Phase 1 Study of Copanlisib With Dose-adjusted EPOCH-R in Relapsed and Refractory Burkitt Lymphoma and Other High-Grade B-cell Lymphomas
Phase: PHASE1
Conditions: Burkitt Lymphoma, High-grade B-cell Lymphoma, T-cell/Histocyte-rich Large B-cell Lymphoma, Diffuse Large B-Cell Lymphoma (DLBCL), Germinal Center B-cell Type (GCB)
Sponsor: National Cancer Institute (NCI)

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
1
Abbreviated Title: Copanlisib in BL
NIH Protocol #: 000193
Version Date: 04/24/2023
NCT Number: NCT04933617 
Phase 1 Study of Copanlisib with Dose-adjusted EPOCH-R in Relapsed and Refractory 
Burkitt Lymphoma and other High-Grade B-cell Lymphomas 
NCI Principal Investigator: Mark Roschewski, M.D.
Lymphoid Malignancies Branch (LYMB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
Building 10, Room 4N115
National Institutes of Health (NIH)
Bethesda, MD 20892
Phone: 240-760-6183 
Email:  mark.roschewski@nih.gov
Drug Name:
Copanlisib
Etoposide, Doxorubicin, Vincristine, 
Prednisone, Cyclophosphamide, Rituximab
IND Number:
141280
Sponsor:
Center for Cancer Research, NCI
Center for Cancer Research, NCI
Manufacturer:
Bayer Pharmaceuticals
Generic
Supplier:
Bayer Pharmaceuticals
CC Pharmacy 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
2
PRÉCIS
Background:

Burkitt Lymphoma (BL) is a highly aggressive B‐cell lymphoma that often involves the 
bone marrow and central nervous system (CNS)

Frontline therapy cures 80-85% of adults with BL but patients with CNS involvement or 
those who relapse after frontline therapy are at high risk for treatment failure

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive B-cell 
lymphomas that are successfully cured by frontline therapy in 60-70% of cases

A subset of DLBCL that have MYC gene rearrangement as well as those that have 
transformed from an underlying indolent lymphoma have a lower cure rate

Dose-adjusted (DA)-EPOCH-R is an infusional chemotherapy platform often used as 
frontline therapy for these aggressive B-cell lymphomas and is an effective chemotherapy 
platform from which to rationally design novel therapies for patients with BL, high grade 
B-cell lymphomas- double hit/triple hit (HGBCL-DH/TH), DLBCL and MYC 
rearrangements, and other high-risk DLBCL 

The phosphoinositide 3-kinase (PI3K) pathway is an important signaling pathway for 
cellular responses to growth factors and a downstream event of B-cell receptor signaling. 

Copanlisib targets both PI3K- and PI3K- isoforms and is approved for relapsed FL, 
active as monotherapy in DLBCL, and highly effective in pre-clinical models of BL

Copanlisib crosses the blood brain barrier suggesting it may prevent secondary CNS spread 
in highly aggressive B-cell lymphomas. 

Copanlisib is a rational targeted agent to be added to DA-EPOCH-R in patients with BL, 
HGBCL-DH/TH, and other high-risk B-cell lymphomas.
Objective:

To determine the Maximal tolerated dose (MTD) and Recommended Phase II dose (RP2D) 
of copanlisib in combination with DA-EPOCH-R in subjects with Burkitt lymphoma (BL) 
and high grade B-cell lymphomas- double hit/triple hit (HGBCL-DH/TH) relapsed after or 
refractory to chemo-immunotherapy
Eligibility:

Subjects must have a histologic diagnosis, confirmed by the Laboratory of Pathology, NCI 
with one of the following subtypes and prior therapy, as follows:  
o
Burkitt lymphoma, Burkitt-like lymphoma with 11q aberration, High-grade B-cell 
lymphoma, NOS, High-grade B-cell lymphoma, with MYC and BCL2 and/or 
BCL6 rearrangements – following at least 1 anthracycline-containing regimen
 
OR
o
DLBCL, NOS, Germinal center B-cell type (GCB) type, T-cell/histocyte-rich large 
B-cell lymphoma, following at least 1 anthracycline-containing regimen of the 2 
prior regimens OR be primary refractory to frontline therapy

Age > 18

ECOG performance status 0-2

Adequate bone marrow and organ function 
Design:

Phase 1, open-label, single center, non-randomized

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
3

“3+3” dosing will be used to determine the RP2D and MTD of dose escalated copanlisib 
in combination with DA-EPOCH-R

Maximum 6 cycles (21-day cycles) of combination therapy

Dose expansion at the RP2D or MTD to evaluate efficacy and further evaluate safety

To explore all dose levels, including further evaluation in dose expansion cohort, the 
accrual ceiling will be set at 39

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
4
TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................8
1.1
Study Objectives............................................................................................................8
1.2
Background and Rationale ............................................................................................8
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................18
2.1
Eligibility Criteria........................................................................................................18
2.2
Screening Evaluation...................................................................................................21
2.3
Subject Registration and Status Update Procedures....................................................22
2.4
Baseline Evaluation.....................................................................................................23
3
STUDY IMPLEMENTATION .............................................................................................23
3.1
Study Design ...............................................................................................................23
3.2
Drug Administration....................................................................................................26
3.3
Dose Modifications .....................................................................................................28
3.4
On Study Assessments/Evaluations ............................................................................36
3.5
Treatment Considerations/Exceptions.........................................................................39
3.6
Post-Treatment Evaluations ........................................................................................39
3.7
Study Calendar ............................................................................................................41
3.8
Cost and Compensation...............................................................................................44
3.9
Criteria for Removal from Protocol Therapy and Off Study Criteria .........................44
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................45
4.1
Acceptable/Permitted Medications..............................................................................45
4.2
Prohibited Medications................................................................................................45
4.3
Tumor Lysis Syndrome...............................................................................................46
4.4
Other Considerations (Copanlisib IB).........................................................................47
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................47
5.1
Biospecimen Collection ..............................................................................................47
5.2
Sample Collection and Processing ..............................................................................49
5.3
Biomarker and Research Methods ..............................................................................51
5.4
Sample Storage, Tracking and Disposition .................................................................53
5.5
Samples for Genetic/Genomic Analysis......................................................................55
6
DATA COLLECTION AND EVALUATION .....................................................................56
6.1
Data Collection............................................................................................................56
6.2
Data Sharing Plans ......................................................................................................57

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
5
6.3
Response Criteria ........................................................................................................57
6.4
Toxicity Criteria ..........................................................................................................60
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....60
7.1
Definitions...................................................................................................................60
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING.........60
7.3
NCI Clinical Director Reporting .................................................................................60
7.4
NIH Required Data and Safety Monitoring Plan ........................................................61
8
SPONSOR PROTOCOL/ SAFETY REPORTING...............................................................61
8.1
Definitions...................................................................................................................61
8.2
Assessment of Safety Events.......................................................................................63
8.3
Reporting of Serious Adverse Events .........................................................................63
8.4
Waiver of Expedited Reporting to Sponsor (CCR).....................................................63
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................64
8.6
Reporting Pregnancy ...................................................................................................64
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ...............64
8.8
Sponsor Protocol Deviation Reporting........................................................................65
9
CLINICAL MONITORING..................................................................................................65
10
STATISTICAL CONSIDERATIONS ..................................................................................66
10.1
Objectives and Endpoints............................................................................................66
10.2
Statistical Hypothesis ..................................................................................................67
10.3
Sample Size Determination.........................................................................................68
10.4
Populations for Analyses.............................................................................................69
10.5
Statistical Analyses......................................................................................................69
11
COLLABORATIVE AGREEMENTS..................................................................................70
11.1
Cooperative Research and Development Agreement (CRADA)................................70
12
HUMAN SUBJECTS PROTECTIONS................................................................................70
12.1
Rationale For Subject Selection ..................................................................................70
12.2
Participation of Children .............................................................................................70
12.3
Risk/Benefit Assessment.............................................................................................71
12.4
Consent Process and Documentation ..........................................................................72
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................73
13.1
Study Discontinuation And Closure............................................................................73
13.2
Quality Assurance And Quality Control .....................................................................74
13.3
Conflict Of Interest Policy ..........................................................................................74
13.4
Confidentiality and Privacy.........................................................................................74
14
PHARMACEUTICAL INFORMATION .............................................................................75

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
6
14.1
Copanlisib (BAY 80-6946, Aliqopa) (IND #141280) ..............................................75
14.2
Rituximab ....................................................................................................................79
14.3
Doxorubicin.................................................................................................................80
14.4
Prednisone ...................................................................................................................80
14.5
Vincristine ...................................................................................................................80
14.6
Cyclophosphamide ......................................................................................................81
14.7
Etoposide.....................................................................................................................81
14.8
Vincristine/Doxorubicin/Etoposide Admixture ..........................................................81
15
LIST OF ABBREVIATIONS................................................................................................83
16
REFERENCES ......................................................................................................................86
17
APPENDICES .......................................................................................................................90
Appendix A:  Performance Status Criteria................................................................................90
Appendix B:  Guidelines for Pregnancy and Nursing ...............................................................91
Appendix C: The Lugano Classification Response Criteria......................................................93

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
7
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
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 subject 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 subject 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 subjects 
who provided consent, using a previously approved consent form.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
8
1
INTRODUCTION
STUDY OBJECTIVES 
1.1.1
Primary Objective

To determine the Recommended Phase II dose (RP2D) and Maximal tolerated dose (MTD) 
of copanlisib in combination with DA-EPOCH-R in subjects with Burkitt lymphoma (BL) 
and high grade B-cell lymphomas- double hit/triple hit (HGBCL-DH/TH) who have 
relapsed after or are refractory to chemo-immunotherapy
1.1.2
Secondary Objectives

To assess the safety and tolerability of the combination of copanlisib and DA-EPOCH-R 
in subjects with BL and HGBCL-DH/TH relapsed after or refractory to chemo-
immunotherapy

To determine the complete response rate at the end of therapy, based on Lugano Criteria 
of the combination of copanlisib and DA-EPOCH-R in subjects with BL and HGBCL-
DH/TH relapsed after or refractory to chemo-immunotherapy

To assess progression free survival (PFS), event-free survival (EFS) and overall survival 
(OS) of subjects treated with the combination of copanlisib and DA-EPOCH-R in subjects 
with BL and HGBCL-DH/TH relapsed after or refractory to chemo-immunotherapy
1.1.3
Exploratory Objectives

To explore the molecular correlates of resistance to copanlisib with DA-EPOCH-R

To determine role of circulating tumor DNA to monitor response at the end of therapy

To determine the ability of circulating tumor DNA to predict disease relapse during 
surveillance after therapy is complete

To explore the pharmacokinetics of copanlisib in plasma and cerebrospinal fluid (CSF) 
samples 
BACKGROUND AND RATIONALE
1.1.4
Dose adjusted-EPOCH-R in Burkitt Lymphoma (BL)
Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma characterized by rapidly dividing 
malignant cells that may involve the bone marrow and/or central nervous system (CNS) (1, 2). It 
is the most common B-cell lymphoma in children, but accounts for only 1-2% of adult lymphoma 
(3, 4), except in the setting of HIV where BL reflects 25% of all non-Hodgkin lymphoma (NHL) 
cases. BL is curable with frontline therapy that includes highly dose-intensive chemotherapy 
regimens developed in children and young adults with acute leukemias, but cure rates decline with 
advancing age (5-10). Further, virtually all patients with BL who relapse after frontline therapy 
with highly dose intensive pediatric regimens will succumb to the disease as salvage chemotherapy 
is nearly universally ineffective (11). 
We have demonstrated dose-adjusted (DA)-EPOCH-R (infusional etoposide, doxorubicin, and 
vincristine with prednisone, cyclophosphamide and rituximab) is an effective frontline therapy for 
adults with BL that maintains efficacy with reduced toxicity compared to other regimens. The 
infusional chemotherapy platform utilized with DA-EPOCH-R is based on the hypothesis that drug 
exposure time and not peak concentration is the relevant pharmacodynamic principle to optimize 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
9
the cell death of rapidly proliferating tumor cells (12). In a pilot study of 30 adult patients with 
untreated BL, nearly all patients were cured with DA-EPOCH-R (13). These results were 
confirmed in a multicenter study of risk-adapted therapy in 113 adult patients with untreated BL 
(14). In this study, the median age was 49 years (range 18-86) and 62% of patients were 40 years 
or older. After a median follow-up of 59 months, the event-free survival (EFS) and overall survival 
(OS) for the entire group was 84.5% and 87.0%, respectively. All patients with low-risk BL were 
cured of disease while the EFS of high-risk patients was 82.1%.  In determining risk factors for 
primary treatment failure, age groups and HIV status did not predict outcomes, but the presence 
of disease involving the bone marrow (BM), cerebrospinal fluid (CSF), and/or peripheral blood 
was associated with reduced survival. Deaths on study were equally distributed between disease 
progression and toxic deaths suggesting that intensification of chemotherapy alone is unlikely to 
improve outcomes. Further, only 2 of 9 (22%) patients who relapsed after DA-EPOCH-R remained 
alive after successful salvage therapy. Nearly all patients with relapsed or refractory BL died of 
disease. Thus, despite the high cure rates of BL patients with frontline therapies, improved 
treatment strategies are clearly needed for patients with involvement of the bone marrow or CSF 
and all BL patients who relapse after frontline therapy.
1.1.5
Dose adjusted-EPOCH-R in Diffuse Large B-cell Lymphoma (DLBCL) 
DLBCL encompasses a group of aggressive B-cell NHLs with striking genetic heterogeneity and 
variable clinical presentations.  Even though frontline therapy successfully cures ~75% of DLBCL 
cases, patients with early progression or refractory disease have an OS of only 6 months and are 
often the focus of clinical trials testing novel strategies (15). The molecular heterogeneity of 
DLBCL was initially revealed using gene-expression profiling (GEP) in which molecular subtypes 
of lymphoma emerged with gene expression patterns similar to germinal center B-cells (GCB) or 
activated B-cells (ABC) and thus the classification system became known as “cell of origin” 
(COO). The minority of tumors that could not be classified as ABC or GCB cases were called 
unclassified (16-18). Overall, GCB DLBCL has a better prognosis than ABC DLBCL, but specific 
subsets of GCB DLBCL are at high-risk for treatment failure (19).
The COO classification identifies DLBCL subtypes that arise from B-cells at different stages of 
development, that utilize distinct oncogenic mechanisms for survival signaling, and that have 
dramatically different survival outcomes in response to standard therapies (17, 20, 21). GCB 
DLBCL arises from B-cells with the gene expression program of normal germinal center B-cells 
and frequently express the cell surface marker CD10 (18, 22). ABC DLBCL arises from post-
germinal center B cells, shares a gene expression program with “activated” B-cells and is 
characterized by constitutive activation of the NF-ĸB pathway (23, 24). Up to 20% remain 
unclassified and rare histologic subtypes like T-cell/histiocyte-rich large B-cell lymphoma are not 
captured by COO classification. 
The 2016 revision of the World Health Organization (WHO) classification recognized ABC 
DLBCL and GCB DLBCL as distinct molecular subtypes of DLBCL. Further, approximately 10-
15% of patients with untreated DLBCL have a rearrangement of the MYC oncogene and the WHO 
classification defined a new subset of high-grade DLBCL based on the presence of rearranged 
MYC and BCL-2 and/or BCL-6 [HGBCL-double hit/triple hit 9DH/TH], and is present in 
approximately 8% of DLBCL (25, 26). HGBCL-DH/TH with BCL2 rearrangements are all 
classified as GCB DLBCL (27). HGBCL-DH/TH is not a distinct biologic entity, but identifies 
subsets of DLBCL at risk for treatment failure with R-CHOP.  

