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13.2 trusight oncology 500 assay

In order to be eligible for the study, participants are required to have a cancer that is not amenable to treatment with targeted agents to an EGFR, ALK or ROS1 variant. TruSight Oncology 500 (TSO 500) is not FDA approved for the purpose of testing for these mutations; however, it is being used in this study as a diagnostic device. Validation assays to support the use of the assay have been submitted to the IND. All documentation is in the IND files. According to 21 CFR 812.3(m), a significant risk device presents a potential for serious risk to the health, safety and welfare of a subject and meets the significant risk criteria listed in the table  
| Applicable  to current                                                                                                      | Justification                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
|-----------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| study                                                                                                                       |                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Is an implant                                                                                                               | No                                                                                                                                                                                                                  | The TruSight Oncology 500 assay is not introduced into  the subject                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| Is used in supporting or  sustaining human life                                                                             | No                                                                                                                                                                                                                  | The device is diagnostic  While the device is diagnostic, we do not believe it  presents a potential for serious risk to the health and  welfare of the subject. EGFR, ALK and ROS1  variations are assessed to help to increase the possibility  that all persons enrolling on the study may not be more  likely to benefit from an alternative therapy outside of  this study. Persons that are deemed ineligible to enroll  on the basis of this test may be eligible for other  standard of care or experimental therapies better suited  for their tumor type. |
| Is of substantial  importance in diagnosing  mitigating or treating  disease or preventing  impairment of human  health  No | Testing will be performed on archival samples or on  fresh tissue that is collected at screening for  confirmation of diagnosis. No additional collection of  tissue will occur for purposes of mesothelin testing. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Source: Testing will be performed via an assay developed by the NCI Laboratory of Pathology.  Otherwise poses a risk No     |                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |  
below along with the sponsor's conclusions with regard to the applicability of these criteria to the current study. The device has been assessed by the sponsor as non-significant risk per the below.
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13.3 lmb-100 (ind #123332)

13.3.1 Source: LMB-100 was transferred to the NIH CC Pharmacy by Selecta Biosciences, the drug manufacturer. For this trial, the drug will be supplied by the NIH CC Pharmacy.  
13.3.2 Mechanism of action
LMB-100 is a novel recombinant anti-mesothelin targeted cytolytic fusion protein (cFP) developed for the treatment of patients with solid tumors that express the mesothelin protein. Mesothelin is a suitable candidate for targeted therapy due to its very limited expression in normal/non-malignant tissue and its high expression in several tumor entities including mesothelioma, ovarian cancer, pancreatic cancer, gastric cancer, breast cancer, and lung cancer. To target mesothelin, a humanized Fab fragment of the anti-mesothelin antibody SS1 is linked to a truncated and de-immunized recombinant 24 kDa fragment of Pseudomonas exotoxin (PE24). After binding to mesothelin, the complex is internalized by endocytosis and kills cells by inhibition of eukaryotic elongation factor 2 (eEF2), leading to arrest of protein synthesis and secondarily triggering cell death by apoptosis or necrosis. 13.3.2.1 Molecular Weight: approximately 73 kDa
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13.3.2.2 chemical structure

H1L1 polypeptide structure consisting of one variable heavy chain containing the Pseudomonas  
 Exotoxin A moiety and one variable light change held together
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13.3.3 toxicity

