A Phase I/II Study of PI3Kinase Inhibition (Copanlisib) and Anti-PD-1 Antibody Nivolumab in Relapsed/Refractory Solid Tumors With Expansions in Mismatch-repair Proficient (MSS) Colorectal Cancer
Phase: PHASE1
Conditions: Unresectable or Metastatic Microsatellite Stable (MSS) Solid Tumor, Microsatellite Stable (MSS) Colon Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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TITLE: A phase I/II study of PI3Kinase inhibition (copanlisib) and anti-PD-1 antibody nivolumab 
in relapsed/refractory solid tumors with expansions in MSS colorectal cancer 
 
Johns Hopkins #: 
J1887 / IRB00175864 
BMS Protocol #: 
CA209-8LC 
BAYER Protocol #: 
IIR-US-2018-5354 
ClinicalTrials.gov ID: 
NCT03711058 
 
Principal Investigator: 
Nilofer Azad, MD 
   
 
 
 
 
 
 
 
 
 
BMS Supplied Agent: 
Nivolumab (Opdivo®, BMS-936558) 
 
Bayer Supplied Agent: 
Copanlisib (BAY 80-6946) 
 
IND Number: 
 
139720 
 
 
 
 
 
 
 
IND Sponsor: 
Nilofer Azad, MD 
 
Protocol Version # / Version Date: 
Version 1 / May 31, 2018  
 
Version 2 / July 10, 2018 
 
Version 2.1 / July 13, 2018 
 
Version 2.2 / July 18, 2018 
 
Version 2.3 / July 24, 2018 
 
Version 3.0 / January 10, 2019 
 
Version 4.0 / November 14, 2019 
 
Version 4.1 / June 17, 2020 
 
Version 5.0 / June 25, 2020 
Version 5.1 / March 15, 2021 
Version 5.2 / March 02, 2022 
Version 6.0  /May 11, 2022 
Version 7.0 / January 27, 2023 
 
 
 

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TRIAL SUMMARY 
 
Abbreviated Title 
Copanlisib and nivolumab in relapsed/refractory solid tumors with 
expansions in MSS colorectal cancer 
Trial Phase 
I/II 
Clinical Indication 
Phase I: Relapsed/refractory MSS solid tumors  
Phase II: MSS colorectal cancer 
Trial Type 
Dose Finding / Efficacy and safety 
Type of control 
Single arm (no control) 
Route of administration 
IV 
Trial Blinding 
Open Label 
Treatment Groups  
Copanlisib + Nivolumab 
Number of trial participants 
51-54 
Estimated enrollment period 
18 months 
Estimated duration of trial 
24 months 
 

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TABLE OF CONTENTS 
1. OBJECTIVES ..........................................................................................................................9 
1.1 
Primary Objectives...................................................................................................9 
1.2 
Secondary Objectives...............................................................................................9 
1.3 
Hypotheses ...............................................................................................................9 
1.4 
Study Design ..........................................................................................................10 
2. BACKGROUND ....................................................................................................................11 
2.1 
Copanlisib (BAY 80-6946) ....................................................................................11 
2.2 
Nivolumab..............................................................................................................12 
3. PATIENT SELECTION .......................................................................................................16 
3.1 
Eligibility Criteria ..................................................................................................16 
3.2 
Exclusion Criteria ..................................................................................................17 
3.3 
Inclusion of Women and Minorities ......................................................................20 
4. TREATMENT PLAN ............................................................................................................20 
4.1 
Registration and Enrollment ..................................................................................20 
4.2 
Agent Administration.............................................................................................21 
4.3 
Dose Limiting Toxicities .......................................................................................22 
4.4 
Dose Modification and Toxicity Management ......................................................23 
4.5 
Duration of Therapy and Criteria for Removal from Study Treatment .................36 
4.6 
End of Treatment (EOT) Visit ...............................................................................37 
4.7 
Duration of Follow Up ...........................................................................................37 
5. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................38 
5.1 
Definitions..............................................................................................................38 
5.2 
Relationship ...........................................................................................................40 
5.3 
Assessment of Grade..............................................................................................40 
5.4 
Expectedness ..........................................................................................................41 
5.5 
Handling of Expedited Safety Reports ..................................................................41 
5.6 
Reporting................................................................................................................41 
6. PHARMACEUTICAL INFORMATION ............................................................................44 
6.1 
Nivolumab..............................................................................................................44 
6.2 
Copanlisib ..............................................................................................................45 
7. CORRELATIVE/SPECIAL STUDIES ...............................................................................47 
7.1 
Tumor Tissue .........................................................................................................47 
7.2 
Peripheral Blood Mononuclear Cells (PBMCs) ....................................................48 
7.3 
Plasma ....................................................................................................................48 
7.4 
Diagnostic Tissue Samples ....................................................................................48 
7.5 
Planned Analyses ...................................................................................................48 
7.6 
Investigator Responsibilities for Translational Research ......................................51 
8. STUDY SCHEDULE .............................................................................................................52 
8.1 
Study Calendar – Phase I .......................................................................................52 
8.2 
Study Calendar – Phase II ......................................................................................55 
9. MEASUREMENT OF EFFECT ..........................................................................................58 
9.1 
Definitions..............................................................................................................58 
9.2 
Methods for Evaluation of Measurable Disease ....................................................58 

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10. DATA REPORTING / REGULATORY REQUIREMENTS ...........................................58 
10.1 
Data Management ..................................................................................................59 
10.2 
Safety Meetings .....................................................................................................59 
10.3 
Monitoring .............................................................................................................60 
11. STATISTICAL CONSIDERATIONS .................................................................................60 
11.1 
Sample Size ............................................................................................................60 
11.2 
Statistical Analyses ................................................................................................61 
11.3 
Safety Analyses ......................................................................................................62 
12. REFERENCES .......................................................................................................................64 
APPENDIX A: Performance Status Criteria ............................................................................66 
APPENDIX B: Contraceptive Guidance and Pregnancy Testing ...........................................67 
APPENDIX C: Management Algorithms ..................................................................................69 
APPENDIX D: Average Glycemic Index of Common Foods ..................................................77 
APPENDIX E: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Criteria for Evaluating Response in Solid Tumors .......................................78 
APPENDIX F: Serious Adverse Event (SAE) Reporting Form ..............................................81 
 
 
 

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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
5-HT3 
serotonin receptor 
AE 
adverse event 
AKT 
protein kinase B 
ALT 
alanine aminotransferase (also known as SGPT) 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase (also known as SGOT) 
AUC 
area under the concentration-time curve 
BAY 80-6946 
copanlisib 
BMS 
Bristol-Myers Squibb Company 
BP 
blood pressure 
BRAF 
v-RAD murine sarcoma viral homolog B1 
BUN 
blood urea nitrogen 
C 
cycle 
CBC 
complete blood count 
CCL2 
C-C motif chemokine ligand 2 
CD 
cluster of differentiation (e.g. CD28 = cluster of differentiation 28) 
CEA 
Carcinoembryonic Antigen 
CFR 
code of federal regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum serum concentration 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form 
CRO 
Clinical Research Office 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
CV% 
(% coefficient of variation 
CXCL9 
C-X-C motif chemokine ligand 9 
CYP 
cytochrome P450 
D 
day 
DCR 
disease control rate 
DILI 
drug induced liver injury 
DLT 
dose limiting toxicities 
DoR 
duration of response 
DPP4 
dipeptidyl peptidase 4 
DSMP 
data safety monitoring plan 
e.g. 
exempli gratia, for example 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 

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Abbreviation 
Definition 
EGFR 
epidermal growth factor receptor 
EOT 
end of treatment 
ESR 
expedited safety report 
etc. 
et cetera, and so forth 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FT4 
free T4 (or free thyroxin) 
g 
gram(s) 
GCP 
good clinical practice 
GFR 
glomerular filtration rate 
GVP&E 
Global Pharmacovigilance and Epidemiology 
h 
hour(s) 
H&E 
hematoxylin and eosin 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B serum antigen 
HDL 
high-density lipoprotein 
HepC 
hepatitis C 
HepCAb 
hepatitis C antibody 
HER 
human epidermal growth factor receptor 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
i.e. 
id est, that is 
IB 
Investigator’s brochure 
IC50 
half maximal inhibitory concentration 
IDO 
indoleamine-pyrrole 2,3-dioxygenase 
IF 
immunofluorescence  
IFNγ 
interferon-gamma 
IGF-1R 
insulin-like growth factor 1 receptor 
Ig 
immunoglobulin 
IgG4 
immunoglobulin G4 
IgV-type 
Ig-variable–type 
IHC 
immunohistochemistry 
IL 
interleukin (IL-2 = Interleukin 2, IL-10 = interleukin 10, etc)  
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
JHU 
Johns Hopkins University 
kg 
kilogram 
KRAS 
Kirsten ras oncogene homolog from the mammalian ras gene family 
L 
liter(s) 
LAG3 
lymphocyte-activation gene 3 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LFT 
liver function test 

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Abbreviation 
Definition 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
Med Hx 
medical history 
Met 
mesenchymal epithelial transition factor 
mg 
milligram(s) 
MHC 
major histocompatibility complex 
min 
minute(s) 
mL 
milliliter(s) 
mmHg 
millimeter of mercury 
mmol 
millimoles(s) 
MRI 
magnetic resonance imaging 
MSS 
microsatellite stable 
MTD 
maximum tolerated dose 
MUGA 
Multi-gated acquisition scan 
mTOR 
mammalian target of rapamycin 
N/A 
not applicable 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
nM 
nanomole, nanomolar 
NRAS 
neuroblastoma RAS viral oncogene homolog 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
OI 
opportunistic Infection 
ORR 
overall response rate 
OS 
overall survival 
OTC 
over the counter 
OX-40 
OX40 receptor, also known as CD134, or TNFRSF4 
pAKT 
phosphorylated AKT 
PBMC 
peripheral blood mononuclear cells 
PBS 
phosphate buffered saline 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1 
programmed death-ligand 1 
PD-L2 
programmed death-ligand 2 
PDGFR 
platelet-derived growth factor receptor 
PFS 
progression-free survival 
PI 
Principal Investigator 
PI3K 
phosphatidylinositol 3-kinase 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase 
PIP3 
phosphatidylinositol-3,4,5-trisphosphate 
PJP 
Pneumocystis jiroveci pneumonia 
PK 
Pharmacokinetic(s) 
PKCθ 
protein kinase C-theta 
PO 
per os, orally 

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Abbreviation 
Definition 
PR 
partial response 
pRBC 
packed red blood cell 
PT 
prothrombin time 
PTEN 
phosphate and tensin homolog 
PTT 
partial thromboplastin time 
Q12W 
every 12 weeks 
QT 
time between the start of the Q wave and the end of the T wave in the 
heart's electrical cycle 
QTc 
corrected QT interval 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RNASeq 
RNA sequencing 
RP2D 
recommended phase II dose 
SAE 
serious adverse event 
SD 
stable disease 
SGLT2 
sodium/glucose co-transporter 2 
SGOT 
serum glutamic-oxaloacetic transaminase (also known as AST) 
SGPT 
serum glutamic pyruvic transaminase (also known as ALT) 
SKCCC 
Sidney Kimmel Comprehensive Cancer Center 
SOC 
standard of care 
SubQ 
subcutaneously 
T1/2 
elimination half-life 
T3 
triiodothyronine 
TCR 
T-cell receptor 
TME 
tumor microenvironment 
TNFα 
tumor necrosis factor alpha 
TSH 
thyroid stimulating hormone 
Tx 
treatment 
ULN 
upper limit of normal 
UPCR 
urine protein:creatinine ratio 
USP 
United States Pharmacopeia 
VEGF 
vascular endothelial growth factor 
VLDL 
very low-density lipoprotein 
VNS 
vial, needle, and syringe 
v-RAF 
virus-induced rapidly accelerated fibrosarcoma 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
WT 
wildtype 
 
 
 

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1. OBJECTIVES 
 
1.1 Primary Objectives 
 
1. Phase I: To determine the recommended phase II dose (RP2D) of copanlisib with fixed 
dose nivolumab  
2. Phase II/Clinical: To determine 6-month objective response rate (ORR) of patients 
treated with copanlisib and nivolumab and compare the ORR of patients in Cohort A 
(MSS colorectal cancer patients with PIK3CA mutations) and Cohort B (MSS 
colorectal cancer patients with WT PIK3CA) 
 
1.2 Secondary Objectives 
 
1. To determine the 6-month disease control rate (DCR), duration of response (DoR), 
progression-free survival (PFS), and overall survival (OS) and compare DCR, DoR, 
PFS, and OS of patients in cohort A and cohort B. 
2. To assess safety and characterize toxicities of the combination of copanlisib and 
nivolumab 
 
1.3 Exploratory Objective 
 
1. To determine the effect of copanlisib + nivolumab on markers of immune exhaustion 
and pro-apoptotic factors in CD8+ effector T cells. 
2. To determine the effect of copanlisib + nivolumab on immune cell subpopulations in 
the tumor microenvironment, including CD8+ T cells, PD-1/PD-L1 expression on 
tumor and tumor associated macrophages and monocytes, and MHC 1/2 expression. 
3. To explore the effect of copanlisib and nivolumab on local and systemic immune 
activation pathways and immune suppressive pathways through expression profiling 
 
4. To explore changes in immune cell subsets and cytokine profiles in the peripheral 
circulation 
5. To evaluate potential molecular determinants of response, progression, and disease 
stability using next generation sequencing and other sequencing techniques 
 
1.4 Hypotheses 
 
1. PI3K inhibition with copanlisib in combination with nivolumab will be tolerable and 
result in tumor response in tumor types resistant to immune checkpoint therapy 
2. Treatment with copanlisib in advanced solid tumors in combination with nivolumab 
will result in immunologic changes including: 
- 
increased numbers of CD8+ cytotoxic T cells 
- 
decreased T-cell exhaustion 

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- 
decreased CD4+ T regulatory T cells and myeloid derived suppressor cells  
- 
changes in gene expression resulting in increased immune activation and 
decreased immune suppression pathways 
- 
increased activated cytotoxic T-cells, TCR rearrangements, and decreased 
immune suppressive cells 
 
1.5 Study Design  
 
This is a multi-center, open-label, Phase I/II study.  Phase 1 consists of a 3+3 dose de-escalation 
design to determine the dose of copanlisib for use in combination with nivolumab. 
Approximately 6-18 subjects with solid tumors will be treated in Phase I and will be monitored 
for dose limiting toxicities (DLTs) through their first cycle of treatment.  Complete information 
on the definition of DLTs and dose de-escalation rules can be found in Section 4.3. 
 
The Phase II portion of the study will evaluate the safety and clinical activity of copanlisib and 
nivolumab in two cohorts of patients with previously treated metastatic colon cancer. Cohort 
A will enroll patients with PI3K mutation and Cohort B will enroll patients with wildtype PI3K 
status.  Twenty-one patients are targeted for enrollment in each cohort, for an approximate total 
of 42 patients in Phase II. Enrollment in Phase II will be initiated once the recommended phase 
II dose (RP2D) has been determined in Phase I.  
 
For all patients, the study will consist of a screening period, a treatment period, and a follow-
up period.  Screening evaluations will be done within 28 days prior to the start of study 
treatment.  
 