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
10
A recent study analyzed RNA sequencing data from 157 patients with GCB DLBCL and 
established a gene expression signature (DHITsig) of 104 genes that identifies 27% of GCB 
DLBCL with a 5-year time to progression rate of 57% compared to 81% (HR 2.8, P<0.001) for 
other GCB DLBCL cases after R-CHOP (27). The outcomes in this DHITsig GCB DLBCL 
subgroup were similar to ABC DLBCL. The DHIT signature robustly identifies HGBCL-DH/TH 
with BCL2 rearrangements, but they account for only 50% of the high-risk group. A follow-up 
study with whole genome sequencing demonstrated that high-risk GCB DLBCL by DHITsig may 
have cryptic rearrangements of MYC or BCL2 not detectable by routine testing (28). In another 
study of 400 patients with DLBCL, a molecular high grade (MHG) gene expression signature 
identified 83 (9%) patients with a 3-year PFS of only 37% (95% CI, 24-55) compared to 72% 
(95% CI, 68-77) for those without the signature (29). Interestingly, 75 (90%) of the patients 
classified with the MHG signature were GCB DLBCL. Taken together, these studies clearly 
identify cases of GCB DLBCL that are at high risk for treatment failure after R-CHOP and need 
novel therapeutic approaches.
We performed the only prospective clinical trial in patients with DLBCL and MYC 
rearrangements. In this multicenter prospective study, DA-EPOCH-R was given for up to 6 cycles 
in 53 patients with HGBCL-DH/TH (45%), HGBCL (19%), and DLBCL and MYC rearrangements 
(34%) (30). After a median follow-up of 55.6 months, the 4-year EFS was 71.0% (95% CI, 56-81) 
with an 4-year OS of 76.7% (95% CI, 63-86). No difference in outcome was observed between 
HGBCL-DH/TH and DLBCL with MYC rearrangements, but patients with high-risk IPI scores 
had an inferior outcome.  
Taken together, these results demonstrate a subset of GCB DLBCL are at high risk for treatment 
failure and are not completely captured within the new entity HGBCL-DH/TH. DA-EPOCH-R is 
the most effective chemotherapy platform on which to add rational targeted agents for patients 
with HGBCL-DH/TH, DLBCL and MYC rearrangements, and other high-risk GCB DLBCL.
1.1.6
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(31, 32). 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 (p110, , , and ). 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(33). p110α and p110β are ubiquitously expressed in various 
tissues, p110γ and p110δ are predominantly expressed in leucocytes and hence are attractive drug 
targets for lymphoid malignancies (34). 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
11
Figure 1:  Class IA PI3Ks enzymes
P110 is the only PI3K catalytic subunit isoform that is significantly associated with cancer-
associated somatic mutations in its gene, PIK3CA(35), but other mechanisms of PI3K activation 
exist including the loss of the tumor suppressor, phosphatase and tensin homolog gene, PTEN(36).  
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(32). 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 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
12
PI3K inhibitors has been slowed by the emergence of dose-limiting toxicities and on-target adverse 
events. 
Among the PI3K isoforms, p110δ plays the most decisive role in B-cell function. Mice harboring 
PIK3CD deletions show decreased number of mature B cells in the bone marrow and a significant 
decrease in B cells residing in marginal zone and pleural/peritoneal cavities. PIK3CD depleted B-
cells do not proliferate in vitro in response to BCR or CD40 signal and exhibit increased 
susceptibility to apoptosis and impaired humoral T-cell dependent and T-cell independent 
responses (37) p110δ inactivation in mice also had protective effect against a broad range of 
cancers, including non-hematological solid tumors, through interruption of tumor induced immune 
tolerance and rejuvenation of cytotoxic CD8 (+) T-cells (38).  
1.1.7
Scientific Rationale for Targeting PI3K in Burkitt lymphoma and High-risk GCB DLBCL
In the current molecular era of disease definition, precision medicine strategies aim to add rational 
agents targeting oncogenic drivers to effective chemotherapy combinations (39). Our clinical and 
translational research teams at the NCI characterize aberrant intracellular signaling pathways 
within distinct lymphoma subtypes and develop treatment combinations designed to overcome 
treatment resistance. Pathogenic B-cell receptor (BCR) signaling is a universal feature of 
aggressive B-cell lymphomas, but different modes of BCR signaling are present within different 
molecular subtypes. Targeting these subtype specific modes of BCR signaling with rationally 
designed therapeutics has proven to benefit some of the highest risk group patients that have been 
refractory to standard immunochemotherapy regimens (40). Thus, defining the mechanisms 
underlying survival signaling is of critical importance and could lead to novel therapeutic strategies 
in other high-risk subtypes of lymphoma. We have recently identified novel modes of antigen-
independent BCR signaling (“toncogenic BCR signaling”) in BL and GCB DLBCL that signal 
through the phosphatidylinositol 3-kinase (PI3K) pathway to activate AKT and mTOR (Figure 3) 
(41-43). Clinical trials testing various novel agents are now needed to better define the therapeutic 
potential of targeting BCR signaling in these lymphomas.
Figure 3:Toncogenic BCR Signaling
The normal germinal center B-cell is the presumed cell of origin for both BL and GCB DLBCL, 
but the genetic profiles of these tumors are distinct (Figure 4), suggesting they arise from subtly 
different progenitors. In over 70% of sporadic cases of BL, mutations in TCF3, or its negative 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
13
regulator ID3, have been identified (Figure 4).  Functional studies demonstrated that BL cell lines 
were dependent upon TCF3 expression to control BCR and PI3K activation by repressing a 
negative regulator of BCR signaling, PTPN6 (42). Further evidence supported these claims by 
demonstrating a similar loss of PI3K activity upon knockdown of BCR subunits (CD79A and 
SYK,) overexpression of PTPN6, or treatment with pan-PI3K inhibitors. Importantly, gene 
expression signatures defined in BL cell lines upon treatment with inhibitors of this pathway were 
found to be highly expressed in tumor samples from BL patients.  
Notably, an oncogenic role for the BCR has long been appreciated in ABC DLBCL, yet the same 
techniques that elucidated an oncogenic role in ABC and BL were insufficient to identify a role 
for the BCR in GCB DLBCL. However, recent genome-wide CRISPR-Cas9 genetic knockout 
screens have changed this notion by demonstrating that similar to BL, GCB DLBCL also utilizes 
components of proximal BCR signaling such as CD79A, CD79B, SYK, LYN, CD19, and CD81 
to maintain PI3K and AKT activity (Figure 5 and data not shown) (44). The differences in 
sensitivity to knockdown vs knockout of BCR genes may have to do with different thresholds of 
BCR expression needed to initiate antigen-independent signaling from the IgM vs the IgG BCRs 
found in each respective disease. Yet, in both GCB DLBCL and BL, this oncogenic mode of BCR 
signaling was found to independent of NF-B (as in ABC DLBCL), and instead, relied heavily on 
the PI3K/AKT/mTOR pathways and it was highly sensitive to PI3K and mTOR inhibitors.  Taken 
together, our investigations into BCR signaling in aggressive human lymphomas have 
demonstrated that much like normal B cells, most oncogenic B cells also require their BCR to 
survive. However, each malignancy has evolved grossly (ABC) or subtly (GCB vs BL) different 
oncogenic mechanisms to coopt this dominant survival pathway. Our data not only define how this 
prevalent oncogene (the BCR) functions across aggressive lymphoma subtypes, but also suggests 
novel therapeutic targets that will be effective in subsets of BL and GCB DLBCL patients.
Figure 4. Distinct Genetic Profiles of BL and GCB and ABC DLBCL

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
14
Figure 5.  Genes Essential for Oncogenic Signaling in Lymphoma
1.1.8
 Copanlisib (Aliqopa) for High-risk GCB DLBCL and Burkitt lymphoma
Copanlisib (Aliqopa) is an intraveneous pan-class I PI3K inhibitor with predominant activity 
against the PI3K- and PI3K- 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 dosing (45). Another potential benefit of simultaneous targeting the PI3K- isoform is 
that upregulation of alternative isoforms over time may be a mechanism of resistance to selective 
PI3K- inhibitors (46, 47). Studies in mantle cell lymphoma cell lines and from patient samples 
have shown that p110 expression increased significantly upon relapse after treatment with 
idelalisib, suggesting p100 plays a mechanistic role in resistance. In addition, combined 
inhibition of both p110- and p110- isoforms was a more effective strategy for inhibiting 
constitutive PI3K activation in cell lines (46). Copanlisib has been studied as monotherapy in 
DLBCL and demonstrated an overall response rate of 25%, including complete responses in 
relapsed and refractory cases (48). Further, recent data demonstrates that copanlisib effectively 
crosses the blood brain barrier suggesting it may prevent secondary CNS spread in highly 
aggressive B-cell lymphomas (49). CNS safety pharmacology studies of copanlisib in rats showed 
behavioral abnormalities such as stereotypic licking, swaying gait, vocalization upon touch, and 
reduced muscle tone beginning about 0.5 hours after a dose ≥18 mg/m2. At doses of 54 mg/m2, 
additional CNS effects of piloerection, ptosis, salivation, played limbs, backward walking, 
stereotypic chewing, hypoactivity, and delayed hot-plate response were noted. These effects 
indicate moderate CNS penetration of copanlisib. These data demonstrate that copanlisib has 
activity as monotherapy in aggressive B-cell lymphomas such as DLBCL, including those with 
CNS involvement.
No clinical activity has been demonstrated for copanlisib monotherapy in patients with relapsed 
and refractory BL. However, BL is a rare tumor in adults making up only 1-2% of all lymphomas 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
15
diagnosed and an estimated 400 cases annually in the United States. The rarity of the tumor 
coupled with the high cure rate to frontline therapy results in a paucity of prospective trials in 
relapsed BL. 
1.1.9
Copanlisib combined with chemotherapy for B-cell lymphomas
A phase 1 study added copanlisib to bendamustine and rituximab in 10 patients with relapsed FL 
(n=7), marginal zone lymphoma (n=1), and lymphoplasmacytic lymphoma n=2). There were no 
dose-limiting toxicities (DLTs) but there were 4 discontinuations due to drug-related adverse 
events (3 due to copanlisib + BR and 1 due to BR). The most common treatment related adverse 
events (AEs) were neutropenia (all grade 80%, Grade ≥ 3 50%), nausea (70%, No gr ≥ 3), 
thrombocytopenia (60%, Gr ≥ 3 none), and hyperglycemia (60%, Gr ≥ 3 50%). No cases of non-
infectious pneumonitis were noted and responses were noted in all 7 evaluable patients indicating 
tolerability and safety of this combination. Currently, the phase III study CHRONOS-4 is 
investigating use of copanlisib with standard chemoimmunotherapy (B-R or R-CHOP) and a phase 
1 study (NCT04156828) is assessing R-CGD (carboplatin, gemcitabine, and dexamethasone) with 
copanlisib for R/R grade 3b FL and DLBCL.  Preliminary safety-run in data from CHRONOS-4 
were presented at European Society of Medical Oncology (ESMO) meeting in September, 2020. 
In addition, the authors reported safety and efficacy data on 11 patients who received copanlisib 
in combination with R-CHOP (all with follicular lymphoma; 5 patients at 45 mg and 6 at 60 mg). 
No DLTs were reported at either dose of copanlisib (45 or 60 mg) in either treatment group. Similar 
to prior data, the most frequent treatment-emergent adverse events (TEAEs) were hematologic 
(neutropenia and thrombocytopenia) and on-target effects (hyperglycemia and hypertension). 
Most common TEAEs in copanlisib + RCHOP cohort were hyperglycemia, hypertension, and 
neutropenia, which also were the most frequent grade 3 events (64% each).  The incidence of 
serious TEAEs was 20.0% (2/10) in the R-B group and 72.7% (8/11) in the R-CHOP group. The 
2 serious TEAEs in the R-B group were eosinophilia and lung infection in 1 patient each. The most 
common (≥20%) serious TEAE in the R-CHOP group was lung infection in 3 patients (27.3%). 
Drug-related AEs led to discontinuations in 4 patients in the copanlisib BR group (considered 
related to copanlisib and bendamustine in 4 patients, and bendamustine in 1 patient) vs 5 patients 
in the copanlisib RCHOP cohort (considered copanlisib related in 5 patients, including 2 related 
to copanlisib and R-CHOP). One patient in the RCHOP cohort did experience pneumonitis which 
was an AE of special interest however no colitis was noted. The combination of copanlisib with 
chemotherapy exhibited high ORR, 90% in BR group and 100% in RCHOP group (Zinzani et al 
ESMO 2020).  
The original version of this protocol was written to test copanlisib with DA-EPOCH-R in relapsed 
and refractory germinal center B-cell lymphomas, including Burkitt lymphoma and was written 
with broad inclusion criteria that allowed prior treatment with CAR-T therapy. Accrual to this 
study was halted after 2 of the first 5 patients had a DLT related to hematologic toxicity with the 
regimen.  Specifics of these cases are included here:
The first patient was a 66 y/o male with heavily pre-treated diffuse large B-cell lymphoma of 
germinal center B-cell origin (GCB DLBCL) that had transformed from prior splenic marginal 
zone lymphoma (SMZL).  His prior anti-lymphoma therapies included: 
1) 2016: Splenectomy (for SMZL)
2) 2020: R-CHOP x 6 (for DLBCL)
3) 2021: Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Revlimid (VIPOR) x 
2 (on study at NIH)

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
16
4) 2021: Radiotherapy 30 Gy + 20 Gy boost to thigh lesion
5) 2021: Bendamustine-Rituximab with Polatuzumab 
6) 2021: CAR-19 therapy (Yescarta)
7) 2022: Glofitamab with Gemcitabine, Oxaliplatin and Obinutuzumab on trial
8) 2022: Bispecific CAR-19/20 on trial
At study entry, he was mostly confined to sitting in a chair due to his large lesion affecting his 
right thigh, but his hematologic parameters were normal with an absolute neutrophil count of 1,670 
hemoglobin of 9.3 g/dL, and platelet count of 114,000L.  Nonetheless, given his tenuous clinical 
situation, it was decided to admit him to the hospital for his treatment. He received 30mg of 
Copanlisib on day 1 of his regimen as planned along with dose level 1 of EPOCH-R.  On day 5 of 
the first cycle, his ANC had decreased to 400 and his platelet count was 75,000L. The planned 
day 5 dose of copanlisib was not given and EPOCH-R was finished as scheduled. Throughout the 
course of the first cycle, both the ANC remained severely low (under 200) and the platelet count 
decreased under   20,000 L requiring platelet transfusions.  The ANC did not recover to above 
500 until day 17 of the cycle and the platelet count remained < 25,000 L for over 30 days. Even 
though the patient had an improved thigh lesion and met criteria for a partial response to treatment, 
he was removed from study therapy, and these events were considered a dose-limiting toxicity of 
the regimen. In my opinion, the severe neutropenia and thrombocytopenia were predominantly 
related to the EPOCH-R regimen, but since he had received 1 dose of copanlisib it could not be 
excluded as a contributing factor. The patient did not receive any more therapy and died of 
progressive disease 2 months later.
The second patient was a 59 year old male with heavily pre-treated high-grade B-cell lymphoma, 
double-hit (HGBL-DH) with MYC and BCL2 rearrangements. His prior anti-lymphoma therapies 
included: 
1) 2021: DA-EPOCH-R x 5 cycles
2) 2021: R-ICE x 2 cycles
3) 2021: Rituximab-Polatuzumab with Bendamustine
4) 2022: Fludarabine/Cytoxan followed by CAR-19 therapy (Yescarta)
5) 2022: Rituximab, Gemcitabine, Oxaliplatin x 2
6) 2022:Venetoclax, 
Ibrutinib, 
Prednisone, 
Obinutuzumab, 
Revlimid, 
Polatuzumab x 1 
At study entry, he had disease affecting mostly his left arm and his lungs, but his hematologic 
parameters were normal with an absolute neutrophil count of 8200, a hemoglobin of 9.9 g/dL, and 
platelet count of 135,000L. He also was admitted to the hospital to receive his first cycle of study 
therapy.  He received copanlisib 30mg on days 1 and 5 as scheduled along with dose level 1 of 
EPOCH-R regimen.  On day 6 of therapy, he was doing well clinically with an ANC of 1550, a 
hemoglobin of 11 g/dL, and a platelet count of 39,000L.  He was discharged back home with 
close monitoring by his local oncologist. On day 8 of his first cycle, his platelets were noted to be 
less than 25,000L and his hemoglobin was less than 9g/dL. He was scheduled for transfusions of 
both platelets and red blood cells. He was also noted to have an ANC of less than 500 despite daily 
injection of filgrastim. He was admitted to the hospital due to worsening of his left upper extremity 
edema and left pleural effusion signifying disease progression. After admission, he was transferred 
to the ICU for blood product support, chest tube placement, and broad-spectrum antibiotics. His 
ANC was nearly zero and he was treated for sepsis although no blood cultures were positive. He 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
17
was intubated and required mechanical ventilation for progressive hypoxic respiratory failure due 
to disease progression.  Given his lack of response to therapy, the patient was made DNR/DNI and 
was terminally extubated in the hospital.  He died shortly afterwards.  The event was recorded as 
grade 4 neutropenia and thrombocytopenia attributed to the EPOCH-R regimen and copanlisib.  It 
was felt by the PI and sponsor that the most proximate cause of death was disease progression, but 
a contribution of toxicity from the regimen could not be fully excluded.
We have previously completed many studies combining novel targeted agents with the EPOCH-R 
backbone in the relapsed setting, but this one has had unacceptable hematologic toxicity in 2 of 
the first 5 patients enrolled. In discussions within our Branch and with the safety monitoring 
committee, we feel that the heavily pre-treated nature of some of the patients that we included 
along with the fact that they had received prior CAR-T therapy put them at high-risk of these 
hematologic toxicities. It is our current opinion that it is infeasible to include patients who have 
received CAR-T in a protocol that includes chemotherapy such as the EPOCH-R backbone. Based 
on this information, we have amended this study with a change in treatment schedule and eligibility 
criteria to allow for proper testing of the safety of this regimen.
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.
1.1.10 Study Summary
This is a phase 1 dose escalation study with an expansion cohort of copanlisib in combination with 
standard dosing of DA-EPOCH-R in subjects with highly-aggressive B-cell lymphomas, such as 
relapsed BL and high-risk GCB DLBCL. Correlative research for this study will include analyzing 
the molecular correlates of resistance to copanlisib with DA-EPOCH-R, determining the role of 
circulating tumor DNA in monitoring response to therapy, and determining the ability of 
circulating tumor DNA to predict disease relapse. This study will utilize multiplatform genomic 
analyses of tumor biopsies to identify biomarkers that predict response or resistance. The 
molecular annotation will include a combination of gene-expression profiling, RNA sequencing, 
whole-exome sequencing, and identification of copy number abnormalities via array comparative 
genomic hybridization. Specific aims of these molecular correlates will be based on published 
literature regarding gene expression and molecular signatures that identify subsets of subjects who 
are considered high-risk for early treatment failure. Additionally, we aim to identify mechanisms 
of therapeutic resistance through genomic analysis of circulating tumor DNA and biopsies taken 
before treatment and at time of clinical progression.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Subjects must have a histologic diagnosis, confirmed by the Laboratory of Pathology, 
NCI with one of the following subtypes and prior therapy, as follows:  

At least 1 anthracycline-containing regimen:

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
18
o
Burkitt lymphoma
o
Burkitt-like lymphoma with 11q aberration
o
High-grade B-cell lymphoma, NOS
o
High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 
rearrangements 
OR

Must have had at least 2 prior regimens, 1 of which must have been anthracycline-
containing regimen OR be primary refractory to frontline therapy:
o
DLBCL, NOS, Germinal center B-cell type (GCB) type; 
NOTE: subjects with coexisting or a history of indolent lymphoma are 
eligible (i.e., “transformed lymphoma”)
o
T-cell/histocyte-rich large B-cell lymphoma 
2.1.1.2
Measurable or evaluable disease on imaging scans or bone marrow 
2.1.1.3
No other current systemic anti-lymphoma therapy. NOTE:  Recent short-term (7 days) 
use of corticosteroids or prior radiation to sites of disease involvement is permitted.
2.1.1.4
Any HIV status will be included in this study as long as infection is controlled; in the 
opinion of the investigator. Status must be confirmed at screening and the subject must 
be willing to take any recommended antiretroviral therapy.
2.1.1.5
 18 years of age on day of signing informed consent
2.1.1.6
ECOG performance status < 2 (see Appendix A)
2.1.1.7
Adequate organ function as evidenced by the following laboratory parameters, unless 
dysfunction is secondary to lymphoma involvement as determined by the investigator:  
Absolute neutrophil count 
(ANC)
≥ 1,000 /mm3 
Platelets
≥ 100 x 109 /L 
Hemoglobin
≥ 8 g/dL (unless due to disease itself, transfusion 
permitted to meet criteria) 
Renal function 
Glomerular filtration rate (GFR) >50ml/min/1.73 m2 
as estimated by 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. 
Total bilirubin
≤ 1.5 x ULN OR 
< 1.5-3.0 x ULN for subjects with liver involvement*
AST and ALT 
≤ 3.0 x ULN OR
< 5 x ULN for subjects with liver involvement
*Acceptable range as long as there is no persistent nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia
2.1.1.8
Must have fully recovered from all effects of prior surgery. NOTE: Minor procedures 
requiring “Twilight” sedation, such as tissue biopsies, endoscopies or mediport placement 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
19
require a 24-hour waiting period prior to treatment initiation.
2.1.1.9
Women of childbearing potential (WOCBP) and men with female partners of 
childbearing 
potential 
must 
agree 
to 
use                        
a highly effective method of contraception when sexually active (intrauterine device, 
surgical sterilization, contraceptive rod, abstinence) for the time period between signing 
of the informed consent form and for at least 1 month after the last dose of copanlisib. 
WOCBP and men with female partners of childbearing potential must agree to use an 
effective method of contraception (two of the following: diaphragm, cervical cap, 
contraceptive sponge, condom, hormonal) when sexually active for the time period 
between signing of the informed consent  and for at least 12 months after the last dose of 
rituximab. 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.
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 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 subject 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. See Appendix B for complete details of 
acceptable contraceptive methods.
2.1.1.10 Willingness to have a central venous access line placed if the subject does not already 
have one in place
2.1.1.11 Ability of patient to understand and the willingness to sign a written informed consent 
document
2.1.2
Exclusion Criteria
2.1.2.1
Subjects previously exposed to, intolerant of, or ineligible for PI3K inhibitors and/or their 
combination
2.1.2.2
Brain parenchymal involvement
2.1.2.3
Patients who have been treated with prior CAR-T therapy or any regimen containing 
fludarabine.
2.1.2.4
CMV-positive PCR at screening
2.1.2.5
History of diabetic ketoacidosis
2.1.2.6
Uncontrolled intercurrent illness including, but not limited to the following that may 
limit interpretation of results or that could increase risk to the subject at the discretion of 
the investigator:

Any secondary malignancy that requires active systemic therapy

Diabetes mellitus with Hgb A1C > 8.5

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
20

Clinically significant interstitial lung disease and/or lung disease that severely impairs 
lung function 

Uncontrolled HIV

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.

