untitled h1
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appendix i
performance status criteria

| ECOG Performance Status Scale                           | Karnofsky Performance Scale                                                                                                          |                                            |                                               |
|---------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|-----------------------------------------------|
| Grade                                                   | Description                                                                                                                          | Percent                                    | Description                                   |
| Normal, no complaints, no evidence of  disease.         |                                                                                                                                      |                                            |                                               |
| 0                                                       | Normal activity. Full active, able to carry on all predisease performance without restriction.                                                                                                                                      | 100                                        | Able to carry on normal activity; minor signs |
| 90                                                      | or symptoms of disease.                                                                                                              |                                            |                                               |
| Symptoms, but ambulatory. Restricted in physically      |                                                                                                                                      |                                            |                                               |
| 1                                                       | strenuous activity, but ambulatory and able to carry  out work of a light or sedentary nature (e.g., light  housework, office work). | Normal activity with effort; some signs or |                                               |
| 80                                                      | symptoms of disease.                                                                                                                 |                                            |                                               |
| Cares for self, unable to carry on normal               |                                                                                                                                      |                                            |                                               |
| 70                                                      | activity or to do active work.                                                                                                       |                                            |                                               |
| In bed < 50% of the time. Ambulatory and capable of all | Requires occasional assistance, but is able to                                                                                       |                                            |                                               |
| 2                                                       | self-care, but unable to carry out any work activities.                                                                              | 60                                         | care for most of his/her needs.               |
| Up and about more than 50% if waking hours.             | Requires considerable assistance and frequent                                                                                        |                                            |                                               |
| 50                                                      | medical care.                                                                                                                        |                                            |                                               |
| In bed > 50% of the time. Capable of only limited selfcare, confined to bed or chair more than 50% of                                                         | Disabled, requires special care and assistance.                                                                                      |                                            |                                               |
| 3                                                       | 40                                                                                                                                   |                                            |                                               |
| waking hours.                                           | Severely disabled, hospitalization indicated.                                                                                        |                                            |                                               |
| 30                                                      | Death not imminent.                                                                                                                  |                                            |                                               |
| 100% bedridden. Completely disabled. Cannot carry on    | Very sick, hospitalization indicated. Death                                                                                          |                                            |                                               |
| 4                                                       | any self-care. Totally confined to bed or chair.                                                                                     | 20                                         | not imminent.                                 |
| Moribund, fatal processes progressing                   |                                                                                                                                      |                                            |                                               |
| 10                                                      | rapidly.                                                                                                                             |                                            |                                               |
| 5                                                       | Dead.                                                                                                                                | 0                                          | Dead                                          |  
APPENDIX II
SUBJECT CAPSULE DIARY **FOR TWICE WEEKLY DOSING**
Add or delete columns and rows and revise the information in red as appropriate for the trial.  
Subject Name ______________________ Subject Study ID __________ Today's date ___/___/___ Drug _____________________________ Cycle \#:_______________________________
appendix i
instructions for the subject

1. Complete one form every *4 weeks* (one treatment cycle). 2. You will take ___*number of capsules* of THU 60 minutes before ___*number of capsules* of Decitabine on *______day of week* and
_______*day of week* (twice a week). Take the capsules *with or without food, as you wish.*
3. Record the date, the number of capsules of each drug that you took, and what time you took them. 4. If you have any comments or notice any side effects, please record them in the "Comments" column. 5. Please bring this form and your bottles of THU and Decitabine to your physician when you return for each appointment.  
6. Please sign your name at the bottom of the diary.  
| 6.                                                                                    | Please sign your name at the bottom of the diary.   | # of capsules taken   |                     |         |
|---------------------------------------------------------------------------------------|-----------------------------------------------------|-----------------------|---------------------|---------|
| ___ mg                                                                                | ___ mg                                              | ___                   | Comments            |         |
| ___                                                                                   |                                                     |                       |                     |         |
| mg                                                                                    | mg                                                  |                       |                     |         |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28            | Add/remove days as needed                           |                       |                     |         |
| Time of                                                                               |                                                     |                       |                     |         |
| Day                                                                                   | Date                                                | THU dose              | # of capsules taken | Time of |
| Decitabine dose                                                                       |                                                     |                       |                     |         |
| Subject's Signature: ____________________________________________ Date: _____________ |                                                     |                       |                     |         |
appendix iii
immune related adverse event management

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

Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. Opiates/narcotics may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis.  
  