Each treatment cycle is 28 days.  Patients in both Phase I and Phase II will receive nivolumab 
on Day 1 of each cycle (every 4 weeks) and copanlisib on either Day 1, Day 8, and Day 15 of 
each cycle (3 week on, one week off) or on Day 1 and 15 of each cycle (every 2 weeks), 
depending on the dose level and RP2D.  Complete information on study drug administration, 
schedule, and dosing can be found in Section 4.2. 
 
Phase II enrollment will be carried out in 2 stages so that the study can terminate early if the 
combination of copanlisib and nivolumab is not sufficiently effective. In the first stage, 12 
subjects will be accrued to each cohort. If there are no responders among the first 12 patients, 
the study will be terminated for futility. Otherwise, 9 additional patients will be accrued for a 
total of 21 treated subjects. If 3 out of the 21 patients have a response, then the trial will be 
considered a success for that cohort.  
 
Clinical and immune responses will be evaluated at baseline and during treatment through 
tumor assessments, biopsies, and PBMC and plasma collection. Tumor assessments will be 
made using RECIST 1.1.  
 
All subjects may continue in the treatment period until discontinuation due to disease 
progression, unacceptable toxicity, subject withdrawal, or study closure. Complete criteria for 
removal from treatment are found in Section 4.5.   
 
Subjects will undergo end-of-treatment (EOT) evaluations at the time it is determined they will 

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be discontinuing study treatment. All subjects will be followed for at least 30 days after their 
last dose of study drug for the development of AEs. SAEs that occur within 100 days of the 
last infusion of nivolumab or before initiation of a new antineoplastic treatment should also be 
followed and recorded.  Complete information on safety reporting can be found in Section 5.  
 
After completion of treatment and EOT assessments, all subjects will continue to be followed 
every 3 months by telephone, e-mail, or optional clinic visit until death, withdrawal of consent, 
or closure of study.  Information on survival and new cancer therapies will be collected. 
Subjects that discontinue treatment for reason other than disease progression may also continue 
to be monitored by radiologic imaging every 10 weeks until start of a new anti-cancer therapy, 
disease progression, death, withdrawal of consent, or the close of the study, whichever occurs 
first.   
 
2. BACKGROUND  
 
2.1 Copanlisib (BAY 80-6946) 
 
 

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Copanlisib has been tested in approximately 772 patients with advanced cancers in either 
single-agent or combination studies.  When given as a single agent, the most common drug-
related adverse events (>20% of patients) included hyperglycemia, nausea, and hypertension. 
Other toxicities occurring with copanlisib administration included serious infections (19%), 
grade 4 neutropenia (12%), non-infectious pneumonitis (5%), and transient serious 
hypertension (1%) or hyperglycemia (1%).    
 
For additional preclinical and clinical trial information, refer to the Investigator’s Brochure. 
 
2.2 Nivolumab 
 
Nivolumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death 
ligand 2 (PD-L2).  Based on preclinical in vitro data, nivolumab has high affinity and potent 
receptor blocking activity for PD-1.  Nivolumab has an acceptable preclinical safety profile 
and is in clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies.  OPDIVO™ (nivolumab) is approved for the treatment of several types of cancer 
because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more details 
on specific indications refer to the Investigator brochure. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).1, 2  
 
The structure of murine PD-1 has been resolved.3  PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible 
for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 

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immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-
1 and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved 
in the CD3 T-cell signaling cascade.2, 4-6  The mechanism by which PD-1 down-modulates 
T-cell responses is similar to, but distinct from that of CTLA-4, because both molecules 
regulate an overlapping set of signaling proteins.7, 8  
 
The PK of single-agent nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg 
administered as a single dose or as multiple doses 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 when administered at 
3 mg/kg every 2 weeks, and systemic accumulation was approximately 3.7-fold. The exposure 
to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg 
administered every 2 weeks. 
 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
Recent trials of immune checkpoint blockade have shown striking clinical activity against a 
range of tumors. However, response to immune checkpoint blockade targeting CTLA4 and 
PD-1 is still limited, with only a subset of solid tumor patients showing clinical response9-13. 
Loss of PTEN promotes resistance to T cell–mediated immunotherapy  
 
PTEN is a negative regulator of PI3K, therefore loss of PTEN phenocopies gain of function of 
PI3K. When PTEN is lost, the PI3 Kinase pathway is thought to rely on the  isoform of PI3K 
for signaling14. Melanoma patients with PTEN loss were enriched in nonresponders to anti-
PD-1 and their tumors had fewer infiltrating CD8+ T cells. In a mouse Braf-/- Pten-/- mutant 
model of induced melanoma treated with adoptive transfer of antigen specific T cells and a 
tumor antigen vaccine, synergistic response was seen with GSK2636771, a PI3K inhibitor, 
and anti-PD-115. 
 
Loss of PTEN is associated with resistance to Anti-PD-1 checkpoint blockade therapy in 
metastatic uterine leiomyosarcoma 
  
A single patient experience was described to address a mechanism of resistance to PD-1. A 
patient with metastatic uterine leiomyosarcoma had up front resection followed by enrollment 

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on a Phase II trial of pembrolizumab. The bulk of disease responded, however a single lesion 
progressed on therapy. This lesion was then resected and subject to whole genome and RNA 
sequencing, which was compared to sequencing performed at diagnosis. The only genomic 
difference was biallelic loss of PTEN, leading the authors to hypothesize that this genomic 
difference may underlie differential sensitivity to PD-1 blockade. Decreased inflammation was 
shown in the PTEN null progressive lesion by RNASeq of immune activation genes.16  
 
PI3K inhibition reduces mammary tumor growth and facilitates anti-tumor immunity 
and anti-PD1 responses  
 
Response to PI3K inhibition and PD-1 blockade was studied in orthotopic implants of 
mammary tumor cell lines 4T1 and PyMT. PI3K inhibition was achieved by pan-PI3K 
inhibitor BKM120. BKM120 increased sensitivity to anti-PD-1.  The proposed mechanism in 
this study was recruitment of a myeloid population dependent on PI3Kɣ.17  
                         
PIK3CA H1047R confers resistance to checkpoint blockade  
 
An experimental system was developed to identify genes used by cancer cells to evade immune 
attack using pooled, gain-of-function genetic screens in mouse transplantable models of 
cancer18. Murine tumor cells (MC38 colon carcinoma or B16 melanoma) were transduced with 
a pool of vectors encoding mutant alleles as open reading frames (ORFs) corresponding to a 

 
PI3K Inhibition with copanlisib is synergistic with anti-PD-1 in the A20 mouse lymphoma 
model 

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3. PATIENT SELECTION 
 
3.1 Eligibility Criteria 
 
In order to be eligible for participation in this study, all of the following criteria must apply: 
 
1. Be willing and able to provide written informed consent for the trial 
 
2. Be at least 18 years of age on the day of signing informed consent 
 
3. Have histologically confirmed metastatic or unresectable: 
a. Mismatch-repair proficient (MSS) solid tumor (for phase I dose de-escalation) 
OR 
b. Mismatch-repair proficient (MSS) colorectal cancer with known PI3K-
mutation status (for expansion cohorts). NGS and PCR based testing by a CLIA 
certified lab will be used to determine PI3K status per Section 7.5.1. 
4. In terms of prior therapies: 
a. For phase I dose de-escalation: have received all curative treatment options AND 
at least 2 lines of systemic therapy in the metastatic setting 
b. For MSS colorectal cancer cohorts in phase II expansion: have received at least 2 
prior lines of standard therapy including a fluoropyrimidine, oxaliplatin, and 
irinotecan-containing regimen.  KRAS/NRAS/BRAF wild type patients must have 
received or refused anti-EGFR therapy. 
 
5. Have measurable disease based on RECIST 1.1. Lesions situated in a previously 
irradiated area are considered measurable if progression has been demonstrated in such 
lesions. 
 
6. Have biopsiable disease.  If biopsy is attempted and unsuccessful (the patient undergoes 
an invasive procedure), the patient may still be treated.  
 
7. Have a performance status of 0 or 1 on the ECOG Performance Scale at study entry 
(See Appendix A).  
 
8. Have a life expectancy of 3 months 
 
9. Demonstrate adequate baseline laboratory values as defined below; all screening labs 
should be performed within 21 days of treatment initiation. 
 

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System – Lab 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥ 1500/µL 
Platelets 
≥ 75 000/µL 
Hemoglobin 
≥ 8.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Serum Creatinine  
≤ 1.5 × ULN or 
Glomerular filtration rate (GFR) ≥40 mL/min/1.73  
Urine protein:creatinine ration (UPCR) 
< 3.5 on a random urine sample 
Hepatic/pancreatic 
 
Total bilirubin 
≤ 1.5 ×ULN (< 2 x ULN for patients with Gilbert’s 
syndrome) 
AST (SGOT) and ALT (SGPT) 
≤ 3 × ULN  
Lipase 
< 1.5X ULN 
Endocrine 
 
HbA1c 
≤ 7%  
Glucose 
< 160 mg/dL (fasting) or < 200 mg/dL (non-fasting) 
Coagulation 
 
International normalized ratio (INR) and 
partial thromboplastin time (PTT) 
≤ 1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
Cardiac 
Left ventricular ejection fraction (LVEF) 
≥ 50% 
a Criteria must be met without erythropoietin dependency and without packed red blood cell 
(pRBC) transfusion within last 1 week.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
 
10. Male subjects must agree to use a contraception as detailed in Appendix B of this 
protocol during the treatment period and for at least 6 months after the last dose of 
study drug and refrain from donating sperm during this period. 
  
11. Female subjects must not be pregnant (negative urine or serum test within 72 hours of 
first dose of study drug) or breastfeeding, and at least one of the following conditions 
must apply: 
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix B or 
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix B 
during the treatment period and for at least 6 months after the last dose of study 
drug. 
 
3.2 Exclusion Criteria 
 
Subjects are excluded from the study if any of the following criteria apply: 
 
1. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with 
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-
4, OX-40, CD137). 
 
2. Prior therapy with a PI3K inhibitor 

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3. Has received prior chemotherapy, targeted small molecule therapy, or surgery within 
4 weeks of the first dose of treatment. Participants must have recovered from all AEs 
due to previous interventions to ≤Grade 1 or baseline. Participants with ≤ grade 2 
neuropathy, anemia, and/or alopecia may be eligible. 
 
4. Has received prior radiotherapy within 2 weeks of start of study treatment.  Participants 
must have recovered from all radiation-related toxicities to ≤Grade 1 or baseline, not 
require corticosteroids, and not have had radiation pneumonitis.  A 1-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. 
Participants with ≤ grade 2 neuropathy, anemia, and/or alopecia may be eligible. 
 
5. Is currently participating in or has participated in a study of an investigational agent or 
investigational device within 4 weeks prior to the first dose of study treatment. (i.e. 
must be 4 weeks after the last dose of the previous investigational agent). 
 
6. Has received a live vaccine within 30 days prior to the first dose of study drug.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed. 
 
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy. 
 
8. Has known CNS metastases and/or carcinomatous meningitis.   
9. Has symptomatic ascites or has required a paracentesis in the last 12 weeks 
10. Has known hypersensitivity to nivolumab, copanlisib, or any ingredients in the 
formulation of these study drugs. 
 
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug.  
 
12. Has active autoimmune disease that has required systemic treatment in the past 12 
months, or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents. Subjects with 
vitiligo or resolved childhood asthma/atopy are exceptions. Intermittent use of 
bronchodilators or local steroid injections are not excluded. Replacement therapy (e.g. 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
Autoimmune diagnoses not listed must be approved by the protocol chair. 

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13. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
14. Has an active infection requiring systemic therapy. 
15. Has a known history of Human Immunodeficiency Virus (HIV) infection.   
16. Has a known history of Hepatitis B (HBsAg reactive) or active Hepatitis C virus 
infection (HepCAb followed by HepC RNA if Ab test is positive).  
17. CMV PCR positive 
18. Has a history or concurrent condition of interstitial lung disease or severely impaired 
lung function  (as judged by the investigator) 
19. Has Type I diabetes or Type II diabetes requiring treatment with a sulfonylurea, 
meglitinide, or insulin. 
20. Uncontrolled cardiovascular disease 
a. Congestive heart failure > New York Heart Association (NYHA) class 2 
b. Unstable angina (symptoms at rest), new-onset angina (within the last 3 months).  
c. Myocardial infarction less than 6 months before start of test drug  
d. Uncontrolled arterial hypertension despite optimal medical management 
 
21. Use of anti-arrhythmic therapy (beta blockers or digoxin are permitted) 
 
22. Use of CYP3A4 inhibitors and inducers within 2 weeks of starting study drug and 
throughout treatment. Examples of inhibitors of CYP3A4: ketoconazole, itraconazole, 
clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir.  Examples of inducers 
of CYP3A: rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort.    See 
Table 7 for complete list. 
 
23. Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism 
within 3 months before the start of study medication 
 
24. Non-healing wound, ulcer, or fracture 
25. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding 
event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication  
26. Had a blood or platelet transfusion within 7 days of Cycle 1 Day 1 treatment 
27. Seizure disorder requiring anti-seizure medication 
28. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 

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29. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation 
for the full duration of the study, or is not in the best interest of the subject to participate, 
in the opinion of the treating investigator.   
30. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 6 months after 
the last dose of trial treatment 
 
31. Is a prisoner or is compulsorily detained 
 
3.3 Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. TREATMENT PLAN 
 
4.1 Registration and Enrollment 
 
Eligible patients will be entered on study centrally at the Sidney Kimmel Comprehensive 
Cancer Center at the Johns Hopkins University by the Lead Study Coordinator.  All sites 
should contact the Lead Study Coordinator to verify ongoing study enrollment. The 
Registration Form and Eligibility Checklist will be supplied to each participating site. 
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. 
 
de-identified documents should be completed and sent to 
 Registration Form 
 Signed patient consent form with printed patient name and DOB redacted 
 Eligibility Checklist 
 Participating Sites: copy of required screening tests, scans, and notes used to verify 
eligibility 
 Coordinating Center (Johns Hopkins University): required screening tests, scans, and 
notes will be verified for eligibility through internal electronic clinic system. 
 
The Research Nurse or Lead Study Coordinator at the participating site will then e-mail the 
Protocol Chair to verify eligibility. To complete the registration process, the Lead Study 
Coordinator will: 
 Assign a patient study number 
 Register the patient on the study 
 Fax or e-mail the patient study number to the participating site 
 Call or e-mail the research nurse or data manager at the participating site and verbally 
confirm registration. 

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4.2 Agent Administration 
 
There will be two phases in this study: A Phase I dose-finding stage followed by a Phase II 
expansion.  
 
Copanlisib will be administered as a 60 minute IV infusion (-5min/+10min) at the doses and 
days shown in Table 1 and Table 2 below. Subjects should be observed for a minimum of 30 
minutes after administration of Copanlisib prior to administration of nivolumab. 
 
Nivolumab 480 mg will be administered as a 30 minute IV infusion (-5min/+10min) on Day 1 
of each 28 day cycle. 
 
The Pharmacy Manual contains specific instructions for the preparation and administration of 
these study drugs.  
 
Study treatment should be administered after all procedures/assessments have been completed 
for that visit as detailed on the Study Calendar (Section 8).  Study treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle, up to 1 day after 
the scheduled Day 8, or up to 3 days after Day 15 of each cycle due to administrative reasons 
as long as there is a minimum of 7 days between copanlisib infusions. 
 
