlisib (chemotherapy or biologic agents) 
x Radiation therapy  
x Corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not 
allowed, unless for one of the following exceptions: 
o as a premedication prior to rituximab infusion 
o as a premedication prior to a radiology scan as per local standard practice 
o as treatment for a treatment-emergent toxicity 
Previous corticosteroid therapy must be stopped or reduced to the allowed dose 7 days 
before performing the screening PET-CT and/or CT/MRI, whichever is performed first,  
and again prior to the first study drug administration. If a patient is on chronic corticosteroid 
therapy, corticosteroids should be de-escalated to the maximum allowed dose after the 
patient has signed the IC. Patients may be using topical or inhaled corticosteroids. 
x Immunosuppressive therapy 
x Anti-arrhythmic therapy (beta blockers or digoxin are permitted) 
x Herbal preparations/medications.  These include but are not limited to St. John’s wort, 
Kava, ephedra (ma huang), ginkgo biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng. Patients should stop using these herbal medications 7 days prior to 
first dose of study drug 
x CYP3A4 inhibitors and inducers. Copanlisib is primarily metabolized by CYP3A4. 
Therefore, concomitant use of strong inhibitors of CYP3A4 and strong inducers of CYP3A  
are not permitted.  Moderate inhibitors should be used with caution.    

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Lastly, we aim to identify mechanisms of therapeutic resistance through comparative genomic 
analysis of circulating tumor DNA and of biopsies taken before treatment and at time of clinical 
progression. 
 

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x
Genomic DNA will be extracted from peripheral blood mononuclear cells using the 
QIAmp DNA blood mini-kit (Qiagen, Inc, Valencia, CA). This method has been previously 
utilized for the isolation of genomic DNA in the BPC 13 and has resulted in DNA yields 
of approximately 50-400 ng/0.5ml of serum (Price, DK. personal communication).
x
Saliva DNA will be collected using Salviette/Oragene® kit for saliva. The samples will be 
processed and DNA extracted/isolated per kit instructions and established techniques. 
x
Analyses to be performed: DNA will be analyzed on a Pharmacoscan (ThermoFisher 
Scientific) genotyping platform that tests for 4,627 genetic variations in 1,191 drug 
disposition genes, including cytochrome P450s (CYPs), Glutathione transferases (GSTs), 
sulfotransferases (SULTs), as well as genes involved in facilitation of drug transporters, 
global regulation of drug metabolizing/transporting proteins, drug binding proteins, and 
drug targets.
Circulating Tumor DNA (ctDNA) and plasma banking
x
Collect blood in cell-free DNA (e.g., Streck BCT/collection tubes) gently invert the tubes 
8-10 times immediately after collection.  
x
Plasma will be isolated and frozen at -80ºC until analysis (e.g., centrifuged at 1800 x g for 
10 minutes at room temperature; plasma transferred/frozen in aliquots of 1.5-2 mL each). 
Pharmacokinetics (PK) Sampling 
PK sampling will be performed in all patients for copanlisib, its metabolite M-1 and other 
metabolites as follows:
x
Collect blood in specified tubes (e.g., 4 mL vacutainer tubes containing lithium-heparin)
x
Immediately after collection, tubes must be gently inverted several times to mix with 
anticoagulant, and placed on ice.  
x
Within 10-15 after collection, plasma will be isolated (e.g., 1000 g for 10 minutes at 4°C), 
transferred to a cryovial (e.g., 2mL screw cap polypropylene cryovial), and frozen upright 
at -60C to -80C within 60 minutes after the blood draw.
x
Samples will be stored until shipment/transfer for analysis to NEBA.
Peripheral Blood Mononuclear Cells (PBMCs) 
x
Collect blood in Cell Preparation Tubes with sodium citrate (blue/black speckled top); 
gently invert the tubes 8-10 times immediately after collection. 
x
PBMCs will be isolated per routine laboratory techniques.
5.2.3
Blood Samples – NCI Laboratory of Pathology
The blood samples for flow cytometry should be sent to the NCI Laboratory of Pathology; please 
contact NCI Laboratory of Pathology for questions and for notification of samples.
Flow cytometry
x
Collect blood, bone marrow, and/or lymph node samples in NaHep (sodium heparin) tubes; 
gently invert the tubes 8-10 times immediately after collection.  
x
Send samples to the NCI Laboratory of Pathology for specialized flow cytometry 
processing and analysis.  
x
Studies to be performed on these samples include:  multi-parameter flow cytometry to 
determine the percentage of aberrant lymphoma cells.  Reagents to be used include but are 

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not limited to characteristic B-cell markers including: CD10, CD19, CD20, CD21, CD22, 
CD23, Bcl-2, Bcl-6, kappa and lambda light chain as well as various T-cell markers 
including: CD3, CD5, CD4 and CD8.
5.2.4
Tissue Samples
Archival tissue
Archival block(s) or slides (i.e., at least 20 unstained slides, 5-microns) are required at baseline; 
these may also be required in follow-up in case of future routine procedures or in case additional 
tissue is needed even in the event of optional tumor biopsy.  
Lymph node excision or core needle biopsy procedure
Lymph node excision or core needle biopsy will be performed per routine standard of care, by 
Surgery Consultants or Interventional Radiology, as appropriate.  A procedure-specific consent 
form will be signed by the patient prior to the procedure.  Every attempt will be made to perform 
excisional lymph node biopsies to obtain the best quality tissue for translational investigation.  
Consideration of alternative biopsy methods (e.g., core needle biopsy) will only be made if 
follow-up excisional biopsy is not possible/safe or patient is unwilling to undergo repeat 
excisional lymph node biopsy.
In the event that a surgical biopsy procedure is performed, more than one lymph node and at 
more than one anatomic site may be collected, provided the additional procedures do not present
unacceptable risk to the patient.  In the event of core needle biopsy, these are obtained typically 
by using a 16-18G needle at the discretion of the provider performing the procedure.  Conscious 
sedation or general anesthesia may be used, if warranted, and the use and risks are acceptable 
to the patient.  
Potential site(s) of biopsy include, but are not limited to:  bone marrow lesions, bony lesions, 
extramedullary disease/masses, and lymph nodes.  The type of procedure to be done and manner 
in which it will proceed (e.g., excision/core, single vs. multiple sites of biopsy) will be discussed 
with the patient prior to the biopsy procedure.  The patient will be reminded that all sampling 
for research is voluntary. 
Sample handling/processing
When performed, excisions or core biopsies will be placed in sterile collection/core cylinder 
tubes with appropriate media (e.g., formalin or sterile saline); gently invert/inspect tubes with 
media 8-10 times immediately after collection to ensure the core(s) is completed immersed in 
the media.Tissue samples will be handled/processed as below prior to planned analyses, as 
appropriate:
x
Any required routine review for histopathologic confirmation of diagnosis and/or grade 
will occur per standard of care (e.g., H&E, immunohistochemistry), if required.  
x
Formalin samples will be fixed and paraffin-embedded per routine techniques.  
5.2.5
Other Samples
Germline DNA
Germline DNA will be collected by blood, buccal swab, and/or saliva samples (preferred).  These 
will ideally be collected at baseline; however, may be collected at any point on study based on 
supplies.  Standardized, commercial collection kits or tubes will be used (e.g., 1, 5-10 mL 
K2EDTA tube for blood; Isohelix SK-1 for buccal swabs; Salviette/Oragene® for saliva).  In the 