Information in this section is based on clinical studies of tLMB-100. Toxicities Observed in Participants Receiving LMB-100 Alone or in Combination  
| NCI Common Terminology  Criteria for Adverse Events  (CTCAE) Term   | # of Subjects     | % of Subjects   |       |
|---------------------------------------------------------------------|-------------------|-----------------|-------|
| Blood and Lymphatic system  Disorders                               | Anemia            | 36              | 29.03 |
| Atrial fibrillation                                                 | 7                 | 5.65            |       |
| Atrial flutter                                                      | 1                 | 0.81            |       |
| Chest pain - cardiac                                                | 1                 | 0.81            |       |
| Myocarditis                                                         | 1                 | 0.81            |       |
| Palpitations                                                        | 4                 | 3.23            |       |
| Pericardial effusion                                                | 8                 | 6.45            |       |
| Pericardial tamponade                                               | 2                 | 1.61            |       |
| Pericarditis                                                        | 3                 | 2.42            |       |
| System Organ Class Cardiac Disorders                                | Sinus tachycardia | 24              | 19.35 |
| Ear and Labyrinth Disorders                                         | External ear pain | 1               | 0.81  |
| Endocrine Disorders                                                 | Hypothyroidism    | 1               | 0.81  |
| Eye disorders - Other,                                              |                   |                 |       |
| Eye Disorders                                                       | specify           | 1               | 0.81  |
| Abdominal distension                                                | 2                 | 1.61            |       |
| Gastrointestinal Disorders                                          | Abdominal pain    | 9               | 7.26  |
| Ascites                                                             | 1                 | 0.81            |       |  
| NCI Common Terminology  Criteria for Adverse Events  (CTCAE) Term         | # of Subjects             | % of Subjects   |       |
|---------------------------------------------------------------------------|---------------------------|-----------------|-------|
| Constipation                                                              | 5                         | 4.03            |       |
| Diarrhea                                                                  | 5                         | 4.03            |       |
| Dry mouth                                                                 | 1                         | 0.81            |       |
| Dyspepsia                                                                 | 4                         | 3.23            |       |
| Nausea                                                                    | 29                        | 23.39           |       |
| Upper gastrointestinal  hemorrhage                                        | 1                         | 0.81            |       |
| Vomiting                                                                  | 14                        | 11.29           |       |
| Chills                                                                    | 5                         | 4.03            |       |
| Edema face                                                                | 7                         | 5.65            |       |
| Edema limbs                                                               | 38                        | 30.65           |       |
| Fatigue                                                                   | 54                        | 43.55           |       |
| Fever                                                                     | 25                        | 20.16           |       |
| General disorders and  administration site conditions  - Other, specify   | 1                         | 0.81            |       |
| Generalized edema                                                         | 1                         | 0.81            |       |
| Irritability                                                              | 1                         | 0.81            |       |
| Localized edema                                                           | 22                        | 17.74           |       |
| Malaise                                                                   | 1                         | 0.81            |       |
| Non-cardiac chest pain                                                    | 6                         | 4.84            |       |
| System Organ Class General Disorders and  Administration Site  Conditions | Pain                      | 10              | 8.06  |
| Immune System Disorders                                                   | Allergic reaction         | 1               | 0.81  |
| Immune system disorders -  Other, specify                                 | 1                         | 0.81            |       |
| Herpes simplex reactivation                                               | 1                         | 0.81            |       |
| Infections and infestations -  Other, specify                             | 1                         | 0.81            |       |
| Infections and Infestations                                               | Lung infection            | 1               | 0.81  |
| Injury, Poisoning and                                                     | Fall                      | 1               | 0.81  |
| Procedural Complications                                                  | Infusion related reaction | 14              | 11.29 |
| Alanine aminotransferase  increased                                       | 31                        | 25              |       |
| Alkaline phosphatase  increased                                           | 11                        | 8.87            |       |
| Aspartate aminotransferase  increased                                     | 47                        | 37.9            |       |
| Cardiac troponin I increased                                              | 5                         | 4.03            |       |
| CPK increased                                                             | 5                         | 4.03            |       |
| Investigations                                                            | Creatinine increased      | 33              | 26.61 |  
| NCI Common Terminology  Criteria for Adverse Events  (CTCAE) Term     | # of Subjects    | % of Subjects   |      |
|-----------------------------------------------------------------------|------------------|-----------------|------|
| Ejection fraction decreased                                           | 1                | 0.81            |      |
| Investigations - Other,  specify                                      | 1                | 0.81            |      |
| Lymphocyte count decreased                                            | 54               | 43.55           |      |
| Neutrophil count decreased                                            | 9                | 7.26            |      |
| Platelet count decreased                                              | 14               | 11.29           |      |
| Thyroid stimulating hormone  increased                                | 3                | 2.42            |      |
| Urine output decreased                                                | 1                | 0.81            |      |
| Weight gain                                                           | 42               | 33.87           |      |
| Weight loss                                                           | 3                | 2.42            |      |
| White blood cell decreased                                            | 21               | 16.94           |      |
| Anorexia                                                              | 23               | 18.55           |      |
| Dehydration                                                           | 5                | 4.03            |      |
| Hypercalcemia                                                         | 1                | 0.81            |      |
| Hyperglycemia                                                         | 1                | 0.81            |      |
| Hypernatremia                                                         | 2                | 1.61            |      |
| Hyperuricemia                                                         | 2                | 1.61            |      |
| Hypoalbuminemia                                                       | 99               | 79.84           |      |
| Hypocalcemia                                                          | 7                | 5.65            |      |
| Hypokalemia                                                           | 8                | 6.45            |      |
| Hypomagnesemia                                                        | 2                | 1.61            |      |
| Hyponatremia                                                          | 49               | 39.52           |      |
| System Organ Class Metabolism and Nutrition  Disorders                | Hypophosphatemia | 5               | 4.03 |
| Arthralgia                                                            | 6                | 4.84            |      |
| Arthralgia                                                            | 6                | 4.84            |      |
| Back pain                                                             | 4                | 3.23            |      |
| Flank pain                                                            | 3                | 2.42            |      |
| Generalized muscle  weakness                                          | 3                | 2.42            |      |
| Myalgia                                                               | 33               | 26.61           |      |
| Neck pain                                                             | 1                | 0.81            |      |
| Pain in extremity                                                     | 2                | 1.61            |      |
| Musculoskeletal and  Connective Tissue Disorders                      | Rhabdomyolysis   | 1               | 0.81 |
| Neoplasms Benign,  Malignant and Unspecified  (Incl Cysts And Polyps) | Tumor pain       | 3               | 2.42 |
| Confusion                                                             | 2                | 1.61            |      |
| Nervous System Disorder                                               | Dizziness        | 12              | 9.68 |
| Dysgeusia                                                             | 1                | 0.81            |      |  
| NCI Common Terminology  Criteria for Adverse Events  (CTCAE) Term   | # of Subjects               | % of Subjects   |      |
|---------------------------------------------------------------------|-----------------------------|-----------------|------|
| Headache                                                            | 8                           | 6.45            |      |
| Lethargy                                                            | 1                           | 0.81            |      |
| Peripheral motor neuropathy                                         | 1                           | 0.81            |      |
| Peripheral sensory  neuropathy                                      | 8                           | 6.45            |      |
| Presyncope                                                          | 1                           | 0.81            |      |
| Somnolence                                                          | 1                           | 0.81            |      |
| Syncope                                                             | 1                           | 0.81            |      |
| Tremor                                                              | 1                           | 0.81            |      |
| Psychiatric Disorders                                               | Insomnia                    | 2               | 1.61 |
| Acute kidney injury                                                 | 5                           | 4.03            |      |
| Renal and Urinary Disorders                                         | Proteinuria                 | 9               | 7.26 |
| Reproductive System and  Breast Disorders                           | Pelvic pain                 | 1               | 0.81 |
| Allergic rhinitis                                                   | 1                           | 0.81            |      |
| Cough                                                               | 2                           | 1.61            |      |
| Dyspnea                                                             | 27                          | 21.77           |      |
| Hypoxia                                                             | 5                           | 4.03            |      |
| Pleural effusion                                                    | 7                           | 5.65            |      |
| Pleuritic pain                                                      | 5                           | 4.03            |      |
| Pneumonitis                                                         | 1                           | 0.81            |      |
| Productive cough                                                    | 1                           | 0.81            |      |
| Pulmonary edema                                                     | 1                           | 0.81            |      |
| Respiratory failure                                                 | 1                           | 0.81            |      |
| Sore throat                                                         | 2                           | 1.61            |      |
| System Organ Class Respiratory, Thoracic and  Mediastinal Disorders | Upper respiratory infection | 1               | 0.81 |
| Alopecia                                                            | 10                          | 8.06            |      |
| Dry skin                                                            | 1                           | 0.81            |      |
| Periorbital edema                                                   | 2                           | 1.61            |      |
| Skin and Subcutaneous                                               | Pruritus                    | 3               | 2.42 |
| Tissue Disorders                                                    | Rash maculo-papular         | 4               | 3.23 |
| Skin and subcutaneous tissue  disorders - Other, specify            | 1                           | 0.81            |      |
| Capillary leak syndrome                                             | 11                          | 8.87            |      |
| Flushing                                                            | 2                           | 1.61            |      |
| Vascular Disorders                                                  | Hypertension                | 4               | 3.23 |
| Hypotension                                                         | 34                          | 27.42           |      |
| Thromboembolic event                                                | 1                           | 0.81            |      |
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13.3.3.1 risk of immunogenicity and