All trial treatments will be administered on an outpatient basis.  
 
Phase I – Dose De-Escalation 
 
Phase I will use a standard 3+3 design.  The initial dose being tested is the recommended phase 
2 dose of both study drugs as single agents, so the doses of copanlisib and nivolumab will not 
escalate higher than dose level 1.  However, if the recommended phase II dose (RP2D) is 
exceeded in dose level 1, the dose of copanlisib will de-escalate as indicated below in Table 1.  
A maximum of 18 eligible subjects will be enrolled into this phase.  All patients enrolled at 
each dose level will be evaluated for dose limiting toxicities (DLTs) during the first 28 day 
cycle for the purpose of determining the RP2D when given concurrently with nivolumab. 
DLTs and dose de-escalation rules are defined in Section 4.3 and Table 3, respectively. 
 
Table 1 – Phase I Dose Levels and Regimen (listed in order of administration) 

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Phase II – Expansion Cohorts 
 
Phase II will enroll patients with mismatch-repair proficient colorectal cancer with known 
PI3K-mutation status.  21 patients will be enrolled into Cohort A (PIK3CA mutation) and 21 
patients will be enrolled into Cohort B (PIK3CA WT).  Both cohorts will receive the same 
treatment regimen. The dose of copanlisib given in Phase II will be the RP2D determined 
during Phase I of this study.   
 
Table 2 - Phase II Regimen (listed in order of administration) 
 
4.3 Dose Limiting Toxicities 
 
Dose limiting toxicities (DLTs) are defined as any AE occurring within the first cycle of 
treatment that is temporally related to study drug administration, which is not due to the 
subject’s underlying malignancy, for which there is no clear evidence for an alternative 
etiology, and that meets one of the following NCI CTCAE criteria: 
 
Hematologic Toxicities  
- Grade 4 anemia  
- Grade ≥ 3 neutropenia lasting ≥ 14 days  
- Grade ≥ 3 febrile neutropenia 
- Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with clinically significant 
bleeding  
 
Other Toxicities  
- 
Treatment-related ≥ grade 4 AEs, except transient hyperglycemia  
- 
Grade ≥ 3 Pneumonitis or recurrent Grade 2 pneumonitis 
- 
Grade ≥ 3 Nephritis 
- 
Grade ≥ 3 elevated AST, ALT 
- 
Grade ≥ 2 eye pain or reduction of visual acuity that does not respond to topical 
therapy and does not improve to ≤ grade 1 severity within 2 weeks of starting therapy, 
or requires systemic therapy 
- 
Any other Grade ≥ 3 toxicities except 
- 
Grade 3 nausea, vomiting, or diarrhea that resolves to Grade ≤ 1 within 7 
days, with or without appropriate supportive therapy  
- 
Grade 3 rash that resolves to Grade ≤ 2 within 7 days  
- 
Grade 3 fatigue that resolves to ≤ Grade 2 within 14 days  

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- 
Grade 3 transient hypertension and transient hyperglycemia 
- 
Grade ≥ 3 laboratory abnormalities that, in the judgment of the investigator, 
are not clinically significant  
- 
Asymptomatic amylase/lipase elevation 
 
Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 hours 
if clinically indicated and monitored as necessary to determine if event meets toxicity criteria. 
 
Table 3 – Dose De-Escalation Rules 
Number of Patients 
with DLT at a 
Given Dose Level 
Dose De-Escalation Decision Rule  
(dose levels found in Table 1) 
0-1 out of 3 
Enter 3 more patients at this dose level 
 
 If ≤ 1 of 6 subjects in this cohort experience a DLT, this is 
the recommended phase II dose (RP2D) 
 If ≥ 2 of 6 patients in this cohort experience a DLT, this dose 
level exceeded the RP2D. 3 patients will be entered at the 
next lower dose level. 
≥ 2 out of 3 
This dose level exceeded the RP2D. 3 additional patients will be 
entered at the next lower dose level. 
 
4.4 Dose Modification and Toxicity Management 
 
4.4.1 Dosing Delays and Modifications 
 
Study treatments are scheduled on a 3 weeks on, 1 week off schedule.   
 
 Start of a treatment cycle (Day 1) will be delayed for toxicity until retreatment 
criteria are met. The Principal Investigator must approve retreatment if delays last 
longer than 1 week. If delays are required due to toxicity related to one study drug 
but not the other, all study treatment will be delayed.   
 
 If the day 8 or day 15 dose of copanlisib needs to be delayed longer than 2 days due 
to toxicity, the dose(s) should be skipped and the remainder of the cycle continued 
once retreatment criteria are met.  The intention here is to keep the length of each 
cycle to 4 weeks, when possible.  Skipped doses will be documented in the study 
database. 
 
There will be no dose reductions to nivolumab. Dose reductions to copanlisib will use the 
dose levels outlined in Table 1 and dose reduction criteria outlined in Table 4. If a patient 
is already receiving the lowest dose level of copanlisib and meets criteria for further 
decrease, study treatment will be discontinued permanently. There will be no dose re-
escalation for DLTs.  Dose re-escalation may be allowed for non-DLTs at the PI’s 
discretion after patient has fully recovered from the toxicity and in the absence of any other 

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adverse events that require dose-reduction, with the exception of non-infectious 
pneumonitis. 
 
Dosing of study therapy will be delayed for the following criteria (or Table 4 criteria):  
 AST/ALT >3 × ULN 
 Total bilirubin > 1.5 x ULN  (> 2.0 × ULN for subjects with Gilbert’s syndrome) 
 Creatinine > 1.5 × ULN or GFR < 40 mL/min/1.73 m2 
 Hemoglobin < 8 g/dL 
 ANC < 1250/uL (day 1) and < 1000 (days 8 and 15) – hold both study drugs 
 Platelets < 75 × 103/uL 
 Fasting Glucose (Cycle 1 Day 1) >125 mg/dL (non-diabetic patients) or ≥160 mg/dL 
(diabetic patients) 
 Fasting glucose (all other days) > 160 mg/dL 
 CMV PCR > 500 IU/mL (tested each cycle for cycles 1-6, and every 3 months 
thereafter) 
 Any Grade ≥  2 non-skin, nivolumab-related adverse event, with the following 
exceptions: 
 Grade 2 fatigue 
 Grade 2 lab abnormalities 
 Grade 2 hypothyroidism or thyroiditis 
 Any Grade  ≥  3 skin nivolumab-related AE 
 Any Grade  ≥  3 nivolumab-related laboratory abnormality with the following 
exceptions: 
 Grade 3 lymphopenia 
 Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not 
associated with symptoms or clinical manifestations of pancreatitis 
 Isolated grade 3 or 4 electrolyte imbalances/abnormalities that are not 
associated 
with 
clinical 
sequelae 
and 
are 
corrected 
with 
supplementation/appropriate management 
 Any AE, laboratory abnormality, or inter-current illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.

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Table 4 - Dose modification and toxicity management guidelines for AEs associated with copanlisib 
Drug-related 
AEs 
Grade (CTCAE 
v5.0) or 
measurement 
Action taken to 
study drugs 
Retreatment 
Dose Level 
AE management 
Monitor and follow-up 
Hyperglycemia 
Grade 1: 
Asymptomatic 
glucose above 
baseline with no 
medical 
intervention 
Withhold until 
pre-infusion 
glucose is <160 
mg/dL (fasting)  
No change in dose 
 Hydration as appropriate 
 May follow without glucose-
lowering tx if repeated glucose 
value is decreasing and hydration 
status is normal 
 Repeat glucose testing  
 Endocrinologist consult recommended 
 Consider prophylaxis with oral 
glucose lowering tx for next dose:  
 Recommended (preferred order): 
SGLT2 inhibitor, DPP4 inhibitor, 
metformin, and/or thiazolidinedione 
 Not recommended: Use of 
sulphonylurea/ metaglinides, insulin 
secretagogues to manage increased 
glucose levels post drug infusions 
Symptomatic or 
persisting glucose 
>250mg/dL 1 
Withhold until 
pre-infusion 
glucose is <160 
mg/dL (fasting)  
No change in dose 
 Hydration as clinically 
appropriate 
 Glucose-lowering medication 
should be given: 
 Recommended (preferred 
order): SGLT2 inhibitor, DPP4 
inhibitor, metformin, and/or 
thiazolidinedione 
 Not recommended: Use of 
sulphonylurea/ metaglinides, 
insulin secretagogues to manage 
increased glucose levels post 
drug infusions 
 Assess hydration status 
 Repeat glucose testing 
 Consult with endocrinologist 
 Consider prophylaxis with oral 
glucose lowering tx for next dose: 
 Recommended (preferred order): 
SGLT2 inhibitor, DPP4 inhibitor, 
metformin, and/or thiazolidinedione 
 Not recommended: Use of 
sulphonylurea/ metaglinides, insulin 
secretagogues to manage increased 
glucose levels post drug infusions 
Persistent glucose  
>500 mg/dL1  
Withhold until 
pre-infusion 
glucose is <160 
mg/dL (fasting)  
Decrease by one dose 
level if repeated after 2 
infusions.  
Discontinue if persistent 
at lowest dose level after 
at least one cycle, despite 
optimal tx and consult 
with diabetes specialist.  
Max glucose  
>200mg/dL on 
subsequent days 
after infusion 
N/A 
N/A 
 Treatment with glucose-lowering 
medication per local standards 
 Recommended (preferred 
order): SGLT2 inhibitor, DPP4 
inhibitor, metformin, and/or 
thiazolidinedione 
 Not recommended: Use of 
sulphonylurea/ metaglinides, 
insulin secretagogues to manage 
increased glucose levels post 
drug infusions 
 Endocrinologist consult 
recommended 

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Table 4 - Dose modification and toxicity management guidelines for AEs associated with copanlisib 
Drug-related 
AEs 
Grade (CTCAE 
v5.0) or 
measurement 
Action taken to 
study drugs 
Retreatment 
Dose Level 
AE management 
Monitor and follow-up 
Arterial 
Hypertension 
Pre-dose BP 
>150/90 mmHg 
Withhold2  
No change in dose 
 Consider BP-lowering 
medication 
 Measure BP every 5-10 minutes (no 
more than 4 measurements) until 
acceptable for treatment.   
BP during 
infusion  
>160/100 mmHg 
Interrupt if having 
symptoms 
attributable to 
hypertension2  
Next dose reduced by one 
dose level at PI’s 
discretion 
 Initiate BP lowering medication 
according to standard of care 
 Monitor BP as clinically indicated 
until <150/90. 
Post-dose BP 
>160/100 mmHg3 N/A 
 Monitor BP as clinically indicated. 
Grade 4 
Permanently 
discontinue 
N/A 
Non-infectious 
Pneumonitis 
Grade 2 
Withhold  
Decrease by one dose 
level 
 
 
Grade 3 or 4  
or recurrent 
Grade 2 
Permanently 
discontinue 
N/A 
Infections 
Grade 3 or higher Withhold 
N/A 
 
 
Suspected PJP 
infection of any 
grade 
Withhold.  
Resume once 
infection resolves 
N/A 
If confirmed PJP, treat infection 
until resolution 
Treat with concomitant PJP prophylaxis 
after resolution/ restarting of copanlisib 
Dermatologic / 
Cutaneous AEs 
Grade 23 
Withhold 
1st: no dose change 
2nd-3rd: decrease by one 
dose level 
4th: discontinue 
 
 
Grade 33 
Withhold 
1st-2nd: decrease by one 
dose level 
3rd: discontinue 
Grade 4 
Permanently 
discontinue 
N/A 
Hematological 
toxicitiy4  
Grade 2 
neutropenia or 
thrombocytopenia 
on day 1 of each 
cycle 
Withhold 
No change in dose 
 
 

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Table 4 - Dose modification and toxicity management guidelines for AEs associated with copanlisib 
Drug-related 
AEs 
Grade (CTCAE 
v5.0) or 
measurement 
Action taken to 
study drugs 
Retreatment 
Dose Level 
AE management 
Monitor and follow-up 
Grade ≥ 3  
Withhold 
Decrease by one dose 
level at the PI’s discretion 
 Treatment with transfusion or 
growth factors allowed at PI’s 
discretion 
Other non-
hematological 
toxicities 
Grade 3 
Withhold 
1st: no dose change  
2nd-3rd: decrease by one 
dose level 
4th: discontinue   
 
 
Grade 4 or any 
toxicity requiring 
delay for >21 
days 
Permanently 
discontinue 
N/A 
1. Persistent occurrence is defined as repeated post-infusion blood glucose measurements taken at different times during the cycle despite optimal glucose-
lowering therapy in consultation with endocrinologist  
2. Infusion may proceed/resume on scheduled day if BP recovers to <150/90 mmHg for 2 consecutive measurements and symptoms (if present) resolve.  
3. Despite maximum supportive therapy 
4. Thrombocytopenia, neutropenia, febrile neutropenia, anemia, INR or PTT with bleeding 
 
General instructions: 
 
For situations where drug is withheld due to a copanlisib-related AE, treatment can be resumed after AE has been reduced to Grade 1 or 0 unless otherwise 
indicated. Treatment should be permanently discontinued if AE does not resolve within 12 weeks of last dose.  
 
If patient is already on lowest dose level and meets criteria for further decrease, study drug will be discontinued permanently. 
 
Dose re-escalation may be allowed at the PI’s discretion after patient has fully recovered from the toxicity and in the absence of any other adverse events 
that require dose-reduction, with the exception of non-infectious pneumonitis. 
 
Abbreviations:  SGLT2 = Sodium/Glucose co-transporter 2; DPP4 = Dipeptidyl peptidase 4; PJP= pneumocystis jiroveci pneumonia 
 
 

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In order to standardize the management of AEs for all subjects, treatment management 
algorithms are included in Appendix C. Additional AE treatment management algorithms 
included in the nivolumab IB might be considered for individual cases. 
 
Subjects who require a delay in study treatment should be re-evaluated weekly or more 
frequently if clinically indicated and resume dosing when re-treatment criteria are met. 
 
Subjects may resume treatment with study drug when the nivolumab-related AE(s) resolve 
to grade ≤1 or baseline value, with the following exceptions:  
 Subjects may resume treatment in the presence of grade 2 fatigue. 
 Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin adverse event 
 Treatment-related pulmonary toxicity, diarrhea, or colitis must have resolved to 
baseline before treatment is resumed. 
 Treatment-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment, which include grade 2 hyperglycemia, 
hypothyroidism and thyroiditis. 
 
Subjects should be permanently discontinued if AE does not resolve within 12 weeks of 
last dose or corticosteroids cannot be reduced to ≤ 10 mg prednisone or equivalent per day 
within 12 weeks. 
 
