Conditions: Recurrent Diffuse Large B-Cell Lymphoma Recurrent Primary Mediastinal Large B-Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma Refractory Primary Mediastinal Large B-Cell Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
This phase II trial studies how well copanlisib hydrochloride and nivolumab work in treating patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma that has come back (recurrent) or does not responded to the treatment (refractory). Copanlisib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving copanlisib hydrochloride and nivolumab may work better in treating patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma compared to standard of care.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess overall response rate (ORR) defined as complete response rate (CR) plus partial response rate (PR) (ORR = CR + PR) of the combination of copanlisib hydrochloride (copanlisib) and nivolumab in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL).

SECONDARY OBJECTIVES:

I. To evaluate the safety of the combination of nivolumab and copanlisib in patients with relapsed/refractory DLBCL and PMBCL.

II. To determine the progression free survival, duration of response, complete response rate and overall survival of the combination of copanlisib and nivolumab in patients with relapsed or refractory DLBCL and PMBCL.

CORRELATIVE STUDY OBJECTIVES:

I. To characterize the effects of the copanlisib and nivolumab combination regimen on tumor cells, tumor microenvironment and the immune response in relapsed/refractory DLBCL and PMBCL.

II. To assess predictors of response of the combination in relapsed/refractory DLBCL and PMBCL.

OUTLINE:

Patients receive copanlisib hydrochloride intravenously (IV) over 1 hour on days 1, 8 and 15 of cycles 1-8 and days 1 and 15 of subsequent cycles. Patients also receive nivolumab IV over 30 minutes on days 1 and 15 of cycles 1-8 and on day 1 of subsequent cycles. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for up to 100 days.

Arms:
arm 1: Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8 and 15 of cycles 1-8 and days 1 and 15 of subsequent cycles. Patients also receive nivolumab IV over 30 minutes on days 1 and 15 of cycles 1-8 and on day 1 of subsequent cycles. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Copanlisib Hydrochloride intervention 2: Nivolumab
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV

Protocol document:
Prot_SAP_000.pdf: 
NCI Protocol #: 
10193 
Local Protocol #: 
MC1787 
Protocol Version Date:   July 13,, 2021 
 
i 
 
 
TITLE:  Phase 2 Study of Copanlisib in Combination with Nivolumab in Subjects with 
Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Primary Mediastinal Large  
B-Cell Lymphoma 
 
I. 
Investigator Amendment Request: 
Additions in bold, deletions are noted as strikethrough 
# 
Section 
Comments 
1. 
Header 
Protocol version date changed to July 13, 2021 
2. 
Title Page 
 
Amendment 7 / Version 14 / July 13, 2021 
 
 
3. 
3.2.12 
3.2.12  Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
non-healing wound or ulcer, or bone fracture, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, known history of atrial fibrillation except 
those with 1 event that has resolved more than 1 year ago without recurrence, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
4. 
10.0 
f:   Perform an evaluation of cardiac function including ECG and echocardiogram and Troponin 
for all patients at screening, and thereafter as clinically indicated. Also perform an evaluation 
for patients with evidence of CHF, MI, cardiomyopathy, or myositis including lab tests and 
cardiology consultations including ECG, echocardiogram, CPK and troponin as clinically 
indicated 
 
5. 
4.2.2 
4.2.2 Requirements For  10193 Site Registration 
 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
• Site Initiation Visit 
• ETCTN Specimen Tracking Training 
 
 


NCI Protocol #: 
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Local Protocol #: 
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TITLE:  Phase 2 Study of Copanlisib in Combination with Nivolumab in Subjects with 
Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Primary Mediastinal Large  
B-Cell Lymphoma 
 
Corresponding Organization: LAO-MA036 / Dana-Farber – Harvard Cancer Center LAO 
 
Principal Investigator: 
Nora Bennani, M.D. 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Telephone: (507) 284-2511 
Email: bennani.nora@mayo.edu 
 
Co-Investigators: 
Stephen Ansell, M.D., Ph.D. 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Telephone: (507) 284-2511 
 
Email: ansell.stephen@mayo.edu 
 
 
Grzegorz S. Nowakowski, M.D. 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Telephone: (507) 284-2511 
 
Email: Nowakowski.Grzegorz@mayo.edu 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
 
 
 


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Statistician 
 
Project Manager  
Pamela Atherton, M.S. 
Katie Gano 
Mayo Clinic  
Mayo Clinic 
Telephone: (507) 284-0660 
Telephone (480) 342-6082 
Email: atherton.pamela@mayo.edu 
 
 
Email: gano.katherine@mayo.edu 
 
ClinicalTrials.gov identifier: NCT03484819 
 
NCI-Supplied Agent(s):   
 
Copanlisib (NSC 784727) 
Nivolumab (NSC 748726)  
 
IND Sponsor: DCTD, NCI.   
 
Protocol Type / Version # / Version Date: 
 
Original / Version 1 / January 31, 2018 
Revision / Version 2 / April 30, 2018 
Revision / Version 3 / June 7, 2018 
Revision / Version 4 / July 17, 2018 
Revision / Version 5 / September 11, 2018 
Revision / Version 6 / September 24, 2018 
Revision / Version 7 / October 12, 2018 
Amendment 1 / Version 8 / February 7, 2019 
Amendment 2 / Version 9/ March 29, 2019  
Amendment 3 / Version 10 / August 5, 2019 
Amendment 4 / Version 11 / August 3, 2020 
Amendment 5 / Version 12 / September 7, 2020 
Amendment 6 / Version 13 / February 16, 2021 
Amendment 7 / Version 14 / July 13, 2021 
 
*Protocol types:  Original, Revision, or Amendment 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Cycle length = 28 days 
 
2. Copanlisib is to be administered prior to Nivolumab 
 
Registration 
 
Treatment1, 2 
 
Cycles 1-8:  
Copanlisib: Days 1, 8 and 15 of each cycle  
Nivolumab: Days 1 and 15 of each cycle at 240mg flat dose  
Cycle 9 onwards: 
Copanlisib: Days 1and 15 of each cycle  
Nivolumab (N) will be given IV day 1 only starting at 480 mg flat dose 
Continue until 
A maximum of 2 years or disease progression, unacceptable adverse events or 
patient refusal 


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TABLE OF CONTENTS 
SCHEMA 
......................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objective ....................................................................................................7 
1.2 
Secondary Objectives ...............................................................................................7 
1.3 
Correlative Study Objectives ...................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
DLBCL and PMBCL ...............................................................................................7 
2.2 
CTEP IND Agents .................................................................................................11 
2.3 
Rationale for Combination .....................................................................................15 
3. 
PATIENT SELECTION ....................................................................................................16 
3.1 
Eligibility Criteria ..................................................................................................16 
3.2 
Exclusion Criteria ..................................................................................................18 
3.3 
Inclusion of Women and Minorities ......................................................................21 
4. 
REGISTRATION PROCEDURES ...................................................................................21 
4.1 
Investigator and Research Associate Registration with CTEP ..............................21 
4.2 
Site Registration .....................................................................................................22 
4.3 
General Guidelines .................................................................................................25 
5. 
TREATMENT PLAN ........................................................................................................27 
5.1 
Agent Administration .............................................................................................27 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................31 
5.3 
Duration of Therapy ...............................................................................................32 
5.4 
Duration of Follow Up ...........................................................................................33 
6. 
Dosing Delays/Dose Modifications for Copanlisib and Nivolumab .................................33 
6.1 
Dose Modification rules for transient post-infusion hyperglycemia .....................43 
6.2 
Treatment of blood pressure increases associated with copanlisib ........................43 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................44 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............44 
7.2 
Adverse Event Characteristics ...............................................................................53 
7.3 
Routine Adverse Event Reporting .........................................................................57 
7.4 
Pregnancy ...............................................................................................................57 
7.5 
Secondary Malignancy ...........................................................................................57 
7.6 
Second Malignancy ................................................................................................58 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................58 
8.1 
CTEP IND Agent(s) ...............................................................................................58 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................63 


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9.1 
Biomarker Plan ......................................................................................................63 
9.2 
Integrated Correlative Studies ................................................................................68 
9.3 
Exploratory/Ancillary Correlative Studies ............................................................72 
10. 
STUDY CALENDAR .......................................................................................................77 
11. 
MEASUREMENT OF EFFECT........................................................................................79 
11.1 
Antitumor Effect – Hematologic Tumors ..............................................................79 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................84 
12.1 
Study Oversight .....................................................................................................84 
12.2 
Data Reporting .......................................................................................................85 
12.3 
CTEP Multicenter Guidelines ................................................................................87 
12.4 
Collaborative Agreements Language .....................................................................87 
12.5 
Genomic Data Sharing Plan ...................................................................................88 
12.6 
Incidental/Secondary Findings Disclosure Procedure ...........................................88 
13. 
STATISTICAL CONSIDERATIONS...............................................................................89 
13.1 
Study Design/Endpoints: .......................................................................................89 
13.2 
Sample Size/Accrual Rate ......................................................................................91 
13.3 
Inclusion of Women and Minorities ......................................................................92 
13.4 
Grouping Factors ...................................................................................................93 
13.5 
Evaluation of Response ..........................................................................................93 
13.6 
Evaluation of Toxicity: ..........................................................................................94 
13.7 
Results Reporting on ClinicalTrials.gov: ...............................................................95 
REFERENCES 
....................................................................................................................96 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................100 
APPENDIX B: Patient clinical trial wallet card ..........................................................................101 
APPENDIX C 
MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, 
AND SKIN ADVERSE EVENTS ...................................................................................102 
APPENDIX D 
MANAGEMENT OF TRANSIENT GLUCOSE INCREASE ON THE 
DAY OF COPANLISIB INFUSION ...............................................................................109 
APPENDIX E 
MANAGEMENT OF TRANSIENT GLUCOSE INCREASE ON 
SUBSEQUENT DAYS FOLLOWING COPANLISIB INFUSION ...............................110 
APPENDIX F 
DOSE MODIFICATION OF COPANLISIB FOR ARTERIAL 
HYPERTENSION ...........................................................................................................111 
APPENDIX G 
BIOASSAY TEMPLATES .....................................................................112 


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Appendix H: Shipping Manifest for Lymph3Cx Cell-of-Origin (COO) molecular subtyping assay 
 
..................................................................................................................117 
Appendix I: Blood Collection Kit Mayo Clinic Lymphoma Laboratory ....................................119 
 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objective 
 
1.1.1 To assess overall response rate (ORR) defined as complete response rate (CR) plus 
partial response rate (PR) (ORR = CR + PR) of the combination of copanlisib and 
nivolumab in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) 
and primary mediastinal large B-cell lymphoma (PMBCL). 
 
1.2 
Secondary Objectives 
 
1.2.1 To evaluate the safety of the combination of nivolumab and copanlisib in patients with 
relapsed/refractory DLBCL and PMBCL. 
 
1.2.2 To determine the progression free survival, duration of response, complete response rate 
and overall survival of the combination of copanlisib and nivolumab in patients with 
relapsed or refractory DLBCL and PMBCL. 
 
1.3 
Correlative Study Objectives   
 
1.3.1 To characterize the effects of the copanlisib and nivolumab combination regimen on 
tumor cells, tumor microenvironment and the immune response in relapsed/refractory 
DLBCL and PMBCL. 
 
1.3.2 To assess predictors of response of the combination in relapsed/refractory DLBCL and 
PMBCL. 
 
 
2. BACKGROUND 
 
2.1 
DLBCL and PMBCL 
 
Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative 
malignancies with differing patterns of behavior and responses to treatment.  The 
prognosis depends on the histologic type, stage, and response to therapy.  The NHLs can 
be divided into two prognostic groups: the indolent lymphomas and the aggressive 
lymphomas.  In Western populations, the majority of NHL (~85%) are of B-cell origin. 
NHL is a significant medical problem.  Last year, the American Cancer Society estimated 
that 71,850 persons were diagnosed with NHL, and despite recent advances in therapy, 
19,790 died from this disease (Siegel et al. 2016).  Diffuse large B-cell lymphoma 
(DLBCL) in itself is recognized to be an aggressive B-cell NHL, often presents clinically 
in a more symptomatic manner than indolent lymphoma, but a considerable number of 
these patients can be cured using intensive combination chemotherapy regimens.  The 
standard treatment for patients with aggressive lymphoma who do not obtain a complete 
response with frontline treatment —or for those who relapse — is intensive salvage 


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chemotherapy followed by autologous stem cell transplant (ASCT).  Not all patients are 
suitable candidates for this aggressive treatment option.  In addition, relapsed or 
progressive disease after auto-SCT occurs in more than 50% of patients with NHL (Philip 
et al. 1995); for these patients, prognosis is poor, with a median overall survival of 7 to 
11 months (Paltiel et al. 2003).  Currently there is no consensus treatment for patients 
who have relapsed or refractory disease after auto-SCT.  
DLBCL is comprised of two major molecular subtypes: germinal center B cell-like 
(GCB) DLBCL and activated B cell-like (ABC) DLBCL (Alizadeh et al. 2000).  All 
DLBCL lymphomas express the BCR on their cell surface and ABC DLBCLs rely on B-
cell receptor (BCR) signaling for their survival.  Downstream of the BCR are critical 
transducers that regulate DLBCL pathogenesis.  These include proximal BCR signaling 
effectors SYK, BTK, BLNK, PLCγ2, PI3Kδ and PKCβ.  The pathways downstream of 
the BCR include the PI3K-AKT-mTOR signaling pathway, which provides a direct 
conduit from diverse stimuli, including cell surface receptors and metabolic changes 
within the cell, to downstream pathways affecting cellular growth, size, survival and 
angiogenesis (Yuan and Cantley 2008). Therefore, the targeting of the PI3K-AKT-mTOR 
has strong rationale. 
Primary mediastinal B-cell lymphoma (PMBCL), originally described in the 1980s, 
accounts for up to 10% of DLBCL.  It is epidemiologically, clinically, and biologically 
distinct from the other subtypes of DLBCL (GCB].  Similar to nodular sclerosing 
Hodgkin lymphoma arising in the mediastinum, it is likely derived from a thymic B cell 
and typically presents in adolescents and young adults with an anterior mediastinal mass, 
which may invade local structures.  Studies of gene expression profiling demonstrate a 
significant overlap between PMBCL and nodular sclerosing Hodgkin lymphoma.  In fact, 
PMBCL shares a third of its genes with NSHL (Rosenwald et al. 2003).  Among the most 
common genetic alterations in PMBCL are abnormalities on chromosome 9p (up to 75%) 
and 2p (approximately 50%).  Although these abnormalities have been described in 
NSHL, they are typically not found in the other DLBCL subtypes.  The 9p region 
encodes Janus kinase 2 (JAK2), which then activates the transcription factor signal 
transducer and activator of transcription (STAT) 6 through phosphorylation (Rosenwald 
et al. 2003).  Also, in the 9p region, programmed death ligands (PD-L) 1 and 2 are 
rearranged at a frequency of 20% (Twa et al. 2014), which higher than what is seen in 
other subtypes of DLBCL.  
The optimal therapeutic approach to PMBCL is controversial, with a paucity of 
prospective studies.  PMBCL is frequently treated like other DLBCL subtypes.  The cure 
rate for progressive or recurrent disease after primary therapy is low.  Across the disease 
spectrum, relapsed/refractory NHL continues to represent an unmet medical need.  Given 
the few treatment options available for patients with relapsed or refractory lymphoma, 
novel therapies providing clinical benefit are needed.  Treatment with conventional 
cytotoxic chemotherapy results in promising responses, however a great majority of 
subjects relapse due to emergence of molecularly resistant clones.  Evasion of the host 
immune responses is an important mechanism for inducing resistance to cancer therapy 
(Schreiber et al. 2011).  Over the last several years, drug development in oncology has 
seen the emergence of immune therapies.  Strategies to block molecular and cellular 
mediators of cancer induced immunosuppression such as Cytotoxic T-Lymphocyte 


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Antigen 4 (CTLA4, CD152), Programmed Death -1 receptor (PD-1, CD279) or T 
regulatory cells (T reg) have been explored both in solid and hematologic malignancies 
with some success.  
 
Tumor cells up regulate expression of the immune check point receptors (ICR) such as 
CTLA4, PD-1 and the ligands (PD-L1, B7-H1/CD274) ICR which effectively attenuates 
the T-cell proliferation and anti-tumor effects.  While the necessary machinery for an 
effective antitumor immune response is present in lymphoma patients, the immune 
response appears ineffective and most lymphomas escape immune surveillance and 
progress.  In prior work (Wilcox et al. 2009a; Wilcox et al. 2009b; Yang et al. 2012; 
Yang et al. 2006), we have shown that the tumor microenvironment is highly 
immunosuppressive due to the presence of regulatory T (Treg) cells, suppressive 
monocytes and immunosuppressive cytokines.  Furthermore, we have found that PD-
L1/PD-1 signaling is a dominant mechanism accounting for immune suppression present 
in the tumor microenvironment (see Figure 1) (Wilcox et al. 2009a; Yang et al. 2012).  
PD-1 immune check point inhibition has been shown to result in up regulation of genes 
associated with effector, NK cell function and cytolytic effects (Keir et al. 2008).  The 
cardinal biological effects of PD-1 immune check point inhibition are manifested by 
reversal of exhaustive CD8+T cells, averting depletion of memory B cells, depleting 
Foxp3+iTreg cells and restoring robust Th1 immunity (Keir et al. 2008).  Targeting PD-
1immune check points has the potential to play a major role in cancer therapy by 
reversing tumor immune escape. 


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Figure 1: DC-associated PD-L1 
promotes the induction of FoxP3+ 
regulatory T cells. (A-B) Purified CD4+ 
T cells were depleted of CD25hi natural 
Tregs and cultured alone or with normal 
donor monocyte-derived iDCs in 
triplicate for 6 days. TGF-β (25 ng/mL) 
was included in the cultures shown in 
panel A or as indicated. Either an 
isotype control or blocking anti–PD-L1 
(4 μg/mL) antibody was included. The 
frequency of CD25hiFoxP3+ cells was 
determined by flow cytometry. 
Representative dot plots are shown in 
panel A. Data shown are representative 
of at least 3 similarly performed 
experiments. (C-D) 
Immunohistochemical staining for both 
PD-L1 and FoxP3 was performed on 
paraffin-embedded PTCL biopsy 
specimens (n = 48; in triplicate). PD-L1 
and FoxP3 staining from multiple areas 
of the same biopsy specimen are 
shown in panel C. (Inset) Original 
magnification ×200. (D) FoxP3+ cells in 
each high-power field (± 95% 
confidence interval is shown) were 
counted and DC staining for PD-L1 
determined. For the purpose of our 
analysis, core biopsy specimens were 
considered PD-L1+ if any portion of the 
specimen contained PD-L1+ DCs. 


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2.2 
CTEP IND Agents 
 
2.2.1 Nivolumab 
Nivolumab is a fully human, IgG4(ⱪ) isotype mAb that binds PD-1 on activated immune 
cells and disrupts engagement of the receptor with its ligands PD-L1(B7-H1/CD274) and 
PD-L2 (B7-DC/CD273), abrogating the inhibitory signals and augmenting host antitumor 
immune response (Keir et al. 2008).  Nivolumab has demonstrated efficacy in solid and 
hematological malignancies (Ansell et al. 2015; Brahmer et al. 2012).  In early phase 
trials in hematologic malignancies, both nivolumab and pembrolizumab were found to be 
well tolerated and demonstrated clinical responses in various disease histologies.  In 
Hodgkin lymphoma patients, both agents were highly effective with very durable 
responses (Ansell et al. 2015). In the nivolumab trial, an analysis of the responses seen in 
patients with other histological subtypes of lymphoma also showed clinically promising 
results (Lesokhin et al. 2014).  While not quite as impressive as the results seen in the 
Hodgkin cohort, an overall response rate (ORR) in follicular lymphoma of 40% was seen.  
In patients with diffuse large B-cell lymphoma, 36% of patients responded to treatment.  
Though recent unpublished data from a phase 2 trial suggests a much lower ORR in 
DLBCL, in the low teens. A phase 1b multi-cohort trial in heavily pre-treated 
relapsed/refractory PMBCL using pembrolizumab showed that it was safe and active in 
these patients, with an ORR of 41% (7/17) (Zinzani et al. 2017); with a median follow-up 
of 11.3 months, median duration of response (DOR) was not reached. 
 
2.2.1.1 
Nivolumab pharmacokinetics were assessed using a population PK approach, over a 
dose range of 0.1 to 20 mg/kg administered as a single dose or multiple doses as a 60-
minute intravenous infusion every 2 or 3 weeks.  Nivolumab clearance decreases over 
time, with a mean maximal reduction (% coefficient of variation [CV%]) from 
baseline values of approximately 24.5% (47.6%) resulting in a geometric mean steady 
state clearance (CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in CLss is not 
considered clinically relevant. The geometric mean volume of distribution at steady 
state (Vss) (CV%) is 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 
25 days (77.5%). Steady-state concentrations of nivolumab were reached by 
approximately 12 weeks whenadministered at 3 mg/kg every 2 weeks, and systemic 
accumulation was approximately 3.7-fold. The exposure to nivolumab increases dose 
proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. 
The predicted exposure of nivolumab after a 30-minute infusion is comparable to that 
observed with a 60-minute infusion.  Based on dose/exposure efficacy and safety 
relationships, there are no clinically significant differences in safety and efficacy 
between a nivolumab dose of 240 mg or 3 mg/kg every 2 weeks in patients with 
melanoma, NSCLC, RCC, urothelial carcinoma, MSI-H CRC, and HCC The 
population PK analysis suggested that the following factors had no clinically 
important effect on the clearance of nivolumab: age weight, gender, race, baseline 
LDH, PD-L1 expression, solid tumor type, tumor size, renal impairment, and mild 
hepatic impairment. 
 


