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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*  
| 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                                |  
Supported by: Fox Chase Cancer Center, Merck and Bayer  
  
Statistician: Eric Ross, PhD
Fox Chase Cancer Center 333 Cottman Avenue Philadelphia, PA-19111 Phone: 215-728-2891 Email: eric.ross@fccc.edu
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ind number 127581

Amendment 4: 08/08/2018 Amendment 5: 01/23/2019 Amendment 6: 03/25/2019 Amendment 7: 01/13/2020  
| TRIAL SUMMARY.                                                                                |                                                                                                                                                                 |
|-----------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.0                                                                                           |                                                                                                                                                                 |
| 2.0                                                                                           | TRIAL DESIGN                                                                                                                                                    |
| 2.1                                                                                           | Trial Schema                                                                                                                                                    |
| OBJECTIVES .                                                                                  |                                                                                                                                                                 |
| 3.0                                                                                           | Cohort 1 .                                                                                                                                                      |
| 3.1                                                                                           | Primary Objective Cohort 1 ............................................................................................................. 8                      |
| 3.1.1                                                                                         |                                                                                                                                                                 |
| 3.1.2                                                                                         | Secondary Objectives Cohort 1                                                                                                                                   |
| 3.1.3                                                                                         | Exploratory Objective Cohort 1 ........................................................................................................ 8                       |
| 3.2 Cohort 2 .                                                                                |                                                                                                                                                                 |
| 3.2.1                                                                                         | Primary Objective Cohort 2 ................................................................................................................ 8                   |
| 3.2.2                                                                                         | Secondary Objectives Cohort 2                                                                                                                                   |
| BACKGROUND & RATIONALE                                                                        |                                                                                                                                                                 |
| 4.0                                                                                           | Background .................................................................................................................................................. 9 |
| 4.1                                                                                           | Pharmaceutical and Therapeutic Background ............................................................. 9                                                       |
| 4.1.1                                                                                         |                                                                                                                                                                 |
| 4.1.2                                                                                         | Preclinical and Clinical Trial Data..................................................................................... 10                                     |
| 4.2 Rationale                                                                                 |                                                                                                                                                                 |
| 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                                                                                                                                         |
| 5.0                                                                                           | METHODOLOGY                                                                                                                                                     |
| 5.1                                                                                           | Entry Criteria .                                                                                                                                                |
| 5.1.1                                                                                         | Subject Inclusion Criteria                                                                                                                                      |
| 5.1.2                                                                                         | Subject Exclusion Criteria ....................................................................................................................... 18           |
| 5.2 Trial Treatments .                                                                        |                                                                                                                                                                 |
| 5.2.1                                                                                         | Dose Selection/Modification                                                                                                                                     |
| 5.2.2                                                                                         | Dose Administration                                                                                                                                             |
| 5.2.3                                                                                         | Participant Registration                                                                                                                                        |
| 5.3 Concomitant Medications/Vaccinations (allowed & prohibited) .......................... 31 |                                                                                                                                                                 |
| 5.3.1                                                                                         | Acceptable Concomitant Medications .                                                                                                                            |
| 5.3.2                                                                                         | Prohibited Concomitant Medications                                                                                                                              |
| 5.4 Supportive Care and Management of Immune-related Adverse Events............... 33         |                                                                                                                                                                 |
| 5.5 Diet/Activity/Other Considerations                                                        |                                                                                                                                                                 |
| 5.5.1                                                                                         | Diet                                                                                                                                                            |
| 5.5.2                                                                                         | Contraception                                                                                                                                                   |
| 5.5.3                                                                                         | Use in Pregnancy .                                                                                                                                              |
| 5.5.4                                                                                         | Use in Nursing Women                                                                                                                                            |
| 5.6 Participant Withdrawal/Discontinuation Criteria.                                          |                                                                                                                                                                 |  
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                                                                                                                               |                                                                   |  
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.                                                                                                            |                                                                                                   |
| 12.6 Study Agents                                                                                                                     |                                                                                                   |
| 12.7 Informed Consent                                                                                                                 |                                                                                                   |
| 12.8 Data Reporting.                                                                                                                  |                                                                                                   |
| LIST OF REFERENCES .                                                                                                                  |                                                                                                   |
| 13.0                                                                                                                                  | APPENDICES .                                                                                      |
| 14.0                                                                                                                                  |                                                                                                   |
| 14.1 ECOG Performance Status                                                                                                          |                                                                                                   |
| 14.2 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) .................... 68                                              |                                                                                                   |
| 14.3 Measurement of Effect .                                                                                                          |                                                                                                   |
| 14.3.1 Complete Response                                                                                                              |                                                                                                   |
| 14.3.2  Partial Response (PR)                                                                                                         |                                                                                                   |
| 14.3.3  Stable Disease (SD)                                                                                                           |                                                                                                   |
| 14.3.4  Progression (PD) and Relapse                                                                                                  |                                                                                                   |
| 14.3.5 Response Endpoints                                                                                                             |                                                                                                   |
| 14.3.6  Duration of Response .                                                                                                        |                                                                                                   |
| 14.3.7  Overall Survival .                                                                                                            |                                                                                                   |
| 14.3.8  Progression-free Survival                                                                                                     |                                                                                                   |
| 14.4 Events of Clinical Interest (ECI) guidance                                                                                       |                                                                                                   |
| 14.4.1 List of ECI                                                                                                                    |                                                                                                   |
| 14.4.2  Pneumonitis                                                                                                                   |                                                                                                   |
| 14.4.3  Colitis                                                                                                                       |                                                                                                   |
| 14.4.4  Endocrine                                                                                                                     |                                                                                                   |
| 14.4.5  Hyperthyroidism and Hypothyroidism .                                                                                          |                                                                                                   |
| 14.4.6 Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia                                                            |                                                                                                   |
| 14.4.7  Hematologic                                                                                                                   |                                                                                                   |
| 14.4.8  Hepatic                                                                                                                       |                                                                                                   |
| 14.4.9  Neurologic                                                                                                                    |                                                                                                   |
| 14.4.10 Ocular .                                                                                                                      |                                                                                                   |
| 14.4.11 Renal                                                                                                                         |                                                                                                   |
| 14.4.12 Skin                                                                                                                          |                                                                                                   |
| 14.4.13 Other                                                                                                                         |                                                                                                   |
| 14.4.14   Follow-up to Resolution                                                                                                     |                                                                                                   |
| 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 2stage 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.
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3.0 objectives 3.1 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.
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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
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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
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3.2 cohort 2 3.2.1 primary