4.4.2 Toxicity-Related Treatment Discontinuation  
 
In addition to the discontinuation criteria listed in Table 4 above, permanent 
discontinuation of study treatment should be considered for any severe or life-threatening 
treatment-related AEs, including, but not limited to, any of the following (the IND Sponsor 
and BMS must be notified in the event of these AEs): 
 Any grade 2 treatment-related uveitis, eye pain, or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within 2 weeks 
of starting therapy OR requires systemic treatment 
 Any grade 3 non-skin, drug-related AE lasting > 7 days, with the following 
exceptions: 
o Grade 3 treatment-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
myocarditis, neurologic toxicity, hypersensitivity reaction, or infusion reaction 
of any duration requires discontinuation 
o Grade 3 treatment-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation. Treatment 
should be discontinued for grade 3 adrenal insufficiency. 
o Grade 3 treatment-related laboratory abnormalities do not require treatment 
discontinuation except: 
 Grade 3 treatment-related thrombocytopenia > 7 days or that is associated 
with bleeding requires discontinuation 

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 Any treatment-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation: 
 
Total bilirubin > 5 × ULN 
 
Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN 
 
 Any grade 4 treatment-related AE or laboratory abnormality, except for the 
following events which do not require discontinuation: 
o Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations, or radiographic signs of pancreatitis.  
o Isolated grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset. 
o Grade 4 lymphopenia and leukopenia. 
o Grade 4 treatment-related endocrinopathy adverse events, such as ACTH 
deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or 
are 
adequately 
controlled 
with 
physiologic 
hormone 
replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, 
may not require discontinuation after discussion with and approval from the 
IND Sponsor. 
 
4.4.3 Infusion Reactions  
 
Nivolumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  Infusion-related reactions to copanlisib may also occur. Monitor patients for 
signs and symptoms of infusion-related reactions from the start of each infusion until at 
least 30 minutes after the end of the infusion, in an area containing resuscitation equipment 
and medications necessary for advanced life support and cardiopulmonary resuscitation.  
Toxicity management guidelines on drug-related infusion reactions are provided in Table 
5. 
 
 
 
 
 
 
 
 
 
 

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Table 5 - Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at  
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Monitor vital signs as medically indicated 
until the participant is deemed medically 
stable in the opinion of the investigator. 
Participant may be premedicated at 
least 30 minutes before infusion of 
nivolumab with:  
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine)  
and/or  
Acetaminophen 325-1000 mg PO 
(or equivalent dose of analgesic) 
Grade 2 
Moderate reaction; requires 
therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Begin IV normal saline, and treat subject 
with diphenhydramine 50 mg IV (or 
equivalent) and/or acetaminophen 325-
1000 mg; monitor subject until resolution 
of symptoms.  Corticosteroid and/or 
bronchodilator therapy may also be 
administered as appropriate.  
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion 
rate. Otherwise dosing will be held until 
symptoms resolve and the participant 
should be premedicated for the next 
scheduled dose.   
If symptoms recur, then no further 
nivolumab will be administered at that 
visit.   
Participant may be premedicated at 
least 30 minutes before infusion of 
nivolumab with: 
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine). 
and/or 
Acetaminophen 325-1000 mg PO 
(or equivalent dose of analgesic). 
If necessary, corticosteroids (up to 
25 mg of SoluCortef or equivalent) 
may be used. 
 
Grades 3 or 4 
Grade 3: Severe reaction; 
prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae  
Grade 4: Life-threatening; 
urgent intervention 
indicated 
Stop Infusion. 
Begin IV normal saline and treat as 
follows: 
Investigators should follow institutional 
guidelines for the treatment of anaphylaxis.   
Recommended bronchodilators, 
epinephrine 0.2-1 mg of a 1:1000 solution 
for SubQ or a 0.1-0.25 mg of a 1:10,000 
solution injected slowly IV (or equivalent), 
as needed. 
Subject should be monitored until 
symptoms resolve and the investigator is 
comfortable that the symptoms will not 
recur.   
Participant is permanently discontinued 
from further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. 
 
 
 

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31 
4.4.4 Additional Toxicity Monitoring and Prevention 
 
4.4.4.1 Glucose and Diet Monitoring 
Table 6 - Fasting requirements and pre-dose glucose levels 
Period 
Fasting ≥ 12 h 
required before 
first glucose 
measurement 
Pre-dose glucose levels 
Day 1 of Cycle 1 
Yes  
<125 mg/dL (non-diabetic patients) 
<160 mg/dL (diabetic patients)   
Subsequent infusions 
after Cycle 1 Day 1 
Yes 
<160 mg/dL (fasting) 
<200 mg/dL (non-fasting) 
 
Fasting refers to a ≥ 12 hour fast.   Non-fasting status includes any caloric intake such as 
meals, juice, snack, as well as other caloric intake not consistently called a meal. 
From Cycle 1 Day 1 onwards, glucose measurements may be done either by laboratory 
analysis or in capillary blood. 
Because of its inhibitory effect on the PI3K α-isoform, which is implicated in insulin 
metabolism, copanlisib infusions could be associated with a temporary increase in blood 
glucose. Addition of a meal in close proximity to copanlisib infusion may exacerbate 
glucose increase.  
On infusion days a low calorie or low carbohydrate diet is recommended. It is 
recommended that timing and content of caloric intake as well as additional glucose 
testing (if clinically indicated) on infusion days is monitored by the investigators based 
on glucose response patterns during prior treatment days. Consultation with a 
diabetologist or endocrinologist is advised. 
All glucose measurements, 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.  
 
Glucose monitoring on study 
 
Management of hyperglycemia and dose delay parameters are outlined in Table 4 
 
The following assessments should be performed on Day 1, 8, and 15 of each cycle before 
receiving copanlisib unless otherwise specified: 
 Patients should be fasting for at least 12 hours prior to the pre-dose glucose 
measurement.  For details on fasting requirements and glucose measurement during 
C1D1 please refer to Table 6 
 Blood glucose will be measured at 0 hours (pre-dose) and 1 hour after completion 
of copanlisib (+/- 15min) infusion. If 1 hour post-infusion blood glucose is ≥35 
mg/dL higher than pre-dose level, recheck in another hour (2 hours post-infusion) 
to ensure decline in blood glucose. Additional measurements to be performed as 
clinically indicated.  

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32 
NOTE: If patient needs to take a low glycemic meal, then glucose test should be 
taken prior to meal intake. 
 Prior to first cycle, patients should be educated on the signs and symptoms of 
hyperglycemia, such as frequent urination, increased thirst, blurred vision, 
headaches and difficulty concentrating and must report these to the investigator or 
their physician immediately.  
 
4.4.4.2 Blood pressure measurement on treatment days 
 
Blood pressure will be measured every 5 – 10 minutes prior to each copanlisib dose (no 
more than 4 measurements) until there are two consecutive results < 150/90 mmHg. If 
blood pressure is ≥ 150/90 mmHg, the investigator can consider a medical intervention 
or delaying the infusion of study drug. The patient should rest for 5-10 minutes before 
next blood pressure is recorded. 
 
On infusion days, blood pressure will be measured at 0 h (pre-dose), 30 min (mid-
infusion), 60 min (end of infusion), and 1 h and 2 hours after the end of copanlisib 
infusion  
 
Note: a window of ±15 min is allowed for all BP measurements, except for the 0 h (pre-
dose) measurement, which may happen any time prior to infusion on the day of treatment. 
 
4.4.4.3 Hyperlipidemia monitoring 
 
Measurements for cholesterol, LDL and triglycerides. 
Total cholesterol, LDL and triglycerides will be tested only at Screening, on Day 1 of 
every 2nd cycle starting from Cycle 2, and at the EOT visit. On these dates patients must 
be fasting prior to sampling according to local standards. If a patient can’t adhere to 
fasting requirements, the evaluation of lipid-panels including triglycerides is considered 
not feasible. 
 
Management of hyperlipidemia 
As lipids are monitored for the duration of this study it is recommended to treat 
significant deviations from normal range with standard interventions and therapy in 
standard doses according to local medical practice. Goals of therapy are to keep fasting 
triglycerides < 300 mg/dL (3.4 mmol/L) and low-density lipoproteins (LDL) < 190 
mg/dL (4.9 mmol/L) (lower LDL depending on cardiovascular risk) in patients with a 
life expectancy >1 year. The goals for fasting triglycerides can be raised to < 500 mg/dL 
(5.6 mmol/L) for patients with life expectancy <1 year (31). 
 
Although there is a paucity of data on the effects of hyperlipidemia and cancer outcomes, 
these goals have been chosen to decrease risk of established complications of 
hypertriglyceridemia (pancreatitis) and hypercholesterolemia (cardiovascular events). 
For evaluation of lipid-panels including triglycerides the patient would be required to be 
fasted for 11 hours prior to sampling. For patients who cannot adhere to these fasting 
requirements the evaluation of lipid-panels including triglycerides and determination of 

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33 
treatment is considered as not feasible 
 
4.4.4.4 Opportunistic Infection (OI) Monitoring 
 
In addition to the weekly clinical review and laboratory tests outlined in the schedule of 
assessment, the following should be performed in all patients prior to IV infusion of 
copanlisib: 
 
Evaluation of any new onset or worsening of pulmonary symptoms (i.e. cough, 
dyspnea or fever) that includes a lung examination at each visit prior to infusion  
 
Labs: WBC, Lymphocyte count, CD4 (for patients with signs of infection), blood 
cultures (per local SOC if patient develops febrile neutropenia or ANC CTCAE 
of grade 4), PCR for CMV (monthly for first 6 months of treatment and every 3 
months thereafter) 
- 
Note: If PCR test for CMV > 500 IU/mL, treatment should be delayed 
until level reduces to ≤ 500 IU/mL. Treatment of CMV should be initiated 
based on local SOC. Re-treatment with copanlisib will be allowed without 
dose reduction once PCR test for CMV is ≤ 500 IU/mL. 
 
Enhanced monitoring when prior medical history or laboratory parameters could be 
associated with one of the following risk factors:  
 
Intensive chemotherapy (≥ 2 lines of myelosupressive cytotoxic therapy) 
 
History of CMV, herpes 
 
History of lower respiratory tract infection, history of  immunodeficiency in the 
last 12 months 
 
Lymphocytes count < 500 while on treatment in clinical study 
 
For patients with identified risk factors and those who developed OI, additional 
assessments will include: 
 
CD4 and CD8 count and ratio, CRP, blood cultures  
 
Any additional laboratory and diagnostic methods according to local SOC 
reported as unscheduled laboratory and diagnostic methods of assessment 
 
Radiological imaging (i.e. CXR or CT Scans) 
 
Note: Treatment of developed OI should be based on local standards of care (SOC). 
 
Prophylaxis of OI 
 
Mandatory prophylactic therapy is not recommended in all patients: 
 
Review of Copanlisib data do not support risk benefit ratio favoring prophylaxis 
in all patients  
 
Mandatory prophylaxis may cause a  higher risk of side effects associated with 
supportive treatment where no risks factors are present  
 
Currently implemented schedule of assessment, and additional enhancements 
provide frequent monitoring and flexibility for prophylaxis based on local SOC 
 
Although not mandated in all patients, OI prophylaxis may be initiated at the discretion 
of the treating investigator’s judgment of the benefit/risk ratio in any patient, irrespective 

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34 
of whether a high-risk feature is present, per local SOC.   If so, treatment, dosage and 
route of administration must be reported as concomitant medications. 
 
Prophylactic treatment of OI should be initiated based on SOC in patients when high risk 
factors are identified (see above risk factors).  For example: Bactrim or equivalent, 
Acyclovir or equivalent. Treatment, dosage and route of administration must be reported 
as concomitant medications. 
 
4.4.5 Prohibited and Restricted Therapies 
 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Any non-study anticancer or immunotherapy agent 
 Any non-study investigational agents  
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed at the investigator’s discretion.   
 Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 
BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., 
FluMist®) are live attenuated vaccines and are not allowed.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from 
an adverse event of suspected immunologic etiology.  Steroid treatment should be 
completed at least 14 days prior to resuming study-related treatments. The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Protocol Chair. 
 Strong inhibitors or inducers of CYP3A4/5 (see Table 7 below for examples) 
 Medications that carry a strong risk for QT prolongation 
 Herbal medications/preparations except for vitamins (see Table 7 below for 
examples) 
 Anti-arrhythmic therapy other than beta blockers or digoxin 
 
Table 7: List of prohibited medications during the study 
Category 
Drug name 
Strong CYP3A 
Inhibitors 
Voriconazole, boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, eltegravir/ritonavir, grapefruit juice, 
indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, saquinavir/ritonavir, 

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35 
telaprevir, telithromycin, tipranavir/ritonavir, troleandomycin, 
Strong CYP3A 
Inducers 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampin (rifampicin), St. John's wort (hypericum 
perforatum) 
Herbal Preparations/ 
Medications 
Herbal preparations/medications are prohibited throughout the 
study. These herbal medications include, but are not limited to: St. 
John’s wort, Kava, ephedra (ma huang), ginkgo biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and 
ginseng. Patients should stop using these herbal medications 7 
days prior to first dose of study drug 
 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards 
of medical care.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue 
the participant on study treatment requires the mutual agreement of the investigator, the 
Sponsor and the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
4.4.6 Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care.  All concomitant medication will be recorded on the case report form 
(CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.   
Permitted concomitant therapy 
 Standard therapies for concurrent medical conditions 
 Treatment with non-conventional therapies (for example herbs or acupuncture), and 
vitamin/mineral supplements is acceptable provided that they do not interfere with the 
study endpoints, in the opinion of the Investigator. St John’s Wort is not permitted. 
 Bisphosphonates 
 Patients who are therapeutically treated with an agent such as warfarin or heparin will 
be allowed to participate provided that their medication dose and INR/PTT is stable. 
Close monitoring is recommended according to standard of care. If either of these 
values is above the therapeutic range, the doses should be modified and the assessments 
should be repeated weekly until it is stable. 
 Antiemetics: Prophylactic anti-emetics may be administered according to standard 
practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as 

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36 
granisetron, ondansetron, or an equivalent agent, is allowed as needed. The use of 
corticosteroids as antiemetics prior to copanlisib administration will be not allowed. 
 Palliative and supportive care for the other disease-related symptoms and for toxicity 
associated with treatment will be offered to all patients in this trial. 
 Patients may receive palliative and supportive care for any underlying illness 
 Palliative irradiation shall be permitted provided that: 
o In the opinion of the investigator, the patient does not have PD. 
o The radiation field does not encompass a target lesion 
o The radiation field does not encompass a lung field (to reduce the risk of 
pneumonitis). 
 Low-dose aspirin (maximum 100 mg/day) and low-dose heparin are permitted. 
 Patients taking narrow therapeutic index medications should be monitored proactively, 
if these medications cannot be avoided. These medications may include quinidine, 
cyclosporine, and digoxin 
 Calcium channel blockers to control pre-existing hypertension. Non-dihydropyridine 
calcium channel blockers (Verapamil and diltiazem) are permitted.  
 Short term (up to 7 days) systemic corticosteroids above 15 mg prednisone or 
equivalent will be allowed for the management of acute conditions (e.g. treatment of 
non-infectious pneumonitis).  
 Therapeutic drugs known to be sensitive substrates of the renal drug transporter 
MATE2K (e.g. metformin, cimetidine, procainamide and N methylnicotinamide) 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. 
 
4.5 Duration of Therapy and Criteria for Removal from Study Treatment  
 
In the absence of treatment delays due to adverse event(s), treatment may continue indefinitely 
until one of the following criteria applies.  The reason for study treatment removal and the date 
the patient was removed must be documented in the Case Report Form.  
 