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2.2.1.2 
Rationale for Modification of the Dosage of Nivolumab After 8 Cycles 
 
Data obtained from manufacturer (Bristol-Myers Squibb) indicates that nivolumab 
administered as 480 mg Q4W over 30-minutes is expected to offer the same clinical 
benefit as 3 mg/kg Q2W in subjects with melanoma, squamous non-small cell lung 
cancer (SQ NSCLC), non-squamous NSCLC (NSQ, NSCLC), renal cell carcinoma 
(RCC), squamous cell carcinoma of the head and neck (SCCHN), urothelial carcinoma 
(UC), and classical Hodgkin’s lymphoma (cHL).  This information is based upon data 
gathered in the course of the extensive nivolumab development program across multiple 
tumor types as well as robust clinical pharmacology and quantitative systems 
pharmacology (QSP) analyses. 
 
The proposed dose modification is based on the comprehensive understanding of 
nivolumab pharmacology and mechanism of action taken together with the following 
data and analyses: 
 
• Comparison of nivolumab exposures achieved by 240 mg Q2W, 480 mg Q4W and 3 
mg/kg Q2W in subjects with melanoma, NSCLC, RCC, SCCHN, cHL, and UC 
 
• Efficacy bridging evaluation 
o Comparison of the efficacy of nivolumab 3 mg/kg Q2W, 240 mg Q2W, and 
480 mg Q4W in melanoma, NSCLC, and RCC with respect to the following 
endpoints: overall survival(OS), objective response (OR) 
o Comparison of predicted receptor occupancy (RO) with nivolumab 3 mg/kg 
Q2W, 240 mg Q2W, and 480 mg Q4W, including sensitivity of RO to 
parameters that may vary across solid tumor types 
 
• Safety bridging evaluation 
o Assessment of safety margins, by comparison of predicted exposures with 240 
mg Q2W and 480 mg Q4W relative to the well-tolerated 10 mg/kg Q2W 
regimen 
o Comparison of the safety of nivolumab 3 mg/kg Q2W, 240 mg Q2W, and 480 
mg Q4W in subjects with melanoma, SQ and NSQ NSCLC, RCC, SCCHN, 
cHL, and UC with respect to the following 3 endpoints: Adverse events 
leading to discontinuation or death (AEDC/D), Grade 3+ adverse events (AE-
Grade 3+), and Grade 2+ immune-mediated adverse events (AE-IM Grade 2+) 
o Clinical safety data from subjects treated with nivolumab 480 mg Q4W 
administered over a 30-minute infusion 
 
The exposure-response efficacy analysis between the 3 mg/kg Q2W and the 480 mg 
Q4W regimens demonstrated that the hazard ratios for survival with the 480 mg Q4W 
regimen are very similar to the 3 mg/kg Q2W regimen, resulting in a similar hazard ratio 
relative to the standard of care treatment studied in each respective phase 3 clinical trial. 
In addition, these analyses indicated that similar outcomes would be achieved when using 
an early efficacy measure of response rate (objective response; OR) as well.  The 
exposure-efficacy response trends were consistent across different tumor types with 


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varying tumor immunogenicity and mutational burdens.  Hence, in cases where 
nivolumab 3 mg/kg Q2W has been proven to be superior to standard of care, nivolumab 
480 mg Q4W is predicted to provide comparable benefit, irrespective of tumor type. 
 
This position is further supported by results of the analysis using a mechanistic 
quantitative systems pharmacology model incorporating transport to site of action, 
binding kinetics and varied physiological factors representing highly perfused or stromal 
tumors.  The median intratumoral RO predicted with this model is high for nivolumab 3 
mg/kg Q2W, 240 mg Q2W and 480 mg Q4W trough levels over a range of possible 
physiological parameter values.  It is postulated that high RO at the tumor site will 
initiate the immuno-stimulatory cascade resulting in similar efficacy with 3 mg/kg Q2W, 
240 mgQ2W, and 480 mg Q4W regimens. 
 
Safety bridging was conducted using robust clinical data for the 10 mg/kg Q2W regimen 
that had a similar safety profile to the 3 mg/kg Q2W regimen.  The nivolumab exposure 
parameters, including Cmax, resulting from 480 mg Q4W were well below Cmaxss 
values achieved with 10 mg/kg, providing a robust exposure safety margin. In addition, 
there were negligible differences in the probabilities of experiencing an adverse event 
irrespective of severity or adverse event type.  Moreover, key safety results from the 
interim safety analysis of CA209511 (Part 2) demonstrate that the safety profile of 
nivolumab 480 mg IV over 30 minutes Q4W is consistent with the established safety 
profile of nivolumab (240 mg Q2W or 3 mg/kg Q2W administered IV over 60 minutes) 
across multiple indications and Summary of Product Characteristics [SmPC].  Taken 
together, these findings indicated that the safety profile of nivolumab is expected to be 
unaltered by the proposed dosing regimen changes. 
 
Based on extensive quantitative clinical pharmacology analyses and safety analyses 
summarized in this submission, the nivolumab 480 mg Q4W regimen administered over 
30 minutes is predicted to have similar efficacy and safety profiles to those established 
with the 3 mg/kg Q2W dosing regimen administered over 60 minutes. Thus, the provided 
analyses support the proposed nivolumab dosing regimen of 480 mg Q4W administered 
over 30 minutes as a convenient treatment option. 
 
Based on this information the dosage of Nivolumab will be 240 mg IV every 2 weeks for 
the first 8 cycles on the study.  After 8 cycles, Nivolumab will be administered at the 
dose of 480 mg IV every 4 weeks. Both dosage strengths will be infused over 30 minutes. 
 
2.2.2 Copanlisib (BAY 80-6946) 
 
The B-cell receptor (BCR) signaling pathway is critical for the development, 
proliferation, and survival of malignant B-cells.  Drugs targeting BCR pathway kinases, 
including the Bruton’s tyrosine kinase inhibitor ibrutinib [2] and the phosphatidylinositol 
3-kinase (PI3K)-δ isoform inhibitor idelalisib [3], have proven to be effective treatment 
options in patients who have relapsed or are refractory to standard therapy.  However, 
fatal and/or serious toxicities have been associated with idelalisib use [3, 4] and, recently, 


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frequent serious adverse events, including hepatic and gastrointestinal toxicity, colitis, 
opportunistic infections, autoimmune toxicities, and pneumonitis, have raised safety 
concerns around idelalisib in combination with standard therapies [5–7].  Therefore, new 
approaches, such as dual inhibition of PI3K-δ and PI3K-α, are necessary to both mitigate 
toxicity issues and improve efficacy [8–10]. 
Copanlisib (BAY 80-6946; Bayer AG, Berlin, Germany) is an intravenous pan-class I 
PI3K inhibitor with predominant activity against the PI3K-α and PI3K-δ isoform (Liu et 
al. 2013).  A first-inhuman phase 1 study established the maximum tolerated dose of 
copanlisib as 0.8 mg/kg administered on days 1, 8, and 15 of a 28-day cycle (Patnaik et 
al. 2016).  In an expansion cohort including NHL patients, severe toxicities were low and 
there were early signs of efficacy, including complete response (CR) or partial response 
(PR) in all six patients with relapsed or refractory follicular lymphoma, and one of three 
patients with DLBCL (Patnaik et al. 2016).  A phase 2 study of copanlisib conducted in 
indolent and aggressive lymphomas (Dreyling et al. 2017), the ORR was 43.7% (14/32) 
in the indolent cohort and 27.1% (13/48) in the aggressive cohort including mantle cell 
lymphoma, Peripheral T-cell lymphoma and DLBCL; median progression-free survival 
(PFS) was 70 days (range, 0–897) in the aggressive cohort with a median DOR of 166 
days (range, 0–786).  In the 15 patient with DLBCL out of  a total of 34 patients with 
aggressive lymphomas, only 1 PR was seen with an ORR of 6.7%, Common adverse 
events included hyperglycemia (57.1%; grade ≥ 3, 23.8%), hypertension (54.8%; grade ≥ 
3, 40.5%), and diarrhea (40.5%; grade ≥ 3, 4.8%), all generally manageable. Neutropenia 
occurred in 28.6% of patients (grade 4, 11.9%) (Dreyling et al. 2017). In a phase 2 study 
of 40 patients with relapsed/refractory DLBCL after 1 or more lines of therapy, the ORR 
was 25%. Higher responses were seen in the ABC subtype (37.5%) as compared to the 
GCB subgroup (13.6%) (Lenz et al. 2017). To date, there is no data with copanlisib in 
PMBCL.    
Copanlisib Pharmacokinetics:  
Copanlisib demonstrated dose-proportional increases in the plasma exposures (Cmax and 
[AUC(0 25)] over the dose range of 0.1 to 1.2 mg/kg (absolute dose range: 5 to 93 mg) 
with a terminal elimination half-life of 39.1 h. There is no time-dependency and no 
accumulation in the pharmacokinetics of copanlisib. The recommended (Phase 2) and 
approved dose of monotherapy copanlisib is 60 mg given i.v. as a one hour IV infusion 
on an intermittent weekly schedule on days 1, 8 and 15 in a 3 weeks on/1 week off 
schedule.  
Copanlisib is eliminated predominantly via feces (64%; unchanged 30%) compared to 
urine (22%; unchanged 15%). Population pharmacokinetic analyses showed that age, 
gender, race, smoking status, body weight, mild hepatic impairment, and mild to 
moderate renal impairment had no clinically significant effect on the pharmacokinetics of 
copanlisib and therefore no dose recommendation is needed for these specific 
populations. Based on the preliminary categorical analyses and the central tendency, 
copanlisib does not prolong the QT/QTc interval. 
 
Copanlisib metabolism is primarily mediated by CYP3A (>90%) with minor contribution 


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of CYP1A1 (<10%).  Concomitant use of copanlisib with strong cytochrome P450 3A 
(CYP3A) inducers may decrease copanlisib AUC and should be avoided. Concomitant 
use of copanlisib with strong CYP3A inhibitors increases copanlisib AUC and a dosage 
reduction to 45 mg is advised if patients required strong inhibitors. Copanlisib has low 
risk for clinical drug-drug interactions of concomitant drug products through inhibition or 
induction of CYP enzymes, inhibition of uridine diphosphate glucuronosyltransferase 
(UGT) enzymes. Copanlisib is not an inhibitor of P-gp, BCRP, multi-drug resistance-
associated protein (MRP2), bile salt export pump (BSEP), OATP1B1, OATP1B3, OAT 
1, OAT3, OCT1, OCT2, and MATE1 at therapeutic 60 mg dose plasma concentrations. 
Copanlisib is an inhibitor of MATE2-K at therapeutic 60 mg dose plasma concentrations. 
Further details can be found in the latest available version of the investigator's brochure 
(2017), Which contains comprehensive information on the study drug and the United 
States Package Insert (USPI). 
 
2.3 
 Rationale for Combination 
 
In a preclinical mouse model, p110δ inactivation in regulatory T cells (Treg) unleashes 
CD8+ cytotoxic T cells and induces tumor regression (Ali et al. 2014).  Thus, p110δ 
inhibitors can break tumor-induced immune tolerance.  In the A20 DLBCL syngeneic 
mouse model with tumor intrinsic regulation of the immunosuppressive environment, 
treatment with copanlisib resulted in effective down regulation of tumor‐infiltrating Tregs 
and an increase of INFg+ CD44+ cells in tumors (Liu 2017).  PR were observed in 75% 
of mice treated with copanlisib in combination with a surrogate anti‐mouse PD‐1 (aPD‐1, 
BioXCell) compared to 0% PR in the monotherapy groups.  These data support the 
rational for the combination of copanlisib and nivolumab in DLBCL. 
 
 
 
 
 


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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have a histopathologically confirmed diagnosis of diffuse large B-cell 
lymphoma (DBLCL) or primary mediastinal large B-cell lymphoma. 
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that is ≥ 15 mm (≥ 
1.5 cm) in the longest axis on cross-sectional imaging and measurable in two 
perpendicular dimensions per spiral CT scan or PET-CT scan.   
 
3.1.3 Patients must have disease that is recurrent or refractory to standard therapy.    Patients 
must have failed front-line therapy and declined or are not candidates for autologous stem 
cell transplant (ASCT) or have failed prior ASCT. 
 
3.1.4 Age ≥ 18 years. 
Because no dosing or adverse event data are currently available on the use of copanlisib 
and nivolumab combination in patients <18 years of age, children are excluded from this 
study, but will be eligible for future pediatric trials. However, if pediatric colleagues and 
centers are interested in including patients ages 12 to 18 in this trial, this trial then could 
be available to this group of patients. 
 
3.1.5 ECOG performance status of 0, 1 or 2 (See Appendix A). 
 
3.1.6 Life expectancy of greater than 12 weeks 
 
3.1.7 Patients must have normal organ and marrow function as defined below: 
 
− 
White blood cell (WBC) ≥ 2000/mm3 
− 
Absolute neutrophil count (ANC) ≥ 1000/mm3 
− 
Platelet count  100,000/mm3 
− 
Hemoglobin > 9.0 g/dL 
− 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except patients with Gilbert 
Syndrome, who can have total bilirubin < 3.0 mg/dL) 
− 
Aspartate transaminase (AST)  2.5 x ULN 
− 
Serum creatinine ≤ 2.0 mg/dL  
OR 
− 
Calculated creatinine clearance (CrCl) ≥ 30 mL/min (if using the Cockcroft-Gault 
formula below): 
 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/dL 
Male CrCl = (140 - age in years) x weight in kg   
72 x serum creatinine in mg/dL  
 
 


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3.1.8 Negative urine or serum pregnancy test for females of child bearing potential within 7 
days prior to registration. 
 
The effects of copanlisib and nivolumab on the developing human fetus are unknown.  
For this reason, and because the study drugs used in this trial are known to be teratogenic, 
females of child-bearing potential must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry, for the duration of study 
participation and for 5 months after the last dose of study drug.  Males who are the sexual 
partners of a female of child-bearing potential must use any contraceptive method with a 
failure rate of less than 1% per year for the duration of study participation and for a 
period of 7 months after the last dose of study drug.  These periods of required use of 
contraception have been calculated using the upper limit of the half-life for nivolumab 
(25 days) and are based on the protocol requirement that females of child-bearing 
potential use contraception for 5 months and males who are the sexual partners of 
females of child-bearing potential use contraception for 7 months. 
 
Females must not breast-feeding for 1 month after last dose. 
 
Females of child bearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the 
start of nivolumab. 
 
A female of child-bearing potential is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) or who is not postmenopausal.  Menopause is defined clinically as 12 
months of amenorrhea in a female over 45 in the absence of other biological or 
physiological causes.  In addition, females under the age of 55 must have a documented 
serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.   
 
 Females who are not of childbearing potential (i.e., who are postmenopausal or 
surgically sterile) and azoospermic males do not require contraception.   
 
Should a female of child-bearing potential become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she (or the participating partner) 
should inform the treating physician immediately. 
 
3.1.9  Ability to understand and the willingness to sign a written informed consent document.  
 
 


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3.2 
Exclusion Criteria 
 
3.2.1 Any high grade B-cell lymphoma 
 
3.2.2 Patients who have had chemotherapy within 2 weeks (6 weeks for nitrosoureas or 
mitomycin C), anticancer antibodies within 4 weeks, radio or toxin immunoconjugates 
within 2 weeks, radiation therapy within 3 weeks or major surgery within 2 weeks prior 
to entering the study. 
 
Palliative (limited-field) radiation therapy is permitted if the patient has additional 
measurable lesions to assess response of therapy.  
 
3.2.3 Patients who have not recovered to grade 1 or less from any adverse events due to agents 
administered more than 4 weeks earlier (excluding alopecia).  
 
3.2.4 Patients who are receiving any other investigational agents. 
 
3.2.5 Patients should be excluded if they have had prior treatment with a Pi3 kinase inhibitor, 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug 
specifically targeting T-cell co-stimulation or immune checkpoint pathways. Note:  
Patients who previously received CART therapy and progressed will be eligible.   
 
3.2.6 Patients who have received autologous stem cell transplant (ASCT) ≤ 8 weeks prior to 
the first dose of study drug or no adequate count recovery. 
 
3.2.7 Patients with a prior history of allogeneic stem cell or solid organ transplantation. 
 
3.2.8 Patients with evidence of active disease in the central nervous system (CNS) defined as 
either the presence of active lesions on MRI obtained within 4 weeks of registration or 
progressive neurological decline.  
 
Patients with primary CNS lymphoma who develop systemic recurrence following 
standard therapy may be included as long as no active CNS disease is present at the time 
or enrollment. Similarly, patients with secondary involvement of the CNS from a 
systemic lymphoma may be included as long as the CNS disease has been optimally 
treated and they demonstrate no evidence of active CNS disease. 
 
 
3.2.9 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to copanlisib and/or nivolumab. 
 
3.2.10 History of severe hypersensitivity reaction to any monoclonal antibody. 
 


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3.2.11 Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study or 
interfere significantly with the proper assessment of safety and toxicity of the prescribed 
regimens. 
 
3.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
non-healing wound or ulcer, or bone fracture, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, known history of atrial fibrillation except 
those with 1 event that has resolved more than 1 year ago without recurrence, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.13 Pregnant women are excluded from this study because copanlisib and nivolumab are 
agents with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with copanlisib or nivolumab, breastfeeding should be discontinued for 1 
month after last dose if the mother is treated with copanlisib or nivolumab.   
 
3.2.14 Patients with human immunodeficiency virus (HIV):   
Patients with human immunodeficiency virus (HIV) are eligible for the study provided 
they meet the other protocol criteria in addition to the following:  
− 
Undetectable HIV load by standard PCR clinical assay 
− 
Absolute CD4 count of ≥ 200 mm3 
− 
Willing to maintain adherence to combination antiretroviral therapy 
− 
No history of AIDS defining condition (other than lymphoma or CD4 cell count < 
200 mm3) 
− 
Likely to have near normal lifespan if not for the presence of relapsed/refractory 
lymphoma 
 
The Patients with evidence of HBV are eligible provided there is minimal hepatic injury 
and the patient has undetectable HBV on suppressive HBV therapy.  Patient must be 
willing to maintain adherence to HBV therapy. 
 
Patients with previously treated and eradicated HCV who have minimal hepatic injury are 
eligible. 


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3.2.15 Patients with active autoimmune disease or history of autoimmune disease that might 
recur, which may affect vital organ function or require immune suppressive treatment 
including systemic corticosteroids, should be excluded.  These include but are not limited 
to patients with a history of immune related neurologic disease,  multiple sclerosis, 
autoimmune (demyelinating)  neuropathy, Guillain-Barre syndrome, myasthenia gravis; 
systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, 
inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and patients 
with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or 
phospholipid syndrome should be excluded because of the risk of recurrence or 
exacerbation of disease.  Patients with vitiligo, endocrine deficiencies including 
thyroiditis managed with replacement hormones including physiologic corticosteroids are 
eligible.  Patients with rheumatoid arthritis and other arthropathies, Sjögren’s syndrome 
and psoriasis controlled with topical medication and patients with positive serology, such 
as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the 
presence of target organ involvement and potential need for systemic treatment but 
should otherwise be eligible.  
 
3.2.16 Patients are permitted to enroll if they have vitiligo, type 1 diabetes mellitus, residual 
hypothyroidism due to autoimmune condition only requiring hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger (precipitating event). However, Patients with uncontrolled 
Type I or II diabetes mellitus will be excluded; uncontrolled diabetes is defined as HbA1c 
>8.5%. 
 
3.2.17 Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration.  Inhaled or topical steroids and 
adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease.  Patients are permitted to use topical, ocular, intra-
articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption).  
Physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 
mg/day prednisone equivalents.  A brief course of corticosteroids for prophylaxis (e.g., 
contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by contact allergen) is permitted. 
 
3.2.18 Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, 
and GI obstruction which are known risk factors for bowel perforation should be 
evaluated for the potential need for additional treatment before coming on study. 
 
3.2.19 Patients with other active malignancy ≤ 3 years prior to registration for which active 
treatment is required must be excluded.  Patients with composite lymphomas that have a 
non-B-cell component must be excluded. 
EXCEPTIONS: Non-melanotic skin cancers or carcinoma-in-situ of the cervix. 
 