LMB-100 may cause the formation of ADAs. These may trigger hypersensitivity reactions or immune complex-mediated responses. The development of ADAs to LMB-100, an improved cytolytic fusion protein with a humanized targeting moiety directed against mesothelin and a dehumanized, truncated Pseudomonas exotoxin A is expected to be less likely than SS1P. Clinical trials with SS1P have led to the development of neutralizing ADAs in 75% and 88% of patients after 1 cycle of therapy, in the IV bolus and continuous infusion trials respectively.(48) Patients will be monitored at regular intervals for the development of ADAs and cytokines. In particular, any clinical signs and symptoms suggestive of a hypersensitivity reaction and/or an immune complex-mediated reaction possibly due to ADA formation will be carefully investigated.
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13.3.4 handling

LMB-100 is to be handled following all hazardous precautions. There is no evidence currently available to determine the hazardous status of the product. The Clinical Center will exercise caution and categorize LMB-100 as a hazardous agent.
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13.3.5 formulation and preparation

LMB-100 drug product (20 mg/20 mL) is provided for syringe infusion as a sterile, colorless to brownish, preservative-free liquid in single-use, 20 mL vials. The nominal fill volume is 20 mL and the approximate concentration of LMB-100 recombinant fusion protein in the vials is 1 mg/mL. 13.3.6 Stability and Storage 13.3.6.1 Stability Stability tests are ongoing for intact LMB-100 vials.  
13.3.6.2 LMB-100 does not contain antimicrobial preservatives and should be used immediately after preparing into dosing syringes. If prepared dosing syringes are not used immediately, total in-use storage times of prepared syringes for infusion should not exceed 24 hours when stored under refrigeration (2°– 8°C). 13.3.6.3 Storage Store intact vials in the refrigerator (2 - 8°C), protected from light. Do not shake and do not freeze drug vials. LMB-100 should be protected from exposure to direct sunlight during preparation and administration. 13.3.7 Administration procedures Please refer to section **3.2.1**. 13.3.8 Incompatibilities Pharmacodynamic drug interaction studies have not been conducted. LMB-100 is contraindicated in subjects with a history of severe allergic anaphylactic reactions to humanized, chimeric or mouse peptides/antibodies or to any components of the product. Other drugs that require parenteral co-administration (if applicable) should be delivered via separate infusion lines and at separate infusion sites and should not be mixed with the study drug. LMB-100 is compatible with non-DEHP, latex-free, lipid resistant, non-PVC extension sets.
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13.4 pembrolizumab (keytruda) 13.4.1 source

Commercially available pembrolizumab will be supplied by NIH Clinical Center Pharmacy. 13.4.2 Clinical Supplies Disclosure This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or lists are not provided.
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13.4.3 toxicity