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case of buccal swabs, two (2) samples may be collected in order to ensure adequate DNA 
collection.     
The samples will be processed and DNA extracted/isolated per kit instructions and established 
techniques. These will also be handled by the BPC lab (see Section 5.2.2 for contact information). 
5.3 
BIOMARKER AND RESEARCH METHODS 
The technology platforms that are able to interrogate genomic structure and function are constantly 
in flux; therefore, the exact nature of the methodologies that will be employed will be assessed at 
the time that the samples are collected and ready for analysis.  
Note: Platforms and procedures may be adjusted based upon current technology and/or 
collaborations in place at the time of actual analyses.  
The following are technologies that are currently in use for each planned analysis:   
5.3.1 Tumor Profiling 
Immunohistochemical (IHC) analyses, including FISH for BCL2, will be done on every patient’s 
baseline tumor biopsy.  The routine IHC panel for diagnosis of FL will be performed on tumor 
tissue samples, including but not necessarily limited to CD3, CD5, CD10, CD20, CD21, CD23, 
BCL2, BCL6, MUM1 and MIB-1. 
5.3.2 Microenvironment Tissue Profiling 
IHC analyses will also take place on tumor tissue samples to assessment for contribution of the 
tumor microenvironment.  IHC that will be performed may include  but are not necessarily limited 
to CD4, CD8, CD11c, CD21, CD23, CD25, C35, CD68, CD163, PD-L2, PD-1, FOXP3, FOXP1, 
CXCR4, CXCR5, CXCL13, IRF-8, IgD, ICOS, and ICOS-L. 
5.3.3 Immune Subset Analysis 
Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry 
for immune subsets including but not necessarily limited to CD8+ T-cells, CD4+Foxp3- T-cells, 
Tregs, Tex, Th1, Th2 and Th17+ CD4+ T-cells, monocyte subsets, MDSC subsets. Assessment 
may include functional markers, i.e. PD-1, Tim-3, CTLA-4, PD-L1, HLA-DR, Ki67 and/or CD40. 
5.3.4 DNA/RNA Sequencing  
Genomic DNA and total RNA will be extracted from tumor samples using a Qiagen All-prep kit. 
For individual target genes that are recurrently mutated in FL, classical Sanger sequencing will be 
performed on PCR amplicons, using primers surrounding the known sites of mutation. To broadly 
assess mutations, next generation sequencing (e.g., on an Illumina HiSeq 2000 platform) will be 
employed, using a paired end sequencing strategy of libraries constructed from tumor DNA. DNA 
will either be sequenced in its entirety from a whole genome library or will be first enriched for 
exonic sequences using the Agilent Sure Select system, aiming for 30X or 100X average coverage 
per base, respectively. The sequence fragments will be mapped back to the genome using the BWA 
algorithm. Of sequences overlapping a particular base pair in the genome, the percent mutant calls 
greater that 20% with a minimum of 25X coverage will be considered as an arbitrary threshold for 
single nucleotide variants (SNVs). SNVs that are not present in the matched normal sample will 
be considered candidate somatic mutations.  
A related technology, RNA-Seq, utilizes RNA from the tumor specimen to create a cDNA library 
for high-throughput sequencing. RNA-seq will be performed using Illumina kits followed by high-

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throughput sequencing on an Illumina HighSeq 2000 machine. The cutoffs for coverage and 
percent mutant calls mentioned above will also be used to identify putative SNVs. RNA 
sequencing will also be used to read out digital gene expression across the genome as described.
Recent advances in genomic technologies enable GEP at the single cell level, a distinct advantage 
over conventional GEP which cannot always distinguish tumor vs non-tumor gene expression(60, 
61).  Single-cell approaches allow identification of the evolution of rare populations of resistant 
tumor cells, as well as identification of TME cells critical for the survival of the tumor. The Center 
for Cancer Research (CCR) has recently opened a single cell analysis core facility within the CCR 
Genomics Core.  This facility has the ability to take purified viably frozen cells banked from 
patient biopsies and prepare them, using well-validated 10X Genomics technology, for single-cell 
RNA sequencing.  This core is directly integrated with the NCI Sequencing core facility to provide 
high-quality, deep-sequencing of the single cell RNA-SEQ samples, as well as ‘first-pass’ data 
processing and analysis.  Data will then be transferred to lymphoma researchers and bio-
informaticians in the Staudt lab for further analysis of gene expression patterns and cellular 
population dynamics.
5.3.5
DNA Copy Number Analysis 
Array comparative genomic hybridization (e.g., on Agilent 240K or Affy SNP 6.0 microarrays) 
will be used to assess DNA copy number alterations as described, in tumor DNA to yield 
somatically acquired regions of copy number gain and loss.
5.3.6
Pharmacokinetics (PK)
Coded (linked) samples (Section 5.4.2) will be sent to a contracted laboratory at the request of 
Bayer for analysis of copanlisib pharmacokinetics:  NorthEast Bioanalytical Laboratories, LLC
(NEBA) under the direction of Vipin Agarwal, Ph.D., MBA. 
NEBA will run subject samples for PK analysis in batches of approximately 30 samples each; with 
the intent for reanalysis of samples due to out of calibration range concentration (i.e., secondary 
to large difference in parent and metabolite concentrations).  
The laboratory contact information is as follows:
NorthEast Bioanalytical Laboratories LLC
925 Sherman Avenue
Hamden,CT 06514
5.3.7
Detecting Minimal Residual Disease (MRD)/ circulating tumor DNA (ctDNA)
Rationale for MRD assessment
Detecting Minimal Residual Disease (MRD) can be a powerful tool to monitor patients’ 
response to treatment and early detection of relapse.  It is of research interest to determine if 
circulating tumor DNA before, during, or after therapy is predictive of long-term disease-free 
survival. Foresight Diagnostics will assess whether circulating tumor DNA from the Human 
Material can be used as biomarkers that correlate with disease-free survival. Foresight 
Diagnostics will utilize their proprietary Phased variant Enrichment and Detection Sequencing 
(PhasED-Seq) which leverages multiple somatic mutations within individual DNA fragments 
to improve sensitivity of minimal residual disease (MRD) in patients with B-cell lymphomas
beyond what can be achieved with other methods. Data from experiments conducted by 

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Foresight Diagnostics using the human material will be provided to NCI and such data provided 
by Foresight Diagnostics to NCI may be used by NCI for any purpose.
Samples to be sent to Foresight Diagnostics
Bloods from the storage/future use samples collected from select patients at the following time 
points may be sent, if available:
x
Baseline 
x
Post-window/pre-C1D1
x
Each response assessment
x
Follow-up surveillance
Sample collection and processing
Portions of the other samples collected, including blood (serum, plasma and/or buffy coat), 
frozen or formalin fixed and paraffin embedded (FFPE) human tissue, and data from select 
patients will be sent.  
Shipping information
Only coded (linked) samples will be shared as described (see Section 5.4.2) for process of 
coding, and sample request instructions.  The samples and data will sent in batches to ForeSight 
Diagnosticsat the address listed below.
ForeSight Diagnostics (c/o Jake Chabon) 
12635 E. Montview Blvd Suite 224 
Aurora CO 80045
5.3.8
CCP-32 assay
De-identified FFPE (Formalin-fixed, paraffin-embedded) tissue from up to 60 FL patients enrolled 
on the copanlisib-rituximab study will be analyzed using the CCP-32 assay to identify patients in 
the poor prognosis group. This data will be correlated with other prognostic markers in FL
including FLIPI, genetic profile of the tumor, baseline levels of circulating tumor DNA, and TME 
signatures defined by RNA (Ribonucleic Acid) sequencing. The clinical outcomes (rates of CR, 
duration of CR, and PFS).
General Handling Considerations
FFPE tissues are not considered to be infectious, but gloves are still recommended whenhandling 
all study materials.
Study specimens are FFPE tissue from previously diagnosed FL. Study specimens are being 
catalogued and will undergo a pathology QC at banking site. By shipping samples to MDAZL, 
the banking site attests that all inclusion/exclusion criteria from the study are satisfied.
Handling conditions (based on MDAZL policies/procedures)
x
Stability studies performed in MDAZL have yielded reproducible results of nCounter 
assays from unstained tissue sections stored at ambient laboratory conditions for up to 52 
months. 
x
USS should be transported at room temperature. Cool packs are recommended to be 
utilized during the months of April through October.