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 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
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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
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4.0 background & rationale 4.1

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 found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune Tcell 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 preclinical 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.
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4.1.2 preclinical and clinical trial

Refer to the Investigator's Brochure for Preclinical and Clinical data for each agent.
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4.2 rationale 4.2.1 rationale for

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 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

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.
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4.2.3 rationale for pembrolizumab and

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

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 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 |                 |                 |
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dose levels for phase 1

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.
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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
- 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 antiinflammatory 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.
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4.2.3.3 phase ii portion of

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.
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4.2.4 rationale for endpoints 4.2.4.1

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 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.
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4.2.4.2 biomarker research 4.2.4.2.1 pd-1

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, PDL1, in the tumor or tumor microenvironment as well as presence of TIL be associated with outcomes.  
6063
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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
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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 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.
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4.2.4.2.4 exploration of predictive biomarkers

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.
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4.2.4.2.5 identification of copanlisib induced

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

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.  
| 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 ≥70,000 / mcL, OR Platelets ≥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) ≤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. Activated Partial Thromboplastin Time (aPTT)   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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.
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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.  
- 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 antiCytotoxic 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 20 of 94 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
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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                                 | Route of        |                   |          |                     |              |
|--------------------------------------------------------------------------------------------|-----------------|-------------------|----------|---------------------|--------------|
| Frequency                                                                                  | Administra tion | Regimen/Treatment | Use      |                     |              |
| Period                                                                                     |                 |                   |          |                     |              |
| Pembroli                                                                                   | 200 mg          | Every 3 weeks     | IV       | 36 cycles (2 years) | Experimental |
| zumab                                                                                      | (fixed dose)    | (Q3W)             | infusion |                     |              |
| The pembrolizumab dosing interval may be increased due to toxicity as described in Section |                 |                   |          |                     |              |  
| Table 2B Trial Treatment (Cohort 2) Drug Dose/Potenc Dose                            | Route of     |                                    |                   |         |              |
|--------------------------------------------------------------------------------------|--------------|------------------------------------|-------------------|---------|--------------|
| y                                                                                    | Frequency    | Administra tion                    | Regimen/Treatment | Use     |              |
| Period                                                                               |              |                                    |                   |         |              |
| Pembroliz                                                                            | 200 mg       | Every 3 weeks                      | IV                | 2 years | Experimental |
| umab                                                                                 | (fixed dose) | (Q3W)                              | infusion          |         |              |
| Copanlisib                                                                           | RP2D         | Day 1 +/- day  8 of every 3  weeks | IV                | 2 years | Experimental |
| infusion                                                                             |              |                                    |                   |         |              |
| The pembrolizumab and copanlisib dosing interval may be increased due to toxicity as |              |                                    |                   |         |              |  
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
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.
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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.
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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).
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5.2.1.2 pembrolizumab (mk-3475) and copanlisib

