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CTEP Protocol \#880 Clinical Center Protocol \# 12-C-0009 TLE:  Phase Ib Study of the Combination of Pazopanib, an Oral VEGFR Inhibitor, and ARQ 197 (Tivantinib), an Oral MET Inhibitor, in Patients With Refractory Advanced Solid Tumors  
| Institution:                           | Developmental Therapeutics Clinic (NCIDTC)   |                      |
|----------------------------------------|----------------------------------------------|----------------------|
| National Cancer Institute              |                                              |                      |
| 10 Center Drive                        |                                              |                      |
| Bethesda, MD 20892                     |                                              |                      |
| A. P. Chen, MDA-E, DCTD/NCI/NIH        |                                              |                      |
| Principal Investigator:                | 31 Center Drive                              |                      |
| NCI Associate                          | James H. Doroshow, MDA-E                     | D, NCI               |
| DCTD, NCI                              |                                              |                      |
| Investigators:                         | Alice Chen, MDA-E                            | DCTD, NCI            |
| Richard Piekarz, MDA-E                 |                                              |                      |
| Howard Streicher, MDA-E                | DCTD, NCI                                    |                      |
| Donald P. Bottaro, PhDE                | UB, CCR, NCI                                 |                      |
| Geraldine O'Sullivan Coyne, MD, PhDA-E | D, NCI                                       |                      |
| Non-NCI Associate                      | Lamin Juwara, CRNPA,B,E                      | Leidos Biomed, FNLCR |
| Investigators:                         | Apurva Srivastava, PhDE                      | Leidos Biomed, FNLCR |
| Responsible Research Nurse:            | Jennifer Zlott, RN                           |                      |
| Statistician:                          | arry Rubinstein, PhD, BRB/DCTD               |                      |  
Abbreviated Title: Phase I of Pazopanib and ARQ 197 in Solid Tumors.  
  
Clinical Center Protocol \# 12-C-0009 CTEP Monitors: John J. Wright, MD, PhD  
| NCI Supplied Agents:   | Pazopanib (NSC 737754)  ARQ 197 (NSC 750832)   |
|------------------------|------------------------------------------------|
| Protocol Version Date: | October 16, 2017                               |
| NCT Number:            | NCT01468922                                    |  
Roles: Aobtains information by intervening or interacting with living individuals for research purposes; Bobtains identifiable private information about living individuals; Cobtains the voluntary informed consent of individuals to be subjects; Dmakes decisions about subject eligibility; Estudies, interprets, or analyzes identifiable private information or data/specimens for research purposes 2
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precis background

- Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) signal transduction pathways have synergistic effects on promoting angiogenesis and growth factor expression. Hypoxia caused by treatment with VEGF inhibitors results in the upregulation of c-MET, the receptor for HGF. In a mouse model, combined blockade of VEGFR and c-Met significantly prolonged survival compared with inhibition of either target alone.  
- We hypothesize that co-administration of the MET inhibitor ARQ 197 will prevent the adaptive response to hypoxia resulting from treatment with the VEGFR inhibitor pazopanib, and conversely, that co-administration of pazopanib will prevent the effect of increased VEGF and reduced thrombospondin 1 in tumors after treatment with ARQ 197. Therefore, the combination of these agents may result in improved antitumor effects.  
Objectives:
- Establish the safety and tolerability of the combination of pazopanib with ARQ 197 in patients with refractory advanced solid tumors.  
- Establish the maximum tolerated dose (MTD) of the combination of pazopanib with ARQ 197 in patients with refractory advanced solid tumors.  
- Evaluate changes in MET and phospho-MET following treatment with pazopanib and ARQ 197 in patients with refractory advanced solid tumors.  
- Determine the pharmacokinetics (PK) of pazopanib and ARQ 197.  
- Determine and compare levels of total MET, phospho MET, HIF-1α, and epithelial-mesenchymal transition markers (e-cadherin, beta catenin) in tumor biopsy samples prior to and following administration of the study drugs.  
- Determine and compare levels of circulating levels of HGF, soluble MET (sMET), VEGF-A, and soluble VEGFR2 (sVEGFR2) prior to and following administration of the study drugs.  
- Determine polymorphisms in the CYP2C19 and correlate these with the observed toxicities, and the PK of ARQ 197.  
- Evaluate antitumor activity of the combination of pazopanib and ARQ 197 in patients with refractory advanced solid tumors.  
Eligibility:
- Adults with advanced, refractory solid tumors. Patients enrolling in the expansion cohorts must have advanced sarcoma, gastric cancer, and MET-expressing malignancies, have disease amenable to biopsy, and be willing to undergo pre-and post-treatment biopsies.  
Study Design:
- ARQ 197 will be administered orally twice daily and pazopanib orally once daily, in 28-day cycles.  
- Dose escalation will proceed using the traditional 3+3 design. - Once the MTD is established, an additional cohort will be accrued for pharmacodynamic (PD)
studies in tumor biopsies (required in the expansion phase). For the first week, patients will receive pazopanib alone to compare PK and PD results; combination therapy will be given from week 2 onwards.  
3 Clinical Center Protocol \# 12-C-0009  
| SCHEMA: DOSE ESCALATION PHASE Cycle 1 Cycle 2 onwards   |    |     |       |     |     |
|---------------------------------------------------------|----|-----|-------|-----|-----|
| D1                                                      | D8 | D15 | D22   | D28 |     |
| P + Aa                                                  | D1 | D8  | D15   | D22 | D28 |
| P + Aa                                                  |    |     |       |     |     |
| Tumor  Biopsyb                                          | D8 |     |       |     |     |
| PD  Samplingc                                           | D1 | D15 | C2 D1 |     |     |
| PK  Samplingd                                           | D1 | D15 |       |     |     |
| PG Samplinge                                            |    |     |       |     |     |  
a Pazopanib (P) po q day and ARQ 197 (A) po bid continuously throughout in patients on the dose escalation phase. Pazopanib will be taken on an empty stomach 1 hour before a meal and ARQ 197 will be taken with food.  
b Tumor biopsies (optional during the dose escalation phase) will be performed at baseline (pre-treatment)
and on C1D8, 8-12 hours after the Day 7 evening dose of ARQ 197 (taken 1 hour after pazopanib).  
c Blood samples for PD analyses collected at baseline (pre-treatment), on C1D1 (2, 4, and 6 hours after pazopanib), on C1D15 (pre-study drug administration), and on C2D1 (pre-study drug administration).  
d Blood samples for PK analyses will be collected on C1D1, before drug administration and 1, 2, 4, 6, and 12 hours after administration of pazopanib (12-hour time point is pre-second dose of ARQ 197), and on C1D15 before drug administration and 1, 2, 4, and 6 hours after administration of pazopanib.  
e A blood sample for pharmacogenomic (PG) analyses will be collected prior to drug administration on C1D1.
4  
| Cycle 1        | Cycle 2 onwards   |       |       |        |    |     |     |     |
|----------------|-------------------|-------|-------|--------|----|-----|-----|-----|
| D1             | D8                | D15   | D22   | D28 D1 | D8 | D15 | D22 | D28 |
| Cohort A       | P                 | P + A | P + A |        |    |     |     |     |
| a              |                   |       |       |        |    |     |     |     |
| Tumor  Biopsyb | D8                |       |       |        |    |     |     |     |
| PD  Samplingc  | D1                | C2 D1 |       |        |    |     |     |     |
| PK  Samplingd  | D8                |       |       |        |    |     |     |     |
| D1             | D7                |       |       |        |    |     |     |     |
| PG Samplinge   |                   |       |       |        |    |     |     |     |
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schema expansion phase

