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appendix iii

| AE Terms & Descriptions                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Dose Modification Algorithms                                                                                                                                                                                                                                                                                                                                             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Hypertension (A). Asymptomatic and persistent SBP of  140 and <170 mmHg, or DBP 90 and  <110 mmHg, or a clinically significant  increase in DBP of 20 mmHg (but still  below 110 mmHg).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Step 1. Continue investigational product (IP) at the current dose.  Step 2. Adjust current or initiate new antihypertensive medication(s). Step 3. Titrate antihypertensive medication(s) during next 2 weeks as  indicated to achieve well-controlleda blood pressure (BP). If BP is not wellcontrolled within 2 weeks, consider referral to a specialist and go to  scenario (B). Step 1.Consider reducing or interrupting IP, as clinically indicated.                                                                                                                                                                                                                                                                                                                                                                          |
| (B). Asymptomatic SBP 170 mmHg, or  DBP 110 mmHg, or failure to achieve  well-controlled BP within 2 weeks in  scenario (A).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Step 2. Adjust current or initiate new antihypertensive medication(s).  Step 3. Titrate antihypertensive medication(s) during next 2 weeks as  indicated to achieve well-controlled BP.  Step 4. Once BP is well-controlled, restart IP dose-reduced by 200 mg if  IP was interrupted.                                                                                   |
| (C). Symptomatic hypertension or  recurring SBP 170 mmHg, or DBP  110 mmHg, despite modification of  antihypertensive medication(s)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Step 1. Interrupt IP  Step 2. Adjust current or initiate new antihypertensive medication(s).  Step 3. Titrate antihypertensive medication(s) during next 2 weeks as  indicated to achieve well-controlled BP. Referral to a specialist for further  evaluation and follow-up is also recommended. Step 4. Once BP is well-controlled, restart IP dose-reduced by 200 mg. |
| (D). Refractory hypertension                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Discontinue IP and continue follow-up per protocol.                                                                                                                                                                                                                                                                                                                      |
| unresponsive to above interventions. Prolongation of QTc Interval: If the QTc is prolonged, the ECG should be manually read to ensure accuracy of the  reading. The values below refer to manually-read ECGs.  QTc  480 < 500 msec Continue IP; monitor as clinically indicated. QTc 500 msec Discontinue IP and continue follow-up per protocol. Proteinuria UPC <3 Continue pazopanib at the current dose; monitor as clinically indicated UPC ≥3 or 24-h urine protein 3g Step 1. Interrupt IP. Step 2. Weekly UPC or 24-hr urine protein monitoring until UPC is <3 or  24-hr urine protein is <3 grams. Then restart pazopanib dose-reduced  by 200 mg. Step 3. If UPC ≥3 or 24-h urine protein 3g recurs, repeat steps 1 and 2. Step 4. If UPC ≥3 or 24-hr urine protein ≥3 recurs and the pazopanib |                                                                                                                                                                                                                                                                                                                                                                          |  
Table A. Dose Modification Algorithms for Potential Pazopanib Treatment-related Adverse Events  
| AE Terms & Descriptions                                                                    | Dose Modification Algorithms   |
|--------------------------------------------------------------------------------------------|--------------------------------|
| dose can no longer be reduced, discontinue pazopanib and continue  follow-up per protocol. |                                |
| Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding Grade 1 For hemoptysis, interrupt pazopanib and contact the Sponsor to discuss  whether further treatment with pazopanib is appropriate. For other Grade I hemorrhage/bleeding events, continue pazopanib at the  current dose; monitor as clinically indicated. Grade 2 Step 1. If pulmonary or GI bleed (other than hemorrhoidal bleeding),  discontinue IP and continue follow-up per protocol. Otherwise, interrupt IP  until the AE resolved to  Grade 1.  Step 2. Restart IP; consider reducing dose and monitor as clinically  indicated.  Grade 3 or 4, or  Discontinue IP and continue with follow-up per protocol.    Recurrent  Grade 2 event after dose  interruption/reduction. Venous Thrombosis (DVT, PE) Grade 2 Continue IP at the current dose; monitor as clinically indicated Grade 3 Step 1. Interrupt IP.  Step 2. Initiate and monitor anticoagulation as clinically indicated.  