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3.2.20 Copanlisib is primarily metabolized by CYP3A4.  Therefore, the concomitant use of 
strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, 
indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (e.g. rifampin, 
phenytoin, carbamazepine, phenobarbital, St. John’s Wort) are not permitted from 14 
days prior to enrollment until the end of the study.   
Note:  Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated medical reference.  APPENDIX B (Patient Drug 
Information Handout and Wallet Card) should be provided to patients.  As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product. 
Other medications that are prohibited while on copanlisib treatment:  
• Herbal medications/preparations (except for vitamins) 
• Anti-arrhythmic therapy other than beta blockers or digoxin 
For the list of specific medications prohibited while on copanlisib treatment refer to the 
APPENDIX B). 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their 
subpopulations be included in all NIH-supported biomedical and behavioral research 
projects involving NIH-defined clinical research unless a clear and compelling rationale 
and justification establishes to the satisfaction of the funding Institute & Center (IC) 
Director that inclusion is inappropriate with respect to the health of the subjects or the 
purpose of the research.  Exclusion under other circumstances must be designated by the 
Director, NIH, upon the recommendation of an IC Director based on a compelling 
rationale and justification.  Cost is not an acceptable reason for exclusion except when 
the study would duplicate data from other sources.  Women of childbearing potential 
should not be routinely excluded from participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
This study will be available to all eligible patients regardless of race or ethnic group. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators.  NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually.  To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE or acting as 
a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation 


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requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at  
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following:  
• An active Federal Wide Assurance (FWA) number 


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• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office.  For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 10193 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-MN026 
and protocol 10193. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements For  10193 Site Registration 
 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
• Site Initiation Visit 
• ETCTN Specimen Tracking Training 


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• All data entry users (Clinical Research Associate role) at each 
participating site will need to complete the Theradex-led training. 
• Theradex will provide a certificate of completion, which will need to be 
submitted to the CTSU through the Regulatory Submission Portal. 
• The training is a one-time only requirement per individual.  If an 
individual has previously completed the training for another ETCTN 
study, the training does not need to be completed again nor does the 
certificate of completion need to be resubmitted to the CTSU. However, 
new versions of the Specimen Tracking system may require new training. 
• This training will need to be completed before first/further patient 
enrollment at a given site. 
• Peter Clark and Diana Vulih are the main points of contact at Theradex for 
the training (PClark@theradex.com and DVulih@theradex.com, Theradex 
phone: 609-799-7580). 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab 
→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website. 
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status given only reflects compliance with IRB documentation and 


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institutional compliance with protocol-specific requirements as outlined by the Lead 
Network. It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their 
affiliated networks. 
Patient Registration 
 
4.2.5 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.2.6 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type.     
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and Health 
Insurance Portability and Accountability Act (HIPAA) authorization form. 
 
4.2.7 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
4.3 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 14 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 


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5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.   The study drugs will be 
administered in sequence, copanlisib must be administered before nivolumab.  Do not 
administer study drugs concurrently.  For patients receiving both drugs, the intravenous 
catheter must be flushed with 0.9% sodium chloride between the two infusions.  Pre-
medication is not needed unless a patient develops an infusion reaction. 
 
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat 
the patient's malignancy. 
 
5.1.1 Copanlisib 
 
Copanlisib is administered by the 1 hour IV infusion weekly for 3 weeks (days 1, 8, and 
15) of each 28-day cycle.  Copanlisib dose will be determined using a safety cohort in 6 
patients with Copanlisib 60 mg weekly days 1,8,15 with Nivolumab 240 mg IV on days 1 
and 15 each cycle.  Copanlisib could be reduced to 45 mg if toxicity was observed with 
the combination, and the safety cohort will be re-evaluated  (Investigator’s Brochure, 
2016).  Cycle 9 and beyond treatment will be given as follows:  Copanlisib: Days 1and 
15 of each cycle Nivolumab (N) will be given IV day 1 only starting at 480 mg flat dose. 
 
Cycle 1, Day 1 (C1D1) 
The following assessments should be performed on Cycle 1, Day 1 before receiving study 
treatment unless otherwise specified. 
• On Cycle 1 Day 1, patients are not required to be fasting prior to the pre-dose 
glucose measurement.   
 
• Glucose will be measured at pre-dose and post dose 1 hour and 2 hours after the 
end of copanlisib infusion, (window of  10 min is allowed except for the pre-
dose measurement). Additional measurements to be performed at the clinic as 
clinically indicated.  
 
NOTE: If patient needs to take a meal, then glucose test should be take prior to meal 
intake. 
 
Subsequent visits after C1D1 visit 
 
Fasting is not required prior to pre-dose glucose measurement. 
 


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• Glucose will be measured at pre-dose and post dose 1 hour after the end of 
copanlisib infusion (window of  10 min is allowed except for the pre-dose 
measurement). Additional measurements to be performed at the clinic as 
clinically indicated.  
 
• Review of the blood glucose measurements/meal timing/insulin 
administration/oral glucose lowering medication, if applicable. 
• Note: If patient needs to take a meal, then glucose test should be taken prior to 
meal intake. 
 
The requirements for fasting and pre-dose glucose levels are presented in Table 5.1. 
 
Table 5.1 
Fasting requirements and pre-dose glucose levels 
Period 
Fasting ≥ 8 
h required 
before first 
glucose 
measuremen
t 
        Pre-dose glucose 
levels  
    (first glucose 
measurement) 
 
  
Day 1 of 
cycle 1 
No a 
  ≤160 mg/dL (fasting) 
  <200 mg/dL (non-
fasting) 
 
 
Subsequent 
infusions 
after 
Cycle 1 Day 
1  
 
No b 
  <160 mg/dL (fasting) 
  < 200 mg/dL (non-
fasting)  
 
 
 
 
 
a: Diabetic patients who take insulin treatment at any cycle visit:  
Timing and content of meal intake will be managed by the investigator. 
Consultation with treating physician or diabetes/endocrinologist is 
advised.  
 
b: The decision regarding meal timing and fasting can be made by the 
investigator based on glucose response patterns during prior treatment 
days  
 
• Fasting refers to a ≥ 8 h fast. 
• Non-fasting status includes any caloric intake such as meals and also juice, snacks, 
and other caloric intake not consistently called a meal. 


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From Cycle 1 Day 1 onwards, glucose measurements at the site may be done either by 
laboratory analysis or in capillary blood. 
Because of inhibitory effect on PI3K α-isoform, which is implicated in insulin 
metabolism, copanlisib infusions could be associated with temporarily increase in blood 
glucose. Addition of meal in close proximity to copanlisib infusion may exacerbate 
glucose increase.  
On infusion days, a low carbohydrate diet is recommended, the timing and content of 
caloric meal intake and additional glucose testing (if clinically indicated) is managed and 
monitored by the investigators based on glucose response patterns during prior treatment 
days.  
All glucose measurements done at the site, oral glucose lowering medication and/or 
insulin administration, if applicable, fasting/non-fasting status and meal intake timing on 
infusion days will be collected as part of the clinical source documentation. 
 
 
The use of corticosteroids as antiemetics prior to copanlisib administration is not allowed. 
After administration, flush the line with 0.9 % sodium chloride to ensure complete dose is 
given. No IV glucose preparations should be administered on the days of infusion. 
 
5.1.2 Nivolumab 
 
Nivolumab will be given intravenously at a dose of 240 mg on days 1 and 15 of each 28-
day cycle for cycles 1 through 8 and at a dose of 480 mg on day 1 of cycle 9 and all 
subsequent cycles. 
 
Nivolumab is to be administered as a 30-minute IV infusion, using a volumetric pump 
with a 0.2-1.2 micron in-line filter at the protocol-specified dose. Fixed dose (eg, 240 mg, 
360 mg, or 480 mg flat dose) nivolumab injection can be infused undiluted or diluted 
with 0.9% normal saline so as not to exceed a total infusion volume of 160 mL. It is not 
to be administered as an IV push or bolus injection. At the end of the infusion, flush the 
line with a sufficient quantity of normal saline. 
 
5.1.3 Safety Cohort 
 
No dose escalation will be utilized, but a safety run-in of 6 patients with DLBCL or 
PLBCL will be enrolled to evaluate the safety of the treatment combination.  Patients will 
be enrolled to receive 60 mg of Copanlisib and 240 mg IV of Nivolumab as per the dose 
schedule in Table 5.1.3 
 
Table 5.1.3 
 
 
 
 
 
Dose level 
Copanlisib 
Nivolumab** 
 -2 
45 mg Days 1 and 15 
240 mg IV Days 1 and 15 
-1 
60 mg Days 1 and 15 
240 mg IV Days 1 and 15 
*1 
60 mg Days 1, 8, 15 
240 mg IV  Days 1 and 15 


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*safety run-in dose level  
**480mg on day 1 only cycle 9 and beyond 
 
Copanlisib: Given IV on days 1, 8 and 15 during every 28-day cycle for cycles 1-8.  Cycle 9 and 
beyond, IV will be given on days 1 and 15 
 
Nivolumab:  All patients: 240 mg given IV on days 1 and 15 for cycles 1 through 8 followed by 
480 mg on day 1 only of all subsequent cycles thereafter 
 
5.1.3.1 Six patients will be treated at the planned dose and observed for a minimum of 28 days 
before accruing the rest of the patients.  If no DLTs are observed (as per section 5.24) the 
study will open to complete accrual.  If at least 2 of 6 patients experience a DLT, then 6 
patients will be accrued at the -1 dose level and observed for a minimum of 28 days.  If at 
least 2 of 6 patients at the -1 dose level experience a DLT, this study will cease accrual.  
If 1 or less patients experience a DLT at the -1 dose level, the study will open to complete 
accrual. If 1 or less patients experience DLTs at dose level 1, the study will open to 
complete accrual.  
 
5.1.3.3 Definitions of DLT 
 
A DLT is defined by the occurrence of any of the following toxicities (CTCAE v.5) 
within the first cycle of treatment of dose escalation cohorts, which is possibly, probably, 
or definitely related to copanlisib and/or nivolumab in order to evaluate potential toxicity 
related treatment delays or any event within the first cycle of treatment that requires 
permanent discontinuation of copanlisib, and/or nivolumab. 
 
5.1.3.3.1 Non-Hematological DLT 
 
Any Grade 3 or Grade 4 non-hematological toxicity that is possibly, probably or 
definitely attributable to the treatment regimen is considered a DLT, including the 
following: 
o Non-hematologic toxicity that causes a delay of >14 days in initiating cycle 2. 
o Any type of grade 3-4 hypersensitivity reaction (i.e.: allergic reaction, 
anaphylaxis, serum sickness, skin disorders, etc.), regardless of attribution, that 
necessitate discontinuation of study drug. 
o Any type of grade 3-4 immune related adverse event including skin reactions. 
o Grade 3 or greater colitis and bowel perforation 
o Grade 3 ALT/AST elevation or 10 x ULN 
o Grade 3-4 pneumonitis 
o Grade 4 hyperglycemia: persistent post-infusion grade 4 hyperglycemia despite 
optimal glucose lowering therapy in consultation with an endocrinologist. 
Definition of persistent occurrence is based on repeated fasting blood glucose 
measurement following treatment with copanlisib. 
 
 
5.1.3.3.2 The following events are exclusions and are NOT considered a DLT for this protocol, 


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regardless of attribution or specific type: 
o Grade 3 nausea, vomiting, diarrhea, or oral mucositis with < 3 days duration 
o Grade 3 fever 
o Grade 3 infection 
o Grade 3 peripheral sensory neuropathy that is decreased by at least one grade 
within 7 days 
o Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia 
responsive (i.e.: decreased by at least one grade) to oral supplementation within 7 
days 
o Grade 3 hypertriglyceridemia that returns to < Grade  2 prior to the beginning of 
cycle 2 
• Grade 3 hyperglycemia that returns to < Grade 2 (with or without the use of insulin or 
oral diabetic agents) prior to the beginning of cycle 2. Transient infusion-related 
hyperglycemia lasting < 7 days are also excluded. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of copanlisib and nivolumab with other 
concomitantly administered drugs, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.   
 
The Principal Investigator should be alerted if the patient is taking any agent known to 
affect or with the potential for drug interactions. The known potential targets for drug 
interaction are CYP3A4 inducers or inhibitors, as well as drugs modulating MATE2K 
function. APPENDIX B (Patient Drug Information Handout and Wallet Card) should be 
provided to patients. 
• Sensitive substrates of the renal drug transporter MATE2K (e.g. metformin) need 
to be used with caution. Metformin should be interrupted for 48 hours after 
receiving iodinated contrast media. Please see prescribing information for further 
information. 
• Patients taking medications with narrow therapeutic index should be proactively 
monitored if these medications cannot be avoided. These medications may 
include quinidine, cyclosporine, and digoxin. 
• Systemic corticosteroid therapy at a daily dose higher than 10 mg prednisone or 
equivalent is not permitted while on study. Previous corticosteroid therapy must 
be stopped or reduced to the allowed dose at least 7 days prior to the CT/MRI 
screening. If a patient is on chronic corticosteroid therapy, corticosteroids should 
be de-escalated to the maximum allowed dose before the screening. Patients may 
be using topical or inhaled corticosteroids. Short-term (up to 7 days) systemic 
corticosteroids above 10 mg prednisolone or equivalent will be allowed for the 
management of acute conditions (e.g., treatment non-infectious pneumonitis). The 
use of corticosteroids as antiemetics prior to copanlisib administration will not be 
allowed. 
• Patients should stop using herbal medications at least 7 days prior to the first dose 
of copanlisib. Herbal medications include, but are not limited to: St. John’s Wort, 


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Kava, ephedra, gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, black cohosh and ginseng. 
• Patients with NHL, particularly after several lines of therapy are at risk for 
opportunistic infections.  Patients will be monitored symptomatically very closely 
at every visit prior to each cycle. If any symptoms were to arise suggestive of an 
opportunistic infection, evaluation guided by the presenting symptom will be 
initiated immediately such as chest X-ray, CT scan of the chest and bronchoscopy 
if needed. Appropriate supportive care measures and antibiotic coverage will be 
started.  
 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for a 
maximum of 2 years or until one of the following criteria applies: 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Patient decides to withdraw from the study 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
• 
Clinical progression 
 
• 
Patient non-compliance 
 
• 
Pregnancy 
 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
• 
Termination of the study by sponsor 
 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and 
the corresponding dates must be documented in the Case Report Form (CRF). 


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5.4 
Duration of Follow Up 
 
Patients will be followed for 100 days after removal from study or until death, whichever 
occurs first.  Patients removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
 
6. Dosing Delays/Dose Modifications for Copanlisib and Nivolumab 
 
Below are dose modification tables applicable to all patients participating in this study for 
the following adverse events.   
 
Patients who develop adverse events while being treated must have one or both drugs 
held or discontinued according to the guidance provided in the tables below.   
 
Please use as written and contact the drug monitor for any proposed changes.  Note that if 
a patient experiences several adverse events and there are conflicting recommendations, 
the investigator should use the recommended treatment modification for the most serious 
event that has a higher level of modification, i.e. going off study treatment versus holding 
drug. 
 
Dose hold = study drugs must be held as indicated.  Day 1 of the next cycle is given when the 
patient meets the protocol criteria to restart drugs.  The current cycle will include all days until 
the patient resumes treatment and may be longer than 28 days. 
 
Skin Rash 
and Oral 
Lesions 
 
Management/Next Dose  
for Nivolumab 
 
Management/Next Dose  
For Copanlisib 
 
≤ Grade 1 
No change in dose * 
NA 
Grade 2 
Hold* until 1≤ Grade resolved (#).  
Resume at same dose level.  
NA 
Grade 3 
Hold* until ≤ Grade 1.  Resume at 
same level at investigator discretion  
NA 
Grade 4 
Off protocol therapy 
NA 
 
*Patients with purpuric or bullous 
lesions must be evaluated for 
vasculitis, Steven-Johnson 
syndrome, TEN, and autoimmune 
bullous disease including oral 
lesions of bullous 
pemphigus/pemphagoid.  Pruritus 
may occur with or without skin rash 
and should be treated 
symptomatically if there is no 
NA 


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Skin Rash 
and Oral 
Lesions 
 
Management/Next Dose  
for Nivolumab 
 
Management/Next Dose  
For Copanlisib 
 
associated liver or GI toxicity.  Note 
skin rash typically occurs early and 
may be followed by additional 
events particularly during steroids 
tapering.   
Recommended management:  AE management guidelines 
 
Liver 
Function 
AST, ALT, 
Bilirubin   
Management/Next Dose  
for Nivolumab 
 
Management/Next Dose  
For Copanlisib 
 
≤ Grade 1 
Hold until UNL or baseline #.   
Resume at same dose level. 
Continue therapy 
Grade 2 
Hold until UNL or baseline.  
Resume at same dose level.  
Hold until UNL or baseline. Resume 
using alternative dosing schedule at 60 
mg on D1, and D15 
Grade 3 
Off nivolumab therapy  
  Hold until Grade≤1. Resume at 45 mg 
dose on D1 and D15. If a dose reduction 
beyond 45 mg on D1 and 15 of each 
cycle is required, copanlisib will be 
discontinued 
Grade 4 
Off protocol therapy 
Off Protocol 
 
Continued treatment of active 
immune mediated hepatitis may 
exacerbate ongoing inflammation.  
Holding drug to evaluate LFT 
changes and early treatment are 
recommended.  LFT changes may 
occur during steroid tapers from 
other events and may occur together 
with other GI events including 
cholecystitis/pancreatitis.  
 
Recommended management:  see Hepatic AE management algorithm 
 
Diarrhea/ 
Colitis  
Management/Next Dose 
for Nivolumab 
 
Management/Next Dose  
For Copanlisib 
  
≤ Grade 1 
Hold until baseline #.  No change 
in dose 
No change in dose 
Grade 2 
Hold until baseline.  No change in 
Hold until baseline, then resume using 


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Diarrhea/ 
Colitis  
Management/Next Dose 
for Nivolumab 
 
Management/Next Dose  
For Copanlisib 
  
dose 
alternative dosing schedule at 60 mg on 
D1, and D15 
Grade 3 
Off protocol therapy. 
Hold* until < Grade 2.  Resume at one 
dose level lower, 45 mg dose given on 
D1 and D15.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
  
 See GI AE Algorithm for 
management of symptomatic 
colitis.  
Patients with grade 2 symptoms but 
normal colonoscopy and biopsies 
may be retreated after resolution.  
Patients who require steroids 
should be taken off study treatment. 
Please evaluate pituitary function 
prior to starting steroids if possible 
without compromising acute care.   
Evaluation for all patients for 
additional causes includes C. diff, 
acute and self-limited infectious 
and foodborne illness, ischemic 
bowel, diverticulitis, and IBD.  
*Patients requiring a delay of >2 weeks 
should go off protocol therapy. 
** Patients requiring a dose reduction 
beyond 45 mg on D1 and 15 of each 
cycle, copanlisib will be discontinued. 
Recommended management:  
Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, 
followed by 2 mg with each loose 
motion until diarrhea-free for 12 hours 
(maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is 
permitted and should be recorded when 
used. 
Recommended management:  see GI AE 
management Algorithm 
 
 
Pancreatitis 
Amylase/Lipase  
Management/Next Dose 
for Nivolumab 
 
Management/Next Dose  
For Copanlisib 
 
≤ Grade 1 
Hold until baseline. Resume at 
same dose level if 
asymptomatic 
No change in dose  
Grade 2 
Hold until baseline.  Resume at 
same dose level if 
asymptomatic 
 
 Hold until baseline.  Resume at same 
dose level if asymptomatic 
Grade 3 
Hold until baseline.  Resume at 
same dose level if 
asymptomatic. Patients who 
develop symptomatic 
pancreatitis or DM should be 
Hold until Grade 1 or less. Resume at 
60mg D1 and D15 


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Pancreatitis 
Amylase/Lipase  
Management/Next Dose 
for Nivolumab 
 
Management/Next Dose  
For Copanlisib 
 
taken off treatment  
Grade 4 
Hold  until baseline.  Resume at 
same dose level if 
asymptomatic. Patients who 
develop symptomatic 
pancreatitis or DM should be 
taken off treatment  
Off protocol therapy 
 
Patients may develop 
symptomatic and radiologic 
evidence of pancreatitis as well 
as DM and DKA.  Lipase 
elevation may occur during the 
period of steroid withdrawal 
and with other immune 
mediated events or associated 
with colitis, hepatitis, and 
patients who have 
asymptomatic lipase elevation 
typically have self-limited 
course and may be retreated. 
For treatment management of 
symptomatic pancreatitis 
please follow the Hepatic 
Adverse Event Management 
Algorithm  
 
 
 
Pneumonitis 
 
Management/Next Dose  
for Nivolumab 
 
 
Management/Next Dose  
For Copanlisib 
 
≤ Grade 1 
Hold dose pending evaluation and 
resolution to baseline including baseline 
pO2.  Resume no change in dose after 
pulmonary and/or ID consultation excludes 
lymphocytic pneumonitis.  
No Change 
Grade 2 
Hold dose pending evaluation. Resume no 
change in dose after pulmonary and/or ID 
consultation excludes nivolumab and 
associated lymphocytic pneumonitis as the 
cause of the pneumonitis. Off study if 
steroids are required. ^  
Dose Interruption Until 
recovery to ≤grade 1.Resume at 
45mg D1 and D15. No re-
escalation allowed after this 
dose reduction. If second 
recurrence, permanent 


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Pneumonitis 
 
Management/Next Dose  
for Nivolumab 
 
 
Management/Next Dose  
For Copanlisib 
 
discontinuation. 
Grade 3 
Hold dose pending evaluation. Resume 
without change in dose after pulmonary 
and/or ID consultation excludes nivolumab 
and associated lymphocytic pneumonitis as 
the cause of the pneumonitis. Off study if 
steroids are required  
Hold dose pending evaluation. 
If non-infectious pneumonitis 
excluded, may resume until 
grade ≤1 at 45mg D1 and D15. 
No re-escalation allowed after 
this dose reduction. If second 
recurrence, permanent 
discontinuation. Discontinue if 
proven non-infectious 
pneumonitis.  
Grade 4 
Off protocol therapy 
Permanent Discontinuation 
 
Distinguishing inflammatory pneumonitis 
is often a diagnosis of exclusion for 
patients who do not respond to antibiotics 
and have no causal organism identified 
including influenza.  Most patients with 
respiratory failure or hypoxia will be 
treated with steroids.  Bronchoscopy may 
be required and analysis of lavage fluid for 
lymphocytic predominance may be 
helpful.  Patients with new lung nodules 
should be evaluated for sarcoid like 
granuloma.  Please consider 
recommending seasonal influenza killed 
vaccine for all patients. 
The investigator is requested to 
differentiate between non-
infectious pneumonitis, and 
infectious pneumonitis (viral, 
bacterial, or fungal), aspiration 
pneumonitis, or other 
pneumonitis clearly not due to a 
potential hypersensitivity 
reaction to the copanlisib 
infusion; and provide the basis 
for his/her assessment that it is 
infectious or other, as 
appropriate.  The investigator is 
requested to report with the 
most specific clinical terms to 
describe the condition, not 
simple “pneumonitis”. 
Recommended management:  See Pulmonary Adverse Event 
Management Algorithm  
 
 
Nausea/Vomiting 
Management/Next Dose for 
[Nivolumab] 
Management/Next Dose for 
[copanlisib] 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1 or baseline.  
Resume at same dose level. 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3 
Off protocol 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 


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Nausea/Vomiting 
Management/Next Dose for 
[Nivolumab] 
Management/Next Dose for 
[copanlisib] 
Recommended management: antiemetics. 
 