a Pazopanib (P) po q day taken on an empty stomach 1 hour before a meal and ARQ 197 (A) po bid taken with food.  
Cohort A: Single-agent pazopanib from C1D1 to D7, then the combination of ARQ 197 and pazopanib from C1D8.  
b Tumor biopsies (mandatory during the expansion phase) for **Cohort A** at baseline (pretreatment) **and** on C1D8 after pazopanib but before the first dose of ARQ 197.  
c Blood samples for PD analyses collected at baseline (pre-treatment), on C1D1 (2, 4, and 6 hours after pazopanib), on C1D8 (pre-study drug administration), and on C2D1 (pre-study drug administration).  
d Blood samples for PK analyses will be collected prior to drug administration and at multiple time points after drug administration in cycle 1 only: Cohort A: D1, pre-dose and 1, 2, 4, 6, and 12 hours after administration of pazopanib; D7, pre-dose and 1, 2, 4, and 6 hours after administration of pazopanib.  
e A blood sample for pharmacogenomic (PG) analyses will be collected prior to drug administration on C1D1. Clinical Center Protocol \# 12-C-0009 Dose Escalation:  
| Pazopanib                                                          | ARQ 197   |            |
|--------------------------------------------------------------------|-----------|------------|
| Dose Level                                                         | po q day  | po         |
| -2                                                                 | 200 mg    | 120 mg QD  |
| -1                                                                 | 400 mg    | 120 mg QD  |
| 1                                                                  | 400 mg    | 120 mg BID |
| (starting dose) 2                                                  | 600 mg    | 120 mg BID |
| 3                                                                  | 600 mg    | 240 mg BID |
| 4                                                                  | 800 mg    | 240 mg BID |
| 5                                                                  | 800 mg    | 360 mg BID |
| 6*                                                                 | 600 mg    | 360 mg BID |
| *If dose level 5 is above the MTD, dose level 6 will be evaluated. |           |            |  
| TABLE OF CONTENTS             |                                                                                                                                                                       |                                                                                             |
|-------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|
| PRÉCIS .                      |                                                                                                                                                                       |                                                                                             |
| SCHEMA: DOSE ESCALATION PHASE |                                                                                                                                                                       |                                                                                             |
| SCHEMA: EXPANSION PHASE       |                                                                                                                                                                       |                                                                                             |
| 1                             | OBJECTIVES ........................................................................................................................................................ 9 |                                                                                             |
| 1.1                           | Primary Objectives                                                                                                                                                    |                                                                                             |
| 1.2                           | Secondary Objectives                                                                                                                                                  |                                                                                             |
| 2                             | BACKGROUND ................................................................................................................................................ 9         |                                                                                             |
| 2.1                           | Targeting the VEGF and HGF Pathways                                                                                                                                   |                                                                                             |
| 2.2                           | Pazopanib                                                                                                                                                             |                                                                                             |
| 2.3                           | ARQ 197                                                                                                                                                               |                                                                                             |
| 2.4                           | Correlative Studies Background .                                                                                                                                      |                                                                                             |
| 2.5                           | RATIONALE                                                                                                                                                             |                                                                                             |
| 3                             | PATIENT SELECTION                                                                                                                                                     |                                                                                             |
| 3.1                           | Eligibility Criteria .                                                                                                                                                |                                                                                             |
| 3.2                           | Exclusion Criteria .                                                                                                                                                  |                                                                                             |
| 3.3                           | Inclusion of Women and Minorities                                                                                                                                     |                                                                                             |
| 3.4                           | Screening Evaluation .                                                                                                                                                |                                                                                             |
| 4                             | REGISTRATION PROCEDURES                                                                                                                                               |                                                                                             |
| S                             | TREATMENT PLAN .                                                                                                                                                      |                                                                                             |
| 5.1                           | Agent Administration                                                                                                                                                  |                                                                                             |
| 5.2                           | Definition of Dose-Limiting Toxicity                                                                                                                                  |                                                                                             |
| 5.3                           | General Concomitant Medication and Supportive Care Guidelines                                                                                                         |                                                                                             |
| 5.4                           | D Duration of Therapy                                                                                                                                                 |                                                                                             |
| 5.5                           | D Duration of Follow Up                                                                                                                                               |                                                                                             |
| 5.6                           | Criteria for Removal from Study                                                                                                                                       |                                                                                             |
| 6                             | DOSING DELAYS/DOSE MODIFICATIONS .                                                                                                                                    |                                                                                             |
| Dose Reduction .              |                                                                                                                                                                       |                                                                                             |
| 6.1                           | ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................ 48                                                                                       |                                                                                             |
| 7                             | 7.1                                                                                                                                                                   | Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ........................ 48 |
| 7.2                           | Adverse Event Characteristics                                                                                                                                         |                                                                                             |
| 7.3                           | Expedited Adverse Event Reporting                                                                                                                                     |                                                                                             |
| 7.4                           | Routine Adverse Event Reporting                                                                                                                                       |                                                                                             |
| 7.5                           | Secondary Malignancy                                                                                                                                                  |                                                                                             |
| 7.6                           | Second Malignancy                                                                                                                                                     |                                                                                             |
| 8                             | PHARMACEUTICAL INFORMATION                                                                                                                                            |                                                                                             |
| 8.1                           | Pazopanib (GW786034) (NSC 737754)                                                                                                                                     |                                                                                             |
| 8.2                           | ARQ 197 (NSC 750832)                                                                                                                                                  |                                                                                             |
| 8.3                           | Agent Ordering .                                                                                                                                                      |                                                                                             |
| 8.4                           | Agent Accountability .                                                                                                                                                |                                                                                             |  
CTEP Protocol \#880  
| Clinical Center Protocol # 12-C-0009                                                                                                                              |                                                                                                                                     |                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------|--------------------|
| CORRELATIVE/SPECIAL STUDIES                                                                                                                                       |                                                                                                                                     |                    |
| 9                                                                                                                                                                 | 9.1                                                                                                                                 | Pharmacodynamics . |
| 9.2                                                                                                                                                               | Pharmacokinetics .                                                                                                                  |                    |
| 9.3                                                                                                                                                               | Pharmacogenetics (PG)                                                                                                               |                    |
| 10 STUDY CALENDAR                                                                                                                                                 |                                                                                                                                     |                    |
| 10.1                                                                                                                                                              | Dose Escalation Phase                                                                                                               |                    |
| 10.2                                                                                                                                                              | Expansion Phase                                                                                                                     |                    |
| MEASUREMENT OF EFFECT                                                                                                                                             |                                                                                                                                     |                    |
| 11                                                                                                                                                                | Antitumor Effect - Solid Tumors                                                                                                     |                    |
| 11.1                                                                                                                                                              |                                                                                                                                     |                    |
| 11.2                                                                                                                                                              | Methods for Evaluation of Measurable Disease .......................................................................... 78          |                    |
| 1.3                                                                                                                                                               | Response Criteria                                                                                                                   |                    |
| Duration of Response                                                                                                                                              |                                                                                                                                     |                    |
| 11.4                                                                                                                                                              |                                                                                                                                     |                    |
| 11.5                                                                                                                                                              | Confirmatory Measurement .                                                                                                          |                    |
| DATA REPORTING / REGULATORY REQUIREMENTS                                                                                                                          |                                                                                                                                     |                    |
| 12                                                                                                                                                                |                                                                                                                                     |                    |
| 12.1                                                                                                                                                              | DATA Reporting .                                                                                                                    |                    |
| 12.2                                                                                                                                                              | CTEP Multicenter Guidelines                                                                                                         |                    |
| Collaborative Agreements Language.                                                                                                                                |                                                                                                                                     |                    |
| 12.3                                                                                                                                                              |                                                                                                                                     |                    |
| STATISTICAL CONSIDERATIONS .                                                                                                                                      |                                                                                                                                     |                    |
| 13                                                                                                                                                                |                                                                                                                                     |                    |
| 13.1                                                                                                                                                              | Study Design/Endpoints                                                                                                              |                    |
| 13.2                                                                                                                                                              | Sample Size/Accrual Rate                                                                                                            |                    |
| 13.3                                                                                                                                                              | Analysis of Secondary Endpoints                                                                                                     |                    |
| Reporting and Exclusions .                                                                                                                                        |                                                                                                                                     |                    |
| 13.4                                                                                                                                                              |                                                                                                                                     |                    |
| 14                                                                                                                                                                | HUMAN SUBJECTS PROTECTIONS                                                                                                          |                    |
| Justification for Subject Selection                                                                                                                               |                                                                                                                                     |                    |
| 14.1                                                                                                                                                              |                                                                                                                                     |                    |
| 14.2                                                                                                                                                              | Evaluation of Benefits and Risks/Discomforts ................................................................................... 87 |                    |
| 14.3                                                                                                                                                              | Consent and Assent Process and Documentation .................................................................................. 87  |                    |
| 14.4                                                                                                                                                              | Procedure for Protecting Against or Minimizing Any Potential Risks                                                                  |                    |
| 14.5                                                                                                                                                              | Patient Advocate .                                                                                                                  |                    |
| REFERENCES                                                                                                                                                        |                                                                                                                                     |                    |
| APPENDIX A: PERFORMANCE STATUS CRITERIA...................................................................... 92                                                  |                                                                                                                                     |                    |
| APPENDIX B: POTENTIAL DRUG INTERACTIONS ...................................................................................................................... 93 |                                                                                                                                     |                    |
| APPENDIX C: MEDICATIONS THAT MAY CAUSE QTc PROLONGATION ............. 98                                                                                          |                                                                                                                                     |                    |
| APPENDIX D: NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC                                                                                                  |                                                                                                                                     |                    |
| DISEASE                                                                                                                                                           |                                                                                                                                     |                    |
| APPENDIX E: PATIENT'S MEDICATION DIARY .                                                                                                                          |                                                                                                                                     |                    |
| APPENDIX F: LVEF DOSE MODIFICATION TABLE                                                                                                                          |                                                                                                                                     |                    |
| APPENDIX G: FACSIMILE TRANSMISSION FORM FOR SAMPLE SHIPMENT .... 105                                                                                              |                                                                                                                                     |                    |
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1 objectives 1.1 primary objectives