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x
A shipping manifest listing all slides (H&E and USS) must be included with each 
shipment, verified by two people at both the shipping site and MDAZL. The template 
document and training for its use will be provided by MDAZL.
x
MDAZL considers both physical and electronic signatures as valid per Mayo Clinic 
Policy.
Test Requirements:
x
Minimum of 60% tumor content by area, which may be achieved by macrodissection if 
necessary. This review may be performed at either the banking site or MDAZL 
(Molecular Diagnostics - Arizona Laboratory) as needed.
x
A standard H&E (Hematoxylin and Eosin) slide must be cut in proximity with the 
section(s) used for analysis for QC (Quality Control) to be valid.
x
USS from the diagnostic block, cut between 5-10 microns in thickness, mounted on 
positively charged slides.
o
The number of USS to be used for RNA extraction per sample is approximated by 
the following table, which assumes slides are at 5 microns thickness. Thicker 
sections (up to 10 microns) or more than the recommended number of slides may 
be sent and/or used at the discretion of pathologists or technologists.
o
If during review it is discovered that insufficient sections are available for a 
specimen, an alternate block may be sourced, the specimen may be excluded from 
the study, or the specimen may be included in the study with the consensus of 
study leadership.
Table 8 Unstained Tissue Slide Input Requirements
Tumor Surface
Area
Number of Slides @ 5μ thickness
Minimum Required #
Recommended #
4 mm2
5
10
5–11 mm2
4
8
12–24 mm2
3
6
25–99 mm2
2
4
≥ 100 mm2
1
2
Tissue Review Procedure
Tissue review will be performed by a board-certified hematopathologist and trained laboratory 
staff at either site:
x
H&E slides will be routed to a study hematopathologist using established protocols. It is 
recommended to use a standard H&E recut procedure to ensure the H&E has reasonable 
proximity to the USS.
x
Hematopathologist or designee will use established protocols to review the H&E for 
tumor content and area. A batch tissue review form may be utilized to record tumor 
percentage, area, and number of slides to be cut. The template may be provided by 
MDAZL.
x
Hematopathologist or designee utilizes Table 8 to determine the appropriate number of 
USS to request per established protocols. If the minimum slide number criterion cannot 

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be met, the specimen may either be excluded from the study or included at the discretion 
and consensus of the study leadership.
x
Proceed to Shipping and Receiving Procedure.
Shipping and Receiving Procedure
The following is to be performed by study staff at both banking and receiving locations:
x
USS will be cut according to the specifications in the General Handling section and 
prepared for shipment, using banking site-specific procedures. It is recommended to 
protect the slides well from movement during shipping to reduce the risk of breakage.
x
Two people at the banking site shall confirm the contents of all sample shipments prior to 
shipment by signing a printed copy of the sample manifest. If performed at the banking 
site, a copy of the pathology QC form should also accompany the shipment. The manifest 
will include a statement verifying that the patient and samples have met the inclusion 
criteria and do not meet any of the exclusion criteria.
x
The banking site will communicate with testing site the details of the batch shipment.
This may include the shipment tracking number, an electronic copy of the sample 
manifest, and any other relevant documentation.
x
The shipment will be sent overnight. Slides should be shipped at ambient temperature, 
and cool packs are recommended to be utilized between the months of April through 
October.
x
Two staff members at MDAZL will verify the contents of the shipment against the 
shipping manifest, sign, and retain a copy of the manifest. A copy of the signed manifest 
may be sent to the banking site if desired.
Two people are required to independently verify package contents, including number of 
slides, specimen IDs, and condition in which specimens are received. If there are any 
discrepancies or problems, the banking site will be notified, and resolution confirmed by 
MDAZL.
x
MDAZL will store the original manifest with signatures. An electronic copy will also be 
retained.
x
Slides will be stored at ambient laboratory conditions until they are used for the study.
Unused slides may be returned to the banking site upon completion of the study if 
requested.
x
MDAZL will proceed with nucleic acid isolation and the nCounter assay on qualified 
specimens per established protocols.
Shipping Address
Unstained slides as well as one H&E should be shipped to:
Colleen Ramsower
Mayo Clinic Arizona
13400 E. Shea Blvd
CRB 1-250 MDAZL
Scottsdale, AZ 85259
Phone: 480-301-4934

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An email to notify that a shipment has been sent including the tracking number should be sent to 
Ramsower.Colleen@mayo.edu. 
5.3.9
Other Analyses
Other analyses include the following:
x
Cell analysis and histological (e.g., H&E), immunohistochemical review and analysis per 
standard and established research techniques (e.g., FISH for BCL2 translocation, and other 
IHC analyses in blood and tissue).
x
cfDNA/ctDNA for liquid genotyping as a non-invasive dynamic monitoring of disease as 
well as monitoring for individual molecular aberrations that herald progression or disease 
transformation; specifically, amplification and sequencing of the VDJ segment of the 
immunoglobulin receptor is planned
5.3.10 Future Use
Any blood, tissue, or other products or portions leftover from other analyses will be stored for 
future research.  
5.4
SAMPLE STORAGE, TRACKING AND DISPOSITION
5.4.1
General
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required. 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described below.  The 
study will remain open so long as sample or data analysis continues.  Samples from consenting 
patients will be stored until they are no longer of scientific value or if a subject withdraws consent 
for their continued use, at which time they will be destroyed.  The PI will record any loss or 
unanticipated destruction of samples as a deviation. Reporting will be per the requirements of 
section 7.2.
If the patient withdraws consent his/her data will be excluded from future distributions, but data 
that have already been distributed for approved research use will not be able to be retrieved.
5.4.2
Clinical Pharmacology Program/ Biospecimen Processing Core (BPC)
Sample Data Collection
All samples sent to the Biospecimen Processing Core (BPC) of the Clinical Pharmacology 
Program will be barcoded, with data entered and stored in the Labmatrix utilized by the BPC. 
This is a secure program, with access to Labmatrix limited to defined BPC lab personnel, who 
are issued individual user accounts. Installation of Labmatrix is limited to computers specified 
by the BPC. These computers all have a password restricted login screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be 
traced back to patients without Labmatrix access. Data will be recorded for each sample (e.g., 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location). Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.).

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Sample Storage 
Barcoded samples are stored in barcoded boxes in a locked freezers at appropriate temperatures 
(e.g., -20ºC to -80ºC) according to stability requirements.  These freezers are located onsite in 
the BPC and offsite.
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator 
to ensure that the samples requested are being used in a manner consistent with IRB approval.
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of 
the Labmatrix. It is critical that the sample remains linked to patient information such as race, 
age, dates of diagnosis and death, and histological information about the tumor, in order to 
correlate genotype with these variables.
5.4.3
Hematopathology Section of Laboratory of Pathology (Tissue samples)
Archival and/or freshly collected and processed tumor tissue may be stored in the 
Hematopathology Section of Laboratory of Pathology until ready for planned and/or future 
research assays if the patient has agreed to allowing specimens to be used in future research studies.  
IRB approval will be obtained before using any samples to conduct studies that are not described 
within this protocol.  Samples will be stored under conditions appropriate to the type of sample 
and processing (e.g., ambient or frozen).  
Tissue that is given to the technician will be assigned an accession number (HP#) in the HP Case 
Log book; sample tracking also takes place with a FileMaker Pro data base called HP Patient 
Information and Specimen Inventory.  A Patient background sheet may be filled out and filed with 
any accompanying paperwork, with final reports and any supplemental reports that follow added 
as completed.
5.5
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.5.1
Description of the scope of genetic/genomic analysis
The research correlates for this study are expected to include DNA/RNA sequencing of tumors, 
including circulating tumor (ct) DNA. In addition, whole exome sequencing may include 
evaluation for known lymphoma mutations.  For any genetic studies performed, the results will be 
deposited in a database such as dbGaP per NIH requirements.  Although there is controlled access 
to such a database, such a submission carries theoretical risks of revealing the identity of the 
subject.  This is discussed in the consent.
5.5.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Confidentiality for genetic samples will be maintained as described (Section 5.4).  In addition, a 
Certificate of Confidentiality has been obtained for this study.
5.5.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered.  Clinically 
actionable findings for this study are defined as disorders appearing in the American College of 