Active hepatitis B infection. NOTE: Patients who are hepatitis B surface antigen 
(HbsAg) or hepatitis B core antibody (HbcAb) positive will need to have a negative 
HBV PCR result before enrollment. Those with a positive PCR for hepatitis B are 
excluded. Those who are hepatitis B surface antigen (HbsAg) or hepatitis B core 
antibody (HbcAb) positive with a negative PCR for hepatitis B will be treated with 
antivirals designed to prevent hepatitis B reactivation (e.g., entecavir) throughout 
therapy and for 12 months after therapy and have monitoring for hepatitis B 
reactivation with PCR as per Section 3.1.13.2.  

Clinically significant, uncontrolled heart disease and/or cardiac repolarization 
abnormalities, including any of the following:
o
History of acute coronary syndromes (including myocardial infarction, unstable 
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or 
symptomatic pericarditis within 6 months prior to screening
o
Congestive heart failure (New York Heart Association functional classification 
III-IV)
o
Unstable angina
o
Left Ventricular Ejection Fraction (LVEF) <40% as determined by echocardiogram 
(ECHO) at screening
o
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete 
left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz 
type II and third-degree AV block)
o
Long QT syndrome or family history of idiopathic sudden death or congenital 
long QT syndrome, or any of the following:
Long QT syndrome or family history of idiopathic sudden death or 
congenital long QT syndrome, or any of the following:
Inability to determine the QT interval on screening (QTcF, using 
Fredericia’s correction)
Long QT syndrome or family history of idiopathic sudden death or 
congenital long QT syndrome

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 subject 
inappropriate for entry into the study.
2.1.2.7
Requirement to continue on any of the medications that are excluded (see Section 0)
2.1.2.8
Breast-feeding subjects. Because there is an unknown but potential risk for adverse events 
in nursing infants secondary to treatment of the mother with these agents, breastfeeding 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
21
should be discontinued if the mother is treated on study.
2.1.3
Recruitment Strategies
This protocol may be abstracted into a plain language announcement posted on NIH websites and 
on NIH social media platforms. Study subjects will be recruited from the population of subjects 
screened in the lymphoid malignancy clinics of the National Institutes of Health. These will 
include both referrals from outside physicians as well as subject self-referrals. In addition, we 
participate in a locoregional consortium of eight academic institutions within the mid-Atlantic 
region that shares information regarding active clinical protocols and aims to enhance subject 
recruitment across the region. 
SCREENING EVALUATION
2.1.4
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: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc.  

Review of existing  MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
2.1.5
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the screening consent 
for this study OR the consent for study 01C0129 (provided the procedure is permitted on that 
study) on which screening activities will be performed. Assessments performed at outside facilities 
or on another NIH protocol within the timeframes below may also be used to determine eligibility 
once a subject has signed the consent.
NOTE:  Assessments and procedures to confirm study eligibility should be completed within 28 
days prior to treatment (unless otherwise noted).  See also the Study Calendar (Section 0).  
2.1.5.1
Clinical Evaluations

Disease history, including:  diagnosis, prior radiation treatment (if applicable), and 
significant prior/ongoing side effects and symptoms

Complete medical history, including: all active conditions considered to be clinically 
significant by the treating investigator

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 
2.1.5.2
Laboratory Evaluations 
NOTE:  Results from outside NIH are accepted.

CBC with differential

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
22

Chemistry panels (as noted) or specific analyte required for eligibility, including:  
Creatinine (i.e., or Acute Care 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)

Urinalysis 

CMV HBV and HCV PCR and HBV serology (within 3 months allowed, also see 
Section 3.1.13 and 3.1.13.2) 

HIV antibody (within 3 months allowed)

Hemoglobin A1C

Urine and/or serum HCG in women of childbearing potential (within 7 days prior to 
treatment)
2.1.5.3
Imaging Studies 
NOTE:  Results from outside NIH are accepted.

CT chest, abdomen and pelvis with contrast

PET Imaging (i.e., whole body 18F-FDG PET/CT)

MRI of brain
2.1.6
Other Procedures

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.

Bone marrow aspiration and biopsy (results from outside NIH are accepted)

Echocardiogram (ECHO) and electrocardiogram (EKG)
SUBJECT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a subject is taken off protocol therapy and when a 
subject is taken off-study) will take place per CCR SOP ADCR-2, CCR Subject Registration & 
Status Updates found at  
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.1.7
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure subjects, 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.
Individuals who do not meet the criteria for participation in this trial (screen failure) (e.g., 
laboratory parameter) may be rescreened.
2.1.8
Treatment Assignment Procedures
NOTE:  For NCI CCR registration purposes only.   

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
23
2.1.8.1
Cohorts
Number
Name
Description
1
Dose Escalation
Relapsed/refractory aggressive B-cell lymphomas (see 
inclusion criteria for subtypes)
2
Dose Expansion
Relapsed/refractory aggressive B-cell lymphoma (see 
inclusion criteria for subtypes)
2.1.8.2
Arms 
Number
Name
Description
1
Dose Escalation, 
original
*Closed with approval 
of Amendment 
02/22/2023
Copanlisib (IV) per dose level (30 mg, 45 mg, or 60 
mg) on days 1 and 5 of each 21-day cycle in 
combination with standard dosing DA-EPOCH-R to 
determine RP2D and MTD of copanlisib. Up to 6 
cycles total. 
2
Dose Escalation, 
modified
Copanlisib (IV) per dose level (30 mg, 45 mg, or 60 
mg) on day 1 of each 21-day cycle in combination with 
standard dosing DA-EPOCH-R to determine RP2D 
and MTD of copanlisib. Up to 6 cycles total.
3
Dose Expansion
Copanlisib (IV) at the RP2D or MTD on day 1 of each 
21-day cycle in combination with standard dosing DA-
EPOCH-R. Up to 6 cycles total. 
2.1.8.3
Arm Assignment
Five subjects in Cohort 1 were enrolled onto Arm 1 which has been closed to enrollment. All future 
subjects in Cohort 1 will now be assigned to treatment Arm 2. All subjects in Cohort 2 will be 
assigned to treatment Arm 3.
BASELINE EVALUATION
The baseline evaluations should be performed within 14 days prior to the first dose of copanlisib 
unless otherwise noted; tests performed as part of screening do not need to be repeated if they were 
performed within the specified window.  See the Study Calendar (Section 0) for details.
3
STUDY IMPLEMENTATION
STUDY DESIGN
This is a phase 1 dose escalation study with an expansion cohort of copanlisib in combination with 
standard dosing of DA-EPOCH-R in subjects with highly-aggressive B-cell lymphomas, such as 
relapsed BL and high-risk GCB DLBCL. 
Copanlisib will be administered via IV at escalating doses, with a starting dose of 30mg, on day 1 
of each 21-day cycle (see Table 1 for dose levels and schedule), with a standard 3+3 design for 
dose escalation. A dose expansion cohort will enroll an additional 10 subjects to be treated at the 
MTD or RP2D to obtain more safety data as well as initial preliminary efficacy data.
Treatment will continue for a maximum of 6 cycles or until toxicity (i.e., dose limiting toxicity as 
found in Section 3.1.1 or toxicity requiring discontinuation as defined in Section 0) or progressive 
disease. Response evaluation will occur after cycles 1, 3, and 6. After treatment has ended, subjects 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
24
undergo follow-up as follows: every 3 months for the first 2 years post-treatment and then every 
6 months from years 2-5 post-treatment, and then annually after that. Follow-up is anticipated to 
end at 5 years post-treatment in the last participant.
3.1.1
Dose Limiting Toxicity
A dose-limiting toxicity (DLT) is defined as: any treatment-emergent, clinically relevant, and 
related severe (grade ≥ 3) toxicity, i.e., toxicity deemed possibly, probably or definitely related to 
copanlisib or to the combination therapy, by the PI or designee and occurring during the DLT 
observation time, defined as Cycle 1 of treatment (i.e., 21 days). Subjects who withdraw before 
completing DLT assessment for reasons other than a DLT, will not be evaluable for assessment of 
DLT and will be replaced. 
The following toxicities and conditions will be recorded; however, they will not be considered to 
be DLTs:
3.1.1.1
Non-hematologic AEs

Grade 3 nausea, vomiting, or diarrhea that persist ≤ 7 days with supportive care 

Grade 3 fatigue 

Grade 3 infection that improves to ≤ grade 2 after initiation of antimicrobials

Grade 3 electrolyte disturbances that improve to ≤ grade 1 ≤ 7 days with appropriate 
medical management 

Grade 3 infusion related reaction

Any grade 3 laboratory abnormality that is asymptomatic and deemed by the investigator 
to be not clinically significant 
3.1.1.2
Hematologic AEs 

Grade 3 or 4 neutropenia that lasts < 7 days. NOTE: Grade 3 or 4 febrile neutropenia will 
only be considered a DLT if the neutropenia lasts 7 days

Grade 3 or 4 thrombocytopenia not associated with significant bleeding and lasts < 7 days

Grade 3 anemia that is not medically significant  

Grade 3 or 4 lymphopenia
3.1.2
Dose Escalation
Dose escalation for copanlisib will proceed according to the following schedule (Table 1) and 
rules (Table 2). Each subject will continue treatment at the dose level on which he/she is 
enrolled – there will be no intra- subject dose escalation. Subjects may not be enrolled to a new 
dose level until all subjects treated at the previous dose level have completed the DLT 
observation period defined in Section 3.1.1.
Each dose-escalation or de-escalation decision will be documented in the study file. The report, 
including the supporting safety data and delineation of each criteria met, with the dose-
escalation/de-escalation decisions will be provided to and approved by the Sponsor 
(OSROSafety@nih.gov) before additional participants will initiate study therapy. The Dose 
Escalation 
Determination 
form 
on 
the 
sponsor 
website: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions  may be used for 
this purpose.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
25
Table 1: Copanlisib Dose Escalation Schedule
Dose Level
Copanlisib
Level 1
30 mg on Day 1
Level 2
45 mg on Day 1
Level 3
60 mg on Day 1
Table 2: Dose Escalation Rules
Number of subjects with 
DLT at a Given Dose Level
Escalation Decision Rule
0 out of 3
Enter up to 3 subjects at the next dose level
1 out of 3
Enter up to 3 more subjects at this dose level.

If 0 of these 3 subjects experience DLT, proceed to the 
next dose level.

If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose. UP to three (3) additional 
subjects will be entered at the next lowest dose level if 
only 3 subjects were treated previously at that dose.
> 2
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered). Up to three (3) additional subjects will be 
entered at the next lowest dose level if only 3 subjects were 
treated previously at that dose.
<1 out of 6 at highest dose 
level below the maximally 
administered dose
This is the MTD and is generally the recommended phase 2 
dose. At least 6 subjects must be entered at the 
recommended phase 2 dose.
3.1.3
Dose Expansion
Once the last subject enrolled to Cohort 1 Arm 2 completes the first cycle of treatment and the 
MTD or RP2D is determined, the study will proceed to the dose expansion phase with enrollment 
of an additional 10 subjects to a Cohort 2 “expansion cohort” to obtain more safety data as well as 
initial preliminary efficacy data. 
As an additional stopping rule for safety, if at any time after 3 subjects have enrolled in the 
expansion cohort, ≥1/3 subjects cumulatively treated in the expansion are identified as having a 
DLT, no further subjects will enroll.  See also Section 0.
DRUG ADMINISTRATION
3.1.4
Drug Administration
Each cycle is 21 days (3 weeks). Delays may apply based on toxicities. Treatment can continue 
for up to 6 cycles. 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
26
Treatment will be administered on an outpatient basis during days 1-5 of a cycle, however, may 
be given as an inpatient for matters of convenience or investigator preference in case of additional 
monitoring. Reported adverse events and potential risks are described in Section 14. Appropriate 
dose modifications are described in Section 0. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
subject’s malignancy. 
3.1.5
Study Dosing Schema
Drug
Daily Dose 
Route
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6-15
Copanlisib
Per dose level
IV
X
Rituximab
375 mg/m2
IV
X
Etoposide
50 mg/m2
CIVI
X
X
X
X
Vincristine
0.4 mg/m2
CIVI
X
X
X
X
Doxorubicin
10 mg/m2
CIVI
X
X
X
X
Cyclophosphamide
750 mg/m2
IV
X
Prednisone
60 mg/m2 BID
Oral
X
X
X
X
X
No drug(s)
3.1.6
Copanlisib
All subjects will receive copanlisib (at a dose based on the dose level they are enrolled to) 
administered via IV on Day 1 of Cycles 1-6. Dosing is not based upon subject weight (i.e., “fixed” 
dose). Infusions may be done peripherally or via central venous access device. 
Copanlisib will be administered as a 60-minute infusion and prior to EPOCH-R on day 1 of each 
cycle. 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, subject’s blood pressure will be monitored at 0 h (pre-dose), 30 (±10) 
min (mid-infusion), 60 (±10) min (end of infusion) (See Section 3.1.9.5).
No premedications are required for copanlisib; however, premedications including corticosteroids 
may be used in specific subjects at treating investigator discretion or as directed per toxicity 
management.  
3.1.7
Dose-adjusted (DA) EPOCH-R Regimen
Study treatment administration for EPOCH-R will take place as outlined in Section 3.1.5, unless 
the subject experiences unacceptable toxicity or disease progression. Dose adjustment for 
subsequent cycles will be determined by the absolute neutrophil count (ANC) or platelet nadir 
from the previous cycle (whichever is lowest). Subsequent treatment doses are determined by 
hematological toxicity experienced on the previous cycle (see Section 0 for dose adjustments).  
Investigators should refer to prescribing information for storage and handling, and detailed 
instructions on the administration of rituximab, cyclophosphamide, etoposide, doxorubicin, 
vincristine, and prednisone. Rituximab biosimilar drugs are not permitted in this study. Biosimilar 
drugs have not been validated with DA-EPOCH-R in these tumors, therefore, we do not allow 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
27
their inclusion. All IV drugs should be administered per local practice. All subjects will receive 
DA-EPOCH-R and pre-medications for Cycles 1-6 at the following doses:

EPOCH-R chemotherapy
o
Rituximab 375 mg/m2 IV per protocol on Day 1 prior to EPOCH agents
o
Vincristine 0.4 mg/m2/day (no cap) CIVI on Days 1-4* (total 1.6 mg/m2 96 hours)
o
Doxorubicin 10 mg/m2/day CIVI on Days 1-4* (total 40 mg/m2 96 hours)
o
Etoposide 50 mg/m2/day CIVI on Days 1-4* (total 200 mg/m2 96 hours)
o
Cyclophosphamide 750 mg/m2 IV on Day 5 (following infusions)
o
Prednisone 60 mg/m2 PO BID Days 1-5 (total 120mg/m2/day)
*NOTE: Taking into account copanlisib administration on day 1, the 96 hours of 
EPOCH-R administration ends on day 5 of each cycle.   
3.1.8
Supportive Medications
NOTE: Supportive and pre-medications may be adjusted at the discretion of the investigator.
3.1.8.1
Premedication
Approximately 30-60 minutes prior to rituximab:

Acetaminophen 650 mg PO x 1

Diphenhydramine 50 mg PO x 1
3.1.8.2
CNS prophylaxis
Subjects with active CSF disease will receive methotrexate 12 mg intrathecal (IT) twice weekly 
until 2 weeks past CSF clears (minimum 8 doses); then, weekly for 6 doses, followed by monthly 
for 6 doses. 
3.1.8.3
Ancillary medications for DA-EPOCH-R
NOTE: Alternative ancillary medications (e.g., H2 blocker) may be used at recommended dosages 
at discretion of the investigator. 

Pegfilgrastim 6mg subcutaneous injection one time dose on Day 6 or Filgrastim at 
300mcg/dose if body weight < 75kg or 480mcg/dose if body weight  75 kg starting on 
Day 6 and continued once daily by subcutaneous injection until ANC > 5000/mm3 after the 
neutrophil nadir for ALL cycles

Omeprazole 20 mg/day PO (or equivalent) 

Colace 100mg PO twice daily OR Docusate/Senna2-4 tablets QD

Lactulose 20g PO every 6 hours PRN until resolution for treatment of constipation

Trimethoprim/sulfamethoxazole DS 1 tablet PO three times weekly (or equivalent if 
allergic), if indicated

Entecavir, 0.5mg PO daily, if indicated.
3.1.8.4
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. 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
28
Subjects allergic to either component may receive inhaled pentamidine 300 mg once a month or 
other standard treatments. Treatment will begin with initiation of treatment (i.e., Day 1 of the 
copanlisib) and will be stopped upon completion of therapy unless continued administration 
beyond this point is deemed necessary based on inadequate immune reconstitution.  
3.1.8.5
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.
DOSE MODIFICATIONS 
3.1.9
Copanlisib
Adverse events may occur shortly after the first dose of copanlisib and it must be withheld for all 
drug-related toxicities considered severe or life-threatening as per below.  For all AEs/SAEs, the 
treating investigator may use discretion with regards to dose holds and supportive care.  The dose 
of copanlisib should not be modified during the DLT window. 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 
blood pressure. Based on this knowledge the investigator may decide on the necessary dose 
modifications during cycles 2 through 6 as per Table 3.
Table 3:  Dose levels of copanlisib
Dose level 3:
60 mg of copanlisib 
Dose level 2:
45 mg of copanlisib 
Dose level 1:
30 mg of copanlisib 
For subjects entered onto a starting dose of dose level 1, no dose reductions are allowed, and 
subjects who do not tolerate copanlisib dose of 30 mg must discontinue study treatment 
permanently. Subjects who start at dose level 2 may have the dose of copanlisib dose reduced to 
dose level 1 during cycles 2 through 6 at the discretion of the investigator for toxicities that are 
probably or definitely related to copanlisib. For subjects who start at dose level 3, they can have 
the dose of copanlisib dose reduced to dose level 2 during cycles 2 through 6 at the discretion of 
the investigator for toxicities though probably or definitely related to copanlisib, but cannot be 
dose reduced to dose level 1.  After having fully recovered from the toxicity that led to dose 
reduction, re-escalation to the original starting dose level will be allowed at the investigator’s 
discretion, with the exception of non-infectious pneumonitis (NIP). 
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, subject 
vacation, and/or holidays) but should be discouraged. Subjects 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.  
3.1.9.1
Unacceptable Toxicity – Withdrawal Criteria

CTCAE Grade 4 hypertension 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
29

CTCAE Grade 4 dermatologic toxicity

CTCAE Grade ≥ 3 non-infectious pneumonitis 

Persistent post-infusion hyperglycemia despite optimal glucose lowering therapy 

Drug-induced pancreatitis

Development of a new malignancy. New malignancy will be reported as an SAE, with the 
serious criterion of “important medical event”.