A participant must be discontinued from study treatment but continue to be monitored in the 
study follow-up for any of the following reasons: 
 The participant  or participant’s legally acceptable representative requests to 
discontinue study treatment 
 Confirmed radiographic disease progression outlined in Section 9 and Appendix E 
o As immunotherapy has been shown to cause pseudo-progression, patients are 
eligible to remain on study after progression if they are clinically stable, if they 
desire and their treating physician agrees it is in the interest of the patient.  If 
subsequent imaging confirms progression, the patient’s date of progression will 
be the date of first progression 
 Clinical progression or deterioration 

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37 
 Progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment 
 Unacceptable adverse experiences as described in Section 4.4.2 Exceptions must be 
approved by the IND Sponsor. 
 The participant has a medical condition or personal circumstance which, in the opinion 
of the investigator and/or sponsor, placed the participant at unnecessary risk from 
continued administration of study treatment. 
 Investigator’s decision to withdraw the subject 
 The participant has a confirmed positive serum pregnancy test 
 Noncompliance with study treatment or procedure requirements 
 
4.6 
End of Treatment (EOT) Visit 
 
After a patient is discontinued from treatment, an End of Treatment (EOT) Visit should be 
performed approximately 30 days after the last infusion of study medication (or within 7 days 
prior to initiation of a new anti-cancer treatment, whichever comes first).  Procedures and 
assessments performed at this visit and beyond should follow the guidelines described in the 
Study Calendar in Section 8 as appropriate.  The patient will be monitored for adverse events 
up to the mandatory Off Study/Safety Follow-Up Visit.   
 
4.7 
Duration of Follow Up   
 
Subjects who discontinue from treatment should continue to follow up with their primary 
oncologist and be contacted every 3 months (+/- 2 weeks) to monitor OS for up to 3 years or 
death, whichever occurs soonest.  Effort should be made to collect information regarding 
disease status until the start of new anti-neoplastic therapy, disease progression, death, or end 
of study. Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated.  
  
Subjects who are discontinued from the study treatment due to an unacceptable drug-related 
AE will be monitored for safety until the resolution of the AE to ≤ grade 1, or stabilization, or 
until initiation of a new therapy for their cancer, whichever occurs first. 
  
All subjects will be followed for at least 30 days after their last dose of study drug for the 
development of AEs. SAEs that occur within 100 days (+ 14 day reporting window) of the last 
infusion of nivolumab or before initiation of a new antineoplastic treatment should also be 
followed and recorded. 
 
 

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5. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
This study will use the descriptions and grading scales found in the revised National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 for adverse 
event 
reporting 
that 
can 
be 
found 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other means, 
will be collected, recorded, and followed as appropriate.  
 
The PI has the primary responsibility for continuous internal monitoring for safety, protocol 
compliance, and identification, grading, coding, and required reporting of all anticipated and 
unanticipated adverse events and protocol problems. Although this responsibility is usually shared 
among the PI, research nurse, and data manager, the PI is ultimately responsible for grading and 
attribution of all events. 
 
5.1 Definitions 
 
5.1.1 Adverse Event 
 
An adverse event (AE) is defined as any undesirable sign, symptom or medical condition 
occurring after starting the study drug (or therapy) even if the event is not considered to be 
related to the study. An undesirable medical condition can be symptoms (e.g., nausea, chest 
pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram). Medical conditions/diseases present before starting 
the study treatment are only considered adverse events if they worsen after starting the study 
treatment (any procedures specified in the protocol). Symptoms / medical conditions 
occurring before starting the study treatment but after signing the informed consent form will 
not be recorded as AEs. Additionally, expected progression of the disease being studied will 
not be recorded as an adverse event.  
 
 Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be 
recorded as pre-treatment signs and symptoms in a medical history CRF. After study 
treatment administration, all grade 3 and 4 clinical laboratory results that represent an 
increase in severity from baseline will be reported as adverse events. A grade 1 or 2 clinical 
laboratory abnormality should be reported as an adverse event only if it is considered 
clinically significant by the investigator, induces clinical signs or symptoms, or requires 
therapy. 
 
5.1.2 Serious Adverse Event (SAE) 
 
A serious adverse event (SAE) is an adverse event which:  
 Results in death  
 Is life threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe)  

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 Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see note below for exceptions) > 24 hours 
 Results in persistent or significant disability/incapacity  
 Is a congenital anomaly/birth defect (note: reports of congenital anomalies/ birth 
defects must also be reported on the Pregnancy Supplemental Form)  
 Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.). Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization). 
 Suspected transmission of an infectious agent (e.g. pathogenic or nonpathogenic) via 
the study drug is an SAE. 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and new 
cancers are not always serious by regulatory definition, these events must be handled as 
SAEs. 
Drug induced liver injury (DILI) is defined as:  
An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as determined 
by way of protocol-specified laboratory testing or unscheduled laboratory testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology.  
 
Events not considered to be serious adverse events are hospitalizations for the:  
 Admissions as per protocol for a planned medical/surgical procedure or to facilitate 
a procedure 
 Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy)  
 Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases  
 Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
 
5.1.3 Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must 
be reported as SAEs. In the event of overdose, the participant should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 

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5.2 
Relationship 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
 No (unrelated, not related, no relation):  The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.  
 
 Yes (related): The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal relationship 
and no other cause (concomitant drugs, therapies, complications, etc.) can be identified.  
 
The following factors should also be considered:  
 The temporal sequence from study drug administration - The event should occur after 
the study drug is given. The length of time from study drug exposure to event should 
be evaluated in the clinical context of the event.  
 Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have.  
 Concomitant medication - The other medications the subject is taking or the treatment 
the subject receives should be examined to determine whether any of them might be 
recognized to cause the event in question.  
 Known response pattern for this class of study drug - Clinical and/or preclinical data 
may indicate whether a particular response is likely to be a class effect.  
 Exposure to physical and/or mental stresses - The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.  
 The pharmacology and pharmacokinetics of the study drug - The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug 
should be considered. 
 
5.3 
Assessment of Grade      
 
The investigator will make an assessment of grade for each AE and SAE reported during the 
study, which will be recorded in the CRF. The assessment will be based on the National Cancer 
Institute’s CTCAE (Version 5.0) and graded as shown below: 
 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 

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41 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
 
Any AE that changes in grade during its course will have each change of grade recorded on 
the adverse event case report forms. 
 
5.4 Expectedness 
 
Unexpected adverse event: An adverse event, which varies in nature, intensity or frequency 
from information on the investigational drug/agent provided in the Investigator’s Brochure, 
package insert or safety reports. Any adverse event that is not included in the informed consent 
is considered “unexpected”.  
 
Expected (known) adverse event: An adverse event, which has been reported in the 
Investigator’s Brochure. An adverse event is considered “expected”, only if it is included in 
the informed consent document as a risk. 
 
5.5 Handling of Expedited Safety Reports 
 
In accordance with local regulations, the IND Sponsor will notify investigators of all SAEs 
that are unexpected (i.e. not previously described in the Investigator Brochure), and definitely, 
probably, or possibly related to nivolumab or copanlisib. This notification will be in the form 
of an expedited safety report (ESR) that is to be faxed to the investigators and the study 
coordinators. Upon receiving such notices, the investigator must review and retain the notice 
with the Investigator’s Brochure and where required by local regulations, the investigator will 
submit the ESR to the appropriate IRB. The investigator and IRB will determine if the informed 
consent requires revision. The investigator should also comply with the IRB procedures for 
reporting any other safety information.  
 
5.6 Reporting 
 
5.6.1 General 
 
All adverse events (both expected and unexpected) will be captured on the appropriate study-
specific case report forms (CRFs).  
 
Adverse events experienced by subjects will be collected and reported from the first dose of 
the study drug, throughout the study, and will only be followed for 30 days (or within 7 days 
prior to initiation of a new anti-cancer treatment, whichever comes first) unless related to the 
study drug(s). Adverse events related to the study drug(s) will be monitored for resolution of 
toxicity to ≤ grade 1, stabilization, or determined to be irreversible by the investigator.  
 
SAEs that occur following the subject’s written consent to participate in the study through 
100 days (+ 14 day reporting window) after the last infusion of study drug (or within 7 days 
prior to initiation of a new anti-cancer treatment, whichever comes first) will be collected 
and reported. 
 

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All SAEs, regardless of causality to study drug, must be reported within 24 hours of initial 
notification of the SAE to the IND Sponsor, BMS, and Bayer using the SAE Reporting Form 
found in Appendix F. If this falls on a weekend or holiday, an email notification is acceptable 
but must be followed by an SAE reporting form on the next business day. 
 
SAE reports and any other relevant safety information are to be sent to: 
 
After the initial SAE report, the investigator is required to proactively follow each subject 
and provide further information to the safety department in regards to the subject’s condition. 
 
 
All SAE(s) will be followed until: 
 Resolution 
 The condition stabilizes 
 The event is otherwise explained 
 The subject is lost to follow-up 
 Death 
 
As soon as relevant information is available, a follow-up SAE report will be submitted to the 
IND Sponsor, BMS, and Bayer. 
 
The Sponsor will reconcile the clinical database SAE cases (case level only) transmitted to 
BMS Global Pharmacovigilance 
. 
 The Investigator will request from BMS GPV&E 
the SAE reconciliation report and include the BMS protocol number every 3 months 
and prior to data base lock or final data summary. 
 GPV&E will send the investigator the report to verify and confirm all SAEs have 
been transmitted to BMS GPV&E. 
 The data elements listed on the GPV&E reconciliation report will be used for case 
identification purposes. If the Investigator determines a case was not transmitted to 
BMS 
GPV&E, 
the 
case 
should 
be 
sent 
immediately 
to 
BMS 
 
5.6.2 Pregnancy Reporting 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
who has provided written consent to provide information regarding pregnancy, that occurs 
during the trial or within 6 months of completing the trial.  All subjects who become pregnant 
must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious adverse events 
(Important Medical Events). Pregnancy and non-serious pregnancy outcomes should be 
reported as Events of Clinical Interest. If the pregnancy continues to term, the outcome (health 

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5.6.3 Institutional Review Board (IRB)  
 
Participating sites will be responsible for reporting to their IRB. All serious adverse events 
will be reported to the IRB per institutional standards. Upon receipt, follow-up information 
will be given to the IRB (as soon as relevant information is available) per institutional 
standards. 
 
5.6.4 Food and Drug Administration (FDA) 
 
All reporting to the FDA will be completed by the IND Sponsor. 
 
5.6.4.1 Expedited IND Safety Reports: 
 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the 
investigational agent.  Such reports are to be telephoned or faxe
 to the 
FDA within 7 calendar days of first learning of the event.   
 
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any serious adverse event that is 
unexpected and possibly related to the investigational agent in a written IND Safety 
Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND 
concerning similar events should be analyzed.  The new report should contain comments 
on the significance of the new event in light of the previous, similar reports.  
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA 
within 15 calendar days of first learning of the event. Follow-up information will be 
submitted to the FDA as soon as relevant information is available. 
 
5.6.4.2 IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 60 days 
of the anniversary date that the IND went into effect submit a brief report of the adverse 
events and progress of the investigation.  Please refer to Code of Federal Regulations, 21 
CFR § 312.33 for a list of the elements required for the annual report.  All IND annual 
reports will be submitted to the FDA by the IND Sponsor. 
 
 

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44 
6. PHARMACEUTICAL INFORMATION 
 
6.1 Nivolumab 
 
6.1.1 Agent Accountability 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
6.1.2 Mode of Action 
 
Nivolumab is a fully human monoclonal immunoglobulin (Ig) G4 antibody that binds to 
the PD-1 cell surface membrane receptor, a negative regulatory molecule expressed by 
activated T and B lymphocytes. 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. 
  
6.1.3 Description 
 
Nivolumab Injection, 100 mg/vial (10 mg/mL) 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 at 10 mg/mL in sodium 
citrate, sodium chloride, mannitol, diethylenetriamine pentaacetic acid and polysorbate 80 
(Tween™ 80), pH 6.0 and includes a 0.7-mL overfill to account for vial, needle, and 
syringe (VNS) holdup. It is supplied in 10-cc type I flint glass vials, stoppered with butyl 
rubber stoppers and sealed with aluminum seals. 
 
6.1.4 Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. This trial is open-label; therefore, the participant, the trial site personnel, 
the Sponsor and/or designee are not blinded to treatment.  
 
6.1.5 Preparation 
 
Nivolumab injection should be diluted with 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP to protein concentrations as low as 1 mg/mL. Care must be taken 
to assure sterility of the prepared solution as the product does not contain any anti-
microbial preservative or bacteriostatic agent. No incompatibilities between nivolumab 
and polyolefin bags have been observed. Recommended safety measures for preparation 
and handling of nivolumab include laboratory coats and gloves. Detailed instructions on 
the preparation of nivolumab for administration will be provided in the Investigator’s 
Brochure. 
 
6.1.6 Storage and Handling Requirements 
 

J1887/Version 7.0 / January 27, 2023 
45 
Clinical supplies must be stored in a secure, limited-access location. Nivolumab vials must 
be stored at a temperature of 2°C to 8°C and should be protected from light and freezing. 
If stored in a glass front refrigerator, vials should be stored in the carton. Receipt and 
dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
6.1.7 Stability 
 
The administration of nivolumab infusion must be completed within 24 hours of preparation. 
If not used immediately, the infusion solution may be stored under refrigeration conditions 
(2°-8°C, 36°-46°F) for up to 24 hours, 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 8-hour period 
under room temperature and room light conditions includes the product administration 
period. 
 
6.1.8 Route of Administration 
 
Nivolumab is to be administered as a 30 minute IV infusion, using a volumetric pump 
with a 0.2/0.22 micron in-line filter at the protocol-specified dose. 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.  
 
6.1.9 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from BMS or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. BMS will be notified of all destruction of study drug. 
 
6.2 Copanlisib 
 
6.2.1 Agent Accountability 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
6.2.2 Mode of Action 
 
Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant 
and potent activity against the PI3K-δ and PI3K-α isoforms. The PI3K pathway is a 

J1887/Version 7.0 / January 27, 2023 
46 
prominent pathway that promotes cellular survival and is found to be constitutively activated 
in many cancer types.  Inhibition of this pathway is expected to lead to impaired cellular 
uptake of glucose, with a subsequent reactive rise in plasma insulin and glucose levels.  
 
6.2.3 Description 
 
Copanlisib is supplied as lyophilized preparation in a 6-mL injection vial. The total amount 
of BAY 80-6946 per vial is 60 mg. The solution for IV infusion is obtained after 
reconstitution of the lyophilisate with 0.9% sodium chloride solution. 
 
6.2.4 Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. Open label kits will be provided for patient dosing. 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text. 
 
6.2.5 Preparation 
 
Refer to the Pharmacy Manual for preparation instructions. 
 
6.2.6 Storage and Handling Requirements 
 
Copanlisib must be stored between +2°C and +8°C and should not be transported above 
+30°C. Clinical supplies must be stored in a secure, limited-access location.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. Clinical supplies may not be used for any purpose other than that stated in the 
protocol. 
 
6.2.7 Stability 
 
Refrigeration is not required if reconstituted copanlisib is used immediately (within max of 
4 hours). If not used immediately, store reconstituted solution in the vials or in the infusion 
bag at +2°C to +8°C (36°F to 46°F). Allow the product to adapt to room temperature after 
refrigeration. It takes approximately 60 minutes for a 100 mL dilution filled in bags to return 
to room temperature after refrigeration. The overall storage time must not exceed 24 hours 
including preparation and administration.  Avoid exposure of the diluted solution to direct 
sunlight.  
 