 
Nivolumab: 
 
Please refer to the Nivolumab Investigator Brochure or Appendix C to the protocol for 
toxicity management algorithms which include specific treatment guidelines.  These 
algorithms should be followed unless there are specific clinical circumstances for which 
the treating physician decides an alternative treatment approach is clinically appropriate.  
Consultation with the study PI or drug monitor is recommended.  
 
In several places there are differences from the algorithms regarding protocol directed 
drug modifications and these are identified with (#).  In these cases please follow the 
protocol specific guidelines in this section.  
  
 
Generally we strongly encourage early evaluation while withholding drug, and 
appropriate treatment as indicated in the management tables and event specific 
guidelines.  
 
 
 
ALL OTHER 
EVENTS 
Management/Next Dose  
≤ Grade 1 
No change in dose  
Grade 2 
Hold until ≤ Grade 1 OR baseline (exceptions as noted below)     
Grade 3 
Off protocol therapy (exceptions as noted below)   
Grade 4 
Off protocol therapy 
 
Recommended management:  As clinically indicated  
 
 
o Any grade 2 drug-related uveitis or eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within the re-
treatment period OR requires systemic treatment should go off protocol treatment  
 
o Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, presents a substantial clinical risk to the subject with 
continued study drug dosing should go off protocol treatment.  
 
o Any grade 3 or 4 drug-related laboratory abnormality or electrolyte abnormality, 
that can be managed independently from  underlying organ pathology with 
electrolyte replacement, hormone replacement, insulin or  that does not require 
treatment does not require discontinuation.  
 


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o Lymphopenia is an expected event for both study drugs.  Asymptomatic 
lymphopenia does not constitute reason to hold or discontinue the study drugs, 
regardless of the grade 
 
 
Other GI  
(not Nausea and 
Vomiting)  
Management/Next Dose  
≤ Grade 1 
No change in dose.  
Grade 2 
Hold pending evaluation for gastritis duodenitis and other immune 
adverse events or other causes.  Resume at same dose level after 
resolution to ≤ Grade 1.   
Grade 3 
Hold pending evaluation until ≤ Grade 1.  Resume at same dose level. If 
symptoms do not resolve within 7 days with symptomatic treatment  
patients should go off protocol therapy. 
Grade 4 
Off protocol therapy 
Patients with grade 2 or 3 N-V should be evaluated for upper GI inflammation and other 
immune related events.   
 
Fatigue  
Management/Next Dose  
≤ Grade 1 
No change in dose. 
Grade 2 
No change in dose. 
Grade 3 
Hold until ≤ Grade 2.  Resume at same dose level. 
Fatigue is the most common adverse event associated with immune checkpoint therapy.  Grade 
2 or greater fatigue should be evaluated for associated or underlying organ involvement 
including pituitary, thyroid, and hepatic, or muscle (CPK) inflammation  
 
Neurologic events  
 
Management/Next Dose  
≤ Grade 1 
Hold dose pending evaluation and observation (#). Resume with no 
change in dose when resolved to baseline.   
Grade 2 
Hold dose pending evaluation and observation.  (#) Hold until ≤ Grade 
1. Off protocol therapy if treatment with steroids is required.  Resume at 
same dose level for peripheral isolated n. VII (Bell’s palsy)^  
Grade 3 
Off protocol therapy.  
Grade 4 
Off protocol therapy.  
Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic 
hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial neuropathy (other 
than peripheral n. VII), GB syndrome and myasthenia gravis should be off study.   
Recommended management:  See Neurologic Adverse Event Management Algorithm  
 


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Endocrine 
Hypophysitis 
Adrenal 
Insufficiency  
 
Management/Next Dose  
≤ Grade 1 
Asymptomatic TSH elevation.*  Continue therapy.  
Grade 2 
Hold until patients are on a stable replacement hormone regimen.  If 
treated with steroids patients must be stable off steroids for two weeks. 
Resume at same dose level. Endocrine consult recommended 
Grade 3 
Off study treatment. 
Grade 4 
Off protocol therapy. 
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but 
including severe headache or enlarged pituitary on MRI should be considered grade 3 events.  
Isolated thyroid or testosterone deficiency may be treated as grade 2 if there are no other 
associated deficiencies and adrenal function is monitored.  
Please evaluate pituitary function before beginning steroid therapy or replacement therapy of 
any kind.  
*Note patients with thyroiditis may be retreated on replacement therapy.  Patients must be 
evaluated to rule out pituitary disease prior to initiating thyroid replacement. 
Recommended management: See Endocrine Management Algorithm  
 
Renal   
Management/Next Dose  
≤ Grade 1 
No change in dose.  Monitor toxicity weekly until returned to baseline. 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 4 
Off treatment. 
Recommended management: See Renal Management Algorithm  
 
Infusion reaction  
Management/Next Dose  
≤ Grade 1 
Infusion rate may be slowed or interrupted and restarted at 50% of the 
original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 
100% of the original infusion rate.  Monitor patient closely. See Section 
5.7 for details on management of Infusion Reactions. 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 4 
Off treatment. 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever  
 
Fever  
Management/Next Dose  
 
 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until ≤ Grade 1.  Resume at same dose level. 


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Fever  
Management/Next Dose  
Grade 4 
Off treatment. 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over the 
course of 1-2 weeks should be done for other autoimmune events that may present as fever  
See section 5.    infusion reactions   
 
 
 
o Drug will be held for grade 2 cardiac dysfunction pending evaluation 
o Drug will be permanently discontinued for grade  3 or 4 cardiac dysfunction and 
grade 2 events that do not recover to baseline or that reoccur 
o Treatment with steroids as clinically indicated  
 
If treatment is delayed > 6 weeks for an adverse event, the patient must be permanently 
discontinued from study therapy.  
  
Patients requiring high dose steroid treatment for autoimmune or inflammatory events 
should go off study treatment except for a short course of tapering steroids for infusion 
reaction, skin rash or endocrine events.  
 
Cardiac *   
Management/Next Dose for Nivolumab  
Cardiac Toxicities  
≤ Grade 1  
Hold dose pending evaluation and observation.**  Evaluate for signs and 
symptoms of CHF, ischemia, arrhythmia or myositis.  Obtain history EKG, 
CK (for concomitant myositis), CK-MB.  Repeat troponin, CK and EKG 2-
3 days.  If troponin and labs normalize may resume therapy.   If labs 
worsen or symptoms develop then treat as below.  Hold pending evaluation  
Grade >2 with 
suspected 
myocarditis 
Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out MI and 
other causes of cardiac disease.  Cardiac Monitoring.  Cardiac Echo.  
Consider cardiac MRI and cardiac biopsy.  Initiate high dose 
methylprednisolone.  If no improvement within 24 hours, add either 
infliximab, ATG or tacrolimus. Consult algorithm for more details.  
Resume therapy if there is a return to baseline and myocarditis is excluded 
or considered unlikely. 
Grade >2 with 
confirmed 
myocarditis   
Off protocol therapy.  Admit to CCU (consider transfer to nearest Cardiac 
Transplant Unit).  Treat as above.  Consider high dose methylprednisolone   
Add ATG or tacrolimus if no improvement.   Off treatment. 
* Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other 
event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been 
established.  Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.   


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Patients with grade 3 thyroiditis and skin rash may continue therapy with resolution and 
stable replacement treatment. 
 
Patients with thyroiditis or hypopituitarism who are stable as above may be restarted with 
replacement hormones including thyroid hormone and physiologic doses of 
corticosteroids.  
 
Please note that grading and for hypophysitis with symptoms of headache, visual or 
neurologic changes or radiologic evidence of pituitary enlargement and other CNS events 
such as aseptic meningitis or encephalitis should be considered grade 3 events.  
Any patients who require additional immune suppressive treatment beyond steroids 
should go off study treatment. 
 
Patients requiring > two dose delays for the same event should go off protocol therapy. 
 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate 
endocrine testing including cortisol, ACTH, TSH and T4 must be obtained to document 
baseline.  
 
Please note that in some cases the treatment algorithms recommend steroids if symptoms 
do not resolve in 7 days.  However, this recommendation is not meant to delay steroid 
treatment at any time it is clinically indicated.   
 
Patients may be dose-delayed for evaluation and restarted depending on results.  
Any patient started on corticosteroids initially who is determined to not require steroid 
treatment for an autoimmune adverse event may resume therapy after a 2 week 
observation period without further symptoms at the discretion of the PI or investigator. 
 
 
Copanlisib: 
 
Neutropenia 
 
Management/Next Dose  
for Copanlisib 
 
≤ Grade 1 
ANC≤1500/mm3 
No change in dose 
Grade 2  
ANC<1500-
1000/mm3 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
ANC<1000-
500/mm3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 
Grade 4 
ANC<500/mm3 
Off protocol therapy. 


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Neutropenia 
 
Management/Next Dose  
for Copanlisib 
 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
Thrombocytopenia 
Platelet counts 
 
Management/Next Dose  
for Copanlisib 
 
≤ Grade 1 
≤ 75’000/mm3  
No change in dose 
Grade 2 
<75’000-50’000/mm3 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
<50’000-25’000/mm3 
Hold* until < Grade 2.  Resume at one dose level lower, if 
indicated.** 
Grade 4 
<25’000/mm3 
Off protocol therapy. 
 
6.1 
Dose Modification rules for transient post-infusion hyperglycemia 
 
Patients who develop transient post-infusion glucose>250 mg/dL after study drug administration 
may continue treatment.  However, the next infusion must be delayed until the patient’s pre-
infusion glucose levels return to <160 mg/dL (fasting) or <200 mg/dL (non-fasting). Guidelines 
for the management of transient glucose increases are given in APPENDIX D and APPENDIX  
E.  Continuing occurrence of post-infusion blood glucose >400 mg/dL, based on repeated 
laboratory analysis despite optimal glucose lowering therapy after 2 infusions of copanlisib, will 
require dose reduction by one dose level. 
• 
Further dose reduction (where appropriate per study design/population) is allowed as 
long as discontinuation criteria was not met. 
• 
Dose re-escalation is allowed when a patient has achieved controlled glucose levels per 
investigator’s judgment. 
• 
Persistent occurrence of post-infusion blood glucose >400 mg/dL based on laboratory 
analysis which occurred at the lowest dose level despite optimal glucose lowering therapy 
(after at least one cycle of treatment) with consultation of a diabetes specialist requires 
permanent discontinuation of the study drug. 
 
6.2 
Treatment of blood pressure increases associated with copanlisib 
 
It is important that patients with pre-existing arterial hypertension adhere to their regular 
medication schedule and take their usual doses on the days of study drug infusion.  
The management of acute blood pressure (BP) increases following copanlisib will need to be 
individualized for each patient, but experience from a Bayer-sponsored phase 1 study with 


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copanlsisib has suggested the benefit of dihydropyridine calcium channel blockers (i.e., 
amlodipine, felodipine).  Topical nitrates and non-dihydropyridine should also be considered.  
Addition of non-dihydropyridine can be considered because of low significant clinical DDI 
potential with these drugs based on results with itraconozole data  In general, it is advisable for 
sites to be prepared, so that anti-hypertensive medication is readily available in case of need.  
In the event of the occurrence of arterial hypertension ≥150/90 mmHg during infusion of 
copanlisib at any cycle, antihypertensive treatment is suggested.  In the event of the occurrence of 
grade 3 arterial hypertension (≥160/100 mmHg) during infusion of copanlisib, the infusion should 
be interrupted and anti-hypertensive treatment as suggested above is administered.  Infusion can 
be resumed when BP has returned to <150/90 mmHg. 
Blood pressure measurement on treatment days 
Blood pressure will be measured every 5-10 min prior to each copanlisib dose (no more than 4 
measurements) until there are two consecutive results <150/90 mmHg.  If blood pressure is ≥ 
150/90 mmHg, the investigator can consider a medical intervention or delaying the infusion of 
study drug. The patient should rest for 5-10 min before blood pressure is recorded. 
On infusion days, blood pressure will be measured at 0 hour (pre-dose), 30 min (mid-infusion), 60 
min (end of infusion), and 1 hour and 2 hours after the end of infusion.  
NOTE: A window of ±10 min is allowed for all BP measurements, except for pre-dose (0 hour) 
measurement. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Sections 7.2 and 
7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
 
7.1.1 CAEPRs for CTEP IND Agent(s) 
 
7.1.1.1 
CAEPR for Copanlisib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride, NSC 784727) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 


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protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 702 patients. Below is the CAEPR for 
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
 
 
Version 2.2, June 18, 20191 
 
 Adverse Events with Possible Relationship to  
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) 
 (CTCAE 5.0 Term) 
[n= 702] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
Infection2 
 
 
 Infection2 (Gr 2) 
INVESTIGATIONS 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
Hyperglycemia 
 
 
 Hyperglycemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis3 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythroderma 
  
 
 
Pruritus 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 


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distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
3Pneumonitis is a group term that includes interstitial lung disease, dyspnea, dyspnea at rest, and 
dyspnea exertional. 
 
 
Adverse events reported on Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) 
trials, but for which there is insufficient evidence to suggest that there was a reasonable 
possibility that Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Eosinophilia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Left ventricular systolic 
dysfunction; Myocardial infarction; Sinus tachycardia 
GASTROINTESTINAL DISORDERS - Abdominal pain; Colitis; Constipation; Dry mouth; 
Dyspepsia; Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; Oral dysesthesia; 
Oral pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death 
NOS; Fever; General disorders and administration site conditions - Other (failure to thrive); 
Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Infusion 
related reaction; Injury, poisoning and procedural complications - Other (drug eruption) 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine 
aminotransferase increased; Alkaline phosphatase increased; Aspartate aminotransferase 
increased; Blood bilirubin increased; CPK increased; Ejection fraction decreased; 
Electrocardiogram QT corrected interval prolonged; Electrocardiogram T wave abnormal; 
Investigations - Other (electrocardiogram U wave abnormal); Lipase increased; Lymphocyte 
count decreased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypertriglyceridemia; 
Hyperuricemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (blood insulin increased) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; 
Generalized muscle weakness; Musculoskeletal and connective tissue disorder - Other (psoriatic 
arthropathy); Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor hemorrhage 
NERVOUS SYSTEM DISORDERS - Amnesia; Dizziness; Dysesthesia; Dysgeusia; Headache; 
Paresthesia; Peripheral sensory neuropathy; Presyncope; Reversible posterior 
leukoencephalopathy syndrome 
PSYCHIATRIC DISORDERS - Confusion 


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RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - 
Other (renal insufficiency) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea3; 
Hypoxia; Pleural effusion; Pulmonary hypertension; Respiratory failure; Respiratory, thoracic 
and mediastinal disorders - Other (pulmonary congestion) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Purpura; Rash 
acneiform; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hypotension; Thromboembolic event; Vascular disorders - Other 
(circulatory collapse) 
 
 
Note: Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) in combination with other 
agents could cause an exacerbation of any adverse event currently known to be caused by the 
other agent, or the combination may result in events never previously associated with either 
agent. 
 
7.1.1.2 
CAEPR for Nivolumab 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
BMS-936558 (Nivolumab, MDX-1106, NSC 748726) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2069 patients. Below is the CAEPR for 
BMS-936558 (Nivolumab, MDX-1106). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
Version 2.4, December 2, 
20201 
 
 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  


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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2 
  
 
 
Pericarditis 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency3  
  
 
Hypophysitis3 
 
  
 
Hyperthyroidism3 
 
  
 
Hypothyroidism3 
 
  
EYE DISORDERS 
  
 
 
Blurred vision  
  
 
 
Dry eye 
  
 
 
Eye disorders - Other 
(diplopia)3 
  
 
 
Eye disorders - Other 
(Graves ophthalmopathy)3   
 
 
Eye disorders - Other (optic 
neuritis retrobulbar)3 
  
 
 
Eye disorders - Other 
(Vogt-Koyanagi-Harada) 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis3 
 
  
 
 
Colonic perforation3 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Enterocolitis 
  
 
 
Gastritis 
  
 
 
 Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   


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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - 
Other (immune-mediated 
hepatitis) 
  
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release syndrome5   
 
 
Immune system disorders - 
Other (GVHD in the setting 
of allotransplant)3,6  
  
 
 
Immune system disorders - 
Other (sarcoid granuloma)3    
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related 
reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased3 
 
 Alanine aminotransferase 
increased3 (Gr 3)  
 
Aspartate 
aminotransferase 
increased3 
 
 Aspartate aminotransferase 
increased3 (Gr 3)  
 
Blood bilirubin 
increased3 
 
 Blood bilirubin increased3 
(Gr 2)  
 
CD4 lymphocytes 
decreased 
 
 CD4 lymphocytes decreased 
(Gr 4) 
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count 
decreased 
 
 Lymphocyte count decreased 
(Gr 4) 
  
Neutrophil count 
decreased 
 
  


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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Platelet count decreased  
  
 
Serum amylase 
increased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus with ketoacidosis)3 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and 
connective tissue disorder - 
Other (polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  
 
 
Guillain-Barre syndrome3 
  
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - 
Other (demyelination 
myasthenic syndrome) 
  
 
 
Nervous system disorders - 
Other (encephalitis)3 
  
 
 
Nervous system disorders - 
Other 
(meningoencephalitis) 
  
 
 
Nervous system disorders - 
Other (meningoradiculitis)3   
 
 
Nervous system disorders - 
Other (myasthenic 
syndrome) 
  
 
 
Peripheral motor 
neuropathy 
  


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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Peripheral sensory 
neuropathy 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  
 
 
Renal and urinary disorders 
– Other (immune-mediated 
nephritis) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - 
Other (bronchiolitis 
obliterans with organizing 
pneumonia)3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  
 
Pruritus3 
 
 Pruritus3 (Gr 2)  
 
Rash maculo-papular3 
 
 Rash maculo-papular3 (Gr 
2)  
 
 
Skin and subcutaneous 
disorders -Other (bullous 
pemphigoid)  
  
 
Skin and subcutaneous 
disorders - Other 
(Sweet’s Syndrome)3 
 
  
 
Skin hypopigmentation3  
  
 
 
 Stevens-Johnson syndrome   
 
 
 Toxic epidermal necrolysis   
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 


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2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3 Nivolumab being a member of class of agents involved in the inhibition of “immune 
checkpoints”, may result in severe and possibly fatal immune-mediated adverse events probably 
due to T-cell activation and proliferation.  This may result in autoimmune disorders that can 
include (but are not limited to) autoimmune hemolytic anemia, acquired anti-factor VIII immune 
response, autoimmune aseptic meningitis, autoimmune hepatitis, autoimmune nephritis, 
autoimmune neuropathy, autoimmune thyroiditis, bullous pemphigoid, exacerbation of Churg-
Strauss Syndrome, drug rash with eosinophilia systemic symptoms [DRESS] syndrome, facial 
nerve disorder (facial nerve paralysis), limbic encephalitis, hepatic failure, pure red cell aplasia, 
pancreatitis, ulcerative and hemorrhagic colitis, endocrine disorders (e.g., autoimmune 
thyroiditis, hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, 
thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia gravis, polymyositis, 
and Guillain-Barre syndrome. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with 
accompanying fever and pancytopenia. 
 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have 
occurred in patients receiving allo stem cell transplant (SCT) after receiving Nivolumab.  These 
complications may occur despite intervening therapy between receiving Nivolumab and allo-
SCT. 
 
7Infusion reactions, including high-grade hypersensitivity reactions which have been observed 
following administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, 
hypertension or hypotension, or difficulty breathing during and immediately after administration 
of nivolumab. 
 
Adverse events reported on Nivolumab trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Nivolumab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; 
Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital 
edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; 
Gastrointestinal disorders - Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
limbs; Malaise; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other 
(autoimmune thrombotic microangiopathy); Immune system disorders - Other (limbic 


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encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper 
respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - 
Other (protein total decreased); Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal 
and connective tissue disorder - Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(Histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other 
(tubulointerstitial nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; 
Cough; Dyspnea; Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; 
Pain of skin; Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other 
(rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
Note: Nivolumab in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4 will be utilized for AE reporting.  All appropriate treatment areas should have access to 
a copy of the CTCAE version 4.  A copy of the CTCAE version 4 can be downloaded 
from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 


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• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
• PRO-CTCAE is not intended for expedited reporting, real time review or safety 
reporting. 
 