The most frequently reported adverse events that were considered by the investigator to be "possibly," "probably," or "definitely" related to pembrolizumab are displayed below in **Table 9**.  
The 5 most frequently reported AEs considered drug related by the investigator were fatigue
(24.2%), pruritus (16.7%), rash (13.8%), diarrhea (12.3%), and nausea (10.9%).  
| Reference Safety Dataset for Pembrolizumab                                                              |      |        |
|---------------------------------------------------------------------------------------------------------|------|--------|
| Preferred Term                                                                                          | a    |        |
| N                                                                                                       | (%)  |        |
| Subjects in population                                                                                  | 2799 |        |
| Fatigue                                                                                                 | 678  | (24.2) |
| Pruritus                                                                                                | 467  | (16.7) |
| Rash                                                                                                    | 386  | (13.8) |
| Diarrhea                                                                                                | 343  | (12.3) |
| Nausea                                                                                                  | 304  | (10.9) |
| Arthralgia                                                                                              | 281  | (10.0) |
| Decreased appetite                                                                                      | 255  | (9.1)  |
| Asthenia                                                                                                | 218  | (7.8)  |
| Hypothyroidism                                                                                          | 213  | (7.6)  |
| Vitiligo                                                                                                | 159  | (5.7)  |
| Myalgia                                                                                                 | 146  | (5.2)  |
| Every subject is counted a single time for each applicable row and column. MedDRA version used is 18.1. |      |        |  
| Reference Safety Dataset for Pembrolizumab   |                                                                                                                                                        |
|----------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|
| Preferred Term                               | a                                                                                                                                                      |
| N                                            | (%)                                                                                                                                                    |
| a.                                           | Includes all subjects who received at least one dose of MK-3475 in KN001 Part B1, B2, B3, D, C, F1,  F2, F3; KN002 (original phase), KN006, and KN010. |  
Table 10. **Serious Adverse Reactions Considered Expected for Pembrolizumab**  
| Table 10. Serious Adverse Reactions Considered Expected for Pembrolizumab System/Category Adverse Reaction (MedDRA Preferred Terms) NOTE: Adverse reaction term is considered expected for all  indications unless otherwise noted. Those terms followed by  parentheses with notations afterward, are expected only in the  indications noted. Blood and lymphatic system   Anemia (NSCLC Combo Tx, UC) disorders  Hemolytic anemia  Autoimmune myocarditis Cardiac  Cardiac failure (MEL)  Myocarditis  Adrenal insufficiency  Adrenocortical insufficiency acute  Autoimmune thyroiditis  Hyperthyroidism  Hypophysitis  Hypopituitarism  Hypothyroidism  Lymphocytic hypophysitis  Secondary adrenocortical insufficiency  Thyroid disorder  Thyroiditis Endocrine disorders  Autoimmune uveitis  Iridocyclitis  Iritis  Ocular myasthenia  UveitisEye disorders   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| System/Category                                         | Adverse Reaction (MedDRA Preferred Terms) NOTE: Adverse reaction term is considered expected for all  indications unless otherwise noted. Those terms followed by  parentheses with notations afterward, are expected only in the  indications noted.   |                                |
|---------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------|
|                                                        | Abdominal discomfort (UC)                                                                                                                                                                                                                               |                                |
|                                                        | Abdominal pain (MEL, UC)                                                                                                                                                                                                                                |                                |
|                                                        | Abdominal pain lower (UC)                                                                                                                                                                                                                               |                                |
|                                                        | Abdominal pain upper (UC)                                                                                                                                                                                                                               |                                |
|                                                        | Autoimmune pancreatitis                                                                                                                                                                                                                                 |                                |
|                                                        | Colitis                                                                                                                                                                                                                                                 |                                |
|                                                        | Colitis microscopic                                                                                                                                                                                                                                     |                                |
|                                                        | Constipation (MEL, NSCLC, NSCLC Combo Tx, UC)                                                                                                                                                                                                           |                                |
|                                                        | Diarrhea                                                                                                                                                                                                                                                |                                |
|                                                        | Enterocolitis                                                                                                                                                                                                                                           |                                |
|                                                        | Enterocolitis hemorrhagic                                                                                                                                                                                                                               |                                |
|                                                        | Frequent bowel movements (UC)                                                                                                                                                                                                                           |                                |
|                                                        | Gastroenteritis (cHL, UC)                                                                                                                                                                                                                               |                                |
|                                                        | Nausea (MEL, NSCLC, NSCLC Combo Tx, cHL, UC)                                                                                                                                                                                                            |                                |
|                                                        | Oral lichen planus                                                                                                                                                                                                                                      |                                |
|                                                        | Pancreatitis                                                                                                                                                                                                                                            |                                |
|                                                        | Pancreatitis acute                                                                                                                                                                                                                                      |                                |
|                                                        | Pancreatitis necrotizing                                                                                                                                                                                                                                |                                |
|                                                        | Vomiting (MEL, NSCLC, NSCLC Combo Tx, HNSCC, cHL, UC)                                                                                                                                                                                                   |                                |
| Gastrointestinal disorders                              |                                                                                                                                                                                                                                                        | Asthenia (MEL, NSCLC, cHL, UC) |
|                                                        | Face edema (HNSCC)                                                                                                                                                                                                                                      |                                |
|                                                        | Fatigue (MEL, NSCLC, NSCLC Combo Tx, HNSCC, cHL, UC)                                                                                                                                                                                                    |                                |
|                                                        | Generalized edema (MEL)                                                                                                                                                                                                                                 |                                |
|                                                        | Generalized physical health deterioration (MEL)                                                                                                                                                                                                         |                                |
|                                                        | Malaise (UC)                                                                                                                                                                                                                                            |                                |
|                                                        | Edema peripheral (NSCLC Combo Tx, UC)                                                                                                                                                                                                                   |                                |
|                                                        | Pyrexia                                                                                                                                                                                                                                                 |                                |
| General disorders and administration  site conditions  | Autoimmune hepatitis                                                                                                                                                                                                                                    |                                |
|                                                        | Drug-induced liver injury                                                                                                                                                                                                                               |                                |
|                                                        | Hepatic pain (UC)                                                                                                                                                                                                                                       |                                |
|                                                        | Hepatitis                                                                                                                                                                                                                                               |                                |
|                                                        | Hepatitis acute                                                                                                                                                                                                                                         |                                |
|                                                        | Hepatitis fulminant                                                                                                                                                                                                                                     |                                |
|                                                        | Hepatitis toxic (UC)                                                                                                                                                                                                                                    |                                |
|                                                        | Hyperbilirubinemia (UC)                                                                                                                                                                                                                                 |                                |
|                                                        | Liver injury (UC)                                                                                                                                                                                                                                       |                                |
| Hepatobiliary disorders                                 |                                                                                                                                                                                                                                                         |                                |  
| System/Category                        | Adverse Reaction (MedDRA Preferred Terms) NOTE: Adverse reaction term is considered expected for all  indications unless otherwise noted. Those terms followed by  parentheses with notations afterward, are expected only in the  indications noted.   |                                                 |
|----------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|
|                                       | Gastroenteritis (cHL, UC)                                                                                                                                                                                                                               |                                                 |
|                                       | Herpes zoster (cHL)                                                                                                                                                                                                                                     |                                                 |
|                                       | Pneumonia (NSCLC, HNSCC, cHL, UC)                                                                                                                                                                                                                       |                                                 |
|                                       | Rash pustular                                                                                                                                                                                                                                           |                                                 |
|                                       | Septic shock (cHL)                                                                                                                                                                                                                                      |                                                 |
|                                       | Sepsis (UC)                                                                                                                                                                                                                                             |                                                 |
|                                       | Upper respiratory tract infection (NSCLC Combo Tx, cHL)                                                                                                                                                                                                 |                                                 |
|                                       | Urinary tract infection (UC)                                                                                                                                                                                                                            |                                                 |
|                                       | Urosepsis (UC)                                                                                                                                                                                                                                          |                                                 |
| Infections and infestations            |                                                                                                                                                                                                                                                        | Anaphylactic reaction                           |
|                                       | Anaphylactoid reaction                                                                                                                                                                                                                                  |                                                 |
|                                       | Cytokine release syndrome                                                                                                                                                                                                                               |                                                 |
|                                       | Drug hypersensitivity                                                                                                                                                                                                                                   |                                                 |
|                                       | Graft versus host disease (cHL)                                                                                                                                                                                                                         |                                                 |
|                                       | Hypersensitivity                                                                                                                                                                                                                                        |                                                 |
|                                       | Serum sickness                                                                                                                                                                                                                                          |                                                 |
| Injury, poisoning and procedural       |                                                                                                                                                                                                                                                        | Infusion related reaction                       |
| complications Immune system disorders  |                                                                                                                                                                                                                                                        | Alanine aminotransferase increased (UC)         |
|                                       | Aspartate aminotransferase increased (UC)                                                                                                                                                                                                               |                                                 |
|                                       | Blood bilirubin increased (UC)                                                                                                                                                                                                                          |                                                 |
|                                       | Blood creatinine increased (UC)                                                                                                                                                                                                                         |                                                 |
|                                       | Hepatic enzyme increased (NSCLC, UC)                                                                                                                                                                                                                    |                                                 |
|                                       | Liver function test increased (UC)                                                                                                                                                                                                                      |                                                 |
|                                       | Neutrophil count decreased (NSCLC Combo Tx)                                                                                                                                                                                                             |                                                 |
|                                       | Transaminases increased (UC)                                                                                                                                                                                                                            |                                                 |
|                                       | Weight decreased (UC)                                                                                                                                                                                                                                   |                                                 |
| Investigations                         |                                                                                                                                                                                                                                                        | Decreased appetite (MEL, NSCLC, NSCLC Combo Tx, |
|                                       | HNSCC, UC)                                                                                                                                                                                                                                              |                                                 |
|                                       | Diabetic ketoacidosis                                                                                                                                                                                                                                   |                                                 |
| Metabolism and nutritional disorders  | Fulminant type 1 diabetes mellitus                                                                                                                                                                                                                      |                                                 |
|                                       | Hyponatremia (UC)                                                                                                                                                                                                                                       |                                                 |
|                                       | Latent autoimmune diabetes in adults                                                                                                                                                                                                                    |                                                 |
|                                       | Type 1 diabetes mellitus                                                                                                                                                                                                                                |                                                 |  
| System/Category                                                                        | Adverse Reaction (MedDRA Preferred Terms) NOTE: Adverse reaction term is considered expected for all  indications unless otherwise noted. Those terms followed by  parentheses with notations afterward, are expected only in the  indications noted.   |                           |
|----------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|
|                                                                                       | Arthralgia (MEL, NSCLC, NSCLC Combo Tx, cHL, UC)                                                                                                                                                                                                        |                           |
|                                                                                       | Arthritis                                                                                                                                                                                                                                               |                           |
|                                                                                       | Back pain (MEL, NSCLC, cHL, UC)                                                                                                                                                                                                                         |                           |
|                                                                                       | Bone pain (cHL, UC)                                                                                                                                                                                                                                     |                           |
|                                                                                       | Flank pain (UC)                                                                                                                                                                                                                                         |                           |
|                                                                                       | Immune-mediated necrotizing myopathy                                                                                                                                                                                                                    |                           |
|                                                                                       | Musculoskeletal chest pain (cHL, UC)                                                                                                                                                                                                                    |                           |
|                                                                                       | Musculoskeletal discomfort (cHL, UC)                                                                                                                                                                                                                    |                           |
|                                                                                       | Musculoskeletal pain (cHL, UC)                                                                                                                                                                                                                          |                           |
|                                                                                       | Myalgia (cHL, UC)                                                                                                                                                                                                                                       |                           |