6.2.8 Route of Administration 
 
Copanlisib is administered in a normal saline solution, intravenously, over 1 h.  
No intravenous glucose preparations should be administered on the days of infusion. 
6.2.9 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received 

J1887/Version 7.0 / January 27, 2023 
47 
from Bayer or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 
 
7. CORRELATIVE/SPECIAL STUDIES 
 
Detailed instructions for collection, processing, and storage of tumor and blood samples are 
provided in the Laboratory Manual. Results from the sequencing studies will not be released 
to the patients. These studies are for research purposes only and are not using a clinically 
validated platform. 
 
 
7.1 Tumor Tissue  
 
Patients in both phases of the study will have paired biopsies – one prior to treatment and one 
after six weeks on therapy (4-6 cores per time point).  This will be prior to Cycle 2 Day 15 
treatment, after two doses of nivolumab and three or five doses of copanlisib (depending on 
the dose level).  Patients will also be asked for an optional biopsy at the time of progression.   
 
Tumor biopsy will not be performed if the tumor is not accessible or if biopsy is considered 
not in the patient’s best interest.   
 
Attempts will be made to obtain archived tissue samples from all subjects.  Archived FNA 
biopsy samples do not contain sufficient tissue and will not be collected.   
 
We will assess tumor immune infiltrate using immunohistochemistry (IHC) and flow 
cytometry of disaggregated tumor samples. Expression of PD-L1 and of a series of biomarkers 
will be assessed by IHC. CD8+ T cells will be enriched by magnetic separation from 
disaggregated tumor samples and stimulated ex vivo to query markers of T cell exhaustion and 
cytokine production. We will also use single cell RNASeq for an unbiased assessment not only 
of cellular composition but also of functional status as assessed by gene expression profiles. 
From single cell expression data, we hope to identify gene expression profiles of tumor cells 
that are correlated with response to therapy. 
Tumor Sample Requirements: 
Slides 
H&E 
10 unstained FFPE 
Tissue 
50mg fresh (flow cytometry) 
50mg fresh (ex vivo T cell stimulation) 
25 mg fresh/frozen (single cell RNASeq) 

J1887/Version 7.0 / January 27, 2023 
48 
 
7.2 Peripheral Blood Mononuclear Cells (PBMCs)  
 
Up to 100 cc of whole blood for isolation of PBMCs will be collected at baseline prior to first 
dose of study drug, at 2 weeks after first dose, on Day 1 of each odd cycle, and at progression 
or EOT visit.  Phenotypic and functional analysis of PBMCs via flow cytometry will be 
performed. 
 
7.3 Plasma 
 
Up to 20 cc whole blood for plasma will be collected at baseline prior to first dose of study 
drug, at 2 weeks after first dose, on Day 1 of each odd cycle, and at progression or EOT visit.     
 
Peripheral Cytokines will be measured by standard luminex assays from patient plasma. We 
will measure cytokine levels from peripheral blood including but not limited to IFNγ, TNFα, 
TGFβ, IL-10, CXCL9, CCL2, IL-6, IL-12, IL-2 and IL-17.  
 
7.4 Diagnostic Tissue Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat or 
diagnose immune-related toxicities. 
 
7.5 Planned Analyses 
 
7.5.1 PI3K mutation assessment 
PI3K mutation assessment will be performed centrally in batched analysis using NGS and 
PCR based testing by a CLIA certified lab.  All PI3K mutations will be noted, but the 
patient will be considered to have PI3K mutations if they have a known-activating mutation 
of PIK3 as defined in Table 8.  Additional mutations may be added to this definition in the 
face of emerging discovery. 
 
Table 8 – Activating PIK3 Mutations 
G106R 
R108H 
P124L 
V344G 
N345K 
C420R 
E542K 
E543_I459del 
E545K, E545A, E545Q, E545G 
Q546K 
Q546R, Q546P 
H1047R, H1047L 
G1049R 
 

J1887/Version 7.0 / January 27, 2023 
49 
7.5.2 Determining effect of copanlisib on tumor immune subpopulations.   
Expected results include 1) an increase in the number of infiltrating CD8+ T cells following 
treatment with copanlisib and nivolumab and/or 2) a decrease in immunosuppressive cells 
including CD4+, FOXP3+ Treg cells or functional myeloid derived suppressor cells 
(MDSCs).  Objectives related to tumor immune subsets will be accomplished by three 
techniques, and tissue prioritized as below. Intended comparisons are between paired 
biopsy specimens from the same patient, where a change in populations can be correlated 
with treatment, as well as inter-patient comparisons for correlation with clinical response.   
 
1. Multiplex IHC/IF 
A series of biomarkers will be assessed on tissue from this study. A sample of immune and 
other markers in Table 9 will be the stains of high priority for these exploratory 
investigations, in order of priority based on amount and quality of tissue obtained. Briefly, 
tumor samples will be stained on a quantitative multiplex immunohistochemical platform 
developed at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center that was 
previously published22. This technology incorporates a computational image processing 
workflow, including image cytometry, that enables simultaneous evaluation of 12 
biomarkers in one formalin fixed paraffin-embedded tissue section. This platform is readily 
adaptable to assess a variety of markers including lymphoid and myeloid lineage markers, 
in addition to those listed in Table 9. After staining, slides will be analyzed in the Cell 
Imaging Core Facility at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center to 
quantitate the percentage and intensity of cells for each marker(s) in the TME. The 
biomarker data will be captured for samples according to a digital image workflow. Briefly, 
this encompasses three steps: image preprocessing, visualization, and quantitative image 
analysis using state-of-the-art software in the Core Lab. This system allows for true 
quantitative data on dual staining in patient samples. These IHC and IF analyses will be 
conducted under the guidance o
 To ensure the rigor of these analyses, 
samples will be batch run when possible, with appropriate positive (i.e. tonsil tissue for 
immunostains) and negative controls (secondary Ab only) along with serial sections from 
a single archival colon carcinoma tumor specimen as a qualitative control to for intensity 
and any batch-to-batch variability between reagents used in IHC or IF assays. 
 
Table 9 - Planned Immunohistochemical (IHC) and Immunofluorescence (IF) analysis 
(*denotes primary biomarker) 
Immunohistochemistry 
Immunofluorescence 
 
CD8*, CD4, PD-L1, PTEN 
CD8+, Ki67+, CD8+Nur77+, 
CD4+FoxP3+ 
Priority 1 
CD11c, CD19, CD68, CD163, CTLA4, 
PD-1, PD-L2, IDO1, LAG3, p-AKT 
CD33+S100+, CD4+IL-17+ 
Priority 2 
 
2. Flow cytometry 
When adequate fresh tissue can be obtained, tumor will be disaggregated using a 
combination of enzymatic and mechanical disruption23. Resulting suspension will be 
analyzed by flow cytometry with markers shown in Table 10. Included in this panel is 
analysis of a subset of CD8+ T cells identified by 

J1887/Version 7.0 / January 27, 2023 
50 
(CD8+Ki67+) that displays a proliferative burst after PD-1 blockade and may be a potential 
biomarker of response to anti-PD-1 therapy24.  Populations will be normalized to tumor 
weight using counting beads.  
 
Table 10 - Planned markers for flow cytometry of disaggregated tumor biopsies. 
Cell population 
Marker 
CD8+ T cell 
CD8, GZMB, PD-1, Tim3, Lag3, 2B4, Ki67 
Regulatory CD4+ FOXP3+ T Cell 
CD4, FOXP3 
MDSC 
CD11b, HLA-DR, CD14, CD15, CD33, 
Lin-(CD3/14/15/19/56) 
NK 
CD56 
B cell 
CD19 
 
3. Single cell/nuclei RNASeq 
Single cell RNASeq will provide an unbiased assessment of cellular composition and of 
functional status as assessed by individual cell gene expression profiles. Single cell 
sequencing of tumor biopsies will be performed using droplet technology (10X genomics), 
whereby single cells from tumor suspensions are partitioned and a unique transcriptome 
barcode applied prior to lysis and whole transcriptome amplification. High-quality data 
will be generated from 6-10,000 tumor and immune cells from each biopsy. Each biopsy 
will contain both tumor, stromal and immune cells, which will allow the broadest analysis 
of the tumor microenvironment.  Initial analysis based on signature enrichment will allow 
the deconvolution of tumor vs. non-tumor (stroma, immune cell) populations. Subsequent 
analyses will include reconstruction of TCR sequences and tracking of TCR clones 
throughout subpopulations25, arrangement of cells in pseudotemporal space with 
Monocle26, differential expression analysis based on mixture models to account for the 
zero-inflation of single cell transcriptional data27, and calculation of cell-by-cell gene-set 
signature scores28 to probe for pathway and phenotype-level differences between 
subpopulations. 
 
7.5.3 Determining Effect of Copanlisib on CD8 T cell function 
CD8+ T cells are expected to not only increased in number in copanlisib-treated tumors 
but to also be more functional, as measured by cytokine production and decreased 
expression of inhibitory ligands.  CD8+ T cells will be enriched by magnetic separation 
from disaggregated tumor samples and stimulated ex vivo.  Production of cytokines IFNγ 
and TNFα will be measured by flow cytometry.  Inhibitory ligands commonly expressed 
on exhausted T cells including PD-1, Tim3, Lag3, and 2B4 will be measured by flow 
cytometry as described above.   
 
7.5.4 Determining Effect of Copanlisib on Peripheral Blood Immune Subsets 
Peripheral blood mononuclear cells will be isolated from blood samples following removal 
of the plasma layer. This will be accomplished via standard methods using density gradient 

J1887/Version 7.0 / January 27, 2023 
51 
centrifugation with ficoll-paque plus29. Following isolation PBMCs will be resuspended in 
PBS, counted via trypan blue exclusion and aliquoted into tubes for phenotypic and 
functional analysis via flow cytometry staining per standard techniques. Markers and cell 
populations analyzed will be the same as indicated in Table 9.  
 
7.5.5 Determining Effect of Copanlisib on Peripheral Blood Cytokines 
Cytokine levels from peripheral blood including but not limited to IFNγ, TNFα, TGFβ, IL-
10, CXCL9, CCL2, IL-6, IL-12, IL-2 and IL-17 will be measured by standard luminex 
assays from patient plasma.                 
                                                            
7.6 Investigator Responsibilities for Translational Research    
                  
that we will have approximately 40 paired biopsies (75% success rate based on previous 
studies) as well as ~6-12 time points for blood draws to assess changes in circulating immune 
parameters. We estimate 20% of patients would allow a progression biopsy. 
 
 

J1887/Version 7.0 / January 27, 2023 
52 
8. STUDY SCHEDULE 
8.1 
Study Calendar – Phase I 
 Baseline1 
Treatment (1 cycle = 28 days) 
EOT21 
Survival 
Follow-Up22  
Q12 weeks  
(± 2 weeks) 
Cycle 1 
Cycle 2 and higher 
 
Procedure 
(-28 to 0) 
D1 
(±3 
days) 
D8 
(+1 
day) 
D15 
(+3 
days) 
D1 
(±3 
days) 
D8 
(+1 
day) 
D15 
(+3 
days) 
30 days (+/-4 
days) after last  
study drug 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Demographics and Med Hx2 
X 
 
 
 
 
 
 
 
 
Copanlisib  
 
X 
X 
X 
X  
X 
X 
 
 
Nivolumab 
 
X 
 
 
X 
 
 
 
 
Post-study anticancer therapy 
and survival status 
 
 
 
 
 
 
 
 
X 
Clinical Assessments 
Physical Examination, ECOG3 
X 
X 
X 
X 
X 
 
X 
X 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Pressure (infusion days)5 
 
X 
X 
X 
X 
X 
X 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
Height (may be from prior visit) 
X 
 
 
 
 
 
 
 
 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
 
Con Med Review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Assessments  
CBC with Differential6, 16 
X 
X 
X 
X 
X 
 X 
X 
X 
 
Chemistry Panel7, 16 
X 
X 
X 
X 
X 
X 
X 
X 
 
Glucose8 
 
X 
X 
X 
X 
X 
X 
 
 
Hemoglobin A1C16 
X 
 
 
 
X9 
 
 
X 
 
Lipid Panel10, 16 
X 
X 
X 
X 
X(even 
cycles) 
 
 
X 
 
TSH11, 16 
X 
X 
 
X 
X 
 
X 
X 
 
PT, INR and aPTT16 
X 
 
 
 
 
 
 
 
 
HBsAg, HCV Ab, HIV12 
X 
 
 
 
 
 
 
 
 
CMV PCR13,16 
X 
 
 
 
X 
 
 
 
 
Pregnancy Test14, 16 
X 
X 
 
 
X 
 
 
X 
 
Urinalysis15, 16 
X 
 
 
 
X(even 
cycles) 
 
 
 
 
Urine protein:creatinine ratio 
(UPCR) 
X 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
MUGA or echocardiogram17 
X 
 
 
 
 
 
 
X 
 
CEA 
X 
X 
 
 
X 
 
 
X 
 
Efficacy Assessments 
Tumor Imaging18 
X 
 
 
 
X(odd 
cycles) 
 
 
X 
 
Tissue and Blood for Correlative Studies 
Fresh Tumor Biopsy19 
X 
 
 
 
 
 
X 
X 
 
Archival Tumor Sample 
X 
 
 
 
 
 
 
 
 
Blood for PBMC (180cc)20, 16 
 
X 
 
X 
X(odd 
cycles) 
 
 
X 
 

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53 
 Baseline1 
Treatment (1 cycle = 28 days) 
EOT21 
Survival 
Follow-Up22  
Q12 weeks  
(± 2 weeks) 
Cycle 1 
Cycle 2 and higher 
 
Procedure 
(-28 to 0) 
D1 
(±3 
days) 
D8 
(+1 
day) 
D15 
(+3 
days) 
D1 
(±3 
days) 
D8 
(+1 
day) 
D15 
(+3 
days) 
30 days (+/-4 
days) after last  
study drug 
Blood for plasma (20 cc) 20, 16 
 
X 
 
X 
X(odd 
cycles) 
 
