Clinical trial NCT02535247
Conditions: Lymphoma, T-Cell, Peripheral
Sponsor: Fox Chase Cancer Center
Start date: 2016-01-05; Completion date: 2020-02-25
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, single-arm, open label, study consisting of two cohorts. Cohort 2 explores the combination of copanlisib and pembrolizumab in patients with relapsed or refractory NKTCL, who have received at least 1 prior systemic therapy. Cohort 2 will include a phase 1 portion (cohort 2a) to determine the recommended phase 2 dose (RP2D) utilizing a standard 3+3 design, followed by a phase II portion where patients will be treated at the RP2D (cohort 2b). The primary endpoint for cohort 1 was progression-free survival; the primary endpoint for cohort 2a will be to determine RP2D for the combination therapy; and overall response rate at the end of 4 treatment cycles for cohort 2b. Patients will be assessed for response with PET CT or CT every 12 weeks using the revised Cheson criteria. Correlative endpoints will be exploratory and assess PD-1 expression on peripheral blood lymphocytes; peripheral blood T-cell and NK-cell functional assays; PD-1 and PD-L1 expression on tumor tissue; tumor infiltrating lymphocytes and gene expression panels using the nanostring technology as prognostic and predictive biomarkers, as well as monitoring of minimal residual disease via high-throughput sequencing of cell free tumor DNA, and exosome analysis.

Detailed description:
Patients with relapsed or refractory (RR) NK and T-cell Lymphoma (NKTCL), who have received at least 1 prior systemic therapy, were enrolled in cohort 1. The study design for cohort 1 was a single arm phase II 2-stage design, to explore monotherapy with the PD-1 antibody pembrolizumab (or MK-3475) given intravenously at a fixed dose of 200mg every 3 weeks for up to 36 cycles. Enrollment to this cohort has been completed.

Arms: arm 1: MK-3475 given intravenously at a fixed dose of 200mg every 3 weeks for up to 36 cycles arm 2: MK-3475 is given intravenously at a fixed dose of 200mg every 3 weeks Copanlisib is given intravenously at RP2D determined from Phase I study
Interventions: intervention 1: MK-3475 intervention 2: Copanlisib
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase I/II study to determine feasibility and safety pembrolizumab (MK-3475) alone or in 
combination with copanlisib in relapsed or refractory NK and T-cell Non-Hodgkin lymphoma 
 
Supported by: Fox Chase Cancer Center, Merck and Bayer 
 
Sponsor Investigator: 
Henry Fung, MD 
 
Fox Chase Cancer Center 
 
333 Cottman Avenue  
 
Philadelphia PA  19111 
 
Phone: 215-728-2674/215-214-3129 
 
Fax: 215-728-3639 
 
 
Email: Henry.Fung@tuhs.temple.edu 
 
Study Co-Chair                                 Stefan Barta, MD 
                                                            Perelman Center 
                                                            University of Pennsylvania 
                                                            Philadelphia, PA 19104 
                                                            Phone: 215-615-6506 
                                                            Email: Stefan.Barta@pennmedicine.upenn.edu  
 
Co-Investigators: 
Richard I. Fisher, MD 
 
Fox Chase Cancer Center 
 
333 Cottman Avenue  
 
Philadelphia PA  19111 
 
Phone: 215-214-3129 
 
Email: richard.fisher@fccc.edu 
 
Correlative Studies: 
Kerry Campbell, PhD 
 
 
 
Fox Chase Cancer Center 
 
333 Cottman Avenue  
 
Philadelphia PA  19111 
 
Phone: 215-728-7761 
 
Email: kerry.campbell@fccc.edu 
 
 
 


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Statistician: 
Eric Ross, PhD 
 
Fox Chase Cancer Center 
 
333 Cottman Avenue 
 
Philadelphia, PA-19111 
 
Phone: 215-728-2891 
 
Email: eric.ross@fccc.edu   
 
IND Number:  
 
127581 
 
Amendment 4:  08/08/2018 
Amendment 5: 01/23/2019 
Amendment 6: 03/25/2019 
Amendment 7: 01/13/2020 
 
 


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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 6 
2.0 
TRIAL DESIGN.......................................................................................................... 7 
2.1 Trial Schema................................................................................................................ 7 
3.0 
OBJECTIVES ............................................................................................................. 8 
3.1 Cohort 1 ....................................................................................................................... 8 
3.1.1 Primary Objective Cohort 1 .................................................................................. 8 
3.1.2 Secondary Objectives Cohort 1............................................................................. 8 
3.1.3 Exploratory Objective Cohort 1 ............................................................................ 8 
3.2 Cohort 2 ....................................................................................................................... 8 
3.2.1 Primary Objective Cohort 2 .................................................................................. 8 
3.2.2 Secondary Objectives Cohort 2............................................................................. 9 
4.0 
BACKGROUND & RATIONALE ............................................................................ 9 
4.1 Background ................................................................................................................. 9 
4.1.1 Pharmaceutical and Therapeutic Background ...................................................... 9 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 10 
4.2 Rationale .................................................................................................................... 10 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 10 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 12 
4.2.3 Rationale for pembrolizumab and copanlisib combination treatment ................ 12 
4.2.4 Rationale for Endpoints ...................................................................................... 14 
5.0 
METHODOLOGY ................................................................................................... 17 
5.1 Entry Criteria ............................................................................................................ 17 
5.1.1 Subject Inclusion Criteria.................................................................................... 17 
5.1.2 Subject Exclusion Criteria .................................................................................. 18 
5.2 Trial Treatments ....................................................................................................... 20 
5.2.1 Dose Selection/Modification .............................................................................. 21 
5.2.2 Dose Administration ........................................................................................... 28 
5.2.3 Participant Registration ....................................................................................... 31 
5.3 Concomitant Medications/Vaccinations (allowed & prohibited) ......................... 31 
5.3.1 Acceptable Concomitant Medications ................................................................ 32 
5.3.2 Prohibited Concomitant Medications.................................................................. 32 
5.4 Supportive Care and Management of Immune-related Adverse Events ............... 33 
5.5 Diet/Activity/Other Considerations ......................................................................... 38 
5.5.1 Diet ...................................................................................................................... 38 
5.5.2 Contraception ...................................................................................................... 38 
5.5.3 Use in Pregnancy ................................................................................................ 39 
5.5.4 Use in Nursing Women ....................................................................................... 39 
5.6 Participant Withdrawal/Discontinuation Criteria................................................. 39 


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5.7 Clinical Criteria for Early Trial Termination........................................................ 40 
5.8 Retreatment ............................................................................................................... 40 
6.0 
TRIAL FLOW CHART ........................................................................................... 41 
7.0 
TRIAL PROCEDURES ........................................................................................... 45 
7.1 Trial Procedures........................................................................................................ 45 
7.1.1 Administrative Procedures .................................................................................. 45 
7.1.2 Clinical Procedures/Assessments ........................................................................ 46 
7.1.3 Laboratory Procedures/Assessments .................................................................. 48 
7.1.4 Other Procedures ................................................................................................. 50 
7.1.5 Visit Requirements .............................................................................................. 50 
8.0 
Assessing And Recording Adverse Events .............................................................. 51 
8.1 Severity Rating .......................................................................................................... 52 
8.2 Attribution/Relationship to study drug .................................................................. 52 
8.3 Expectedness .............................................................................................................. 52 
9.0 
Recording and Reporting Responsibilities ............................................................. 53 
9.1.1 Investigative Site Recording Responsibilities: ................................................... 53 
9.1.2 Investigative Site Reporting Responsibilities: .................................................... 53 
9.1.3 Sponsor Reporting Responsibilities: ................................................................... 54 
9.2 Definition of an Overdose ......................................................................................... 56 
9.3 Events of Clinical Interest ........................................................................................ 56 
9.4 Reporting of Pregnancy and Lactation to the Sponsor-Investigator and to Merck and 
Bayer .......................................................................................................................... 57 
10.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 58 
10.1 Statistical Analysis Plan (cohort 1) .......................................................................... 58 
10.2 Statistical Analyses Plan (cohort 2) ......................................................................... 58 
11.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
..................................................................................................................................... 59 
11.1 Investigational Product ............................................................................................ 59 
11.2 Packaging and Labeling Information ..................................................................... 60 
11.3 Clinical Supplies Disclosure ..................................................................................... 60 
11.4 Storage and Handling Requirements ...................................................................... 60 
11.5 Returns and Reconciliation ...................................................................................... 60 
12.0 
Administrative, Regulatory, Data Monitoring and Safety Details ....................... 60 
12.1 Monitoring Plan ........................................................................................................ 60 
12.2 Data Safety Monitoring Committee ........................................................................ 60 


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12.3 Compliance with Law, Audit and Debarment ....................................................... 61 
12.4 Compliance with Trial Registration and Results Posting Requirements ............ 61 
12.5 Retention of Records................................................................................................. 61 
12.6 Study Agents .............................................................................................................. 61 
12.7 Informed Consent ..................................................................................................... 61 
12.8 Data Reporting .......................................................................................................... 62 
13.0 
LIST OF REFERENCES ......................................................................................... 63 
14.0 
APPENDICES ........................................................................................................... 68 
14.1 ECOG Performance Status ...................................................................................... 68 
14.2 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ................... 68 
14.3 Measurement of Effect ............................................................................................. 69 
14.3.1 Complete Response ............................................................................................. 70 
14.3.2 Partial Response (PR) ......................................................................................... 70 
14.3.3 Stable Disease (SD) ............................................................................................ 71 
14.3.4 Progression (PD) and Relapse............................................................................. 71 
14.3.5 Response Endpoints ............................................................................................ 72 
14.3.6 Duration of Response .......................................................................................... 72 
14.3.7 Overall Survival .................................................................................................. 72 
14.3.8 Progression-free Survival .................................................................................... 72 
14.4 Events of Clinical Interest (ECI) guidance ............................................................. 74 
14.4.1 List of ECI ........................................................................................................... 75 
14.4.2 Pneumonitis ......................................................................................................... 75 
14.4.3 Colitis .................................................................................................................. 77 
14.4.4 Endocrine ............................................................................................................ 78 
14.4.5 Hyperthyroidism and Hypothyroidism ............................................................... 79 
14.4.6 Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia ............. 79 
14.4.7 Hematologic ........................................................................................................ 80 
14.4.8 Hepatic ................................................................................................................ 81 
14.4.9 Neurologic ........................................................................................................... 83 
14.4.10 Ocular ............................................................................................................... 83 
14.4.11 Renal ................................................................................................................. 84 
14.4.12 Skin ................................................................................................................... 85 
14.4.13 Other ................................................................................................................. 87 
14.4.14 Follow-up to Resolution ................................................................................... 87 
14.4.15 ECI APPENDIX 1 – Past Medical History Related to Dermatologic Event ... 89 
14.4.16 ECI APPENDIX 2 – Presentation of the Dermatologic Event ........................ 90 
14.4.17 ECI APPENDIX 3 – Focused Skin Examination ............................................. 92 
14.4.18 Appendix 4- Low Glycemic Meals .................................................................. 93 
14.4.19 Appendix 5- prohibited medications ................................................................ 94 
 
 
 


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1.0 TRIAL SUMMARY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Title 
Pembrolizumab alone or in combination with copanlisib for Relapsed or 
Refractory Peripheral T-cell Lymphoma 
Trial Phase 
Phase 1/2 
Clinical Indication 
Relapsed or refractory NK or T cell lymphoma 
Trial Type 
Multicenter, open-label single arm 
Type of control 
None 
Route of administration 
Pembrolizumab is given intravenously at a fixed dose of 200mg every 3 
weeks 
Copanlisib is given intravenously at RP2D determined from Phase I study 
Trial Blinding 
None 
Treatment Groups  
Single arm 
Number of trial subjects 
18 in cohort 1 (pembrolizumab alone; completed); up to 30 in Cohort 2; 
4-12 in cohort 2a (phase I); 18 in cohort 2b (phase II). Total up to 48 
Estimated duration of trial 
3.5 years 
Duration of Participation 
2 years 


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2.0 TRIAL DESIGN 
This is a multicenter, single-arm, open label, study consisting of two cohorts. Patients with relapsed or refractory (RR) NK and T-cell Lymphoma 
(NKTCL), who have received at least 1 prior systemic therapy, were enrolled in cohort 1. The study design for cohort 1 was a single arm phase II 2-
stage design, to explore monotherapy with the PD-1 antibody pembrolizumab (or MK-3475) given intravenously at a fixed dose of 200 mg every 3 
weeks for up to 36 cycles. Enrollment to this cohort has been completed. Cohort 2 explores the combination of copanlisib and pembrolizumab in 
patients with relapsed or refractory NKTCL, who have received at least 1 prior systemic therapy. Cohort 2 will include a phase 1 portion (cohort 2a) 
to determine the recommended phase 2 dose (RP2D) utilizing a standard 3+3 design, followed by a phase II portion where patients will be treated at 
the RP2D (cohort 2b). The primary endpoint for cohort 1 was progression-free survival; the primary endpoint for cohort 2a will be to determine RP2D 
for the combination therapy; and overall response rate at the end of 4 treatment cycles for cohort 2b. Patients will be assessed for response with 
PET CT or CT every 12 weeks using the revised Cheson criteria. Correlative endpoints will be exploratory and assess PD-1 expression on peripheral 
blood lymphocytes; peripheral blood T-cell and NK-cell functional assays; PD-1 and PD-L1 expression on tumor tissue; tumor infiltrating lymphocytes 
and gene expression panels using the nanostring technology as prognostic and predictive biomarkers, as well as monitoring of minimal residual 
disease via high-throughput sequencing of cell free tumor DNA.  
 
2.1 
Trial Schema 
 
Cohort 1 (enrollment completed) 
> 6 Patients 
progression free 
≤ 6 Patients 
progression free 
Terminate Trial for Futility
Enroll an 
additional 11 
Patients
Treatment with 
MK-3475 (Q3W) 
for 3 months
Enroll 13 
Patients
Treatment with 
MK-3475 for 3 months 
(6 months total)
≥ 10 Patients 
Progression Free
Reject Null Hypothesis 
(Treatment is Effective)
< 10 Patients 
Progression Free
Accept Null Hypothesis 
(Treatment is NOT Effective)
 
 
Cohort 2a and 2b 
Phase I (cohort 2a)                                                                                                                                       Phase II (cohort 2b) 
 Enroll 4-12 
patients 
Treatment 
with 
pembrolizumab 
+ 
Copanlisib 
Determine RP2D 
Enroll 
18 
more 
patients 
Treatment 
with 
pembrolizumab 
+ 
Copanlisib at RP2D 
Induction Phase 
Administration of 
Copanlisib alone 


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3.0 OBJECTIVES  
3.1 
Cohort 1 
3.1.1 Primary Objective Cohort 1 
To estimate the progression-free survival (PFS) defined as time elapsed from date of registration 
to disease progression or death in patients with relapsed or refractory NKTCL treated with single 
agent pembrolizumab. 
 
3.1.2 Secondary Objectives Cohort 1 
1. To assess the safety and tolerability of single agent pembrolizumab 
2. To estimate the overall response rate (ORR: complete response plus partial responses) as 
defined by the revised Response Criteria for Lymphoma (Cheson criteria)1 
3. To estimate the ORR as defined by the Lugano criteria2 
4. To estimate overall survival (OS) and PFS at 6 months and 1 year 
5. To estimate duration of response 
 
3.1.3 Exploratory Objective Cohort 1 
1. To assess expression of PD-1, PD-L1 and extent of tumor infiltrating lymphocytes (TILs) in the 
primary tumor at the time of relapse 
2. To compare PD-1 expression and leukocyte activation markers on circulating lymphocytes 
pre-treatment, at weeks 3 and 6, and at time of disease progression 
3. To compare functional responses (degranulation and IFN gamma production) by NK and T 
cells pre-treatment, at weeks 3 and 6, and at end of treatment 
4. To explore the association of the degree of tissue PD-1 and PD-L1 expression with the rate of 
CR  
5. To explore the association of the degree of tissue PD-1 and PD-L1 expression with 1-year PFS 
and OS 
6. To explore the association of changes in circulating PD-1 positive lymphocytes with disease 
status 
7. To assess cell free tumor DNA analysis as minimal residual disease marker in NKTCL 
8. To assess gene expression profiles using the nanostring platform as prognostic or predictive 
biomarker 
 
3.2 
Cohort 2 
3.2.1 Primary Objective Cohort 2 
3.2.1.1 Cohort 2a (Phase I portion): To determine the recommended phase II dose (RP2D) of the 
combination of pembrolizumab and Copanlisib in patients with RR NK/T-cell lymphoma 
 


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3.2.1.2 Cohort 2b (Phase II portion): To determine the overall response rate [ORR: complete and 
partial response] by 4 cycles of the combination of pembrolizumab and copanlisib in 
patients with RR NK/T-cell lymphoma  
3.2.2 Secondary Objectives Cohort 2 
1. To assess the safety and tolerability of the combination of pembrolizumab and copanlisib  
2. To estimate overall survival (OS) and PFS at 6 months and 1 year 
3. To estimate duration of response 
4. To identify potential pretreatment biomarkers of response to clinical outcome 
5. To identify copanlisib-induced changes in immune cell biomarkers 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades.3 Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies.4-8  In particular, the 
presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors. 
 
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 Ig superfamily member related to CD28 and CTLA-4, which has been 
shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2).9,10 The structure of murine PD-1 has been resolved.11  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand 
binding and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70, 
which are involved in the CD3 T-cell signaling cascade.9,12-14 The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4, as both molecules regulate an 
overlapping set of signaling proteins.15,16 PD-1 was shown to be expressed on activated lymphocytes 
including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.17,18 Expression has also 
been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of 
macrophages and dendritic cells.19  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in various 
tumors.15,20-22 Both ligands are type I transmembrane receptors containing both IgV- and IgC-like 
domains in the extracellular region and contain short cytoplasmic regions with no known signaling 
motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 


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found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune T-
cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues.15 Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate 
tumor-specific T-cell expansion in subjects with melanoma (MEL).23 This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an attractive target 
for therapeutic intervention. 
 
Pembrolizumab (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2.   
 
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one 
of the prominent pathways that promote cellular survival and constitutively is activated in many types 
of cancers (11, 12). Class I PI3K is downstream of most cancer-associated tyrosine kinase growth factor 
receptors (such as epidermal growth factor receptor [EGFR]/ human epidermal growth factor receptor 
[HER], insulin-like growth factor 1 receptor [IGF-1R], platelet-derived growth factor receptor [PDGFR], 
vascular endothelial growth factor [VEGF], c-KIT or mesenchymal epithelial transition factor [Met]). 
 
Four of these PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ) are categorized as class I enzymes because 
they can use phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) as a substrate to generate 
phosphatidylinositol-3,4,5-trisphosphate (PIP3). Elevated PIP3 in cellular membranes drives several 
hallmarks of the cancer phenotype: cell proliferation, survival, metabolic reprogramming, and migration. 
PI3Kα and β are ubiquitous; PI3Kγ and δ are expressed mostly in hematopoietic tissues.  
 
As expected from its pharmacological properties, copanlisib, a small molecule pan-class 1 PI3K inhibitor 
with predominant activity against PI3Kα and PI3K isoforms, demonstrated anti-tumor activity in pre-
clinical models characterized by activating genetic aberrations of the PI3K pathway. 
 
Copanlisib exhibits potent kinase inhibitory effect on all four isoforms with biochemical IC50 values of 
0.5 nM, 0.7 nM, 3.7 nM and 6.4 nM for PI3Kα, PI3Kδ, PI3Kβ and PI3K, respectively.  Copanlisib also 
potently regulates nuclear localization of the forkhead family members resulting in the induction of 
transcriptional programs that lead to rapid cell death by apoptosis. 
 
For additional background information, please refer to the Investigator’s Brochure.  
 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data for each agent. 
 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
The peripheral T-cell lymphomas (PTCL) are a diverse group of mature T-cell and natural killer (NK) cell 
neoplasms accounting for 10-15% of non-Hodgkin lymphoma (NHL) diagnoses in the United States.24-26 


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The number of diagnoses has increased nearly 3-fold over the past 2 decades.27 In the WHO 
classification, the diverse mature T-cell and NK-cell neoplasms are listed individually. The PTCL 
histologies include PTCL-NOS, angioimmunoblastic T-cell Lymphoma (AITL), anaplastic large cell 
lymphoma (ALC) ALK positive and negative (the 3 most common histologies in the US), as well as the less 
common extranodal NK/T-cell lymphoma, nasal type, enteropathy-associated T-cell lymphoma (EATL), 
hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma and adult T-cell 
leukemia/lymphoma (ATLL).28,29 Therapy for the PTCLs is largely based on aggressive B-cell lymphoma 
regimens. Outcomes though are generally worse when compared to B-cell NHL with 5-year survival rates 
of 35-43% and for the rarer PTCLs 22%-24%.30 A recent analysis showed that the median time from initial 
diagnosis to relapse or progression after primary therapy is only 6.7 months.31  
 
In the absence of hematopoietic stem cell transplantation (HSCT) treatment is usually palliative in the 
relapsed/refractory setting with a median overall survival (OS) and progression-free survival (PFS) after 
relapse or progression of only 5.5 and 3.1 months, respectively.31 Even with high-dose therapy followed 
by autologous stem cell transplantation for chemosensitive disease, survival is poor (PFS <12 months; 
OS <18 months).32 There is currently no accepted standard of care for the treatment of r/r PTCL. Multiple 
combination and single agent regimens have been studied with limited success. The two most recently 
FDA approved agents for this indication are pralatrexate and romidepsin based on an overall response 
rate (ORR) of 29% and 25%, respectively.33,34 Overall survival appears only marginally better in patients 
who receive chemotherapy at relapse (6.5 vs. 3.7 months, respectively)31 identifying an unmet need. 
 