Step 3. Resume IP at reduced dose <proposed: same dose> only if all of  the following criteria are met:   The subject must have been treated with anticoagulant at the  desired level of anticoagulation for at least one week.  No Grade 3 or 4 or clinically significant Grade 2, hemorrhagic  events have occurred while on anticoagulation treatment. Subject should be monitored as clinically indicated during anticoagulation  treatment and after resuming study treatment. When treating with warfarin,  international normalized ratio (INR) should be monitored within three to  five days after any change in IP dosing (eg, re-initiating, escalating/deescalating, or discontinuing IP), and then at least weekly until the INR is  stable. The dose of warfarin (or its derivatives) may need to be adjusted to  maintain the desired level of anticoagulation Grade 4 and/or PE Discontinue IP and continue follow-up per protocol.  Arterial Thrombosis/Ischemia Any Grade Discontinue IP and continue follow-up per protocol.                                                                                            |                                |  
| Thrombocytopenia/Neutropenia/Anemia: Investigate and document underlying cause Grade 1 or 2 Continue IP with current dose; monitor as clinically indicated.  Grade 3 or 4 Step 1. Interrupt IP until toxicity resolves to ≤ Grade 2. Step 2. Restart IP dose-reduced by 200 mg and monitor as clinically  indicated.  If no recovery to ≤ Grade 2 or recurrent Grade 3 or 4, discontinue IP and  follow-up per protocol. Palmar-plantar Erythrodysesthesia Syndrome Grade 1 Minimal skin changes or dermatitis  without pain (erythema, oedema, hyperkeratosis) 1. Continue IP at present dose Grade 2 Skin changes with pain; limiting  instrumental activities of daily living  (ADLs) (peeling, blisters, oedema, bleed,  hyperkeratosis) 1. Hold IP  2. Treat as clinically appropriate 3. Upon resolution to Level 1 or better restart IP with a dose  reduction to 400 mg 4. If recurrent consider a further dose reduction to 200mg or  discontinuation Grade 3 Severe skin changes with pain and  limiting self care ADLs 1. Discontinue IP Other Clinically Significant Adverse Eventsb Grade 1 Continue IP; monitor as clinically indicated. Grade 2 or 3, if clinically significant Step 1. Interrupt IP until toxicity resolves to  Grade 1. Step 2. Restart IP dose-reduced by 200 mg and monitor as clinically  indicated.  Grade 4 Discontinue IP and continue follow-up per protocol.  a. Well-controlled BP defined as SBP <140 mmHg and mean DBP <90 mmHg. b. AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 (NCI CTCAE v4)   |
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| Event                                                                                                                                                                                                                                              | Dose Modification Algorithms                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (A). ALT of ≤ 3.0 x ULN                                                                                                                                                                                                                            | Continue pazopanib at current dose with full panel LFTsa monitored as per protocol.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| (B). ALT >3.0 x ULN to  ≤8.0 x ULN without bilirubin elevation (defined  as total bilirubinb <2.0 x  ULN or direct bilirubin  ≤35%) and without  hypersensitivity symptoms  (e.g., fever, rash)                                                    | Liver Event Monitoring Criteria: (1) Continue pazopanib at current dose levels.  (2) Monitor subject closely for clinical signs and symptoms; perform full panel LFTsa weekly or  more frequently if clinically indicated until ALT/AST is reduced to Grade 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| (C). ALT >8.0 x ULN  without bilirubin elevation  (defined as total bilirubinb <2.0 x ULN or direct  bilirubin ≤35%) and  without hypersensitivity  symptoms (e.g., fever, rash)                                                                   | 1 st occurrence - Liver Event Interruption Criteria: (1) Interrupt pazopanib until toxicity resolves to Grade 1 or baseline. Report the event to  Sponsor as an SAE within 24 hours of learning of its occurrence. Make every reasonable  attempt to have subjects return to the clinic within 24 to 72 hours for repeat liver chemistries  and liver event follow up assessments. (2) Liver imaging and other laboratory investigations should be considered as clinically  appropriate. (3) Monitor subject closely for clinical signs and symptoms; perform full panel LFTs a weekly or  more frequently if clinically indicated until ALT/AST is reduced to Grade 1.  (4) If the subject is benefiting from the study treatment, contact Sponsor for possible re-challenge.  Re-treatment may be considered if ALL following criteria are met:  - ALT/AST reduced to Grade 1 - Total bilirubin <1.5 x ULN or direct bilirubin 35% - No hypersensitivity signs or symptoms - Subject is benefiting from therapy.  (5) Reintroduce pazopanib at a reduced dose of 400 mg once daily and measure serum liver  tests weekly for 8 weeks.  Recurrence - Liver Event Stopping Criteria: Discontinue pazopanib permanently and monitor subject closely for clinical signs and symptoms;  perform full panel LFTs a weekly or more frequently if clinically indicated until ALT/AST is reduced  to Grade 1. |