- Establish the safety and tolerability of the combination of pazopanib with ARQ 197 in patients with refractory advanced solid tumors.  
- Establish the maximum tolerated dose (MTD) of the combination of pazopanib with ARQ 197 in patients with refractory advanced solid tumors.  
- Evaluate changes in MET and phospho-MET following treatment with pazopanib and ARQ
197 in patients with refractory advanced solid tumors.
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1.2 secondary objectives

- Determine the pharmacokinetics (PK) of pazopanib and ARQ 197.  
- Determine and compare levels of total MET, phospho MET, HIF-1α, and epithelialmesenchymal transition markers (e-cadherin, beta catenin) in tumor biopsy samples prior to and following administration of the study drugs.  
- Determine and compare levels of circulating levels of HGF, soluble MET (sMET), VEGF-A,
and soluble VEGFR2 (sVEGFR2) prior to and following administration of the study drugs.  
- Determine polymorphisms in the CYP2C19 and correlate these with the observed toxicities, and the PK of ARQ 197.  
- Evaluate antitumor activity of the combination of pazopanib and ARQ 197 in patients with refractory advanced solid tumors.
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2 background 2.1 targeting the

Activation of the independent vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) signal transduction pathways has synergistic effects on promoting the formation of new blood vessels and inducing the expression of a number of growth factors, chemokines, and cytokines, including c-MET, the tyrosine kinase receptor for HGF [1-3]. The mechanism for this synergistic interaction is not known, but overexpression of HGF and c-MET are associated with aggressive tumors and poor prognosis in several cancers [4-6]. Combination therapy with inhibitors of HGF and VEGF signaling might therefore have superior anti-angiogenic activity in patients with cancer than either agent alone [7]. Sennino and colleagues investigated whether inhibiting VEGF and c-MET had an effect on tumor growth and survival in a mouse model using XL184 (BMS-907351), a tyrosine kinase inhibitor that blocks VEGFR and c-MET, and an antibody selective for mouse VEGF [8]. This study also evaluated whether treatment with a VEGF inhibitor upregulates the expression of cMET, as no in vitro data indicates that treatment with VEGF inhibitors results in both antitumor 9 activity and promotion of metastasis [9-11]. It has been suggested that one response to the hypoxia caused by treatment with VEGF inhibitors is upregulation of c-MET [12].  
As shown in Figure 1, combination blockade of VEGFR and c-MET with XL184 significantly  
  
(P < 0.05) prolongs survival compared to treatment with vehicle or anti-VEGFR antibody alone in the RIP-Tag2 transgenic mouse model, a spontaneous and highly vascularized pancreatic islet cell cancer [8].  
Figure 1: Increased survival of RIP-Tag2 transgenic mice following treatment with the VEGFR and c-MET inhibitor XL184 compared to treatment with anti-VEGF
antibody or vehicle.  
The extent of liver metastasis was also less in RIP-Tag2 mice treated with combination blockade of VEGFR and c-MET than in mice treated with anti-VEGF antibody alone (Figure 2).  
  
Figure 2: Confocal micrographs of liver sections stained for SV40 T-antigen (expression is limited to islet insulin-producing β cells) from RIP-Tag2 mice treated from 14 to 17 weeks of age with vehicle (A), anti-VEGF antibody **(B)** or XL184 (C). The number and size of liver metastases (indicated with white arrows) are greatest after treatment with anti-VEGF antibody, less prevalent (i.e., smaller and scattered) after treatment with vehicle, and undetectable after treatment with XL184 (P < 0.05, measured mm2).  
Of relevance to this protocol is that c-MET expression was significantly increased in pancreatic  
 islet cell tumors in RIP-Tag2 mice after treatment with anti-VEGF antibody (Figure 3) [8]. Overexpression of c-MET is sufficient to induce hepatocellular carcinomas in transgenic mice [13, 14]. Data from the Vande Woude lab also support a role for HGF in promoting angiogenesis through upregulated expression of VEGF and downregulated expression of thrombospondin 1 (TSP-1), a key negative regulator of angiogenesis [4]. Agents that inhibit c-MET and VEGF are therefore of great clinical interest [7, 13, 15, 16].  
Figure 3: PCR measurements of c-MET expression in pancreatic islet cell tumors in transgenic RIP-Tag2 mice after treatment with vehicle or anti-VEGF antibody for 1 week.  
N = 5 mice/group. *P < 0.05 vs. vehicle.
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2.2 pazopanib