|                                                                                       | Myopathy                                                                                                                                                                                                                                                |                           |
|                                                                                       | Myositis                                                                                                                                                                                                                                                |                           |
|                                                                                       | Neck pain (cHL, UC)                                                                                                                                                                                                                                     |                           |
|                                                                                       | Necrotizing myositis                                                                                                                                                                                                                                    |                           |
|                                                                                       | Pain in extremity (cHL, UC)                                                                                                                                                                                                                             |                           |
|                                                                                       | Polymyositis                                                                                                                                                                                                                                            |                           |
|                                                                                       | Psoriatic arthropathy                                                                                                                                                                                                                                   |                           |
|                                                                                       | Rhabdomyolysis                                                                                                                                                                                                                                          |                           |
|                                                                                       | Spinal pain (UC)                                                                                                                                                                                                                                        |                           |
| Neoplasms benign, malignant and                                                       | Tumor pain (UC)                                                                                                                                                                                                                                         |                           |
| unspecified (incl cysts and polyps) Musculoskeletal and connective  tissue disorders  | Axonal neuropathy                                                                                                                                                                                                                                       |                           |
|                                                                                       | Demyelinating polyneuropathy                                                                                                                                                                                                                            |                           |
|                                                                                       | Diabetic ketoacidotic hyperglycemic coma                                                                                                                                                                                                                |                           |
|                                                                                       | Dizziness (NSCLC Combo Tx)                                                                                                                                                                                                                              |                           |
|                                                                                       | Dysesthesia (cHL)                                                                                                                                                                                                                                       |                           |
|                                                                                       | Dysgeusia (NSCLC Combo Tx)                                                                                                                                                                                                                              |                           |
|                                                                                       | Guillain-Barré syndrome                                                                                                                                                                                                                                 |                           |
|                                                                                       | Headache (MEL, NSCLC Combo Tx, cHL)                                                                                                                                                                                                                     |                           |
|                                                                                       | Hypoesthesia (cHL)                                                                                                                                                                                                                                      |                           |
|                                                                                       | Lethargy (UC)                                                                                                                                                                                                                                           |                           |
|                                                                                       | Miller Fisher syndrome                                                                                                                                                                                                                                  |                           |
|                                                                                       | Myasthenia gravis                                                                                                                                                                                                                                       |                           |
|                                                                                       | Myasthenia gravis crisis                                                                                                                                                                                                                                |                           |
|                                                                                       | Myasthenic syndrome                                                                                                                                                                                                                                     |                           |
|                                                                                       | Myelitis                                                                                                                                                                                                                                                |                           |
|                                                                                       | Neuropathy peripheral (MEL, cHL)                                                                                                                                                                                                                        |                           |
|                                                                                       | Paresthesia (cHL)                                                                                                                                                                                                                                       |                           |
|                                                                                       | Peripheral sensory neuropathy (cHL)                                                                                                                                                                                                                     |                           |
|                                                                                       | Polyneuropathy (MEL, cHL)                                                                                                                                                                                                                               |                           |
| Nervous system disorders Psychiatric                                                   |                                                                                                                                                                                                                                                        | Confusional state (HNSCC) |
|                                                                                       | Insomnia (NSCLC Combo Tx)                                                                                                                                                                                                                               |                           |  
| System/Category                                  | Adverse Reaction (MedDRA Preferred Terms) NOTE: Adverse reaction term is considered expected for all  indications unless otherwise noted. Those terms followed by  parentheses with notations afterward, are expected only in the  indications noted.   |                                             |
|--------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------|
|                                                 | Acute kidney injury (NSCLC Combo Tx, UC)                                                                                                                                                                                                                |                                             |
|                                                 | Autoimmune nephritis                                                                                                                                                                                                                                    |                                             |
|                                                 | Chromaturia (UC)                                                                                                                                                                                                                                        |                                             |
|                                                 | Glomerulonephritis                                                                                                                                                                                                                                      |                                             |
|                                                 | Glomerulonephritis membranous                                                                                                                                                                                                                           |                                             |
|                                                 | Hematuria (UC)                                                                                                                                                                                                                                          |                                             |
|                                                 | Nephritis                                                                                                                                                                                                                                               |                                             |
|                                                 | Nephrotic syndrome                                                                                                                                                                                                                                      |                                             |
|                                                 | Tubulointerstitial nephritis                                                                                                                                                                                                                            |                                             |
| Reproductive system and breast                   |                                                                                                                                                                                                                                                        | Pelvic pain (UC)                            |
| disorders Renal and urinary disorders            |                                                                                                                                                                                                                                                        | Cough (MEL, NSCLC, NCSLC Combo Tx, cHL, UC) |
|                                                 | Dyspnea (MEL, NSCLC, NSCLC Combo Tx, HNSCC, cHL, UC)                                                                                                                                                                                                    |                                             |
|                                                 | Dyspnea exertional (cHL, UC)                                                                                                                                                                                                                            |                                             |
|                                                 | Interstitial lung disease*                                                                                                                                                                                                                              |                                             |
|                                                 | Pleural effusion (HNSCC)                                                                                                                                                                                                                                |                                             |
|                                                 | Pneumonitis*                                                                                                                                                                                                                                            |                                             |
|                                                 | Productive cough (cHL, UC)                                                                                                                                                                                                                              |                                             |
|                                                 | Respiratory failure (HNSCC)                                                                                                                                                                                                                             |                                             |
|                                                 | Wheezing (cHL, UC)                                                                                                                                                                                                                                      |                                             |
| Respiratory, thoracic and mediastinal  disorders |                                                                                                                                                                                                                                                         |                                             |  
| System/Category                         | Adverse Reaction (MedDRA Preferred Terms) NOTE: Adverse reaction term is considered expected for all  indications unless otherwise noted. Those terms followed by  parentheses with notations afterward, are expected only in the  indications noted.   |            |
|-----------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|
|                                        | Acute febrile neutrophilic dermatosis                                                                                                                                                                                                                   |            |
|                                        | Dermatitis                                                                                                                                                                                                                                              |            |
|                                        | Dermatitis acneiform (cHL, UC)                                                                                                                                                                                                                          |            |
|                                        | Dermatitis bullous                                                                                                                                                                                                                                      |            |
|                                        | Dermatitis contact (cHL, UC)                                                                                                                                                                                                                            |            |
|                                        | Dermatitis exfoliative                                                                                                                                                                                                                                  |            |
|                                        | Dermatitis psoriasiform (cHL)                                                                                                                                                                                                                           |            |
|                                        | Drug eruption                                                                                                                                                                                                                                           |            |
|                                        | Drug reaction with eosinophilia and systemic symptoms                                                                                                                                                                                                   |            |
|                                        | Eczema                                                                                                                                                                                                                                                  |            |
|                                        | Eczema asteatotic (cHL, UC)                                                                                                                                                                                                                             |            |
|                                        | Erythema (UC)                                                                                                                                                                                                                                           |            |
|                                        | Erythema multiforme                                                                                                                                                                                                                                     |            |
|                                        | Lichen planus                                                                                                                                                                                                                                           |            |
|                                        | Lichenoid keratosis (UC)                                                                                                                                                                                                                                |            |
|                                        | Palmar-plantar erythrodysesthesia syndrome                                                                                                                                                                                                              |            |
|                                        | Pemphigoid                                                                                                                                                                                                                                              |            |
|                                        | Perivascular dermatitis                                                                                                                                                                                                                                 |            |
|                                        | Pruritus                                                                                                                                                                                                                                                |            |
|                                        | Psoriasis                                                                                                                                                                                                                                               |            |
|                                        | Rash                                                                                                                                                                                                                                                    |            |
|                                        | Rash erythematous                                                                                                                                                                                                                                       |            |
|                                        | Rash generalized                                                                                                                                                                                                                                        |            |
|                                        | Rash macular                                                                                                                                                                                                                                            |            |
|                                        | Rash maculo-papular                                                                                                                                                                                                                                     |            |
|                                        | Rash morbilliform                                                                                                                                                                                                                                       |            |
|                                        | Rash papular                                                                                                                                                                                                                                            |            |
|                                        | Rash pruritic                                                                                                                                                                                                                                           |            |
|                                        | Skin disorder                                                                                                                                                                                                                                           |            |
|                                        | Skin hypopigmentation (MEL)                                                                                                                                                                                                                             |            |
|                                        | Skin necrosis                                                                                                                                                                                                                                           |            |
|                                        | Skin reaction (UC)                                                                                                                                                                                                                                      |            |
|                                        | Skin toxicity                                                                                                                                                                                                                                           |            |
|                                        | Stasis dermatitis                                                                                                                                                                                                                                       |            |
|                                        | Stevens-Johnson syndrome*                                                                                                                                                                                                                               |            |
|                                        | Subacute cutaneous lupus erythematosus                                                                                                                                                                                                                  |            |
|                                        | Toxic epidermal necrolysis*                                                                                                                                                                                                                             |            |
|                                        | Vitiligo (MEL)                                                                                                                                                                                                                                          |            |
| Vascular disorders                      |                                                                                                                                                                                                                                                        | Vasculitis |
| Skin and subcutaneous tissue  disorders |                                                                                                                                                                                                                                                         |            |  
System/Category Adverse Reaction (MedDRA Preferred Terms)  
NOTE: Adverse reaction term is considered expected for *all* indications unless otherwise noted. Those terms followed by parentheses with notations afterward, are expected *only* in the indications noted.  
cHL = Classical Hodgkin Lymphoma; MEL = Melanoma; HNSCC = Head and Neck Squamous Cell Carcinoma; NSCLC = Non-Small Cell Lung Cancer; NSCLC Combo Tx = Non-Small Cell Lung Cancer participants receiving KEYTRUDA in combination with chemotherapy (pemetrexed and carboplatin); and UC = Urothelial Carcinoma For the purpose of safety reporting in clinical trials only serious adverse reactions are considered expected *Term also considered expected with fatal outcome  
13.4.4 Formulation and preparation 13.4.5 Stability and Storage  
| Product Name & Potency    | Dosage Form            |
|---------------------------|------------------------|
| Pembrolizumab 100 mg/ 4mL | Solution for Injection |  
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on the label. Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. Clinical supplies may not be used for any purpose other than that stated in the protocol. 13.4.6 Administration procedures Please refer to section **3.2.3**. 13.4.7 Incompatibilities None 13.4.8 Returns and Reconciliation The investigator is responsible for keeping accurate records of the clinical supplies received from Merck or designee, the amount dispensed to and returned by the participants and the amount remaining at the conclusion of the trial. Upon completion or termination of the study, all unused and/or partially used investigational product will be destroyed at the site per institutional policy. It is the Investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
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14 references