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Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis.  
5.5.4 Genetic Counseling 
Subjects will be contacted with a request to provide a sample to be sent to a CLIA certified 
laboratory.  If the research findings are verified in the CLIA certified lab, the subject will be offered 
the opportunity to come to NIH to have genetic education and counseling to explain this result; at 
the time of any such event(s), these activities will be funded by the NCI/CCR in consideration of 
the specific circumstances.  If the subject does not want to come to NIH, a referral to a local genetic 
healthcare provider will be provided (at their expense). 
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
5.6 
EXPLORATORY ANALYSIS OF EARLY [18F]-FDG-PET/CT AND CT SCANS 
An exploratory objective of this study is to  identify a mutational or gene-expression signature that 
predicts early clinical response to copanlisib monotherapy. The post-copanlisib window early 
imaging assessment will be done to assess early response to copanlisib. The post-copanlisib 
window early imaging assessment will entail one [18F]-FDG PET/CT and one CT scan.  The [18F]-
FDG PET/CT scan will entail the injection of 10mCi dose for all ages and body sizes.   
Response will be calculated as described in Section 6.3. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
6.1.1 Summary 
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness.  
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts.  Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.   
Document AEs from the first administration of study drug through 30 days post the last 
administration of study drug. After 30 days, only adverse events which are serious and related to 
the study intervention need to be recorded.  
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  

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6.1.2
Data Collection/Recording Exceptions
Abnormal Laboratory Values
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:
x
Results in discontinuation from the study
x
Is associated with clinical signs or symptoms 
x
Requires treatment or any other therapeutic intervention
x
Is associated with death or another serious adverse event, including hospitalization. 
x
Is judged by the Investigator to be of significant clinical impact
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
Hospitalizations
Any cases of planned or prolonged hospitalization are not considered reportable serious adverse 
events if for the following reasons:
x
Technical, practical, or social reasons, in absence of an AE
x
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition, including scheduled therapy or standard procedure for the 
target disease of the study, and those required to allow efficacy measurement for the 
study
x
Diagnostic or elective surgical procedures for preexisting conditions or a procedure 
that is planned (e.g., planned prior to starting of treatment on study)
x
Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria
x
Hospitalizations for administration of IV antibiotics required due to bacterial 
resistance, and not infection severity, will not be considered SAEs and will not require 
expedited reporting
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
_X_ Coded, linked data in an NIH-funded or approved public repository.  
_X_ Coded, linked data in another public repository
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_X_ Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:

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7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/hrpp-policy-guidelines/. 
NOTE: Only IND Safety Reports that meet the definition of an unanticipated problem or present 
new information that might affect the willingness of participants to enroll or remain on the study 
will need to be reported per these policies. 
7.2.2 IRB Requirments for PI Reporting at Continuing Review  
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/hrpp-policy-guidelines/.  
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet approximately weekly when patients are being actively treated 
on the trial to discuss each patient. Decisions about trial continuation will be made based on the 
efficacy data from prior patients at appropriate time points per the statistical plan.   
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in section 
7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8 
SPONSOR PROTOCOL/SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 

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medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
x 
Death, 
x 
A life-threatening adverse event (see 8.1.3) 
x 
Inpatient hospitalization or prolongation of existing hospitalization 
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
x 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
x 
A congenital anomaly/birth defect. 
x 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32) 
8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
x Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 

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x Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution (return to baseline or stabilization) of the event, seriousness and outcome. The 
assessment of severity and relationship to the study product will be done only by those with the 
training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal 
investigator or sub-investigator.  AEs occurring during the collection and reporting period will be 
documented appropriately regardless of relationship.  AEs will be followed through resolution 
(return to baseline or stabilization). 
SAEs will be: 
x 
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or sub-investigator. 
x 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
x 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4. 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets  protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.4. 
All SAE reporting must include the elements described in section 8.2. 
SAE reports will be submitted via an electronic SAE reporting system (e.g. HiLIT). In the event 
of system downtime or issues, SAE reports will be submitted using the CCR SAE Report form to 
the sponsor at: OSROSafety@mail.nih.gov.  CCR SAE report form and instructions can be found 
at: 
https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-Communications/SitePages/Forms-and-
Instructions.aspx?csf=1&web=1&e=uWBXtI.  
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.  
8.4 
WAIVER OF EXPEDITED REPORTING TO CCR  
As death/hospitalization due to disease progression is part of the study objectives (DOR, PFS, 
OS), and captured as an endpoint in this study, they will not be reported in expedited manner to 

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the sponsor. However, if there is evidence suggesting a causal relationship between the study 
drug and the event, report the event in an expedited manner according to section 8.3 
8.5 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
The Principal Investigator is responsible for all of the pharmacovigilance obligations and safety 
reporting pursuant to the applicable laws and regulations in the country/countries where the study 
is performed. 
Additionally, the Principal Investigator/designee shall immediately, within 24 hours at the latest, 
report 
the 
following 
to 
BAYER 
by 
fax 
and/or 
e-mail 
(i.e., 
973-709-2185 
or 
DrugSafety.GPV.US@bayer.com) all of the following (CCR Safety will follow-up also with final 
reports within two [2] business days):   
x all Serious Adverse Events occurring after start of administration of copanlisib, 
independent of their causal relationship to the study treatment 
x any other relevant safety information including but not limited to: 
o reports of drug exposure via mother / father with and without adverse events (exposure 
during conception, pregnancy, childbirth and breastfeeding) including their outcome; 
o if linked to a serious adverse event, reports of misuse, abuse, overdose, medication 
error and other uses outside what is foreseen in the protocol, drug dependency, 
occupational exposure suspected transmission of an infectious agent, withdrawal 
syndrome, drug interactions with respect to the copanlisib; 
x any communication concerning safety related information to regulatory authorities or 
ethics committees including but not limited to: 
o Development Safety Update Report  for the study; 
o Any other safety related reports, issues and queries that are either raised by or 
communicated to regulatory authorities or ethics committees (e.g., reportable non-
serious cases); 
x the following events of special safety interest: 
o Non-infectious pneumonitis (NIP) 
Based on data from lymphoma clinical studies with copanlisib, as soon as there is 
reasonable suspicion of NIP, the investigator should immediately notify Bayer (within 
24 hours) regardless of whether the event is assessed as causally related/not related to 
the study drug, or as serious/non-serious. The AESI should be entered on an SAE form 
and if the event is assessed as non-serious, the non-serious assessment should be noted 
in the form. 
o Pregnancies 
 The investigator must report any pregnancy occurring in a female study patient 
during her participation in this study. The outcome of the pregnancy should be 
followed up carefully, and any outcome of the mother and the child at delivery 
should be reported. 

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 For a pregnancy in the partner of a male study patient, all efforts will be made 
to obtain similar information on course and outcome, subject to the partner’s 
consent. 
 The investigator should submit them within the same timelines as an SAE.  
8.6 
REPORTING PREGNANCY  
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-
Communications/SitePages/Forms-and-Instructions.aspx?csf=1&web=1&e=uWBXtI.  
8.6.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known, 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (8.1.2) should be reported as SAEs.  
The outcome of all pregnancies should be followed up and documented. 
8.6.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm for at least 1 month after the 
last dose of copanlisib and 12 months after the last dose of rituximab, whichever is later.  
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies occurring from the date of the first dose until at least 1 month after the last dose of 
copanlisib and 12 months after the last dose of rituximab,  should, if possible, be followed up and 
documented. Pregnant partners may be offered the opportunity to participate in an institutional 
pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to provide data about the 
outcome of the pregnancy for safety reporting purposes. 
8.7 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the study product and 
the adverse event.  CCR will notify FDA and all participating investigators (i.e., all investigators 
to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND 
safety report of potential serious risks from clinical trials or any other source, as soon as possible, 
in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
8.8 
SPONSOR PROTOCOL DEVIATION REPORTING 
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of 
Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial. 