- 
. 
Expedited Adverse Event Reporting 
 
7.2.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.2.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.2.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 


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Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR 
Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse 
Events, whether or not they are considered related to the investigational 
agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to 
the NCI via electronic submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found 
in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 
24 hours of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 


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o “10 Calendar Days” - A complete expedited report on the AE must be submitted 
electronically within 10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite 
require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 
radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was 
last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
7.2.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4): 
 
 
CTCAE SOC 
Adverse Event 
CTCAE Grade at 
which the event will 
not require 
expedited reporting1 
Investigations 
Neutrophil count decreased 
≤ Grade 2 
Platelet count decreased 
≤ Grade 2 
White blood count  
≤ Grade 2 
Lymphocyte count decreased 
≤ Grade 4 
Blood and lymphatic system 
disorders 
Anemia 
≤ Grade 2 
 
1. These exceptions only apply if the adverse event does not result in ≥24 hours hospitalization. 
 If the adverse event results in hospitalization, then the standard expedited adverse events 
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The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
• Hospitalizations for respite care 
• Planned hospitalizations required by the protocol 
• Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
• Hospitalization for elective procedures unrelated to the current disease and/or treatment on 
this trial 
• Hospitalization for administration of study drug or insertion of access for administration of 
study drug 
• Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 
• Hospitalization, or other serious outcomes, for signs and symptoms of progression of the 
cancer. 
 
7.3 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.4 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 


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NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
 
 
8.1.1 
CTEP IND Copanlisib (NSC 784727) 
 
Chemical Name or Amino Acid Sequence: 2-amino-N-[7-methoxy-8-(3-morpholin-4-
ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide 
dihydrochloride 
 
Other Names: BAY 80-6946 (free base); BAY 84-1236 (dihydrochloride salt) 
 
Classification: Pan class I PI3K inhibitor  
 
Molecular Formula: C23H28N8O4 2HCl 
 
 
 
M.W.: 553.45 g/mol 
 
Approximate Solubility: Freely soluble in water and 0.1 M hydrochloric acid (HCl) 
 
Mode of Action: Copanlisib is a pan class I PI3K inhibitor with potent activity against the 
delta and alpha isoforms.  Class I PI3K is downstream of most cancer associated tyrosine 
kinase growth factor receptors or mesenchymal epithelial transition factor. PI3K delta has 
a critical role in regulating downstream events of the B-cell receptor. 


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Description: The powder is white to yellow solid substance. 
 
How Supplied: Copanlisib is supplied by Bayer HealthCare AG and distributed by the 
Pharmaceutical Management Branch, CTEP, DCTD, NCI.  The agent is available as a 
lyophilized product containing 60 mg of copanlisib in a 6 mL injection vial.  The excipients 
are mannitol, sodium hydroxide, citric acid, and water for injection. 
 
Preparation:  Using appropriate aseptic technique, reconstitute the 60 mg vial of copanlisib 
with 4.4 mL of 0.9% sodium chloride resulting in a concentration of 15 mg/ml.  Gently 
shake well for 30 seconds and allow the vial to stand for 1 minute to let bubbles rise to the 
surface. Repeat if undissolved substance is still present. The reconstituted solution may be 
slightly yellow and should be clear prior to being withdrawn from the vial.   Withdraw the 
appropriate volume of the reconstituted solution and further dilute by adding to a 50-200 mL 
0.9% sodium chloride bag. Mix well by inverting.  
 
Storage: Store intact vials between 2°C and 8°C.  
 
If a storage temperature excursion is identified, promptly return copanlisib to between 
2°C and 8°C and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Stability studies of the vials are ongoing.  The diluted solution should be used 
immediately (stored up to 4 hours at room temperature including preparation and 
administration).  If the diluted solution for infusion is not used immediately, it is stable for 
up to 24 hours refrigerated between 2°C and 8°C. It takes approximately 60 minutes for the 
100 mL diluted solution to return to room temperature after refrigeration.  The infusion 
should be completed within 24 hours of preparation. 
 
CAUTION:  The single-use lyophilized dosage form contains no antibacterial 
preservatives.  Therefore, it is advised that the reconstituted product be discarded 6 hours 
after initial entry.  
 
Route of Administration: IV infusion  
 
Method of Administration:  The diluted solution for infusion is administered IV over 1 
hour. After administration, flush the line to ensure complete dose is given.  No IV glucose 
preparations should be administered on the days of infusion. 
 
Potential Drug Interactions:   
In vitro, copanlisib is metabolized primarily via CYP 3A4 and to a minor extent by 
CYP1A1.  It is also a substrate of P-gp and BCRP, but not a substrate of MATEs, OCTs, 
OATs, or OATPs. Concomitant administration with strong inhibitors or inducers of 
CYP3A4 should be avoided.  Use caution when administered with strong inhibitors and 
inducers of CYP1A1, P-gp, and BCRP.  Smoking tobacco may reduce drug exposure since 


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tobacco induces CYP1A1 activity.  
 
In vitro, copanlisib is a strong inhibitor of MATE2K.  Copanlisib and its metabolite M-1 
have a low risk for inhibition or induction of CYP isoforms, inhibition of UGT isoforms, 
and inhibition of dihydropyrimidine dehydrogenase.  Copanlisib does not inhibit P-gp, 
BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, bile salt export pump (BSEP), 
MRP2, or MATE1 at therapeutic 60 mg dose plasma concentrations. Use caution when 
administered with sensitive drug substrates of MATE2K.   
 
Copanlisib is not an inducer of CYP1A2, 2B6, and 3A. 
 
Copanlisib and its metabolite M-1 have low protein binding. 
 
Special Handling: Copanlisib is not genotoxic in vitro or in vivo.  Copanlisib is expected to 
adversely affect male and female reproduction. 
 
Patient Care Implications:. Females of child-bearing potential and male patients must use 
adequate contraception while receiving copanlisib and for 1 month after last dose of 
copanlisib.  Do not breastfeed during treatment with copanlisib and for at least 1 month after 
the last dose of copanlisib. 
 
Hypertension is frequently observed within the first 3 hours after start of infusion and 
hyperglycemia is frequently observed persisting for approximately 1-3 days after study 
drug administration. Refer to protocol document for treatment and monitoring guidelines. 
 
Availability 
 
CTEP IND Copanlisib is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
 
CTEP IND Copanlisib is provided to the NCI under a Collaborative Agreement between 
the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 CTEP and/or CIP IND Nivolumab (NSC 748726) 
 
Amino Acid Sequence:  4 polypeptide chains, which include 2 identical heavy chains with 
440 amino acids and 2 identical light chains. 
 
Other Names: BMS-936558, MDX1106 
 
Classification: Anti-PD-1MAb 
 
M.W.:  146,221 Daltons 
 
Mode of Action:  Nivolumab targets the programmed death–1 (PD-1, cluster of 


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differentiation 279 [CD279]) cell surface membrane receptor. PD-1 is a negative regulatory 
receptor expressed by activated T and B lymphocytes. Binding of PD-1 to its ligands, 
programmed death–ligand 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Nivolumab inhibits the binding of PD-1 to PD-L1 and PD-L2.  
Inhibition of the interaction between PD-1 and its ligands promotes immune responses and 
antigen-specific T-cell responses to both foreign antigens as well as self-antigens. 
 
Description:  Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; 
light (few) particulates may be present. The drug product is a sterile, nonpyrogenic, single-
use, isotonic aqueous solution formulated in sodium citrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid) and polysorbate 80 (Tween® 80), and 
water for injection.  Dilute solutions of hydrochloric acid and/or sodium hydroxide may be 
used for pH adjustment (pH 5.5-6.5). 
 
How Supplied:  Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg vials (10 mg/mL) with 
a 0.7mL overfill.  It is supplied in 10 mL type I flint glass vials, with fluoropolymer film-
laminated rubber stoppers and aluminum seals. 
 
Preparation:  Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 
0.9% Sodium Chloride Injection, USP.  When the dose is based on patient weight (i.e., 
mg/kg), nivolumab injection can be infused undiluted or diluted to a final concentration of 
1-10mg/mls. When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab 
injection can be infused undiluted or diluted so as not to exceed a total infusion volume of 
160 mL.  For patients weighing less than 40 kilograms (kg), the total volume of infusion 
must not exceed 4 mL per kg of patient weight. During drug product preparation and 
handling, vigorous mixing or shaking is to be avoided. 
 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers 
and infusion sets, and glass bottles. 
 
Storage:  Vials of Nivolumab injection must be stored at 2°- 8°C (36°- 46°F) and protected 
from light and freezing.  The unopened vials can be stored at room temperature (up to 25°C, 
77°F) and room light for up to 48 hours.  
 
If a storage temperature excursion is identified, promptly return Nivolumab to 2°C-8°C and 
quarantine the supplies.  Provide a detailed report of the excursion (including documentation 
of temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov 
for determination of suitability. 
 
Stability:  Shelf-life surveillance of the intact vials is ongoing. 
 
The administration of undiluted and diluted solutions of Nivolumab must be completed 
within 24 hours of preparation.  If not used immediately, the infusion solution may be stored 
up to 24 hours in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of the total 
24 hours can be at room temperature (20°-25°C, 68°-77°F) and room light.  The maximum 


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8-hour period under room temperature and room light conditions includes the product 
administration period. 
 
CAUTION:  The single-use dosage form contains no antibacterial preservative or 
bacteriostatic agent.  Therefore, it is advised that the product be discarded 8 hours after 
initial entry.  
 
Route of Administration:   Intravenous infusion over 30 minutes.  Nivolumab can be 
safely infused over 30 minutes in subjects with cancer.  Do not administer as an IV push or 
bolus injection. 
 
Method of Administration:   Administer through a 0.2 micron to 1.2 micron pore size, 
low-protein binding (polyethersulfone membrane) in-line filter.  
 
Potential Drug Interactions:  The indirect drug-drug interaction potential of nivolumab 
was assessed using systemic cytokine modulation data for cytokines known to modulate 
CYP enzymes.  There were no meaningful changes in cytokines known to have indirect 
effects on CYP enzymes across all dose levels of nivolumab. This lack of cytokine 
modulation suggests that nivolumab has no or low potential for modulating CYP enzymes, 
thereby indicating a low risk of therapeutic protein-drug interaction. 
 
Patient Care Implications:  Women of childbearing potential (WOCBP) receiving 
nivolumab must continue contraception for a period of 5 months after the last dose of 
nivolumab. Men receiving nivolumab and who are sexually active with WOCBP must 
continue contraception for a period of 7 months after the last dose of nivolumab. 
 
Availability 
 
CTEP IND Nivolumab is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
CTEP IND Nivolumab is provided to the NCI under a Collaborative Agreement between 
the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.3 Agent Ordering and Agent Accountability 
 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution. 
 


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In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
 
8.1.3.1 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.4 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status 
a “current” password, and active person registration status Questions about IB access 
may be directed to the PMB IB Coordinator via email. 
 
 
8.1.5 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:   RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP  
• CTEP Identity and Access Management (IAM) account 
https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Plan  
 


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List of Biomarker Assays in Order of Priority 
Prioritization list: Category 1 correlatives (i.e., first to be done): Cell of origin; PD-1/PD-L1/IHC and gene amplification/copy 
number; Intra-tumoral immune cell locations and number. Category 2 correlative (next in line): PTEN loss and phospho-AKT.  
Category 3 correlatives:  Changes in T-cell profile; cytokine profile; gamma interferon gene signature.  Category 4 correlative: 
cfDNA, mutational burden 
 
Priority Biomarker 
Name 
Biomarker 
Assay 
Biomarker 
Type and 
Purpose 
M/O 
Timing 
Specimen 
Quantity 
Needed 
Laboratory 
1 
Cell of 
origin 
Lymph3Cx/
Gene 
expression 
profiling 
Integrated 
help determine 
whether COO 
predicts 
response to 
therapy 
 
M 
Baseline
/at time 
of 
screenin
g 
Tissue 
biopsy 
(new or 
archived) 
FFPE 
see 
section 
9.2.1.2 
Molecular 
Diagnostics 
– Arizona 
Laboratory, 
Mayo Clinic 
Arizona  
2 
PD1/PD-
L1 
Immunohist
ochemistry 
Exploratory 
 
To be studied 
as a predictor 
of response 
 
 
M 
Baseline
/at time 
of 
screenin
g and 
any 
addition
al 
subsequ
ent 
optional 
biopsies 
Tissue 
biopsy 
(new or 
archived) 
1x 5-μm 
paraffin-
embedde
d sections 
Stephen 
Ansell 
Laboratory, 
Mayo clinic 
(Ansell.step
hen@mayo.
edu) 
3 
PD1/PD-
L1  
Gene 
amplificatio
n/copy 
number by 
FISH 
Exploratory 
 
To be studied 
as a predictor 
of response 
M  
Baseline
/at time 
of 
screenin
g and 
Tissue 
biopsy 
(new or 
archived)  
1 x 5-μm 
paraffin-
embedde
d sections  
Stephen 
Ansell 
Laboratory, 
Mayo clinic 


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65 
 
Priority Biomarker 
Name 
Biomarker 
Assay 
Biomarker 
Type and 
Purpose 
M/O 
Timing 
Specimen 
Quantity 
Needed 
Laboratory 
 
any 
addition
al 
subsequ
ent 
optional 
biopsies  
4 
Intratumora
l Immune 
cell 
location 
and 
number 
Immunohist
ochemistry 
Exploratory 
 
To assess the 
effects of 
copanlisib/niv
olumab on the 
immune 
system within 
the tumor and 
tumor 
microenviron
ment 
M 
Baseline
/at time 
of 
screenin
g and 
any 
addition
al 
subsequ
ent 
optional 
biopsies 
(if 
possible 
D8, at 
time of  
progress
ion of 
disease) 
Tissue 
biopsy 
1x 5-μm 
paraffin-
embedde
d sections 
Stephen 
Ansell 
Laboratory, 
Mayo clinic 
5 
PTEN Loss Immunohist
ochemistry 
Exploratory 
 
To assess for 
predictors of 
M 
Baseline
/at time 
of 
screenin
Tissue 
biopsy 
1x 5-μm 
paraffin-
embedde
d sections 
Stephen 
Ansell 
Laboratory, 
Mayo clinic 


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Priority Biomarker 
Name 
Biomarker 
Assay 
Biomarker 
Type and 
Purpose 
M/O 
Timing 
Specimen 
Quantity 
Needed 
Laboratory 
response or 
non-response 
to therapy 
g 
6 
Phospho 
AKT 
Immunohist
ochemistry 
Exploratory 
 
To assess 
target 
inhibition by 
copanlisib 
O 
 
Baseline
/at time 
of 
screenin
g and 
any 
addition
al 
subsequ
ent 
optional 
biopsies 
(if 
possible 
D8, at 
time of  
progress
ion of 
disease) 
Tissue 
biopsy 
1x 5-μm 
paraffin-
embedde
d sections 
Stephen 
Ansell 
Laboratory, 
Mayo clinic 
7 
Changes in 
T-cell 
exhaustion 
or 
activation 
profile 
Flow 
cytometry 
Exploratory 
 
To define 
changes in 
peripheral 
blood cell 
populations 
after treatment 
M 
At 
baseline
, day 8, 
day 15, 
cycle 4 
and at 
time of 
progress
Whole 
Blood 
1x 10 ml 
purple 
top tubes 
(EDTA)  
Stephen 
Ansell 
Laboratory, 
Mayo clinic 


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67 
 
Priority Biomarker 
Name 
Biomarker 
Assay 
Biomarker 
Type and 
Purpose 
M/O 
Timing 
Specimen 
Quantity 
Needed 
Laboratory 
ion 
8 
Serum 
Cytokine 
Profile 
ELISA 
Exploratory 
 
 
M 
At 
baseline
, day 8, 
day 15, 
cycle 4 
and at 
time of 
progress
ion 
Serum 
1x 10 ml 
Red top 
tube  
Stephen 
Ansell 
Laboratory, 
Mayo clinic 
9 
Mutational 
burden 
determinati
on 
Whole 
exome 
sequencing 
Exploratory 
 
To assess 
predictors of 
response to 
therapy 
O 
Baseline
/at time 
of 
screenin
g 
Tissue  
1 x -5-
μm 
paraffin-
embedde
d sections  
 
Stephen 
Ansell 
Laboratory, 
Mayo clinic 
10 
cfDNA 
Digital 
droplet PCR 
and Next 
generation 
sequencing 
Exploratory  
 
To correlate 
response to 
therapy with 
cfDNA 
M 
Baseline
, day8, 
day 15 
of cycle 
1 then 
cycle 3 
and then 
at time 
of 
progress
ion 
Whole 
blood 
one 
cfDNA 
Streck 
tubes, 10 
ml 
Stephen 
Ansell 
Laboratory, 
Mayo clinic  
Specimen Collection Schedule 
Please provide the type of specimen and the timepoint (study cycle/day) of each specimen collection procedure, and mark the 
appropriate boxes with an “X” to denote collection on that study day. 


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68 
 
 
 
Correlative 
Study  
Mandatory or 
Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume 
to collect 
per tube 
(# of 
tubes to 
be 
collected) 
Baselin
e 
Cycle 
1-Day 
8  
Cycles 
1-Day 
15  
Cycle 3 Cycle 4 
 
 
At 
time 
of 
PMD 
or PD 
 
Tumor 
biopsy 1 
Mandatory 
Tumor  
 
FFPE 
see above 
table for 
quantity 
X1 
X2 
 
 
 
       
     X2 
Peripheral 
blood  
Mandatory  
Whole 
Blood 
EDTA 
(purple 
top) 
10 mL 
 (1 tube) 
X 
X 
X 
 
X 
 
X 
Peripheral 
blood 
Mandatory  
Serum 
Red top 
tube 
10 mL 
 (1 tube) 
X 
X 
X 
 
X 
X 
Peripheral 
blood 
Mandatory  
Whole 
blood 
Streck 
Cell-Free 
DNA 
tubes 
10 mL  
(1 tubes) 
X 
X 
X 
 
X 
 
 
X 
1 Only obtained when a clinical biopsy is needed. Archival tissue maybe used. If no archival tissue is available, a biopsy then is 
needed.  
2 Optional additional biopsies at Day 8 Cycle 1 and at time of progression  
 
 
 
 
 
9.2 
   Integrated Correlative Studies


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9.2.1 Lymph3Cx Cell-of-Origin (COO) molecular subtyping assay – Integrated Laboratory 
Correlative Study #1 (See Appendix G for more details).  
 
The “Lymph3Cx” assay provides molecular Cell-of-Origin (COO) subtyping of large B cell 
lymphomas into Germinal Center B cell (GCB), Activated B Cell (ABC), Unclassifiable (UNC), 
and Primary Mediastinal B Cell Lymphoma (PMBCL) types, which have different biological 
features such as genomic alterations, gene expression and mutation profiles, signal pathway 
activation, and prognosis. We hypothesize that, as an integrated biomarker, the Lymph3Cx assay 
will identify those patients in this trial who benefited from the addition of Copanlisib in 
combination with Nivolumab.   
 
PMBCL is recognized as a distinct lymphoma entity in the current World Health Organization 
classification. However, the diagnosis relies on integration of clinical characteristics at time of 
presentation since reliable distinction from DLBCL solely based on morphological or 
immunophenotypic features can be difficult and non-reproducible. Gene expression profiling 
(GEP) studies provide evidence that PMBCL can be distinguished from DLBCL on a molecular 
level and support a strong relationship between PMBCL and classical Hodgkin lymphoma 
(Rosenwald et al., J Exp Med 2003; Savage et al., Blood 2003). Because these studies were 
performed using snap-frozen tissue specimens, the molecular classification of PMBCL has not 
penetrated into clinical practice. The Lymphoma and Leukemia Molecular Profiling Project 
research consortium (LLMPP), of which Dr. Rimsza (Rimsza.Lisa@mayo.edu ) is the current 
Principal Investigator, recently developed a robust and accurate molecular assay for the 
distinction of PMBCL from DLBCL using GEP techniques applicable to routinely available 
formalin-fixed, paraffin-embedded tissue (FFPE) biopsies.  
 
The Lymph3Cx assay that will be used in this clinical trial is builds upon the well-established 
Lymph2Cx assay with the addition of a gene expression “module” that specifically identifies 
PMBCL in addition to the DLBCL subtypes (ABC, GCB, UNC).  The Lymph3Cx assay is run 
on the same platform as Lymph2Cx, the nCounter system by NanoString. The Lymph2Cx assay 
is now going through commercial development to become an FDA-cleared test. The Lymph2Cx 
is the only DLBCL cell-of-origin assay at such an advanced stage of development, indicating the 
quality of the assays by the LLMPP.  
For Lymph3Cx assay development, all cases used were centrally reviewed by a panel of expert 
hematopathologists in the LLMPP. Gene selection was performed using data previously 
generated on Affymetrix U133 plus 2.0 microarrays and the NanoString platform. The training 
cohort for the new Lymph3Cx assay consisted of 68 cases (48 DLBCL and 20 PMBCL), and the 
independent validation cohort was comprised of 88 PMBCL and 78 DLBCL (42 GCB, 26 ABC, 
10 unclassified). Cases were required to have a tumor content of > 60% (after macrodissection) 
and nucleic acids were extracted from 10 µm FFPE scrolls. Digital gene expression was 
performed using 200 ng RNA and the NanoString technology (Seattle, WA). Fresh versus 14 day 
old unstained tissue sections, at ambient temperature, were compared and yielded the same 
results on 5 samples indicating a 2 week time lag between cutting the samples and initiating 
testing is acceptable. Reproducibility between 2 different technical staff members, pathologists, 
and instruments was 100% for 9 samples repeated 2 weeks apart. Precision was assessed by 
repeating 5 cases on 3 different occasions, with 100% concordance. Dilution studies 
demonstrated that 100ng was the minimal reliable input for the assay. Potentially interfering 


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70 
substances, including all reagents used in the assay, were tested and demonstrated no 
interference. The final Lymph3Cx gene set consisted of 64 probes and included the previously 
described 20 genes of the Lymph2Cx assay. A classifier score was then modeled to account for 
error probabilities of the pathological classification and cut-points were defined at the 0.1 and 0.9 
probability scores. The model, including coefficients and thresholds was then “locked” and 
applied to the independent validation cohort. The assay yielded gene expression data of sufficient 
quality in 157/166 cases (94.6 %). Among the pathologically-defined PMBCL, 85% were also 
classified as such based on the molecular signature. Ten percent were allocated in the 
“uncertain” category and 5% of cases showed a molecular signature of DLBCL. Among the 
pathologically-defined DLBCL cases, 83% were classified as DLBCL by the assay, 14% were 
“uncertain” and 3% were predicted to be PMBCL based on GEP. The newly developed and 
validated Lymph3Cx assay clearly distinguishes PMBCL and DLBCL based on gene expression 
signatures and shows high concordance with the pathological classification of an expert 
hematopathologist panel. 
 