Pazopanib is a highly selective and potent inhibitor of VEGFR-1, -2 and -3, PDGFR-alpha, PDGFR-beta, and c-kit tyrosine kinases which are integral components of several cell signaling pathways aberrantly activated during carcinogenesis (Figure 4) [17-19]. Pazopanib has been shown to selectively inhibit VEGF-induced endothelial cell proliferation, angiogenesis and tumor growth in multiple human tumor xenograft models, including prostate, colon, lung, melanoma, breast, and renal cancer. Preclinical PK/PD studies have shown that a plasma concentration of ≥40 µmol/L pazopanib is required for optimal inhibition of VEGFR-2 in vivo [17]. Clinically, pazopanib has demonstrated activity in patients with renal cell cancer; current Phase I, II, and III trials of pazopanib as single therapy and in combination with paclitaxel or the tyrosine kinase inhibitor of HER2 and EGFR, lapatinib, are ongoing or planned. These trials are accruing patients with several tumor types including liver cancer, metastatic renal cell carcinoma, malignant glioma, non-small cell lung cancer, advanced breast cancer, multiple myeloma, ovarian cancer, and various types of sarcomas.
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clinical experience

Approximately 3000 subjects with cancer have been enrolled in clinical studies of pazopanib as of September 2009. In October 2009, the FDA approved pazopanib tablets for the treatment of subjects with advanced renal cell carcinoma (RCC). In addition, several clinical studies evaluating pazopanib in non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, soft tissue sarcoma (STS), cervical cancer, hepatocellular cancer (HCC), multiple myeloma (MM), and glioma are in progress or have been completed.
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clinical efficacy

In a randomized, double-blind, placebo-controlled phase 3 study evaluating the efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated subjects with advanced RCC, the median progression-free-survival (PFS) was significantly prolonged with pazopanib compared with placebo in the overall study population (9.2 vs. 4.2 months). The objective response rate (RR) was 30% with pazopanib and only 3% with placebo (28). In subjects with ovarian cancer, 31% of subjects experienced a CA-125 response to pazopanib, with a median time to response of 29 days and median duration of response of 113 days (Investigator's Brochure, 2010). Median PFS was 84 days and the overall RR was 18%. In advanced or metastatic STS, the rate of PFS at 12 weeks was 43.9% for leiomyosarcoma, 48.6% for synovial sarcoma, 26.3% for adipocytic sarcoma, and 39% for other types of sarcoma (29). In a phase 2 trial of subjects with early-stage NSCLC, 86% of subjects experienced a reduction in tumor volume after short-term, preoperative use of pazopanib (~2-6 weeks) as assessed by high-resolution CT scanning (30). Interim results from a phase 2 study of pazopanib in subjects with recurrent or metastatic breast invasive breast cancer showed that the clinical benefit rate was 26% (31). The median TTP was 3.7 months, and 50% of subjects with measurable target lesions had some decrease in size. PFS at 3 and 6 months was 55% and 28%, respectively. Preliminary results from a randomized study in subjects with first-line advanced ErbB2-positive advanced or metastatic breast cancer showed that a higher response rate (36.2% vs. 22.2%) was  
observed in subjects on combination lapatinib 1000 mg once daily + pazopanib 400 mg once daily compared to monotherapy lapatanib 1500 mg once daily (32). In a randomized phase 2 study of pazopanib vs. lapatinib vs. the combination of pazopanib/lapatinib in advanced and recurrent cervical cancer, there was a 34% reduction in risk for progression in subjects receiving pazopanib relative to lapatinib. The median PFS was 17.1 weeks in the lapatinib group and 18.1 weeks in the pazopanib group (33). Interim analysis of data from 26 subjects showed that pazopanib has both a favorable toxicity profile and promising clinical activity in subjects with advanced and progressive differentiated thyroid cancers (34). Five confirmed partial responses (PRs) (19%) were reported. Pazopanib has not shown efficacy in phase 2 studies conducted in MM or glioma (Investigator's Brochure, 2010)
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safety

The randomized, phase 3 study in mRCC subjects provided a key comparison of safety with pazopanib compared to placebo (28). The overall frequency of adverse events (AEs) reported during the study was higher in the pazopanib arm (92%) compared with placebo (74%). The most common AEs reported in >20% of subjects in the pazopanib arm were diarrhea (52%), hypertension (40%), hair color change (depigmentation; 38%), nausea (26%), anorexia (22%), and vomiting (21%). Most of the events were grade 1 or 2. A higher number of grade 3 AEs were reported in the pazopanib arm (33%) compared with the placebo arm (14%). The most frequent grade 3 AEs in the pazopanib arm were increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), hypertension, and diarrhea. The frequency of grade 4 and grade 5 AEs was similar between the pazopanib and placebo arms: grade 4 in 7% and 6%, respectively; grade 5 in 4% and 3%, respectively. A comprehensive review of all completed and ongoing pazopanib clinical trials with a cut-off date of September 2009, lists 15 most commonly occurring serious AEs (SAEs) (Investigator's Brochure, 2010). Vomiting and diarrhea are the most commonly reported SAEs across all the pazopanib studies. As a consequence of this, dehydration is also seen with pazopanib treatment. For most reports, the AEs resolved after supportive treatment such as antiemetics, antidiarrheal agents, and IV fluids. GI perforation is commonly associated with VEGF pathway inhibitors. This may manifest as abdominal pain which is not uncommon in cancer subjects for many reasons. Of the 42 subjects in pazopanib trials with SAEs of abdominal pain, only three had a documented underlying intestinal perforation. In July 2006, the DCTD, NCI, issued an Action Letter to investigators using pazopanib describing the occurrence of bowel perforations in subjects on pazopanib clinical trials. Dyspnea is also frequently seen in pazopanib-treated subjects and may reflect the underlying disease under treatment. Anemia is commonly seen in cancer subjects in association with chemotherapy, hemorrhage, or infection. The SAEs of pyrexia were attributed to multiple causes: concurrent infections, the underlying malignancy, hepatic events, other concomitant medications, and unknown causes. Hepatic events are thought to be on-target tyrosine kinase inhibitor (TKI) class effects, as hepatic enzyme elevations have been seen with other agents of this class. Careful clinical evaluation is, therefore, warranted in subjects with hepatic abnormalities. Pneumonia can be a complication of chemotherapy or can result from debilitation and advanced disease. Review of the 33 SAEs showed the presence of an underlying cause other  
than pazopanib in 19 of the 30 subjects. Fatigue and asthenia are commonly reported and have multiple causes. Hypertension observed with pazopanib is a known class effect. There have been 30 SAEs of hypertension and 3 SAEs of hypertensive crisis in pazopanib clinical trials. There were 28 subjects who were effectively treated with antihypertensive medication initiation or dose adjustment, while 4 had no such treatment. Although there were 29 SAEs of pleural effusion, the body of data does not suggest that any of these cases were due to pazopanib. There have been 24 SAEs of pulmonary embolism (PE) reported in pazopanib trials. This is of particular relevance since other members of this class have been associated with PE and other venous thromboembolic events. In addition, there have been reports of cardiac and cerebral ischemic events, GI perforation or hemorrhage, pulmonary hemorrhage, cerebrovascular hemorrhage, QT prolongation, and Torsades de Pointes in pazopanib clinical trials. Cases of hepatic failure, including fatalities, have been reported during the use of pazopanib. Two of 977 patients (0.2%) died with disease progression and hepatic failure in trials that supported the renal cell carcinoma (RCC) indication. One of 240 patients (0.4%) died of hepatic failure in the randomized soft tissue sarcoma (STS) trial. In RCC monotherapy trials using pazopanib, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported as very common (≥10%), and abnormal hepatic function and hyperbilirubinemia have been reported as common (≥1% to <10%) adverse reactions. In STS monotherapy trials using pazopanib, increased ALT and AST have been reported as common (≥1% to <10%) adverse reactions. Elevated ALT (>3X ULN) and concurrent elevated ALT (>3X ULN) and bilirubin (>2X ULN) have been observed primarily between weeks 3 and 9 of therapy in pazopanib clinical trials. A comparison across trials with pazopanib indicates ALT >3X ULN in 1% and approximately 5% of treated patients at weeks 2 and 3, respectively. Most new cases of ALT >3X ULN occurred by week 9. More frequent monitoring between weeks 3 and 9 may lead to earlier detection of elevated serum liver tests and hepatotoxicity in patients taking pazopanib.
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clinical pharmacokinetics