PD-L1 expression has been demonstrated for a variety of B- and T-cell lymphomas, specifically for the 
PTCL subtypes ALC, ATLL and extranodal NK-T-cell NHL.35-37 PD-L1 is also highly expressed in malignant 
lymphocytes of patients with cutaneous T-cell lymphomas.38 Additionally, expression of PD-1 peripheral 
blood CD4+ and CD8+ lymphocytes is markedly elevated in patients with lymphomas, including T-cell 
NHL, especially at the time of relapse.39 These findings, in addition to the observation that reconstitution 
of an immune anti-lymphoma effect following allogeneic stem cell transplantation (“graft-versus-
lymphoma” effect) can result in durable remissions for patients with  PTCL,40,41 indicate the essential role 
of an effective immune response for lymphoma control.  
 
Whilst multiple trials exploring PD-1 blockade in hematological malignancies are ongoing, published data 
supports its safety and efficacy. A phase 1 trial by Berger et al demonstrated that PD-1 blockade is safe 
in patients with hematological malignancies, even after allogeneic stem cell transplantation.42 Since then 
two other larger phase 2 studies with the PD-1 antibody pidilizumab for patients with diffuse large B-cell 
lymphoma following ASCT and follicular lymphoma have shown that PD-1 blockade is not only safe, but 
also has promising efficacy in lymphomas.43,44 The same appears to be the case for PD-L1 and CTLA-4 
blockade.45,46 While “active” immunotherapy by immune checkpoint blockade might not be applicable 
to all subtypes of PTCL, an additional anti-lymphoma effect of PD-1 antibodies by “passive” immune 
mechanisms could be postulated for T-cell NHL with high PD-1 expression (e.g. AITL).47-49 For this 
subgroup of patients with high PD-1 expression, binding of the PD-1 monoclonal antibody (mAb) could 
lead to direct cytotoxicity, although with an IgG4 mAbs such as pembrolizumab less antibody-dependent 
(ADCC) or complement mediated cytotoxicity is expected than with IgG1 mAbs.50 
 
In conclusion, strong preliminary evidence warrants the exploration of the PD-1 antibody 
pembrolizumab in patients with r/r PTCL. 


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4.2.2 Rationale for Dose Selection/Regimen/Modification (cohort 1) 
The choice of the 200 mg every 3 weeks (Q3W) as an appropriate dose for fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed dose of 
200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with 
the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure range 
established in melanoma as associated with maximal efficacy response and 3) will maintain individual 
patients exposure in the exposure range established in melanoma that are well tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to reduce 
potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the logistical chain at 
treatment facilities and reduce wastage. 
 
The rationale for the dose of 2 mg/kg and comparable doses of pembrolizumab Q3W is based on: 1) 
similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in 
melanoma patients, 2) the flat exposure-response relationships of pembrolizumab for both efficacy and 
safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or 
indication on distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) 
the assumption that the dynamics of pembrolizumab target engagement will not vary meaningfully with 
tumor type. 
 
4.2.3 Rationale for pembrolizumab and copanlisib combination treatment (cohort 2) 
Enrollment to cohort 1, where patients with RR NKTCL were enrolled and treated with single agent 
pembrolizumab, has been completed. Out of 18 enrolled patients, all patients were evaluable for toxicity 
and 15 were evaluable for response.  Four patients achieved a complete response, and 1 patient 
achieved partial response resulting in a 27% complete response (CR) rate (95% CI 5%-49%) and overall 
response rate (ORR) of 33% (95% CI 9-55%). Remissions were durable with 2 patients remaining on study 
(1 patient >12 months, 1 patient >10 months) as of February 2018. Only 3 came off study for toxicity 
(17%, 95% CI 0%-34%; pneumonitis n=1; vasculitis, n=1; hyperbilirubinemia, n=1). However, although 
the response rate with single agent pembrolizumab is comparable to other approved agents in this 
setting, as only 5 pts had not progressed by 3 months, the futility endpoint was not met and enrollment 
to cohort 1 was halted early for futility as per original statistical design.  
 
Copanlisib similarly demonstrated single agent activity in T-cell NHL with an overall response rate of 
21%.52  
 
While both agents alone have moderate activity, there is preclinical evidence that supports synergy 
between PD1-inhibitors and PI3K inhibitors. Inhibition of PI3Kβ, PI3Kγ, and PI3Kδ enhances antitumor 
immunity and susceptibility to immune checkpoint inhibitors and can potentially overcome resistance 
to either drug alone.53-57 furthermore, inhibition of the PI3K pathway may abrogate a possible disease 
flare with PD-1/PDL-1 blockade in NKTCL.58  
 
We hypothesize that the combination of the PD1-inhibitor pembrolizumab with the copanlisib will be 
safe and result in synergistic efficacy in the treatment of mature NK/T-cell NHL. Therefore, Cohort 2 has 
been added to the original study to explore the combination treatment 


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4.2.3.1 Study design for cohort 2  
As the recommended phase II dose of Copanlisib in combination with pembrolizumab (MK-3475) has not 
been established, there will be a phase 1 part (cohort 2a), during which the recommended phase 2 dose 
(RPTD) of the combination of pembrolizumab and copanlisib will be determined. This will be followed by 
a phase 2 portion (cohort 2b), which will explore safety and efficacy of the combination. The phase 1 
part follows a classical ‘3+3’ dose escalation/de-escalation design with up to 3 dose levels (-1, 0, and 1). 
Based on preclinical data, the copanlisib dose and dosing frequency will change with dose levels (dose 
level -1: 45 mg on day 1 q21d; dose level 0: 45 mg days 1 & 8 q21d; dose level 1: 60 mg days 1 & 8 q21d), 
while the pembrolizumab dose will remain a flat dose of 200 mg on day 1 of every 21 day cycle for each 
dose level. In the initial cohort up to 3 patients will be treated on dose level 0. Should less than 1 patient 
experience a dose-limiting toxicity (DLT) during cycle 1, then the next 3 patients will be treated at dose 
level 1.  However, should 1 out of 3 of the initial patients treated on dose level 0 experiences a DLT, 3 
more patients will be enrolled on the same dose level.  Should no further patient experience a DLT, we 
will proceed to dose level 1, where 3 patients will be treated. If 0 out of 3 experience a DLT, 3 more 
patients will be added.  However, should at any time 2 patients on dose level 0 experience a DLT, the 
dose will be de-escalated to dose level -1, where up to 6 patients will be treated.  If 2 or more patients 
on dose level -1 experience a DLT, the trial will be terminated.  The highest dose level, at which ≤1/6 
patients experience a DLT will be defined as the RP2D.   
 
Dose levels for Phase 1 portion of Cohort 2 
 
Dose Level 
Pembrolizumab 
Copanlisib 
-1 
200 mg D1 
45 mg D1 
0 
200 mg D1 
45 mg D1 and D8 
+1 
200 mg D1 
60 mg D1 and D8 
 
D-day; cycle length: 21 days 
 
Maximum Tolerated Dose: The maximum tolerated dose (MTD) is defined as the highest dose tested in 
which none or only one patient experienced DLT attributable to the study drug(s), when 6 patients have 
been treated at that dose and are evaluable for toxicity.  
 
Recommended Phase II dose (RP2D): MTD will be considered as the RP2D, unless there are other safety 
concerns. 
 
4.2.3.2 DLT definition 
DLT window for the phase I portion of this study is 21 days or 1 cycle.  
 
DLT will be defined as any of the below AE occurring during cycle 1 that are considered by the 
investigator as at least possibly related to study treatment with copanlisib and pembrolizumab: 
- 
CTCAE grade 4 neutropenia lasting > 7 days despite growth factor support 
- 
CTCAE grade 4 febrile neutropenia  
- 
CTCAE grade 3 thrombocytopenia with bleeding that requires transfusion therapy 


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- 
Treatment delays by treatment-related toxicity causing > 14 days in the start of a subsequent 
cycle of treatment  
- 
Non-hematologic toxicities of CTCAE ≥ grade 3 except for the following: 
o Alopecia of any grade 
o CTCAE grade 3 fatigue for < 72 hours,  
o Isolated, asymptomatic grade 3 changes in biochemistry laboratory values that last for ≤ 
7 days. This includes electrolyte abnormalities that respond to medical intervention. 
Exceptions are Bilirubin elevation ≥ CTCAE grade 3; and Bilirubin ≥ grade 2 with ALT ≥ 
CTCAE grade 3 – those count as DLT. 
o ≥ CTCAE grade 3 vomiting or nausea that can be controlled (i.e. <grade 3) within 72h 
with optimal anti-emetic treatment 
o ≥ CTCAE grade 3 diarrhea that can be controlled within 72h (i.e. <grade 3) with the use 
of optimal anti-diarrheal treatment 
o ≥ CTCAE grade 3 hypothyroidism/hyperthyroidism 
o ≥ CTCAE grade 3 hyperglycemia that resolves within 7 days 
o CTCAE grade 3 arthralgias/myalgias that resolve within 7 days with the use of anti-
inflammatory drugs 
o CTCAE grade 3 infusion reactions that resolve within 6 hours with appropriate 
management in the absence of steroid and antihistamine prophylactic premedication 
 
AEs occurring in the “induction phase” of copanlisib only treatment (i.e. days -1 to day -21 of the 
induction phase) will not be considered a DLT in terms of determining the RPTD. Treatment-related 
AE ≥ CTCAE grade 3 or grade 2 treatment-related AE that lead to dose interruption of >6 weeks and 
that occur after cycle 1 may be considered a DLT after discussion with the sponsor/study chair. 
Patients who come off during the induction phase for any reason will be replaced.  
 
4.2.3.3 Phase II portion of Cohort 2 
We will enroll up to 18 patients treated at the RPTD in the phase II portion in order to define safety and 
feasibility of the combination of pembrolizumab and copanlisib (total of 24 patients treated at the RPTD 
in the phase I and II portions combined). Furthermore, there will be a “induction phase” treatment with 
2 weekly doses of copanlisib (days -21 and -14) starting 3 weeks prior to day 1 of cycle 1 in order to 
assess potential copanlisib induced changes in peripheral blood immune cell biomarkers. Patients who 
come off during the induction phase for any reason will be replaced and not included in the futility 
analysis.  
 
4.2.4 Rationale for Endpoints 
4.2.4.1 Efficacy Endpoints 
The objective of this trial is to explore the safety and efficacy of pembrolizumab in patients with NKTCL 
(Cohort 1). We will assess efficacy by evaluating progression-free survival (PFS), overall survival (OS) and 
response rate. For cohort 2 the objective is to determine RP2D in phase I portion of the study and then 
to determine objective response rate using the combination therapy in phase II portion. Classical 


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response criteria such as defined by the RECIST,59 the revised Cheson criteria1 or the Lugano criteria2 
may not capture responses seen with immunotherapeutic agents. Therefore, we had chosen PFS as 
primary endpoint rather than response rate in Cohort 1. However, from our experience in cohort 1, all 
patients who remained progression free at 3 months had at least stable disease, and durable responses 
were only seen in patients with at least a partial response on their first response assessment. Therefore, 
response and not PFS was chosen as primary outcome and efficacy of the combination therapy in cohort 
2 will be determined by response as measured by objective response rate defined as complete or partial 
responses. 
 
Measurement of effect is described in Section 14.3 of the Appendix. While we will use the revised Cheson 
criteria to assess disease response, we will allow at the first imaging time point (12 weeks after initiating 
treatment) patients to demonstrate up to 2 new lesions, with sum of all lesions <70% greater than 
baseline by sum of products of the diameters (SPD), or decreasing in size, if they are clinically stable 
without evidence of rapid clinical deterioration. In that case patients may continue to be treated with 
pembrolizumab and clinically observed with imaging repeated after 1 month. If, at that time, there is 
Progression of Disease (POD) by standard Revised Cheson Response Criteria, patients will be removed 
from study. For a more detailed description see Appendix – Section 14.3.5 Response Endpoints. 
 
4.2.4.2 Biomarker Research 
4.2.4.2.1 
PD-1, PD-L1 and tumor infiltrating lymphocytes (TIL)  
We will assess expression of PD-1, PD-L1 and tumor infiltrating lymphocytes (TIL) in pre-treatment tumor 
specimens in order to assess their ability to predict response to pembrolizumab therapy and serve as a 
potential prognostic or predictive biomarker. Multiple studies have implicating expression of PD-1, PD-
L1, in the tumor or tumor microenvironment as well as presence of TIL be associated with outcomes.60-
63 
 
4.2.4.2.2 
Immune cell biomarkers 
Additionally, we will assess PD-1 expression and leukocyte activation markers on circulating lymphocytes 
as well as NK- and T-cell function pre-treatment, during treatment as well as at time of relapse in order 
to assess potential associations with treatment response and outcome. In addition, we will also assess 
PD-L1 and PD-L2 on the surface of peripheral tumor cells when detectable. Preliminary studies of 
immune cell biomarkers, including PD-1, on peripheral blood mononuclear cells in renal cell carcinoma 
by our group have indicated that PD-1 expression on fresh peripheral blood leukocytes may provide a 
useful marker for disease progression. Furthermore, the results suggest that measuring PD-1 levels in 
peripheral blood may assist in identifying patients likely to respond to PD-1 blocking antibodies.64 
 
4.2.4.2.3 
Non-invasive disease monitoring 
High-throughput sequencing (HTS) is an emerging technology enabling quantitative measurement of 
cell-free DNA in peripheral blood.65,66 It is highly sensitive and has been shown to assist with non-invasive 
monitoring of disease status in diffuse large B cell lymphoma66,67 and follicular lymphoma.68 Not only is 
this technology non-invasive, but it provides an opportunity for earlier detection of relapse than 
traditional imaging techniques.67 HTS of the T-cell receptor (TCR) has been utilized for disease monitoring 
in other hematologic malignancies including cutaneous T cell lymphoma,69 acute lymphoblastic 


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leukemia,70 and chronic lymphocytic leukemia.65 HTS can be used to identify clonal evolution68 as well 
as early disease relapse, which has been shown to predict survival70 and may inform therapeutic 
intervention.65,71 This technology has not yet been studied in peripheral T-cell lymphoma, signifying an 
unmet need for investigation. 
 
 
We will utilize HTS commercialized by ImmunoSEQTM to measure pre-treatment levels of 
circulating cell free DNA as well as at pre-determined intervals during treatment. We will investigate the 
relationship between pre-treatment level with PFS and OS. In addition, we will examine the association 
of circulating cell free DNA levels during treatment with disease response to therapy.  
 
 
Genomic DNA from PBMC will be collected and stored for possible future research. 
 
4.2.4.2.4 
Exploration of predictive biomarkers using gene expression profiling via 
Nanostring technology 
 In order to explore biomarkers predictive of response to pembrolizumab we will perform gene 
expression profiling via Nanostring technology using the nCounter® PanCancer Immune Profiling Panel 
as well as the nCounter® PanCancer Pathway Panel on tumor tissue. This will allow us to better 
characterize a) the immune milieu of the tumor microenvironment and b) deregulated pathways in PTCL. 
 
We hypothesize that patterns of differential gene expression as described by the above panels will 
provide gene signatures predictive of response to pembrolizumab.  
 
Additionally, we will design a nanostring gene expression panel composed of up to 30 genes of interest 
in PTCL based on the available literature and preliminary work performed by researchers at the Fox 
Chase Cancer Center. Examples include DLX5, a gene encoding a transcription factor, which is up 
regulated in up to 40% of T cell lymphoid malignancies and associated with aggressive behavior.72,73 
Others include Rpl22, a ribosomal protein gene, and Lin28b, a gene encoding a “stemness” factor and 
others to be potentially involved in T-cell lymphomagenesis and prognosis.74-77  
 
We hypothesize that above analysis can potentially identify additional pathways whose roles in 
pathogenesis or disease progression have previously not been recognized or well described.  
 
4.2.4.2.5 
Identification of copanlisib induced changes in peripheral blood immune cell 
biomarkers 
We will assess the copanlisib induced changes in the immune cell biomarkers. For this the patients will 
be treated with copanlisib alone at day -21 and -14 during the induction phase prior to cycle 1 day 1. The 
blood sample will be collected before drug administration (day -21) and day -7 during the induction 
phase and then for research on cycle 1 day 1 prior to drug administration. The copanlisib induced 
changes in immune biomarkers will also be correlated to the clinical outcome to identify biomarkers of 
response to clinical outcome. 
 


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5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
 
1. Have a histologically or cytologically confirmed relapsed/refractory mature T-cell lymphoma that 
has progressed after a minimum of 1 systemic therapy with any of the following T-cell histologies: 
Peripheral T-cell NHL, not otherwise specified (PTCL, NOS); Anaplastic large cell T-cell lymphoma 
(ALCL) anaplastic lymphoma kinase positive or negative; angioimmunoblastic T-cell lymphoma; 
subcutaneous panniculitis like T-cell lymphoma; primary cutaneous gamma-delta T cell 
lymphoma; enteropathy associated T-cell lymphoma; follicular T-cell lymphoma; nodal 
peripheral T-cell lymphoma with TFH phenotype; monomorphic epitheliotropic intestinal T-cell 
lymphoma (MEITL); hepatosplenic T-cell lymphoma; extranodal NK/T-cell lymphoma, nasal type; 
unclassifiable PTCL; and transformed cutaneous T-cell lymphoma (CTCL) to PTCL with systemic 
involvement (not local skin transformation).  
2. Be willing and able to sign written informed consent for the trial. 
3. Be  18 years of age on day of signing informed consent. 
4. Have measurable disease based as defined by at least one lesion that can be measured in least 2 
perpendicular dimensions and measures at least 1.5 cm in its long axis. 
5. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy 
of a tumor lesion obtained within 28 days prior to study enrollment. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed within 10 days of treatment initiation.   


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Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL, OR 
≥1,000 /mcL if lymphomatous bone marrow involvement 
Platelets 
≥70,000 / mcL, OR 
≥50,000 / mcL if lymphomatous bone marrow involvement 
Patients with documented marrow involvement may be transfused to this value. 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Patients with documented marrow involvement may be transfused to this value. 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine clearance 
(GFR can also be used in place of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥40 mL/min for subject with creatinine levels > 1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver involvement by lymphoma 
Other 
 
Lipase 
≤ 1.5 X ULN 
Coagulation 
International Normalized Ratio (INR) or Prothrombin 
Time (PT) 
 
Activated Partial Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
8. Female subjects of childbearing potential should be willing to use 2 methods of birth control or 
be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 
days after the last dose of study medication (Reference Section 5.5.2).  Subjects of childbearing 
potential are those who have not been surgically sterilized or have not been free from menses 
for > 1 year.  
9. Male subjects should agree to use an adequate method of contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy. 
 
5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating in or has participated in a study of an investigational agent or using an 
investigational device within 2 weeks of the first dose of treatment. 
2. Patients diagnosed with Adult T-cell Leukemia/Lymphoma (ATLL) or T-cell PLL 
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form 
of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
 
4. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more 
than 4 weeks earlier.  
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered agent. 


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- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.   
6. 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 in situ cervical 
cancer that has undergone potentially curative therapy.   
7. Has known active intraparenchymal lymphomatous central nervous system (CNS) lesions and/or 
lymphomatous meningitis.  Subjects with previously treated CNS involvement by lymphoma may 
participate provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain lesions, and are not using steroids for at 
least 7 days prior to trial treatment.   
8. Has an active autoimmune disease requiring systemic treatment within the past 3 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 would be an exception to this rule.  Subjects that require intermittent use of 
bronchodilators or local steroid injections would not be excluded from the study.  Subjects with 
hypothyroidism stable on hormone replacement or Sjoegren’s syndrome will not be excluded 
from the study. 
9. Has evidence of interstitial lung disease or has a history of (non-infectious) pneumonitis that 
required steroids or current pneumonitis 
10. Has an active infection requiring systemic therapy. 
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration of 
the trial, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator.   
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 days after the 
last dose of trial treatment. 
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is 
detected). 
17. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
18. Cohort 2a: Has received an allogeneic stem cell transplant.  
For cohort 2b, patients within the first 100 days of having undergone an allogeneic stem cell 
transplant will be excluded. Otherwise, patients who have received an allogeneic stem cell 


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transplant are allowed as long as they have no evidence of active GVHD or are not taking 
immunosuppressive therapy  
19. Uncontrolled arterial hypertension despite optimal medical management 
20. Uncontrolled Type I or II diabetes mellitus as deemed appropriate by the investigator. Suggested 
guidelines for uncontrolled diabetes: HbA1c > 8.5% 
21. Anti-arrhythmic therapy (beta blockers or digoxin are permitted) 
22. Use of CYP3A4 inhibitors and inducers. Copanlisib is primarily metabolized by CYP3A4. Therefore, 
concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, 
ritonavir, indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A (e.g. rifampin, 
phenytoin, carbamazepine, phenobarbital, St. John’s Wort) are not permitted from Day -14 of 
Cycle 1 until the Safety follow up visit. See Table in Appendix 5 for complete list  
23. Concurrent diagnosis of pheochromocytoma 
24. 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 
25. Prior exposure to PI3K inhibitors, unless on PI3K inhibitor therapy more than 6 months ago AND 
reason for discontinuation of prior PI3K inhibitor therapy was other than progression or toxicity. 
26. Patients with detectable CMV viremia are excluded 
 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2A and 2B 
Table 2A Trial Treatment (Cohort 1) 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administra
tion 
Regimen/Treatment 
Period 
Use 
Pembroli
zumab 
200 mg 
(fixed dose) 
Every 3 weeks 
(Q3W) 
IV 
infusion 
36 cycles (2 years) 
Experimental 
The pembrolizumab dosing interval may be increased due to toxicity as described in Section 
5.2.1.2, but there are no dose reductions allowed for pembrolizumab. 
 
Table 2B Trial Treatment (Cohort 2) 
Drug 
Dose/Potenc
y 
Dose 
Frequency 
Route of 
Administra
tion 
Regimen/Treatment 
Period 
Use 
Pembroliz
umab 
200 mg 
(fixed dose) 
Every 3 weeks 
(Q3W) 
IV 
infusion 
2 years 
Experimental 
Copanlisib 
RP2D 
Day 1 +/- day 
8 of every 3 
weeks 
IV 
infusion 
2 years 
Experimental 
The pembrolizumab and copanlisib dosing interval may be increased due to toxicity as 
described in Section 5.2.1.2, but there are no dose reductions allowed for pembrolizumab. 
Dose reductions are allowed for copanlisib depending upon RP2D 
 


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Trial treatment should begin within 7 days of the date on which treatment is assigned. Cohort 2 will have 
a 21 day long induction phase prior to the beginning of treatment (numbered day -1 to -21, followed 
immediately by Cycle 1 Day 1) cycles during which subjects will receive 2 doses of copanlisib alone, first 
one on day -21 and second dose on day -14 of the induction phase. 
 