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It is the responsibility of the study Staff to document any protocol identified by the Staff or the site 
Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. The entries 
into the PDTS online application should be timely, complete, and maintained per CCR PDTS user 
requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source records 
and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation 
reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance 
with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations. 
9 
CLINICAL MONITORING  
Clinical site monitoring is conducted to ensure: 
x that the rights of the participants are protected;  
x that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and  
x the quality and integrity of study data and data collection methods are maintained. 
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements. 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates. 
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV). 
Some monitoring activities may be performed remotely, while others will occur at the study site(s). 
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports 
will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating 
center (if applicable), and the Sponsor regulatory file. 
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance. 

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10 STATISTICAL CONSIDERATIONS   
10.1 STATISTICAL HYPOTHESIS 
10.1.1 Primary Endpoint 
Complete response (CR) rate after induction therapy, as defined by the proportion of patients who 
achieve a PET-negative CR in accordance with the 2014 Lugano classification of the International 
Working Group Criteria for Non-Hodgkin’s Lymphoma(62) 
10.1.2 Secondary Endpoints 
x Safety 
x Complete molecular remission rate (CMR) 
x Objective tumor response rate (ORR) 
x Continuous complete response rate at 30 months (CR30) 
x Duration of response (DOR) 
x Time to next treatment (TTNT) 
x Progression-free survival (PFS) 
x Overall survival (OS) 
10.1.3 Definitions of Primary and Secondary Endpoints 
x Complete response (CR) rate after induction therapy: the proportion of patients who 
achieve a PET-negative CR in accordance with the 2014 Lugano classification of the 
International Working Group Criteria for Non-Hodgkin’s Lymphoma(62) after induction 
therapy with copanlisib and rituximab 
x Safety: the proportion of patients with adverse events leading to discontinuation of 
induction therapy with copanlisib and rituximab 
x Complete molecular remission (CMR) rate: the proportion of patients who achieve both a 
complete response and are negative on molecular assays for minimal residual disease after 
induction therapy with copanlisib and rituximab 
x Objective tumor response (ORR) rate: proportion of patients who achieve at least a partial 
response (PR) to induction therapy with copanlisib and rituximab 
x Continuous CR rate at 30 months (CR30): proportion of patients who remain in complete 
response at 30 months from study enrollment 
x Duration of response (DOR): time from first documentation of tumor response to disease 
progression 
x Time to next treatment (TTNT): time from the end of induction therapy with copanlisib 
and rituximab until initiation of next treatment  
x Progression-free survival (PFS): time from study enrollment until disease progression or 
death from any cause 
x Overall survival (OS): time from study enrollment until death from any cause 
10.2 SAMPLE SIZE DETERMINATION AND STATISTICAL PLAN 
The primary objectives of this trial are to determine if the combination of copanlisib + rituximab 
is associated with an adequately high complete response rate in patients with previously untreated 

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follicular lymphoma and to obtain preliminary, pilot information on whether the subset of patients 
who are identified subsequently as having a high risk signature by gene-expression profiling (GEP) 
are able to have a modestly high rate of retaining a complete response. As the expected fraction of 
patients who have a high risk GEP signature is expected to be approximately 25%, the sample size 
for this study is initially guided by practical considerations regarding the number of patients who 
may enroll on this trial over a period of 4 years. 
The intended sample size for the trial will be 60 evaluable patients, which is the number which 
may be realistically treated in 4 years at a single institution.  As the objective is to obtain a modest 
number of patients who have a high risk GEP signature, and only 25% of all patients are expected 
to have this high risk signature, the trial will not plan to end enrollment early unless an 
unacceptably low proportion of all patients with a complete response (CR) is identified, since 
enrollment of a large number of patients may be needed to obtain a modest number with the high 
risk signature. 
Since the goal of chemotherapy-free regimens is to develop a cure, then achievement of CR is 
chosen as the primary endpoint.  Based on the published literature, the combination therapy to be 
evaluated in this trial would be estimated to be associated with at least a 25% CR rate, since 
copanlisib monotherapy demonstrated a 12% CR rate in cases of relapsed and refractory FL(63).  
We anticipate that earlier use of copanlisib as well as the combination with rituximab will yield a 
CR rate of at least 25%.  Further, rates of CR that are <25% would be considered uninteresting for 
further clinical development. At the end of the trial, the overall CR rate will be presented along 
with 80% and 95% two-sided confidence intervals.  
As an early stopping rule for futility, after 30 evaluable patients have had their response status 
assessed, if there are 4 or fewer patients with a complete response among the 30 evaluable patients 
(13.3%), the trial will no longer accrue any patients as soon as this can be determined, regardless 
of the number accrued to the trial, since the one-sided upper 90% confidence interval bound on 
4/30 is 24.9%, which is below the anticipated CR rate. 
As an early stopping rule for toxicities, if during the initial 20 patients treated on this trial, there 
are 4 or more patients with grade 3 or higher non-infectious pneumonitis (NIP), then no further 
patients will be enrolled. If after 20 patients have enrolled, there is a cumulative fraction of patients 
with grade 3 or higher NIP which exceeds 20%, then no further patients will be accrued to the trial 
in its present form. Further accrual would only proceed if the dosing of copanlisib were decreased 
and the trial amended to reduce likely occurrence of this toxicity. 
From among all evaluable patients enrolled on the trial, when a high risk GEP signature can be 
identified as being present or absent in the patients, the CR rate will be determined and this will 
be used as preliminary information to guide further, more extensive explorations if warranted. If 
the true probability of a patient having a high risk GEP signature were 25%, then among 60 
patients, the probability of having 11 or more patients with this characteristic is 91.4%, the 
probability of having 12 or more is 85.2%, the probability of having 13 or more is 76.8%, and the 
probability of having 14 or more is 66.5%. As a result, from among 60 evaluable patients, it is 
realistic to expect 11 to 14 who have the high risk GEP signature. From among these expected 11 
to 14 patients, as well as among the expected 46 to 49 patients without the signature, the CR rate 
will be reported separately by category along with two-sided 80% and 95% confidence intervals 
in order to establish in a preliminary, pilot sense if patients who have the high risk signature are 
able to have a potentially beneficial outcome with treatment, as well as to determine if there is a 

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prognostic difference between patients according to presence or absence of the signature. In order 
to allow for a small number of inevaluable patients, the accrual ceiling will be set at 65 patients. 
10.3 POPULATIONS FOR ANALYSES 
10.3.1 Evaluable for Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with copanlisib. 
10.3.2 Evaluable for Objective Response 
Only those patients who have measurable disease present at baseline, have received at least one 
cycle of induction therapy, and have had their disease re-evaluated will be considered evaluable 
for response.  These patients will have their response classified according to the definitions stated 
below.  (NOTE:  Patients who exhibit objective disease progression at any point after receiving at 
least 1 cycle of induction therapy will also be considered evaluable.) 
10.3.3 Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions.  
10.4 STATISTICAL ANALYSES 
10.4.1 General Approach 
The response rate will be determined and reported along with a 95% confidence interval. Other 
time-to-event outcomes will be reported using Kaplan-Meier curves.   
10.4.2 Analysis of the Primary Endpoint 
The CR rate will be determined and reported along with a 95% confidence interval. 
10.4.3 Analysis of the Secondary Endpoints 
The ORR, CMR and the CR30 rate will be determined and reported along with a 95% confidence 
interval. The duration of response (DOR; beginning at the date clinical response is first identified), 
time to next treatment (TTNT), progression free survival (PFS), and overall survival (OS) will be 
estimated using Kaplan-Meier curves with appropriate confidence intervals reported. 
10.4.4 Safety Analyses  
The type, grade and frequency of toxicities will be reported. 
10.4.5 Planned Interim Analyses 
As noted in Section 10.2, the study will be stopped if, after 30 evaluable patients have had their 
response status assessed, there are 4 or fewer patients with a complete response.   
10.4.6 Sub-Group Analyses 
None. 
10.4.7 Tabulation of Individual Participant Data 
None. 

