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10.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisional impaired. For this reason and because there is a prospect of direct benefit from research participation (section **10.4**), all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH  
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisional impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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10.4 evaluation of benefits and

All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent. 10.4.2 Risks of exposure to ionizing radiation This research study involves two CT guided biopsies collected for research purposes only. Subjects undergoing two optional biopsy collections will be exposed to 1.5 rem. This amount of radiation is below the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety Committee. 10.4.3 Research Blood Collection Risks Risks of blood draws include pain and bruising in the area where the needle is placed, lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood cell count (anemia) can develop.
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10.4.4 other risks

Potential risks include the possible occurrence of any of a range of side effects which are listed in section 11 and in the Consent Document. The procedure for protecting against or minimizing risks will be to medically evaluate patients on a regular basis as described.
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10.4.5 benefits

The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor which may or may not have favorable impact on symptoms and/or survival.
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10.5 consent process and documentation

The procedures and tests involved in this study and the associated risks, discomforts and benefits of these processes, will be carefully explained to the patient and a signed informed consent document will be obtained prior to entry onto the study. For the optional biopsies for research in the protocol, the patient will consent at the time of the procedure with the original form going to Medical Records and a copy placed in the research record. If the patient refuses the optional biopsy at that time, the refusal will be documented in the medical record and in the research record. 10.5.1 Re-Consent via Telephone Consent via telephone may only be used when re-consent is required, and the patient is not scheduled to come for a clinic visit in a timely fashion. Telephone consent will be obtained and documented per OHSRP/IRBO and CCR policies and procedures.
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11 pharmaceutical information

Pembrolizumab (Keytruda) is approved for the treatment of patients with metastatic melanoma, NSCLC and HNSCC. Oxaliplatin is approved for the treatment of patients with advanced colon and colorectal cancer. Capecitabine is approved for the treatment of patients with adjuvant colon, metastatic colorectal and metastatic breast cancer. None of these drugs are approved for the treatment of patients with advanced biliary tract carcinoma, the use in the current protocol. The investigation is not intended to support a new indication for use or any other significant changes to labeling or advertising in any of the commercial agents used on the study. The investigation does not involve a route of administration or dosage level in use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug products.
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11.1 pembrolizumab

The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, distribution and usage of investigational product in accordance with the protocol and any applicable laws and regulations.  
Clinical Supplies will be provided by Merck as summarized in **Table 3**.  
Product Name & Potency **Dosage Form** Pembrolizumab 50 mg Lyophilized Powder for Injection Pembrolizumab 100 mg/ 4mL Solution for Injection  
| 11.1.1 Packaging and Labeling Information   |
|---------------------------------------------|  
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 11.2.1 Drug Product Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/ 4 mL vial Pembrolizumab (MK-3475) Solution for Infusion is a sterile, non-pyrogenic aqueous solution supplied in single-use Type I glass vial containing 100 mg/4 mL of pembrolizumab (MK-3475). The product is preservative-free solution which is essentially free of extraneous particulates. Cap color of MK-3475 (Pembrolizumab) 100 mg vials: Both red and salmon color caps may be used. Though the cap color may be different, the product inside the vial is the same MK-3475 drug product.  
11.1.2 Stability and Handling of Drug Product Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/ 4 mL vial: pembrolizumab (MK3475) Solution for Infusion vials should be stored at refrigerated conditions (2 - 8 °C) and protected from light.  
Note: vials should be stored in the original box to ensure the drug product is protected from light. Pembrolizumab (MK-3475) infusion solutions should be prepared in **0.9% Sodium Chloride**
Injection, USP (normal saline) or regional equivalent or 5% Dextrose Injection, USP (5%
dextrose) or regional equivalent and the final concentration of pembrolizumab (MK-3475) in the infusion solutions should be between 1 mg/mL and 10 mg/mL. Please note, the preferred diluent is 0.9% Sodium Chloride and 5% dextrose is only permissible if normal saline is not available. Local guidelines should be followed for collection of diluent information such as manufacturer, lot and expiry. When the diluent is provided by Merck, the drug accountability log should be used for collection of diluent information.
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pembrolizumab (mk-3475) should not be