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 drugrelated 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.  
Table 3: Dose Modification Guidelines for Immune Related Adverse Events  
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|---------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|
| Toxicity                                                                                                                        | Grade                                                                        | Timing for Restarting Treatment                                                                                                                                                           | Treatment Discontinuation                                         |
| Hold until toxicity resolves to Grade 0-                                                                                        |                                                                              |                                                                                                                                                                                           |                                                                   |
| 2-3                                                                                                                             | 1. Restart MK3475 and copanlisib once                                        |                                                                                                                                                                                           |                                                                   |
| Diarrhea/Colitis                                                                                                                | 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                                                                                                                                                                   |                                                                   |
| Hold until toxicity resolves to Grade 0- 1. Restart MK3475 and copanlisib once                                                  |                                                                              |                                                                                                                                                                                           |                                                                   |
| 2                                                                                                                               | Grade ≤1 and decrease copanlisib by  one dose level3 .                       | Discontinue both if toxicity does not resolve within 12 weeks of  last dose.                                                                                                              |                                                                   |
| AST, ALT, or  Increased  Bilirubin                                                                                              | 3-4                                                                          | Permanently discontinue (see exception below)1                                                                                                                                            | Permanently discontinue                                           |
| T1DM new  or 3-4 associated  with  evidence of  β-cell  failure                                                                 |                                                                              |                                                                                                                                                                                           |                                                                   |
| Type 1 diabetes  mellitus (if new  onset) or  hyperglycemia                                                                     | Hold treatment and resume                                                    |                                                                                                                                                                                           |                                                                   |
| pembrolizumab and copanlisib when  patients are clinically and metabolically  stable.                                           |                                                                              |                                                                                                                                                                                           |                                                                   |
| Hypophysitis                                                                                                                    | 2                                                                            | Toxicity does not resolve within 12 weeks of last dose or                                                                                                                                 |                                                                   |
| Hold until toxicity resolves to Grade 0-                                                                                        | inability to reduce corticosteroid to 10 mg or less of prednisone            |                                                                                                                                                                                           |                                                                   |
| 1.                                                                                                                              | or equivalent per day within 12 weeks.                                       |                                                                                                                                                                                           |                                                                   |
| 3-4                                                                                                                             | Hold until toxicity resolves to Grade 0-1  or permanently discontinue at the | Permanently discontinue at the discretion of treating Physician                                                                                                                           |                                                                   |
| discretion of the treating Physician                                                                                            |                                                                              |                                                                                                                                                                                           |                                                                   |
| Hyperthyroidism                                                                                                                 | 3-4                                                                          | Hold or Permanently discontinue at the  discretion of treating Physician                                                                                                                  | Permanently discontinue at the discretion of treating Physician   |
| Therapy with pembrolizumab can be                                                                                               | Therapy with pembrolizumab can be continued while thyroid                    |                                                                                                                                                                                           |                                                                   |
| Hypothyroidism                                                                                                                  | 2-4                                                                          | continued while thyroid replacement                                                                                                                                                       | replacement therapy is instituted.                                |
| therapy is instituted                                                                                                           |                                                                              |                                                                                                                                                                                           |                                                                   |
| Infusion Reaction                                                                                                               | 3-4                                                                          | Permanently discontinue                                                                                                                                                                   | Permanently discontinue                                           |
| Hold until toxicity resolves to Grade 0- 1. Restart MK3475 and copanlisib once                                                  |                                                                              |                                                                                                                                                                                           |                                                                   |
| 2                                                                                                                               | Grade ≤1 and decrease copanlisib by                                          |                                                                                                                                                                                           |                                                                   |
| Pneumonitis                                                                                                                     | 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                                                                                                                       | Permanently discontinue                                                      | Permanently discontinue                                                                                                                                                                   |                                                                   |
| Grade 2                                                                                                                         | Toxicity does not resolve within 12 weeks of last dose or                    |                                                                                                                                                                                           |                                                                   |
| Renal Failure or                                                                                                                | 2                                                                            | Hold until toxicity resolves to Grade 0-1                                                                                                                                                 | inability to reduce corticosteroid to 10 mg or less of prednisone |
| Nephritis                                                                                                                       | or equivalent per day within 12 weeks.                                       |                                                                                                                                                                                           |                                                                   |
| 3-4                                                                                                                             | Permanently discontinue                                                      | Permanently discontinue                                                                                                                                                                   |                                                                   |
| Hold until toxicity resolves to Grade 0.  Restart MK3475 and copanlisib once                                                    |                                                                              |                                                                                                                                                                                           |                                                                   |
| 1-2                                                                                                                             | 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                                     |                                                                                                                                                                                           |                                                                   |
| Myocarditis                                                                                                                     |                                                                              |                                                                                                                                                                                           |                                                                   |  
| 15-1020                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Page 24 of 94                                                                                                                                                                            |                                               |                                               |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------|-----------------------------------------------|
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Grade                                                                                                                                                                                    | Timing for Restarting Treatment               | Treatment Discontinuation                     |
| Dermatological Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Any                                                                                                                                                                                      | No change                                     | No change                                     |
| appearance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                          |                                               |                                               |
| Grade 2b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | 1 st                                                                                                                                                                                     | Interruption until Grade ≤1                   | No change                                     |
| appearance 2 nd                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Interruption until Grade ≤1. Restart                                                                                                                                                     |                                               |                                               |
| appearance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | MK3475 and copanlisib once Grade ≤1  and decrease copanlisib by one dose  level3                                                                                                         |                                               |                                               |
| 3 rd                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Interruption until Grade ≤1. Restart                                                                                                                                                     |                                               |                                               |
| appearance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | MK3475 and copanlisib once Grade ≤1  and decrease copanlisib by one dose  level3                                                                                                         |                                               |                                               |
| 4 th                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Permanently discontinue                                                                                                                                                                  | Permanently discontinue copanlisib and MK3475 |                                               |
| appearance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                          |                                               |                                               |
| Grade 3b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | 1 st                                                                                                                                                                                     | Interruption until Grade ≤ 1. Restart         |                                               |
| appearance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | MK3475 and copanlisib once Grade ≤1  and decrease copanlisib by one dose  level3                                                                                                         |                                               |                                               |
| 2 nd                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Interruption until Grade ≤1. Restart                                                                                                                                                     |                                               |                                               |
| appearance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | MK3475 and copanlisib once Grade ≤1  and decrease copanlisib by one dose  level3                                                                                                         |                                               |                                               |
| 3 rd                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Permanently discontinue                                                                                                                                                                  | Permanently discontinue copanlisib and MK3475 |                                               |
| appearance                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                          |                                               |                                               |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | 1 st                                                                                                                                                                                     | Permanently discontinue                       | Permanently discontinue copanlisib and MK3475 |
| appearance Intolerable /persistent                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Hold until toxicity resolves to Grade 0-1                                                                                                                                                |                                               |                                               |
| Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Hold until toxicity resolves to Grade 0- 1. Restart MK3475 and copanlisib once                                                                                                           |                                               |                                               |
| 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Grade ≤1 and decrease copanlisib by  one dose level3 .                                                                                                                                   |                                               |                                               |
| All Other                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                          |                                               |                                               |
| immune-Related  Toxicity2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Permanently discontinue                                                                                                                                                                  | Permanently discontinue                       |                                               |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                          |                                               |                                               |
| 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. |                                                                                                                                                                                          |                                               |                                               |
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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 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        |
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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   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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.cIf 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
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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       | For next course of therapy   |
|-----------------|-----------------------|-----------------------------|------------------------------|
| therapy         |                       |                             |                              |
| Grade 1-2       | Any appearance        | No change                   | No change                    |
| Grade 3b        | 1 st appearance       | Delay until Grade ≤ 2       | No change                    |
| 2 nd appearance | Delay until Grade ≤ 2 | Decrease by one dose levelc |                              |
| 3 rd appearance | Delay until Grade ≤ 2 | Decrease by one dose levelc |                              |  
| 4 th appearance   | Permanently  discontinue        |                          |
|-------------------|---------------------------------|--------------------------|
| Grade 4           | Any appearance                  | Permanently  discontinue |
| a.                | Toxicities according to CTCAE 5 |                          |
| b.                | Despite maximum supportive care |                          |
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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                                                           | 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                            | No dose should be given  until recovery to  < 150/90 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 |  
27 of 94  
| 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 |                                                                                                                                                                                                                                                                                                                 |  
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/nonfasting 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/nonfasting 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.
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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 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.
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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. 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.
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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.
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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.
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all subsequent infusions after induction