During treatment cycles, on the days both pembrolizumab and copanlisib are administered, copanlisib 
must be administered first, followed by pembrolizumab. 
 
5.2.1 Dose Selection/Modification 
The attribution of causality of any AE to the test drugs specifically may be difficult. However, in Phase I 
and II trials, certain toxicities were seen only in relation to copanlisib, e.g., transient increases in glucose 
and blood pressure. If a particular AE is attributed to pembrolizumab or copanlisib then the specific drug 
can be interrupted according to the dose modification criteria while the other may continue. Both drugs 
may need to be interrupted if attribution is not clear. If toxicity is not resolved such that the drug/s 
cannot be administered 21 days beyond their scheduled administration the patient will be off treatment. 
If the toxicity that results in treatment discontinuation is clearly due to one of the drugs, then the patient 
can be treated on monotherapy after discussion with the sponsor-investigator. Dosing interruptions are 
permitted in the case of medical / surgical events or logistical reasons not related to study therapy (e.g., 
elective surgery, unrelated medical events, patient vacation, and/or holidays). Subjects should be placed 
back on study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with 
the Sponsor. The reason for interruption should be documented in the patient's study record. 
 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background and 
Rationale.   
 
The dose amount required to prepare the pembrolizumab and copanlisib infusion solution will be a fixed 
dose (i.e. not dependent upon patient’s weight).   
 
5.2.1.2 Pembrolizumab (MK-3475) and copanlisib Dose Modification 
(Escalation/Titration/Other) for immune-related events 
Adverse events (both non-serious and serious) associated with pembrolizumab and/or copanlisib 
exposure may represent an immunologic etiology.  These adverse events may occur shortly after the 
first dose or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening immune-related AEs as per Table 3 below. For guidelines 
on the management of adverse events with potential immunological etiology see Section 5.4 Supportive 
Care and Management of Immune-related Adverse Events, including use of corticosteroids. 
 


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Table 3: Dose Modification Guidelines for Immune Related Adverse Events 


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Toxicity 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Hold until toxicity resolves to Grade 0-
1. Restart MK3475 and copanlisib once 
until Grade ≤1 and decrease copanlisib 
by one dose level3. 
Discontinue both drugs if toxicity does not resolve within 12 
weeks of last dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Hold until toxicity resolves to Grade 0-
1. Restart MK3475 and copanlisib once 
Grade ≤1 and decrease copanlisib by 
one dose level3. 
Discontinue both if toxicity does not resolve within 12 weeks of 
last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
hyperglycemia 
T1DM new 
or  
3-4 
associated 
with 
evidence of 
β-cell 
failure 
Hold treatment and resume 
pembrolizumab and copanlisib when 
patients are clinically and metabolically 
stable. 
 
Hypophysitis 
2 
Hold until toxicity resolves to Grade 0-
1.  
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
3-4 
Hold until toxicity resolves to Grade 0-1 
or  permanently discontinue at the 
discretion of the treating Physician 
Permanently discontinue at the discretion of treating Physician 
Hyperthyroidism  
3-4 
 
Hold or Permanently discontinue at the 
discretion of treating Physician 
 
Permanently discontinue at the discretion of treating Physician 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Hold until toxicity resolves to Grade 0-
1. Restart MK3475 and copanlisib once 
Grade ≤1 and decrease copanlisib by 
one dose level3 
Discontinue both if toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
3-4 or 
recurrent 
Grade 2 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Hold until toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Myocarditis 
1-2 
Hold until toxicity resolves to Grade 0. 
Restart MK3475 and copanlisib once 
Grade <1 and decrease copanlisib by 
one dose level3. 
Discontinue both if toxicity does not resolve within 12 
weeks of last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per day within 
12 weeks. 
3-4 
Permanently discontinue study 
treatment 


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Toxicity 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Dermatological 
 
 
 
Grade 1 
Any 
appearance 
No change 
No change 
Grade 2b 
1st 
appearance 
Interruption until Grade ≤1 
No change 
 
2nd 
appearance 
Interruption until Grade ≤1. Restart 
MK3475 and copanlisib once Grade ≤1 
and decrease copanlisib by one dose 
level3 
 
 
3rd 
appearance 
Interruption until Grade ≤1. Restart 
MK3475 and copanlisib once Grade ≤1 
and decrease copanlisib by one dose 
level3 
 
 
4th 
appearance 
Permanently discontinue 
Permanently discontinue copanlisib and MK3475 
Grade 3b 
1st 
appearance 
Interruption until Grade ≤ 1. Restart 
MK3475 and copanlisib once Grade ≤1 
and decrease copanlisib by one dose 
level3 
 
 
2nd 
appearance 
Interruption until Grade ≤1. Restart 
MK3475 and copanlisib once Grade ≤1 
and decrease copanlisib by one dose 
level3 
 
 
3rd 
appearance 
Permanently discontinue 
Permanently discontinue copanlisib and MK3475 
Grade 4 
1st 
appearance 
Permanently discontinue 
Permanently discontinue copanlisib and MK3475 
All Other 
immune-Related 
Toxicity2 
Intolerable
/persistent 
Grade 2 
Hold until toxicity resolves to Grade 0-1 
 
3  
Hold until toxicity resolves to Grade 0-
1. Restart MK3475 and copanlisib once 
Grade ≤1 and decrease copanlisib by 
one dose level3. 
Discontinue both if toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
4 or 
recurrent 
Grade 3 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% 
relative to baseline and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue 
study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 
within 12 weeks of the last dose. 
3 Not applicable to dose level -1 of copanlisib. In that case, patient has the option of continuing on pembrolizumab alone.  
 
5.2.1.3 Copanlisib Dose Modifications 
Treatment interruptions for copanlisib must be done according to the guidelines in hematological 
toxicity and non-hematological toxicity sections (5.2.1.3.1 and 5.2.1.3.2) except for immune related 
adverse events, in which case, instruction from section 5.2.1.2 and Table 3 should be followed. The 
investigator may judge a more conservative dose modification if appropriate. If dose reduction below 
30mg is required, the patient has the option of continuing on pembrolizumab alone.  Furthermore, if 
copanlisib is discontinued due to non-immune-related toxicities or toxicities clearly related to copanlisib 


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alone, the patient has the option of continuing on pembrolizumab alone. Patients can continue with 
pembrolizumab while copanlisib is being held.  
 
 
Dose Level 
Copanlisib 
-1 
30 mg  
0 
45 mg 
+1 
60 mg  
 
5.2.1.3.1 
Hematological Toxicities 
Neutropenia and febrile neutropenia are listed in the current version of IB as expected adverse events. 
The guidelines described below should be followed. 
 
Dose modification of copanlisib for hematological toxicity  
Hematological toxicity (any of the following) 
Study treatment action (for any toxicity) 
 CTCAE Grade ≥ 3 thrombocytopenia (platelet 
< 50,000/mm3)  
 Febrile neutropenia a 
 CTCAE Grade ≥ 3 neutropenia (ANC < 1000/mm3)  
 INR or PTT CTCAE Grade ≥3 with bleeding b 
 CTCAE Grade ≥ 3 anemia (Hb < 8 g/dL)  
Delay infusion until criteria displayed in  
Table: ‘Laboratory test criteria for Day 1 dose of 
subsequent cycles are met’.d (section 5.2.2.2)  
Patient can be treated at one dose level lower at the 
investigator’s discretion.c If more dose reductions are 
required than allowed per protocol, discontinue 
copanlisib permanently. The lowest dose level is 30 
mg. 
ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria of Adverse Events, version 5; Hb = hemoglobin; 
INR = international normalized ratio; PTT = partial thromboplastin time 
a: These patients should recover from neutropenia (Table 1), without fever 
b: International normalized ratio (INR) and partial thromboplastin time (PTT) should have returned to ≤ 1.5 and ≤ 1.5 x ULN, 
respectively, with no signs of bleeding  
c: After having fully recovered from toxicity and in the absence of any criteria for further dose reduction or study drug 
discontinuation, re-escalation to dose level -1 or 1 is allowed at the investigator’s discretion 
d: Treatment with transfusion or growth factors is allowed at the investigator’s discretion 
 
5.2.1.3.2 
Non-hematological toxicities (non-immune related) 
Dose modifications for non-hematologic toxicities attributable to copanlisib except glucose increases, 
blood pressure increases, and immune related events (see table 3) are outlined in Table below. 
Dose modification of copanlisib for non-hematological toxicity (except immune-related events) 
 
 
 
 
Toxicitya 
Occurrence 
For current course of 
therapy 
For next course of therapy 
Grade 1-2 
Any appearance No change 
No change 
Grade 3b 
1st appearance 
Delay until Grade ≤ 2 
No change 
 
2nd appearance 
Delay until Grade ≤  2 
Decrease by one dose levelc 
 
3rd appearance 
Delay until Grade ≤  2 
Decrease by one dose levelc 


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4th appearance 
Permanently 
discontinue 
 
Grade 4 
Any appearance Permanently 
discontinue 
 
a. Toxicities according to CTCAE 5 
b. Despite maximum supportive care 
c. 
Not applicable to dose level -1 
 
 
5.2.1.3.3 
Arterial Hypertension 
No dose should be given if blood pressure is ≥ 150/90 mmHg. Antihypertensive medication may be given 
to control the increased blood pressure. Dosing can proceed on the scheduled day if there are at least 2 
consecutive measurements <150/90 mmHg apart. Otherwise dosing must be delayed.  
 
If drug-related arterial hypertension (post-dose blood pressure of CTCAE Grade 3 or  160/100 mmHg) 
is not manageable with optimal antihypertensive treatment, the dose for the subsequent copanlisib 
administrations may be reduced by 1 or 2 dose levels at the investigator’s discretion. Patients with a 
post-dose blood pressure that may have life-threatening consequences (e.g. malignant arterial 
hypertension, transient or permanent neurologic deficit, hypertensive crisis) must permanently 
discontinue copanlisib. 
 
Table: Dose modification for copanlisib for arterial hypertension 
Toxicitya 
Study drug action 
Recommendation 
Pre-dose 
Measurements 
BP≥150/90mmHg 
No dose should be given 
until 
recovery 
to 
< 150/90 mmHg. 
Consider BP lowering medication. Dosing can 
proceed on the scheduled day if after at least 
2 consecutive measurements BP returns to 
< 150/90 mmHg. If BP doesn’t return to < 150/90 
mmHg, delay dosing until next visit. 
During infusion: 
CTCAE 
hypertension of 
grade 3  
or ≥ 160/100 
mmHg 
Infusion can be interrupted 
or 
slowed 
down 
and 
administration 
of 
BP 
lowering therapy should be 
initiated. 
Infusion may be resumed when BP has returned 
to < 150/90 mmHg at the investigator’s discretion 
or skipped. 
Subsequent study drug administrations may be 
reduced by 1 dose level at the investigator’s 
discretion.b 


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Post-dose: 
Drug-related 
CTCAE 
hypertension of 
grade 3 
or ≥ 160/100 
mmHg a 
 
Administration of BP lowering therapy should be 
initiated according to local standard of care.   
Additional measurements to be performed as 
clinically 
indicated 
until 
recovery 
to 
< 150/90 mmHg. 
Subsequent study drug administrations may be 
reduced by 1 dose level at the investigator’s 
discretion.b 
CTCAE 
hypertension of 
grade 4 
 
Permanently discontinue 
 
CTCAE = Common Terminology Criteria for Adverse Events V 5.0; BP = Blood pressure 
a: Not manageable despite optimal antihypertensive treatment. 
         b: The lowest dose level is 30mg. 
 
5.2.1.3.4 
Hyperglycemia 
Pre-dose fasting blood 
glucose 160 mg/dl or 
more or random/non-
fasting blood glucose of 
200 mg/dl or more 
Withhold copanlisib until fasting glucose is 160 mg/dl or less, or 
random/non-fasting blood glucose of 200 mg/dl or less 
Pre-dose or post-dose 
blood glucose 500 mg/dl 
or more 
On first occurrence 
withhold copanlisib until 
fasting glucose is 160 
mg/dl or less, or 
random/non-fasting 
blood glucose of 200 
mg/dl or less. Then dose 
reduce by one level 
On subsequent 
occurrences, withhold 
copanlisib until fasting 
glucose is 160 mg/dl or 
less, or random/non-
fasting blood glucose of 
200 mg/dl or less. Then 
dose reduce by one 
level 
On next occurrence 
discontinue 
copanlisib 
 
Patients who develop infusion related hyperglycemia > 250 mg/dL (13.9 mmol/L) after study drug 
administration may continue treatment. However, the next infusion must be delayed until the patient’s 
pre-infusion glucose levels return to < 160 mg/dL (8.9 mmol/L) (fasting) or < 200 mg/dL (11.1 mmol/L) 
(non-fasting). 
Persistent infusion related hyperglycemia > 200 mg/dL (11.1 mmol/L) based on repeated laboratory 
analysis despite glucose lowering therapy after 2 infusions of study drug will require dose reduction by 
one dose level. Further dose reduction (where appropriate per study design/population) is allowed as 
long as discontinuation criteria was not met. 
 
5.2.1.3.5 
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 


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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. 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 treatment is considered as not feasible. 
 
5.2.2 Dose Administration 
5.2.2.1 Pembrolizumab  
Pembrolizumab should be administered on Day 1 of each cycle after all procedures/assessments have 
been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be administered 
up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. 
 
All trial treatments will be administered on an outpatient basis. 
 
Pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle intervals may be 
increased due to toxicity as described in Section 5.2.1.2).  Sites should make every effort to target 
infusion timing to be as close to 30 minutes as possible.  However, given the variability of infusion pumps 
from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: 
-5 min/+10 min). 
 
The following infusion set materials are compatible with pembrolizumab (MK-3475): 
•      PVC Infusion set that is plasticized using DEHP 
•      PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 
•      Polyethylene lined PVC infusion set 
•      PVC Infusion set that is plasticized using Di-2-ethylhexyl Terephthalate (DEHT) 
•      Polyurethane set. 
 
 A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of polyethersulfone (PES) 
must be used during administration to remove any adventitious particles.  If the infusion set does not 
contain 0.2 to 5 µm in-line filter, it is recommended to use 0.2 to 5 µm add-on filter which may contain 
an extension line. 
 
Attach the infusion line to the pump and prime the line, either with normal saline (at least 25 mL) or with 
infusion solution as per local SOP, before starting the infusion. 
 
Infuse pembrolizumab (MK-3475) over approximately 30 minutes, with a window of -5 and +10 minutes, 
through a peripheral line or indwelling catheter. 
 
Ensure the entire contents of the bag are dosed and all remaining drug solution in the line is administered 
according to institutional guidelines for saline flushing. 


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Document volume administered according to data entry guidelines. 
 
Vital signs will be monitored every 15 minutes during the infusion and for 60 minutes after completion 
of each infusion.  
 
Whenever possible, the lowest infusion rate should be used that will allow completion of the infusion 
within the 30 minutes. Maximum rate of infusion should not exceed 6.7 mL/min. through a peripheral 
line or indwelling catheter. However, when it is necessary to infuse a larger volume (i.e. 250 mL), the 
flow rate may go as high as 10 mL/min (maximum) in order to keep the infusion within the window as 
defined above. 
 
5.2.2.2 Copanlisib  
Before commencing copanlisib, all patients should have CMV status assessed. CMV seronegative patients 
should receive CMV-negative or filtered blood products. For seropositive patients, CMV quantitative 
polymerase chain reaction (PCR) testing with every cycle is recommended. Interrupt Copanlisib in 
patients with evidence of active CMV infection of any grade or viremia until the viremia has resolved. 
Ganciclovir or valganciclovir should be preemptively initiated in patients with positive CMV PCR and 
symptoms consistent with CMV infection, patients presenting with fever and no clear source in whom 
quantitative CMV testing is unavailable, and asymptomatic patients with increasing viral load. 
 
Copanlisib should be administered on Day 1 +/- Day 8 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0). Day 1 drug administration has a 
window of +/- 3 days. Copanlisib is supplied as lyophilized preparation in a 6-mL injection vial. The total 
amount of copanlisib per vial is 60 mg. The solution for IV infusion is obtained after reconstitution of the 
lyophilisate with 0.9% sodium chloride solution. 
 
Study drug is administered in a normal saline solution, intravenously, over 1 hr. No intravenous glucose 
preparations should be administered on the days of infusion. 
Induction phase:   
Fasting is required (8 hours minimum) only during the induction phase visits before the first glucose 
measurement on date of infusion. A low glycemic index meal may be taken 2 hours post-infusion unless 
the patient needs to have a low glycemic meal and unable to fast for this period of time, then glucose 
test should be taken prior to meal intake. 
It is imperative that the induction phase visits fall on Mon-Thurs during the week so that there is enough 
time to ship the blood collected for correlative studies to Fox Chase Cancer Center to be processed within 
the required window (blood may not be processed during the weekend). Also, blood collection must be 
scheduled so that it reaches Fox Chase Cancer Center on a working day, and not on a holiday.  
All subsequent infusions after Induction phase: 
The decision regarding meal timing can be made by the investigator based on glucose response patterns 
during prior treatment days. 
 


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NOTE: If patient needs to have a low glycemic meal prior to the infusion, then glucose test should be 
taken prior to the meal and/or at 1-2 hours after the meal.  
 
After the induction phase, a low glycemic index meal may be taken at least 4 h before the start of the 
study drug infusion for patients who have their infusions scheduled at a later treatment time or due to 
their age or medical condition when fasting prior to infusion is not viable. 
 
Fasting requirements and pre-dose glucose levels 
Period 
Fasting ≥ 8 h required 
before first glucose 
measurement 
Pre-dose glucose levels 
 
Fasting required before study 
drug infusion 
Day 1 of 
cycle 1 
Yes 
<160 mg/dL (8.9 mmol/L) 
 
Yesb 
Day 1 of subsequent 
cycles 
No 
<160 mg/dL (fasting) (8.9 mmol/L) 
< 200 mg/dL (11.1 mmol/L) (non-fasting or 
random) c 
Conditional  ͣ ,b, d 
Days 8   
of each cycle 
No 
<160 mg/dL (8.9 mmol/L) (fasting) 
<200 mg/dL(11.1 mmol/L) (non-fasting or 
random) 
Conditional ͣ ,b, d 
a: The decision regarding meal timing and fasting can be made by the investigator based on glucose response patterns during prior treatment 
days. 
b: Diabetic patients who take insulin treatment at any cycle visit:  
Timing and content of caloric intake on infusion days will be managed by the investigator. Consultation with treating physician or 
diabetes/endocrinologist is advised. 
c: In case of non-compliance with the fasting requirement. 
d. A small, light low glycemic index meal may be taken at least 4 hours before the start of the copanlisib infusion for patients who have their 
infusions scheduled at a later hour, or due to their age or medical condition when fasting prior to infusion is not viable. 
 
Laboratory test criteria for Day 1 dose of subsequent cycles 
 
Lab Test 
Criteria for Day1 dose (cycle 2 and higher) 
Glucose 
< 160 mg/dL (8.9mmol/L) (fasting) or < 200 mg/dL (11.1 mmol/L) (non-
fasting) 
Hemoglobin 
≥ 8 g/dL a 
ANC 
≥ 1,500/mm3 
Platelets 
≥ 75,000/mm3 
ALT 
<2.5 x ULN b 
AST 
<2.5 x ULN c 
Total bilirubin 
within normal limits d 
GFR (MDRD) 
≥ 40 mL/min/1.73 m2 
ANC = Absolute neutrophil count; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GFR = Glomerular filtration rate; 
MDRD = Modification of Diet in Renal Disease; ULN = Upper limit of normal. 
a: If hemoglobin is < 8 g/dL but ≥ 6 g/dL on the day of planned study drug administration it is permissible to give the study drug dose as 
scheduled and transfuse within 48 hours after the dose, if the patient is hemodynamically stable and in opinion of investigator 
benefits outweigh risks. Rationale and treatment should be recorded in source document and eCRF.  
b: < 5 x ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to lymphoma. 
c: < 5 x ULN in patients with documented liver involvement by lymphoma or with biliary obstruction due to lymphoma. 
d: <3 x ULN in patients with Gilbert syndrome, patients with cholestasis due to compressive adenopathies of the hepatic hilum or 
documented liver involvement by lymphoma. 


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A blood count will be performed and assessed prior to study drug infusion on Day 8 of each cycle. On 
day 8 the dose of copanlisib will be administered if, on the day of scheduled dosing, the laboratory test 
criteria for hemoglobin, ANC and platelets are met. 
 
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 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 infusion  
Note: a window of ±10 min is allowed for all BP measurements, except for the 0 h (pre-dose) 
measurement 
 
5.2.3 Participant Registration 
Participants may be registered from 8:00 am to 4:00 pm EST excluding holidays by emailing the 
Investigator-Sponsored Research Unit (ISRU) at: FCCC.MONITOR@fccc.edu. Eligible participants will be 
entered on study centrally once the following items have been received by email: 
 
 Completed registration form  
 Consent and HIPAA signature pages  
 Eligibility checklist 
 
Following registration, participants must begin protocol treatment within 7 days of registration.  Issues 
that would cause treatment delays must be discussed with the Sponsor-Investigator.  If a registered 
participant does not receive protocol therapy following registration, the participant will be recorded as 
withdrawn from study.  The Study Monitor must be notified as soon as possible if a participant does 
not begin protocol treatment as scheduled. For additional registration questions, please email 
FCCC.MONITOR@fccc.edu  
 
The FCCC ISRU will notify the site by email once registration is confirmed and the sequence number has 
been assigned.  Participants must be registered and have received a sequence number prior to the 
initiation of treatment.   
 
Exceptions to the current registration policies will not be permitted.  
 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be required.  