 
X 
 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted 
for in-person clinical trial visits or portions of clinical trial visits where determined to be appropriate 
and where determined by the investigator not to increase the participants risks.  Prior to initiating 
telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails 
and confirm that the study participant is in agreement and able to proceed with this method.  In the event 
telemedicine is not deemed feasible, the study visit will proceed as an in-person visit.  Telemedicine visits 
will be conducted using HIPAA compliant method approved by the Health System and within licensing 
restrictions.  
1. Baseline evaluations should occur within 28 days prior to registration, unless otherwise noted.  
No window applies to demographics, consent, or height at baseline.   
2. Includes history of lung disease, cardiovascular disease, diabetes, HIV, hepatitis B or C 
infection, and complete cancer history, including primary site of cancer, gross location of 
primary tumor, histology, histologic grade, date of initial diagnosis, date of metastatic diagnosis, 
prior cancer therapy regimens 
3. A complete physical exam will be performed at baseline; focused physical exams will be done 
thereafter. Physical exams and AE assessments can be done up to 3 days prior to dosing. 
4. Temperature, pulse, blood pressure, respiratory rate, and pulse oxygen will be collected at 
baseline, and prior to each dose of study drug, and at EOT visit.  
5. Blood pressure will be measured every 5-10 minutes prior to each copanlisib dose (no more than 
4 measurements) until there are 2 consecutive results ≤ 150/90 mmHg. If the blood pressure is 
≥ 150/90 mmHg, the investigator can consider a medical intervention e.g. administration of 
dihydropyridine calcium channel blocker), or delaying the infusion of the study drug. Blood 
pressure will be measured at pre-dose, 30 min (mid-infusion), 60 min (end of infusion), and 1h 
and 2h after the end of copanlisib infusion (±15 minute window for all BP measurements). 
6. CBC with differential includes: absolute neutrophil count, absolute lymphocyte count, absolute 
eosinophil count, and platelet count 
7. Chemistry panel includes: albumin, alkaline phosphatase, total bilirubin (direct bilirubin if total 
bili is > ULN), bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium, LDH, magnesium, phosphorus, uric acid. 
Amylase and lipase to be down at screening and Day1 of every cycle. 
8. Fasting glucose will be measured at 0h (pre-dose), and 1 hour (+/- 15 min) after completion of 
copanlisib infusion and subsequently if clinically indicated at the discretion of the investigator. 
NOTE: if patient needs to take a low glycemic meal on infusion days, then glucose test should 
be taken prior to meal intake. Glucose measurements may be done by laboratory analysis or in 
capillary blood.  
9. HbA1c to be tested at screening, on Day 1 of every three cycles (4, 7, 10, etc) starting at cycle 
4, and at the EOT visit 
10. HDL, LDL, triglycerides, total cholesterol; performed at Screen, Cycle 1 Day 1, Day 8, and Day 
15; then Day 1 of every other cycle (starting at Cycle 2) 

J1887/Version 7.0 / January 27, 2023 
54 
11. If TSH is abnormal, T3 and FT4 will be assessed. 
12. Patients with positive tests for HBsAg or HIV are excluded from study.  Patients with positive 
test for anti-HCV antibody will be eligible if they are negative for HCV-RNA. These patients 
should perform HCV RNA test with PCR monthly through treatment and 6 months thereafter. 
If viral load becomes positive, patient should be withdrawn from the study. 
13. CMV PCR may be done up to 7 days prior to each Day 1 visit. CMV PCR should be done with 
every cycle through cycle 6, then every 3 cycles thereafter. 
14. Serum or urine pregnancy test required for WOCBP only. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test is required 
15. Bilirubin, hemoglobin, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC 
count, and specific gravity.  Performed at baseline and Day 1 of every other cycle (starting at 
cycle2). 
16. Labs and research blood should be collected within a window of 3 days prior to dosing. Labs 
may be repeated prior to dosing if needed. 
17. MUGA scan or echocardiogram to measure LVEF; the method chosen at baseline must be the 
same throughout the whole study period (baseline and EOT); at EOT visit must be done if not 
previously done within 4 weeks 
18. Radiologic evaluations and tumor measurements will be performed at baseline (within 28 days 
of dosing), prior to each odd cycle (up to 1 week prior), and at End of Treatment visit.  If patient 
comes off study for reasons other than disease progression, subject may have additional 
radiologic evaluations every 8 weeks until progression or start of new anti-cancer therapy. CT 
of the chest/abdomen/pelvis with contrast will be used, however, non-contrast CT chest and 
MRI abdomen/pelvis will be done for patients with contrast allergies. 
19. Biopsy to be collected at baseline and 6 weeks after first dose of study drug (± 3 days, but before 
Cycle 2 Day 15 study drug administration).  An optional biopsy may be performed at the time 
of progression. Approximately 6 core biopsy specimens will be obtained at each biopsy. 
20. Blood for PBMC and plasma will be collected at baseline/prior to first dose, 2 weeks after first 
dose, on Day 1 of each odd cycle, and at progression or EOT visit.     
21. EOT Clinical assessments do not need to be repeated if they were done within last 7 days.  
Hemoglobin A1C, 12-lead ECG, and MUGA or echocardiogram do not need to be repeated if 
they were done within the last 4 weeks. 
22. Subjects who discontinue treatment will be followed (by phone, email or visit) every 12 weeks 
(± 2 weeks) after completion of EOT visit for up to 2 years or study closure to monitor overall 
survival.  Information on other cancer therapies and disease status will also be collected. In 
addition, SAEs that occur within 100 days (+14 day reporting window) of the end of treatment 
or before initiation of a new antineoplastic treatment should also be followed and recorded. 
 
 
 

J1887/Version 7.0 / January 27, 2023 
55 
8.2 
Study Calendar – Phase II 
 Screen1 
Treatment (1 cycle = 28 days) 
EOT21 
Survival 
Follow-Up22  
Q12 weeks  
(± 2 weeks) 
Cycle 1 
Cycle 2 and higher 
Procedure 
D -28  
to 0 
D1 
(±3 
days) 
D8 
(+1 
day) 
D15 
(+3 
days) 
D1 
(±3 
days) 
D8 
(±1 
day) 
D15 
(-1/+3 
days) 
30 days 
(+/-4 days) 
after last  
study drug 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Demographics and Med Hx2 
X 
 
 
 
 
 
 
 
 
Copanlisib  
 
X 
X 
X 
X 
X 
X 
 
 
Nivolumab  
 
X 
 
 
X 
 
 
 
 
Post-study anticancer therapy 
and survival status 
 
 
 
 
 
 
 
 
X 
Clinical Assessments 
Physical Examination, ECOG3 
X 
X 
 
X 
X 
 
X 
X 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Pressure (infusion days)5 
 
X 
X 
X 
X 
X 
X 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
 
Con Med Review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Assessments 
CBC with Differential6, 16 
X 
X 
X 
X 
X  
X 
X 
X 
 
Chemistry Panel7, 16 
X 
X 
X 
X 
X 
X 
X 
X 
 
Glucose8 
 
X 
X 
X 
X 
X 
X 
 
 
Hemoglobin A1C16 
X 
 
 
 
X9 
 
 
X 
 
Lipid Panel10, 16 
X 
 
 
 
X(even 
cycles) 
 
 
X 
 
TSH11, 16 
X 
X 
 
X 
X 
 
X 
X 
 
PT, INR and aPTT16 
X 
 
 
 
 
 
 
 
 
HBsAg, HCV Ab, HIV12 
X 
 
 
 
 
 
 
 
 
CMV PCR13,16 
X 
 
 
 
X 
 
 
 
 
Pregnancy Test14, 16 
X 
X 
 
 
X 
 
 
X 
 
Urinalysis15, 16 
X 
 
 
 
X(even 
cycles) 
 
 
 
 
Urine protein:creatinine ration 
(UPCR) 
X 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
X  
 
MUGA or echocardiogram17 
X 
 
 
 
 
 
 
X  
 
CEA 
X 
X 
 
 
X 
 
 
X 
 
Efficacy Assessments 
Tumor Imaging18 
X 
 
 
 
X(odd 
cycles) 
 
 
X 
 
Tissue and Blood for Correlative Studies 
Fresh Tumor Biopsy19 
X 
 
 
 
 
 
X 
X 
 
Archival Tumor Sample 
X 
 
 
 
 
 
 
 
 
Blood for PBMC (100cc)20, 16 
 
X 
 
X 
X(odd 
cycles) 
 
 
X 
 
Blood for plasma (20 cc) 20, 16 
 
X 
 
X 
X(odd 
cycles) 
 
 
X 
 
 

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56 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted 
for in-person clinical trial visits or portions of clinical trial visits where determined to be appropriate 
and where determined by the investigator not to increase the participants risks.  Prior to initiating 
telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails 
and confirm that the study participant is in agreement and able to proceed with this method.  In the event 
telemedicine is not deemed feasible, the study visit will proceed as an in-person visit.  Telemedicine visits 
will be conducted using HIPAA compliant method approved by the Health System and within licensing 
restrictions.  
1. Baseline evaluations should occur within 28 days prior to registration, unless otherwise noted.  
No window applies to demographics, consent, or height at baseline.   
2. Includes history of lung disease, cardiovascular disease, diabetes, HIV, hepatitis B or C 
infection, and complete cancer history, including primary site of cancer, gross location of 
primary tumor, histology, histologic grade, date of initial diagnosis, date of metastatic diagnosis, 
prior cancer therapy regimens 
3. A complete physical exam will be performed at baseline; focused physical exams will be done 
thereafter. Physical exams and AE assessments can be done up to 3 days prior to dosing. 
4. Temperature, pulse, blood pressure, and respiratory rate, and pulse oxygen will be collected at 
baseline, and prior to each dose of study drug, and at EOT visit.  
5. Blood pressure will be measured every 5-10 minutes prior to each copanlisib dose (no more than 
4 measurements) until there are 2 consecutive results ≤ 150/90 mmHg. If the blood pressure is 
≥ 150/90 mmHg, the investigator can consider a medical intervention (e.g. administration of 
dihydropyridine calcium channel blocker), or delaying the infusion of the study drug. Blood 
pressure will be measured at 0h (pre-dose), 30 min (mid-infusion), 60 min (end of infusion), and 
1h and 2h after the end of copanlisib infusion (±15 minute window for all BP measurements). 
6. CBC with differential includes: absolute neutrophil count, absolute lymphocyte count, absolute 
eosinophil count, and platelet count 
7. Chemistry panel includes: albumin, alkaline phosphatase, total bilirubin (direct bilirubin if total 
bili is > ULN), bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium, LDH, magnesium, phosphorus, uric acid. 
Amylase and lipase to be down at screening and Day1 of every cycle. 
8. Fasting glucose will be measured at 0h (pre-dose), and 1 hour (+/- 15min) after completion of 
copanlisib infusion and subsequently if clinically indicated at the discretion of the investigator. 
NOTE: if patient needs to take a low glycemic meal on infusion days, then glucose test should 
be taken prior to meal intake. Glucose measurements may be done by laboratory analysis or in 
capillary blood. 
9. HbA1c to be tested at screening, on Day 1 of every three cycles (4, 7, 10, etc) starting at cycle 
4, and at the EOT visit. 
10. HDL, LDL, triglycerides, total cholesterol; performed at Screen and Day 1 of every other cycle 
(starting at Cycle 2) 
11. If TSH is abnormal, T3 and FT4 will be assessed. 
12. Patients with positive tests for HBsAg or HIV are excluded from study.  Patients with positive 
test for anti-HCV antibody will be eligible if they are negative for HCV-RNA. These patients 
should perform HCV RNA test with PCR monthly through treatment and 6 months thereafter. 
If viral load becomes positive, patient should be withdrawn from the study. 
13. CMV PCR may be done up to 7 days prior to each Day 1 visit. CMV PCR should be done with 

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57 
every cycle through cycle 6, then every 3 cycles thereafter. 
14. Serum or urine pregnancy test required for WOCBP only. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test is required.  
15. Bilirubin, hemoglobin, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC 
count, and specific gravity. Performed at baseline and Day 1 of every other cycle (starting at 
cycle2). 
16. Labs and research blood should be collected within a window of 3 days prior to dosing. Labs 
may be repeated prior to dosing if needed. 
17. MUGA scan or echocardiogram to measure LVEF; the method chosen at baseline must be the 
same throughout the whole study period (baseline and EOT); at EOT visit must be done if not 
previously done within 4 weeks. 
18. Radiologic evaluations and tumor measurements will be performed at baseline (within 28 days 
of dosing), prior to each odd cycle (up to 1 week prior), and at End of Treatment visit.  If patient 
comes off study for reasons other than disease progression, subject may have additional 
radiologic evaluations every 8 weeks until progression or start of new anti-cancer therapy. CT 
of the chest/abdomen/pelvis with contrast will be used, however, non-contrast CT chest and 
MRI abdomen/pelvis will be done for patients with contrast allergies. 
19. Biopsy to be collected at baseline and 6 weeks after first dose of study drug (± 3 days, but before 
Cycle 2 Day 15 study drug).  An optional biopsy may be performed at the time of progression. 
Approximately 6 core biopsy specimens will be obtained at each biopsy. Tumor biopsy will not 
be performed if the tumor is not accessible or if biopsy is considered not in the patient’s best 
interest. 
20. Blood for PBMC and plasma will be collected at baseline/prior to first dose, 2 weeks after first 
dose, on Day 1 of each odd cycle, and at progression or EOT visit.   
21. EOT Clinical assessments do not need to be repeated if they were done within last 7 days.  
Hemoglobin A1C, 12-lead ECG, and MUGA or echocardiogram do not need to be repeated if 
they were done within the last 4 weeks. 
22. Subjects who discontinue treatment will be followed (by phone, email or visit) every 12 weeks 
(± 2 weeks) after completion of EOT visit for up to 2 years or study closure to monitor overall 
survival.  Information on other cancer therapies and disease status will also be collected. In 
addition, SAEs that occur within 100 days (+14 day reporting window) of the end of treatment 
or before initiation of a new antineoplastic treatment should also be followed and recorded. 
 
 

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58 
9. MEASUREMENT OF EFFECT 
 
9.1 Definitions 
 
Evaluable for toxicity. All subjects are evaluable for toxicity after receiving first dose of study 
treatment. 
 
Evaluable for objective response.  All patients who have received at least one dose of study 
drug at any time during the study will be considered evaluable for response, with the exception 
of patients that withdraw consent prior to disease re-evaluation. Patients who withdraw consent 
before disease re-evaluation may be replaced.  Patients who come off study prior to disease re-
evaluation with imaging due to clinical deterioration will be coded as progressing. Response 
criteria will be classified by RECIST 1.1 criteria (Appendix E) 
 
9.2 Methods for Evaluation of Measurable Disease 
 
Imaging should include the chest, abdomen, and pelvis. Tumor imaging is strongly preferred 
to be acquired by computed tomography (CT).  For the abdomen and pelvis, contrast-enhanced 
magnetic resonance imaging (MRI) may be used when CT with iodinated contrast is 
contraindicated, or when local practice mandates it. The same imaging technique regarding 
modality, ideally the same scanner, and the use of contrast should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the assessment of response or progression based on 
imaging. Body scans should be performed with breath-hold scanning techniques, if possible. 
 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and no more than 28 days before the beginning of the treatment.  The site study team 
must review screening images to confirm the participant has measurable disease per RECIST 
1.1. Subjects will be evaluated for anti-tumor effect by follow-up imaging as outlined in the 
study calendar. All subsequent scans (post-treatment) will be compared to the same 
pretreatment scan that was used prior to initiating of study treatment. 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.   
 
 
The definition of measurability of lesions on CT scan is based on the assumption that CT slice 
thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness.   
 
10. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event guidelines and instructions for AE reporting can be found in Section 5. 
 
Dr. Nilofer Azad will hold the IND for this study. She will comply with all regulated reporting 
requirements to the FDA. 
 
 

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59 
10.1 
Data Management 
 
All information will be collected on study-specific case report forms (CRFs) by study staff. 
These data will be reviewed for completeness and accuracy by the Principal Investigator at 
each site.  
 