| (D). ALT >3.0 x ULN with  concomitant elevation in  bilirubinb (defined as total  bilirubin 2.0 x ULN; with  direct bilirubin >35%) or  with hypersensitivity  symptoms (e.g., fever, rash) or bilirubin is >3.0 x ULN  regardless of ALT values. | Liver Event Stopping Criteria: (1) Discontinue pazopanib immediately, report the event to Sponsor as an SAE within 24 hours of learning of its occurrence. Make every reasonable attempt to have subjects return to the  clinic within 24 hours for repeat liver chemistries and liver event follow up assessments. (2) Monitor subject closely for clinical signs and symptoms; record the appearance or worsening  of clinical symptoms of hepatitis, or hypersensitivity, such as fatigue, nausea, vomiting, right  upper quadrant pain or tenderness, fever rash or eosinophilia as relevant on the AE report  form. Perform full panel LFTs a weekly or more frequently if clinically indicated until LFTs are  reduced to Grade 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
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table b. guidelines for management

| Event                                                                                                                    | Dose Modification Algorithms                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                        |
|--------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| For isolated total bilirubinb elevation (>1.5 x to 3x ULN) without concurrent ALT  increases (defined as ALT  <3 X ULN). | (1)                                                                                                                                                                                                                                                                                                                                                    | Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT or other signs/symptoms of  liver injury) does not require dose modification. Pazopanib inhibits UGT1A1 and OATP1B1,  which can cause elevation of indirect (unconjugated) bilirubin in the absence of liver injury. |
| (2)                                                                                                                      | If bilirubin is >1.5 x ULN in the absence of ALT elevation, fractionation of bilirubin elevation  should be performed. If bilirubin is >35% direct (conjugated), further evaluation for  underlying cause of cholestasis should be performed. The dose of pazopanib should be  reduced to 200 mg per day in patients with moderate hepatic impairment. |                                                                                                                                                                                                                                                                                        |
| a.                                                                                                                       | Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin. Coagulation tests should be performed  as clinically indicated.                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                        |  
(1) Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT or other signs/symptoms of  
liver injury) does not require dose modification. Pazopanib inhibits UGT1A1 and OATP1B1, which can cause elevation of indirect (unconjugated) bilirubin in the absence of liver injury.  
(2) If bilirubin is >1.5 x ULN in the absence of ALT elevation, fractionation of bilirubin elevation  
should be performed. If bilirubin is >35% direct (conjugated), further evaluation for underlying cause of cholestasis should be performed. The dose of pazopanib should be  
reduced to 200 mg **per day in patients with moderate hepatic impairment.**  
a. Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin. Coagulation tests should be performed  
as clinically indicated.  
b. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable and a subject meets the  
criterion of total bilirubin >1.5 x ULN, then the event should be promptly reported as an SAE.  
Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; IP investigational product; LFT liver function tests; SAE serious adverse event; ULN upper limit of normal  
Appendix IV. General Chemotherapy Guidelines:  
For 21 day cycles, a patient will be permitted to have a new cycle of chemotherapy delayed up to 7 days (without this being considered to be a protocol violation) for major life events (e.g., serious illness in a family member, major holiday, vacation which is unable to be re-scheduled). Documentation to justify this decision should be provided.
It will be acceptable for individual chemotherapy doses to be delivered within a "24-hour window before and after the protocol-defined date" for "Day 1" treatment of 21 day cycles. If the treatment due date is a Friday, and the patient cannot be treated on that Friday, then the window for treatment would include the Thursday (1 day earlier than due) through the Monday (day 3 past due).  
For weekly regimens, it will be acceptable for individual chemotherapy doses to be delivered within a "24-hour window," for example; "Day 8 chemotherapy" can be delivered on Day 7, Day 8, or Day 9 and "Day 15 chemotherapy" can be given on Day 14, Day 15, or Day 16.  
Chemotherapy doses can be "rounded" according to institutional standards without being considered a protocol violation (most institutions use a rule of approximately +/- 5% of the calculated dose).  
Chemotherapy doses will be based on the subject's weight at baseline and will remain the same throughout the study. However, the doses will be recalculated if the patient has a weight change of greater than or equal to 10% from baseline.  
Maximum body surface area used for chemotherapy dose calculations will be 2.0 m2. For chemotherapy dose calculations that use mg/kg, there will be no maximum kilogram amount used (doses will be calculated on actual weight in kg).