The decision regarding meal timing can be made by the investigator based on glucose response patterns during prior treatment days.  
NOTE: If patient needs to have a low glycemic meal prior to the infusion, then glucose test should be taken prior to the meal and/or at 1-2 hours after the meal. After 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 Fasting ≥ 8 h required  Period before first glucose  measurement                                   | Pre-dose glucose levels   | Fasting required before study  drug infusion   |                   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|------------------------------------------------|-------------------|
| Day 1 of                                                                                                                                            | <160 mg/dL (8.9 mmol/L)   | Yesb                                           |                   |
| cycle 1                                                                                                                                             | Yes                       | <160 mg/dL (fasting) (8.9 mmol/L)              |                   |
| Day 1 of subsequent  cycles                                                                                                                         | No                        | < 200 mg/dL (11.1 mmol/L) (non-fasting or      | Conditional ͣ,b, d |
| random) c                                                                                                                                           |                           |                                                |                   |
| <160 mg/dL (8.9 mmol/L) (fasting)                                                                                                                   |                           |                                                |                   |
| of each cycle                                                                                                                                       | No                        | Conditional ͣ,b, d                              |                   |
| <200 mg/dL(11.1 mmol/L) (non-fasting or  random)                                                                                                    |                           |                                                |                   |
| Days 8 a : The decision regarding meal timing and fasting can be made by the investigator based on glucose response patterns during prior treatment |                           |                                                |                   |  
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) (nonfasting)  
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.  
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.
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blood pressure measurement on treatment