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11. Zhang J, Khanna S, Jiang Q, Alewine C, Miettinen M, Pastan I, et al. Efficacy of Antimesothelin Immunotoxin RG7787 plus Nab-Paclitaxel against Mesothelioma Patient-Derived Xenografts and Mesothelin as a Biomarker of Tumor Response. Clinical cancer research : an official journal of the American Association for Cancer Research. 2017;23(6):1564-74. 12. Weldon JE, Xiang L, Zhang J, Beers R, Walker DA, Onda M, et al. A recombinant immunotoxin against the tumor-associated antigen mesothelin reengineered for high activity, low off-target toxicity, and reduced antigenicity. Molecular cancer therapeutics. 2013;12(1):48-57. 13. Liu W, Onda M, Lee B, Kreitman RJ, Hassan R, Xiang L, et al. Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(29):11782-7. 14. Alewine C, Xiang L, Yamori T, Niederfellner G, Bosslet K, Pastan I. Efficacy of RG7787, a next-generation mesothelin-targeted immunotoxin, against triple-negative breast and gastric cancers. Molecular cancer therapeutics. 2014;13(11):2653-61. 15. Disis ML. Immune regulation of cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(29):4531-8. 16. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005;23(10):2346-57. 17. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 2008;358(25):2698-703. 18. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515-48. 19. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(24):13866-71. 20. Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004;20(3):337-47. 21. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004;173(2):945-54.  
22. Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits Tcell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574(1-3):37-41. 23. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25. 24. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219-42. 25. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543-53. 26. Labrijn AF, Buijsse AO, van den Bremer ET, Verwilligen AY, Bleeker WK, Thorpe SJ, et al. Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo. Nat Biotechnol. 2009;27(8):767-71. 27. van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martinez-Martinez P,
Vermeulen E, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317(5844):1554-7. 28. Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(10):633-59. 29. Dostalek M, Gardner I, Gurbaxani BM, Rose RH, Chetty M. Pharmacokinetics, pharmacodynamics and physiologically-based pharmacokinetic modelling of monoclonal antibodies. Clin Pharmacokinet. 2013;52(2):83-124. 30. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(8):493-507. 31. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-50. 32. Tukaj C. Enhanced proliferation of aortal smooth muscle cells treated by 1,25(OH)2D3 in vitro coincides with impaired formation of elastic fibres. Int J Exp Pathol. 2008;89(2):117-24. 33. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-33. 34. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-92. 35. Alley EW, Lopez J, Santoro A, Morosky A, Saraf S, Piperdi B, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2017;18(5):623-30. 36. Kindler H, Karrison T, Carol Tan Y-H, Rose B, Ahmad M, Straus C, et al. OA13.02 Phase II Trial of Pembrolizumab in Patients with Malignant Mesothelioma (MM): Interim Analysis. Journal of Thoracic Oncology. 2017;12(1):S293-S4. 37. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515(7528):577-81. 38. Leshem Y, O'Brien J, Liu X, Bera TK, Terabe M, Berzofsky JA, et al. Combining Local Immunotoxins Targeting Mesothelin with CTLA-4 Blockade Synergistically Eradicates Murine Cancer by Promoting Anticancer Immunity. Cancer Immunol Res. 2017;5(8):685-94. 39. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019;37(7):537-46. 40. Siegall CB, Liggitt D, Chace D, Mixan B, Sugai J, Davidson T, et al. Characterization of vascular leak syndrome induced by the toxin component of Pseudomonas exotoxin-based immunotoxins and its potential inhibition with nonsteroidal anti-inflammatory drugs. Clinical cancer research : an official journal of the American Association for Cancer Research. 1997;3(3):339-45. 41. Kuan CT, Pai LH, Pastan I. Immunotoxins containing Pseudomonas exotoxin that target LeY damage human endothelial cells in an antibody-specific mode: relevance to vascular leak syndrome. Clinical cancer research : an official journal of the American Association for Cancer Research. 1995;1(12):1589-94. 42. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(7):1148-59. 43. Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, et al. Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst. 2004;96(6):487-8. 44. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1999;17(11):3461-7. 45. Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK, et al. Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst. 2000;92(18):1534-5. 46. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e52. 47. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10(1):1-10. 48. Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, et al. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007;13(17):5144-9.
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15 appendices