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral crticosteroids.
renal adverse event management algorithm
gi adverse event management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy  
  
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
pulmonary adverse event management algorithm
gi adverse event management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging
pulmonary adverse event management algorithm
hepatic adverse event management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for
pulmonary adverse event management algorithm
endocrinopathy management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider visual field testing,  
  
switching to the equivalent dose of oral corticosteroids.
pulmonary adverse event management algorithm
skin adverse event management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.  
  
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.  
*Refer to NCI CTCAE v4 for term-specific grading criteria.
neurological adverse event management algorithm
skin adverse event management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.  
oce sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
appendix iv
a) recist criteria

Measurable Disease Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
appendix iv
non-measurable disease

All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are considered non-measurable disease. Bone lesions, CNS metastases, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable.
appendix iv
target lesions

All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor response.
appendix iv
non-target lesions

All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline. Non-target lesions include measurable lesions that exceed the maximum numbers per organ or total of all involved organs as well as non-measurable lesions. Measurements of these lesions are not required but the presence or absence of each should be noted throughout follow-up.
appendix iv
guidelines for evaluation of measurable

All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. Note: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the antitumor effect of a treatment.
appendix iv
clinical lesions

Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.
appendix iv
chest x-ray

Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable.
appendix iv
conventional ct and mri

These techniques should be performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and neck tumors and those of extremities usually require specific protocols.
appendix iv
ultrasound (us)

When the primary endpoint of the study is objective response evaluation, US should not be used to measure tumor lesions. It is, however, a possible alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules. US might also be useful to confirm the complete disappearance of superficial lesions usually assessed by clinical examination.
appendix iv
endoscopy and laparoscopy

The utilization of these techniques for objective tumor evaluation has not yet been fully and widely validated. Their uses in this specific context require sophisticated equipment and a high level of expertise that may only be available in some centers. Therefore, the utilization of such techniques for objective tumor response should be restricted to validation purposes in reference centers. However, such techniques can be useful to confirm complete pathological response when biopsies are obtained.
appendix iv
tumor markers n/a cytology and

These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain).
appendix iv
response criteria evaluation of target

Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded from the time treatment was started or from the time treatment was held or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment was started or held.
appendix iv
evaluation of non-target lesions

Complete Response (CR): Disappearance of all non-target lesions Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions Although a clear progression of "non-target" lesions only is exceptional, in such circumstances, the opinion of the treating physician should prevail, and the progression status should be confirmed at a later time by the review panel (or study chair). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response.
appendix iv
evaluation of best overall response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria  
Target Lesions Non-target Lesions New Lesions Overall Response  
| CR          | CR         | No        | CR   |
|-------------|------------|-----------|------|
| CR          | Incomplete | No        | PR   |
| response/SD |            |           |      |
| PR          | Non-PD     | No        | PR   |
| SD          | Non-PD     | No        | SD   |
| PD          | Any        | Yes or No | PD   |
| Any         | PD         | Yes or No | PD   |
| Any         | Any        | Yes       | PD   |  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be classified as having "symptomatic deterioration." Every effort should be made to document the objective progression, even after discontinuation of treatment. In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete response status.
appendix iv
confirmatory measurement/duration of response confirmation

The duration of overall response is measured from the time measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that progression of disease is objectively documented **while on study drugs** (taking as reference for progressive disease the smallest measurements recorded since the treatment was started or since treatment was last initiated). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.
appendix iv
duration of stable disease

Stable disease is measured from the start of the treatment until the criteria for progression are met **while on study drugs**, taking as reference the smallest measurements recorded since the treatment started or since treatment was last initiated.
appendix iv
time to disease progression

Time to disease progression will be recorded from the first day of protocol therapy until the criteria for disease progression are met while on sunitinib treatment, patient death from any cause or removal of the patient from study for any reason, whichever comes first.