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10.4.8 Exploratory Analyses
The exploratory objectives such as seeking to identify potential biomarkers that are associated with 
response, will be assessed using descriptive statistics as well as non-parametric methods such as 
exact Wilcoxon rank sum tests. The analyses will be done without formal adjustment for multiple 
comparisons, but in the context of the number of tests performed.  
11
COLLABORATIVE AGREEMENTS
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)
A CRADA between the National Cancer Institute and Bayer Pharmaceuticals has been fully  
executed (#03256) 05 August 2019.  
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
Follicular lymphoma affect all races and sexes and only occasionally (~5% of cases) affects adults 
under the age of 40 years. Overall, we anticipate an even sex distribution. This trial is directed at 
assessing a novel targeted therapy using copanlisib in patients with untreated FL. Pregnant or 
nursing mothers are excluded because of the potential teratogenic effects of therapy.
12.2 PARTICIPATION OF CHILDREN
Children under the age of 18 will not be eligible for participation on this protocol because FL is 
rare in young patients, and the inclusion of an occasional young patient will not provide 
generalizable information that would justify their inclusion on this study.
12.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
Patients may obtain direct benefit from treatment with copanlisib with rituximab. The most 
common adverse reactions (≥10%) attributable to copanlisib observed in clinical trials were 
hyperglycemia, hypertension, diarrhea, decreased general strength and energy, neutropenia,
nausea, lower respiratory tract infections and thrombocytopenia. Although the potential for serious 
adverse events exists for these patients, the incidence of them is decidedly lower compared to 
combination chemotherapy regimens when added to rituximab and management algorithms have 
been developed. The potential toxicity of copanlisib is reasonable in relation to the potential benefit 
to this group of patients who have few treatment options.
12.3.1 Risks Related to Study Procedures
Blood Collection
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
Biopsy Collection – Tumor
The risks of the biopsies include pain, bleeding and infection at the biopsy site. Conscious sedation 
or general anesthesia may be used for pain management, if warranted, and the use and risks are 
acceptable to the patient.  
Biopsy Collection – Bone Marrow
Bone marrow biopsy is minimally invasive and is typically a very safe procedure. Usually the
hipbone is numbed with anesthesia. Conscious sedation or general anesthesia may be used, if 
warranted, and the use and risks are acceptable to the patient. Using a needle, the solid and liquid 

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portion of bone marrow is taken out. This procedure causes some pain. Very rarely, infection or 
bleeding may occur at the needle site.
Conscious Sedation
The common side effects of conscious sedation include drowsiness, delayed reflexes, hypotension, 
headache, and nausea. These are generally mild and last no more than a few hours.
General Anesthesia
The risks of general anesthesia include decreased breathing rate, aspiration, low heart rate, 
deacreased heart rate, decreased blood pressure.
Imaging
In addition to the radiation risks discussed below, scans may include the risks of an allergic 
reaction to the contrast. Participants might experience hives, itching, experience a metallic taste, 
headache, difficulty breathing, hypotension, increased heartrate and swelling. Furthermore, the IV 
catheter used to administer the contrast may cause bleeding, infection or inflammation of of the 
skin and vein with pain and swelling.  Participants undergoing gadolinium enhanced MRIs may 
also be at risk for kidney damage. MRIs include the additional risk of damage to hearing.
Radiation Exposure 
The procedures for performing the [18F]-FDG PET/CT scans, CT scans, and CT-guided biopsies 
will follow clinical policies, no special procedures apply this additional assessment for research 
purposes.
In summary, subjects may receive radiation exposure from up to seven CT scans, six [18F]-FDG 
PET/CT scans, and four CT-guided biopsies inclusive of screening assessments. 
The total radiation dose for research purposes will be approximately 19.5 rem. The risk of getting 
cancer from the radiation exposure in this study is 1.6% and of getting a fatal cancer 0.8%.
Other Procedures
There are no physical risks associated with other procedures (e.g., urine or saliva collection, cheek/ 
buccal swabs). There are minimal risks associated with electrocardiogram (ECG) as it is a 
relatively safe procedure.
12.4 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting.  A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will be 
given, including an opportunity to discuss it with friends, family members and/or other advisors, 
and to ask questions of any designated study investigator. A signed informed consent document 
will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant. Whether in person or remote, the privacy of the subject will be 
maintained. Consenting investigators (when in person) will be located in a private area (e.g., clinic 

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consult room). When consent is conducted remotely, the participant will be informed of the private 
nature of the discussion and will be encouraged to relocate to a more private setting if needed.  
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below. When required, 
witness signature will be obtained similarly as described for the investigator and participant.  
Manual (non-electronic) signature on electronic document: 
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures: 
x 
Adobe platform (which is not 21 CFR Part 11 compliant); or,   
x 
iMedConsent platform (which is 21 CFR Part 11 compliant)  
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location but is not required.   
Both the investigator and the subject will sign the document using a finger, stylus or mouse.  
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found at:  
https://nih.sharepoint.com/sites/NCI-CCR-OCD-Communications/SitePages/OEC-
Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit. 
12.4.1 Request for Waiver of Consent for Screening Activities 
Prior to the subject signing the consent for this study pre-screening activities listed in section 2.2.1 
may be performed.  
We request a waiver of consent for these activities as they involve only minimal risk to the subjects.  
A waiver will not adversely affect the rights and welfare of the subjects given that the activities 
are only intended to determine suitability for screening for participation in research protocols.  
These activities could not practicably be carried out without the wavier as central recruiting 
services, utilized in the NIH Clinical Center, perform pre-screening activities for multiple studies 
and obtaining consent for each one is beyond their resources.  The subjects will be provided with 
additional pertinent information after participation as they will be informed whether or not they 
are eligible to sign a consent for additional screening. 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS  
13.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to IND sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 

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x Determination of unexpected, significant, or unacceptable risk to participants 
x Demonstration of efficacy that would warrant stopping   
x Insufficient compliance to protocol requirements 
x Data that are not sufficiently complete and/or evaluable 
x Determination that the primary endpoint has been met 
x Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA). 
13.2 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council for Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
13.3 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the NIH has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
13.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 

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The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by the clinical sites and by NCI CCR research staff will be secured and password protected. At the 
end of the study, all study databases will be archived at the NIH. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants. 
14 PHARMACEUTICAL INFORMATION 
14.1 COPANLISIB (BAY 80-6946, ALIQOPA) (IND #141280) 
Refer to the FDA approved package insert for complete product information. 
14.1.1 Source  
Copanlisib (commercial/marketed supplies) will be provided by Bayer Pharmaceuticals for use by 
subjects in this clinical trial. 
14.1.2 Chemical formula and molecular structure 
BAY 80-6946 is the active ingredient (free base) of BAY 84-1236, the dihydrochloride salt, which 
is used to prepare the freeze dried medicinal product. BAY 84-1236 is isolated either in its 
pseudopolymorphic form hydrate I (containing 11-17% water) or dried to a water content below 
10%. Copanlisib has been assigned as the International Nonproprietary Name (INN) for BAY 80-
6946. 
 