The oral bioavailability of pazopanib reflects absorption that is limited by solubility above doses of 800 mg once daily (Investigator's Brochure, 2010). Increases in doses above 800 mg to 2000 mg, in the fasted state will not result in increased systemic exposure. Geometric mean pazopanib t½ values ranged from 18.1-52.3 hours. The mean t½ was 30.9 hours in the 800 mg once daily group, in phase 2 and 3 trials. Oral absorption is significantly enhanced when dosed with food; therefore, it is recommended to administer pazopanib on an empty stomach, at least 12 hours after a meal. Preliminary information on the pharmacokinetics (PK) of pazopanib administered in combination with lapatinib has been reported (35). Thirty-three subjects received doses of lapatinib ranging from 750-1500 mg once daily along with pazopanib at doses of 200-500 mg  
daily. Preliminary mean plasma concentrations 24 hours after administration (C24) on day 22 were ~19 mcg/mL and 23 mcg/mL after pazopanib doses of 250 mg and 500 mg, respectively. These values are similar to the mean C24 values observed after administration of 800 mg pazopanib alone (23.1 mcg/mL). Plasma lapatinib concentrations at 750-1500 mg daily were similar to those observed after monotherapy. Concurrent administration of pazopanib and lapatinib was generally well tolerated; coadministration of lapatinib may alter the PK of pazopanib (Dejonge et al., 2006). Preliminary PK information on the combination of pazopanib and paclitaxel administered to subjects with advanced cancer has been reported (36). Twelve subjects received paclitaxel (1580 mg/m2 on days 1, 8, and 15 every 28 days) and pazopanib at 400 or 800 mg/day starting on day 2 of the first cycle. Coadministration of pazopanib increased paclitaxel mean Cmax and AUC0-8 approximately 20-35% (36). Age, body weight, gender, and race had no significant influence on pazopanib PK.
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potential drug interactions

Pazopanib is metabolized primarily by CYP3A4, and systemic exposure to pazopanib is altered by inhibitors and inducers of this enzyme. The concomitant use of strong CYP3A4 inhibitors should be avoided. If co-administration of a strong CYP3A4 inhibitor is warranted, a dose reduction to 400 mg is recommended. Grapefruit may also increase plasma concentrations of pazopanib and should be avoided. CYP3A4 inducers such as rifampicin may decrease plasma concentrations; therefore, an alternative concurrent medication with none or minimal enzyme induction should be used. Concommitant use of medications that have narrow therapeutic windows and that are substrates of CYP3A4, CYP2D6 or CYP2C8 should occur only with caution. Concommitant medications that have narrow therapeutic windows and are substrates of CYP3A4, CYP2D6 or CYP2C8 should be used with caution. If possible, medications that are not substrates for these enzymes and/or do not have narrow therapeutic windows should be substituted.
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2.3 arq 197

The c-MET RTK mediates the signals for a variety of physiological processes that have implications for oncogenesis, including migration, invasion, cell proliferation, and angiogenesis. A wide variety of human cancers exhibit constitutively dysregulated c-MET activity, either through over-expression of the c-MET kinase, activating mutations in c-MET, or increased autocrine or paracrine secretion of the c-MET ligand hepatocyte growth factor/scatter factor (HGF/SF). These alterations have been strongly implicated in tumor progression and metastasis in a variety of cancers, and a high constitutive activation of the c-MET RTK has been correlated with poor clinical prognosis. c-MET can be activated in both a ligand-dependent manner, by the overexpression of c-MET and/or its ligand HGF, or a ligand-independent manner as in the case of activating mutations of c-MET such as those described in certain gastric carcinoma-derived cell lines. The cell line  
MKN-45, has amplified MET gene in the absence of mutation and superabundance of MET
protein at the cell surface, which is fully active in the complete absence of HGF. Activation and autophosphorylation of c-MET results in the binding and phosphorylation of adaptor proteins such as Gab1, Grb2, Shc and c-Cbl, and results in the subsequent activation of signaling pathways, including the PI3K/Akt, FAK, STAT and Ras/MEK/Erk pathways that play various roles in cell survival, proliferation, invasion, and angiogenesis. In the melanocyte lineage, cMET expression is upregulated by microphthalmia-associated transcription factor (MITF), which has been implicated in the oncogenesis of melanoma and other cancers [20, 21]. The presence of c-MET in most cancers, and its role in controlling multiple signal transduction pathways involved in tumor growth render this enzyme a logical therapeutic target for human cancer. ARQ 197 is a potent non-ATP competitive RTK inhibitor with high selectivity for the c-MET RTK, as determined by biochemical and cellular assays. ARQ 197 has growth inhibitory activity in breast, prostate, colon and pancreatic carcinoma xenograft models. ARQ 197 has also been shown to inhibit metastasis in a metastatic orthotopic colon cancer xenograft model [13, 22, 23]. A comprehensive review of ARQ 197 can be found in the ARQ 197 Investigator's Brochure (2010).
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2.3.1 nonclinical pharmacology in vitro

ARQ 197 selectively inhibits the *in vitro* biochemical activity of recombinant c-MET
with a Ki of approximately 355 nM. The potency of ARQ 197 inhibition of c-MET
activity was independent of ATP concentration, suggesting that the mode of inhibition of ARQ 197 is of a non-competitive nature. While ARQ 197 inhibits c-MET kinase activity, it is not a promiscuous kinase inhibitor. When ARQ 197 was profiled against 230 protein kinases at a nominal concentration of 5 or 10 μM, ARQ 197 inhibited only 4 protein kinases greater than 20%. These data suggest that ARQ 197 is a highly selective c-MET kinase inhibitor. In cell-based kinase assays, ARQ 197 inhibited HGF-induced activation of c-MET
(gauged by autophosphorylation) with an IC50 between 0.1–0.5 μM in multiple human cancer cell lines. This suppression was effective for at least 8 to 12 hours after withdrawal of ARQ 197, demonstrating a sustained durability of c-MET inhibition by ARQ 197. Furthermore, ARQ 197 decreased phosphorylation of most of the c-MET downstream effectors including FAK, STAT-3, Erk-1 and Erk-2, but not Akt. This suggests that, through c-MET inhibition, ARQ 197 also induces a decrease in the phosphorylation and activation of many downstream targets in the pathways served by this oncogenic kinase. ARQ 197 showed broad-spectrum *in vitro* anticancer activity against human tumor lines, including those derived from breast, pancreas, colon, gastric, and lung. The potency of ARQ 197 in cancer cells expressing detectable c-MET ranges from 0.1–0.6 μM. By contrast, human cells lacking or minimally expressing c-MET such as NCI-H661 (nonsmall cell lung cancer; NSCLC) and NCI-H446 (small cell lung cancer) yielded IC50 values approximately 10-fold higher, indicating a correlation between the presence of c-  
MET and the sensitivity of the cells towards ARQ 197. The ability of ARQ 197 to inhibit c-MET phosphorylation correlates with its ability to inhibit growth and induce apoptosis in c-MET expressing cancer cells. Overexpression of c-MET correlates with tumor cell migration and invasiveness, and invasion assays demonstrated that ARQ 197 potently inhibited invasion in c-MET
expressing tumor cell lines (IC50s of approximately 0.3–0.45 μM), but less so in non-cMET expressing lines (IC50 = 5.4 μM). In a wound healing assay, ARQ 197 also inhibited migration of NCI-H441 cells (human lung adenocarcinoma) in response to HGF. Overall, these results indicate that ARQ 197 has anticancer activity, an effect which is mediated via c-MET inhibition. Another study assessed a panel of 64 human cancer cell lines encompassing a spectrum of genotypes and tissue origins. The combination of ARQ 197 and sorafenib showed synergistic cytotoxicity in nine cell lines, including three NSCLC cell lines, two breast cancer cell lines, a melanoma cell line, a renal clear cell carcinoma cell line, a cervical carcinoma cell line, and a squamous cell carcinoma cell line. An additive effect was seen with the ARQ 197/sorafenib combination across a wide range of 40 human cancer cell lines including, but not limited to, 5 colon cancer lines, 5 breast cancer cell lines, 4 additional NSCLC cell lines, and 3 hepatocellular carcinomas (HCC).
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in vivo efficacy