An important pre-analytical variable is percentage of tumor, which should be a minimum of 60% 
based on a second dilution study demonstrating that 60% and 50% gave reliable results, but that 
40%, 30%, and 20% did not. To be conservative, 60% was chosen to allow for slight variability 
in tumor content estimates and successive cuts off of the block. To address the tumor percent, an 
H&E stained section of each case will be assessed by Dr. Rimsza, who will estimate tumor 
purity. If needed, macro-dissection of the tissue sections will be performed to increase tumor 
content. Optimal input is 1 x 10 micron thick section for a 50mm2 biopsy. For smaller biopsies, 
proportionally more sections will be taken. Dr. Rimsza will measure the size of the tumor area 
and determine the number of needed sections at the same time that she determines the tumor 
content. A Pathology Quality Assurance form is used to document the tissue input specifics 
(size/number of needed sections and percent tumor). At this time, only formalin fixed biopsies 
(not other fixatives) have been assessed. The Pathology reports on the biopsies will be reviewed 
to determine whether formalin or another fixative was used. The average raw count of the 
housekeeping genes in the assay is used as a final quality control marker – samples with <20 
counts for this metric are reported as “Poor Quality”. The materials for this study will be 
analyzed in the exact same manner as the samples in the clinical laboratory that are tested for 
medical care. A positive and negative control and up to ten samples can be included in each 12-
well cassette. Positive control is an equimolar mixture of oligonucleotides which hybridizes with 
all probes in the assay. This will be lyophilized, reconstituted into stock solutions, and pooled by 
the manufacturer. The negative control is a well in the cassette that includes all reagents and 
probes, but no RNA.  Importantly, there is a 100% concordance of 10 cases between 3 different 
laboratories using the Lymph3Cx assay. For these reasons, we chose the Lymph3Cx assay as the 
molecular method of choice. We have standardized operating procedures, controls, and a 
completely locked algorithm. Scoring is not applicable in this assay. 
The lab performing this assay will be the Molecular Diagnostics – Arizona Laboratory, Mayo 
Clinic Arizona, CLIA #03D2113087; Medical Director: Dr. Lisa Rimsza; Performing 
technologist: Colleen Ramsower, MB(ASCP) and Tameson Yip, MB(ASCP). “MB” indicates 
these staff members are certified in molecular biology by the American Society of Clinical 
Pathologists. Testing for the proposed trial will follow the exact same procedures as are used for 
the samples in the clinical laboratory. Dr. Rimsza has extensive experience with the assay. She is 
the senior author on both the Lymph2Cx publication and Lymph3Cx abstract (manuscript in 


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preparation), co-inventor on both assay patents, and the Medical Director of a CAP-CLIA 
certified laboratory performing the Lymph2Cx assay, which is actively testing Mayo Clinic 
patients since December 2016. This is the first clinical laboratory in the country to offer the 
Lymph2Cx COO test for patient care. Dr. Rimsza both directs the laboratory and signs the 
medical results cases. 
 
9.2.1.1 
Collection of Specimen(s) 
 
The specimens will be formalin fixed, paraffin embedded (FFPE) tissue sections from the 
diagnostic pre-treatment biopsies of the patients, processed under standard clinical protocols at 
each participating site.  
 
 
9.2.1.2 
Shipping of Specimen(s) 
 
An H&E cut contiguously with the unstained sections is required. Tumor Cellularity must be >= 
60% (by area), but we have the ability to macrodissect if it is lower. 
 
If the tumor area (based on area containing 60% or more tumor cellularity) is: 
• Greater than or equal to 15mm2: send 3 unstained sections (4-5 microns thick) 
mounted on positively-charged slides, plus one H&E (cut contiguously with unstained 
sections) 
• Less than 15mm2: send 6 unstained sections (4-5 microns thick) mounted on positively-
charged slides, plus one H&E (cut contiguously with unstained sections) 
 
Label the slides with the following information: 
Protocol # 10193 
LM3CX 
Patient Study ID and Initials 
Date of sectioning 
“H&E” or “USS” (depending on whether it is the H&E or the unstained section) and the 
section # (i.e. H&E-1, USS-2, USS-3, etc., in the order they were cut.  Does not have to 
start with 1, but should be contiguous.). 
 
Performing Lab: Molecular Diagnostics – Arizona Laboratory (MDAZL), Mayo Clinic Arizona, 
CLIA #03D2113087.  Laboratory Director: Lisa M. Rimsza, M.D. 
Lab Contact:  Colleen Ramsower 
Email: Ramsower.Colleen@Mayo.edu 
Lab Phone: 480-301-4934 
 
Alternate Contact: Betty Glinsmann-Gibson 
Email: Glinsmann-Gibson.Betty@Mayo.edu 
Lab Phone: 480-301-9244 
 
 
 


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Shipping address: 
 
Attn: Colleen Ramsower 
Mayo Clinic Arizona 
13400 E. Shea Blvd. 
SC CR 01 250 MDAZL 
Scottsdale, AZ 85259 
480-301-4934 
 
Place the slides into shipping containers, and seal in a plastic bag.  Ship the slides overnight in a 
padded envelope, Monday through Thursday only (packages cannot be received on 
weekends). 
 
During the months of April-October, include a cool pack with the shipment (bagged separately 
from the slide containers). [If we don’t have some sort of web registration] Email Colleen 
Ramsower or Betty Glinsmann-Gibson a copy of the manifest as well as the shipment’s Tracking 
Number prior to sending.   
 
9.2.1.3 
Site(s) Performing Correlative Study 
 
Performing lab: Molecular Diagnostics – Arizona Laboratory, Mayo Clinic Arizona; Medical 
Director: Dr. Lisa Rimsza; Performing technologist: Colleen Ramsower, MB(ASCP)CM., 
Quality Specialist: Tameson Yip, MB (ASCP)cm 
 
9.3 
Exploratory/Ancillary Correlative Studies 
Unless otherwise indicated, we will follow the same steps for all correlative studies in terms of 
collection, handling and shipping as stated below in section 9.3.2 and 9.3.3. 
 
 
9.3.1 Background and Methodology 
We propose to obtain tumor tissue, peripheral blood mononuclear cells and serum for biomarker 
and correlative studies:  
• To characterize the effects of the copanlisib and nivolumab combination regimen on 
tumor cells, tumor microenvironment and the immune response in relapsed/refractory 
DLBCL and PMBCL 
• To assess predictors of response of the combination in relapsed/refractory DLBCL and 
PMBCL. 
 
We will use the PD1/PD-L1 expression, gene amplification, number and location of immune 
cells, genetic mutations in the tumor, peripheral cell subtypes and activation status, as well as 
cytokine profile to develop an immune signature that is associated with response to PD-1 
blockade in combination with copanlisib. 
 
Blood/blood product/Tissue samples will be collected for the following research:  
1.  Identification of intratumoral immune cells by immunohistochemistry (IHC). To assess 
whether the location or number of intratumoral immune cells predicts response to therapy, serial 


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5-μm paraffin-embedded sections will be deparaffinized and endogenous peroxidase quenched 
by incubation in 50% methanol/H2O2.  All sections will be pretreated with 50 mmol/L EDTA 
and staining will be done automatically on DAKO Autostainer using antibodies to CD11c (Leica 
Microsystems 5D11), CD14 (Cell Marque EPR 3653), CD163 (DAKO 1F8), CD68 (DAKO PG-
M1), CXCL13 (R&D Systems 53610), FOXP3 (Abcam 236AE/7), CD3 (R&D Systems), PD-L1 
(405.9A11), PD-L2 (366C.9E5) and PD-1 (Abcam NAT). Sections will be viewed with an 
Olympus BXFA51 microscope and photos taken with an Olympus DP71 camera. 
 
2.  Determine whether genetic amplification or copy number gain resulting in PD-L1/2 is 
associated with response to therapy in our patients.  FISH will be performed to assess copy 
number on chromosome 9p24.1.  The bacterial artificial chromosome probes (CHORI; 
www.chori.org) RP11-599H2O, which maps to 9p24.1 and includes PD-L1 (labeled with 
Spectrum Orange), and RP11-635N21, which also maps to 9p24.1 and includes PD-L2 (labeled 
with Spectrum Green), will be cohybridized.  A control centromeric probe, Spectrum Aqua–
labeled CEP9 (Abbott Molecular) that maps to 9p11-q11, will be hybridized according to the 
manufacturer's recommendations.  Nuclei with a target:control probe ratio of at least 3:1 will be 
classified as amplified, those with a probe ratio of more than 1:1 but less than 3:1 will be 
classified as relative copy gain, and those with a probe ratio of 1:1 but with more than two copies 
of each probe will be classified as polysomic for chromosome 9p. 
 
3.  Serum cytokine profile. To determine whether a serum cytokine profile can be used as a 
predictive biomarker, serum specimens will be subjected to multiplex ELISA (Invitrogen, 
Camarillo, CA) to measure 30 serum cytokines in pre-treatment and subsequent blood samples.  
Luminex-200 system version 1.7 will be used for reading plates and MasterPlex QT1.0 system 
(MiraiBio) will be used to analyze data. Cytokines will include epidermal growth factor (EGF), 
eotaxin, basic fibroblast growth factor (FGF-b), granulocyte macrophage colony stimulating 
factor (GM-CSF), hepatocyte growth factor (HGF), IFN-α, IFN-ϒ, interleukin 1 receptor 
antagonist (IL-1RA), IL-1β,IL-2, IL-2R , IL-4, 5, 6, 7, 8, 10,12,13,15,17, Inducible protein-10 
(IP10/CXCL10), monocyte chemotactic protein 1(MCP-1), monokine induced by interferon γ, 
(MIG/CXCL9), MIP-1α (CCL3), MIP1β (CCL4), regulated on activation normal T-cell 
expressed and secreted (RANTES),TNF-α and vascular endothelial growth factor (VEGF). 
Internal control serum will be included in all assays to control for interassay variation. 
 
4.  Changes in T-cell subsets by flow cytometry. To define changes in peripheral blood cell 
populations after treatment, peripheral blood mononuclear cells will be stained with 
fluorochrome-conjugated antibodies to human CD69 (R&D Systems), CD3 (clone HIT3a), 
CD19 (clone 4G7), PD1 (clone EH12.1), CD14 (clone M5E2), CD163 (clone GH1/61), CD21 
(clone B-ly4), PD-L2 (clone M1H18), PD-L1 (clone M1H1), TIM3 (clone 344823), and CD23 
(clone EBVCS-5; all obtained from BD Biosciences) and the data will be analyzed using 
CellQuest software (Becton Dickinson). 
 
5.  Sequencing to determine mutational burden. To determine whether increased numbers of 
mutations correspond to increased responses to therapy, genomic DNA will be extracted from 
formalin-fixed, paraffin- embedded tissue blocks for mutational analysis. DNA will be extracted 
using the Qiagen FFPE DNA extraction kit. DNA quantitation will be performed using a Qubit 
fluorometer prior to sequencing. Whole-exome capture libraries constructed via the Agilent 


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Sure-Select Human All Exon v2.0, 44Mb baited target with the Broad in-solution hybrid 
selection process will be used. Enriched exome libraries will be sequenced on the HiSeq 2000 
platform (Illumina) to generate paired-end reads (2x76bp) to a goal of 150X mean target 
coverage (Broad Institute, Cambridge, MA). Targeted resequencing using a custom panel of 376 
loci to a target coverage of 500X will be performed using Ampliseq (Life Technologies). 
 
6.  Screening for PTEN Loss. The following methods were developed and validated using 
standard approaches for clinical test validation, in line with CLIA provisions and CAP 
requirements at MDACC (in collaboration with Dr. Timothy Yap) clinical IHC laboratory, which 
is certified under the provisions of the United States Clinical Laboratory Improvement Act 
(CLIA) and accredited by the College of American Pathologists (CAP). This laboratory is also 
the central laboratory for the PTEN immunohistochemical study for the National Cancer Institute 
(NCI) Molecular Analysis for Therapy Choice (MATCH) trial.   The anti-human PTEN antibody 
clone 6H2.1 (isotype IgG2a, kappa) is manufactured by Dako and registered with the Food and 
Drug Administration (FDA) for in vitro diagnostic use (IVD).  Per  Dako, the immunogen 
against which the antibody is produced is the full-length recombinant human PTEN protein.   
This is a monoclonal mouse anti-PTEN clone 6H2.1 which identifies a single band at the 55 kD-
predicted molecular weight for PTEN in western blots of MCF-7, T-47D and MDA-MB-435S 
PTEN-homozygous cell lines. PTEN-null cell lines BT-549 and MDA-MB-468 were unreactive 
with clone 6H2.1 by western blot analysis. Immunoblots of MCF-7 cells induced to express 
PTEN demonstrated an increased band intensity at the expected size, while a weak band was 
observed on immunoblots of ZR-75-1 cell lysates containing a hemizygous deletion of PTEN 
and a missense mutation in the remaining allele. Immunohistochemical staining of sections from 
FFPE blocks of Ishikawa 3-H-12 cells transfected with PTEN stained positively, whereas PTEN-
deficient 3-H-12 cell block sections were unreactive. The anti-PTEN antibody is provided in 
liquid form as a tissue culture supernatant (containing fetal bovine serum) at a concentration of 
222.4 mg/L dialyzed against 0.05 mol/L Tris-HCl, pH 7.2, and 0.015 mol/L sodium azide, and 
containing stabilizing protein. 
 
This antibody can be used to perform IHC on formalin-fixed paraffin-embedded (FFPE) tissue 
sections and has been in use since 2010. The final protocol is validated for use on 4 um FFPE 
tissue sections. In brief, following deparaffinization and rehydration of the tissues sections, 
antigen retrieval is performed at 100 °C for 20 minutes with Tris-EDTA buffer, pH 6.0.  
Endogenous peroxidase is blocked with 3% peroxide for 5 minutes. Primary PTEN antibody 
(Dako, clone 6H2.1) is applied at 1:100 dilution.  Primary antibody detection is carried out using 
a commercial polymer system (Bond Polymer Refine Detection, Leica), and staining 
development is achieved by incubation with DAB and DAB Enhancer (Leica) 
 
A positive and negative control is added to every IHC run (batch control) and is reviewed by a 
member of the IHC medical directorship team. Records of batch control results are documented 
daily in internal laboratory records. 
 
Correlatives (1 to 6) will be done at Stephen Ansell’s laboratory (Chair of lymphoma disease 
oriented group). Dr. Ansell has extensively studied the effects of immunotherapy on the tumor 
and tumor microenvironment and has published several papers in the topic. These correlatives 
will be exploratory. 


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7.  Circulating free DNA (cfDNA). Correlate effects of therapy on cfDNA and correlation with 
degree of response and use as an early predictor of progression of disease.  Plasma samples from 
patients will be screened for cfDNA at the end of the trial. We will develop and optimize digital 
droplet PCR-based assays on the customizable RainDrop Digital PCR System 
(http://raindancetech.com/digital-pcr-tech/raindrop-digital-pcr-system).  We will use the best 
technology available at the end of the trial as this is a rapidly evolving area of research. 
 
9.3.2 Handling and shipping of blood specimen(s) 
 
9.3.2.1 
Kits 
• Kits will be used for this study. Kits will contain supplies and instructions for 
collection, processing and shipping specimens 
• Participating sites may obtain kits by emailing: henderson.kimberly@mayo.edu. 
Email requests should include address, contact information and number of kits 
being requested. 
• Kits will be sent via FedEx Ground at no additional cost to participating sites. 
Allow 3-4 business days to receive kits. 
 
9.3.2.2  
Packing and Shipping Instructions:  
Peripheral blood samples should be shipped the same day they are collected 
(Monday-Thursday). They should be shipped priority overnight taking care to 
avoid Friday collection and shipping. 
 
If unavoidable, Friday shipping with Saturday delivery can be arranged 
contacting the laboratory in advance. Please notify Mayo Clinic by email 
henderson.kimberly@mayo.edu or phone (507) 284-3805 to notify laboratory 
when specimens are being shipped. 
 
See Appendix I for additional details 
 
Please email Kim Henderson at Henderson.kimberly@mayo.edu or call 
507-284-3805 to notify the laboratory when samples are being shipped. 
Indicate the protocol number MC1787/10193, the Fed Ex tracking 
number, name and phone number of the contact person. The samples in 
prepared kits should be shipped to the following:  
 
Mayo Clinic 
Attn: Stacey Lehman 
Stabile 613 
221 4th Avenue SW Stabile  
Rochester, MN 55905 
 
 
 


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9.3.3 Handling and shipping of tissue specimen(s) 
 
9.3.3.1 Collection of Specimen(s): FFPE tumor tissue  
9.3.3.2 Handling and Shipping of Specimen(s): FFPE tumor blocks are preferred. Alternatively, 
unstained glass slides from FFPE are acceptable. Please include a copy of the de-identified 
surgical pathology report, as well as study, site and patient study numbers. All FFPE specimens 
for correlative studies may be shipped together.  
Shipping Procedure:  
1. Place the block or slides in small zip-lock bag and seal.  
2. Insert the bag containing the block or the slides in a bubble wrap bag.  
3. Place wrapped samples inside the largest compartment of specimen biohazard bag and 
seal.  
4. Insert a copy of the de-identified surgical pathology report in the outer pocket of the 
specimen biohazard bag.  
5. Include a refrigerated cold pack (not frozen) if shipping in the summer months.  
6. Place the specimen biohazard bag into the box and close.  
7. Complete the transport documents and place into waybill pouch; affix to box.  
8. Ship package to Mayo Clinic at the address below.  
9. Please send email on the day of the shipment.  
 
Please send FFPE tissue to:  
Mayo Clinic 
Attn: Stacey Lehman 
Mayo Clinic  
Stabile 613  
221 4th Avenue SW  
Rochester, MN 55905


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77 
10. STUDY CALENDAR 
 
Baseline laboratory evaluations are to be conducted within 14 days prior to start of protocol 
therapy.  Scans and x-rays must be done < 4 weeks prior to the start of therapy. Pre-study labs 
must be done ≤7 days prior to start of therapy. Windows of ± 1 to 2 days are permissible for 
cycles 1, 2 and 3; windows of ± 3 days are permissible for cycles 4 and beyond.  In the event that 
the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. 
 
 
Pre-
Study 
Cycle 1 
Cycle 2 
Cycle 3-8 
Cycle 9 and 
beyond 
 
Off  
Studye 
D1 
D8 
D15 
D1 
D8 
D15 D1 D8 D15 D1 D8 D15 
 
Copanlisib 
 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
 
C 
 
Nivolumab 
 
N 
 
N 
N 
 
N 
N 
 
N 
N 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam1 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Oxygen saturation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Lab tests a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of 
Cardiac Functionf  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Radiologic 
evaluation 
X 
Radiologic measurements should be performed every 12 weeks.  
Documentation (radiologic) must be provided for patients removed from study 
for progressive disease 
FFPE for 
correlatives 
Xc 
 
Xc 
 
 
 
 
 
 
 
 
 
 
Xc 
Blood for 
correlativesd 
X 
 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
C: Copanlisib: Dose to be determined after a safety run-in given IV on days 1, 8 and 15 during 
every 28-day cycle for cycles 1-8.  Cycle 9 and beyond, IV will be given on days 1 and 15. 
 