Pembrolizumab (MK-3475) solutions may be stored at room temperature for a cumulative time of up to 4 hours. This includes room temperature storage of admixture solutions in the IV bags and the duration of infusion In addition, IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for up to 20 hours. If refrigerated, allow the IV bags to come to room temperature prior to use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Discard the drug product vial if extraneous particulate matter other than translucent to white proteinaceous particles is observed. Sites should follow their SOPs for drug transport and delivery, with all possible effort to minimize agitation of the drug product between the pharmacy and the clinic
- Do not use PEMBROLIZUMAB (MK-3475) if discoloration is observed.  
- DO NOT SHAKE OR FREEZE THE VIAL(S). - DO NOT ADMINISTER THE PRODUCT AS AN (INTRAVENOUS (IV) PUSH OR
BOLUS).  
- DO NOT COMBINE, DILUTE OR ADMINISTER IT AS AN INFUSION WITH
OTHER MEDICINAL PRODUCTS.  
- Any departure from the guidance listed in this manual, must be discussed with sponsor 11.1.3 Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or lists are not provided. 11.1.4 Storage and Handling Requirements Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. Clinical supplies may not be used for any purpose other than that stated in the protocol. 11.1.5 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 subjects and the amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational product will be destroyed at the site per institutional policy. It is the Investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
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11.2 oxaliplatin

Oxaliplatin will be supplied by the local pharmacy using supply purchased from commercial sources. 11.2.1 Toxicity The most common side effects of oxaliplatin include:  
- neutropenia, anemia, thrombocytopenia, hypertension, diarrhea, nausea, vomiting, constipation, oral mucositis, abdominal pain, anorexia, fatigue, injection site reactions, alopecia and dehydration
- Potentially serious toxicities include: - Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin has been observed in 2-3% of colon cancer patients. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy or desensitization protocol for continuation of therapy.  
- Peripheral sensory neuropathy (acute ≤ 14 days and persistent > 14 days) was reported in adjuvant patients treated with ELOXATIN as part of FOLFOX with a frequency of 92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6-month follow-up (Grade 1=31%, Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, Grade 3=1%).  
- Overall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) events. Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer.  
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES,
Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.
- Pulmonary Toxicity. oxaliplatin has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) and < 1% (grade 3) with no grade 4 events in the oxaliplatin plus infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5- fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the oxaliplatin combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the oxaliplatin plus 5-fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-fluorouracil/leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, ELOXATIN should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.  
- Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs.  
34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the oxaliplatin combination arm than in the control arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and venoocclusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases 11.2.2 Formulation
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11.2.2.1 powder

ELOXATIN is supplied in single-use vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free lyophilized powder for reconstitution. Lactose monohydrate is also present as an inactive ingredient.
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11.2.2.2 solution

ELOXATIN is supplied in single-use vials containing 50 mg, 100 mg or 200 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/ml. Water for Injection, USP is present as an inactive ingredient.
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11.2.3 preparation 11.2.3.1 powder

Reconstitution or final dilution must never be performed with a sodium chloride solution or other chloride containing solutions.  
The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the reconstituted solution without further dilution. The reconstituted solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP. After reconstitution in the original vial, the solution may be stored up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. ELOXATIN is not light sensitive. 11.2.3.2 Solution Do not freeze and protect from light the concentrated solution. A final dilution must never be performed with a sodium chloride solution or other chloride containing solutions. The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP. After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution, protection from light is not required. ELOXATIN is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.
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11.2.4 general

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present. Needles or intravenous administration sets containing aluminum parts that may come in contact with oxaliplatin should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds. 11.2.5 Stability and Storage Powder for solution for infusion: Store under normal lighting conditions at 25°C (77°F); excursions permitted to 15-30°C (5986°F). Concentrate for solution for infusion: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Do not freeze and protect from light (keep in original outer carton). 11.2.6 Administration procedures Please see section 3.3.2.2.
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11.2.7 incompatibilities

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 oxaliplatin and 5-fluorouracil/leucovorin has been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 oxaliplatin dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds; although, this has not been specifically studied.
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11.3 capecitabine

Chemical Name: 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine Other Names: xeloda Classification: Fluoropyrimidine carbamate M.W.: 359.35 11.3.1 Source Capecitabine will be supplied by the local pharmacy using supply purchased from commercial sources.
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11.3.2 toxicity

Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported.  
Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥**5% of**  
Patients  
| Patients Adverse Event                      | Capecitabine (n=596)   |         |    |
|---------------------------------------------|------------------------|---------|----|
| Total                                       | Grade 3                | Grade 4 |    |
| %                                           | %                      | %       |    |
| Number of Patients With > One Adverse Event | 96                     | 52      | 9  |
| Body System/Adverse Event GI Diarrhea       | 55                     | 13      | 2  |
| Nausea                                      | 43                     | 4       | -  |
| Vomiting                                    | 27                     | 4       | <1 |
| Stomatitis                                  | 25                     | 2       | <1 |
| Abdominal Pain                              | 35                     | 9       | <1 |
| Gastrointestinal Motility Disorder          | 10                     | <1      | -  |
| Constipation                                | 14                     | 1       | <1 |
| Oral Discomfort                             | 10                     | -       | -  |
| Upper GI Inflammatory Disorders             | 8                      | <1      | -  |
| Gastrointestinal Hemorrhage                 | 6                      | 1       | <1 |  
| Version Date: 03/19/2020 Adverse Event       | Capecitabine (n=596)   |         |    |
|----------------------------------------------|------------------------|---------|----|
| Total                                        | Grade 3                | Grade 4 |    |
| %                                            | %                      | %       |    |
| Number of Patients With > One Adverse Event  | 96                     | 52      | 9  |
| Body System/Adverse Event Ileus              | 6                      | 4       | 1  |
| Skin and Subcutaneous Hand-and-Foot Syndrome | 54                     | 17      | NA |
| Dermatitis                                   | 27                     | 1       | -  |
| Skin Discoloration                           | 7                      | <1      | -  |
| Alopecia                                     | 6                      | -       | -  |
| General Fatigue/Weakness                     | 42                     | 4       | -  |
| Pyrexia                                      | 18                     | 1       | -  |
| Edema                                        | 15                     | 1       | -  |
| Pain                                         | 12                     | 1       | -  |
| Chest Pain                                   | 6                      | 1       | -  |
| Neurological Peripheral Sensory Neuropathy   | 10                     | -       | -  |
| Headache                                     | 10                     | 1       | -  |
| Dizziness*                                   | 8                      | <1      | -  |
| Insomnia                                     | 7                      | -       | -  |
| Taste Disturbance                            | 6                      | 1       | -  |
| Metabolism AppetiteDecreased                 | 26                     | 3       | <1 |
| Dehydration                                  | 7                      | 2       | <1 |
| Eye Eye Irritation                           | 13                     | -       | -  |
| Vision Abnormal                              | 5                      | -       | -  |
| Respiratory Dyspnea                          | 14                     | 1       | -  |
| Cough                                        | 7                      | <1      | 1  |
| PharyngealDisorder                           | 5                      | -       | -  |
| Epistaxis                                    | 3                      | <1      | -  |
| Sore Throat                                  | 2                      | -       | -  |
| Musculoskeletal Back Pain                    | 10                     | 2       | -  |
| Arthralgia                                   | 8                      | 1       | -  |  
| Adverse Event                                          | Capecitabine (n=596)   |         |    |
|--------------------------------------------------------|------------------------|---------|----|
| Total                                                  | Grade 3                | Grade 4 |    |
| %                                                      | %                      | %       |    |
| Number of Patients With > One Adverse Event            | 96                     | 52      | 9  |
| Body System/Adverse Event Vascular VenousThrombosis    | 8                      | 3       | <1 |
| Psychiatric Mood Alteration                            | 5                      | -       | -  |
| Depression                                             | 5                      | -       | -  |
| Infections Viral                                       | 5                      | <1      | -  |
| Blood and Lymphatic Anemia                             | 80                     | 2       | <1 |
| Neutropenia                                            | 13                     | 1       | 2  |
| Hepatobiliary Hyperbilirubinemia                       | 48                     | 18      | 5  |
| - Not observed * Excluding vertigo NA = Not Applicable |                        |         |    |  
Tablets: 150 mg and 500 mg XELODA is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients in XELODA include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides. 11.3.4 Stability and Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). KEEP TIGHTLY CLOSED. Care should be exercised in the handling of XELODA. XELODA tablets should not be cut or crushed. Procedures for the proper handling and disposal of anticancer drugs should be considered. Any unused product should be disposed of in accordance with local requirements, or drug take back programs. Several guidelines on the subject have been published. 11.3.5 Administration procedures Please see section 3.3.2.1 11.3.6 Incompatibilities  
- Anticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in order to adjust the anticoagulant dose as needed.  
.  
- Phenytoin: Monitor phenytoin levels in patients taking XELODA concomitantly with phenytoin. The phenytoin dose may need to be reduced.  
- Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin.  
- CYP2C9 substrates: Care should be exercised when XELODA is co-administered with CYP2C9 substrates.  
- Food reduced both the rate and extent of absorption of capecitabine.
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13 appendices 13.1 appendix a-performance