Severe allergic reaction to study drug (such as CTCAE Grade 3 or 4 hypersensitivity 
reaction).
3.1.9.2
Hematologic toxicity
Dose modifications and treatment interruptions for copanlisib must be done according to the 
guidelines in Table 4. 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 subjects’s medical record.
Table 4:  Dose modification of copanlisib/for hematological toxicity
Hematological toxicity (any of the following)
Study treatment action (for any toxicity)
CTCAE Grade ≥ 3 thrombocytopenia (platelet 
< 50,000/mm3) 
Febrile neutropenia a
CTCAE Grade ≥ 3 neutropenia (ANC < 1000/mm3) 
CTCAE Grade ≥ 3 anemia (Hb < 8 g/dL) 
Delay infusion until criteria displayed in 
Section 3.1.14 are met. Subject can be 
treated at one dose level lower at the 
investigator’s discretion. If more dose 
reductions are required than allowed per 
protocol, discontinue copanlisib 
permanently. The lowest dose level is 30 
mg.
ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria of Adverse Events; Hb = hemoglobin 
a: These subjects should recover from neutropenia, without fever
Neutropenia and febrile neutropenia are listed in the current version of the IB as expected adverse 
events. If the guidelines given in Table 4 are not followed, the rationale for other measures is to 
be documented in detail in the subject’s medical record.
3.1.9.3
Non-hematologic toxicity
Dose modification recommendations for non-hematologic toxicities attributable to copanlisib 
other than glucose increases (Section 3.1.9.6), non-infectious pneumonitis (Section 3.1.9.4), and 
blood pressure increases (Section 3.1.9.5) are outlined below in Table 5. 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 subject’s medical 
record. 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
30
Table 5:  Dose modification of copanlisib for non-hematological toxicity*
Study Drug Action
Toxicity a
Occurrence
For current course of 
therapy
For next course of therapy
Grade 1-2
Any appearance
No change
No change
Grade 3b
1st appearance
Delay until Grade  2
No change
2nd appearance
Delay until Grade  2
Decrease by one dose level c
3rd appearance
Permanently discontinue
Grade 4
Any appearance
Permanently discontinue 
– 
Toxicity requiring delay for 
> 21 days
Permanently discontinue
– 
* except glucose increases, dermatologic toxicity, non-infectious pneumonitis and blood pressure increases
a: Toxicities according to CTCAE
b: Despite maximum supportive therapy
c: Not applicable for 30 mg dose level
3.1.9.4
Non-infectious pneumonitis (NIP)
In the event of suspected NIP of any grade, copanlisib must be interrupted and a diagnostic 
examination of a subject experiencing pulmonary symptoms should be conducted. If NIP is the 
final diagnosis, copanlisib must be permanently discontinued if CTCAE grade ≥3; for CTCAE 
grade 2 treat until resolution or ≤ CTCAE 1 and resume copanlisib at a reduced dose (i.e., 1 lower 
dose level; Table 3). If grade 2 NIP recurs or if the subject is already at the lowest dose level of 
copanlisib, discontinue copanlisib (see Table 6). Pneumonitis is to be reported as such only in the 
event of NIP. Treat NIP with systemic steroids at the discretion of treating investigator. The 
investigator is requested to differentiate between non-infectious pneumonitis (NIP), and infectious 
pneumonitis (viral, bacterial, fungal), aspiration pneumonitis, or other pneumonitis clearly not due 
to a potential hypersensitivity reaction to the copanlisib infusion; and provide the basis for his/her 
assessment that it is infectious or other, as appropriate. 
Table 6:  Dose adjustment in cases of non-infectious pneumonitis (NIP)
Suspected or confirmed NIP per 
CTCAE
Action Taken
Re-treatment dose
after recovery
Grade 1
No Change
NA
Grade 2
Dose Interruption Until 
recovery to ≤ grade 1
Decrease dose to the next 
lowest dose level a
Grade 2 second occurrence
Permanent Discontinuation
NA
Grade 3
Permanent Discontinuation
NA
Grade 4
Permanent Discontinuation
NA
a: Not applicable for 30 mg dose level
3.1.9.5
Hypertension
No dose of copanlisib should be given if blood pressure is ≥ 150/90 mmHg. Antihypertensive 
medication may be given to control the increased blood pressure. Dosing can proceed on the 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
31
scheduled day if there are at least 2 consecutive measurements <150/90 mmHg, about 5-10 (+5) 
minutes apart. Otherwise dosing must be delayed (see Table 7). 
Subjects with a post-dose blood pressure that may have life-threatening consequences (e.g., 
malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis) must 
permanently discontinue the study drug.
Table 7:  Dose modification of copanlisib for hypertension
Toxicity (CTCAE)
Study drug action
Recommendation
Pre-dose measurements:
BP ≥ 150/90 mmHg
No dose should be 
given until recovery to 
< 150/90 mmHg.
Consider BP lowering medication. Dosing can 
proceed on the scheduled day if after at least 
2 consecutive BP measurements about 5-10 (+5) 
minutes  apart returns to < 150/90 mmHg. If BP 
does not return to < 150/90 mmHg, delay dosing 
until next visit.
During infusion:
CTCAE hypertension of 
grade 3 
or ≥ 160/100 mmHg
Infusion can be 
interrupted or slowed 
down and 
administration of BP 
lowering therapy 
should be initiated.
Infusion may be resumed when BP has returned to 
< 150/90 mmHg at the investigator’s discretion or 
skipped.
Subsequent study drug administrations may be 
reduced by 1 dose level at the investigator’s 
discretion.b
All other times:
Drug-related
CTCAE hypertension of 
grade 3
or ≥ 160/100 mmHg a 
–
Administration of BP lowering therapy should be 
initiated according to local standard of care.  
Additional measurements to be performed as 
clinically indicated until recovery to 
< 150/90 mmHg.
Subsequent study drug administrations may be 
reduced by 1 dose level at the investigator’s 
discretion.b
CTCAE hypertension of 
grade 4
Permanent 
discontinuation
–
CTCAE = Common Terminology Criteria for Adverse Events; BP = Blood pressure
a: Not manageable despite optimal antihypertensive treatment.
b: The lowest dose level is 30mg.
The management of acute blood pressure increases following copanlisib will need to be 
individualized for each subject, but experience in Phase I has suggested the benefit of 
dihydropyridine calcium channel blockers (i.e., amlodipine, felodipine). Nitrates should also be 
considered. In general, it is advisable for investigators to be prepared, so that antihypertensive 
medication is readily available in case of need. 
In the event of the occurrence of hypertension ≥ 150/90 mmHg during infusion of copanlisib at 
any cycle, antihypertensive treatment is suggested as indicated (Table 7). In the event of the 
occurrence of CTCAE Grade 3 hypertension during infusion of copanlisib, the infusion should be 
interrupted, and antihypertensive treatment administered. Infusion can be resumed when blood 
pressure has returned to <150/90 mmHg.
Blood pressure will be measured every 5-10 minutes prior to each copanlisib dose (no more than 
4 measurements) until there are two consecutive results < 150/90 mmHg. If blood pressure is ≥ 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
32
150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion of 
study drug. The subject should rest for 5-10 minutes before blood pressure is recorded.
On infusion days, blood pressure will be measured at 0 h (pre-dose), 30 (±10) min after infusion 
starts (mid-infusion), and 60 (±10) min (end of infusion).
3.1.9.6
Blood glucose
Because of its inhibitory effect on the PI3K α-isoform, which is implicated in insulin metabolism, 
copanlisib infusions could be associated with a temporary increase in blood glucose. Addition of 
a meal in close proximity to copanlisib infusion may exacerbate glucose increase. It is 
recommended that timing and content of caloric intake on infusion days is monitored by the 
investigators. For subjects with type 1 or type 2 diabetes, consultation with an endocrinologist will 
be done prior to first infusion of copanlisib. The investigator will review the glucose profile during 
and post the copanlisib infusions; see Table 8 for requirements.
Table 8:  Fasting requirements and pre-dose glucose levels 
Period
Fasting ≥ 8 h 
required before 
first glucose 
measurement
Pre-dose glucose levels
Fasting required before 
study drug infusion
Day 1 of each 
cycle
No
<160 mg/dL (fasting) (8.9 mmol/L)
< 200 mg/dL (11.1 mmol/L) (non-
fasting or random)
Conditional  ͣ ,b, c
a. The decision regarding meal timing and fasting can be made by the investigator based on glucose response 
patterns during prior treatment days (see text below regarding meal timing on infusion days for further 
details).
b. Diabetic subjects who take insulin treatment at any cycle visit: 
Timing and content of caloric intake on infusion days will be managed by the investigator. Consultation 
with treating physician or diabetes/endocrinologist is advised.
c. A small, light low glycemic index meal may be taken at least 4 hours before the start of the copanlisib 
infusion for subjects who have their infusions scheduled at a later hour, or due to their age or medical 
condition when fasting prior to infusion is not viable.
Timing and content of caloric intake on infusion days will be managed by the investigator. 
Consultation with treating physician or diabetes/endocrinology physician is advised.  Post-infusion 
glucose monitoring will be added in all subjects with pre-existing diabetes mellitus and subjects 
who have random non-fasting glucose levels exceeding 200mg/dL.
The investigator may manage the timing of post infusion meals based on the glucose profile during 
prior infusion(s) to minimize glucose increases. This is in addition to glucose lowering medication.  
Subjects may require home glucose monitoring if hyperglycemia is persistent.  The specific type 
of monitoring will be individualized with consultation from an endocrinologist, but may include 
pre-meal and post-meal monitoring of blood glucose monitoring.
All glucose measurements, oral glucose lowering medication and/or insulin administration, if 
applicable, and meal timing will be collected as part of the clinical source documentation. 
NOTE: Caloric intake and timing recommendations for diabetic subjects 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.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
33
3.1.9.6.1 Glucose measurements
Cycle 1 Day 1:  
Fasting is required (8-hour minimum) only on Cycle 1 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 subjects 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 1 Day 1:
The decision regarding meal timing can be made by the investigator based on glucose response 
patterns during prior treatment days.
NOTE: If subjects 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 1 Day 1, a low glycemic index meal may be taken at least 4 h before the start of the 
study drug infusion for subjects 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.
3.1.9.6.2 Glucose monitoring
Treatment Cycle 1, Day 1:
The following assessments should be performed on Cycle 1, Day 1 before receiving study 
treatment unless otherwise specified.

On Cycle 1 Day 1, subjects 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 1 Day 1 please refer to Table 8. 

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. Subjects 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. 
All subsequent infusions after Cycle 1 Day 1:
If hyperglycemia noted less than 250 mg/dL on Cycle 1 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: 

For all subjects (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 
the next day. If glucose reading is < 100 mg/dL (5.5 mmol/L) (non-diabetic) or < 160 
mg/dL (8.9 mmol/L) (diabetic) record and stop further glucose measurements until the next 
copanlisib infusion. If glucose is > 100 mg/dL (5.5 mmol/L) (non-diabetic) or > 160 
mg/dL(8.9 mmol/L) (diabetic), the study nurse or investigator should be informed.  If the 
subject has known diabetes and already monitors his/her blood glucose as part of routine 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
34
diabetes care, the routine measurements should not be replaced by the study-specific 
measurements. In this situation, subjects should add the study-specific measurements to 
their routine. 

In non-diabetic subjects who experience persisting glucose > 250 mg/dL (13.9mmol/L) or 
who require treatment to maintain optimal glucose levels; consultation with 
endocrinologist is recommended. These non-diabetic subjects will be trained how to 
measure their capillary blood glucose levels at home. If applicable, subjects will be 
provided with glucose meter and supplies (lancets, test strips and diary) to register 
measured values and record oral glucose lowering medication and/or insulin 
administration.
3.1.9.6.3 Management of infusion-related hyperglycemia 
Mild to moderate asymptomatic increases of blood glucose may occur with copanlisib infusion, 
and with larger increases potentially occurring post-prandially. Please refer to table below for 
dose modifications and management of hyperglycemia.
Glucose Increase
Assessment
Management
Asymptomatic glucose 
increases ≤ 250mg/dL 
(13.9 mmol/L)
Does not generally require treatment 
with glucose lowering medication.
Oral Hydration
Glucose increase > 
250mg/dL (13.9 mmol/L)
Hydration status should be clinically 
assessed. 
Initiate IV fluids to maintain a 
urine output of at least 
150cc/hour and recheck blood 
glucose within 4 hours.
Consider short acting insulin 
if glucose persists at > 250 
mg/dL (13.9 mmol/L) despite 
IV fluids or if the subject is 
symptomatic 
Glucose increase > 
500mg/dL
Repeat glucose testing every 2-4 hours.
If glucose value is decreasing, glucose 
levels  may be followed without glucose 
lowering medication treatment if 
hydration status is normal as clinically 
assessed
Consultation with endocrinologist can 
be considered
Initiate IV fluids to maintain a 
urine output of at least 
150cc/hour and recheck blood 
glucose within 4 hours.
Initiate short acting insulin if 
glucose persists at > 500 
mg/dL (13.9 mmol/L) despite 
IV fluids or if the subject is 
symptomatic 
3.1.10 Rituximab
There will be no dose reductions for rituximab or prednisone. Rituximab should be held for any 
grade 3 or 4 toxicity felt to be probably or definitely related to rituximab and clinically significant.  
Rituximab should be held until the adverse event returns to baseline or resolves. Detailed dosing 
instructions for infusion reactions are provided in the product label.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
35
3.1.11 EPOCH Modifications
Treatment with EPOCH will be initiated at Dose Level 1 (as shown below). After Cycle 1 of 
EPOCH-R, subsequent treatment doses for doxorubicin, etoposide, and cyclophosphamide will be 
based on measurements of the previous cycle ANC or platelet nadir, whichever is lower. Dose 
adjustments will be based on measurements of twice weekly CBC only, even if additional CBCs 
are obtained. Dose escalation to higher dose levels applies to doxorubicin, etoposide, and 
cyclophosphamide but only cyclophosphamide is reduced in dose levels -1 and -2.
3.1.11.1 Dose Levels and Drug Doses for DA-EPOCH-R
The following table describes the dose levels and drug doses for DA-EPOCH-R:
Dose Levels and Daily Drug Doses
Drug Agents
-2
-1
1
2
3
4
5
6
Doxorubicin (mg/m2/day)
10
10
10
12
14.4
17.3
20.7
24.8
Etoposide (mg/m2/day)
50
50
50
60
72
86.4
103.7
124.4
Adjusted 
Agents
Cyclophosphamide 
(mg/m2/day)
480
600
750
900
1080
1296
1555
1866
Rituximab (mg/m2/day)
375
375
375
375
375
375
375
375
Vincristine (mg/m2/day; No 
cap)
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
Non-
Adjusted 
Agents
Prednisone (mg/m2 BID)
60
60
60
60
60
60
60
60
3.1.11.2 Hematologic Toxicity - Dose Level Adjustments for EPOCH
To begin a cycle, ANC must be 1,000 cells/l and platelets must be 75,000 cells/l.  Delay 
cycle by up to 2 weeks if these values are not met on Day 1 of cycle. Filgrastrim may be used 
for several days to increase ANC. If delay is greater than 2 weeks, then contact PI.
Event
Dose Modification
If Nadir ANC  500/µl on all measurements
 One level above last cycle
If Nadir ANC  500/µl on 1 or 2 measurements
   Same level as last cycle
If Nadir ANC  500/µl  3 measurements
 One level below last cycle
If nadir platelet  25,000/µl on  1 measurement
 One level below last cycle
3.1.11.3 Ileus and Constipation
Symptomatic ileus/constipation may occur with vincristine. If ileus or constipation require 
hospitalization, the next dose of vincristine should be reduced by 25%. If symptoms do not 
recur at the reduced dose, then the vincristine dose may be re-escalated on subsequent cycles
3.1.11.4 Renal dysfunction
Etoposide should be reduced 25% on cycle one for creatinine clearance < 50 cc/min on the day 
of starting a new cycle. If the creatinine clearance remains low on subsequent cycles, etoposide 
should remain at the reduced level as in the previous cycle. Etoposide should be returned to full 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
36
dose (or escalated if indicated) once creatinine clearance > 50 cc/min. No other dose 
modifications for abnormal renal indices will be made for enrolled patients.
3.1.11.5 Hyperbilirubinemia

Doxorubicin
No doxorubicin dose modifications will be made for increased bilirubin < 7 mg/dL. 
Doxorubicin should be held for bilirubin > 7 mg/dL, until it returns to < 7 mg/dL.

Vincristine
Vincristine dose will be decreased for elevated bilirubin according to the following scale:
Bilirubin (mg/dL)
Vincristine dose
> 1.5 - < 3.0
Decrease by 25%
 3.0
Decrease by 50%
Vincristine dose can be re-escalated as hyperbilirubinemia improves.
3.1.11.6 Neuropathy
Sensory and motor neuropathy may occur with vincristine. Vincristine doses should only be 
reduced if the subject develops neuropathy that interferes with activities of daily living.  Most 
vincristine associated neuropathy resolves after treatment completion.  

Sensory neuropathy: 
Grade
Vincristine dose (%)
2
100
3
50
4
0

Motor neuropathy:
Grade
Vincristine dose (%)
1
100
2
75
3
25
4
0
If neuropathy resolves to lower grade, doses for that lower grade may be reinstituted at investigator 
discretion. If the grade of neuropathy increases after being re-escalated, doses must be reduced for 
the appropriate toxicity grade and may not be re-escalated, even if neuropathy resolves again to a 
lower grade.
ON STUDY ASSESSMENTS/EVALUATIONS
3.1.12 Description of Evaluations and Procedures
Upon confirmation of eligibility and successful registration, and following completion of the 
Screening/Baseline visit, subjects will begin treatment with copanlisib. After Cycle 1 of combined 
copanlisib and DA-EPOCH-R, pre-treatment assessments may be performed up to 3 days prior to 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
37
Day 1 of a cycle, except where otherwise noted. The results from all procedures/tests must be 
reviewed prior to initiation of each cycle of treatment for consideration of dose modifications.  
Copanlisib and DA-EPOCH-R will continue until disease progression, unacceptable treatment-
related toxicity, or other reasons outlined in Section 3.1.22, or a maximum of 6 cycles each 21 
days, whichever occurs first.
Refer to the Study Calendar (Section 0) for the timing of all tests and procedures to be conducted 
on study/during treatment. The following is a description of all procedures: 
For screening procedure details, refer to section 0. Baseline/C1D1 evaluations do not need to be 
repeated if performed at screening. All evaluations will be done within 14 days before treatment 
initiation on Day 1 of Cycle 1 (except for pregnancy test which should be performed within 7 
days). If treatment does not start within 28 days after enrollment, screening evaluations will be 
repeated. For all subsequent cycles, all evaluations are to be done within 3 days of cycle treatment 
initiation. Dose administration can be delayed by no more than 3 weeks for scheduling conflicts. 
The timepoints for assessments are listed in the Study Calendar (Section 0). The following 
describes the assessments to be done:  

Physical exam:  review of organ systems, weight, and vital signs (i.e., temperature, pulse, 
respirations, blood pressure). Height will only be required at screening. After initiation of 
study drug, symptom-directed physical examinations will be performed as clinically 
indicated in the investigator’s judgment.