When administered via daily oral dosing, ARQ 197 was efficacious against multiple human cancer xenograft models. Beginning at a dose level of 200 mg/kg, tumor growth inhibition was seen in breast (79%), colon (39%), pancreatic (58%), prostate (72%), and gastric (52%) models. Increasing the dose to 300 mg/kg improved tumor inhibition in colon (55%), pancreatic (60%), and prostate (77%) models. ARQ 197 was well tolerated in these studies with no drug related clinical signs or deaths. There was no significant change in body weight at any of the dose levels tested. Furthermore, the antitumor activity of ARQ 197 is accompanied by the ablation of c-MET activity, as assessed by the decreased level of phosphorylated c-MET in the dissected xenograft tumor tissue. This suggests a potential mechanism-based clinical biomarker. A study conducted with the NCI-H522 NSCLC cell line suggests that antitumor effects of ARQ 197 and sorafenib were modestly additive in human tumor xenograft models. The combination was well tolerated, with no body weight changes or deaths observed.
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nonclinical pharmacokinetics

The pharmacokinetics of ARQ 197 were evaluated and compared in mice, rats, and dogs using different dosing routes, levels, and formulations. In general, exposure to ARQ 197 increased as the dose was increased. Overall, the corresponding increases in AUC0-inf and Cmax were not dose proportional. The t1/2 of ARQ 197 generally ranged from 1–4.5 hours across all studies and all species, though there were some exceptions. For instance, rats displayed a highly variable t1/2 (1.48 - 37.8 hours), the reason for which is unknown.  
Bioavailability after single dosing was somewhat variable between species: 16-35% in rats, 33-60% in dogs, and 21-37% in mice. After multiple dosing in 7- day, 28- day, 8-  
week, and 26- week studies, there were no consistent changes in Cmax and AUC values in rat or dog, indicating no marked accumulation of ARQ 197.
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metabolism

Mass balance and tissue distribution studies indicated that the primary route of elimination of ARQ 197 is fecal and that ARQ 197 generally did not accumulate (after 96 hours) in any of the tissues tested. Data from *in vitro* metabolism studies suggest that ARQ 197 is relatively stable in human liver microsomes with a t1/2 of 29 min. The t1/2 of ARQ 197 in male dog liver microsomes was similar to that of human liver microsomes with a t1/2 of 29 min (t1/2 in female dog liver microsomes was 20.5 min).  
From studies conducted with individual CYP P450 isozymes, ARQ 197 was rapidly metabolized by CYP2C19 (t1/2 = 2.83 min) and moderately metabolized by CYP 3A4 (t1/2 = 16.3 min). The t1/2 values for the other CYP P450s (1A2, 2C9, 2D6, and 2C8) tested were all greater than 27.4 min. Drugs which affect the activity of CYP2C19 or CYP3A4 may markedly alter the plasma concentration of ARQ 197. The IC50 of ARQ 197 was evaluated for each CYP 450 isoform (1A2, 2C8, 2C9, 2C19, 2E1 and 3A4), and all were greater than 10 μM.
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nonclinical toxicology

Preclinical toxicity for ARQ 197 was assessed in the rat and beagle dog in single and repeat dose studies of up to 26 weeks in duration. In 28-day repeat-dose studies, clinical pathology signs typically observed at the high dose (45 mg/kg) included lower red cell mass, lower absolute reticulocyte count, and lower absolute neutrophil and monocyte counts for males and females. In addition, females had lower absolute lymphocyte and eosinophil counts. Microscopic findings at high doses included depletion of lymphocytes in the thymus, femur and sternum bone marrow depletion, and hypertrophy and vacuolation in peripherolobular hepatocytes. Importantly, these clinical and anatomic pathology findings were reversed by 2 weeks after cessation of dosing.
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2.3.2 clinical experience

The pharmacokinetics, metabolism, safety, and efficacy of ARQ 197 have been investigated in multiple phase 1 and 2 clinical trials in cancer patients. Two phase 1 dose escalation trials (ARQ 197-101 and ARQ 197-103) have defined the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for continuous doses of ARQ 197 as a single agent. Another phase 1 study (ARQ 197-111) evaluated the MTD and RP2D of ARQ 197 administered in combination with erlotinib on a continuous schedule. Additional ongoing phase 1 and phase 1/2 trials evaluating ARQ 197 include ARQ 197114 (monotherapy in HCC); ARQ 197-116 (combination with sorafenib); and ARQ 197117 (combination with gemcitabine). In addition, there are two active phase 2 clinical trials: ARQ 197-204 is evaluating the efficacy of ARQ 197 in patients with MITF-associated tumors, while ARQ 197-209 is an ongoing global, randomized, placebo controlled, double-blind phase 2 trial comparing  
treatment with erlotinib plus ARQ 197 versus treatment with erlotinib plus placebo in patients with previously treated NSCLC. Clinical experience to date suggests that ARQ 197 has a favorable safety profile [23]. Detailed information for each of these studies, including pharmacokinetic data, can be found in the Investigator's Brochure (2010). Safety and efficacy results are summarized below.
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phase 1 studies

Studies **ARQ 197-101** and **ARQ 197-103** were phase 1 dose escalation trials of ARQ 197 in adult patients with locally advanced or metastatic solid tumors. In ARQ 197-101 trial, 13 dose levels ranged from 10–360 mg BID and 2 dosing schedules (intermittent versus continuous) were explored and no dose-limiting toxicities (DLTs) were reported at doses below 360 mg BID. In ARQ 197-103 trial, ARQ 197 was given twice daily continuously and the MTD was found to be 360 mg BID. The most common drug-related adverse events (AEs; ≥5% and ≥2 events) seen in these studies were fatigue (13.9% and 15.7%, respectively), nausea (13.9%, 13.7%), vomiting (10.1%, 11.8%), and diarrhea (6.3%, 7.8%). Serious adverse events (SAEs) reported at a >3% incidence were disease progression, dehydration, anemia, nausea, renal failure acute, and vomiting, febrile neutropenia.  
Study **ARQ 197-114** is an ongoing safety study of ARQ 197 in cirrhotic subjects with HCC. ARQ 197 is administered continuously at a dose level of 360 mg BID. The most common drug-related AEs (>5% and >2 events) are asthenia (47.6%), neutropenia (42.9%), anemia (42.9%), leukopenia (38.1%), anorexia (38.1%), diarrhea (28.6%), alopecia (19.0%), thrombocytopenia (14.3%), vomiting (14.3%), hepatobiliary disorders (14.3%), hyperbilirubinemia (14.3%), lymphopenia (9.5%), bradycardia (9.5%), dysgeusia (9.5%), and oropharyngeal pain (9.5%). Drug-related SAEs leading to discontinuation from the study include three cases of neutropenia.  
Study **ARQ 197-111** is an ongoing phase 1 dose escalation trial of ARQ 197 administered in combination with erlotinib in adult patients with advanced solid tumors. A dose of 360 mg ARQ 197 BID in combination with erlotinib 150 mg daily has been identified as the RP2D (one DLT of neutropenia). The most commonly-reported drugrelated AE in this study was bradycardia, with 15 episodes reported in 4 patients; these events were generally mild and asymptomatic (grade 1), and 14 of these events occurred at the 360 mg BID dose level of ARQ 197.
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phase 2 studies