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
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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.
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exceptions to the current registration

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.  
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.
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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, overthe-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.
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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 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.
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5.4 supportive care and management

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.
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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.
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diarrhea/colitis

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.
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type 1 diabetes mellitus (if

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.
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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.
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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.
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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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Acetaminophen                                                                                                                                                                                 |                                       |
| < =24 hrs                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 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 | No subsequent dosing                  |
| 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.                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                               |                                       |
| 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

| and management of hyperglycemia. Asymptomatic glucose  increases ≤ 250mg/dL  (13.9 mmol/L) Does not generally require treatment with   | Oral Hydration                                                                                                                                                                                                                                           |                                                                                        |                                                                                                                                                    |                                                                                                                                                      |
|----------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|
| glucose lowering medication.                                                                                                           |                                                                                                                                                                                                                                                          |                                                                                        |                                                                                                                                                    |                                                                                                                                                      |
| 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                                                                                      | - Oral and or IV Hydration as appropriate                                              |                                                                                                                                                    |                                                                                                                                                      |
| -                                                                                                                                      | Consultation with endocrinologist is  recommended                                                                                                                                                                                                        |                                                                                        |                                                                                                                                                    |                                                                                                                                                      |
| 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                                                                                                                   | -                                                                                                                                                                                                                                                        | Will require dose reduction for                                                        |                                                                                                                                                    |                                                                                                                                                      |
| increase > 500mg/dL                                                                                                                    | 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                                                                                    | -                                                                                      | 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.                                                                                                                |                                                                                        |                                                                                                                                                    |                                                                                                                                                      |
| Consultation                                                                                                                           | with                                                                                                                                                                                                                                                     | endocrinologist                                                                        | is                                                                                                                                                 |                                                                                                                                                      |
| recommended                                                                                                                            |                                                                                                                                                                                                                                                          |                                                                                        |                                                                                                                                                    |                                                                                                                                                      |
|                                                                                                                                       | Management of persistent infusion-related hyperglycemia on subsequent days:                                                                                                                                                                              |                                                                                        |                                                                                                                                                    |                                                                                                                                                      |
| Criteria                                                                                                                               | Recommendation                                                                                                                                                                                                                                           | Suggested Treatment                                                                    |                                                                                                                                                    |                                                                                                                                                      |
| Persistent glucose >  200 mg/dL (11.1  mmol/L)(nonfasting) 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 |
| Confidential Limited Access                                                                                                            |                                                                                                                                                                                                                                                          |                                                                                        |                                                                                                                                                    |                                                                                                                                                      |  
| (fasting)   | post   |                                                                                                 |
|-------------|--------|-------------------------------------------------------------------------------------------------|
| infusion    |       | Treatment with glucose lowering medication suggested  according the local standards of practice |
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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.
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5.5.1.1 recommendations on meal timing

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.
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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 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.
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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.
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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.
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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 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 nonstudy 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.
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5.7 clinical criteria for early

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.