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The investigator should discuss any questions regarding this with the Sponsor.  The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the subject's primary physician.  
However, the decision to continue the subject on trial therapy or vaccination schedule requires the 
mutual agreement of the Investigator, the Sponsor, and the subject. Ganciclovir or valganciclovir should 
be preemptively initiated in patients with positive CMV PCR and symptoms consistent with CMV 
infection, patients presenting with fever and no clear source in whom quantitative CMV testing is 
unavailable, and asymptomatic patients with increasing viral load. 
 
Bactrim Prophylaxis:  Bactrim DS 1 tablet three times weekly, or 1 SS tablet daily, or equivalent (if sulfa 
allergic) for PJP prophylaxis will be administered to the patients. 
 
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’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.  If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 days 
after the last dose of trial treatment must be recorded.  Concomitant medications administered after 30 
days after the last dose of trial treatment must be recorded for SAEs and ECIs as defined in Sections 8.2 
and 8.3. Growth factors and blood product transfusions are allowed at the investigator’s discretion in 
order to maintain adequate blood counts in patients with documented bone marrow involvement.  
 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase 
(including retreatment for post-complete response relapse) of this trial: 
 Anti-cancer systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab or copanlisib 
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
after consultation with Sponsor.   
 Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; however intranasal 
influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.  
 Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology or acute medical reasons (e.g. asthma exacerbation), 
but not solely as an anti-tumor therapy.  The use of physiologic doses of corticosteroids may be 


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approved after consultation with the Sponsor. Patients may be using topical or inhaled 
corticosteroids. The use of corticosteroids as antiemetics prior to copanlisib administration will 
not be allowed 
 Strong inhibitors or inducers of CYP3A4/5 (see appendix 5) 
 Substrates of CYP3A4/5 with narrow therapeutic index 
 Medications that carry a strong risk for QT prolongation 
 Herbal medications/preparations (except for vitamins) 
 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.4 Supportive Care and Management of Immune-related Adverse Events 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the use of oral 
or intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.   Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are intended to 
be applied when the investigator determines the events to be related to pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator is instructed to 
follow the ECI reporting guidance but does not need to follow the treatment guidance (as outlined in the 
ECI guidance document). Refer to Section 5.2.1.2 for dose modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
 
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids (initial dose of 1-2 mg/kg 
prednisone or equivalent). When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 Diarrhea/Colitis:  


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Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 Administer anti-hyperglycemic in participants with hyperglycemia. 
 
 Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on 
clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 


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o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids (initial dose of 0.5-1 mg/kg prednisone or 
equivalent) followed by taper 
o For Grade 3-4 events, treat with intravenous corticosteroids (initial dose of 1-2 mg/kg 
prednisone or equivalent) for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids (prednisone 1-2 mg/kg or equivalent). 
o For Grade 3-4 events, treat with systemic corticosteroids (prednisone 1-2 mg/kg or equivalent). 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.  
 Myocarditis 
o Based on the severity of AE administer corticosteroids 
o Ensure adequate evaluation to confirm etiology and/or exclude other causes 
 All other Immune-related AEs 
o Based on type of and severity of AE administer corticosteroids 
o Ensure adequate evaluation to confirm etiology and/or exclude other causes 
 
 
Management of Pembrolizumab Infusion Reactions: Signs and symptoms usually develop during 
or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
prophylactic medications indicated for 
< =24 hrs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the original 
infusion rate (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms resolve and the subject 
should be premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration. 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
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 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration. 
 
 
 Treatment of blood pressure increases associated with copanlisib  
It is important that patients with pre-existing arterial hypertension adhere to their regular 
medication schedule and take their usual doses on the days of study drug infusion.  
The management of acute blood pressure increases following copanlisib will need to be 
individualized for each patient, but prior experience suggested the benefit of dihydropyridine 
calcium channel blockers (i.e. amlodipine, felodipine). Nitrates should also be considered. Verapamil 
and diltiazem (non-dihydropyridine calcium channel blockers and moderate inhibitors of CYP 3A4) 
should be used with caution due to a potential CYP 3A4 interaction. In general, it is advisable for sites 
to be prepared, so that antihypertensive medication is readily available in case of need.  
In the event of the occurrence of arterial hypertension ≥ 150/90 mmHg during infusion of copanlisib 
at any cycle, antihypertensive treatment is suggested as indicated in section 5.2.1.3.5. In the event 
of the occurrence of CTCAE Grade 3 arterial hypertension (≥ 160/100 mmHg) during infusion of 
copanlisib, the infusion should be interrupted and antihypertensive treatment as suggested in 
section 5.2.1.3.5 should be administered. Infusion can be resumed when blood pressure has returned 
to <150/90 mmHg. 


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 Management of infusion-related hyperglycemia  
Mild to moderate asymptomatic increases of blood glucose may occur with copanlisib infusion, and with 
larger increases potentially occurring post-prandially. Please refer to table below for dose modifications 
and management of hyperglycemia. 
Asymptomatic glucose 
increases ≤ 250mg/dL 
(13.9 mmol/L) 
Does not generally require treatment with 
glucose lowering medication. 
Oral Hydration 
Asymptomatic glucose 
increase  > 250 mg/dl 
(13.9 mmol/L) 
• Repeat glucose testing. 
• If glucose value is decreasing, glucose level  
may be followed without glucose lowering 
medication treatment if hydration status is 
normal as clinically assessed 
• Consultation with endocrinologist is 
recommended 
• Oral and or IV Hydration as appropriate  
 
Symptomatic 
or 
persisting 
glucose 
increase               > 
250mg/dL 
(13.9 
mmol/L) 
• Hydration status should be clinically assessed.  
• If clinical assessment is consistent with 
dehydration, fluids should be given as 
clinically appropriate (orally or IV). 
• Laboratory test confirming increase should be 
repeated. If the repeated glucose value is 
persistent and/or patient is symptomatic 
and/or the hydration status indicates the 
need for hydration, glucose lowering 
medication should be administered. 
• Prompt input from an endocrinologist should 
be obtained.  
• Keep well hydrated rapid/ short acting 
insulin may be given if glucose 
persisting at > 250 mg/dL (13.9 
mmol/L), and the patient is 
symptomatic  
• 
Rapid/short acting insulin   according 
to the institution sliding scale coverage 
of glucose persisting at > 250 mg/dL 
(13.9 mmol/L) is recommended, with 
oral or IV hydration as clinically 
appropriate  
Asymptomatic Glucose 
increase > 500mg/dL 
• 
Will require dose reduction for 
subsequent treatment infusions. 
• 
Repeat glucose testing. 
• 
If glucose value is decreasing, glucose 
levels may be followed without glucose 
lowering medication treatment if 
hydration status is normal as clinically 
assessed 
Consultation 
with 
endocrinologist 
is 
recommended 
• Keep well hydrated rapid/ short acting 
insulin may be given if glucose 
persisting at > 250 mg/dL (13.9 
mmol/L), and the patient is 
symptomatic  
• For insulin naïve patients, monitor for 
signs of hypoglycemia 3 hours post 
insulin administration due to risk for 
hypoglycemic events. 
 Management of persistent infusion-related hyperglycemia on subsequent days: 
Criteria 
Recommendation 
Suggested Treatment 
Persistent glucose > 
200 mg/dL (11.1 
mmol/L)(non-
fasting) 
or 
>160 
mg/dL (8.9 mmol/L) 
 Oral Glucose Lowering 
Medication, and  consultation 
with endocrinologist 
recommended 
 The use of sulphonylurea/metaglinides, insulin 
secretagogues medications to manage increased 
glucose levels post drug infusions is not recommended 


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(fasting) 
post 
infusion  
 
 Treatment with glucose lowering medication suggested 
according the local standards of practice 
 
 
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
 
5.5.1.1 Recommendations on meal timing on infusion days (copanlisib) 
Because of its inhibitory effect on the PI3K α-isoform, which is implicated in insulin metabolism, 
copanlisib infusions could be associated with a temporary increase in blood glucose. Addition of a meal 
in close proximity to copanlisib infusion may exacerbate glucose increase. It is recommended that timing 
and content of caloric intake on infusion days is monitored by the investigators. Consultation with a 
diabetologist or endocrinologist is advised. 
The investigator will review the glucose profile during and post the copanlisib infusions.  
Timing and content of caloric intake on infusion days will be managed by the investigator. Consultation 
with treating physician or diabetes/endocrinology physician is advised. 
The investigator may manage the timing of post infusion meals based on the glucose profile during prior 
infusion(s) to minimize glucose increases. This is in addition to glucose lowering medication.  
Low glycemic index meals (see Appendix 4) should be provided for patients who are kept in clinic for 
continued observation.  
A low glycemic index diet is recommended for the first 48 hours after study drug infusion. However, 
caloric restriction is not intended for the population under study. 
All glucose measurements, oral glucose lowering medication and/or insulin administration, if applicable, 
and meal timing will be collected as part of the clinical source documentation.  
NOTE: Caloric intake and timing recommendations for diabetic patients who require insulin treatment 
prior to the infusion at any cycle visit should be managed by the investigator based on consultation with 
treating physician or diabetes/endocrinologist physician. 
 
5.5.2 Contraception 
Pembrolizumab and copanlisib may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if pembrolizumab and copanlisib have transient adverse effects on the composition of sperm.  
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses 
for greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a barrier 


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method plus a hormonal method to prevent pregnancy. Subjects should start using birth control from 
study Visit 1 throughout the study period up to 120 days after the last dose of study therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the 
partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal contraceptives will 
include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study.  In order to participate in the study, they 
must adhere to the contraception requirement (described above) for the duration of the study and 
during the follow-up period. If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
 
5.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab and/or copanlisib, 
the subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the Sponsor, Merck and Bayer without delay and within 
24 hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or 
other disabling or life-threatening complication to the mother or newborn).  The study investigator will 
make every effort to obtain permission to follow the outcome of the pregnancy and report the condition 
of the fetus or newborn to the Sponsor.   If a male subject impregnates his female partner the study 
personnel at the site must be informed immediately and the pregnancy reported to the Sponsor, Merck, 
Bayer and followed. 
 
5.5.4 Use in Nursing Women 
It is unknown whether pembrolizumab and copanlisib is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment. 
 
5.6 
Participant Withdrawal/Discontinuation Criteria 
Participants may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a participant may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial plan 
is violated, or for administrative and/or other safety reasons.  Specific details regarding discontinuation 
or withdrawal are provided in Section 7.1.4 – Other Procedures. 
 
A participant must be discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws consent. 
 Disease progression (for definition see Appendix 12.3 Measurement of Effects) 
 Unacceptable adverse experiences as described in Section 5.2.1.2 
 Intercurrent illness that prevents further administration of treatment 


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 Investigator’s decision to withdraw the subject 
 The participant has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Completed 36 cycles of treatment with pembrolizumab (Cohort 1) 
Note: Subjects who stop pembrolizumab after 36 cycles may be eligible for up to 18 cycles of 
additional study treatment if they progress after stopping study treatment provided they meet 
the requirements detailed in Section 5.8. 
 Administrative reasons 
 Completed 36 cycles with the combination of MK3475 and copanlisib 
 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) and 
Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be followed for 30 days 
for adverse event monitoring (events of clinical interest will be collected for 90 days after the end of 
treatment as described in Section 5.4).  Subjects who discontinue for reasons other than progressive 
disease will have post-treatment follow-up for disease status until disease progression, initiating a non-
study cancer treatment, withdrawing consent, end of study or becoming lost to follow-up.  After 
documented disease progression each subject will be followed by telephone for overall survival until 
death, withdrawal of consent, or the end of the study, whichever occurs first. 
 
5.7 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
 
In the event of Merck or Bayer decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
5.8 
Retreatment 
Patients will be eligible for retreatment with pembrolizumab and/or copanlisib after completion of the 
trial treatment IF they achieved a complete response during the treatment phase AND remained in a 
complete remission until completion of the trial phase (36 cycles) AND experience a documented relapse 
within one year after completion of the trial phase. Retreatment will have to be discussed with the 
sponsor and will at most be for another 18 cycles. Prior to retreatment the patient will have to fulfill all 
the initial eligibility criteria as outlined in Section 5.1 Entry Criteria. 
 
 


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6.0 TRIAL FLOW CHART 
Trial Period: 
Screening Phase 
Induction Phase 
(Day -21 to -1) 
Treatment Cycles A 
End 
of 
Treat
ment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screenin
g  
Main 
Study 
Screeni
ng  
 
 
 
1 
2  
3 
4 
To be 
repeated 
after Cycle 
8 
At 
time 
of 
Disco
n 
Safety 
Follow-
up 
Follow 
Up Visits 
B  
Survival 
Follow-Up 
 
 
 
5-8 
 
Scheduling Window (Days): 
 
-50 to -
22 
Day 
-21 
Day  
-14 
Day 
-7 
D1 
± 3 
D8o 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
 
30 days 
post 
discon 
Every 12 
weeks 
post 
discon 
 
 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Pembrolizumab AdministrationQ 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Copanlisib AdministrationM, Q 
 
 
XN 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Full Physical Examination  
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Vital Signs I and Weight 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 


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Trial Period: 
Screening Phase 
Induction Phase 
(Day -21 to -1) 
Treatment Cycles A 
End 
of 
Treat
ment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screenin
g  
Main 
Study 
Screeni
ng  
 
 
 
1 
2  
3 
4 
To be 
repeated 
after Cycle 
8 
At 
time 
of 
Disco
n 
Safety 
Follow-
up 
Follow 
Up Visits 
B  
Survival 
Follow-Up 
 
 
 
5-8 
 
Scheduling Window (Days): 
 
-50 to -
22 
Day 
-21 
Day  
-14 
Day 
-7 
D1 
± 3 
D8o 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
 
30 days 
post 
discon 
Every 12 
weeks 
post 
discon 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum 
B-HCG 
 
X H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
 
X G 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
 
X G 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum Chemistry 
Panel J 
 
X G 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LDH 
 
X G 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Uric Acid 
 
X G 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Phophorus 
 
X G 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Magnesium 
 
X G 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X G 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipase and amylase 
 
XG 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
T3, FT4 and TSH C 
 
X G 
 
 
 
X 
 
X 
 
X 
 
X 
 
XC 
 
X 
X 
  
 
CMV monitoring P 
 
XG 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging D,L 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 XD 
 
X 
 
X E 
 


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Trial Period: 
Screening Phase 
Induction Phase 
(Day -21 to -1) 
Treatment Cycles A 
End 
of 
Treat
ment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screenin
g  
Main 
Study 
Screeni
ng  
 
 
 
1 
2  
3 
4 
To be 
repeated 
after Cycle 
8 
At 
time 
of 
Disco
n 
Safety 
Follow-
up 
Follow 
Up Visits 
B  
Survival 
Follow-Up 
 
 
 
5-8 
 
Scheduling Window (Days): 
 
-50 to -
22 
Day 
-21 
Day  
-14 
Day 
-7 
D1 
± 3 
D8o 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
 
30 days 
post 
discon 
Every 12 
weeks 
post 
discon 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained 
Tissue Collection 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood 
Collection F, K 
 
 
X F, K 
 
XF 
 
 
XF 
 
XF 
 
 
 
XK 
 
X F, K 
 
X K 
 
 
A 
Total of 36 treatment cycles  
B 
Patients should be assessed every 12 weeks (84 ± 7 days) for the first 2 years (or until disease progression) clinically for disease status - see section 7.1.5.4. Once a subject experiences confirmed disease progression 
or starts a new anti-cancer therapy they move into survival follow-up  
C 
Check during treatment phase once every cycle. 
D 
Preferably FDG PET/CT at baseline, but if unavailable a contrast-enhanced CT scan is allowed. If PET CT is performed, the CT component must be of diagnostic quality. Subsequent imaging should be of the same 
modality as the imaging at baseline – see Sections 7.1.2.6 and 12.3.  Once a patient achieved at PET-negative CR after completion of treatment, subsequent imaging can be a contrast-enhanced CT scan only. The first 
imaging during the treatment phase will be within 1 week prior to or on the day of starting treatment cycle 5; subsequent imaging will be every 12 weeks (± 3days) thereafter during the treatment phase (i.e.  within 
1 week prior to or on the day of starting treatment C9D1, C13D1, C17D1,…etc). Scan at the end of treatment should be performed within 14 days of the visit. 
E 
Radiologic imaging to monitor disease status will be performed every 12 weeks (84 ± 7 days) for the first 24 months (year 1&2 of follow-up), then every 26 weeks (182 ± 14 days) for the next year after completing 
therapy (year 3 of follow-up).  After 3 years, patient will be followed clinically every 3-6 months with diagnostic imaging only as clinically indicated. 
F 
Peripheral blood samples will be collected immediately prior to the induction phase on day -21 (time 1); induction on day -7 (time 2); cycle 2 day 1, immediately prior to dose 2 (time 3); prior to dose 3, cycle 3  day 1 
(time 4); prior to dose 5, cycle 5 day 1 (time 5); prior to dose 9, cycle 9 day 1 (time 6); and at time of progression (time 7) or end of treatment due to toxicity. Blood for correlative studies must be collected from Mon-
Thurs so that it can be processed immediately at Fox Chase Cancer Center. Also, blood for correlative must not be collected a day before a holiday. Blood must reach Fox Chase Cancer Center on a working day. 
G 
Within 10 days of treatment initiation 
H 
Within 72 hours of treatment initiation if participant is a woman of child bearing potential. After that as per institutional practice.  
I 
Vital signs consist of temperature, pulse, respiration, and blood pressure and will be monitored every 15 minutes during the pembrolizumab infusion and for 60 minutes after completion of each infusion. Copanlisib 
administration will have blood pressure measured through observation period. 
J 
A direct bilirubin must be performed if the total bilirubin is above the upper limit of normal. Serum chemistry includes test for albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, potassium, sodium, total protein, SGOT [AST], SGPT [ALT]. 


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Trial Period: 
Screening Phase 
Induction Phase 
(Day -21 to -1) 
Treatment Cycles A 
End 
of 
Treat
ment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screenin
g  
Main 
Study 
Screeni
ng  
 
 
 
1 
2  
3 
4 
To be 
repeated 
after Cycle 
8 
At 
time 
of 
Disco
n 
Safety 
Follow-
up 
Follow 
Up Visits 
B  
Survival 
Follow-Up 
 
 
 
5-8 
 
Scheduling Window (Days): 
 
-50 to -
22 
Day 
-21 
Day  
-14 
Day 
-7 
D1 
± 3 
D8o 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
D1 
± 3 
D8 
± 3 
 
30 days 
post 
discon 
Every 12 
weeks 
post 
discon 
 
K 
Cell free DNA/ImmunoSeq TCR at baseline and every 12 weeks for 2 yrs then every 6 months for 1 yr and at time of progression or end of treatment due to toxicity 
L    For patients undergoing PET/CT, response will also be assessed using the 5-point scale (Deauville criteria).2 Refer to section 13 for measurements of effect. 
M  Blood glucose levels and Blood pressure measurement (not more than 4 per visit) must be done before copanlisib administration on day -21 and day -14 and conditions as described in section 5.2.2.2 must be met for 
drug administration during the induction phase alone. During copanlisib administration, blood pressure should be measured at 30 min (during infusion), and 60 min (end of infusion) from start of the infusion, 1 hr 
and 2 hr (after the infusion). 
N.  Patients in cohort 2 who will receive copanlisib must be fasting for at least 8 hours before the drug administration on Day -21 of the induction phase. Blood glucose level should be monitored and copanlisib may not 
be given if blood glucose level is higher than 160 mg/dl. Follow guidelines as described in section 5.2.2.2 for copanlisib administration. 
O. Day 8 treatment of each cycle with copanlisib may not take place (see section 4.2.3.1) if RP2D is dose level -1. If Day 8 treatment does not take place all visit related activities on day 8 will also not happen. 
P. Before starting copanlisib, all patients should have CMV status assessed. For seropositive patients, CMV quantitative polymerase chain reaction (PCR) testing with every cycle. Interrupt Copanlisib in patients with 
evidence of active CMV infection of any grade or viremia until the viremia has resolved. Ganciclovir or valganciclovir should be preemptively initiated in patients with positive CMV PCR and symptoms consistent with 
CMV infection, patients presenting with fever and no clear source in whom quantitative CMV testing is unavailable, and asymptomatic patients with increasing viral load. Patients can continue with pembrolizumab 
while copanlisib is being held. 
Q   In cohort 2, on the days when patients receive both the drugs, sequence of administration must be copanlisib, followed by pembrolizumab.  
 


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7.0 TRIAL PROCEDURES 
7.1 
 Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or Merck, 
Bayer for reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional 
informed consent be obtained from the subject.  In these cases, such evaluations/testing will be 
performed in accordance with those regulations. 
 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating in 
a clinical trial. 
 
7.1.1.1.1 
General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation in the 
trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB’s approval/favorable opinion in 
advance of use.  The subject or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial.  The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form that captures the 
subject’s dated signature or by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the protocol 
level.   
 
The informed consent will adhere to IRB requirements, applicable laws and regulations and Sponsor 
requirements. 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure 
that the subject qualifies for the trial.  
 


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7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history will include 
all active conditions, and any condition diagnosed within the prior 10 years that are considered to be 
clinically significant by the Investigator.  Details regarding the disease for which the subject has enrolled 
in this study will be recorded separately and not listed as medical history.   
 
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 
Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-specified 
washout requirement, and record prior medication taken by the subject within 28 days before starting 
the trial.  Treatment for the disease for which the subject has enrolled in this study will be recorded 
separately and not listed as a prior medication.  
 
7.1.1.4.2 
Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during the trial.  
All medications related to reportable SAEs and ECIs should be recorded as defined in Section 8.0. 
 
7.1.1.5 Disease Details and Treatments 
 
7.1.1.5.1 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
 
7.1.1.5.2 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
 
7.1.1.5.3 
Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the last 
dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days after the last dose 
of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose of the new therapy.  
Once new anti-cancer therapy has been initiated the subject will move into survival follow-up.  
 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or worsening 
AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  Adverse experiences 
will be graded and recorded throughout the study and during the follow-up period according to NCI 
CTCAE Version 5.0 (see Section 14.2).  Toxicities will be characterized in terms regarding seriousness, 
causality, toxicity grading, and action taken with regard to trial treatment.  
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to determine 
if it is possibly an event of clinical interest (ECI) of a potentially immunologic etiology (irAE).  See Section 


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5.4 regarding the identification, evaluation and management of AEs of a potential immunological 
etiology.   
 