| Grade                                                                                                                                                                                                                     | Descriptions  Normal activity. Fully active, able                                                                      |            |            |     |             |       |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|------------|------------|-----|-------------|-------|
| 0                                                                                                                                                                                                                         | to                                                                                                                     | carry      | on         | all | pre-disease |       |
| performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous  activity, but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light  housework, office work). |                                                                                                                        |            |            |     |             |       |
| 1                                                                                                                                                                                                                         | In                                                                                                                     | bed        | <50%       | of  | the         | time. |
| Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                                                                                      |                                                                                                                        |            |            |     |             |       |
| 2                                                                                                                                                                                                                         | In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours. |            |            |     |             |       |
| 3                                                                                                                                                                                                                         | 100%                                                                                                                   | bedridden. | Completely |     |             |       |
| disabled. Cannot carry on any  self-care. Totally confined to bed or chair.                                                                                                                                               |                                                                                                                        |            |            |     |             |       |
| 4  5                                                                                                                                                                                                                      | Dead.                                                                                                                  |            |            |     |             |       |
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13.2 appendix b- modified immune-related

This new classification is based on the recent learning from clinical studies with cancer immunotherapies that even if some new lesions appear at the beginning of a treatment or if the total tumor burden does not increase substantially, tumor regressions or stabilizations might still occur later. The irRC were created using bi-dimensional measurements (as previously widely used in the World Health Organization criteria). For this trial, the concepts of the irRC are combined with RECIST 1.1 to come up with the modified irRC. For modified irRC, only target and measurable lesions are taken into account. In contrast to the RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and response by imaging at 6 weeks after initial imaging and (b) do not necessarily score the appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and measurable new lesions does not increase by ≥ 20%. The same method of assessment and the same technique should be used to characterize each identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All measurements should be recorded in metric notation. The modified irRC based on RECIST 1.1 are displayed below.  
| Measurable Response                                                                                      | Non-Measurable Response   | Overall Response   |       |
|----------------------------------------------------------------------------------------------------------|---------------------------|--------------------|-------|
| Using Modified irRC                                                                                      |                           |                    |       |
| Index and New, Measurable                                                                                | Non-Index Lesions         | New, Non-          |       |
| Lesions (Tumor Burden)¹                                                                                  | Measurable Lesions        |                    |       |
| Decrease 100%                                                                                            | Absent                    | irCR²              |       |
| Absent                                                                                                   |                           |                    |       |
| Decrease 100%                                                                                            | Stable                    | Any                | irPR² |
| irPR²                                                                                                    |                           |                    |       |
| Decrease 100%                                                                                            | Unequivocal progression   | Any                |       |
| Decrease ≥ 30%                                                                                           | Absent / Stable           | Any                | irPR² |
| Decrease ≥ 30%                                                                                           | Unequivocal progression   | Any                | irPR² |
| Decrease < 30% to increase <                                                                             | Absent / Stable           | irSD               |       |
| Any                                                                                                      |                           |                    |       |
| 20%                                                                                                      |                           |                    |       |
| Decrease < 30% to increase <                                                                             | Unequivocal progression   | Any                | irSD  |
| 20%                                                                                                      |                           |                    |       |
| Increase ≥ 20%                                                                                           | Any                       | Any                | irPD  |
| Decreases assessed relative to baseline                                                                  |                           |                    |       |
| Assuming that the response (irCR and irPR) and progression (irPD) are confirmed by a second, consecutive |                           |                    |       |
| assessment at least 4 weeks apart (normally it should be done 6 weeks apart).                            |                           |                    |       |  
Overall Responses Derived from Changes in Index, Non-Index, and New Lesions assessment at least 4 weeks apart (normally it should be done 6 weeks apart).
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13.3 appendix c patient's medication

Cycle___________________ Patient's ID ___________________ INSTRUCTIONS TO THE PATIENT:
1. Complete one form for each cycle of treatment 2. You will take capecitabine _________mg twice a day. You should take the tablets with food at approximately the same time each day.  
3. Dose: ____________150 mg ______________ 500 mg 4. Record the date, the number of tablets that you took, and when you took them.  
5. If you have any comments or notice any side effects, please record them in the comments column.  
| 6.                                                                  | Please bring this form and your bottles of capecitabine when you come for your clinic visits.   |                   |                    |                   |                    |          |
|---------------------------------------------------------------------|-------------------------------------------------------------------------------------------------|-------------------|--------------------|-------------------|--------------------|----------|
| Day                                                                 | Date                                                                                            | Time of  AM  Dose | # of Tablets Taken | Time of  PM  Dose | # of Tablets Taken | Comments |
| 150 mg                                                              | 500mg                                                                                           |                   |                    |                   |                    |          |
| 150 mg                                                              | 500mg                                                                                           |                   |                    |                   |                    |          |
| 1  2  3  4  5  6  7  8  9  10  11  12  13  14  Patient's signature: | ___________________________________________________                                             |                   |                    |                   |                    |          |