| 15.1                                                                                                   | APPENDIX A: PERFORMANCE STATUS CRITERIA ECOG Performance Status Scale                                                  | Karnofsky Performance Scale   |                                                                    |           |                                 |                                   |                                 |
|--------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|-------------------------------|--------------------------------------------------------------------|-----------|---------------------------------|-----------------------------------|---------------------------------|
| Grade                                                                                                  | Descriptions                                                                                                           | Percent                       | Description                                                        |           |                                 |                                   |                                 |
| 100                                                                                                    | Normal,                                                                                                                | no                            | complaints,                                                        | no        |                                 |                                   |                                 |
| evidence of disease.                                                                                   |                                                                                                                        |                               |                                                                    |           |                                 |                                   |                                 |
| Normal activity. Fully active, able                                                                    |                                                                                                                        |                               |                                                                    |           |                                 |                                   |                                 |
| 0                                                                                                      | to                                                                                                                     | carry                         | on                                                                 | all       | pre-disease                     | Able to carry on normal activity; |                                 |
| performance without restriction.                                                                       | 90                                                                                                                     | minor                         | signs                                                              | or        | symptoms                        | of                                |                                 |
| disease.                                                                                               |                                                                                                                        |                               |                                                                    |           |                                 |                                   |                                 |
| Symptoms,                                                                                              | but                                                                                                                    | ambulatory.                   |                                                                    |           |                                 |                                   |                                 |
| Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or | Cares for self, unable to carry on                                                                                     |                               |                                                                    |           |                                 |                                   |                                 |
| sedentary                                                                                              | nature                                                                                                                 | (e.g.,                        | light                                                              | 70        | normal activity or to do active |                                   |                                 |
| housework, office work).                                                                               | work.                                                                                                                  |                               |                                                                    |           |                                 |                                   |                                 |
| 80                                                                                                     | Normal activity with effort; some  signs or symptoms of disease.                                                       |                               |                                                                    |           |                                 |                                   |                                 |
| 1                                                                                                      | Requires                                                                                                               | occasional                    | assistance                                                         |           |                                 |                                   |                                 |
| In                                                                                                     | bed                                                                                                                    | <50%                          | of                                                                 | the       | time.                           | 60                                | but is able to care for most of |
| Ambulatory and capable of all                                                                          | his/her needs.                                                                                                         |                               |                                                                    |           |                                 |                                   |                                 |
| 2                                                                                                      | self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                  | 50                            | Requires considerable assistance  and frequent medical care.       |           |                                 |                                   |                                 |
| 40                                                                                                     | Disabled, requires special care  and assistance.                                                                       |                               |                                                                    |           |                                 |                                   |                                 |
| 3                                                                                                      | In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours. | 30                            | Severely disabled, hospitalization  indicated. Death not imminent. |           |                                 |                                   |                                 |
| 20                                                                                                     | Very                                                                                                                   | sick,                         | hospitalization                                                    |           |                                 |                                   |                                 |
| indicated. Death not imminent.                                                                         |                                                                                                                        |                               |                                                                    |           |                                 |                                   |                                 |
| 4                                                                                                      | 100%                                                                                                                   | bedridden.                    | Completely                                                         |           |                                 |                                   |                                 |
| disabled. Cannot carry on any selfcare. Totally confined to bed or  chair.                                                                                                        | 10                                                                                                                     | Moribund,                     | fatal                                                              | processes |                                 |                                   |                                 |
| progressing rapidly.                                                                                   |                                                                                                                        |                               |                                                                    |           |                                 |                                   |                                 |
| 5                                                                                                      | Dead.                                                                                                                  | 0                             | Dead.                                                              |           |                                 |                                   |                                 |
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15.2 appendix b contraception requirements