Please refer to section 8.0 for detailed information regarding the assessment and recording of AEs.   
 
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history.  A full physical 
exam will also be performed every 3 cycles during the treatment phase, 30 days post treatment, and 
every 3 months during follow-up. 
 
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to trial treatment 
administration.   
 
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart (Section 
6.0).  Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure.  Height 
will be measured at screening only. 
 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 14.1) at screening, prior to 
the administration of each dose of trial treatment and discontinuation of trial treatment as specified in 
the Trial Flow Chart.  After Cycle 8 assessment of ECOG status will be performed every other cycle in 
conjunction with the directed or full physical exam. 
 
7.1.2.6 Tumor Imaging and Assessment of Disease 
Scans will be performed at baseline, and thereafter every 12 weeks (± 3 days) while on treatment.  
Imaging during follow up is outlined in section 7.1.5.4. It is critical that all FDG PET/CT or CT scans be 
performed in an identical way to the baseline scan with the same scan direction and consistent arm 
pointing. The interval between FDG injection and initiation of emission scanning should be the same or 
similar to the baseline scan. If tumor flare is suspected, the patient must undergo a second scan within 
a month of the first scan and the case must be discussed with the principle investigator. If progression is 
documented at that time, patient must come off study. A scan should be performed within 14 days of 
the end of treatment visit. 
 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 For details in regards to tumor tissue collection please see Section 7.1.3.1.2 Tumor tissue collection for 
central pathology review and correlative studies and the trial lab manual. 
 


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Peripheral blood samples will be collected immediately prior to the first dose of pembrolizumab (time 
1), at cycle 2 (immediately prior to dose 2; time 2) and cycle 3 (immediately prior to dose 3; time 3) and 
at time of progression (time 4) for correlative studies as outlined in Section 6.0 Trial Flow Chart.  
 
In evaluating the effect of the treatment on altering immunity, quantity of main interest is the change in 
the percentage of activated T cells and Natural Killer cells from Time 1 to Time 2, and from Time 2 or 
Time 3 to Time 4. 
 
The results of these studies are for the purposes of the trial only and will not be returned to the site or 
reported to the patient.  
 
Processing of blood samples will occur at FCCC as outlined in the Lab Manual. Blood samples will be 
shipped to Protocol Support Laboratory (PSL) at Fox Chase.  Samples will be distributed from the PSL at 
Fox Chase to Kerry Campbell’s lab. Remaining cells will be stored in the PSL.  
 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below.  
 
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   
 
Laboratory tests for screening should be performed within 10 days prior to the first dose of treatment.  
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing.  Results 
must be reviewed by the investigator or qualified designee and found to be acceptable prior to each 
dose of trial treatment.  
 
7.1.3.1 Biomarker Evaluations 
7.1.3.1.1 
Blood Collection for correlative studies/biomarkers 
Sample collection, processing, storage, and shipment instructions for samples will be provided in the 
trial Lab Manual. 
The time points for blood sampling for correlative studies are described in Section 6.0 – Trial Flow Chart. 
Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase 
(AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If 
abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide  
results are noted 
Free tyroxine (T4) 


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Hematology 
Chemistry 
Urinalysis 
Other 
 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone 
(TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper limit 
of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.   
 
7.1.3.1.2 
Tumor tissue collection for central pathology review and correlative studies 
Pathology samples from the confirmatory relapse biopsies taken within 28 days of enrollment are to be 
submitted within one (1) month following registration or collection. Representative FFPE tumor tissue 
blocks from confirmatory relapse specimen (MANDATORY) are to be submitted to the Fox Chase 
Cancer Center PSL in addition to any available specimens and reports from the original tumor biopsy at 
diagnosis.  
 
The following pathology material needs to be submitted: 
 Paraffin embedded biopsy or cell block, and  
 Any available pathology report related to that tumor sample, including flow cytometry, genetic 
and molecular reports.    
 
NOTE: If a block is unavailable for submission, slides are to be submitted. All slides must be adequately 
labeled, with slides numbered sequentially in the order cut. Alternative submission requirement:  
 One (1) H&E slide, and  
 Fifteen (15) 4 μm unstained air-dried on plus slides. 
 
Original diagnostic material (from initial diagnostic material) will also be reviewed at Fox Chase if 
available. These include: 
 Pathology reports of the initial tumor biopsy at diagnosis, including flow cytometry reports, 
cytogenetic and molecular reports, and  
 Any available H&E and IHC slides of the initial tumor biopsy at diagnosis. 
NOTE: Original material will be sent back to the referring institution. 
 


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Shipment of pathology samples is outlined in the lab manual for this trial. 
 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled for 
the final trial visit should be performed at the time of discontinuation.  Any adverse events, which are 
present at the time of discontinuation/withdrawal, should be followed in accordance with the safety 
requirements outlined in Section 8.0 - Assessing and Recording Adverse Events.  Subjects who a) attain 
a CR or b) complete 36 cycles of treatment with pembrolizumab may discontinue treatment with the 
option of restarting treatment if they meet the criteria specified in Section 5.1.  After discontinuing 
treatment following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described 
in Section 7.1.5.4). 
 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.    
 
7.1.5.1 Screening 
7.1.5.1.1 
Screening Period 
Subjects will be screened within 28 prior to protocol treatment. Study procedures and information 
regarding the nature of the study will be reviewed with potential subjects and written informed consent 
will be obtained prior to any study related procedures. Screening procedures are described in Section 
6.0 – Trial Flow Chart. 
 
7.1.5.2 Treatment Period 
Subjects will be treated every 3 weeks of pembrolizumab for up to 36 cycles. During the treatment phase 
patients will be evaluated prior to any treatment dose of pembrolizumab for toxicities and every 3 
months for disease progression as outlined in detail in Section 6.0 – Trial Flow Chart. 
 
7.1.5.3 Post-Treatment Visits 
7.1.5.3.1 
Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of 
trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs 
that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with a study drug attributable 
AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a 
new anti-neoplastic therapy, whichever occurs first.  Events of Clinical Interest that occur within 90 days 
of the end of treatment or before initiation of a new anti-cancer treatment should also be followed and 
recorded.   
 


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7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move into the 
Follow-Up Phase and should be assessed every 12 weeks (84 ± 7 days) for the first 2 years clinically for 
disease progression. Radiologic imaging (see Section 14.3 Measurement of Effect) to monitor disease 
status will be performed every 12 weeks (84 ± 7 days) for the first 24 months (year 1 & 2 of follow-up), 
then every 26 weeks (182 ± 14 days) for the next year after completing therapy (year 3 of follow-up).  
After 3 years patient will be followed clinically every 3-6 months with diagnostic imaging only as clinically 
indicated. Every effort should be made to collect information regarding disease status until the start of 
new anti-neoplastic therapy, disease progression, death, end of the study or if the subject begins 
retreatment with pembrolizumab as detailed in Section 5.8.  Information regarding post-study anti-
neoplastic treatment will be collected if new treatment is initiated. 
 
7.1.5.4.1 
Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase. Survival follow-up will take place approximately every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first. This contact can be done by telephone, medical record search, office visit, etc.  
After 3 years of follow-up this contact can go to every 6 month.  
 
8.0 Assessing and Recording Adverse Events 
Adverse Events (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the use of a medicinal (investigational) product, 
treatment or procedure regardless of whether it is considered related to the medical treatment or 
procedure (NCI CTEP Guidelines March 28, 2011)  
 
Serious Adverse Event (SAE) is an AE that results in the following outcomes- 
 
 Death 
 Life threatening adverse event 
 Requires inpatient hospitalization or prolongation of existing hospitalization (for > 24 
hours),  
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
 Congenital anomaly/ birth defect.  
 
A “life-threatening” adverse event places the patient at immediate risk of death in the 
judgment of the investigator or sponsor. 
 
NOTE: Important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent any of the above 
outcomes.   


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8.1 
Severity Rating  
The investigator will evaluate the severity of each adverse event.  NCI Common Terminology Criteria 
for Adverse Events (CTCAE v.5.0) or study specific toxicity tables provided in the protocol define 
severity.  If not included in CTCAE v.5.0, severity is expressed in numerical grade using the following 
definitions: 
 
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 ADL. 
 
Grade 3: Severe-severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4: Life-threatening consequences; urgent intervention indicated.  
 
Grade 5: Death related to AE 
 
8.2 
Attribution/Relationship to study drug  
 Definite – clearly related 
 Probable – likely related 
 Possible – may be related 
 Unlikely – doubtfully related 
 Unrelated – clearly not related 
 
8.3 
Expectedness 
 An Expected Adverse Event is one where the specificity or severity is consistent with the current 
information available from the resources. 
An Unexpected Adverse Event is one where the nature, severity, or frequency of the event is related to 
participation in the research is not consistent with either: 
 
1. The known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in (a) the protocol-related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-approved 
informed consent document, and (b) other relevant sources of information, such as product 
labeling and package inserts: or 
 
2. The expected natural progression of any underlying disease, disorder, or condition of the 
subject (s) experiencing the adverse event and the subjects(s) predisposing risk factor profile 
for the adverse event. 
       (OHRP Guidance on reviewing unanticipated problems 2007) 
 


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9.0 RECORDING AND REPORTING RESPONSIBILITIES 
9.1.1 Investigative Site Recording Responsibilities: 
1. Upon identification of an AE or SAE, the site investigator will utilize the above 
definitions to properly classify attribution and expectedness of the event.  These must 
be recorded for each event. 
 
2. All AEs and SAEs will be recorded in the “AE case report forms” (CRF) and in progress 
reports with details about the grade and attribution of each episode, action taken with 
respect to the study drug, and the patient’s outcome will be recorded in the CRF.  All 
events will be recorded on case report forms for the duration of the study until they 
resolve. 
 
3. All SAEs will be recorded on the FDA MedWatch form 3500a. The attribution and 
expectedness must be recorded on the MedWatch form. If this information is not 
available at the time of initial reporting, a final report must be documented with 
attribution and expectedness.  It may be necessary to submit follow up reports to the 
Sponsor should the event require further investigation. All subsequent SAEs must be 
recorded for up to 30 days after the last treatment. 
 
4. All patient data must be recorded in eCRFs by the investigative site within 7 days of the 
patient’s visit. eCRFs will be available through Oncore electronic data capture system. 
 
9.1.2  Investigative Site Reporting Responsibilities: 
1. The investigator/ site is responsible to report all SAEs that occur on or after the first 
day of study treatment to the sponsor within 24 hours of becoming aware of the 
event. It may be necessary to submit a final SAE report if the initial report did not 
have the complete information. All subsequent SAEs must be recorded for up to 30 
days after the last treatment.  
 
 
Each investigator is responsible to report all AEs/SAEs to their local IRB following 
guidelines set by that IRB.  The FCCC OCR reserves the right to request an event be 
reported to the IRB at their discretion.  Copies of events reviewed by the IRB must 
be sent by email to SAE.FCCC@fccc.edu. 
 
2. If the investigator or IRB feels the event warrants a revision to the informed consent 
that was not already initiated by the ISRU, draft revisions will be made in track 
changes and submitted to the ISRU for consideration.  Any consent revisions must 
receive ISRU approval prior to submission to the IRB. 
 
3. Any investigator who is in doubt of whether a particular AE needs to be reported is 
directed to call the Study Monitor for confirmation with the Sponsor-Investigator 
 
4. If the results of an investigator or ISRU investigation show an adverse event not 
initially determined to be reportable is so reportable (to IRB or FDA), the investigator 


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will report the event following the above guidelines based on the date the 
determination is made. 
 
5. Investigative site should report Reportable New Information (RNI) to their local IRB 
according to the local IRB guidelines. This information should also be sent to ISRU. At 
minimum serious unexpected events that are associated with the treatment are 
considered to be reportable. Expected AEs that are experienced at a higher 
frequency or severity than expected in the patient population according to the 
investigator brochure are considered to be reportable. 
 
6. Copies of all related correspondence and reporting documents must be submitted to 
the ISRU and will be maintained in the trial master file.  
 
 
                                Participating sites should report events to: 
 
Investigator-Sponsored Research Unit 
Office of Clinical Research 
  
           Fox Chase Cancer Center 
SAE.FCCC@fccc.edu 
 
9.1.3 Sponsor Reporting Responsibilities: 
 Adverse events which meet all of the following criteria must be reported to all 
participating institutions for IRB submission within 2 weeks of notification of the 
event.   
 Unexpected (in terms of nature, severity, or frequency) given  
i. (a) the research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and  
ii. (b) the characteristics of the subject population being studied; 
 Possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
 Serious (refer to above definition) or otherwise one that suggests that the 
research places subjects or others at a greater risk of physical or psychological 
harm than was previously known or recognized. 
 If the adverse event requires modification of the study protocol and informed consent, 
these changes will be provided to all participating institutions in the form of an 
amendment from the ISRU for each site’s IRB of record along with the report of the 
adverse event.   
 All participating sites must be notified of all amendments approved by FCCC IRB; or if 
the study is suspended such that the participating sites cannot accrue patients in the 
study until further notification. 
 All participating sites must be notified when the study is closed by IRB. 


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 Copies of all related correspondence and reporting documents will be maintained in a 
centralized regulatory file for this study at ISRU. 
 SAEs that are fatal or life threatening are reportable through the Food and Drug 
Administration (FDA) MedWatch program by telephone or fax no later than 7 calendar 
days after initial receipt of the information. Further information on the timing of 
submissions are as directed by FDA guidelines can be found in the following link: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedan
dApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm362555
.htm.    
 
SAEs that are serious, unexpected and at least possibly related to the study drug 
(unexpected suspected adverse events) or events that suggest significant clinical risk 
will be submitted to FDA within 15 calendar days after initial receipt of this 
information. The 15 day report has to be submitted by in paper format (or electronic 
submission if that is available) to the IND as described in the “safe to proceed” letter. 
 
The FAX number for reporting SAE to FDA (7-day reporting) can be found in the FDA 
“Study may proceed” letter.  
 
The SAE report can also be submitted by email to the Regulatory Project Manager 
and/or the Chief, Project Management Staff described in the “Study May Proceed” 
letter. 
 
 Reportable New Information (RNI) to IRB according to the IRB guidelines. This 
information should also be sent to all participating sites if associated with safety 
concern. At minimum serious unexpected events that are associated with the treatment 
are considered to be reportable. Expected AEs that are experienced at a higher 
frequency or severity than expected in the patient population according to the 
investigator brochure are considered to be reportable. 
 All SAEs and reports of overdose with and without an adverse event will be reported to 
Merck Global Safety within 2 working days of receipt. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) 
 A copy of all Annual Progress Reports submitted as required by FDA and non-
serious Events of Clinical Interest will be forwarded to Merck Global Safety and 
will be handled in the same manner as SAEs.  
 As soon as there is reasonable suspicion of the following AE, the investigator should 
immediately notify Bayer (within 24 hours) regardless of whether the event is assessed 
as causally related/not related to the study drug, or as serious/non-serious. The AESI 
should be entered on a Medwatch form and if the event is assessed as non-serious, the 
non-serious assessment should be noted in the form. 
 Non-infectious pneumonitis (NIP) 
 The following should be reported within 24 hours after the initial receipt of information 
to BAYER by fax and/or e-mail: (973) 709-2185; DrugSafety.GPV.US@bayer.com 


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 All Serious Adverse Events occurring after start of administration of BAYER 
product, independent of their causal relationship to the STUDY DRUG 
 Any other relevant safety information including but not limited to: 
i. reports of drug exposure via mother / father with and without adverse 
events (exposure during conception, pregnancy, childbirth and 
breastfeeding) including their outcome; 
ii. if linked to a serious adverse event, reports of misuse, abuse, overdose, 
medication error and other uses outside what is foreseen in the protocol, 
drug dependency, occupational exposure suspected transmission of an 
infectious agent, withdrawal syndrome, drug interactions with respect 
to the STUDY DRUG; 
                                  and 
 Any communication concerning safety related information to regulatory 
authorities or ethics committees including but not limited to: 
 Development Safety Update Reports / relevant parts of IND reports for the 
STUDY; 
 Any other safety related reports, issues and queries that are either raised by or 
communicated to regulatory authorities or ethics committees (e.g., reportable 
non-serious cases); 
 
9.2 
Definition of an Overdose  
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for 
pembrolizumab by 20% over the prescribed dose. No specific information is available on the treatment 
of overdose of pembrolizumab. In the event of overdose, pembrolizumab should be discontinued and 
the subject should be observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the adverse 
event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of 
Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse effect.” 
 
9.3 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and 
must be recorded as such on the Adverse Event case report forms/worksheets and reported within 24 
hours to the Sponsor, who will report this information within 2 working days to Merck Global Safety. 
 
Events of clinical interest for this trial include: 


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1.  An overdose of Merck product, as defined in Section 9.2, that is not associated with clinical symptoms 
or abnormal laboratory results.  
2.  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. 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event should be 
reported as an ECI to the Sponsor within 24 hours, who will report this information within 2 working 
days to Merck Global Safety: 
 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥ 3 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or hyperthyroidism 
 
A comprehensive list of ECI is also provided in the appendix (Appendix 13.4 - Events of Clinical Interest 
(ECI) guidance). This appendix provides guidance regarding identification, evaluation and management 
of ECIs and irAEs.  Additional ECIs are identified in this guidance document and also need to be reported 
to the Sponsor within 24 hours, who will report this information within 2 working days to Merck Global 
Safety.   
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be evaluated and 
subjects should be asked for signs and symptoms suggestive of an immune-related event.  Subjects who 
develop an ECI thought to be immune-related should have additional testing to rule out other etiologic 
causes.  If lab results or symptoms indicate a possible immune-related ECI, then additional testing should 
be performed to rule out other etiologic causes.  If no other cause is found, then it is assumed to be 
immune-related.  
 
ECIs that occur in any subject from the date of first dose through 90 days following cessation of 
treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not related to 
the Merck’s product, must be reported within 24 hours to the Sponsor, who will report this information 
within 2 working days to Merck Global Safety. 
 
9.4 
Reporting of Pregnancy and Lactation to the Sponsor-Investigator and to Merck and Bayer 
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), that occurs during the trial or within 120 days of completing the trial completing the 
trial, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier.  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 events (Important Medical Events).  If the pregnancy continues to term, the outcome (health of 
infant) must also be reported to Merck and Bayer. 
 


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10.0 STATISTICAL ANALYSIS PLAN 
10.1 Statistical Analysis Plan (cohort 1) 
The primary endpoint is based on the median progression free survival (PFS). Estimates are based on 
historical controls from published data.31,33,34,78 We will test the null hypothesis that median PFS is at 
most 3 months versus the alternative that it is at least 6 months. We will use a two-stage design with 
early stopping rules79 and enroll an initial cohort of 13 patients. We will terminate the study for futility 
unless more than 6 patients are progression-free (as defined alive and achieving SD, PR or CR as per 
revised Cheson response criteria) at 3 months. Otherwise we will recruit an additional 11 patients and 
evaluate these 11 plus all eligible patients from the initial cohort (n=13) who were progression-free at 3 
months at 6 months. If at least 10 out of 24 patients have not progressed at 6 months we will reject the 
null hypothesis. Only those patients who have measurable disease present at baseline, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. (Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will also 
be considered evaluable.) Patients who are not evaluable for response will be replaced. However, all 
patients who received at least 1 dose of the study drug will be included in the safety analysis. The study 
has 80% power and 4.7% type I error. The chance of early stopping, after 13 patients, is 50% under the 
null and 5.5% in error.  
 
Early stopping rules for safety/adverse events:  
Adverse events will be assessed continuously throughout the study. If ever during evaluation of the first 
cohort of 13 eligible patients, 3 patients have to discontinue study treatment due to treatment related 
adverse events the study will be interrupted for consideration of dose reduction or termination. If ever 
4 of the 24 eligible patients have to discontinue study treatment due to treatment related adverse events 
the study will be suspended and early termination for excess toxicity will be considered after careful 
investigation of the causes of the higher than expected toxicities. Once the root of the higher than 
anticipated toxicities has been determined, the study team will confer with the FCCC DSMC and IRB to 
make a determination whether accrual can be resumed or the study will be terminated early. The chance 
of early termination with a true toxicity of 25% is 67%. The chance of early termination when true toxicity 
is 5% is 2.5%. The overall chance of study termination under the null of 5% true toxicity is 4.2% and is 
89% if true toxicity is 25%.  
 
Correlative studies: Due to this limited sample size, all exploratory analyses of associations of biomarkers 
with outcomes and changes in marker levels pre- and during treatment will be largely descriptive in 
nature. Multiple imputation will be used to account for missing data in order to provide an unbiased 
estimate.  
 
 
10.2 Statistical Analyses Plan (cohort 2) 
There will be a phase 1 part (cohort 2a), during which the recommended phase 2 dose (RPTD) of the 
combination of pembrolizumab and copanlisib will be determined, followed by a phase 2 portion (cohort 
2b), which will explore safety and efficacy of the combination. The phase 1 portion will follow a standard 
‘3+3’ escalation/de-escalation design as outlined above. A minimum of 4 and a maximum of 12 patients 
will be included in the phase 1 portion. For the phase 2 portion, an optimal Simon’s two-stage design 
will be used. The null hypothesis that the true response rate is 30% will be tested against the alternative 


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hypothesis of a true response rate ≥60%. Response is defined as either a partial or complete response 
by Revised Cheson criteria (see 13.3) by 4 cycles of treatment. All eligible and evaluable patients who 
received at least 1 dose of the combination regimen will be included in this response analysis. Patients 
who come off study prior to second clinic visit for reasons other than progressive disease will be 
replaced. Patients who are lost to follow-up after re-evaluation will be counted as failures and will not 
be replaced. For the first stage, 8 patients will be treated at the RPTD of the combination. If at least 4 
patients achieve a response, we will accrue 16 more for a total of 24 patients treated at the RPTD 
(including those patients treated during the phase 1 portion at the RPTD). If of the first 8 patients, 3 or 
less respond, the trial will be stopped. The null hypothesis will be rejected if 11 or more responses are 
observed in 24 patients and the combination deemed worthy of further consideration. This design yields 
a power of 80% with a type I error of 5% when the true response rate is ≥60% ORR. The probability of 
early stopping under the null hypothesis is 80%. 
 