Protocol **ARQ 197-204** is a phase 2 study of ARQ 197 in patients with MITF-associated tumors, including translocation-associated renal cell carcinoma (t-RCC), alveolar softpart sarcoma (ASPS), and clear-cell sarcoma (CCS). The initially enrolled patients received 120 mg ARQ 197 BID; patients enrolled after the RP2D was determined (in ARQ 197-103) received 360 mg ARQ 197 BID. Among 47 patients treated in this study, ARQ 197 demonstrated a favorable safety profile and was well tolerated at both doses. The most common (≥5% and ≥2 events) drug-related AEs were fatigue, pyrexia, nausea,  
vomiting, diarrhea, retching, anemia, lymphopenia, pain in extremity, anorexia, headache, insomnia, dyspnea, cough, neutrophil count decreased, decreased white blood cell count, increased alanine aminotransferase level, increased aspartate aminotransferase level, decreased hemoglobin level, sinus bradycardia, and rash. To date, 45 patients are evaluable for efficacy. One patient with CCS demonstrated a confirmed PR. Twentyseven patients demonstrated SD, including 21 with ASPS, three with t-RCC, and three with CCS. Overall, 12 subjects have had SD for >24 weeks. Currently, two phase 2 trials are ongoing; ARQ 197 plus erlotinib versus ARQ 197 plus placebo in patients with previously treated NSCLC (**ARQ 197-209**) and single agent ARQ 197 in patients with HCC (**ARQ 197-215**).
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pharmacokinetics

Approximately 345 subjects with cancer and over 100 healthy subjects participated in phase 1 studies of ARQ 197. Clinical PK data are available from multiple clinical studies using ARQ 197 as either the amorphous solid or 1 of 2 crystalline forms designated form A or form B. Overall, following oral administration ARQ 197 is moderately absorbed with a Tmax ranging from 2–6 hours. In general, ARQ 197 exposure increases with increases in dose; however, exposure is not dose proportional. There is wide intersubject variability in ARQ 197 PK. Based on population pharmacokinetic (PopPK) analysis, this variability is partly due to CYP2C19 polymorphism, fed status during ARQ 197 administration, ARQ 197 form (amorphous versus crystalline A versus crystalline B), and also possibly ethnicity differences (Caucasian versus Japanese). In vitro human liver microsome studies indicate involvement of both CYP2C19 and cytochrome P450 3A4 (CYP3A4) in ARQ 197 metabolism. In humans, ARQ 197 showed a genotype exposure relationship dictated mainly by CYP2C19 genotype. In healthy subjects, CYP2C19 poor metabolizers (PMs) had much higher exposure than extensive metabolizers (EMs), as reflected by AUC0-48 and Cmax (11-fold and 3-fold higher, respectively) and lower clearance (mean of 2.4 L/h versus mean of 33.9 L/h).  
However, based on steady state exposure data in cancer subjects the PM exposure (AUC012) is only 1.4- to 4-fold greater than EM exposure. Hence, differences in CYP2C19 metabolism will contribute to variability in PK between subjects. In a phase 1 doseescalation study, 10 of 43 patients were characterized as PMs. Additional studies comparing the PK of the amorphous form of ARQ 197 to the crystalline forms A and B of ARQ 197 showed that the amorphous form of ARQ 197 resulted in higher exposure
(Cmax, AUC) than either crystalline form A or B. Specifically, Cmax was approximately 60% to 70% lower for forms A and B, respectively, compared with the amorphous form. Similarly, AUC was 20% to 30% lower for crystalline forms A and B, respectively, relative to the amorphous form. When ARQ 197 was administered immediately after a high-fat meal to healthy subjects, the exposure was 3 times greater than the exposure under fasted conditions (fasted versus fed: AUC0-last, 4858 +1793 ng/hr/mL versus 13356 +5385 ng/hr/mL and AUC0-inf, 6166
+2393 versus 13558 +6397 ng/hr/mL). However, the observed exposure under fed conditions was similar to that observed in the prior clinical studies in subjects with cancer and less than the MTD exposure. Additionally, in cancer subjects (study ARQ 197-117), the exposure when ARQ 197 crystalline B was administered 360 mg BID (the phase 3 dose) under fed versus fasting (at least 1 hour before and 2 hours after a meal) condition were similar (fed versus fasting: 12251 versus 10453 ng/hr/mL). Furthermore, when administered under fed conditions, the variability in ARQ 197 exposure is generally lower compared with the fasted condition.
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2.4 correlative studies background 2.4.1

Serial evaluation of the tumor biopsy samples will be performed with quantitative sandwich chemiluminescence immunoassays to measure drug effect on modulation of intact c-MET and 2 known key domains in intact c-MET: the tyrosine kinase (TK) domain and the C-terminal signaling/mediator docking domain (multiple docking site). Phosphorylation status of tyrosine at positions 1235 and 1356 denotes the activation state of the TK domain and multiple docking site, respectively. Three quantitative ELISAbased immunoassay for the measurement of c-MET (intact MET) and two c-MET
phosphorylated isoforms (pY1235 and pY1356) have been developed in the laboratory of Dr. Apurva Srivastava, SAIC-Frederick, and are currently under validation for use to assess target modulation. The amount of intact MET serves as a denominator to determine the fraction of MET phosphorylated at either pY1235 or pY1356. Assay readout is based on relative light units from a Tecan luminometer after addition of chemiluminescent substrate. Six quantitative MET standards over a 30-fold range are loaded into a plate along with testing samples for calculating the MET values. Two assay controls (low-C and High-C) are included in each run plate to monitor consistency of the assay. Manuscripts describing these assays are in preparation. Analytical validation and fit-for-purpose modeling in preclinical studies are currently underway. Preliminary results indicate adequate analytical performance, and >60%
inhibition in phosphorylation of Y1235 within 4 hours of treatment with two selective cMET inhibitors, as compared to the vehicle-treated group. Intra-tumor variability of cMET was 18-37% in biopsy specimens among vehicle treated groups.  
Sequencing for known mutations in the MET kinase and ligand binding domains will also be performed in tumor biopsies.
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2.4.1.1 measurement of met/phospho-met