Performance status (ECOG):  an assessment of activities of daily living; see Appendix A.

Laboratory assessments:  the following comprises the required tests/analytes per panel.  
These may be performed outside NIH and results forwarded to the study team for review 
and management.
o
CBC with differential:  includes Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils, WBC, RBC, Hemoglobin, Hematocrit, RBC Indices, 
MCV, RDW, Platelet. 
o
Panels:

Acute care panel includes Sodium (NA), Potassium (K), Chloride (CL) 
Total CO2 (Bicarbonate), Creatinine, Glucose, Urea nitrogen, eGFR.

Hepatic panel includes Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin.

Mineral panel includes Albumin, Calcium, Magnesium, Phosphorus.
o
Other: LDH, HBV reactivation monitoring- see Section 3.1.13., and CMV 
reactivation monitoring- see Section 3.1.12.
o
Hemoglobin A1C

Pregnancy test:  Urine or serum HCG for women of child-bearing potential.

Urinalysis

Lumbar puncture- with cytology and flow cytometry if clinically indicated, at the end of 
treatment only if positive at baseline

Bone marrow aspiration/biopsy- at the end of treatment only if positive at screening; 
repeat in follow-up to confirm response or progression.  

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
38

Peripheral blood flow cytometry 

CT scans- chest, abdomen and pelvis; may be adjusted to assess additional known sites of 
disease, as needed.

18F-FDG-PET/CT scans

Study drug administration schedule- see Section 0

Adverse events and concomitant medication review:  Adverse events and concomitant 
medication will be continuously monitored throughout the study until disease progression 
or end of treatment visit. Adverse events that occur beyond 30 days after the last 
administration will be recorded per 0.

Follow-up after treatment:  See Section 0 

Correlative studies:  Refer to section 5.
3.1.13 Additional Monitoring and Considerations
3.1.13.1 Cytomegalovirus (CMV) Reactivation 
CMV reactivation can occur in subjects treated with copanlisib and is manifested by positive CMV 
PCR without evidence of active CMV infection or organ involvement.  CMV screening will be 
performed in all subjects before study enrollment.  This will include CMV IgM and IgG status as 
well as baseline CMV PCR.  
Subjects with a positive CMV PCR at screening will not be enrolled onto the study per exclusion 
criteria (Section 2.1.2.3).  All subjects will have CMV PCR drawn before each new cycle, and 
each surveillance visit until 6 months after therapy is complete (see Study Calendar, Section 0).  If 
a surveillance CMV PCR becomes positive during therapy, then they will be assessed for evidence 
of organ involvement.  If no organ involvement, subjects can continue on study therapy at the 
discretion of the PI and will be managed according to local standards including use of anti-CMV 
medications such as valganciclovir. If subjects develop CMV infection associated with organ 
involvement, they will be treated with anti-CMV medications and removed from study therapy.
3.1.13.2 Hepatitis B Reactivation 
Patients who test positive for either Hepatitis B surface antigen (HBsAg) or hepatitis B core 
antibody (HBcAb) and not actuely infected are at varying risk for reactivation of Hepatitis B 
especially when combined with novel agents like copanlisib and/ or rituximab. Participants  may 
be included in the study provided that they have HBV DNA levels below the World Health 
Organization’s cutoff of 100 IU/mL prior to starting therapy. These patients will be treated with 
entecavir (or equivalent) during treatment and for 12 months after treatment has ended to prevent 
hepatitis B reactivation and should have HBV DNA levels obtained monthly for at least 12 months 
after the last cycle of therapy by means of real-time PCR with the use of an assay that has a 
sensitivity of at least 10 IU/mL. 
If the HBV DNA assay becomes positive during combination therapy, study treatment should be 
held, and the patient should be immediately referred to a gastroenterologist or hepatologist for 
management.
If the HBV DNA assay becomes positive and is  100 IU/mL, the patient should be retested within 
2 weeks. If the assay is still positive, study treatment must be held, and the patient should be 
immediately referred to a gastroenterologist or hepatologist for management.  

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
39
If a patient’s HBV DNA level exceeds 100 IU/mL while the patient is receiving antiviral 
medication, study treatment must be permanently discontinued 
TREATMENT CONSIDERATIONS/EXCEPTIONS  
3.1.14 Laboratory Criteria For Initiating A Cycle of Copanlisib with EPOCH-R
In order to initiate a subsequent cycle of treatment, subjects must meet minimum requirements for 
laboratory criteria as indicated below:  

Glucose 
< 200 mg/dL (non-fasting)

ANC
≥ 1,000/mm3

Platelets
≥ 75,000/mm3

ALT
<2.5 x ULN a

AST
<2.5 x ULN b
a.
< 5 x ULN in subjectss with documented liver involvement by lymphoma or with biliary obstruction due to 
lymphoma.
b.
< 5 x ULN in subjects with documented liver involvement by lymphoma or with biliary obstruction due to 
lymphoma.
POST-TREATMENT EVALUATIONS
When a subject completes all 6 cycles of treatment or discontinues early, all applicable activities 
scheduled for the End of Treatment Visit should be performed at the time of discontinuation (see 
Study Calendar- Section 0 ). Any adverse events which are present at the time of discontinuation 
should be followed in accordance with the safety requirements outlined in Section 7.  
Regardless of a subject’s disease status, follow-up must continue for at least 3 years after the last 
dose of study drug to meet the reporting requirements of the industry supporters (e.g., for purposes 
of reporting of secondary malignancies; see Section 0).
All post-treatment visit(s) may be completed by remote visit with a member of the study team 
(e.g., if the subject is not able to return to the NIH CC). Remote visits will be conducted in 
compliance with NIH guidelines and FDA regulations. Required clinical labs/scans can be 
obtained by a local provider, with results sent for review and any suggested management by the 
study team. For clinical laboratory evaluations conducted with local providers, interlaboratory 
variability is not a concern as the lab tests are all routine; correlative samples are required only in 
follow-up visits that occur at NIH. A subject may be referred to their local provider or asked to 
come to the NIH CC for an in-person assessment, if clinically indicated, and at the discretion of 
the investigator; otherwise, physical exams are not required at these time points.  In the case of 
any visits with subjects’ local providers, records will be obtained for the research records.
3.1.15 End of Treatment/ Disease Progression
Subjects will be evaluated at the end of study treatment (about 21 days following initiation of the 
last cycle of treatment [+/-7 days]), and post-treatment prior to (or at) disease progression. 
3.1.16 Safety Follow-Up Visit
The safety follow-up visit should occur 30 days (±7 days) after the last dose of trial treatment, or 
before the initiation of a new anti-cancer treatment, whichever comes first. Required testing is as 
noted in the Study Calendars 0.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded. See section 6.1.1 for documentation of AEs after study treatment has ended.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
40
3.1.17 Follow-Up Visits – Prior to Disease Progression
Subjects who discontinue trial treatment for a reason other than disease progression will move into 
the Follow-Up Phase and should be assessed every 3 months for the first 2 years post-treatment 
and then every 6 months from years 2-5 post-treatment. The list of required assessments to be 
performed including disease evaluation; however, may include other necessary standard of care as 
clinically indicated at the discretion of the investigator (e.g., physical exam, CBC, chemistries).  
See the Study Calendar in Section 0. 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.
3.1.18 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 0, Study Calendar).

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
41
STUDY CALENDAR
Treatment
Response 
Assessment
Follow-Up
Procedure  
Screening1
Baseline2
Before 
Cycles 
2-6 
C1D1
C1D5
Post
Cycles 
1-6
After Cycle 
1, 3 and 6
End of 
Treatment
Safety
(Day 30)
Follow-Up
(Prior to PD)
Survival
(Post-PD/ 
Other Therapy)
Scheduling Window (Days):
-28 to 
-14
-3
±1
Last 7 days 
of the cycle
Treatment 
discon./PD3
+7
Every 3 or 6 
months4
Every 3 months5
Confirmation of Diagnosis17
X
Medical History
X
X
X
X
Physical Exam6
X
X
X
X
X
ECOG PS
X
X
X
X
X
CBC with Differential
X
X
X
X
X
X
Chemistry Panels7 
X
X
X
X
X
X
Hemoglobin A1C
X
X
X
X
X
ECHO and EKG
X
LDH
X
X
X
X
Urinalysis
X
X
X
X
X
Pregnancy Test (urine/serum; WOCBP) 8
X
X
X
HCV PCR  and HIV Testing
X
HBV serology 
X
HBV PCR
X
X16
X16
X16
X16
CMV PCR and CMV IgM and IgG9
X
X
X
Lumbar Puncture10
X
X
Bone Marrow Aspiration/Biopsy11
X
X
Lymphocyte Phenotype (T, B, NK cell subsets)
X
X
X
Peripheral Blood Flow Cytometry
X
X
CT Scans12
X
X
X
X
X
18F-FDG-PET/CT Scan13
X
X
X
X 
MRI brain
X
Symptoms/Adverse Events Assessment, 
Concomitant Medication Review
X
X
X
X
X
X
Research Tissues (archival/fresh biopsy)14
X
X (PD)

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
42
Treatment
Response 
Assessment
Follow-Up
Procedure  
Screening1
Baseline2
Before 
Cycles 
2-6 
C1D1
C1D5
Post
Cycles 
1-6
After Cycle 
1, 3 and 6
End of 
Treatment
Safety
(Day 30)
Follow-Up
(Prior to PD)
Survival
(Post-PD/ 
Other Therapy)
Scheduling Window (Days):
-28 to 
-14
-3
±1
Last 7 days 
of the cycle
Treatment 
discon./PD3
+7
Every 3 or 6 
months4
Every 3 months5
Research Saliva/Buccal (baseline only), Research 
Blood Samples15
X
X
X
X
X
X
Survival Status
X
NOTE:  Additional assessments may be done as clinically indicated (e.g., necessary standard of care). See Section 0 for details on drug 
administration and Section 5 for details on correlative studies to be performed.
1
Screening evaluations should be performed within 28 days prior to confirmation of eligibility with the following exceptions:  Confirmation of diagnosis 
(no time limit); HIV antibody, HBV, HCV and CMV PCR (within 3 months). 
2
Any screening tests performed within the specified time frame for baseline do not need to be repeated. Baseline assessments to performed within 14 
days prior to treatment with the following exceptions:  bone marrow aspiration and biopsy (within 1 month); pregnancy test (within 7 days).
3
To be done at treatment discontinuation (+/- 2 weeks) or may coincide with the safety follow-up visit.  If treatment is discontinued for a reason other 
than disease progression, assessments should be repeated at the time of progression.  If subject to initiate new anti-cancer therapy assessments should 
occur before the first dose of the new therapy. 
4
Follow-up to occur about every 3 months (+/- 2 weeks) for first 2 years post-treatment, every 6 months for years 2-5 (+/- 4 weeks), and then annually 
(+/- 6 weeks) at discretion of investigator until the study is stopped.   Any other evaluations and tests should be performed as clinically indicated.
5
After disease progression or initiation of new anti-cancer therapy, contact for survival about every 3 months (+/- 4 weeks). See Section 3.1.18.
6
Physical exams to include review of systems and changes since last visit, vitals, weight, and height (screening only).
7
Chemistry panels include: Acute care, Hepatic, and Mineral.
8
Pregnancy test for WOCBP required within 7 days of enrollment and again within 7 days of D1 in cycle 1 and within 7 days of D1 of each cycle .
9
CMV PCR will be performed at screening and at the start of every cycle.  CMV IgM and IgG will be done at screening only.  CMV PCR testing will be 
done during follow-up visits for the first 6 months after therapy.
10
Lumbar Puncture with cytology and flow cytometry if clinically indicated, at the end of treatment only if positive at baseline 
11
Bone marrow aspiration with flow cytometry and biopsy (within 3 months prior to starting treatment) at the end of treatment only if positive at 
screening; repeat in follow-up to confirm response or progression.  
12
CT scans (preferred) of chest, abdomen and pelvis at screening and baseline; may be adjusted to assess additional known sites of disease, as needed.  
13
PET scans (i.e., whole body 18F-FDG PET/CT) to be performed after cycles 3 and 6 (last 7 days of each cycle). 
14
If adequate archival tissue at baseline, fresh tumor biopsy is optional.  Optional “on-treatment” tumor biopsies will be performed as described in Section 
5.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
43
15
Samples for correlative research blood and saliva (preferred)/buccal swab samples to be collected as indicated in Section 5.
16
Subjects on HBV prophylaxis (Section 2.1.2.6) will have HBV DNA levels obtained monthly for at least 12 months after the last cycle of therapy per 
Section 3.1.13.2.
17
If adequate archival tissue is not available, a fresh biopsy for confirmation of diagnosis will be required. 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
44
COST AND COMPENSATION
3.1.19 Costs
NIH does not bill health insurance companies or subjects for any research or related clinical care 
that subjects receive at the NIH Clinical Center.  If some tests and procedures are performed 
outside the NIH Clinical Center, subjects 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.   
3.1.20 Compensation
Subjects will not be compensated on this study.
3.1.21 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 subject/guardian 
as appropriate. The amount and form of these payments are determined by the NCI Travel and 
Lodging Reimbursement Policy.
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects 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 0.
3.1.22 Criteria for Removal from Protocol Therapy

Completion of protocol therapy

Confirmed clinical or radiographic disease progression

Unacceptable toxicity as listed in Section 3.1.1 or those toxicities listed in Section 0 
that requires treatment to be stopped.

Intercurrent illness that prevents further administration of treatment

Requirement for use of prohibited therapies as listed in Section 0

Pregnancy

Subject’s requests to be withdrawn from protocol therapy

Noncompliance with trial treatment or procedure requirements that requires removal in 
the opinion of the PI

Investigator’s decision to withdraw the subject

Study is cancelled for any reason
3.1.23 Off-Study Criteria

Subject requests to be withdrawn from study

Screen failure

Subject is lost to follow-up

Death

Study is cancelled for any reason

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
45
3.1.24 Lost to Follow-up
A subject will be considered lost to follow-up if he or she fails to return for two (2) scheduled 
visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:

The team will attempt to contact the subject and reschedule the missed visit within 7 
business days and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain if the subject wishes to and/or should continue in the study.

Before a subject is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, 
an IRB approved certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record or study file. 

Should the subject 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 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 specifically prohibited 
during the trial, discontinuation from trial therapy may be required.  
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 subjects in this trial.
All concomitant medication will be recorded 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 should also be included.
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.  
PROHIBITED MEDICATIONS
Subjects are prohibited from receiving the following therapies during treatment on this trial.  
Subjects 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.  Subjects may receive other 
medications that the investigator deems to be medically necessary.

Other therapy for the disease under study not specified in this protocol, unless specifically 
noted as permitted

Investigational agents other than copanlisib (chemotherapy or biologic agents)

Radiation therapy 

Immunosuppressive therapy

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
46

Anti-arrhythmic therapy (beta blockers or digoxin are permitted)

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. Subjects should stop using these herbal medications 7 days prior to 
first dose of study drug

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.
See below table of common medications.  Please refer also to the following listing/ website:  
http://medicine.iupui.edu/CLINPHARM/DDIS   
Category
Drug name
Strong CYP3A Inhibitors
Voriconazole, boceprevir, clarithromycin, cobicistat, 
conivaptan, danoprevir/ritonavir, eltegravir/ritonavir, 
grapefruit juice, indinavir/ritonavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycin,
Moderate CYP3A Inhibitors
Grapefruit, grapefruit hybrids, pummelos, star-fruit, and 
Seville oranges (citrus paradisi fruit juice)
Strong CYP3A Inducers
Avasimibe, carbamazepine, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin), St. John's wort 
(hypericum perforatum)
CYP3A Substrates with NTI
Alfentanil, apixaban (doses >2.5 mg only), aprepitant, 
astemizole, cisapride, cyclosporine, diergotamine, 
dihydroergotamine, ergotamine, fentanyl, lovastatin, 
nicardipine, nisoldipine, pimozide, quinidine, rivaroxaban, 
simvastatin, sirolimus, tacrolimus, terfenadine, thioridazine,
TUMOR LYSIS SYNDROME
Subjects will be monitored closely for laboratory evidence of tumor lysis syndrome (TLS) prior to 
and during treatment. TLS is a risk for subjects with DLBCL or BL who are treated with high 
cell-killing agents. Perform tumor burden assessment with CT scan and CBC with WBC 
differential, assess blood chemistry in all subjects and correct pre-existing chemistry abnormalities 
prior to initiation of treatment with elective admission for fluid hydration, correction of electrolyte 
abnormalities and closer monitoring is permitted at the discretion of the investigators and will not 
be considered an SAE if done in the first cycle (see Section 0).
Subjects who show laboratory evidence of TLS as determined by elevated uric acid with 
hyperkalemia, hyperphosphatemia and/or elevated creatinine will be admitted to the hospital for 
appropriate management with intravenous fluids. Uric-acid lowering agents may include xanthine 
oxidase inhibitor allopurinol with or without rasburicase per the drug product package inserts.  

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
47
OTHER CONSIDERATIONS (COPANLISIB IB)
4.1.1
Diet
Subjects must fast for at least 8 hours prior to the first dose of copanlisib.  After the first dose, 
subjects should maintain a normal diet unless modifications are required to manage an AE such as 
elevated blood glucose, diarrhea, nausea or vomiting.
5
CORRELATIVE STUDIES FOR RESEARCH
BIOSPECIMEN COLLECTION
An important correlative focus of this study is to utilize multiplatform genomic analyses of tumor 
biopsies to identify biomarkers that predict response or resistance.  To achieve this goal, tumor 
biopsies will be collected in all subjects prior to therapy and optional tumor biopsies will be 
performed at the time of disease progression. These optional biopsies will be studied by the Staudt 
lab using integrative analyses to further characterize mechanisms of both intrinsic and acquired 
resistance.
The molecular annotation will include a combination of gene-expression profiling, RNA 
sequencing, whole-exome sequencing, and identification of copy number abnormalities via array 
comparative genomic hybridization. Specific aims of these molecular correlates will be based on 
published literature regarding gene expression and molecular signatures that identify subsets of 
subjects who are considered high-risk for early treatment failure.
Lastly, we aim to identify mechanisms of therapeutic resistance through genomic analysis of 
circulating tumor DNA and biopsies taken before treatment and at time of clinical progression.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
48
Sample
Collection Details
Time Points
Supervising 
Laboratory/ 
Investigator
Blood Samples
ctDNA/cfDNA, 
Plasma banking
1 x 10 mL Streck/BCT
Baseline
Post Cycles 1-6
End of Treatment/ Disease 
Progression (PD)
Follow-up
Figg
PBMCs/ 
Immune subsets
1 x 8 mL CPT (sodium citrate)
Baseline
Post-cycles 1-6 
PD
Follow-up
Figg
Pharmacokinetics
(Copanlisib PK)
1 x 4mL lithium heparin (green) 
– place sample on ice after 
collection
and
CSF: 0.5mL in cryovial*
Cycle 1
Day 1: prior to Copanlisib
Day 1: post-Copanlisib
      1 hour (+/- 15 minutes)
      2 hour (+/- 15 minutes)
      10-12 hours (+/- 15 minutes)
      24 hours (+/- 15 minutes)
Day 5
Figg/
NEBA
Other Samples
Archival
FFPE (block or slides); biopsy is 
required if archival is not adequate 
or unavailable
Baseline only
Tumor Biopsy
(optional)
Excision (single/multiple nodes) or 
core (4-6 passes); placed in 
formalin/FFPE and media per 
routine practice
Screening/Baseline 
PD
NCI LP/
Staudt lab
Germline DNA
Blood, Buccal swab, or Saliva 
(preferred)
Baseline
Figg
*Copanlisib PK samples (both CSF and blood) will be collected at all timepoints in subjects with an Ommaya 
reservoir.  For subjects without an Ommaya reservoir all blood timepoints will be collected, but only a 1 hour post-
Copanlisib CSF sample will be collected and will be optional.
NOTE:

Tubes/media may be adjusted at the time of collection based upon materials available and/or to ensure the 
best viable samples are collected for planned routine and/or research analysis at the time of procedure.