Early stopping rules for safety/adverse events: A discontinuation rate for toxicities related to study 
treatment of ≤30% will be deemed acceptable, while a ≥50% discontinuation rate for toxicities related 
to study treatment will be considered unacceptable. An interim analysis will be conducted when 8 
patients have accrued to determine safety by the Principal Investigator and the statistician. If ≥4 of the 
initial 8 treated patients at the RPTD discontinue due to study related toxicities, the study will be stopped 
for safety. If after 24 patients have been enrolled, or at any time point during the study with treatment 
at the RPTD, 11 or more patients discontinue due to study related toxicities, the study will also be 
stopped for safety. With this design, the probability of stopping early with a ≥50% true toxicity rate is 
64%, and 19% if the true toxicity is ≤30%. The probability of stopping at any point due to a ≥50% true 
toxicity rate is 82%, while it is ≤22% if the true toxicity is 30%. 
 
Accrual: The expected monthly accrual rate is 1-2 patients. Thus, accrual is anticipated to take 
approximately 2.5 years. 
 
11.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
11.1 Investigational Product  
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. 
 
Pembrolizumab will be provided by Merck and copanlisib will be provided by Bayer as summarized in 
Table 6. 
Table 6 Product Descriptions 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4 mL 
Solution for Injection 
Copanlisib 60 mg/vial 
Solution for Injection 
 


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11.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
11.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are 
not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
 
11.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
 
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. 
 
11.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from Merck, 
Bayer or designee, the amount dispensed to and returned by the subjects 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. 
 
12.0 Administrative, Regulatory, Data Monitoring and Safety Details 
12.1 Monitoring Plan  
FCCC ISRU will monitor the medical and study records of each participant accrued throughout the course 
of the study.  In addition, the ISRU will collect and report data to the study Sponsor Investigator who will 
review these data on a regular basis at a rate dependent on subject accrual.  All serious adverse events 
(SAEs) will be reviewed on a real time basis first by the study site PI and subsequently by the ISRU and 
Sponsor Investigator as applicable. 
 
12.2 Data Safety Monitoring Committee 
Interim analysis of toxicity, outcome and ongoing scientific investigations will be performed at least 
every 3 months by the Fox Chase Cancer Center Data Safety Monitoring Committee (FCCCDSMC).  In this 
capacity the FCCCDSMC will serve as an advisory committee to the OCR.  The FCCCDSMC will review 
those aspects of this trial that are outlined in the responsibilities section of the Data and Safety 
Monitoring Plan (DSMP).  If the committee decides that changes should be made to this trial, it will make 
recommendations in writing to the Study Principal Investigator, the Associate Director of Clinical 


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Research, and the Protocol Management Executive Committee, which, in turn, have the authority to 
approve or disapprove these recommendations.  These changes will be discussed with the Study 
Principal Investigator before they are implemented.  These changes may include early termination of 
accrual.  Other changes might include altering the accrual goals or changing the eligibility criteria for the 
trial. 
 
12.3 Compliance with Law, Audit and Debarment 
This study will be conducted in accordance will local, state and Federal regulations and according to 
accepted good clinical practice guidelines. 
 
12.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible for 
determining whether the trial and its results are subject to the requirements for submission to the 
Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate trial locations and trial site contact information.     
 
12.5 Retention of Records 
Time points for the retention of records are described in detail in the contract between the grantor and 
the CTO and passed on to the participating site.  Please refer to the study specific terms for specific time 
points.  In all cases the QA Specialist / Study Monitor must be notified of any plans to move records to 
an offsite location prior to doing so. 
 
12.6 Study Agents 
Any study agent supplied through the CTO from the manufacturer or a third party distributor may not 
be used for any purpose outside the scope of this protocol.  The agent may not be transferred to any 
party not participating in the clinical trial. 
 
12.7 Informed Consent 
The IRB approved informed consent documents must be signed by the patient, or the patient’s legally 
authorized representative, before his or her participation in the study.  The case history for each patient 
shall document that informed consent was obtained prior to participation in the study.  A copy of the 
informed consent documents must be provided to the patient or the patient’s legally authorized 
representative.  If applicable, they will be provided in a certified translation of the local language. 
 
Original signed consent forms must be filed in each patient’s study file or medical record with a copy in 
the study file. 
 


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12.8 Data Reporting 
The FCCC Study Monitor will request case report forms to be completed within 2 weeks of the protocol 
visit.  Participating sites are responsible to respond to queries prior to the next scheduled monitoring 
visit. 
 
The ISRU staff is responsible for compiling and submitting data to the Sponsor Investigator and 
statistician on an ongoing basis for monitoring as described in the data safety monitoring plan and 
reporting to the Data and Safety Monitoring Committee. 
 
All patient information will be stored in an EDC system accessible only to the study team members for 
the purpose of entering, reviewing and analyzing data.  Any paper records, such as case report files, 
produced will be stored in a secure location.  
 
 
 


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tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
 
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to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res 15:6341-7, 
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14.0 
 APPENDICES 
14.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., 
Group Chair. 
 
 
14.2 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events 
(CTCAE) 
version 
5.0 
will 
be 
utilized 
for 
adverse 
event 
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 


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14.3 Measurement of Effect  
Revised Cheson Lymphoma Response Criteria  
 
NOTE: These criteria are based upon the criteria from the Revised Response Criteria for Malignant 
Lymphoma, (Cheson et al.), Journal of Clinical Oncology, 2007, Vol. 25:579-586.  
 
The criteria use the following categories of response: Complete Response (CR), Partial Response (PR), 
Stable Disease (SD), Relapse and Progression (PD). In the case of stable disease, follow-up assessments 
must have met the SD criteria at least once after study entry at a minimum interval of six weeks.  
The following guidelines are to be used for establishing tumor measurements at baseline and for 
subsequent comparison:  
 The six largest dominant nodes or extranodal masses must be identified at baseline.  
 If there are 6 or fewer nodes and extranodal masses, all must be listed as dominant  
 If there are more than 6 involved nodes or extranodal masses, the 6 largest dominant nodes or 
extranodal masses should be selected according to the following features: a) they should be 
clearly measurable in at least two perpendicular measurements; b) they should be from as 
disparate regions of the body as possible; and c) they should include mediastinal and 
retroperitoneal areas of disease whenever these sites are involved.  
 Measurements for all dominant nodes and extranodal masses will be reported at baseline. 
Measurements on non-dominant nodes are not required.  
 The lymph nodes or extranodal masses selected for measurement should be measured in two 
perpendicular diameters, one of which is the longest perpendicular diameter. The lymph nodes 
should be measured in centimeters to the nearest one tenth of a centimeter (e.g.,2.0 cm, 
2.1cm, 2.2 cm, etc.)  
 The two measured diameters of each lymph node site or extranodal mass should be multiplied 
giving a product for each nodal site or extranodal mass. The product of each nodal site should 
be added, yielding the sum of products of the diameters (SPD). The SPD will be used in 
determining the definition of response for those who have less than a complete response.  
 Patients should be assessed with PET/CTs. Where PET is not available, response should be 
assessed as above, but only using CT scans. However, residual masses should not be assigned 
CRu status, but should be considered partial responses. 
 For patients undergoing PET/CT, tumor assessment at all timepoints should also include the 5-
point scale (Deauville criteria) as an adjunct to the Cheson criteria.2 Scoring guidelines for the 5-
point scale are below. A score of 1, 2, or 3 indicates a complete metabolic response. Refer to 
section 14.3.1 for further definition of complete response. 
 
1 
No uptake 
2 
≤ Mediastinal blood pool 
3 
> Mediastinum and ≤ liver 
4 
Moderately > liver at any site 
5 
Markedly increased uptake above liver and/or 
new sites of disease 
X 
New areas of uptake unlikely to be related to 
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14.3.1 Complete Response  
Complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if 
present prior to therapy.  
 
In patients with a typically FDG-avid lymphoma with no pre-treatment PET scan, or for lymphomas for 
which the PET scan was positive prior to therapy: a post-treatment residual mass of any size is 
permitted as long as it is PET-negative. 
 
For variably FDG-avid lymphomas without a pretreatment PET scan, or if a pretreatment PET scan was 
negative: all lymph nodes and extranodal masses must have regressed on CT to normal size (≤ 1.5 cm in 
their greatest transverse diameter for nodes > 1.5 cm prior to therapy). Previously involved nodes that 
were 1.1-1.5 cm in their long axis and > 1.0 cm in their short axis prior to treatment must have 
decreased to ≤ 1 cm in their short axis after treatment 
 
The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical examination 
or CT scan, should not be palpable on physical examination, and nodules related to lymphoma should 
disappear. However, no normal size can be specified because of the difficulties in accurately evaluating 
splenic and hepatic size and involvement. For instance, a spleen considered normal size may contain 
lymphoma, whereas an enlarged spleen may not necessarily reflect the presence of lymphoma, but 
variations in anatomy, blood volume, the use of hematopoietic growth factors, or other causes.  
 
NOTE: Complete Remission/unconfirmed (CRu): Using the above definition for CR and that below for 
PR eliminates the category of CRu.  
 
14.3.2 Partial Response (PR)  
The designation of PR requires all of the following: A ≥ 50% decrease in sum of the product of the 
diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses.  
 
No increase in the size of other nodes, liver or spleen.  
 
No new sites of disease.  
 
For a typically FDG-avid lymphoma with no pretreatment PET scan or one that was PET-positive prior 
to therapy, the post-treatment PET should be positive at any previously involved sites.  
 
For variably FDG-avid lymphomas/FDG-avidity unknown, without a pre-treatment PET scan, or if a 
pretreatment PET scan was negative, CT scan criteria should be used.  
 
Patients who achieve a CR by the above criteria, but who have persistent morphologic bone marrow 
involvement will be considered partial responders.  
 
When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone 
marrow assessment after treatment, patients should be considered partial responders.  


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14.3.3 Stable Disease (SD)  
Failing to attain the criteria needed for a PR or CR, but not fulfilling those for progressive disease (see 
below).  
 
Typically FGD-avid lymphomas: The PET should be positive at prior sites of disease with no new areas 
of involvement on the post-treatment CT or PET.  
 
 For variably FDG-avid lymphomas/FDG-avidity unknown: For patients without a pretreatment PET scan 
or if the pre-treatment PET was negative, there must be no change in the size of the previous lesions 
on the post-treatment CT scan.  
 
14.3.4 Progression (PD) and Relapse  
For determination of relapsed and progressive disease, lymph nodes should be considered abnormal if 
the long axis is more than 1.5 cm, regardless of the short axis. If a lymph node has a long axis of 1.1 to 
1.5 cm, it should only be considered abnormal if the short axis is more than 1 cm. Lymph nodes ≤ 1 x ≤ 
1 cm will not be considered as abnormal for relapse or progressive disease.  
 
Treatment decisions in patients with presumed refractory, relapsed or progressive disease should not 
be made solely on the basis of a single PET scan without histologic confirmation.  
 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if 
other lesions are decreasing in size.  
 
Increased FDG uptake in a previously unaffected site should only be considered relapsed or progressive 
disease after confirmation with other modalities. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. Thus, a therapeutic decision should 
not be made solely on the basis of the PET without histologic confirmation.  
 
At least a 50% increase from nadir in the SPD of any previously involved nodes or extranodal masses, 
or in a single involved node or extranodal mass, or the size of other lesions (e.g. splenic or hepatic 
nodules). To be considered progressive disease, a lymph node or extranodal mass with a diameter of 
the short axis of less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 cm x 1.5 cm or more than 
1.5 cm in the long axis.  
 
At least a 50% increase in the longest diameter of any single previously identified node or extranodal 
mass more than 1 cm in its short axis.  
 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET 
positive before therapy unless the lesion is too small to be detected with current PET systems (< 1.5 cm 
in its long axis by CT).  
 
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. For 
these response criteria, the spleen is considered nodal disease. Disease that is only assessable (e.g., 


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pleural effusions, bone lesions) will be recorded as present or absent only, unless, while an 
abnormality is still noted by imaging studies or physical examination, it is found to be histologically 
negative. 
 
14.3.5 Response Endpoints  
All tumor assessments will be made using Revised Response (Cheson) criteria.  
 
Pembrolizumab is expected to trigger immune-mediated responses, which require activation of the 
immune system prior to the observation of clinical responses. Such immune activation may take weeks 
to months to be evident. Some patients may experience tumor flare with objective volume increase of 
tumor lesions or other disease parameters (based on study indication, ie, hematologic malignancies) 
within 12 weeks following the start of pembrolizumab dosing. Such patients may not have had 
sufficient time to develop the required immune activation or, in some patients, tumor volume or other 
disease parameter increases may represent infiltration of lymphocytes into the original tumor or 
blood. In conventional studies, such tumor volume or relevant laboratory parameter increases during 
the first 12 weeks of the study would constitute PD and lead to discontinuation of imaging to detect 
response, thus disregarding the potential for subsequent immune-mediated clinical response.  
Therefore if at the first imaging time point (12 weeks after initiating treatment) patients demonstrate 
up to 2 new lesions, with sum of all lesions < 70% greater than baseline by SPD, or decreasing in size, 
and stable without evidence of rapid clinical deterioration, patients may be continue to be treated with 
pembrolizumab and clinically observed with imaging repeated after 1 month. If, at that time, there is 
Progression of Disease (POD) by standard Revised Response Criteria patients will be removed from 
study. For patients in whom investigators consider that tumor flare may be playing a role in the 
response seen on initial imaging, this must be documented at time of scan, and discussed with Study 
Chair. This may improve the overall assessment of the clinical activity of pembrolizumab and more 
likely capture its true potential to induce clinical responses. In regards to PFS analysis, the date of 
progression for patients who were initially considered to have tumor flare, but had further progression 
of disease (POD) on the repeat image after 1 month, will be the time of first imaging in which new 
lesions were originally detected. 
 
14.3.6 Duration of Response  
This is measured from the documented beginning of response (CR or PR) to the time of relapse. This is 
measured in responders.  
 
14.3.7 Overall Survival  
Overall survival is defined as the date of study entry to the date of death.  
 
14.3.8 Progression-free Survival 
Progression-free Survival (PFS) is defined as the time from entry onto study until lymphoma progression 
or death from any cause. PFS is often considered the preferable endpoint in lymphoma clinical trials. PFS 
reflects tumor growth and, therefore, occurs prior to the endpoint of overall survival. In addition, PFS is 
not confounded by the administration of subsequent therapy. Whether a prolongation of PFS represents 
direct clinical benefit or a surrogate for clinical benefit depends on the magnitude of the effect and the 


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risk-benefit ratio of the therapy under investigation. Unlike survival, the precise date of progression is 
generally unknown. It may be defined as the first date of documentation of a new lesion or enlargement 
of a previous lesion, or the date of the scheduled clinic visit immediately after radiologic assessment has 
been completed. Where there is missing information, censoring of the data may be defined as the last 
date at which progression status was adequately assessed or the first date of unscheduled new anti-
lymphoma treatment. 
 
 
 


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14.4 Events of Clinical Interest (ECI) guidance 
This appendix offers specific guidance for investigators for the management of ECI based on the 
“PEMBROLIZUMAB PROGRAM (MK-3475) EVENT OF CLINICAL INTEREST 
GUIDANCE DOCUMENT Version 5.0”.  
 
These recommendations should be seen as guidelines and the treating physician should exercise 
individual clinical judgment based on the patient. For any question of dose modification or other 
treatment options, the specific language in the protocol should be followed.  
 
The treatment guidance provides specific direction when to hold and/or discontinue pembrolizumab 
for each immune related adverse event. Of note, when the guidance states to “discontinue” 
pembrolizumab this is the permanent discontinuation of treatment with pembrolizumab. “Hold” 
means to stop treating with pembrolizumab but resumption of treatment may be considered assuming 
the patient meets the criteria for resumption of treatment. 
 


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14.4.1 List of ECI 
 
14.4.2 Pneumonitis 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
– Pneumonitis 
– Interstitial lung disease 


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– Acute interstitial pneumonitis 
 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a 
cardiology consultation should be considered. All attempts should be made to rule out other causes 
such as metastatic disease, bacterial or viral infection. It is important that patients with a suspected 
diagnosis of pneumonitis be managed as per the guidance below until treatment-related pneumonitis 
is excluded. Treatment of both a potential infectious etiology and pneumonitis in parallel may be 
warranted. Management of the treatment of suspected pneumonitis with steroid treatment should 
not be delayed for a therapeutic trial of antibiotics. If an alternative diagnosis is established, the 
patient does not require management as below; however, the AE should be reported regardless of 
etiology. 
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab. 
– Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
– Consider ID consult 
– Conduct an in person evaluation approximately twice per week 
– Consider frequent Chest X-ray as part of monitoring 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the patient 
develops a second episode of Grade 2 or higher pneumonitis. 
 
Grade 3 and 4 events: 
– Report as ECI 
– Discontinue pembrolizumab. 
– Hospitalize patient 
– Bronchoscopy with biopsy and/or BAL is recommended. 
– Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When 
symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg once 
per day or dexamethasone 4 mg every 4 hours) taper should be started and continued over no 
less than 4 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 
to 72 hours, treat with additional anti-inflammatory measures. Discontinue additional anti-
inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 
60 days. If symptoms worsen during steroid reduction, initiate a retapering of steroids starting 
at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer additional 
anti-inflammatory measures, as needed 
– Add prophylactic antibiotics for opportunistic infections. 
 


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14.4.3 Colitis 
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of systemic 
steroids to treat the AE, are considered ECIs and should be reported to the Sponsor within 24 hours of 
the event: 
– Colitis 
– Colitis microscopic 
– Enterocolitis 
– Enterocolitis hemorrhagic 
– Gastrointestinal perforation 
– Intestinal obstruction 
– Necrotizing colitis 
– Diarrhea 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or parasitic 
infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel disease by 
examination for stool leukocytes, stool cultures, a Clostridium difficile titer and endoscopy. However 
the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 hours, 
abdominal pain, mucus or blood in stool): 
– Report as ECI 
– Hold pembrolizumab. 
– Symptomatic Treatment 
– For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood and/or 
mucus, 
o Consider GI consultation and endoscopy to confirm or rule out colitis 
o Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
– When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– If symptoms worsen or persist > 3 days treat as Grade 3 
 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week): 
– Report as ECI 
– Hold pembrolizumab. 
– Rule out bowel perforation. Imaging with plain films or CT can be useful. 
– Recommend consultation with Gastroenterologist and confirmation biopsy with endoscopy. 
– Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral 
steroids 
(prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
Taper over 6 to 8 weeks in patients with diffuse and severe ulceration and/or bleeding. 


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– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 
to 72 hours, consider treatment with additional anti-inflammatory measures as described in the 
literature [5]. 
Discontinue additional anti-inflammatory measures upon symptom relief and initiate a 
prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, 
initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed by a more 
prolonged taper and administer additional anti-inflammatory measures as needed. 
 
Grade 4 events: 
– Report as ECI 
– Permanently discontinue pembrolizumab. 
– Manage as per Grade 3. 
 
14.4.4 Endocrine 
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require 
holding/discontinuation/modification of pembrolizumab dosing, are considered ECIs and should be 
reported to the Sponsor within 24 hours of the event: 
 
– Adrenal insufficiency 
– Hyperthyroidism 
– Hypophysitis 
– Hypopituitarism 
– Hypothyroidism 
– Thyroid disorder 
– Thyroiditis 
 
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or infection. 
However, the AE should be reported regardless of etiology. 
 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or hyperthyroidism 
 
Grade 2-4 events: 
– Report as ECI if appropriate 
– Hold pembrolizumab 
– Rule out infection and sepsis with appropriate cultures and imaging. 
– Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– Pituitary gland imaging should be considered (MRIs with gadolinium and selective cuts of the 
pituitary can show enlargement or heterogeneity and confirm the diagnosis). 
– Treat with prednisone 40 mg p.o. or equivalent per day. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 


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– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– Hypophysitis with clinically significant adrenal insufficiency and hypotension, dehydration, 
and electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes adrenal 
crisis. 
– Consultation with an endocrinologist may be considered. 
 
14.4.5 Hyperthyroidism and Hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events: 
– Report as ECI if appropriate (see Table 1) 
– Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. 
– Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is 
instituted. 
– In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy. 
– In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
– Consultation with an endocrinologist may be considered. 
 
Grade 3 hyperthyroidism events: 
– Report as ECI 
– Hold pembrolizumab. 
– Rule out infection and sepsis with appropriate cultures and imaging. 
– Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by oral 
prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 hyperthyroidism events: 
– Report as ECI 
– Discontinue pembrolizumab. 
– Manage as per Grade 3 
 
14.4.6 Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia 
The following AE terms are considered ECIs and should be reported to the Sponsor within 24 hours of 
the event: 


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– Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA) 
– Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA). Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt 
worsening of preexisting diabetes associated with laboratorial evidence of beta cell failure. All 
attempts should be made to rule out other causes such as type 2 diabetes mellitus (T2DM), 
T2DM decompensation, steroid-induced diabetes, physiologic stress-induced diabetes, or 
poorly controlled pre-existing diabetes (either T1DM or T2DM), but events meeting the above 
criteria should be reported as ECIs regardless of etiology. The patients may present with 
hyperglycemia (abrupt onset or abrupt decompensation) with clinical evidence of diabetic 
ketoacidosis or laboratory evidence of insulin deficiency, such as ketonuria, laboratory evidence 
of metabolic acidosis, or low or undetected c-peptide. 
 
Course of Action 
T1DM should be immediately treated with insulin. 
 
T1DM or Grade 3-4 Hyperglycemia events: 
- Report as ECI if appropriate (see Table 1) 
- Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia 
associated with evidence of beta cell failure, and resume pembrolizumab when patients are 
clinically and metabolically stable. 
- Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria. 
- Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
- Consultation with an Endocrinologist is recommended. 
- Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and insulin 
may be obtained. 
 