N: Nivolumab:  All patients: 240 mg given IV on days 1 and 15 for cycles 1 through 8 followed 
by 480 mg on day 1 only of all subsequent cycles thereafter 
 
1.  Physical exam includes demographics, medical history, concurrent medications, vital signs, 
performance status, weight and at pre-study only, height. 
 
a: Lab tests to be performed at baseline and within 72 hours prior to each study drug 


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78 
administration include CBC with differential and chemistry: albumin, alkaline phosphatase, 
total bilirubin, bicarbonate, BUN/urea, calcium, magnesium, chloride, creatinine, glucose, 
LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, amylase, 
lipase, TSH (with reflexive Free T4 and Free T3).  Laboratory test monitoring will continue 
as long as patient continues to receive study treatment. 
 
b: Serum or urine pregnancy test for females of childbearing potential.  A serum or urine 
pregnancy test is required within 24 hrs of starting study treatment 
 
c.    Archived tumor tissue should be submitted at pre-study.  If no tissue is available, a new 
biopsy must be performed.  Additional optional tumor tissue biopsies can be performed at 
Day 8, Cycle 1 and at time of disease progression.   
 
d: Blood draws for research are performed at pre-study, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 
4 Day 1 and at disease progression. cfDNA will be done at baseline, Cycle 1 Day 8, Cycle 1 
D15, Cycle 3 Day 1 and at time of disease progression.  Blood should be drawn prior to 
treatment.  
 
e: Off-study evaluation to be performed 30 days after the last dose of study drug.   Patients are 
followed for at least 100 days for AE assessment. 
 
f:   Perform an evaluation of cardiac function including ECG and echocardiogram and Troponin 
for all patients at screening, and thereafter as clinically indicated. Also perform an evaluation 
for patients with evidence of CHF, MI, cardiomyopathy, or myositis including lab tests and 
cardiology consultations including ECG, echocardiogram, CPK and troponin as clinically 
indicated 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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79 
11. MEASUREMENT OF EFFECT 
 
If a second confirmatory scan indicates unequivocal disease progression, the subject will be 
discontinued from treatment. The date of the first scan indicating progression will be used for 
analysis purposes. If however the second scan indicates a reduction in tumor burden or stable 
disease from the baseline scan, the subject may continue on treatment in the absence of 
unacceptable toxicity or other reason for treatment discontinuation. 
Notwithstanding, the Investigator is free to remove the patient from treatment at any time during 
the study if it is felt to be in the patient’s best interest. 
 
11.1 
Antitumor Effect – Hematologic Tumors 
 
Lugano Classification Response Criteria 
 
11.1.1 Response Considerations  
 
 
Definitions for clinical response for patients with lymphoma are based on the 
lymphoma response to immunomodulatory therapy criteria or LYRIC.(Cheson et 
al. 2016)  Lymph node measurements should be taken from the CT portion of the 
PET/CT, or other dedicated CT scans where applicable.  Measurement of 
lymphadenopathy for purposes of assessing for PR will be determined by adding 
the sum of the products of the maximal perpendicular diameters of measured 
lesions (SPD). The perpendicular diameter of a single node is sufficient to 
evaluate for PD (see Table 11.1.2).  Measurable extranodal disease should be 
assessed in a manner similar to that for nodal disease.  For these 
recommendations, the spleen is considered nodal disease. Disease that is only 
assessable (e.g., pleural effusions, bone lesions) will be recorded as present or 
absent only, unless, while an abnormality is still noted by imaging studies or 
physical examination, it is found to be histologically and pathologically negative. 
 
 
For response assessment, PET-CT is preferred for staging of FDG-avid 
lymphomas and CT scan is preferred in the other lymphomas 
 
   
Progressive disease is based on either PET-CT based (PMD) or CT based (PD) 
response criteria.  Definition of progressive disease according to LYRIC is same 
as the Lugano classification except that a new category of indeterminate response 
(IR) is added. Patients whose disease fall in the IR category may continue 
treatment for additional 12 weeks if the patient remains clinically stable as judged 
by the treating physician. A repeat imaging study  in 12 weeks (or earlier if 
clinically indicated) is mandatory to confirm or refute disease progression.  PET 
confirmation of progressive disease is per physician discretion.  
 


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80 
11.1.2 Lymphoma Response to Immunomodulatory Therapy Criteria [ LYRIC] (adapted from 
Cheson et al., 2016)  
 
 
PET-CT Based Response 
CT-Based Response 
Complete 
Response 
(CR) 
Complete metabolic response (CMR) 
Complete radiologic response (CR) 
(all of the following) 
Lymph nodes 
and extra 
lymphatic sites  
Score 1, 2, or 3a with or without a residual 
mass on 5PS† 
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic 
uptake or with activation within spleen or 
marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), 
uptake may be greater than normal 
mediastinum and/or liver. In this 
circumstance, complete metabolic 
response may be inferred if uptake at sites 
of initial involvement is no greater than 
surrounding normal tissue even if the 
tissue has high physiologic uptake 
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi 
No extra lymphatic sites of disease 
Non-measured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if 
indeterminate, IHC negative 
Partial 
Response 
(PR) 
Partial metabolic response (PMR) 
Partial remission (PR) 
(all of the following) 
 Lymph nodes 
and extra 
lymphatic sites  
Score 4 or 5† with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
At interim, these findings suggest 
responding disease 
At end of treatment, these findings 
indicate residual disease 
≥ 50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites 
When a lesion is too small to measure 
on CT, assign 5 mm X 5 mm as the 
default value 
When no longer visible, 0 X 0 mm 
For a node > 5 mm X 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
Non-measured 
lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by > 50% 
in length beyond normal 


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81 
 
PET-CT Based Response 
CT-Based Response 
New lesions 
None 
None 
Bone marrow  
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan 
Not Applicable  
No Response 
or Stable 
Disease 
No metabolic response (NMR) 
Stable disease (SD) 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or 
end of treatment 
< 50% decrease from baseline in SPD 
of up to 6 dominant, measurable 
nodes and extranodal sites; no criteria 
for progressive disease are met 
Non-measured 
lesions 
Not applicable 
No increase consistent with 
progression  
Organ 
enlargement 
Not applicable 
No increase consistent with 
progression  
New lesions 
None 
None 
Bone marrow  
No change from baseline 
Not Applicable 
Indeterminate 
Response (IR)  
 
IR(1)b 
 
≥ 50% increase in SPD of up to 6 
measurable lesions in first 12 weeks 
without clinical deterioration. 
 
Note: The measurements from the 
first IR (1) time point becomes the 
reference against which future 
assessment will be compared.  An 
increase of ≥ 10% (in addition to an 
increase of ≥ 5 mm in either 
dimension of ≥ 1 lesion for lesions ≤ 
2cm and 10 mm for lesions > 2 cm) 
constitutes PD 
IR(2) 
 
< 50% increase in SPD of up to 6 
measurable lesions with: 
a. new lesion(s), or 
b. ≥ 50% increase in PPD of a lesion 
or set of lesions at any time during 


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82 
 
PET-CT Based Response 
CT-Based Response 
treatment. 
 
Note: The new or growing lesion(s) 
(unless biopsy proven to be benign) 
should be added to the target 
lesion(s), up to a total of no more than 
6 total lesions. In future assessments, 
if the SPD of the newly defined set of 
target lesions has increased ≥ 50% 
from their nadir value (which may 
precede the IR time point), the patient 
should be considered to have PD. 
IR(3) 
Increase in FDG uptake of 1 or more 
lesion(s) without a concomitant increase 
in lesion size or number. 
 
Note: Because inflammatory responses 
may result in an increase in the 
standardized uptake value of a lesion, the 
patient will not be considered to have PD 
unless there is evidence of PD by an 
increase in lesion size or the development 
of new lesions, as noted below. 
 
Progressive 
disease (PD) 
*** Excludes patients who meet criteria for Indeterminate Response (IR) *** 
Progressive metabolic disease (PMD) 
Progressive disease (PD) 
requires at least 1 of the following 
Individual 
target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity 
of uptake from baseline and/or 
 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment 
An individual node/lesion must be 
abnormal with:  
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir 
and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions >2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior increase 
beyond baseline (e.g., a 15 cm spleen 
must increase to >16 cm).  
If no prior splenomegaly, must 
increase by at least 2 cm from 
baseline 
New or recurrent splenomegaly 
Extranodal 
lesions 
Non-measured 
None 
New or clear progression of 


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83 
 
PET-CT Based Response 
CT-Based Response 
lesions 
preexisting non-measured lesions 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(e.g., infection, inflammation). If 
uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered 
Regrowth of previously resolved 
lesions 
A new node >1.5 cm in any axis 
A new extranodal site >1.0 cm in any 
axis; if <1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance 
imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular 
diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular 
diameters for multiple lesions. 
a.   A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at 
the time of an interim scan. However, in trials involving PET where de-escalation is 
investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid under 
treatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, 
and extranodal lesions selected to be clearly measurable in two diameters. Nodes should 
preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g., liver, 
spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or those noted on palpation. 
Non-measured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal 
masses, and extranodal sites not selected as dominant or measurable or that do not meet the 
requirements for measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In 
Waldeyer’s ring or in extranodal sites (e.g.,, GI tract, liver, bone marrow), FDG uptake may be 
greater than in the mediastinum with complete metabolic response, but should be no higher than 
surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy 
or myeloid growth factors). 
†   PET Deauville 5PS: 1, no uptake above background; 2, uptake ≤  mediastinum; 3, uptake > 
mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver 
and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
b.   If a patient is assessed as having IR and then “true” PD at a subsequent time point (without an 
intervening objective response between IR and PD), the IR assessment should subsequently be 
corrected to PD for reporting purposes to the date of the prior designation of IR. We recognize 
that these lesions may remain stable during the time of observation, but, even if this is the case, 


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84 
 
PET-CT Based Response 
CT-Based Response 
the initial designation of IR should be changed to PD. 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
12.1 
Study Oversight 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
This protocol is monitored at several levels, as described elsewhere in this section.  The Protocol 
Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, 
including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine 
and serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via the mechanism described elsewhere in this section.  
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
 


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85 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Rave Read-Only, Rave CRA (Lab Admin), Rave SLA, or 
Rave Investigator) on either the LPO or participating organization roster at the enrolling site. To 
the hold Rave CRA role or Rave CRA (Lab Admin) role, the user must hold a minimum of an 
AP registration type.  To hold the Rave Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in Rave.  If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on 
the DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted on an 18-36 month basis as part of routine cancer center site 
visits. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission.  For CTMS monitored studies, after users 
have activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 
or by email at CTMSSupport@theradex.com for additional support with Rave and 
completion of CRFs. 
 


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86 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D) and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
 


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87 
 
12.3 
CTEP Multicenter Guidelines 
NA 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  


NCI Protocol #:10193 
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88 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
12.5 
Genomic Data Sharing Plan 
 
NA 
 
12.6 
Incidental/Secondary Findings Disclosure Procedure 
 
NA 
 
 
 
 
 
 


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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints: 
 
13.1.1 Overview 
This is a parallel phase II study of Nivolumab and Copanlisib in patients with 
relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal 
large B-cell lymphoma (PMBCL). It is designed using two separate a one-stage designs 
with an interim analyses based on the Simon optimal design to assess efficacy (ORR 
(CR+PR)).   
 
13.1.2 Primary Endpoint 
The primary endpoint is the proportion of objective responses (either a CR or PR 
according to Lugano criteria). Throughout Section 13.0, CR or PR will be considered 
synonymous with “success”, unless specified otherwise. All patients meeting the 
eligibility criteria who have signed a consent form and have begun treatment will be 
evaluable for response. 
 
 
DLBCL and PMBCL will be analyzed and reported separately. 
 
13.1.3 Statistical Design 
 
13.1.3.1 
Decision Rules are based upon prior response rates reported in sections 2.2.1 and 
2.2.2. 
It is expected that this dose will have response rates similar to those 
presented. 
 
13.1.3.2  Safety Cohort 
This treatment regimen has been explored in previous studies but study results have 
not been reported, thus, it has been determined that a safety cohort is necessary to 
confirm the copanlisib dose. 
 
6 patients will be enrolled on the trial and accrual will cease until these six patients 
have been evaluated for adverse events in 1 cycle.  If 1 or 0 of 6 patients experience a 
DLT as defined in section5.1.3.3 , the study will open enrollment to accrue the rest of 
the patients.  If 2 or more of 6 patients experience a DLT, the trial will be halted 
while the examination of the treatment regimen at a lower dose will be explored.  If it 
is determined that a lower dose is appropriate, 6 patients will be accrued at the lower 
dose and accrual will cease until these six patients have been evaluated for adverse 
events in 1 cycle.  If 1 or 0 of 6 patients experience a DLT as defined in 
section5.1.3.3 , the study will open enrollment to accrue the rest of the patients.  If no 
DLTs are observed at dose level 1, the study will open to complete accrual. If 1 or 
less patients experience DLTs at dose level -1, the study will open to complete 
accrual. If 1 or less patients experience DLTs at dose level 1, the study will open to 
complete accrual. 


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This decision rule is based on the decision rules for a standard cohorts of 3 trial 
design.  The safety cohort will not be separated by lymphoma subtypes as it is 
expected that the treatment regimen will have the same effect on all three lymphoma 
subtypes.  The 6 patients accrued at the acceptable dose will be included in the 
primary analysis. 
 
13.1.3.3 DLBCL: The largest success proportion where the proposed treatment 
regimen would be considered ineffective in DLBCL is 25%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in this 
patient population is 45%. This design uses 44 evaluable patients to test the null 
hypothesis that the true complete response rate is at most 25%. 
 
13.1.3.3.1 Interim Analysis: Enter 14 evaluable patients into the study. If there 
are three or less successes observed in the first 14 evaluable patients, we will 
consider this regimen ineffective in this patient population and terminate this 
study. Otherwise, if the number of successes is at least 4, we will continue 
accrual. 
 
13.1.3.3.2 Final Decision Rule: If 14 or fewer successes are observed in the first 44 
evaluable patients, we will consider this regimen ineffective in this patient 
population. If 15 or more successes are observed in the first 44 evaluable patients, we 
may recommend further testing of this regimen in subsequent studies in this 
population. 
 
13.1.3..3.3 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making process. Analyses involving over accrued patients are discussed in 
Section 16.3.4. 
 
13.1.3.3.4 NOTE: We will not suspend accrual at the interim analysis to allow the 
first 14 patients to become evaluable, unless undue toxicity is observed. Given the 
limited overall sample size and the inclusion of an adverse events stopping rule, we 
feel it is ethical to not halt accrual for the interim analysis. However, if accrual is 
extremely rapid, we may temporarily suspend accrual in order to obtain safety and 
efficacy data on these patients before re-opening accrual to further patients. 
 
13.1.3.4 PMBCL: The largest success proportion where the proposed treatment 
regimen would be considered ineffective in PMBCL is 30%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in this 
patient population is 50%. This design uses 46 evaluable patients to test the null 
hypothesis that the true complete response rate is at most 30%. 
 


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13.1.3.4.1 Interim Analysis: Enter 22 evaluable patients into the study. If there are 7 
or less successes observed in the first 22 evaluable patients, we will consider this 
regimen ineffective in this patient population and terminate this study. Otherwise, if 
the number of successes is at least 8, we will continue accrual. 
 
13.1.3.4.2 Final Decision Rule: If 17 or fewer successes are observed in the first 46 
evaluable patients, we will consider this regimen ineffective in this patient 
population. If 18 or more successes are observed in the first 46 evaluable patients, we 
may recommend further testing of this regimen in subsequent studies in this 
population. 
 
13.1.3.4.3 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making process. Analyses involving over accrued patients are discussed in 
Section 16.3.4. 
13.1.3.4.4 NOTE: We will not suspend accrual at the interim analysis to allow the first 22 
patients to become evaluable, unless undue toxicity is observed. Given the limited overall sample 
size and the inclusion of an adverse events stopping rule, we feel it is ethical to not halt accrual 
for the interim analysis. However, if accrual is extremely rapid, we may temporarily suspend 
accrual in order to obtain safety and efficacy data on these patients before re-opening accrual to 
further patients. 
 
 
13.2 
Sample Size/Accrual Rate  
 
13.2.1 This study is expected to require a minimum of 42 (6 safety cohort, 14 DLBCL and 22 
PMBCL) and a maximum of 96 (6 safety cohort, 44 DLBCL and 46 PMBCL) evaluable 
patients. We anticipate accruing 10 (10%) additional patients to account for ineligibility, 
cancellation, or other reasons. Therefore, the study is expected to accrue a maximum of 
106 patients overall. 
 
13.2.2 Accrual Rate and Study Duration:  The anticipated accrual rate for the safety cohort is 2-
3 months.  The anticipated accrual rate is 3-5 patients per month for the DLBCL cohort 
and 1-2 patients per month for the PMBCL group.  Therefore, after assessing safety, the 
accrual period is expected to be 11 months for the DLBCL cohort, with the primary 
endpoint evaluated at approximately 17 months after the trial opens (or after the last 
patient accrued has been observed for at least 6 months and data collection for the 
induction phase is complete). The accrual period is expected to be 31 months for the 
PMBCL cohort, with the primary endpoint evaluated at approximately 37 months after 
the trial opens. The total study duration is expected to maximally be 6.75 years, or until 
all patients have completed all cycles of treatment. 
 


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13.2.3 Power and Significance Level: Assuming that the number of successes is binomially 
distributed, the significance level is .10, i.e. there is a 10% chance of finding the drug to 
be effective when it truly is not. The probability of declaring that this regimen warrants 
further study (i.e. statistical power) under various success proportions and the probability 
of stopping accrual after the interim analysis can be tabulated as a function of the true 
success proportion. 
 
For DLBCL: 
 
If the true success proportion is... 0.25 
0.30 
0.35 
0.40 
0.45 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.097 
0.286 
0.543 
0.766 
0.901 
and the probability of stopping 
after 
the interim analysis is … 
0.521 
0.355 
0.221 
0.124 
0.063 
 
 
 
 
For PMBCL: 
 
If the true success proportion is... 0.30 
0.35 
0.40 
0.45 
0.50 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.097 
0.279 
0.532 
0.762 
0.905 
and the probability of stopping 
after 
the interim analysis is … 
0.671 
0.474 
0.290 
0.152 
0.067 
 
 
13.2.4 Other considerations: Adverse events, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or changes in 
standard care will be taken into account in any decision to terminate the study. 
 
13.3 
Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender, or ethnic 
origin. 
 
There is no information currently available regarding differential effects of this regimen 
in subsets defined by race, or ethnicity, and there is no reason to expect such differences 
to exist. Therefore, although the planned analysis will, as always, look for differences in 
treatment effect based on racial, the sample size is not increased in order to provide 
additional power for subset analyses. 
The diagnosis is more common in men, as the male:female ratio is approximately 2:1 
(Weisenburger et al. 2011) 


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Based on prior ACCRU studies involving similar disease sites, we expect the  racial 
distribution by gender subsets as shown in the following table: 
 
 
Accrual Estimates by Gender/Ethnicity/Race PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
0 
1 
0 
0 
1 
Asian 
2 
3 
0 
0 
5 
Native Hawaiian or 
Other Pacific Islander 
0 
1 
0 
0 
1 
Black or African 
American 
5 
8 
0 
0 
13 
White 
28 
50 
1 
3 
82 
More Than One Race 
1 
2 
0 
0 
3 
Total 
36 
65 
1 
3 
106 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) OMB No. 0925-0001/0002 
 
 
13.4 
Grouping Factors 
 
13.4.1 
Histology: DLBCL vs PMBCL 
 
13.5 
Evaluation of Response 
 
13.5.1 Primary Outcome Analyses: 
 
13.5.1.1 
The proportion of successes will be estimated by the number of successes divided by 
the total number of evaluable patients. Confidence intervals for the true success 
proportion will be calculated according to the approach of Duffy and Santner (Duffy 
D 1987). 
 


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13.5.2 Secondary Outcome Analyses: These analyses will include all patients meeting the 
eligibility criteria who have signed a consent form and have begun treatment, including 
patients who fail to achieve a complete or partial response. 
 
13.5.2.1 
Adverse Events: All eligible patients that have initiated treatment will be considered 
evaluable for assessing adverse event rate(s). The maximum grade for each type of 
adverse event will be recorded for each patient, and frequency tables will be reviewed 
to determine patterns. Additionally, the relationship of the adverse event(s) to the 
study treatment will be taken into consideration. 
 
13.5.2.2 
Progression free survival time is defined for all evaluable patients as the time from 
registration to relapse or death due to any cause. Patients are censored if they have not 
achieved progression at the time of analysis.  The distribution of progression-free 
survival will be estimated using the method of Kaplan-Meier. In addition, the 
progression-free survival rate at 5 years after registration will be reported. 
 
13.5.2.3 
Duration of response is defined for all evaluable patients who have achieved a CR or 
PR as the date at which the patient’s objective status is first noted to be a CR or PR to 
the earliest date relapse is documented. The distribution of duration of complete 
response will be estimated using the method of Kaplan-Meier. 
 
13.5.2.4 
Overall survival time is defined as the time from registration to death due to any 
cause. Patients are censored if they are alive at the time of analysis.  The distribution 
of survival time will be estimated using the method of Kaplan-Meier (Kaplan and 
Meier 1958).  
 
13.5.3 Over Accrual: If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any decision making 
processes; however, they will be included in final endpoint estimates and confidence 
intervals. 
 
13.6 
Evaluation of Toxicity: 
 
13.6.1 The study statistician will review the study weekly to monitor accrual, endpoints and 
adverse events. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring Board 
(DSMB) is responsible for reviewing accrual and safety data for this trial at least twice a 
year, based on reports provided by the MCCC Statistical Office. 
 