Chemical Name (IUPAC):  
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-
dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide 
dihydrochloride 
 
BAY number:  
 
BAY 80-6946 (free base); BAY 84-1236 (dihydrochloride salt) 

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Chemical formula:  
 
C23H28N8O4 2HCl 
Molecular mass:  
 
553.45 g/mol 
Chemical structure: 
 
 
14.1.3 Mechanism of copanlisib 
Copanlisib is a small molecule pan-class 1 PI3K inhibitor with predominant activity against PI3Kα 
and PI3KG isoforms that first demonstrated anti-tumor activity in pre-clinical models characterized 
by activating genetic aberrations of the PI3K pathway. Copanlisib exhibits potent kinase inhibitory 
effect on all four isoforms with biochemical IC50 values of 0.5 nM, 0.7 nM, 3.7 nM and 6.4 nM 
for PI3Kα, PI3Kδ, PI3Kβ and PI3KJ, respectively.  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 apoptosis. 
14.1.4 Toxicity 
The safety data reflect exposure to copanlisib in 168 adults with follicular lymphoma and other 
hematologic malignancies treated with copanlisib 60 mg or 0.8 mg/kg equivalent in clinical trials. 
The median duration of treatment was 22 weeks (range 1 to 206 weeks). 
Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse 
reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). The 
most common adverse reactions (≥20%) were hyperglycemia, diarrhea, decreased general strength 
and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and 
thrombocytopenia. Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation 
in 27 (16%) patients. The most common reasons for dose reduction were hyperglycemia (7%), 
neutropenia (5%), and hypertension (5%). The most common reasons for drug discontinuation 
were pneumonitis (2%) and hyperglycemia (2%). 
The tables provide the serious adverse reactions occurring in patients receiving copanlisib 
Monotherapy (Table 9), and the treatment-emergent laboratory abnormalities in ≥10% of patients 
and ≥4% of Grade ≥3 treated with copanlisib and rituximab (Table 10). 

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Table 9:  Serious Adverse Reactions From Multiple Clinical Trials 
ADVERSE REACTIONS 
Copanlisib  
N=877 
All SAR 
N (%) 
Life 
threatening  
Fatal  
Metabolism and nutrition disorders 
Hyperglycemia 
 
39 (4.4%) 
 
NA 
 
NA 
Blood and lymphatic system disorders 
 
13 (1.5%) 
 
NA 
 
NA 
Febrile neutropenia 
Neutropenia (including febrile neutropenia) 
14 (1.6%) 
NA 
NA 
Thrombocytopenia 
      2  (0.2%) 
NA 
NA 
General disorders and administration site conditions 
Fatigue 
 
2 (0.2%) 
 
NA 
 
NA 
Gastrointestinal disorders 
 
11 (1.3%) 
 
NA 
 
NA 
Diarrhea 
Colitis 
5 (0.6%) 
NA 
NA 
Pancreatitis 
2 (0.2%) 
NA 
NA 
Vomiting 
2 (0.2%) 
NA 
NA 
Vascular disorders 
Hypertension (includes secondary hypertension) 
 
8 (0.9%) 
 
NA 
 
NA 
Infection 
 
 
41 (4.7%) 
 
NA 
 
NA 
Pneumonia 
Pneumocytis jirovecii 
14 (1.6%) 
NA 
NA 
Lower respiratory infection 
5 (0.6%) 
NA 
NA 
Bronchitis 
4 (0.5%) 
NA 
NA 
Pneumonia, bacterial 
4 (0.5%) 
NA 
NA 
Sepsis 
4 (0.5%) 
NA 
NA 
Herpes Zoster 
3 (0.3%) 
NA 
NA 
Pneumococcal pneumonia 
2 (0.2%) 
NA 
NA 
Pneumonia, viral 
2 (0.2%) 
NA 
NA 
Septic shock 
2 (0.2%) 
NA 
NA 
Metabolism and nutrition disorders  
 
 
39 (4.4%) 
 
NA 
NA 
  Hyperglycemia 
  Hyponatremia 
2 (0.2%) 
NA 
NA 
  Pneumonitis 
33 (3.8%) 
NA 
NA 
  Interstitial lung disease 
11 (1.3%) 
NA 
NA 
Skin and Subcutaneous Tissue Disorders 
Dermatitis exfoliative generalised 
4 (0.5%) 
NA 
NA 
 
 
 
 
 
 
 

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Table 10:  Treatment-emergent Laboratory Abnormalities in ≥10% of Patients and ≥4% of Grade 
≥3 Treated with Copanlisib and Rituximab  
 
Laboratory Parameter 
Copanlisib with Rituximab 
N=307 
Any Grade 
 n (%) 
Grade 3  
n (%) 
Grade 4 
n (%) 
Hematology abnormalities 
 
209 (68%) 
 
15 (5%) 
 
0 
Decreased hemoglobin 
Lymphocyte count decreased 
231 (76%) 
73 (24%) 
13 (4%) 
Platelet count decreased 
182 (60%) 
11 (4%) 
3 (1%) 
Neutrophil count decreased 
226 (74%) 
58 (19%) 
64 (21%) 
Serum chemistry abnormalities 
 
296 (96%) 
 
193 (63%) 
 
14 (5%) 
Hyperglycemia 
Hypophosphatemia 
127 (42%) 
24 (8%) 
4 (1%) 
Hyponatremia 
89 (29%) 
16 (5%) 
1 (0.1%) 
Serum lipase increase 
97 (32%) 
17 (6%) 
3 (1%) 
 
14.1.5 Formulation and Preparation 
The following excipients are used to manufacture the medicinal product: mannitol, NaOH, citric 
acid (except for the 20 mg formulation) and water for injection. The medicinal product is a freeze-
dried product containing either 20 mg of copanlisib (equivalent to 23.04 mg BAY 84-1236) or 60 
mg of copanlisib (equivalent to 69.12 mg BAY 84-1236) or 80 mg of copanlisib (equivalent to 
92.16 mg BAY 84-1236) in a 6 mL injection vial. The IV solution is obtained after reconstitution 
of the lyophilisate with saline solution. The resulting solution contains the active substance in 
concentrations as outlined below: 
 
 
For example, for the 60 mg formulation:  reconstitute copanlisib with 4.4 mL of sterile 0.9% NaCl 
solution leading to a concentration of 15 mg/mL, as follows: 
x Withdraw 4.4 mL of sterile 0.9% NaCl solution by using a 5 mL sterile syringe with needle. 
x Inject the measured volume through the disinfected stopper surface into the vial of 
copanlisib. 
x Dissolve the lyophilized solid by gently shaking the injection vial for 30 seconds. 
x Allow to stand for one minute to let bubbles rise to the surface. 
x Check if any undissolved substance is still seen. If yes, repeat the gentle shaking and 
settling procedure. 
x Inspect visually for discoloration and particulate matter. After reconstitution, the solution 
should be colorless to slightly yellowish 