14.4.7 Hematologic 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic 
steroids to treat the AE, are considered an ECI and should be reported to the Sponsor within 24 hours 
of the event: 
– Autoimmune hemolytic anemia 
– Aplastic anemia 
– Disseminated Intravascular Coagulation (DIC) 
– Haemolytic Uraemic Syndrome (HUS) 
– Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
– Thrombotic Thrombocytopenic Purpura (TTP) 
– Any Grade 4 anemia regardless of underlying mechanism 
 
All attempts should be made to rule out other causes such as metastases, sepsis and/or infection. 
Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, haptoglobin, bone 
marrow biopsy or Coomb’s test, etc., should be considered to confirm the diagnosis. However the AE 
should be reported regardless of etiology. 


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Course of Action 
 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab 
– Prednisone 1-2 mg/kg daily may be indicated 
– Consider Hematology consultation. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 events: 
– Report as ECI 
– Hematology consultation. 
– Hold pembrolizumab Discontinuation should be considered as per specific protocol guidance. 
– Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Report as ECI 
– Hematology consultation 
– Discontinue pembrolizumab for all solid tumor indications; refer to protocol for hematologic 
malignancies. 
– Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate 
 
14.4.8 Hepatic 
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose modification or use 
of systemic steroids to treat the AE), are considered ECIs and should be reported to the Sponsor within 
24 hours of the event: 
– Autoimmune hepatitis 
– Hepatitis 
– Transaminase elevations 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or other 
hepatic diseases. However, the AE should be reported regardless of etiology.  
-Drug Induced Liver Injury (DILI) 
 
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the patient meets 
the laboratory criteria for potential DILI defined as: 
 An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is 
greater than or equal to three times (3X) the upper limit of normal (ULN) and 


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 An elevated total bilirubin lab value that is greater than or equal to two times (2X) ULN and 
 At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 
 As a result of within-protocol-specific testing or unscheduled testing. 
 Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a DILI 
event. 
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total bilirubin >1.5 to 3.0 
times ULN. 
– Monitor liver function tests more frequently until returned to baseline values (consider 
weekly). 
o Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns to 
grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume pembrolizumab per protocol 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or 
equivalent per day within 12 weeks. 
– Permanently discontinue pembrolizumab for patients with liver metastasis who begin 
treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases ≥50% relative to 
baseline and lasts ≥1 week. 
 
Grade 3 events: 
– Report as ECI 
– Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin >3.0 times 
ULN. 
– Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, if 
necessary 
– Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When symptoms 
improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or 
prednisone at 1 to 2 mg/kg should be started and continued over no less than 4 weeks. 
– If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, 
oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not 
recommended due to its potential for hepatotoxicity. 
– Several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Report as ECI 
– Permanently discontinue pembrolizumab 
– Manage patient as per Grade 3 above 
 


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14.4.9 Neurologic 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
– Autoimmune neuropathy 
– Demyelinating polyneuropathy 
– Guillain-Barre syndrome 
– Myasthenic syndrome 
 
All attempts should be made to rule out other causes such as metastatic disease, other medications or 
infectious causes. However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Moderate (Grade 2) – consider withholding pembrolizumab. 
– Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
– Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 and 4 events: 
– Report as ECI 
– Discontinue pembrolizumab 
– Obtain neurology consultation. Consider biopsy for confirmation of diagnosis 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once 
per day. If condition worsens, consider IVIG or other immunosuppressive therapies as per local 
guidelines. When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
14.4.10 Ocular 
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of systemic 
steroids to treat the AE, is considered an ECI and should be reported to the Sponsor within 24 hours of 
the event: 
– Uveitis 
– Iritis 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or other 
ocular disease (e.g. glaucoma or cataracts). However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Evaluation by an ophthalmologist is strongly recommended. 
– Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. 
– Discontinue pembrolizumab as per protocol if symptoms persist despite treatment with 


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topical immunosuppressive therapy. 
 
Grade 3 events: 
– Evaluation by an ophthalmologist is strongly recommended 
– Hold pembrolizumab and consider permanent discontinuation as per specific protocol 
guidance. 
– Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Evaluation by an ophthalmologist is strongly recommended 
– Permanently discontinue pembrolizumab. 
– Treat with corticosteroids as per Grade 3 above 
 
14.4.11 
 Renal 
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor within 24 
hours of the event: 
– Nephritis 
– Nephritis autoimmune 
– Renal failure 
– Renal failure acute 
 
Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic steroids to treat 
the AE. All attempts should be made to rule out other causes such as obstructive uropathy, progression 
of disease, or injury due to other chemotherapy agents. A renal consultation is recommended. 
However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Hold pembrolizumab 
– Treatment with prednisone 1-2 mg/kg p.o. daily. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3-4 events: 
– Discontinue pembrolizumab 
– Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent once 
per day. When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Pembrolizumab Event of Clinical Interest Guidance 
Document 


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14.4.12 
 Skin 
Rash and Pruritus 
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the Sponsor 
within 24 hours of the event: 
– Pruritus 
– Rash 
– Rash generalized 
– Rash maculo-papular 
– In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in the 
physician's judgment, should be treated as an ECI. Clinical significance is left to the physician to 
determine, and could possibly include rashes such as the following: 
o rash with a duration >2 weeks; OR 
o rash that is >10% body surface area; OR 
o rash that causes significant discomfort not relieved by topical medication or temporary 
cessation of study drug. 
 
Other Skin ECIs 
The following AEs should always be reported as ECIs, regardless of grade, and should be reported to 
the Sponsor within 24 hours of the event: 
– Dermatitis exfoliative 
– Erythema multiforme 
– Steven’s Johnson syndrome 
– Toxic epidermal necrolysis 
 
Please note, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 
0.1% cream or hydrocortisone 1%) or urea-containing creams in combination with oral anti-
pruritics (e.g., diphenhydramine HCl or hydroxyzine HCl). 
– Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
 
Grade 3 events: 
– Hold pembrolizumab. 
– Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
– Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or equivalent 
once per day or dexamethasone 4 mg four times orally daily. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 


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Grade 4 events: 
– Permanently discontinue pembrolizumab. 
– Dermatology consultation and consideration of biopsy and clinical dermatology photograph. 
– Initiate steroids at 1 to 2 mg/kg prednisone or equivalent. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
 
14.4.12.1 
Immediate Evaluation for Potential Skin ECIs 
A. Photographs: 
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon as 
possible. Obtain appropriate consent for subject photographs if a consent form addendum is required 
by your IRB/ERC. 
 
– Take digital photographs of: 
o the head (to assess mucosal or eye involvement), 
o the trunk and extremities, and 
o a close-up of the skin lesion/rash. 
– If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed marker of 
distance. 
 
– The time/date stamp should be set in the 'ON' position for documentation purposes. 
– Photographs should be stored with the subject’s study records. 
– The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will 
provide guidance to the site, if needed. 
 
B. Past Medical History: 
Collect past medical history relevant to the event, using the questions in Appendix 1 (Past Medical 
History Related to Dermatologic Event) as a guide. Any preexisting conditions not previously reported 
(e.g., drug allergy) should be entered into the Medical History eCRF. 
 
C. Presentation of the Event: 
Collect information on clinical presentation and potential contributing factors using the questions in 
Appendix 2 (Presentation of the Dermatologic Event) as a guide. This information should be 
summarized and entered in narrative format in the AE eCRF. Please use the available free-text fields, 
such as Signs and Symptoms. Note pertinent negatives where applicable to reflect that the information 
was collected. Any treatments administered should be entered on the Concomitant Medication eCRF. 
 
D. Vitals Signs and Standard Laboratory Tests: 
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the Vital 
Signs in eCRF. Perform standard laboratory tests (CBC with manual differential and serum chemistry 
panel, includingLFTs). 
 
E. Focused Skin Examination: 
Perform a focused skin examination using the questions in Appendix 3 (Focused Skin Examination) as a 
guide. Information should be summarized and entered on the Adverse Experience eCRF as part of the 


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narrative. 
 
F. Dermatology Consult 
Refer the subject to a dermatologist as soon as possible. 
– For a “severe rash”, the subject must be seen within 1-2 days of reporting the event. 
– For clinically significant rash, the subject should be seen within 3-5 days. 
The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory or to a 
pathologist experienced in reviewing skin specimens. The site should provide the dermatologist with all 
relevant case history, including copies of clinical photographs and laboratory test results. 
 
14.4.13 
Other 
The following AEs, regardless of grade, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
– Myocarditis 
– Pericarditis 
– Pancreatitis 
– Any additional Grade 3 or higher event which the physician considers to be immune related 
All attempts should be made to rule out other causes. Therapeutic specialists should be 
consulted as appropriate. However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
– Withhold pembrolizumab. 
– Systemic corticosteroids may be indicated. 
– Consider biopsy for confirmation of diagnosis. 
– If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
 
Grade 3 events: 
– Hold pembrolizumab 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once 
per day. 
– When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment may 
be restarted and the dose modified as specified in the protocol 
 
Grade 4 events: 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once 
per day. 
– Discontinue pembrolizumab 
 
14.4.14 
Follow-up to Resolution 
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information regarding duration and clinical course of the event. Information obtained from the 
consulting specialist, including diagnosis, should be recorded in the appropriate AE fields. Free-text 
fields should be used to record narrative information: 
– Clinical course of the event 
– Course of treatment 
– Evidence supporting recovery 
– Follow-up to the clinical course 
Any treatments administered for the event should also be entered in the Concomitant 
Medication eCRF. 
 
 


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14.4.15 
ECI APPENDIX 1 – Past Medical History Related to Dermatologic Event 
 
 
 


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14.4.16 
ECI APPENDIX 2 – Presentation of the Dermatologic Event 
 
 
 


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14.4.17 
ECI APPENDIX 3 – Focused Skin Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.4.18 
Appendix 4- Low Glycemic Meals 
 
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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14.4.19 
Appendix 5- prohibited medications 
 
 
Table: 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, 
telaprevir, 
telithromycin, tipranavir/ritonavir, troleandomycin, 
Moderate CYP3A Inhibitors 
Grapefruit, grapefruit hybrids, pummelos, star-fruit, and 
Seville oranges (citrus paradisi fruit juice) 
Strong CYP3A Inducers 
Avasimibe, 
carbamazepine, 
mitotane, 
phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin), St. John's wort 
(hypericum perforatum) 
CYP3A Substrates with NTI 
Alfentanil, apixaban (doses >2.5 mg only), aprepitant, 
astemizole, 
cisapride, 
cyclosporine, 
diergotamine, 
dihydroergotamine, 
ergotamine, 
fentanyl, 
lovastatin, 
nicardipine, nisoldipine, pimozide, quinidine, rivaroxaban, 
simvastatin, sirolimus, tacrolimus, terfenadine, thioridazine, 
Other Investigational and 
Antineoplastic Therapies 
Other investigational therapies must not be used while the 
patient is on the study. Anticancer therapy (chemotherapy, 
biologic or radiation therapy, and surgery) other than the study 
treatments must not be given to patients while the patient is on 
the study medication. If such agents are required for a patient 
then the patient must be discontinued from the study. 
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 
 

ICF_001.pdf: 
IRB # 15-1020 
Page 1 of 16  
 
 
Protocol version date: 01/13/2020 
 
INFORMED CONSENT DOCUMENT 
 
A Phase I/II study to determine feasibility and safety of pembrolizumab (MK-3475) 
alone or in combination with copanlisib in relapsed or refractory NK and T-cell 
Non-Hodgkin lymphoma 
 
Principal Investigator: Henry Fung, MD 
 
This is a clinical trial, a type of research study.  Research studies are voluntary and include only 
people who choose to take part. Please read this consent form carefully and take your time 
making your decision. As your study doctor or study staff discusses this consent form with you, 
please ask him/her to explain any words or information that you do not clearly understand. We 
encourage you to talk with your family, friends or family doctor before you decide to take part in 
this research study. 
 
You are being asked to take part in this research study because you have relapsed or refractory 
NK and T-cell Non-Hodgkin lymphoma.  
 
The sponsor-investigator of this study is Henry Fung, MD at Fox Chase Cancer Center. This study 
is supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc and Bayer. 
 
Why is this research study being done? 
 
This is a research study to test an investigational drug, pembrolizumab, also known as MK-3475 
alone or in combination with the investigational drug copanlisib for treatment of NK and T-cell 
Non-Hodgkin lymphoma.  
 
Pembrolizumab is FDA approved for use in other cancers, such as melanoma, lung cancer and 
head and neck. Copanlisib is also FDA approved for use in Follicular Lymphoma (a type of 
cancer). 
 
Your study doctor will discuss what drugs are approved and available as treatment for your 
cancer.  The study doctor will discuss with you any reasons why you may not be allowed to take 
part in this research study.  
 
We do not know if you will benefit from this research study.  It is possible that your condition will 
get better, but it is also possible that there will be no effect on your condition or that your condition 
will get worse.  We can use what we learn from this research study to help other people with the 
same disease.   
 
How many people will take part in this research study? 
 
A total of around 48 people were to take part in this research study, 18 in Phase 1 (completed) 
and up to 30 in Phase 2.  


IRB # 15-1020 
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Protocol version date: 01/13/2020 
 
What will happen if you take part in this research study? 
 
Before you begin the research study: 
 
You will need to have the following exams, tests or procedures to find out if you can be in the 
research study.  These exams, tests or procedures are part of regular cancer care and may be 
done even if you do not join the research study.  If you have had some of them recently, they may 
not need to be repeated.  This will be up to your study doctor. 
 
 
Physical exam which will include height, weight and vital signs  
 
You will be asked questions about your medical history and daily activities 
 
You will be asked about the medicines you are taking or have recently taken (over-the-
counter medications, supplements, prescription medications or illegal drugs) 
 
You will be asked about any side-effects you may be experiencing   
 
You will be asked to provide a tumor sample from a previous biopsy or surgical procedure 
if available. You will also be asked to provide a newly obtained tumor biopsy tissue sample   
o This sample will be tested to ensure it can be evaluated for the specific biomarkers 
to be tested in this study.  Your sample may also be used for the analysis of 
additional biomarkers to investigate ways that the study drug does or does not 
work to shrink tumors 
o Other additional biomarkers which may impact how individuals respond to the 
study drug may also be analyzed   
o Any sample left over after these tests will be stored for future research if you 
consent to the optional Future Biomedical Research (FBR) sub-study 
 
Routine blood tests (about 1 tablespoon) 
o These samples will be used to check blood counts, kidney and liver function, 
thyroid function and the levels of certain enzymes and minerals normally found in 
the blood 
 
Blood (1 teaspoon) to test how fast your blood takes to clot 
 
A PET/CT scan or CT scan of your tumor 
o A PET scan requires an injection of a radioactive material into a vein and produces 
3-D images to see how your cells work.  
o A CT scan is a computerized x-ray that gives your study doctor pictures of the 
inside of your body 
o A PET/CT scan combines the two scans to allow doctors to see the location and 
function of cells within the body 
 
Urine test 
 
Blood pregnancy test (1 teaspoon), if you are a female and able to become pregnant 
 
We will perform a blood test to check the presence of a viral infection (CMV) 
 
During the research study 
 
Study Treatment 
 
This study has two cohorts, cohort 1 and cohort 2. Patients in cohort 1 will be treated with 
pembrolizumab alone while patients in cohort 2 will be treated with the combination of 


IRB # 15-1020 
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Protocol version date: 01/13/2020 
pembrolizumab and copanlisib. Cohort 1 is already completed and therefore you will be enrolled 
in cohort 2.  
 
Cohort 2: This cohort has two phases of treatment, phase 1 and phase 2. In this cohort you will 
be asked to take Bactrim drug either one tablet daily (single strength) or three times a week 
(double strength) to prevent infections. This cohort has an induction phase prior to treatment 
cycles where patients will be infused with one of the drugs, copanlisib, twice- on day -21 and day 
-14 of 21 day period (called day -1 to -21 before treatment with the combination drugs) and blood 
will be collected prior to the first dose and a week after the second dose of the drug (day -21, prior 
to infusion, and day -7). After the 21 days long induction phase, treatment with combination of 
copanlisib and pembrolizumab will begin and administered in a cyclical manner. 
 
Phase 1: Phase 1 portion is to determine the dose of copanlisib that is safe and tolerable in 
combination with pembrolizumab. If you are in this cohort, you will be administered a fixed dose 
of pembrolizumab (200 mg on day 1 of each cycle) and the dose of copanlisib will depend on the 
dose level at which you enter the study. It could either be 45 mg on day 1 or 45 mg on day 1 and 
day 8 or 60 mg on day 1 or day 8 of each cycle. Each cycle is 21 days long.  
 
Phase 2: If you are enrolled in phase II portion you will be administered pembrolizumab 200 mg 
on day 1 of each cycle and copanlisib will be administered as determined to be safe and tolerable 
from phase 1 position. Each cycle is 21 days long.  
 
Tests and Procedures 
 
If the exams, tests and procedures show that you can be in the research study, and you choose 
to take part, then you will need the following tests and procedures.  They are part of regular cancer 
care, but may be done more often because you are in this research study. 
 
 
Physical exam which will include weight and vital signs  
 
We will ask you about your ability to perform daily activities 
 
We will ask you about the medicines you are taking or have recently taken (over-the-
counter medications, supplements, prescription medications or illegal drugs).  
 
We will ask you about all the side-effects that you may be experiencing  
 
Routine blood tests (about 1 tablespoon) 
 
Research blood tests (about 2-3 teaspoons) 
o These samples will be used to discover ways that the study drug does or does not 
work to shrink tumors 
o Other additional biomarkers which may impact how individuals respond to the 
study drug may also be studied 
 
A blood sample will be collected for genetic research 
o Your blood sample contains genes, which are made up of DNA (deoxyribonucleic 
acid) and which serve as the "instruction book" for the cells that make up our 
bodies  
o Genetic research is the study of DNA variation.  Variation in your DNA can affect 
the way you respond to drug treatments   
o The Sponsor will look at variation in your DNA.  Your DNA will be used to 
understand how genetics affect response to the treatment(s) administered    


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Protocol version date: 01/13/2020 
o Your blood may also be used to help develop new tests. The results are for 
research use only 
 
A PET/CT scan or CT scan of your tumor 
 
Blood test, once every cycle, to check the presence of a virus (CMV), only if the virus was 
detected in the test done at the time of the screening 
 
Blood will be collected (1 teaspoon) to test your thyroid function 
 
After you are finished with the study treatment  
 
Follow-up Visits: 
 
We will need to schedule a visit about 30 days after your last dose to see if you are 
experiencing any side effects from the treatment 
 
After the first follow up, you will continue to come in for a follow-up visits about every 12 
weeks for up to two years or documentation of progression of your disease, whichever 
happens earlier, about every 26 weeks for the third year, and then about every 3 to 6 
months for the rest of your life or until the study ends.   
 
If your cancer gets worse or you start a new treatment for your cancer, we would like to 
contact you by telephone about every 12 weeks for three years.  After the third year, we 
would like to contact you about every 6 months. 
Tests and Procedures 
During the follow-up visits we would like to perform the following tests and procedures: 
 
We will ask you about all the side-effects that you may be experiencing 
 
Physical exam which will include weight and vital signs  
 
We will ask you about your ability to perform daily activities 
 
Routine blood tests (about 1 tablespoon) 
 
Research blood tests (about 2-3 teaspoons) 
 
Blood for (1 teaspoon) thyroid function test 
 
Tumor imaging – if you discontinued the study treatment for reasons other than worsening 
of your disease 
 
 
Study Chart  
You will receive Pembrolizumab and copanlisib every three weeks. This 3-week period of time 
is called a cycle. The cycle will be repeated until your disease gets worse. Each cycle is 
numbered in order. The chart below shows what will happen to you during Cycle 1 and future 
treatment cycles as explained previously. The left-hand column shows the day in the cycle and 
the right-hand column tells you what to do on that day. 
 
Day  
What you do… 
Before starting 
study 
 
Provide medical history 
 
Get a physical exam which will include height, weight and vital signs  
 
Report how you are performing your daily activities 
 
Provide all the side-effects you may be experiencing 
 
Report all medicines you are currently taking 
 
Get a routine blood test (1 tablespoon) 


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 
Blood test for minerals, liver and thyroid functions (1 tablespoon) 
 
Blood test for blood clotting (1 teaspoon) 
 
Blood test for CMV infection (1 teaspoon) 
 
Give a Urine sample  
 
Get a blood pregnancy test (1 teaspoon), if you are a female and able to 
become pregnant 
 
A PET/CT scan or CT scan of your tumor 
 
Collect a newly obtained biopsy sample, and if available, collect a cancer 
sample from a previous procedure (called “archival tumor tissue”). 
 
Cycles 1 - 4 
 
Report all medicines you are currently taking 
 
Get routine blood tests (1 tablespoon) 
 
Get research blood tests (about 2-3 teaspoons) 
 
Blood test for minerals, liver and thyroid functions (1 tablespoon) 
 
Blood test for CMV monitoring, if you were positive for CMV infection 
 
Report any side effects 
 
Get a physical exam which will include weight and vital signs 
 
Report how you are performing your daily activities  
 
Receive Pembrolizumab and copanlisib 
    Cycle 5  
 
Get a physical exam which will include weight and vital signs 
 
Report how you are performing your daily activities  
 
Report any side effects 
 
Get a PET/CT scan or CT scan of your tumor 
 
Blood test for Liver and thyroid functions 
 
CMV monitoring 
 
Report all medicines you are currently taking 
 
Get routine blood tests (1 tablespoon) 
 
Receive Pembrolizumab and copanlisib 
 
Future cycles 
Day 
What you do… 
Future Treatments 
Up to Cycle 36  
 
Get a physical exam which will include weight and vital signs 
 
Report any side effects 
 
Report all medicines you are currently taking 
 
Report side-effects you may be experiencing 
 
Report how you are performing your daily activities 
 
CMV monitoring 
 
Blood test for liver and thyroid functions 
 
Get routine blood tests (1 tablespoon) 
 
Get a PET/CT scan or CT scan of your tumor (every 12 weeks) 
 
Receive Pembrolizumab and copanlisb 
End of Treatment 
 
Report all medicines you are currently taking 
 
Report any side effects you may be experiencing 
 
Report how you are performing your daily activities 
 
Get a physical exam which will include weight and vital signs 
 
Get routine blood tests (1 tablespoon) 
 
Get your thyroid function test 


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 
Get a PET/CT scan or CT scan of your tumor 
 
How long will you be in the research study? 
 