All blood/tubes – with the exception of PK samples/tubes – should remain at ambient temperature after 
collection and processed on the day of collection, do not place samples on ice.

All correlative samples to be collected at the NIH; if a subject cannot return to the NIH for the specified visit 
in follow-up, then the correlative research sample is not required.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
49
SAMPLE COLLECTION AND PROCESSING
5.1.1
Summary
The planned analyses described below may be done on leftover and/or shared sample portions 
from the respective laboratories, as needed. In addition to the prospectively collected samples 
below, leftover portions of samples sent for routine laboratory testing (e.g., plasma from 
CBC/hematologies) may also be retrieved for research tests prior to being discarded.  The planned 
prospective analyses are identified below; laboratories may share resources or collaborate on 
analyses, if appropriate (e.g., isolation/analysis of DNA not prospectively planned by one lab may 
be incorporated if needed during the planned analyses).
Portions of all samples may be banked for future research analyses; prospective consent will be 
obtained during the informed consent process.  
5.1.2
Blood Samples – Figg Lab
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred). For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.  The samples 
will be processed, barcoded, and stored in Dr. Figg’s lab until requested by the investigator.  
5.1.2.1
Peripheral Blood Mononuclear Cells (PBMCs)

Collect blood in Cell Preparation Tubes with sodium citrate (e.g., blue/black speckled top); 
gently invert tubes 8-10 times immediately after collection.  

PBMCs will be isolated per routine laboratory techniques.
5.1.2.2
Circulating Tumor DNA (ctDNA) and plasma banking

Collect blood in cell-free DNA (e.g., Streck BCT/collection tubes) gently invert the tubes 
8-10 times immediately after collection.  

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). 
5.1.2.3
Pharmacokinetics (PK) Sampling – Copanlisib blood samples
PK sampling will be performed in all subjects for copanlisib and its metabolite M-1 in the blood.  
CSF will be collected in all subjects with Ommaya reservoirs.  For subjects without Ommaya, 
only a 1 hour post-copanlisib CSF sample will be collected and will be optional.

Collect blood in specified tubes (e.g., 4 mL vacutainer tubes containing lithium-heparin)

Immediately after collection, tubes must be gently inverted several times to mix with 
anticoagulant, and placed on ice until centrifugation. DO NOT SHAKE.

As soon as possible after collection, plasma will be isolated (e.g., 2500 rpm for 15 
minutes at 0-4°C).

Transfer plasma equally to two 2-mL cryovials (e.g., 2mL screw cap polypropylene 
cryovial), and frozen upright at -60oC to -80oC within 60 minutes after the blood draw. 

Store at -80oC until analysis

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
50
5.1.2.4
Pharmacokinetics (PK) Sampling – Copanlisib CSF samples
CSF will be collected at all timepoints in subjects with Ommaya reservoirs.  For subjects without 
Ommaya, only a 1 hour post-copanlisib CSF sample will be collected and will be optional.

Figg BPC lab staff member will add 10 μL of 10% Tween-80 to each cryotube (e.g., NUNC 
cryotube cat. # 366656 or 377224) prior to CSF collection. (NOTE: Do not use 10% 
Tween-80 solution past its expiration date.) Research team/designee will obtain cryotube 
described above from BPC prior to sample collection. 

Ommaya-certified personnel (RN, NP, PA, MD) or person performing lumbar puncture 
will collect 0.5 mL of CSF sample in the cryotube containing 10% Tween-80. The sample 
will be mixed thoroughly using a Vortex mixer and immediately placed in ice bath until 
samples can be processed. 

CSF samples will be centrifuged at 1,000 g for 10 minutes within one hour of collection in 
a clinical refrigerated centrifuge, maintained at approximately 4 °C, to yield supernatant 
cell free CSF from each 0.5 mL CSF sample. 

At least 300 μL of the cell free CSF supernatant will be transferred immediately into 
appropriately pre-labeled cryotubes (e.g., NUNC cryotube cat. # 366656 or 377224) with 
a new pipette tip for each sample. 

The cell-free CSF samples will be stored in an upright position, at –70°C or lower at the 
clinical site. 

The time between CSF collection and freezing the cell free CSF sample will be 
approximately 60 minutes. 
5.1.3
Tissue Samples
5.1.3.1
Archival tissue
Archival block(s) or slides (i.e., at least 20 unstained slides, 5-microns) are preferred 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.  
5.1.3.2
Lymph node excision or core needle biopsy procedure (optional)
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 subject 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 with ultrasound/CT 
guidance, as necessary) will only be made if follow-up excisional biopsy is not possible/safe or 
subject is unwilling to undergo repeat excisional lymph node biopsy.
In the event of core needle biopsy, these are obtained typically by using a 14-18G needle at the 
discretion of the provider performing the procedure.  Conscious sedation may be used, if 
warranted, and the use and risks are acceptable to the subject.  
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 subject prior to the biopsy procedure.  The subject will be reminded that all sampling for 
research is voluntary. 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
51
5.1.3.3
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:

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.  

Formalin samples will be fixed and paraffin-embedded per routine techniques.  
5.1.4
Other Samples
5.1.4.1
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 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 Dr. Figg’s lab (see Section 5.1.2 for contact 
information).
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. 
The following are technologies that are currently in use for each planned analysis:  
5.1.5
Tumor Profiling
Immunohistochemical (IHC) analyses, including FISH for MYC, BCL2 or BCL6, will be done on 
every subject’s baseline tumor biopsy.  The routine IHC panel for diagnosis 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.
5.1.6
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, 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. 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
52
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-
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(50, 
51).  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 with expert staff 
headed by Dr. Michael Kelly within the CCR Genomics Core.  This facility has the ability to take 
purified viably frozen cells banked from subject 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.
5.1.7
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.
5.1.8
Pharmacokinetics (PK)
Coded (linked) samples (Section 5.1.13) 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; 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
5.1.9
Detecting Minimal Residual Disease (MRD)/ circulating tumor DNA (ctDNA)
5.1.9.1
Rationale for MRD assessment
Detecting Minimal Residual Disease (MRD) can be a powerful tool to monitor subjects’ 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. 
Adaptive Biotechnologies Corp will assess whether immune repertoire data (B-cell 
immunoglobulin receptor sequences or T-cell receptor sequences) from the Human Material can 
be used as biomarkers that correlate with disease-free survival. Adaptive Biotechnologies Corp 
will use a proprietary method, Immune Cell Receptor Sequencing (ICRS) platform, for amplifying 
and analyzing immune cell receptor sequences, allowing unprecedented sensitivity and specificity.  

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
53
Data from experiments conducted by Adaptive Biotechnologies Corp using the human material 
will be provided to NCI and such data provided by Adaptive Biotechnologies Corp to NCI may be 
used by NCI for any purpose.
5.1.9.2
Samples to be sent to Adaptive Biotechnologies Corp 
Bloods from the storage/future use samples collected from select subjects at the following time 
points may be sent, if available:

Baseline 

Post C1-C6

End of therapy

Follow-up surveillance
5.1.9.3
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 subjects will 
be sent.  
5.1.9.4
Shipping information
Only coded (linked) samples will be shared as described (see Section 5.1.13) for process of coding, 
and sample request instructions.  The samples and data will sent in batches to Adaptive 
Biotechnologies Corp at the address listed below.
Adaptive Biotechnologies Corp.
1551 Eastlake Ave E
Suite 200 
Seattle WA 98102
5.1.10 Other Analyses
Other analyses include the following:

Cell analysis and histological (e.g., H&E), immunohistochemical review and analysis per 
standard and established research techniques (e.g., FISH for BCL2, MYC, BCL6 
translocation, and other IHC analyses in blood and tissue).

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
5.1.11 Future Use
Any blood, tissue, or other products or portions leftover from other analyses will be stored for 
future research.  
SAMPLE STORAGE, TRACKING AND DISPOSITION
5.1.12 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. 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
54
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 
subjects 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 0.
If the subject 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.
5.1.13 Clinical Pharmacology Program (Figg Lab)
5.1.13.1 Sample Data Collection
All samples sent to the Blood Processing Core (BPC) of the Clinical Pharmacology Program under 
the direction of Dr. Figg 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 Figg lab 
personnel, who are issued individual user accounts. Installation of Labmatrix is limited to 
computers specified by Dr. Figg. 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 subjects without Labmatrix access. The data recorded for each sample includes the subject 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well 
as box and freezer location. Subject demographics associated with the clinical center subject 
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.).
5.1.13.2 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 at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the 
laboratory are required to be accompanied by laboratory staff at all times. 
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 LABrador. 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 subject demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to subject information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.
5.1.14 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 subject has agreed to allowing specimens to be used in future research 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
55
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 subject background sheet may be filled out and filed 
with any accompanying paperwork, with final reports and any supplemental reports that follow 
added as completed. 
5.1.15 Staudt Lab
5.1.15.1 Sample Data Collection
Subject samples, collected for research under this IRB approved protocol, may be archived in the 
Staudt laboratory.  All data associated with archived clinical research samples is entered into the 
web-based NCI Labmatrix database, a centralized system with access controlled via centralized 
login.  Access to this database for samples collected from this study is limited to Dr. Staudt and 
his research staff, each requiring individual login and password.  All staff in the laboratory receive 
annually updated NIH/CITI or other training, as appropriate, and maintain standards of computer 
security.  
The data recorded for each sample may include the subject ID, trial name/protocol number, date 
drawn/collected, treatment cycle/time point, sample source (e.g., peripheral blood, marrow, tissue, 
etc.) as well as box and freezer location.  All received samples will be given a unique bar code 
number, which will be added to the sample NCI Labmatrix database.  Only this bar code will be 
recorded on the sample vial and the vials will not be traceable back to subjects without authorized 
access to the NCI Labmatrix database.
5.1.15.2 Sample Storage 
Samples are stored in freezers at -80°C (e.g., sera, plasma, tissue samples) or under liquid nitrogen 
(e.g., cells), according to established stability requirements.  These freezers are located onsite 
under the direction of Dr. Staudt.  Access to samples from this protocol for research purposes will 
be as outlined in this protocol or by permission of the Principal Investigator only.  
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.1.16 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.
5.1.17 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Confidentiality for genetic samples will be maintained as described (Section 0).  In addition, a 
Certificate of Confidentiality has been obtained for this study.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
56
5.1.18 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 
Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis. (A list of current guidelines is maintained on the CCR 
intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).
5.1.19 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.
6
DATA COLLECTION AND EVALUATION 
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 subject.
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 7.1.1. 
6.1.2
Data Collection/Recording Exceptions
6.1.2.1
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:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
57

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

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 subject’s 
outcome.  
DATA SHARING PLANS
6.1.3
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:
_X_ An NIH-funded or approved public repository.  Insert name or names: ClinicalTrials.gov, 
dbGaP.
_X_ BTRIS (automatic for activities in the Clinical Center)
_X_ Approved outside collaborators under appropriate individual agreements.  
_X_ Publication and/or public presentations.
When will the data be shared?
_X_ Before publication.
_X_ At the time of publication or shortly thereafter.
6.1.4
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
RESPONSE CRITERIA
The response categories being used to assess overall efficacy of combination therapy are based 
on the Revised Response Criteria for Malignant Lymphoma (52).  Tumor response will be 
assessed by the investigator using the Lugano Classification Response Criteria for NHL (see 
Appendix C).  
6.1.5
Complete Response (CR)
For CR determination, all the following criteria must be met:

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
58
1. Complete disappearance of all detectable evidence of disease and disease-related 
symptoms, if present before therapy
2. All lymph nodes and nodal masses must have regressed on CT to normal size (1.5 cm 
in the greatest transverse diameter [GTD] for nodes >1.5 cm before therapy, regardless 
of the short axis). Previously involved nodes that were between 1.1 cm and 1.5 cm in 
the long axis and more than 1.0 cm in the short axis before treatment must have 
decreased to 1.0 cm in the short axis after treatment. All splenic and hepatic nodules 
and other extranodal disease must have disappeared.
3. FDG-PET scan must be negative (for the combined CT+PET assessment of CR). A 
posttreatment residual mass of any size is permitted as long as it is PET-negative. The 
Five-Point Scale (5-PS) Deauville criteria will be used to interpret PET scans with a 
score of 1-3 being considered PET negative and 4-5 considered PET positive (53) 
(Section 6.1.9).
4. The spleen and/or liver, if enlarged before therapy on the basis of physical examination 
or CT scan, should not be palpable on physical examination and should be considered 
normal size by imaging studies.
5. If the bone marrow was involved before treatment, the infiltrate must have cleared on 
repeated bone marrow biopsy.  The biopsy sample on which this determination is made 
must be adequate (with a goal of >20 mm unilateral core). If a sample is indeterminate 
by morphology, it should be negative by IHC (if bone marrow was involved before 
therapy and a radiological CR was achieved, but with no bone marrow assessment after 
treatment, the response should be classified as a PR).
6. No new sites of disease are detected during assessment.
6.1.6
Partial Response (PR)
For PR determination in subjects with measurable disease, all the following criteria must be met:
1. A ≥50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the 
largest dominant nodes or nodal masses.
2. No increase should be observed in the size of other nodes, liver, or spleen, meeting the 
criteria for PD.
3. Splenic and hepatic nodules must regress by ≥50% in the SPD or, for single nodules, 
in the GTD.
4. With the exception of splenic and hepatic nodules, other organs should not have any 
measurable disease.
5. Bone marrow assessment is not required for PR determination.
6. No new sites of disease should be observed.
7. At least 1 PET-positive site of disease (required for the CT+PET assessment of PR).
For PR determination in subjects with evaluable disease that is not measurable, all the following 
criteria must be met:
1. A ≥50% decrease in the SUVmax from baseline PET scan.
2. Bone marrow assessment is not required for PR determination.
3. No new sites of disease should be observed.
4. At least 1 PET-positive site of disease (required for the CT+PET assessment of PR).
6.1.7
Stable Disease (SD) 
Stable disease (SD) is defined as:

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
59
1. A subject is considered to have stable disease when he or she fails to attain the criteria 
needed for a CR, PR, or MR but does not fulfill those for PD.
2. The PET should be positive at, at least 1 previously involved site of disease, with no 
new areas of lymphoma involvement on the posttreatment CT or PET (for the combined 
CT+PET assessment of stable disease).
6.1.8
Progressive Disease (PD) or Relapsed Disease 
Progressive disease or relapsed disease (after CR) is defined as:
1. Appearance of any new nodal lesion ≥1.6 cm in greatest tumor dimension or ≥1.1 cm 
in short axis during or after the end of therapy, even if other lesions are decreasing in 
size.
2. Appearance of any new unequivocal extra-nodal lesion measuring >1.0 cm, not thought 
to be benign by the reviewer, even if other lesions are decreasing in size
3. At least a 50% increase from the nadir in the sum of the product of diameters of any 
previously involved nodes, or in a single involved node, or in the size of other lesions 
(e.g., splenic or hepatic nodules). To be considered PD, a lymph node with a diameter 
of the short axis of <1.0 cm must increase by 50% and to a size of 1.5 x 1.5 cm or 
more than 1.5 cm in the long axis.
4. At least a 50% increase from the nadir in the longest diameter of any single previously 
identified node more than 1 cm in its short axis.
5. Cytology confirmation of DLBCL is required when there is an appearance on CT of a 
new lesion ≥1.5 cm in its long axis and is PET-negative.
6.1.9
The Five-Point Scale (5-PS) Deauville criteria
The five-point scale (5-PS) has been validated for use at interim staging and at the end of treatment 
and was adopted as the preferred reporting method at the First International Workshop on PET in 
Lymphoma in Deauville, France (i.e., Deauville criteria), and in several international trials. 
The 5-PS scores the most intense uptake in a site of initial disease:
1. if present, as follows:no uptake or no residual uptake (when used at interim)
2. slight uptake, but below blood pool (mediastinum)
3. uptake above mediastinal, but below or equal to uptake in the liver
4. uptake slightly to moderately higher than liver
5. markedly increased uptake or any new lesion (on response evaluation)
6.1.10 Best Overall Response
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.
6.1.11 Event-Free Survival
Event-free survival (EFS) is defined as the time from the date of study enrollment until time of 
disease relapse from CR, disease progression, initiation of subsequent systemic anti-lymphoma 
therapy for either PET-positive or biopsy-proven residual disease, or death, whichever occurs first. 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
60
Subjects who have not had any of these events will have their follow-up time censored at the date 
they are last known to be alive and event free.
6.1.12 Progression-Free Survival
Progression-free survival (PFS) is defined as the time from the date of study enrollment until time 
of disease relapse from CR, disease progression, or death, whichever occurs first. Subjects who 
have not had progression and are still alive will have their follow-up censored at the date they are 
last known to be alive without progression.
6.1.13 Overall Survival
Overall survival (OS) is defined as the time from the date of study enrollment until time of death 
from any cause. Subjects who remain alive will have their follow-up censored at the date they were 
last known to be alive.
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
subject while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50).
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.1.1
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/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies.
7.1.2
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/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
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.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
61
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.
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.1.3
Principal Investigator/Research Team 
The clinical research team will meet approximately weekly when subjects are being actively 
treated on the trial to discuss each subject. Decisions about trial continuation will be made based 
on the efficacy data from prior Subjects 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 
7.1.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each subject 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. 
7.1.4
Independent Monitoring Committee
Safety oversight for this study will include an Independent Safety Monitoring Committee
consisting of the Principal Investigator and two qualified investigators who are not
involved in the study and who are independent of the study team. The committee meetings
will initially be contingent on patient accrual. A meeting will be scheduled with every 3
patients accrued during dose escalation and then every 6 patients during dose expansion.
During these meetings, the committee will review all cumulative safety data and adverse
events irrespective of the principal investigator’s attribution of causality. Ad hoc
meetings may be called at more frequent intervals at the request of the independent
reviewers or based on the study participants’ experience or the emergence of any safety
signal. The study monitoring plan and study stopping rules may be amended as needed
based on the accumulating safety and tolerability profile. The PI will be responsible for
promptly alerting the independent reviewers of any suspected emerging safety signals.
All Adverse Events, expected or unexpected, will be described in the routine safety
monitoring reports. Unresolved differences regarding attribution of causality, event
reporting, event management, or stopping criteria will be submitted for appropriate adjudication 
and reported promptly to the IRB.
8
SPONSOR PROTOCOL/ SAFETY REPORTING
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a subject 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 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
62
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:

Death,

A life-threatening adverse event (see 8.1.3)

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 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.

Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions

A congenital anomaly/birth defect.

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 subject 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 subject 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.  

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.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
63
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 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.
SAEs will be:

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.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

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 0. 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
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 0
All SAE reporting must include the elements described in section 0.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
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. 
WAIVER OF EXPEDITED REPORTING TO SPONSOR (CCR)
Death or hospitalization that is deemed to be due to disease progression, and not attributable to the 
intervention, will not be reported as an SAE. The event, and the assessment that it was caused by 
disease progression will be documented in the medical records. The causality assessment of 
hospitalization will be re-evaluated any time when new information is received. If the causality 
assessment changes from disease progression to related to the study intervention, SAE report will 
be sent to the Sponsor immediately in an expedited manner  according to section 0. If there is any 
uncertainty whether the intervention is a contributing factor to the event, the event should be 
reported as AE or SAE as appropriate.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
64
If subjects considered high-risk for tumor lysis syndrome (TLS) are electively admitted to the 
hospital for the first cycle for close monitoring and supportive care to prevent TLS, then this will 
not be considered an SAE.  The new onset of TLS that results in admission is considered an SAE.
The PI will submit a summary table of all grade 3-5 events, whether or not considered related to 
the product, every 6 months. The report shall include the number of participants treated in the 
timeframe, the number of events per AE term per grade which occurred in the 6-month timeframe 
and in total since the start of the study, attribution, and type/category of serious. 
Reports will be submitted to the Center for Cancer Research (CCR) at OSROSafety@mail.nih.gov
The Sponsor might request case summaries for those events if, upon review, the Sponsor 
determines that an aggregate safety report is required (21CFR312.32(c)(1)(iv)).
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement.
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://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
8.1.6
Maternal exposure
If a subject 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.
Pregnancy should be reported using OSRO pregnancy reporting forms at the following location: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
8.1.7
Paternal exposure
Male subjects should refrain from fathering a child or donating sperm for at least 3 months after 
the last dose of copanlisib and 12 months after the last dose of rituximab, whichever is later. 
Pregnancy of the subject’s partner is not considered to be an AE. 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.
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 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
65
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.
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.
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:

that the rights of the participants are protected; 

that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and 

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) 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 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
66
(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.
10 STATISTICAL CONSIDERATIONS  
OBJECTIVES AND ENDPOINTS
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
To determine the 
Recommended Phase II 
dose (RP2D) and Maximal 
tolerated dose (MTD) of 
copanlisib in combination 
with DA-EPOCH-R in 
subjects with Burkitt 
lymphoma (BL) and high 
grade B-cell lymphomas- 
double hit/triple hit 
(HGBCL-DH/TH) who 
have relapsed after or are 
refractory to chemo-
immunotherapy
RP2D, MTD assessed during the first 21 days 
of treatment
Standard endpoint for phase I 
trial, see Section 3.1.1
Secondary
To assess the safety and 
tolerability of the 
combination of copanlisib 
and DA-EPOCH-R in 
subjects with BL and 
HGBCL-DH/TH relapsed 
after or refractory to 
chemo-immunotherapy
Dose level Adverse Events (AE) per CTCAE 
v5.0, by type and grade of toxicity, from first 
dose through end of treatment, see Section 
also 6.1.1
Standard for phase I trials, 
collecting information on all 
major organ function and 
observed toxicity, if any, to 
determine prominent toxicity to 
advise safety and tolerability 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
67
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
To determine the complete 
response rate, based on 
Lugano Criteria of the 
combination of copanlisib 
and DA-EPOCH-R in 
subjects with BL and 
HGBCL-DH/TH relapsed 
after or refractory to 
chemo-immunotherapy
Complete response (CR) rate, time 
measurement criteria are met for CR until the 
first date that progressive disease is 
objectively documented or death, assessed 
every 3-6 months
Standard endpoints for cancer 
clinical trials, CR is the endpoint 
chosen because with these 
diseases, PR is not relevant as all 
subjects will relapse.  Regimens 
will not be moved forward 
unless they can achieve a CR.  
To assess progression free 
survival (PFS), event-free 
survival (EFS) and overall 
survival (OS) of subjects 
treated with the 
combination of copanlisib 
and DA-EPOCH-R in 
subjects with BL and 
HGBCL-DH/TH relapsed 
after or refractory to 
chemo-immunotherapy
- Overall survival (OS)- time from the date of 
study enrollment until death from any cause, 
assessed every 3-6 months 
- Event free survival (EFS)- time from the 
date of study enrollment until time of 
disease relapse from CR, disease 
progression, initiation of subsequent 
systemic anti-lymphoma therapy for either 
PET-positive or biopsy-proven residual 
disease, or death, whichever occurs first, 
assessed every 3-6 months
- Progression free survival (PFS) - time from 
date of study enrollment until time of 
disease relapse, disease progression, or 
death, whichever occurs first, assessed 
every 3-6 months 
Standard endpoints for cancer 
clinical trials. Success of 
regimens will be determined by 
these endpoints.
Tertiary/Exploratory 
To explore the molecular 
correlates of resistance to 
copanlisib with DA-
EPOCH-R
To determine role of 
circulating tumor DNA to 
monitor response to therapy
To determine the ability of 
circulating tumor DNA to 
predict disease relapse
To explore the 
pharmacokinetics of 
copanlisib in plasma and 
cerebrospinal fluid (CSF) 
samples
Each of these will be evaluated using 
descriptive methods and reported as 
exploratory results. If any statistical tests are 
performed in these analyses, the results will 
be presented without adjustment for multiple 
comparisons but reported in the context of the 
number of tests performed. See Section for 0 
collection timepoints.
Exploratory analysis
STATISTICAL HYPOTHESIS

Primary Endpoint
o
Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of 
copanlisib in combination with DA-EPOCH-R 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
68

Secondary Endpoints
o
PFS, EFS, and OS
o
Overall safety profile of regimen
o
Rate of complete response
SAMPLE SIZE DETERMINATION 
The primary objectives of this trial are to determine the safety and MTD or RP2D of the 
combination of dose-adjusted EPOCH-R and copanlisib and to obtain preliminary estimates of 
efficacy in subjects with relapsed Burkitt lymphoma or diffuse large B-cell lymphoma.
The original study design accrued 5 subjects to dose escalation (Arm 1) before it was closed after 
2 subjects had DLTs related to unacceptable hematologic toxicity. After a review of the full safety 
profile, the study was amended with new eligibility criteria and a modified dosing schedule. Arm 
1 was closed to further accrual and the dose escalation phase was resumed with accrual into Arm 
2.
The trial will begin with a new 3 dose-level 3+3 design escalating copanlisib starting at 30 mg 
along with DA-EPOCH-R. With 3 dose levels being explored, the trial may require up to 18 
additional subjects to complete the dose escalation portion. The number of subjects with toxicity 
at each dose level will be reported, along with tables of grade and type of toxicity.
As a stopping rule for safety, if during the modified dose escalation or expansion cohort any grade 
5 adverse events occur that are possibly related to study treatment or 3 or more subjects have 
immune-mediated adverse events that necessitate stopping of copanlisib, then no more subjects 
will be enrolled. If at any point in the study (dose escalation or dose expansion), more than 20% 
of subjects need to stop the EPOCH-R chemotherapy backbone due to hematologic or non-
hematologic toxicity, then further enrollment will be stopped.  These stopping rules apply to the 
entirety of study treatment and not just during the DLT window.
At the MTD or RP2D level with 6 subjects evaluated during the dose escalation portion of study, 
an additional expansion cohort of 10 subjects with either Burkitt lymphoma or DLBCL will be 
enrolled in order to obtain more safety data as well as to obtain preliminary efficacy data, focusing 
primarily on the rate of complete response (CR). The 16 subjects treated in a homogeneous fashion 
at the MTD or RP2D will be evaluated primarily for CR rate using all subjects combined and may 
also be reported in an exploratory fashion by disease type (Burkitt vs. DLBCL). The fraction of 
subjects with a CR will be reported overall as well as by disease type, including 95% confidence 
intervals. If results are promising, more definitive evaluations of efficacy would be planned. PFS, 
EFS, and OS will be reported as a secondary evaluation, based on all subjects in the study as well 
as focusing on the 16 subjects treated in a homogeneous fashion.
As an additional stopping rule for safety, if at any time after 3 subjects have enrolled in the 
expansion cohort, ≥1/3 subjects cumulatively treated in the expansion are identified as having a 
DLT, no further subjects will enroll.  It is expected that 10-12 subjects per year may enroll on this 
study. With a maximum of 5+18+10=33 evaluable subjects, up to 3 years may be required to 
accrue up to 39 subjects, including for a small number of inevaluable subjects or screen failures. 
The increase in accrual is to account for the five subjects enrolled to the now closed Cohort 1 Arm 
1 treated with the original drug dose regimen.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
69
POPULATIONS FOR ANALYSES
10.1.1 Evaluable for Toxicity
All subjects will be evaluable for toxicity from the time of their first treatment with copanlisib.
10.1.2 Evaluable for Objective Response
Only those subjects who have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.  
These subjects will have their response classified according to the definitions stated below.  
(NOTE:  Subjects who exhibit objective disease progression at any point after receiving at least 1 
cycle of therapy will also be considered evaluable.)
10.1.3 Evaluable Non-Target Disease Response
Subjects 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. 
STATISTICAL ANALYSES
10.1.4 General Approach
Toxicity and safety data will be reported descriptively. 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.  
10.1.5 Analysis of the Primary Endpoint
The number of subjects with toxicity at each dose level will be reported, along with tables of grade 
and type of toxicity. 
10.1.6 Analysis of the Secondary Endpoints
Among the subjects treated at the MTD or RP2D, the complete response (CR) rate will be 
determined and reported along with a two-sided 95% confidence interval.  Based on all subjects 
enrolled in the study as well as focusing on the 16 subjects treated in a homogeneous fashion, 
progression-free survival (PFS), event-free survival (EFS)and overall survival (OS) will be 
estimated using the Kaplan-Meier method for each. In addition to providing the curves for each 
endpoint, the median and a 95% confidence interval for the median will be reported. Adverse event 
data will be compiled and tabulated using descriptive statistics. The assessment of OS is estimated 
to end at 5 years after completion of treatment of the last subject. 
10.1.7 Safety Analyses 
The type, grade and frequency of toxicities will be reported.
As a stopping rule for safety, if at any time after 3 subjects have enrolled in the expansion cohort, 
≥1/3 subjects cumulatively treated in the expansion are identified as having a DLT, no further 
subjects will enroll.
If during the modified dose escalation or expansion cohort any grade 5 adverse events occur that 
are possibly related to study treatment or 3 or more subjects have immune-mediated adverse events 
that necessitate stopping of copanlisib, then no more subjects will be enrolled.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
70
If at any point in the study (dose escalation or dose expansion), more than 20% of subjects need to 
stop the EPOCH-R chemotherapy backbone due to hematologic or non-hematologic toxicity, then 
further enrollment will be stopped. 
These stopping rules apply to the entirety of study treatment and not just during the DLT window.
10.1.8 Baseline Descriptive Statistics
Descriptive statistics (including means, standard deviations, and medians for continuous variables 
and proportions and CIs for discrete variables) will be used to summarize data as appropriate.
10.1.9 Planned Interim Analyses
None.
10.1.10Sub-Group Analyses
Analyses by disease type may be performed depending on the number of subjects available for 
inclusion in analyses.
10.1.11Tabulation of Individual Subject Data
None.
10.1.12Exploratory Objectives and Analyses

To explore the molecular correlates of resistance to copanlisib with DA-EPOCH-R

To determine role of circulating tumor DNA to monitor response to therapy

To determine the ability of circulating tumor DNA to predict disease relapse
In addition, the CR rate may also be reported in an exploratory fashion by disease type (Burkitt vs. 
Large Cell).  Moleculare correlates of resistance to copanlisib with DA-EPOCH-R will be reported 
descriptively. ctDNA studies are also exploratory and overall trends in serial measurements may 
support a response (or lack of response) signal to treatment and could be correlated with response 
and PFS as a surrogate marker of disease burden. 
11 COLLABORATIVE AGREEMENTS
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)
A Cooperative Research and Development Agreement (CRADA) between the National Cancer 
Institute and Bayer Pharmaceuticals was executed prior to initiation of the trial (#03390).  
12 HUMAN SUBJECTS PROTECTIONS 
RATIONALE FOR SUBJECT SELECTION
All subjects from both sexes and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria outlined in the protocol. Subjects with HIV infection are included. Pregnant and 
nursing mothers are excluded because of the potential teratogenic effects of therapy. 
PARTICIPATION OF CHILDREN
Children under the age of 18 will not be eligible for participation on this protocol because the 
response to treatments differs significantly between pediatric and adult BL and DLBCL subjects. 
Therefore, the inclusion of younger subjects will not provide generalizable information that would 
justify their inclusion on this study. 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
71
RISK/BENEFIT ASSESSMENT
12.1.1 Known Potential Risks
12.1.1.1 Risks from Study Drugs
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. The potential toxicity of 
copanlisib is reasonable in relation to the potential benefit to this group of subjects who have few 
treatment options.
The most common side effects of DA-EPOCH-R chemotherapy include: infection, bruising, 
fatigue, anemia, constipation, nausea/vomiting, constipation, tingling of fingers and toes, hair loss, 
fingernail discoloration, bony pain and infusion reactions. 
These established risks are not anticipated to be significantly higher with the addition of copanlisib 
with DA-EPOCH-R in this study; however, the grades and frequencies of toxicities will be closely 
monitored and reported.
12.1.1.2 Blood Collection
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
12.1.1.3 Biopsy Collection
The risks of the biopsies include pain, bleeding and infection at the biopsy site. These biopsies 
may be performed with CT guidance.
12.1.1.4 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.
12.1.1.5 ECG
Side effects of ECG are skin irritation where ECG electrodes are placed. 
12.1.1.6 Echocardiogram
Side effects of an echocardiogram are discomfort from the transducer being firmly placed against 
the chest. 
12.1.1.7 Bone Marrow Biopsy
Bone marrow biopsy is minimally invasive and is typically a very safe procedure. Usually the 
hipbone is numbed with anesthesia. Using a needle, the solid and liquid portion of bone marrow 
is taken out. This procedure causes some pain. Very rarely, infection or bleeding may occur at the 
needle site.
12.1.1.8 Lumbar Puncture
Risks of lumbar puncture include headache, dizziness, infection, back discomfort, minor radicular 
numbess and brainstem herniation
12.1.1.9 Imaging
In addition to the radiation risks discussed below, scans may include the risks of an allergic 
reaction to the contrast. Subjects might experience hives, itching, headache, difficulty breathing, 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
72
increased heartrate and swelling. Subjects undergoing gadolinium enhanced MRIs may also be at 
risk for kidney damage.
12.1.1.10
Radiation
The study will involve radiation from the following sources:

Up to 7 CT (chest abdomen pelvis) scans per year for disease assessment

Up to 5 FDG-PET scans per year for disease assessment

Up to 2 CT-guided biopsies
Subjects in this study may be exposed to approximately 2.3 rem during screening and 13 rem 
during the study for a total of 15.3 rem. This amount is more than would be expected from everyday 
background radiation. Being exposed to excess radiation can increase the risk of cancer. The risk 
of getting cancer from the radiation exposure in this study is 1.5 out of 100 (1.5%) and of getting 
a fatal cancer is 0.8 out of 100 (0.8%). 
12.1.1.11
Non-Physical Risks of Genetic Research
Risk of receiving unwanted information, anxiety and stress at the information, and breach of 
confidentiality. 
12.1.1.12
Other Procedures
There are no physical risks associated with other procedures (e.g., urine or saliva collection, 
cheek/ buccal swabs).
12.1.2 Known Potential Benefits 
Subjects may obtain direct benefit from treatment with copanlisib in combination with DA-
EPOCH-R. See Section 1.1.8 and 1.1.9.
CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
subject as applicable 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 subject/consent designee(s).  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 consult room). When consent is conducted remotely, the subject 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, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
73
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:

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

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 participant 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://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
*The informed consent process will involve the use of two consent forms, one labeled “Screening” 
(for all screening procedures) and another labeled “Standard” (for all study treatment/procedures). 
The consent for treatment must be obtained by a designated, appropriately licensed study 
investigator (e.g., MD, NP, PA, DO). Any study investigators not falling into this category (e.g., 
RNs) who are designated as able to obtain consent may do so for screening procedures only. 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS
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 investigators, funding 
agencies, the Investigational New Drug (IND) sponsor and regulatory authorities, as applicable.  
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study subjects, the Institutional Review Board (IRB), and sponsor and will provide the 
reason(s) for the termination or suspension.  Study subjects 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:

Determination of unexpected, significant, or unacceptable risk to subjects

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

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).

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
74
QUALITY ASSURANCE AND QUALITY CONTROL
The 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 Conference on 
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.
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 National Cancer Institute 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.
CONFIDENTIALITY AND PRIVACY
Subject confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s). This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to subjects. 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.
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 subjects in this study. The clinical study 
site will permit access to such records.
The study subject’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.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
75
Study subject 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 subject’s contact or 
identifying information. Rather, individual subjects 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 site and by NCI CCR research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at the NIH.
To further protect the privacy of study subjects, 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 subjects, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to subjects.
14 PHARMACEUTICAL INFORMATION
COPANLISIB (BAY 80-6946, ALIQOPA) (IND #141280)
Refer to the FDA approved package insert for complete product information.
14.1.1 Source, Acquisition and Accountability  
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)
Chemical formula: 
C23H28N8O4 2HCl
Molecular mass: 
553.45 g/mol
Chemical structure:

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
76
14.1.3 Mechanism of copanlisib
Copanlisib is a small molecule pan-class 1 PI3K inhibitor with predominant activity against PI3Kα 
and PI3K 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 PI3K, 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%) subjects. 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%) subjects. 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 subjects 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).

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
77
Table 9:  Serious Adverse Reactions From Multiple Clinical Trials
Copanlisib 
N=877
ADVERSE REACTIONS
All SAR
 N (%)
Life threatening
Fatal
Metabolism and nutrition disorders
Hyperglycemia
39 (4.4%)
NA
NA
Blood and lymphatic system disorders
Febrile neutropenia
13 (1.5%)
NA
NA
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
Diarrhea
11 (1.3%)
NA
NA
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
Pneumonia
41 (4.7%)
NA
NA
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
Hyperglycemia
39 (4.4%)
NA
NA 
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

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
78
Table 10:  Treatment-emergent Laboratory Abnormalities in ≥10% of Patients and ≥4% of Grade 
≥3 Treated with Copanlisib and Rituximab
Copanlisib with Rituximab
N=307
Laboratory Parameter
Any Grade
 n (%)
Grade 3 
n (%)
Grade 4
n (%)
Hematology abnormalities
Decreased hemoglobin
209 (68%)
15 (5%)
0
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
Hyperglycemia
296 (96%)
193 (63%)
14 (5%)
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:

Withdraw 4.4 mL of sterile 0.9% NaCl solution by using a 5 mL sterile syringe with needle.