A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile (see below) Women in the following categories are not considered WOCBP:
Premenarchal  
Premenopausal female with 1 of the following:
o Documented hysterectomy o Documented bilateral salpingectomy o Documented bilateral oophorectomy
Note: Documentation can come from the site personnel's review of the participant's medical records, medical examination, or medical history interview.  
Postmenopausal female o A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.  
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required.  
o Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment.
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male participants

Male participants with female partners of childbearing potential are eligible to participate if they agree to one of the following during the protocol defined time frame in section **2.1.1.12**:
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle
(abstinent on a long term and persistent basis) and agree to remain abstinent  
Use a male condom plus partner use of a contraceptive method with a failure rate of <1%
per year as described in **Table 11** when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant.
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female participants

Female participants of childbearing potential are eligible to participate if they agree to use a highly effective method of contraception consistently and correctly as described in Table 11 during the protocol-defined time frame in section 2.1.2.11.
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table 11 highly effective contraception

Failure rate of < 1% per year when used consistently and correctly.  
- Combined (estrogen- and progestogen- containing) hormonal contraception  
- Oral - Intravaginal - Transdermal - Injectable  
- Progestogen-only hormonal contraception  
- Oral - Injectable  
Highly Effective Methods That Have Low User Dependency Failure rate of <1% per year when used consistently and correctly.  
- Progestogen- only contraceptive implant - Intrauterine hormone-releasing system (IUS) - Intrauterine device (IUD) - Bilateral tubal occlusion - **Vasectomized partner**
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.
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- sexual abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)
Notes: Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical studies.  
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly).  
| PROGRESSIVE DISEASE ON PEMBROLIZUMAB Clinically Stable                                                                                                                                                           | Clinically Unstable                                                                                      |                                                                                                                                   |                                                                                      |                       |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|-----------------------|
| Imaging                                                                                                                                                                                                          | Treatment                                                                                                | Imaging                                                                                                                           | Treatment                                                                            |                       |
| First                                                                                                                                                                                                            | radiologic                                                                                               |                                                                                                                                   |                                                                                      |                       |
| evidence of PD by  RECIST 1.1                                                                                                                                                                                    | Repeat imaging at  4 to 8 weeks to  confirm PD.                                                          | May continue study  treatment at the  Investigator's  discretion while  awaiting confirmatory  tumor imaging by site  by iRECIST. | Repeat imaging at  4 to 8 weeks to  confirm PD per  Investigator's  discretion only. | Discontinue treatment |
| Repeat                                                                                                                                                                                                           | tumor                                                                                                    |                                                                                                                                   |                                                                                      |                       |
| imaging                                                                                                                                                                                                          | confirms                                                                                                 |                                                                                                                                   |                                                                                      |                       |
| PD                                                                                                                                                                                                               | (iCPD)                                                                                                   | by                                                                                                                                |                                                                                      |                       |
| iRECIST                                                                                                                                                                                                          | per                                                                                                      |                                                                                                                                   |                                                                                      |                       |
| Investigator  assessment                                                                                                                                                                                         | No                                                                                                       | additional                                                                                                                        | Discontinue treatment                                                                |                       |
| imaging required.                                                                                                                                                                                                | (exception is possible  upon consultation  with Sponsor).                                                | No                                                                                                                                | additional                                                                           | Not applicable        |
| imaging required.                                                                                                                                                                                                |                                                                                                          |                                                                                                                                   |                                                                                      |                       |
| Repeat                                                                                                                                                                                                           | tumor                                                                                                    |                                                                                                                                   |                                                                                      |                       |
| imaging                                                                                                                                                                                                          | shows                                                                                                    |                                                                                                                                   |                                                                                      |                       |
| iUPD by iRECIST  per Investigator  assessment                                                                                                                                                                    | Repeat imaging at  4 to 8 weeks to  confirm PD. May  occur at next  regularly  scheduled  imaging visit. | Continue                                                                                                                          | study                                                                                |                       |
| treatment                                                                                                                                                                                                        | at                                                                                                       | the                                                                                                                               |                                                                                      |                       |
| Investigator's  discretion.                                                                                                                                                                                      | Repeat imaging at  4 to 8 weeks to  confirm PD per  Investigator's  discretion only.                     | Discontinue treatment                                                                                                             |                                                                                      |                       |
| Repeat                                                                                                                                                                                                           | tumor                                                                                                    |                                                                                                                                   |                                                                                      |                       |
| imaging                                                                                                                                                                                                          | shows                                                                                                    |                                                                                                                                   |                                                                                      |                       |
| iSD, iPR, or iCR by  iRECIST per  Investigator  assessment.                                                                                                                                                      | Continue  regularly  scheduled  imaging  assessments.                                                    | Continue                                                                                                                          | study                                                                                |                       |
| treatment                                                                                                                                                                                                        | at                                                                                                       | the                                                                                                                               |                                                                                      |                       |
| Investigator's  discretion.                                                                                                                                                                                      | Continue  regularly  scheduled  imaging  assessments.                                                    | May                                                                                                                               | restart                                                                              | study                 |
| treatment if condition  has improved and/or  clinically stable per  Investigator's  discretion. Next tumor  image should occur  according to the regular  imaging schedule.                                      |                                                                                                          |                                                                                                                                   |                                                                                      |                       |
| iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified  Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; |                                                                                                          |                                                                                                                                   |                                                                                      |                       |  
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 1.1.
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15.4 appendix d second course

Tumor imaging must be performed within 28 days prior to restarting treatment with pembrolizumab. Investigator assessment with site radiology reading will be used to determine eligibility.  
The first on-study imaging assessment should be performed at 6 weeks ±7 days) after the restart of treatment. Subsequent tumor imaging should be performed every 6 weeks ±7 days or more frequently, if clinically indicated. Per RECIST 1.1, if tumor imaging shows initial PD, tumor assessment should be repeated 4 to 8 weeks later in order to confirm PD with the option of continuing treatment while awaiting radiologic confirmation of progression. Participants who obtain confirmatory imaging do not need to undergo scheduled tumor imaging if it is less than 4 weeks later and may wait until the next scheduled imaging time point, if clinically stable. Imaging should continue to be performed until disease progression, the start of a new anticancer treatment, withdrawal of consent, death, or investigator discretion, whichever occurs first. Disease progression may be confirmed 4 to 8 weeks after the first tumor imaging indicating PD, by the Investigator using iRECIST, in clinically stable participants. In participants who discontinue study treatment, tumor imaging should be performed at the time of treatment discontinuation (±4-week window). If previous imaging was obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not mandatory. In participants who discontinue study treatment due to documented disease progression, this is the final required tumor imaging. In participants who discontinue study treatment without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imaging every 6 weeks ±7 days until either the start of a new anticancer treatment, disease progression, death, or the end of the study, whichever occurs first.