You may receive treatment with pembrolizumab and copanlisib for up to 2 years or until your 
disease gets worse, whichever happens earlier.   
 
Can you stop being in the research study? 
 
Yes. Your participation in this research is completely voluntary. If you agree to participate now 
and change your mind later, you may withdraw at any time.   Tell the study doctor if you are 
thinking about stopping or decide to stop.  He or she will tell you how to stop safely and will discuss 
with you options for withdrawal such as continuing to provide further data collection from routine 
medical care.   
 
Can you be removed from this research study? 
 
The study doctor may stop you from taking part in this research study at any time if he/she 
believes it is in your best interest; if you do not follow the research study rules; or if you suffer 
study related injuries; or if the research study is stopped. 
 
What side effects or risks can you expect from being in the research study? 
 
You may have side effects while on the research study. Everyone taking part in the research study 
will be watched carefully for any side effects. However, doctors don't know all the side effects that 
may happen. Side effects may be mild or very serious. Your health care team may give you 
medicines to help lessen side effects. Many side effects go away soon after you stop taking the 
pembrolizumab and/or copanlisib. In some cases, side effects can be serious, long lasting, or may 
never go away. 
 
You should talk to your study doctor about any side effects that you have while taking part in the 
research study.  
 
Risks and side effects related to the Pembrolizumab include those which are: 
 
Very Common (≥ 10%) 
 
Fatigue – feeling tired 
 
Decreased hunger 
 
Cough 
 
Pruritus- itching of the skin 
 
Diarrhea- loose or watery stool 
 
Rash 
 
Nausea 
 
Shortness of breath 
 
Joint pain 
 
Constipation 
 
Headache 
 
Vomiting 


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 
Asthenia- abnormal physical weakness or lack of energy 
 
Fever 
 
Back pain 
 
Anemia- lack of red blood cells resulting in pale color and weakness 
 
Peripheral edema- swelling or puffiness in the body due to too much liquid accumulation 
in body’s tissues, especially, lower limbs 
 
 
 
Common (1% to 10%) 
 
Pneumonia- infection of the lungs in which your lungs get filled with fluid leading to 
shortness of breath and cough with phlegm or pus, fever, chills. Sometimes this might lead 
to death 
 
Hyperthyroidism- too much thyroid hormone so you may feel anxious, angry, can’t sleep, 
weak, tremble, increased sweating, weight loss, hair loss, tired, have diarrhea 
 
Hypothyroidism- not enough thyroid hormone so you may feel tired, gain wright, feel cold, 
have infrequent or hard stools 
 
Pleural effusion- water in the lungs that may lead to cough, sharp chest pain, or shortness 
of breath 
 
Pneumonitis- inflammation of lungs, symptoms may include shortness of breath, cough, 
fatigue, loss of appetite and unintentional weight loss 
 
Colitis- chronic digestive disease of inflammation of the bowels/ gut, which may cause 
severe pain in your belly with loose or water stools, and black, tarry, sticky stools or stools 
with blood or mucus, loss of appetite 
 
Pulmonary embolism- sudden chest pain and shortness of breath 
 
Uncommon (0.1 to < 1%) 
 
Infusion related reaction (drug hypersensitivity, anaphylactic reaction, hypersensitivity and 
cytokine release syndrome)- allergic reaction to infusion where you may feel dizzy or faint, 
flushed, get a rash, have a fever, feel short of breath at the time of receiving your infusion 
(IV) or just after, or pain at the site of infusion of the drug 
 
Change in taste 
 
Dehydration 
 
Pain in your belly 
 
Acute kidney injury- sudden kidney failure 
 
Skin cancer 
 
Chronic obstructive pulmonary disease (COPD)- symptoms may include shortness of 
breath, wheezing, or a chronic cough 
 
Pericardial effusion- accumulation of water around heart 
 
Cellulitis- a painful bacterial skin infection 
 
Kidney failure 
 
Urinary tract infection- it may cause pelvic pain, increased urge to urinate, pain with 
urination, and blood in the urine 
 
Respiratory failure 


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 
Sepsis- this is caused by body’s over-reaction to infection, symptoms may include fever, 
difficulty in breathing, low blood pressure, fast heart rate and mental confusion 
 
Irregular heartbeat 
 
Hypophysitis- inflammation of the pituitary gland (a gland in the head), which may cause 
you to feel sick to your stomach or have headaches, changes in your behavior, double 
vision, few to no menstrual cycles, weakness, vomiting and dizziness or fainting, extreme 
thirst  
 
Adrenal insufficiency- Adrenal glands (glands on top of the kidneys) that may not make 
enough hormone, which could cause tiredness, weight loss, muscle weakness, feeling 
faint, joint, muscle and belly aches, nausea, vomiting, loose or watery tools, fever, salt 
craving, and sometimes darkening of the skin like a suntan  
 
Type 1 diabetes mellitus (diabetic ketoacidosis)- type 1 diabetes, a condition that can 
cause too much sugar in your blood, feeling thirstier than usual, frequent urination and 
weight loss. You are likely to need regular insulin shots, a diabetic complication where 
body produces too much acid 
 
Hyponatremia- low level of sodium in the body, symptoms may include nausea, headache, 
confusion and fatigue, restlessness and irritability, muscle weakness or spasms, seizure, 
coma 
 
Uveitis (iritis, iridocyclitis)- inflammation of the eye so you may have blurred vision, 
sensitivity to light, eye pain, see floaters or have headaches 
 
Myositis- inflammation of the muscles so you may feel weak or have pain in your muscles 
 
Myocarditis- inflammation of the middle layer of your heart wall that may cause your heart 
to have difficulty pumping blood throughout your body, which can cause chest pain, 
shortness of breath and swelling of the legs. You may experience a fast or irregular 
heartbeat that may cause dizziness or fainting. Sometimes this condition can lead to death 
 
Pancreatitis- inflammation of the pancreas (a gland in your abdomen that controls sugar 
level) so you may have severe pain in the top part of your belly that may move to your 
back, feel sick to your stomach, and vomiting that gets worse when you eat 
 
Hepatitis- inflammation of the liver that may make you feel sick to the stomach and vomit, 
feel like not eating, feel tired, have a mild fever, have pain in the right side of the belly, 
yellow eyes and skin, and dark urine  
 
Nephritis- inflammation of the kidney so you may pass less urine or have cloudy or bloody 
urine, swelling in the face, legs and feet, and lower back pain 
 
 
Rare (0.01% to 0.1%) 
 
Thyroiditis- inflammation of the thyroid gland, an organ that makes and stores thyroid 
hormones. This condition may lead to change in your heart rate, body temperature, and 
the rate at which food is converted into energy, sensitivity to cold, puffy face, dry hair, dry 
skin, weight gain or loss, fatigue, diarrhea or constipation 
 
Severe skin reactions- inflammation of the skin so you may have peeling of the skin, 
itchiness, and/ or skin redness. The skin inflammation (i.e. peeling, itching and redness) 
could also be widespread throughout your body. More severe skin reactions may involve 
the inside of your mouth, the surface of your eye and genital areas, and/ or may cause the 
top layer of your skin to peel from all over your body which can cause severe infection. 
These severe conditions can sometimes lead to death 


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 
Guillain-Barre Syndrome- an autoimmune condition where your immune system attacks 
your nerves that may cause severe lower back pain, muscle weakness in your legs that 
travels to your upper body, prickling or tingling sensation in your fingers and  toes, 
paralysis, loss of bladder control, difficulty moving your eyes or face, talking, chewing or 
swallowing, fast heart rate, difficulty breathing 
 
Myasthenic syndrome- a condition that may make you feel weak and tired and might have 
drooping of the eyelids, blurred or double vision, difficulty swallowing, slurred speech, 
weakness in your arms and legs, or difficulty breathing 
 
Sarcoidosis- the formation of small clusters of immune cells (called granulomas) in parts 
of your body, such as, your lymph nodes, eyes, skin or lungs, symptoms vary depending 
on the organ affected and includes shortness of breath, cough that won’t go away, reddish 
bumps on the skin, fever, fatigue, night sweats, weight loss 
 
Encephalitis- inflammation of the brain with confusion and fever. This may also include: 
disorientation, memory problems, seizures (fits), changes in personality and behavior, 
difficulty speaking, weakness or loss of movement in some parts of your body, and loss of 
consciousness 
 
Toxic epidermal necrolysis- a disorder of skin and outer lining that may cause a painful, 
red are that spreads quickly, skin may peel without blistering, raw areas of skin, discomfort, 
condition may spread to eyes, mouth/throat, and genitals/ urethra/ anus 
 
Stevens-Johnson syndrome- a disorder of the skin and outer lining that may begin with flu 
like symptoms, a painful rash that spreads and blisters follow, peeling of the skin, rash of 
small purplish spots, red spots or bumps, fever, malaise, eye redness, coughing, itching, 
mouth ulcers, sensitivity to light, sore throat or swelling 
 
Other events that may occur but can not be estimated from the available data 
 
Solid organ transplant rejection 
 
Patients treated with pembrolizumab who then go on to allogeneic stem cell transplant (a 
procedure in which a person receives blood-forming stem cells from a donor), should inform their 
transplant physician that they may have received pembrolizumab in the past. 
 
In patients with any hematologic malignancy (cancers of the blood, like, Hodgkin lymphoma, 
multiple myeloma): there is a potential for an increased risk of severe complications following 
allogeneic stem cell transplant in patients who previously received pembrolizumab.  
 
Reports of clotting of blood within the liver and severe graft versus host disease (which may 
include skin, liver and gastrointestinal symptoms), including death, have been received for 
patients who received allogeneic stem cell transplant after pembrolizumab therapy. 
 
Risks and side effects related to the Copanlisib include those which are: 
Very Common (≥ 10%) 
 
Decrease in white blood cells (leukopenia) which can interfere with the ability to fight 
infections  
 
Decreased hemoglobin [anemia, hemoglobin decreased] leading to tiredness and pale 
skin, and may become life-threatening 
 
Raised blood sugar levels [hyperglycemia]. In some instances this may be severe and life-
threatening 


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 
Raised blood pressure [hypertension including hypertensive emergency] 
 
Feeling tired [fatigue and asthenia] 
 
Nausea 
 
Diarrhea 
 
Inflammation of the mouth and lips (stomatitis) with or without oral ulceration and oral pain 
 
Rash 
 
Low phosphate levels in the blood (hypophosphatemia) that can cause muscle weakness, 
respiratory failure and heart failure, seizures and coma 
 
Decreased number of a type of white blood cells called neutrophils [neutropenia]. This 
may occur with other signs of infection and may become life-threatening [neutropenia] 
 
Decreased number of a component of blood called platelets that help with the formation 
of blood clots [thrombocytopenia, platelet count decreased].  
 
Lower respiratory tract infections (including pneumonia, pneumonia due to bacteria, virus 
or a fungal infection). Such infections may be severe and have life threatening or fatal 
outcome. 
Common (≥ 1% to < 10 %): 
 
Low levels of a type of blood cells called lymphocytes (lymphopenia) causing weakness, 
tired, weight loss, chills, fever, night sweats, pain or feeling of fullness in the belly  
 
Change in your sense of taste (dysgeusia) 
 
High level of disease-fighting white blood cells known as eosinophils in the blood 
(eosinophilia) that can cause allergies, asthma, inflammatory conditions in the stomach 
and skin, such as, eczema 
 
Febrile neutropenia- development of fever with infection due to low number of a cell type 
in the blood (neutrophils) that can be life threatening 
 
Dry mouth 
 
Difficulty swallowing (Dysphagia) 
 
Swelling in the lining of intestines (mucosal inflammation) 
 
Injection site reactions 
 
Hypersensitivity reactions (including allergic swelling of the skin (edema and 
angioedema), widening of blood vessels and flushing, and infusion related reaction) 
 
High levels of enzymes lipase and amylase that can cause severe abdominal pain, fever, 
loss of appetite, nausea, vomiting, yellowing of eyes  
 
High lipids, such as cholesterol and triglycerides (hyperlipidemia) 
 
High levels of insulin in the blood (hyperinsulinaemia) causing weight gain, craving or 
sugar, intense hunger at higher frequency, feeling anxious, fatigue and lacking focus 
 
Abnormal feeling of constant thirst (polydipsia paresthesia) 
 
Unpleasant, abnormal sense of touch often present as pain or an inappropriate but not 
discomforting sensation (dysesthesia) 
 
Pneumonitis (including interstitial lung disease and noninfectious pneumonitis) 
 
Sudden hair loss that starts with one or more circular bald patched (alopecia) 
Uncommon (≥0.001% to <1%) 
 
Swelling of the pancreas (pancreatitis) 


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It is possible that if your blood sugar increases (hyperglycemia), glucose lowering medications 
(insulin and/or an oral medication) or even hospitalization may be required. 
 
If you experience respiratory symptoms such as cough, shortness of breath, or fever, it may be 
caused by pneumonitis or respiratory infections (such as pneumonia or lung infections) in some 
cases. These conditions usually respond well to therapy, but may become life-threatening or fatal 
if not promptly treated. Please contact your doctor for further advice if you experience any of these 
symptoms.  
Opportunistic Infections: 
During treatment with copanlisib you may develop bacterial or viral infection. In order to prevent 
developing of such infections additional tests will be performed on a regular basis. Your physician 
may advise using prophylactic treatment for this kind of infection at any time during treatment with 
copanlisib. 
As the study drug is under development, there may be side effects, including allergies that are 
not yet known. Therefore, you must notify your study doctor of any new symptoms that you may 
have whether or not you think they are caused by the study drug. 
You may experience some of these side effects, which are usually temporary and manageable. 
However, this study may include risks that are yet unknown and may cause serious problems or 
even death. 
Radiation Risk for Diagnostic Imaging 
 
It is unlikely that there will be any harmful effects from the radiation exposure you will 
receive from participating in this study 
 
At high levels of exposure, scientists agree that radiation can cause cancer 
 
At low exposure levels most scientists agree that the risk, if any, is very low.  You will have 
low levels of radiation exposure with diagnostic imaging procedures 
 
Risks from exposure to radiation may accumulate over a lifetime 
 
CT Scan: CT scans are used to create images of internal bones and organs using radiation   
o High dose radiation is known to produce cancer cells.  The effect of exposure to 
radiation adds up over a lifetime   
o The amount of radiation exposure involved in this trial will not be significantly 
greater than for subjects with your disease who do not take part in the trial.   
o The contrast solution that may be given for a CT scan may cause an allergic 
reaction (rare)  
 
Severe allergic reactions can be life threatening   
 
CT contrast solution can cause kidney damage, especially if you are 
diabetic, dehydrated (lost body water) or elderly 
 
Blood Draw Risks 
 
Fainting 
 
Lightheadedness 
 
Bleeding at the place on your arm where the blood was drawn or needle inserted 
 
Bruising at the place on your arm where the blood was drawn or needle inserted 
 
Pain at the place on your arm where the blood was drawn or needle inserted 
 
Swelling 
 
Infection (rare) 
 


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IV line Risks 
 
Discomfort 
 
Irritation 
 
Mild bruising 
 
Bleeding 
 
Leakage of drug solution, and rarely, infection, nausea, and lightheadedness.   
 
Biopsy Risks 
 
Bleeding 
 
Pain 
 
Infection, which can be life-threatening or fatal in rare cases 
 
Other less common side effects have been reported with the use of the drugs in this study.  The 
study doctor or staff can discuss these with you.  There may also be other side effects or risks 
that are not known at this time. 
 
Reproductive Risks 
 
Study treatments may make you sterile (unable to have children) 
 
The drugs in this study may affect a baby, before or after the baby is born 
 
If you are pregnant now or if you are breast-feeding now, you may not take part in this 
research study 
 
If you become pregnant while you are on the research study, you must notify the study 
doctor right away.  The study drug will be stopped and you may not continue to take part 
in the research study 
 
For women who can become pregnant: 
 
You should not become pregnant while you are in this study and up to 120 days after the 
last dose of study therapy 
 
You should not breast-feed your baby while taking drugs for this research study 
 
The study doctor will perform blood pregnancy tests before the start of and during the study, 
if you are able to have a baby 
 
For men: 
 
You should not make a woman pregnant while you are in this study and up to 120 days after 
the last dose of study therapy 
 
For women and men: 
 
If you are having sex that could lead to pregnancy, you should use birth control while you 
are in this study 
 
Check with the study doctor about birth control methods and how long to use them.  The 
following birth control methods are allowed during the study   
 
Two (2) of the following barrier methods in combination: 
 
Diaphragm 
 Condom 
 Copper intrauterine device (IUD) 
 Contraceptive sponge 
 Spermicide 
OR 


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One (1) of the above barrier methods in combination with: 
 Hormonal contraceptives (including oral, subcutaneous, intrauterine, or intramuscular) 
that are registered and marketed containing estrogen and/or a progestational agent 
OR 
Abstinence is acceptable if this is your established and preferred contraception 
 
If your partner becomes pregnant during the study you must notify the study doctor right 
away.  If your partner is already pregnant when you begin the study you must use a condom 
(male) during the study and for a period of 120 days after your last dose of pembrolizumab. 
Genetic Information Nondiscrimination Act (GINA) 
 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. This law generally will protect you in the following 
ways: 
Health insurance companies and group health plans may not request your genetic information 
that we get from this research. 
Health insurance companies and group health plans may not use your genetic information when 
making decisions regarding your eligibility or premiums. 
Employers with 15 or more employees may not use your genetic information that we get from this 
research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment. 
All health insurance companies and group health plans must follow this law. All employers with 
15 or more employees must follow this law.  Be aware that this Federal law does not protect you 
against genetic discrimination by companies that sell life insurance, disability insurance, or long-
term care insurance. 
 
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not make your health better. While doctors hope the 
treatment will be more useful against cancer compared to the usual treatment, there is no proof 
of this yet. We do know that the information from this study will help doctors learn more about 
pembrolizumab and copanlisib as a treatment for cancer. This information could help future 
cancer patients. The sponsor does not intend to provide you with ownership or financial benefits 
that may result from this study. 
 
What other choices do you have if you do not take part in this research study? 
 
Your other choices may include: 
 
Getting treatment or care for your cancer without being in a study  
 
Taking part in another study  
 
Getting no treatment  
 
Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep 
you as active and comfortable as possible 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will your medical information be kept private?  


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We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Your personal information may be given out 
if required by law. If information from this study is published or presented at scientific meetings, 
your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
 
Fox Chase Cancer Center and affiliated Joint Centers, The Institutional Review Boards of 
The Fox Chase Cancer Center and Temple University, Temple University, Temple 
University Health system, Inc., and its affiliates or subsidiaries and other authorized 
representatives of these organizations. 
 
Merck Sharp & Dohme Corp., (a subsidiary of Merck & Co. Inc.) 
 
Bayer 
 
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
 
Study team members at collaborating sites  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
You will be given a separate form to review regarding the steps we will take to guard your privacy 
as part of your participation in the research study.  By signing that additional authorization, you 
will be providing your consent to use and disclose information described in that form connected 
with your participation in this research study. 
 
What are the costs? 
  
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study. Some health plans will not pay these costs for people taking 
part in studies. Check with your health plan or insurance company to find out what they will pay 
for. Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment. 
 
Merck will supply pembrolizumab and Bayer will supply copanlisib at no charge while you take 
part in this study. However, the cost of getting the pembrolizumab and copanlisib ready and giving 
it to you will not be covered, so you or your insurance company may have to pay for this. 
 
Study related tests will be provided at no cost to you. 
 
If your insurance will not pay for medicines you may need to help with side effects, you may have 
to pay for them. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 


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Will you be compensated? 
 
You will not get paid for taking part in this research study.   
 
What if you are injured while taking part in this research study? 
 
If you are injured as a result of your participation in this research study, seek immediate medical 
care. Temple University Health System or its subsidiaries will treat the injury, though there is no 
commitment to provide monetary compensation or free medical care. Other financial 
compensation (such as lost wages or pain and suffering) for such injuries is not available.   
 
What are your rights if you take part in this research study? 
 
Taking part in this research study is your choice. You may choose either to take part or not to 
take part in the research study. If you decide to take part in this study, you may leave the study 
at any time. No matter what decision you make, there will be no penalty to you and you will not 
lose any of your regular benefits. Leaving the study will not affect your medical care.  You can still 
get your medical care from our institution.  
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.  
 
New findings 
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
Who can answer your questions about the research study? 
 
If you have questions about: 
Please Call: 
This study, including if you get sick or hurt 
Dr. Fung at 215-728-4300 
If you have a concern or complaint 
Risk Management Department at 215-728-2591 
Your rights as a research participant on this study  
FCCC Institutional Review Board at 215-214-3754 
Your bills or health insurance coverage 
Clinical Trial Financial Counselor at 215-214-3768 
 
Where can you get more information? 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237)  
 
 
You may also visit the NCI website at http://cancer.gov 
 
For NCI's clinical trials information, go to: http://cancer.govclinicaltrials/  
 
For NCI's general information about cancer, go to: http://cancer.gov/cancerinfo/  
 
 
 
By signing below, you tell us that you have gotten all of the information you need; that you have 
received clear answers to your questions, and that you agree to take part in the research study.  
You will receive a copy of this form.  You may also request a copy of the research plan.  
 
 


IRB # 15-1020 
Page 16 of 16  
 
 
Protocol version date: 01/13/2020 
___________________________   ________________________           _____________ 
Signature of Participant 
 
Print Name of Participant              Date 
 
By signing this form, the physician obtaining consent indicates that the research participant has 
been fully informed of all aspects of the research study. 
 
 
____________________________   _______________________  
____________ 
Signature of Physician 
 
Print Name of Physician  
 
Date 
Obtaining Consent  
 
Obtaining Consent 
 
By signing this form, the person obtaining consent indicates that the research participant has been 
fully informed of all aspects of the research study. 
 
 
____________________________   _______________________  
____________ 
Signature of Person  
 
Print Name of Person  
 
Date 
Obtaining Consent  
 
Obtaining Consent