Inject the measured volume through the disinfected stopper surface into the vial of 
copanlisib.

Dissolve the lyophilized solid by gently shaking the injection vial for 30 seconds.

Allow to stand for one minute to let bubbles rise to the surface.

Check if any undissolved substance is still seen. If yes, repeat the gentle shaking and 
settling procedure.

Inspect visually for discoloration and particulate matter. After reconstitution, the solution 
should be colorless to slightly yellowish

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
79

Once the solution is free of visible particles, withdraw the reconstituted solution for further 
dilution.

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 subject 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.
RITUXIMAB
14.1.8 Source, Acquisition and Accountability
Commercial supplies of rituximab will be purchased by the NIH Clinical Center.  Refer to the 
FDA approved package insert for complete product information including toxicity, formulation 
and preparation, stability and storage and incompatibilities.
14.1.9 Administration procedures
A peripheral or central intravenous line will be established. During rituximab infusion, a subject'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.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
80
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 subjects primarily in an outpatient clinic setting.  

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). 

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)
2nd portion (30 – 90 minutes)
Special Note: The 90-minute infusion scheme is not recommended for subjects with 
clinically significant cardiovascular disease or high circulating lymphocyte counts 
(≥5000/mcL).
o
Standard Administration for Second & Subsequent Infusions
Subjects 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.  
DOXORUBICIN
14.1.10Source, Acquisition and Accountability
Doxorubicin is commercially available and will be supplied by the NIH Clinical Center Pharmacy 
Department. Refer to the FDA approved package insert for complete product information 
including toxicity, formulation and preparation, stability and storage and incompatibilities.
Total Dose (mg)
2
0.2 X mL (over 30 min)
Total Dose (mg)
2
0.8 X mL (over 60 min)

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
81
14.1.11Administration Procedures
For Dose-adjusted EPOCH-R, refer to Section 0 for administration procedures.
PREDNISONE
14.1.12Source, Acquisition and Accountability  
Prednisone is commercially available and will be supplied to the subjects enrolled on the study by 
the NIH Clinical Center Pharmacy Department. Refer to the FDA approved package insert for 
complete product information including toxicity, formulation and preparation, stability and storage 
and incompatibilities.
14.1.13Administration Procedures
For Dose-adjusted EPOCH-R, prednisone will be administered twice daily by mouth on Days 1-
5.
VINCRISTINE 
14.1.14Source, Acquisition and Accountability  
Vincristine is commercially available and will be supplied by the NIH Clinical Center Pharmacy 
Department. Refer to the FDA approved package insert for complete product information 
including toxicity, formulation and preparation, stability and storage and incompatibilities.
14.1.15Administration procedures
For Dose-adjusted EPOCH-R refer to Section 0 for administration procedures.
CYCLOPHOSPHAMIDE 
14.1.16Source, Acquisition and Accountability  
Cyclophosphamide is commercially available and will be supplied by the NIH Clinical Center 
Pharmacy Department. Refer to the FDA approved package insert for complete product 
information including toxicity, formulation and preparation, stability and storage and 
incompatibilities.
14.1.17Administration procedures
Cyclophosphamide will be diluted in D5W or 0.9% NaCl and administered as an intravenous 
infusion over 30 minutes.  Subjects will be instructed to drink an adequate amount of fluids and 
empty their bladders frequently during cyclophosphamide administration. All subjects should 
receive 1000 mL 0.9%NaCl @ 300 – 500 mL/hr with 500 mL given before starting 
cyclophosphamide administration and 500 mL given after completion of the cyclophosphamide 
administration.  
ETOPOSIDE
14.1.18Source, Acquisition and Accountability 
Etoposide is commercially available and will be supplied by the NIH Clinical Center Pharmacy 
Department. Refer to the FDA approved package insert for complete product information 
including toxicity, formulation and preparation, stability and storage and incompatibilities.
14.1.19Administration procedures
Refer to Section 0 for administration procedures for Vincristine/Doxorubicin/Etoposide 
Admixture for Dose-adjusted EPOCH-R regimen.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
82
VINCRISTINE/DOXORUBICIN/ETOPOSIDE ADMIXTURE
14.1.20Formulation and preparation
For Dose-adjusted EPOCH-R, vincristine, doxorubicin, and etoposide comprising a daily dose (a 
24-hour supply) will be diluted in 0.9%NS. Product containers will be replaced every 24 hours to 
complete the planned duration of infusional treatment.  Product volumes will be determined by the 
amount of etoposide present in a 24-hour supply of medication. For daily etoposide doses <130 
mg, admixtures will be diluted in approximately 500 mL 0.9%NS.  
14.1.21Stability and Storage 
Stability studies conducted by the Pharmaceutical Development Service, Pharmacy Department, 
NIH Clinical Center, have demonstrated that admixtures of vincristine, doxorubicin, and etoposide 
in 0.9% Sodium Chloride Injection, USP at concentrations, respectively, of 1, 25 and 125 mcg/mL; 
1.4, 35 and 175 mcg/mL; 2, 50 and 250 mcg/mL; and 2.8, 70 and 350 mcg/mL are stable for at 
least 36 hours at room temperature when protected from light. Also, admixtures containing 
vincristine, doxorubicin and etoposide concentrations of 1.6, 40 and 200 mcg/mL are stable for at 
least 30 hours at 32ºC.   
14.1.22Administration procedures
Vincristine + doxorubicin + etoposide admixtures will be administered by continuous IV infusion 
over 96 hours with a suitable rate controller pump via a central venous access device.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
83
15 LIST OF ABBREVIATIONS
ABC
Activated B-cells
AE
Adverse Event/Adverse Experience
ANC
absolute neutrophil count
BCL-2
B-cell lymphoma 2
BCL-6
B-cell lymphoma 6
BL
Burkitt Lymphoma
BM
Bone marrow
CFR
Code of Federal Regulations
CI
Confidence Interval
CMV
Cytomegalovirus
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COO
Cell of origin
CSF
Cerebrospinal fluid
CSR 
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DA
Dose-adjusted
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose-limiting toxicity
ECHO
Echocardiogram
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group – performance status
EFS
Event-free survival
EKG
Electrocardiogram
EPOCH-R
Etoposide phosphate, Prednisone, Vincristine sulfate (Oncovin), 
Cyclophosphamide, Doxorubicin hydrochloride 
(Hydroxydaunorubicin)-Rituximab, combination chemotherapy 
regimen
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
FWA
Federal Wide Assurance
GCB
Germinal center B cell
GCP
Good Clinical Practice

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
84
GEP
Gene-expression profiling
GFR
Glomerular filtration rate
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HGBCL-DH/TH
High grade B-cell lymphomas- double hit/triple hit
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IHC
Immunohistochemical
IND
Investigational New Drug Application
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
LVEF
Left Ventricular Ejection Fraction
MDRD
Modification of Diet in Renal Disease
MRD
Minimal Residual Disease
MRI
Magnetic Resonance Imaging
MTD
Maximal tolerated dose
N
Number (typically refers to subjects)
NDA
New Drug Application
NHL
Non-Hodgkin lymphoma
NIP
Non-infectious pneumonitis
NIH
National Institutes of Health
NOS
Not otherwise specified
OHSR
Office for Human Subjects Research
OS
Overall survival
PCR
Polymerase chain reaction
PET
Positron Emission Tomography
PFS
Progression free survival
PI3K
Phosphoinositide 3-kinase
PI
Principal Investigator
QA
Quality Assurance
QC
Quality Control

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
85
R-CHOP
Rituximab, Cyclophosphamide, Doxorubicin Hydrochloride 
(Hydroxydaunomycin), Vincristine Sulfate (Oncovin), Prednisone – 
drug combination
RNA
Ribonucleic Acid
RP2D
Recommended Phase II dose
SAE
Serious Adverse Event/Serious Adverse Experience
SCT
Stem Cell Transplantation
SOP
Standard Operating Procedure
ULN
Upper limit of normal
US
United States
WHO
World Health Organization
WOCBP
Women of childbearing potential

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
86
16 REFERENCES 
1.
Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM. Human c-myc 
onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma 
cells. Proceedings of the National Academy of Sciences of the United States of America. 
1982;79(24):7824-7.
2.
Ziegler JL, Bluming AZ, Morrow RH, Fass L, Carbone PP. Central nervous system 
involvement in Burkitt's lymphoma. Blood. 1970;36(6):718-28.
3.
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma 
incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107(1):265-
76.
4.
Hochberg J, Waxman IM, Kelly KM, Morris E, Cairo MS. Adolescent non-Hodgkin 
lymphoma and Hodgkin lymphoma: state of the science. British journal of haematology. 
2009;144(1):24-40.
5.
Magrath I, Adde M, Shad A, Venzon D, Seibel N, Gootenberg J, et al. Adults and 
children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated 
with the same chemotherapy regimen. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 1996;14(3):925-34.
6.
Murphy SB, Bowman WP, Abromowitch M, Mirro J, Ochs J, Rivera G, et al. Results of 
treatment of advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia 
with high-dose fractionated cyclophosphamide and coordinated high-dose methotrexate and 
cytarabine. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 1986;4(12):1732-9.
7.
Costa LJ, Xavier AC, Wahlquist AE, Hill EG. Trends in survival of patients with Burkitt 
lymphoma/leukemia in the USA: an analysis of 3691 cases. Blood. 2013;121(24):4861-6.
8.
Kelly JL, Toothaker SR, Ciminello L, Hoelzer D, Holte H, LaCasce AS, et al. Outcomes 
of patients with Burkitt lymphoma older than age 40 treated with intensive chemotherapeutic 
regimens. Clinical lymphoma & myeloma. 2009;9(4):307-10.
9.
Hoelzer D, Walewski J, Dohner H, Viardot A, Hiddemann W, Spiekermann K, et al. 
Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: 
report of a large prospective multicenter trial. Blood. 2014;124(26):3870-9.
10.
Burkhardt B, Oschlies I, Klapper W, Zimmermann M, Woessmann W, Meinhardt A, et 
al. Non-Hodgkin's lymphoma in adolescents: experiences in 378 adolescent NHL patients treated 
according to pediatric NHL-BFM protocols. Leukemia. 2011;25(1):153-60.
11.
Short NJ, Kantarjian HM, Ko H, Khoury JD, Ravandi F, Thomas DA, et al. Outcomes of 
adults with relapsed or refractory Burkitt and high-grade B-cell leukemia/lymphoma. Am J 
Hematol. 2017;92(6):E114-E7.
12.
O'Connor PM, Wassermann K, Sarang M, Magrath I, Bohr VA, Kohn KW. Relationship 
between DNA cross-links, cell cycle, and apoptosis in Burkitt's lymphoma cell lines differing in 
sensitivity to nitrogen mustard. Cancer research. 1991;51(24):6550-7.
13.
Dunleavy K, Pittaluga S, Shovlin M, Steinberg SM, Cole D, Grant C, et al. Low-intensity 
therapy in adults with Burkitt's lymphoma. The New England journal of medicine. 
2013;369(20):1915-25.
14.
Roschewski M, Dunleavy K, Abramson JS, Powell BL, Link BK, Patel P, et al. 
Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With 
Untreated Burkitt Lymphoma. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2020:JCO2000303.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
87
15.
Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. 
Outcomes in refractory diffuse large B-cell lymphoma: results from the international 
SCHOLAR-1 study. Blood. 2017;130(16):1800-8.
16.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types 
of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 
2000;403(6769):503-11.
17.
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of 
molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. 
The New England journal of medicine. 2002;346(25):1937-47.
18.
Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, et al. Molecular 
subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proceedings of the 
National Academy of Sciences of the United States of America. 2008;105(36):13520-5.
19.
Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al. Genetics 
and Pathogenesis of Diffuse Large B-Cell Lymphoma. The New England journal of medicine. 
2018;378(15):1396-407.
20.
Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, et al. Stromal gene signatures in 
large-B-cell lymphomas. The New England journal of medicine. 2008;359(22):2313-23.
21.
Young RM, Phelan JD, Shaffer AL, Wright GW, Huang DW, Schmitz R, et al. Taming 
the Heterogeneity of Aggressive Lymphomas for Precision Therapy. Annu Rev Canc Biol. 
2019;3:429-55.
22.
Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. 
Confirmation of the molecular classification of diffuse large B-cell lymphoma by 
immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-82.
23.
Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB 
activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. The 
Journal of experimental medicine. 2001;194(12):1861-74.
24.
Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, et al. Chronic active B-
cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463(7277):88-92.
25.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 
revision of the World Health Organization classification of lymphoid neoplasms. Blood. 
2016;127(20):2375-90.
26.
Scott DW, King RL, Staiger AM, Ben-Neriah S, Jiang A, Horn H, et al. High-grade B-
cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell 
lymphoma morphology. Blood. 2018;131(18):2060-4.
27.
Ennishi D, Jiang A, Boyle M, Collinge B, Grande BM, Ben-Neriah S, et al. Double-Hit 
Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse 
Large B-Cell Lymphoma. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology. 2019;37(3):190-201.
28.
Hilton LK, Tang J, Ben-Neriah S, Alcaide M, Jiang A, Grande BM, et al. The double-hit 
signature identifies double-hit diffuse large B-cell lymphoma with genetic events cryptic to 
FISH. Blood. 2019;134(18):1528-32.
29.
Sha C, Barrans S, Cucco F, Bentley MA, Care MA, Cummin T, et al. Molecular High-
Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to 
Therapy. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2019;37(3):202-12.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
88
30.
Dunleavy K, Fanale MA, Abramson JS, Noy A, Caimi PF, Pittaluga S, et al. Dose-
adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and 
rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a 
prospective, multicentre, single-arm phase 2 study. Lancet Haematol. 2018;5(12):e609-e17.
31.
Bergholz JS, Roberts TM, Zhao JJ. Isoform-Selective Phosphatidylinositol 3-Kinase 
Inhibition in Cancer. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2018;36(13):1339-42.
32.
Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K 
Pathway in Human Disease. Cell. 2017;170(4):605-35.
33.
Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and 
activation. Nat Rev Immunol. 2003;3(4):317-30.
34.
Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells. 
Annual review of immunology. 2013;31:675-704.
35.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of 
mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554.
36.
Wang X, Huang H, Young KH. The PTEN tumor suppressor gene and its role in 
lymphoma pathogenesis. Aging (Albany NY). 2015;7(12):1032-49.
37.
Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling 
and cancer metabolism. Nature reviews Cancer. 2020;20(2):74-88.
38.
Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, et al. Inactivation of 
PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 
2014;510(7505):407-11.
39.
Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma-treatment 
approaches in the molecular era. Nature reviews Clinical oncology. 2014;11(1):12-23.
40.
Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B 
cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nature medicine. 
2015;21(8):922-6.
41.
Young RM, Phelan JD, Wilson WH, Staudt LM. Pathogenic B-cell receptor signaling in 
lymphoid malignancies: New insights to improve treatment. Immunological reviews. 
2019;291(1):190-213.
42.
Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W, Zhang M, et al. Burkitt 
lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 
2012;490(7418):116-20.
43.
Sander S, Calado DP, Srinivasan L, Kochert K, Zhang B, Rosolowski M, et al. Synergy 
between PI3K signaling and MYC in Burkitt lymphomagenesis. Cancer cell. 2012;22(2):167-79.
44.
Phelan JD, Young RM, Webster DE, Roulland S, Wright GW, Kasbekar M, et al. A 
multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature. 2018.
45.
Liu N, Rowley BR, Bull CO, Schneider C, Haegebarth A, Schatz CA, et al. BAY 80-
6946 is a highly selective intravenous PI3K inhibitor with potent p110alpha and p110delta 
activities in tumor cell lines and xenograft models. Mol Cancer Ther. 2013;12(11):2319-30.
46.
Iyengar S, Clear A, Bodor C, Maharaj L, Lee A, Calaminici M, et al. P110alpha-
mediated constitutive PI3K signaling limits the efficacy of p110delta-selective inhibition in 
mantle cell lymphoma, particularly with multiple relapse. Blood. 2013;121(12):2274-84.
47.
Paul J, Soujon M, Wengner AM, Zitzmann-Kolbe S, Sturz A, Haike K, et al. 
Simultaneous Inhibition of PI3Kdelta and PI3Kalpha Induces ABC-DLBCL Regression by 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
89
Blocking BCR-Dependent and -Independent Activation of NF-kappaB and AKT. Cancer cell. 
2017;31(1):64-78.
48.
Lenz G, Hawkes E, Verhoef G, Haioun C, Thye LS, Heo DS, et al. Phase II study of 
single-agent copanlisib in patients with relapsed or refractory diffuse large B-cell lymphoma 
(DLBCL). 2017;35(15_suppl):7536-.
49.
Grommes C, Gavrilovic I, Miller AM, Stone JB, Kaley T, Madzsar JT, et al. Phase Ib of 
Copanlisib in Combination with Ibrutinib in Recurrent/Refractory Primary CNS Lymphoma 
(PCNSL). Blood. 2019;134(Supplement_1):1598-.
50.
Myklebust JH, Brody J, Kohrt HE, Kolstad A, Czerwinski DK, Walchli S, et al. Distinct 
patterns of B-cell receptor signaling in non-Hodgkins' lymphomas identified by single cell 
profiling. Blood. 2016.
51.
Andor N, Simonds E, Chen J, Grimes S, Wood C, Czerwinski DK, et al. Massively 
Parallel Single Cell RNA-Seq of Primary Lymphomas Reveals Distinct Cellular Lineages and 
Diverse, Intratumoral Transcriptional States. Blood. 2016;128:1090-.
52.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2007;25(5):579-86.
53.
Nanni C, Cottereau AS, Lopci E, Bodet-Milin C, Coronado M, Pro B, et al. Report of the 
6th International Workshop on PET in lymphoma. Leukemia & lymphoma. 2017;58(10):2298-
303.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
90
17 APPENDICES
APPENDIX A:  PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
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).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but is 
able to care for most of his/her 
needs.
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.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
91
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 subjects 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 subjects 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 subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner by using a highly effective form of birth control while receiving copanlisib 
and for 30 days after the last dose of copanlisib:  
Single method (highly effective) 

practice abstinence† from heterosexual activity

intrauterine device (IUD)

vasectomy of a female subject’s male partner 

contraceptive rod implanted into the skin
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner while receiving rituximab and for 12 months after the last dose of rituximab 
by complying with the following:  
Combination method (effective) 
Requires use of two of the following:

diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)

cervical cap with spermicide (nulliparous women only)  

contraceptive sponge (nulliparous women only) 

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection
†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 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
92
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 subjects participating at sites in this country/region.
Subjects 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 subjects 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 (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).  
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 per the collaborative agreement.
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, 
subjects who are breast-feeding are not eligible for enrollment.

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
93
APPENDIX C: THE LUGANO CLASSIFICATION RESPONSE CRITERIA 

Abbreviated Title:  Copanlisib in BL
 
Version Date:  04/24/2023
94