Protocol Chair 
The Protocol Chair and/or designee is responsible for performing the following tasks: 
 Coordinating, developing, submitting, and obtaining approval for the protocol as well 
as its subsequent amendments. 
 Assuring that all participating institutions are using the correct version of the protocol. 
 Taking responsibility for the overall conduct of the study at all participating institutions 
and for monitoring the progress of the study. 
 Reviewing and ensuring reporting of SAE 
 Reviewing data from all sites. 
 
Coordinating Center (Johns Hopkins University) 
The Coordinating Center (or its representative) is responsible for performing the following 
tasks: 
 Ensuring that IRB approval has been obtained at each participating site prior to the first 
subject registration at that site, and maintaining copies of IRB approvals from each site. 
 Monitoring subject registration. 
 Collecting and compiling data from each site. 
 Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties. 
 Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
Participating Sites 
Participating sites are responsible for performing the following tasks: 
 Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
 Submitting data to the Coordinating Center. 
 Consent subjects promptly and enroll eligible subjects in EDC. 
 Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
 Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center. 
 Collecting and submitting data according to the schedule specified by the protocol. 
 
10.2 
Safety Meetings 
 
Scheduled meetings will occur on a regular basis with the frequency dependent on the rate of 
subject accrual and the progress of the study. Meetings will include the protocol principal 
investigator, study coordinator(s), data manager(s), lead research nurses(s), sub-investigators 
(as appropriate), collaborators (as appropriate), and biostatisticians (as appropriate) involved 
with the conduct of the protocol. During these meetings matters related to the following will 

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60 
be discussed: safety of protocol participants, validity and integrity of the data, enrollment rate 
relative to expectation, characteristics of participants, retention of participants, adherence to 
protocol (potential or real protocol violations), data completeness, and progress of data for 
objectives. 
 
Monthly teleconferences will be scheduled to include the Coordinating Center and the clinical 
trial sites. During these meetings, the Coordinating Center and clinical trial sites shall discuss 
the following: study protocol updates, safety data, enrollment status, and progress of data for 
objectives.  
 
10.3 
Monitoring 
 
Eligibility for all sites will be monitored by the Protocol Chair. The protocol will be monitored 
internally by the Principal Investigator at each site. Data monitoring of this protocol will occur 
on a regular basis with the frequency dependent on the rate of subject accrual and the progress 
of the study. External monitoring will occur according to the following guidelines: 
 
Johns Hopkins SKCCC: The SKCCC Compliance Monitoring Program will provide external 
monitoring for JHU-affiliated sites in accordance with SKCCC DSMP (Version 6.0, 
02/21/2019). The SMC Subcommittee will determine the level of patient safety risk and 
level/frequency of monitoring. 
 
Participating site(s): The protocol will be monitored at each participating site by a member of 
the Johns Hopkins study team regulatory staff. A report of the reviews will be submitted to the 
Johns Hopkins principal investigator and SKCCC CRO. 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1 Sample Size 
 
Phase I will be enrolled in a standard 3+3 design with up to 18 patients.  For the purposes of 
dose finding, DLTs will be evaluated during the first cycle for each patient.  An initial cohort 
of 3 patients will be enrolled. If 0-1/3 have a DLT then 3 additional patients will be enrolled 
at the same dose level.  If 2-3/3 DLTs are observed, then the dose will be considered too toxic 
and the next lower dose level will be enrolled.  The RP2D is the dose at which  1/6 patients 
have a DLT (i.e. if 0/3 of the initial patients have a DLT then an additional 3 will be recruited 
at the highest feasible dose to establish the RP2D). 
 
During Phase II 42 patients will be recruited: 21 patients with colorectal cancer with PIK3CA 
mutation (cohort A) and 21 with WT PIK3CA with known lack of sensitivity to immune 
checkpoint inhibitor therapy (cohort B). ORR (CR+PR) at 6 months the primary endpoint and 
will be evaluated separately in each cohort. Enrollment will be carried out in 2 stages so that 
the study can terminate early if the combination of copanlisib and nivolumab is not sufficiently 
effective. A design similar to Simon’s minimax design with relaxed futility stopping will be 
employed to test the null hypothesis that the true ORR is 5% or less.30-31 In the first stage, 12 
subjects will be accrued in each cohort. If there are no responders among the first 12 patients, 
the study will be terminated for futility. Otherwise, 9 additional patients will be accrued for a 

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61 
total of 21 treated subjects. Patients who withdraw consent before disease re-evaluation will 
not be considered evaluable for response and may be replaced. Patients who come off of study 
prior to disease re-evaluation with imaging due to clinical deterioration will be considered 
evaluable for response and will be coded as progressing. If 3 out of the 21 patients have a 
response, then the trial will be considered a success for that cohort.  If the true response rate is 
20% (alternative hypothesis rate), then the probability of a declaring the treatment a success is 
0.80 (power).  If the true response rate is 5% (null hypothesis rate), then the probability of 
declaring the treatment a success is 0.08 (type I error). 
 
11.2 Statistical Analyses 
 
Data will be summarized descriptively within each phase overall and by subgroups of interest 
(e.g. cohort).  The descriptive summary including demographics and baseline variables will 
include counts and percentages for categorical variables and means, medians, standard 
deviations, and quartiles for continuous variables. 
 
ORR at 6 months, the primary outcome for Phase II, will be summarized using counts and 
percentages.  Logistic regression will be used to compare the ORR between the two cohorts as 
well as to identify risk factors associated with ORR.  Other binary outcomes (e.g. disease 
control at 6 months (SD+PR+CR) and immunologic response) will be analyzed using the same 
methods. 
 
Time to event outcomes include overall survival (OS) and progression free survival (PFS).  
Overall survival is defined as the time from the first dose until death.  Individuals without an 
event will be censored at the date of last contact.  Progression free survival is defined as the 
time from the first dose until progression or death.  Individuals who die will be counted as 
having progressed.  Individuals without an event will be censored at the date of the last 
evaluation for progression.   Kaplan-Meier curves will be use to graphically summarize the 
survival function and to estimate the median time to event and the proportion event-free at key 
intervals (e.g. 6 months) along with 95% confidence intervals.  Cox proportional hazards 
models will be used to compare Cohorts A and B and to identify risk factors associated with 
OS and PFS.  Graphical techniques (e.g. log-log plots) and formal statistical testing (e.g. 
Schoenfield tests) will be used to assess the proportional hazards assumption.  If necessary, 
alternate models (e.g. incorporating a time variable) will be considered. 
 
Safety will be monitored continuously throughout the study, including the phase II component.  
Weekly team meetings and a minimum of monthly investigator calls will be conducted to 
review ongoing and resolved toxicity. 
 
Exploratory correlative outcomes are an important part of the study.  Paired tumor biopsies 
will be collected prior to and after initial treatment.  Continuous measurements (e.g. density of 
immune cells, peripheral blood cytokine expression, percentage of CD8+ Tcells expressing >= 
2 inhibitory receptors, and CD8+ cytokine expression) will be evaluated graphically (e.g. 
histograms) and numerically (e.g. means, medians) to determine whether or not a 
transformation (e.g. log) is appropriate.   Once the appropriate scale has been determined, 
graphical techniques, including but not limited to boxplots spaghetti plots, will be used to 
summarize the values at each time point and the change from pre-to post- treatment.   The 

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62 
means and 95% confidence intervals of each of these quantities will be estimated.  A variety 
of tools including Wilcoxon rank-sum tests and linear regression, with the change as the 
outcome variable, will be used to determine whether there is a significant change within each 
group, whether the changes differ between cohorts, and the association between immunologic 
parameters and response status (CR/PR or SD vs PD).  Linear mixed effects models, which 
account for the correlation between repeated measurements from an individual and allow the 
inclusion of additional time points, will also be explored.   The baseline and change scores will 
also be considered as potential risk factors for ORR, OS, and PFS using the analysis techniques 
described above.  Serial samples of PBMC and plasma will be evaluated in a similar manner 
with greater emphasis on the longitudinal modeling due to the greater abundance of repeat 
measurements. 
 
Genomic sequencing library construction, whole genome/exome sequencing, whole 
transcriptome sequencing, microbial sequencing, neoepitope prediction, mutation burden, 
and bioinformatic analysis may be performed either at an on-campus laboratory or at an off-
campus sequencing service. All the samples will be de-identified before sending to any 
laboratory for sequencing.  The FASTQ files, BAM files and VCF files will be generated and 
analyzed. Other sequencing assays may be performed on a subset of samples according to 
specific requirements of collaboration projects. Genomic sequencing data will be stored and 
computations conducted using a JH IT managed subscription of Azure. 
 
11.3 
Safety Analyses 
 
AE data will be listed individually and incidence of AEs will be summarized by system organ 
class and preferred terms within a system organ class for Phase I and Phase II (overall and 
within each cohort). When calculating the incidence of AEs, each AE will be counted only 
once for a given subject.  In analyses of grade and causality, if the same AE occurs on multiple 
occasions, the highest grade and strongest relationship to study drug will be assumed.  If 2 or 
more AEs are reported as a unit, the individual terms will be reported as separate experiences.  
Incidence, measured as time to first AE, will be analyzed for all AEs and by type using the 
methods described above.  In addition, the event rates (which incorporate multiple AEs of the 
same type) will be analyzed using Negative Binomial regression. 
 
Changes in vital signs, hematology and clinical chemistry parameters from baseline to the end 
of the study will be examined.  Toxicity will be tabulated by type and grade. Toxicities will be 
characterized according to the CTCAE version 5.0.  Treatment-emergent changes from normal 
to abnormal values in key laboratory parameters will be identified.  Incidence and rate 
evaluations will follow the methods described for AEs. 
 
11.4 
Safety Monitoring 
The proportion of treated subjects with unacceptable toxicity will be monitored using a 
Bayesian stopping guideline within each cohort (Cohort A: colorectal cancer with PIK3CA 
mutation and Cohort B: WT PIK3CA with known lack of sensitivity to immune checkpoint 
inhibitor therapy) separately during Phase II. A (1.5, 5.5), representing a toxicity rate of 21%, 
the slightly higher than the expected toxicity rate, was used in the development of our 
guidelines.  These guidelines will recommend that recruitment be halted and the trial be 

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63 
reassessed if the posterior probability that the unacceptable toxicity rate exceeds the maximum 
allowable rate (33%) is greater than 0.55.  Once the initial 6 patients are recruited, toxicity will 
be monitored continuously.  Table 11 summarizes the stopping boundaries for unacceptable 
toxicities. 
 
Table 11:  The number of toxicities needed to trigger stopping guidelines throughout the 
course of the study within each cohort. 
Number of Subjects 
Per Cohort  
Number of toxicities 
needed to trigger 
re-evaluation 
6-8 
4 
9-11 
5 
12-14 
6 
15-17 
7 
18-20 
8 
21 
9 
 
The probability of triggering the stopping guidelines was assessed for a range of possible true 
toxicity rates using simulations with 10,000 replicates (Table 12).  The probability of stopping 
to re-evaluate was 9.5% if the true proportion with an unacceptable toxicity was 20%, the 
expected level.  In comparison, the probability of stopping early is 54% and 70% if the true 
proportion with an unacceptable toxicity was 35% or 40%, i.e. above the 33% threshold.   
 
Table 12: Probability of triggering a re-evaluation based upon the proportion with an 
unacceptable toxicity for a range of true toxicity probabilities. 
 
True probability of 
unacceptable toxicity 
Probability of 
triggering 
stopping guidelines 
5% 
< 0.1% 
10% 
0.8% 
15% 
3.1% 
20% 
9.5% 
25% 
21% 
30% 
37% 
35% 
54% 
40% 
70% 
 
 

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64 
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APPENDIX A: Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX B: Contraceptive Guidance and Pregnancy Testing 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
 Premenarchal 
 Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 Postmenopausal female 
○ Defined as no menses for 12 months without an alternative medical cause.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following for the duration of the study and for 7 months after last dose 
of study drug:  
 Agree to be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
 Agree to use a male condom plus partner use of a contraceptive method with a failure rate 
of <1% per year as described in Table 8 when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
○ Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration. 
Note: male participants will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 13 for the 
duration of the study and for 5 months after last dose of study drug:  
 

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Table 13 - Highly Effective Contraception Methods 
 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of < 1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed.  If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least 120 days after the last dose of study treatment. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test.  
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected, after the last dose of study 
treatment, and as required locally.  
 
 
 

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APPENDIX C: Management Algorithms 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the IND Sponsor. The guidance applies to all immuno-oncology (I-O) agents and 
regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory subjects with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used. 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D: Average Glycemic Index of Common Foods  
 
The average Glycemic Index of common foods derived from multiple studies by 
different laboratories 
 
Foods are categorized as having a low-glycemic index if the glucose reference index is ≤ 55. 
High-Glycemic Index foods have a glucose reference index >55. The summary table below 
contains glucose reference for common foods. 
 
 
 
 
 

 
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APPENDIX E: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
 
RECIST version 1.1 will be used in this study for assessment of tumor response.  While either CT 
or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.   
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable unless there is evidence of progression in the irradiated site. Malignant 
lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node must 
be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same subject, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 

 
J1887/Version 7.0 / January 27, 2023 
79 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a subject 
to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 
For Subjects with Measurable Disease (i.e., Target Disease) 
 

 
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80 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of 
a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
Reference 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. 
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer. 2009 
Jan;45(2):228-47. 
 
 
 

 
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APPENDIX F: Serious Adverse Event (SAE) Reporting Form 
 
Serious Adverse Event Reporting Form 
 
 
Protocol Title: 
 
 
A phase I/II study of PI3Kinase inhibition (copanlisib) and anti-PD-1 antibody 
nivolumab in relapsed/refractory solid tumors with expansions in MSS colorectal 
cancer 
Protocol #: 
Principal Investigator: 
 
Signature of PI: 
 
Date: 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria / Outcome 
(check all that apply): 
Death    
Life-threatening 
 Hospitalization or Elongation of 
Existing Hospitalization 
 Persistent or Significant Disability 
 Congenital / Birth Defect 
 Other Important Medical Event 
 New Cancer 
 AE associated with Overdose 
Hospital Admission Date:  
 
 
Hospital Discharge Date: 
 
 
Date Event Discovered: 
 
 
Section A: Subject Information 
Subject ID: 
 
Age (years): 
Gender: 
Male  
Female 
Section B: Event and Study Drug Information 
Event diagnosis or 
symptoms: 
 
 
Copanlisib 
Nivolumab 
Dose and Route: 
 
240mg IV 
Dx for Use (indication): 
 
 
Date of First Dose: 
 
 
Date of Last Dose  
Prior to Event: 
 
 
# of Total Doses: 
 
 
Action Taken  
w/ study drug 
None 
Interrupted 
Discontinued 
Delayed 
None 
Interrupted 
Discontinued 
Delayed 
Event Grade: 
 
 
Event Abated after use 
stopped/ reduced? 
Yes    
No    
N/A 
Yes    
No    
N/A 
Event Reappeared After 
Reintroduction? 
Yes    
No    
N/A 
Yes    
No    
N/A 
Event Onset Date: 
 
Event End Date: 
 
Relationship to: 
Copanlisib 
Nivolumab 
Underlying Disease 
Unrelated 
 
 
 

 
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82 
Related 
 
 
 
Section C: Brief Description of the Event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section D: Relevant Tests/Laboratory Data 
 
Section E: Relevant Medical History 
 
 
Section F: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section G: Comments 
Additional Documents Attached (labs, scans, notes, etc): 
 Please specify, including dates