13.6.2 Adverse Event Stopping Rules: The stopping rules specified below are based on the 
knowledge available at study development. We note that the Adverse Event Stopping 
Rule may be adjusted in the event of either (1) the study re-opening to accrual or (2) at 
any time during the conduct of the trial and in consideration of newly acquired 
information regarding the adverse event profile of the treatment(s) under investigation. 
The study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to this study if at any time we 


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observe events considered at least possibly related to study treatment (i.e. 
an adverse event with attribute specified as “possible,” “probable,” or 
“definite”) that satisfy one of the following: 
• if 2 or more patients in the first 10 treated patients (20%) experience a 
grade 4 or higher non-hematologic adverse event at least possibly 
related to treatment. 
• if after the first 10 patients have been treated, 20% of all patients 
experience a grade 4 or higher non-hematologic adverse event at least 
possibly related to treatment.  
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
 
13.7 
Results Reporting on ClinicalTrials.gov:  
At study activation, this study will have been registered within the 
“ClincialTrails.gov” website. The Primary and Secondary Endpoints along with 
other required information for this study will be reported on ClinicalTrials.gov. 
For purposes of timing of the Results Reporting, the initial estimated completion 
date for the Primary Endpoint of this study is 5.5 years after the study opens to 
accrual. The definition of “Primary Endpoint Completion Date” (PECD) for this 
study is at the time the last patient registered has been followed for at least 2 
months. 
 
 
 


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Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Vose JM (2009) Lenalidomide 
oral monotherapy produces durable responses in relapsed or refractory indolent non-
Hodgkin's Lymphoma. J Clin Oncol 27 (32):5404-5409. doi:10.1200/jco.2008.21.1169 
Yang ZZ, Grote DM, Ziesmer SC, Niki T, Hirashima M, Novak AJ, Witzig TE, Ansell SM 
(2012) IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients 
with follicular B cell non-Hodgkin lymphoma. J Clin Invest 122 (4):1271-1282. 
doi:10.1172/jci59806 
Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM (2006) Attenuation of CD8(+) T-cell 
function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin's lymphoma. 
Cancer Res 66 (20):10145-10152. doi:10.1158/0008-5472.can-06-1822 
Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. 
Oncogene 27 (41):5497-5510. doi:10.1038/onc.2008.245 
Zinzani PL, Ribrag V, Moskowitz CH, Michot JM, Kuruvilla J, Balakumaran A, Zhang Y, 
Chlosta S, Shipp MA, Armand P (2017) Safety & tolerability of pembrolizumab in 
patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 
doi:10.1182/blood-2016-12-758383 
 
 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all 
pre-disease performance without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited 
self-care, confined to bed or chair more than 50% 
of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot 
carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
 
 
 


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APPENDIX B: PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of 
your healthcare 
providers and keep it 
with you in case you go 
to the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:        
Study Drug(S):        
 
 
 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
 
Version mm/yyyy 
 
 
 
 
 
 
 
 


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APPENDIX C 
MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND 
SKIN ADVERSE EVENTS 
 
 
 
 


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APPENDIX D 
MANAGEMENT OF TRANSIENT GLUCOSE INCREASE ON THE 
DAY OF COPANLISIB INFUSION  
 
Criteria 
Recommendation 
Suggested Treatment 
Asymptomatic 
glucose 
increases 
≤250mg/dL 
Does not generally require 
treatment with glucose lowering 
medication. 
None 
Asymptomatic 
glucose increase  
> 250 mg/dl 
• Should have repeated laboratory 
glucose determination. 
• If the repeated glucose value is 
decreasing, the glucose may be 
followed without glucose 
lowering medication treatment if 
hydration status is normal as 
clinically assessed. 
• Consultation with 
endocrinologist is recommended 
• Hydration if appropriate  
• When planning next 
infusion consider 
prophylaxis with oral 
glucose lowering medication 
Symptomatic or 
persisting 
glucose 
increases               
>250mg/dL 
• Hydration status should be 
clinically assessed.  
• If clinical assessment is 
consistent with dehydration, 
fluids should be given as 
clinically appropriate (orally or 
IV). 
• Laboratory test confirming 
increase should be repeated. If 
the repeated glucose value is 
persistent and/or patient is 
symptomatic and/or the hydration 
status indicates the need for 
hydration, glucose lowering 
medication should be 
administered. 
• Prompt input from a diabetes 
specialist should be obtained.  
• Hydration if appropriate  
• Rapid/ short acting insulin 
may be given for glucose 
persisting at >250 mg/dL, or 
if the patient is symptomatic 
during the infusion day. 
• Rapid/short acting insulin 
• 
    according to the 
institution sliding scale 
coverage of glucose 
persisting at >250 mg/dL is 
recommended, with oral or 
IV hydration as clinically 
appropriate When planning 
next infusion consider 
prophylaxis with oral 
glucose lowering 
medication 
 
 


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APPENDIX E 
MANAGEMENT OF TRANSIENT GLUCOSE INCREASE ON 
SUBSEQUENT DAYS FOLLOWING COPANLISIB INFUSION  
 
Criteria 
Recommendation 
Suggested Treatment 
Max post 
infusion 
glucose             
>200 mg/dL 
noted on  
subsequent 
days 
• Oral Glucose Lowering 
Medication Recommended 
on subsequent days.  
• Consultation with 
endocrinologist is 
recommended. 
• The use of 
sulphonylurea/metaglinides, isnulin 
secretagogues medications to manage 
increased glucose levels post drug 
infusions is not recommended. 
• Treatment with glucose lowering 
medication suggested according the 
local standards of practice.  
• Based on mechanisms of action 
and decreased risk of 
hypoglycemia, metformin, SGLT- 
2-inhibitor or DPP4-inhibitor might 
be useful treatment options 
 
 
 


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APPENDIX F 
DOSE MODIFICATION OF COPANLISIB FOR ARTERIAL 
HYPERTENSION 
 
Toxicity (CTCAE) 
Study drug action 
Recommendation 
Pre-dose measurements 
BP ≥150/90 mmHg 
No dose should be given 
until recovery to 
<150/90 mmHg. 
Consider BP lowering medication. 
Dosing can proceed on the 
scheduled day if after at least 
2 consecutive measurements BP 
returns to <150/90 mmHg. If BP 
doesn’t return to <150/90 mmHg, 
delay dosing until next visit. 
During infusion: 
CTCAE hypertension of 
grade 3  
or ≥160/100 mmHg 
Infusion can be 
interrupted or slowed 
down and administration 
of BP lowering therapy 
should be initiated. 
Infusion may be resumed 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 
Post-dose: 
Drug-related 
CTCAE hypertension of 
grade 3 
or ≥160/100 mmHg a  
– 
Administration of BP lowering 
therapy should be initiated 
according to local standard of 
care.   
Additional measurements to be 
performed as clinically indicated 
until recovery to <150/90 mmHg. 
Subsequent study drug 
administrations may be reduced by 
1 dose level at the investigator’s 
discretion.b 
CTCAE hypertension of 
grade 5 
 
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 45 mg. 
 
 
 


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APPENDIX G 
BIOASSAY TEMPLATES 
 
Study Checklist for CTEP-Supported Early Phase Trials with  
BIOMARKER ASSAYS 
 
INSTRUCTIONS: 
For INTEGRAL assay, respond to Items 1-7. 
 
For INTEGRATED assay, respond to Items 1-3 and 5-7. 
(In lieu of completing items 5-6, the biomarker assay templates available at 
http://www.cancerdiagnosis.nci.nih.gov/diagnostics/templates.htm may be utilized.) 
Please submit a response to each of the criteria below and complete one Study Checklist for 
each Biomarker endpoint. 
1. 
Name of marker: Lymph3Cx Cell-of-Origin (COO) molecular subtyping assay for 
Primary Mediastinal B cell Lymphoma (PMBCL) and Diffuse Large B Cell 
Lymphoma (DLBCL) subtypes 
2. 
For an integral or integrated assay, indicate the role(s) of the biomarker assay in the trial: 
A. Eligibility criterion 
B. Assignment to treatment 
C. Stratification variable 
D. Risk classifier or score 
E. Other (describe in detail): This assay provides molecular cell-of-origin (COO) 
subtyping of PMBCL, not PMBCL, and uncertain; and DLBCL, with DLBCL 
further divided into Activated B cell, Germinal Center B cell, and Unclassifiable 
subtypes. These tumor types have different biological features such as gene 
expression, mutation profiles, signal pathway activation, and prognosis.  
Retrospectively, after closure of the trial, the Lymph3Cx results will be analyzed 
with regard to patient response to the novel chemotherapy regimen. The assay 
was developed by the Lymphoma and Leukemia Molecular Profiling Project 
research consortium (LLMPP), of which Dr. Rimsza is the current Principal 
Investigator.   
3. 
Identify the specific individual(s) and laboratory(ies) who are being considered for 
conducting the assay(s) for the trial.  Performing lab: Molecular Diagnostics – Arizona 
Laboratory, Mayo Clinic Arizona; Medical Director: Dr. Lisa Rimsza; Performing 
technologist: Colleen Ramsower, MB(ASCP)CM., Quality Specialist: Tameson Yip, 
MB (ASCP)cm. 
4. 
Integral laboratory assays used for clinical decision-making must be performed in a 
CLIA-certified facility.  Provide the lab’s CLIA number that is performing the integral 
biomarker study(ies) and the expiration date of the certificate. N/A – The Lymph3Cx 
assay will be an Integrated Assay, not used for medical decision-making; 
nevertheless, the study will be conducted in the Molecular Diagnostics of Arizona 
Lab, at Mayo Clinic, CLIA #03D2113087. 
5. 
Describe the assay: -  
A. Specify the analyte(s), technical platform, and sources of assay components (e.g., 
reagents, chips, and calibrators).  The technical platform is the Nanostring 


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nCounter system, which is FDA-cleared for use with the ProSigna breast cancer 
assay.  The RNA extraction kits are commercially available from Roche.  The 64 
fluorescently-labeled tags used in the assay will be from NanoString. The 
positive control is an equimolar mixture of oligonucleotides with complimentary 
sequences to all probes in Lymph3Cx assay. The oligonucleotides will be 
purchased in bulk, lyophilized, reconstituted into stock solutions, and pre-mixed 
by Integrated DNA Technologies similar to our prior work with the Lymph2Cx 
assay (D. Scott et al, Blood 2014).  We have a standard operating procedure for 
storage and dilution of this calibration standard, which has been used for 
normalization in all subsequent studies including the proposed trial. Additional 
PMBCL cell line pellets will be included as positive controls for the Lymph3Cx 
as well. The analysis algorithm is held behind a firewall on a password 
protected, NCI-sponsored website, so as to prevent any “drift” or tweaking.  
 
B. Describe the specimens, and anticipated methods for specimen acquisition, fixation or 
stabilization, and processing.  Provide justification for the timing of specimen 
collection. Describe the scoring procedures and type of data to be acquired: 
• quantitative/continuously distributed 
• semi-quantitative/ordered categorical 
• qualitative/non-ordered categorical  
 
The specimens will be formalin fixed, paraffin embedded (FFPE) tissue sections 
from the diagnostic pre-treatment biopsies of the patients, processed under 
standard clinical protocols at each participating site. Quantitative digital data 
will be generated from the nCounter system then uploaded to an NCI sponsored 
website with the analysis algorithm, which will calculate a probability score and 
assign the results into PMBCL, not PMBCL, or uncertain, and then 3 
DLBCL/not PMBCL categories: DLBCL-ABC, DLBCL-GCB, or DLBCL-UNC.  
The average raw count of the housekeeping genes in the assay is used as a final 
quality control marker – samples with <80 counts for this metric are reported as 
“Poor Quality”. 
A. Provide data on the analytical performance of the assay. -For in vitro tests, describe 
the current status of studies defining the accuracy, precision, reportable range, 
reference ranges/intervals (normal values), turn-around time and failure rate of the 
assay as it is to be performed in the trial.  Describe the use of positive and negative 
controls, calibrators, and reference standards for clinical assays.  Describe any critical 
pre-analytic variables.  For guidance on regulatory requirements for laboratory assays 
please visit: http://www.cms.gov/CLIA/05_CLIA_Brochures.asp   
 
Standard operating procedures (SOPs) for the Lymph3Cx assay have been 
established as presented at the recent International Conference on Malignant 
Lymphoma meeting in Lugano, Italy, June 14-17, 2017 (A. Mottok et al. ICML 
2017, manuscript under preparation for submission). The assay yielded GEP 
data of sufficient quality in 157/166 cases (94.6%).  The Rimsza laboratory 
provided the intra- and inter-laboratory reproducibility data for the Lymph3Cx 


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assay, which was 100% for repeat samples within the same laboratory and 
between laboratories respectively. The laboratory turn-around time for the 
assay is 2.5 days from the receipt of tissue sections including RNA extraction, 
overnight hybridization, digital scanning, and data analysis. There is no 
reference range.  The results are provided as a probability score of classification. 
The failure rate of the assay in the first 119 cases was 0% (all biopsies yielded 
sufficient RNA when assessed for pre-analytical variables as described below) 
using standard chemistry. A positive and negative control and up to ten samples 
can be included in each 12-well cassette.  Positive controls include the mixture of 
oligonucleotides and cell lines which hybridize with all probes in the assay.  The 
negative control is a well in the cassette that includes all reagents and probes, 
but no RNA. An important pre-analytical variable is percentage of tumor, which 
should be a minimum of 60%.  To address this, an H&E stained section of each 
case will be assessed by Dr. Rimsza, who will estimate tumor purity.  If needed, 
macro-dissection of the tissue sections will be performed to increase tumor 
content.  Input is 1 x 10 micron thick section for a 50mm2 biopsy.  For smaller 
biopsies, proportionally more sections will be taken. Dr. Rimsza will measure the 
size of the tumor area and determined the number of needed sections at the same 
time that she determines the tumor content. A Pathology Quality Assurance 
form is used to document the tissue input specifics (size/number of needed 
sections and percent tumor). At this time, only formalin fixed biopsies (not other 
fixatives) have been assessed.  The Pathology reports on the biopsies will be 
reviewed to determine whether formalin or another fixative was used. A 
complete validation packet for the Lymph2Cx assay as a laboratory developed 
test in the clinical Molecular Diagnostics in Arizona Laboratory at the Mayo 
Clinic was completed in November 2016 with on-going patient testing since that 
time. The Lymph3Cx clinical laboratory validation is underway and estimated 
for completion in late 2018. Although not for use in clinical decision making in 
this proposed trial, the Lymph3Cx assay will be run using the same standardized 
operating procedures as in the Mayo clinical laboratory. CLIA lab identification 
number 03D2113087. 
 
 
B. If the assay will be performed at more than one site, describe how inter-laboratory 
variability in the measurements listed in 5A above will be assessed. Describe how 
these sources of variation will be minimized to maintain performance at all sites 
within acceptable limits and to prevent drift or bias in assay. Not applicable, all 
testing will be performed at one site.   
 
6. 
Provide data on the clinical utility of the integral/integrated assay as it will be used in the 
trial: 
A. Provide background information that justifies the use of this assay result as a marker 
for this trial. State the hypothesis and rationale for utilizing the biomarker, with 
supporting preclinical and clinical data, when available.  For example, if the integral 
marker will be used as a stratification or treatment-determining variable, data 


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supporting its prognostic or predictive association with a main trial endpoint should 
be described or referenced.  
 
Note:  If the trial objectives include an evaluation of the association of the 
integral marker with a new clinical endpoint or factor not previously studied, 
explain how the magnitude of the association or effect will be measured and 
provide power calculations for any statistical tests that are planned. 
 
 
The Lymph3Cx assigns the molecular COO subtype of cases of large cell 
lymphomas into PMBCL and DLBCL subtypes with different phenotypes 
and genotypes.  Meaningful analysis of any clinical trial results need to be 
correlated with COO status in order to accurately describe the enrolled 
cohort of patients. Diagnosis of PMBCL is difficult, non-reproducible, and 
relies heavily on clinical presentation in the mediastinum, however, our 
research consortium recently described PMBCL-like tumors outside of the 
mediastinum, and conversely, not every case of large B cell lymphoma 
occurring in the mediastinum is a PMBCL, but could also be a usual DLBCL 
that happens to present there. (A. Rosenwald et al, J Exp Med, 2003; J. Yuan 
et al, Am J Surg Path,  2015). Several assays for COO have been published in 
the literature.  The original methods used snap frozen tissues and the 
Affymetrix gene expression profiling system, which are now accepted by 
experts as a “gold standard” for COO classification of DLBCL and PMBCL 
respectively (G. Wright et al, PNAS 2003; A. Rosenwald J Exp Med 2003); 
but both are expensive, have a poor turn-around time, and the Affymetrix 
platform does not perform well with FFPE tissue input.  The LLMPP 
research consortium, beginning with the original “discovery” methods, 
developed a GEP method that is accurate and useful in FFPE tissues. 
 
B. Describe the expected distribution of the biomarker in the study population.  Justify 
the number of patients and specimens to determine feasibility and to demonstrate that 
the studies are likely to produce interpretable results. 
As per the prior LLMPP publication using GEP on frozen tissues, we expect that 
80% of patients with an initial diagnosis of PMBCL will classify as PMBCL 
using the molecular method with the rest being DLBCL (A. Rosenwald et al, J 
Exp Med, 2003). As per our prior publications we further expect that the 
DLBCL will subtype as approximately 50% GCB, 35% ABC, and 15% UNC (S. 
Kendrick et al, Leuk Lymph 2016). The response rates will be compared to GEP 
classification to determine whether there is a specific subtype that correlates 
with treatment response. Given that this is a phase II study, descriptive statistics 
will be used to explore these COO and treatment associations. 
 
C. If cutpoints will be used, specify the cutpoint(s) and describe how these will be used 
in the trial.  Provide the rationale for the cutpoint(s) selected.  What proportion of 
subjects is expected to have values above and below the proposed assay value 
cutpoints?  What magnitude of effect (e.g., treatment benefit) or outcome (e.g., 
prognosis) is expected for patients with assay results above and below the proposed 
cutpoint(s)? 


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The cut-points for classification are pre-set at a  probability score of 10% and 
90% as generated from the locked Lymph3Cx algorithm, which was previously 
trained and validated. The results are first classified into PMBCL or not-
PMBCL or an uncertain category.  Then the non-PMBCL cases (DLBCL) are 
further classified into one of 3 subtypes such that DLBCL-ABC (equal to or 
greater than 90% probability score), germinal center B cell subtype (less than or 
equal to 10% probability of being an ABC type), and unclassifiable category (for 
all probabilities between 10-90%). It is expected that 60-70% of DLBCL patients 
will have the GCB subtype of DLBCL. We do not know if there will be a 
correlation between PMBCL, DLBCL-GCB or DLBCL-ABC subtype and 
clinical outcome in this trial. The data will be collected retrospectively for 
correlation. 
 
D. Describe the conditions under which treating physicians and or patients will be able 
to access the biomarker assay results. 
The treating physicians will not have access to these biomarker results, only the 
Principal Investigator will have access and then only after the clinical trial has 
completed accrual.  The patients will not have access to the results at any time.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix H: Shipping Manifest for Lymph3Cx Cell-of-Origin (COO) molecular subtyping assay 
 


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Appendix I: Blood Collection Kit Mayo Clinic Lymphoma Laboratory 
Specimen Checklist and Shipping Instructions 
 
** PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND 
HOLIDAYS** 
 
Kit Contents: 
• 
Small Styrofoam box and cardboard mailing sleeve 
• 
Patient Information Form 
• 
FedEx Airbill with pre-printed return address 
• 
10ml EDTA (purple top) collection tube 
• 
10ml Red Top collection tube 
• 
10ml Streck Cell-Free DNA collection tube 
• 
Absorbent tube holder 
• 
Zip lock specimen bag 
 
Packing and Shipping Instructions: 
 
➢ Collect the following specimens: 
➢ Peripheral blood – Draw appropriate tubes per time point: 
• 
10ml in one (1) EDTA tube 
• 
10ml in one (1) Red Top tube 
• 
10ml in one (1) Streck Cell-Free DNA tube 
➢ All specimens are to be clearly labeled with the protocol MC1787, the patient’s initials (last, first, 
middle), study patient ID number (if available) and date of collection. 
➢ Place the tubes in the absorbent holder and seal in the zip lock specimen bag. 
➢ Place the filled specimen bag in the Styrofoam container. 
➢ Loosely pack with paper toweling. 
➢ Place the Styrofoam container and Patient Information form within the cardboard mailing sleeve. 
➢ Prepare the package for shipping, applying packing tape as needed. Adhere the Fed Ex Airbill to the 
exterior of the box.  Ship specimens via priority overnight delivery (next day delivery by 10am) the 
same day collected. 
➢ Notify Federal Express for pick-up and/or leave package at the designated FedEx drop-off location. 
Please e-mail Kim Henderson at Henderson.kimberly@mayo.edu to notify the laboratory when 
samples are being shipped.  Indicate the protocol number MC1787/10193, the Fed Ex tracking 
number, name and phone number of the contact person. The samples should be shipped to the 
following: 
Mayo Clinic 
Attn: Stacey Lehman 
221 4th Avenue SW 
613 Stabile 
Rochester, MN  55905 
 


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Patient Information Form 
 
 
Specimen Date:      /        /           
Patient Initials (last name, first name):                 
Mayo Clinic Number:  
Protocol #: MC1787/10193                                                                                 
Contact Person:                                                                                                           
Institution:                                                                                                           
Address:  
 City                                           State                  Zip 
Phone #:                                                                                                           
 
 
Please indicate which sample time point is being shipped: 
1. Baseline 
2. Cycle 1 Day 8  
3. Cycle 1 Day 15 
4. Cycle 3 
5. Cycle 4 
6. At time of PMD  
7. At time of Progressive Disease 
 
Any questions concerning these samples or to obtain blood collection kits for the MC1787/10193 study, 
please contact: 
 
Stacey Lehman 
Mayo Clinic 
(507)284-3805 
Lehman.stacey@mayo.edu   
Affiliates who anticipate participating in this study should please e-mail in advance for kits. Please include 
the site address, contact information and number of kits being requested.