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x Once the solution is free of visible particles, withdraw the reconstituted solution for further 
dilution. 
x The reconstituted solution is to be diluted with isotonic sodium chloride (NaCl) solution 
without falling below a concentration of 0.3 mg/mL copanlisib.  
Further dilute the reconstituted solution in 100 mL sterile 0.9% NaCl solution for injection. With 
a sterile syringe, withdraw the required amount of the reconstituted solution for the desired dosage: 
60 mg: Withdraw 4 mL of the reconstituted solution with a sterile syringe. 
45 mg: Withdraw 3 mL of the reconstituted solution with a sterile syringe. 
30 mg: Withdraw 2 mL of the reconstituted solution with a sterile syringe. 
Inject the contents of the syringe into the patient infusion bag of 100 mL sterile 0.9% NaCl 
solution. Mix the dose well by inverting. 
14.1.6 Stability and Storage  
The drug product has to be stored between +2°C and +8°C and should not be transported above 
+30°C. Supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  Receipt and dispensing of trial supplies must be recorded by an authorized 
person at the trial site.  Supplies may not be used for any purpose other than that stated in the 
protocol. 
The diluted solution is physically and chemically stable for 24 hours at room temperature, provided 
it is not exposed to direct sunlight. However, for microbiologic consideration, diluted solution 
should be stored between +2°C and +8°C if not administered immediately. 
Use reconstituted and diluted copanlisib immediately or store the reconstituted solution in the vial 
or diluted solution in the infusion bag at 2°C to 8°C (36°F to 46°F) for up to 24 hours before use. 
Allow the product to adapt to room temperature before use following refrigeration. Avoid exposure 
of the diluted solution to direct sunlight. 
14.1.7 Administration procedures 
Copanlisib is administered in a normal saline solution, intravenously, over 1 hour. Administer 
copanlisib as a single agent, following reconstitution and dilution. Mix only with 0.9% sodium 
chloride (NaCl) solution. Do not mix or inject copanlisib with other drugs or other diluents. No 
intravenous glucose preparations should be administered on the days of infusion. 
14.2 RITUXIMAB 
Refer to the FDA approved package insert for complete product information. 
14.2.1 Source 
Commercial supplies of rituximab will be purchased by the NIH Clinical Center.   
14.2.2 Toxicity 
No dose-limiting effects were observed in the Phase I/II studies.  Reported adverse events 
including fever, chills, headache, nausea, vomiting, rhinitis, asthenia, and hypotension, occurred 
primarily during rituximab infusions and typically responded to an interruption of the infusion and 
resumption at a slower rate.   
Other important events include:  fatal infusion reactions, cardiac events, tumor lysis syndrome 
(TLS), renal events, mucocutaneous reactions, infections, hepatitis B reactivation, progressive 
multifocal leukoencephalopathy (PML), bowel obstruction and perforation, and immunogenicity.   

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See the package insert for full information.   
14.2.3 Formulation and Preparation 
Commercially available in single-use vials containing 10 mL (100 mg) or 50 mL (500 mg) of 
rituximab solution at a concentration of 10 mg/mL. Rituximab will be diluted with 0.9% Sodium 
Chloride to prepare a standard product with concentration of 2 mg/ml.  Caution should be taken 
during the preparation of the drug, as shaking can cause aggregation and precipitation of the 
antibody. 
14.2.4 Stability and Storage 
Rituximab vials should be stored in a secure refrigerator at  2º to 8°C. After dilution, rituximab is 
stable at 2-8°C (36-46°F) for 24 hours and for an additional 24 hours at room temperature. 
Please refer to the package insert for additional guidance on study drug preparation, handling, and 
storage. 
14.2.5 Administration procedures 
A peripheral or central intravenous line will be established. During rituximab infusion, a patient's 
vital signs (blood pressure, pulse, respiration, temperature) should be monitored according to the 
standard of care. Medications readily available for the emergency management of anaphylactoid 
reactions should include: epinephrine (1:1000, 1 mg/mL) for subcutaneous injection, 
diphenhydramine hydrochloride for intravenous injection, and resuscitation equipment. 
Prophylaxis against hypersensitivity and infusion-related reactions associated with rituximab will 
include acetaminophen 650 mg and diphenhydramine hydrochloride 50-100 mg administered 30-
60 minutes prior to starting rituximab.  
Rituximab infusions will be administered to patients primarily in an outpatient clinic setting.   
x First dose: 
The initial dose rate at the time of the first rituximab infusion should be 50mg/hour (25 mL/hr) 
for the first 30 minutes. If no toxicity is seen, the dose rate may be escalated gradually in 50 
mg/hour (25 mL/h) increments at 30 minute intervals to a maximum of 400 mg/hour 
(maximum rate = 200 mL/h).  
x Second and Subsequent Doses (select the appropriate administration timing):  
o 90-minute Administration 
If the first dose of rituximab is well tolerated, subsequent doses may be administered 
over 90 minutes with 20% of the total dose given in the first 30 minutes, and remaining 
80% of the total dose administered over the subsequent 60 minutes; e.g.: 
Two-Step Rate Escalation 
Volume to administer (X mL) 
1st portion (0 – 30 minutes) 
Total Dose (mg)
2
0.2  X mL (over 30 min)
 
2nd portion (30 – 90 minutes) 
Total Dose (mg)
2
0.8  X mL (over 60 min)
 

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Special Note: The 90-minute infusion scheme is not recommended for patients with 
clinically significant cardiovascular disease or high circulating lymphocyte counts 
(≥5000/mcL). 
o Standard Administration for Second & Subsequent Infusions 
Patients who tolerate initial treatment without experiencing infusion-related adverse 
effects but for whom the 90-minute infusion scheme during subsequent treatments is 
considered inappropriate, may receive subsequent rituximab doses at the Standard Rate 
for Subsequent Infusions, which is as follows: 
Begin at an initial rate of 100 mg/hour (50 mL/h) for 30 minutes. If administration is 
well tolerated, the administration rate may be escalated gradually in 100-mg/hour (50-
mL/h) increments at 30-minute intervals to a maximum rate of 400 mg/hour (maximum 
rate = 200 mL/h). 
CAUTION:  DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.   

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15 REFERENCES  
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Anderson JR, Armitage JO, Weisenburger DD. Epidemiology of the non-Hodgkin's 
lymphomas: distributions of the major subtypes differ by geographic locations. Non-Hodgkin's 
Lymphoma Classification Project. Ann Oncol. 1998;9(7):717-20. 
2. 
Portlock CS, Rosenberg SA. No initial therapy for stage III and IV non-Hodgkin's 
lymphomas of favorable histologic types. Annals of internal medicine. 1979;90(1):10-3. 
3. 
Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-
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16 APPENDICES 
APPENDIX A:  PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up 
and about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 

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APPENDIX B:  GUIDELINES FOR PREGNANCY AND NURSING  
 
Contraception 
Copanlisib and/or rituximab may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if copanlisib or rituximab have transient adverse effects on the composition of sperm.   
For this trial, male patients will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).   
Female patients will be considered of non-reproductive potential if:  
1. They are postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age 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. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); OR  
2. They have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR  
3. They have a congenital or acquired condition that prevents childbearing. 
Female and male patients of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 180 days after the last 
dose of copanlisib or 12 months after the last dose of rituximab, whichever is later, by complying 
with one of the following:   
1. practice abstinence† from heterosexual activity; OR  
2. use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡: 
Single method  
Use of one of the following is acceptable: 
x intrauterine device (IUD) 
x vasectomy of a female subject’s male partner  
x contraceptive rod implanted into the skin 
Combination method  
Requires use of two of the following: 
x diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
x cervical cap with spermicide (nulliparous women only)   
x contraceptive sponge (nulliparous women only)  
x male condom or female condom (cannot be used together) 
x hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection 

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†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies 
and ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) 
and withdrawal are not acceptable methods of contraception.   
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an 
acceptable method of contraception for patients participating at sites in this country/region. 
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study patients of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period and for at least 1 month after the 
last dose of copanlisib and 12 months after the last dose of rituximab, whichever is later, for 
WOCBP and for men.  If there is any question that a subject of childbearing potential will not 
reliably comply with the requirements for contraception, that subject should not be entered into 
the study. 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on study treatment, the subject will immediately 
be removed from the study treatment.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated.  The outcome 
of the pregnancy will be reported to Bayer without delay and within 2 working days to Bayer if 
the outcome is a serious adverse experience.   
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to Bayer.  If a male subject impregnates 
his female partner the study personnel at the site must be informed immediately and the pregnancy 
reported to Bayer and followed as described above and in Section 8.5. 
Use in Nursing Women 
It is unknown whether copanlisib is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
patients who are breast-feeding are not eligible for enrollment.