With Amendment D (12/7/2012), the primary study objective dealing with biomarker endpoints was revised from determining reduction of phospho-MET in tumor biopsy samples following administration of ARQ 197 in light of preclinical findings and published observations about ARQ 197's mechanism of action. Data suggest that ARQ 197 blocks MET by locking the inactive conformation of MET, thus preventing further activation [24]. In contrast, ARQ 197's effects on constitutively phosphorylated Y1234/35 MET are unclear [25]. We tested ARQ 197 modulation of phospho-MET in gastric tumor xenograft models with constitutively active c-MET (SNU5 and MKN45) [26]. ARQ 197 administered at doses of 200-400 mg/kg/day did not significantly change phospho-MET levels in either the SNU5 or MKN45 model (Figure 6); however, when ARQ 197 was coadministered with pazopanib in the SNU5 model, ARQ 197 prevented pazopanibinduced activation of phospho-MET (Figure 6A and 6B). These results generally support the hypothesis underlying combination clinical trials of VEGFR and MET inhibitors [27], specifically, that ARQ 197 treatment reverses MET activation by pazopanib.  
Unfortunately, the mechanism by which ARQ 197 prevents adaptive response to VEGFR inhibition could not be verified by the phospho-MET biomarker response. Therefore, the objectives of this trial were modified to address evaluation of phospho-MET as an exploratory biomarker for MET activation by pazopanib and subsequent blunting of pazopanib-induced activation of MET by ARQ 197. The study design was revised to support this objective. The number of cohorts in the expansion phase was reduced from 3 to 2 as the originally planned cohort with a 7-day single-agent ARQ 197 lead-in will be less informative and of less potential benefit to patients. Confirmation of MET expression by immunohistochemistry in archival tissue is no longer an eligibility criterion for the expansion phase; MET and pMET levels will be determined from on-study biopsies only, thus expansion–phase eligibility is now open to patients with refractory advanced solid tumors rather than MET-expressing malignancies.  
  
specimens from the combination groups were not evaluable because they did not yield detectable levels of intact MET.  
Note: with Amendment I (v3/4/14), co-administration of pazopanib and ARQ 197 continuously was removed from the study prior to accruning patients to this cohort.
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2.4.2 assessment of hif-1a protein

The basis for this study is that anti-VEGF therapy increases intratumoral hypoxia by causing vascular regression, leading to increased expression of hypoxia-inducible factor–
l α (HIF-1α).  HIF-1α plays a central role in tumor progression by acting as master regulator of how cancer cells adapt to hypoxic conditions.  One reason postulated for the limited efficacy of anti-angiogenic and anti-VEGF agents is that they cause intra-tumoral hypoxia, resulting in the induction and up-regulation of hypoxia-inducible factors (HIF)
such as HIF-1α.  To determine whether the combination of MET inhibitor and anti-VEGF
therapy modulates intra-tumoral levels of HIF-1α expression, we will analyze tumor biopsies using an ELISA that has been validated by the PADIS laboratory (Dr. Bob Kinders) at Frederick National Laboratory for Cancer Research.  The assay detected 4fold higher levels of HIF-1α in PC-3 cells cultured under hypoxic conditions than those cultured under normoxic conditions (Table 1).  Spike-and-recovery experiments during assay validation revealed assay accuracy higher than 99% (Figure 8).
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2.4.3 circulating levels of hgf

Many proteins are proteolytically released from the cell surface by a process known as ectodomain shedding. Shedding occurs under normal physiologic conditions and can be increased in certain pathologies. MET is among the many receptors for which ectodomain shedding has been demonstrated. HGF stimulates mitogenesis, motogenesis, and morphogenesis in a variety of cellular targets during development, homeostasis and tissue regeneration. Inappropriate HGF signaling resulting in unregulated cell proliferation, motility, and invasion occurs in several human malignancies. This can occur through paracrine signaling, autocrine loop formation, receptor mutation, gene amplification or gene rearrangement accompanied frequently with overexpression of ligand and/or receptor proteins. Working under the hypothesis that aberrant MET pathway activation in cancer might result in increased ectodomain shedding MET could be a useful biomarker of tumor progression, Athauda et al. developed a sensitive electrochemiluminescent immunoassay to quantitate MET protein in biological samples [29]. Their study showed significant direct correlations between malignant potential and sMET production in tumor-derived and genetically engineered cell lines, and between tumor burden and plasma sMET levels in mice harboring human tumor xenografts [29]. These preclinical studies supported the hypothesis that sMET might indicate malignant potential and/or tumor burden for cancers where the pathway is active. Several studies of human clinical samples are now underway to investigate the potential utility of sMET to aid diagnosis and patient selection, and as a pharmacodynamic marker for drugs that directly target MET kinase activity. Among these is an ongoing collaboration between GlaxoSmithKline (GSK) and the NCI Urologic Oncology Branch to measure plasma sMET, HGF, VEGF-A and sVEGFR2 in patients in Phase I and II clinical trials of GSK1363089 (GSK'089), an inhibitor of MET and VEGFR2 tyrosine kinases. In a Phase II gastric cancer study, patients treated with GSK'089 on an intermittent dosing schedule showed significantly increased plasma sMET and VEGF-A
during the treatment periods and decreases during drug holidays. Follow-up cell-based studies show that inhibition of MET kinase activity blocks receptor internalization, resulting in increased exposure to cell surface MET sheddase(s), suggesting a direct short-term relationship between sMET levels and drug target inhibition. Increased VEGF-A levels have been reported as a response to VEGFR inhibitors in previous clinical studies. Median tumor burden did not change significantly over the course of the gastric study, so it was not possible to determine whether sMET levels could also reflect tumor burden. This question will be better assessed in an ongoing Phase II clinical trial of GSK'089 in patients with papillary renal cell carcinoma, where changes in tumor burden meeting RECIST criteria were reported in an interim trial report [30].
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2.4.4 pharmacogenetic (pg) assessment of

ARQ 197 is metabolized mainly by CYP2C19. As described earlier in this section, there is wide inter-subject variability in ARQ 197 PK. Based on population pharmacokinetic analysis, this variability is partly due to CYP 2C19 polymorphism, fed status during ARQ 197 administration, ARQ 197 form (amorphous versus Crystalline A versus Crystalline B), and also possibly ethnicity differences (Caucasian versus Japanese). In healthy subjects, CYP 2C19 poor metabolizers (PMs) had much higher exposure than extensive metabolizers (EMs), as reflected by AUC0-48 and Cmax (11-fold and 3-fold higher, respectively) and lower clearance (mean of 2.4 L/h versus mean of 33.9 L/h). However, based on steady state exposure data in cancer subjects, the PM exposure is only 1.4 to 4fold greater than EM exposure. Hence, differences in CYP 2C19 metabolism will contribute to variability in PK between subjects. As a part of this study, a blood sample at screening will be taken to evaluate the CYP2C19 genotype of subjects. The sample will be analyzed only for genes involved in the pharmacokinetics, safety, and efficacy of ARQ 197. It will provide information on how individuals metabolize and react to the study medication. This information may be useful in increasing the knowledge of differences among individuals in the way they metabolize the study medication as well as helping in the development of new drugs or improvement of existing drugs.
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2.5 rationale

We hypothesize that co-administration of the MET inhibitor ARQ 197 will prevent the adaptive response to hypoxia resulting from treatment with the VEGFR inhibitor pazopanib, and conversely, that co-administration of pazopanib will prevent the effect of increased VEGF and reduced TSP-1 in tumors after treatment with ARQ 197. Therefore, the combination of these agents may result in improved antitumor effects.
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3 patient selection 3.1 eligibility

3.1.1 Patients with histologically confirmed (by the Laboratory of Pathology, NIH)
solid tumors that have progressed following at least one line of standard therapy or for whom no standard treatment options exist.  
3.1.2 Patients must have measurable or evaluable disease.  
3.1.3 Patients enrolling in the expansion cohorts must have disease amenable to biopsy, and be willing to undergo pre-and post-treatment biopsies.  
3.1.4 Patients must have completed any chemotherapy, radiation therapy, or biologic therapy ≥ 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C). Patients must be ≥ 2 weeks since any prior administration of a study drug in a phase 0 or equivalent study. Patients must have recovered to eligibility levels from prior toxicity or adverse events. Treatment with bisphosphonates is permitted.  
3.1.5 Patients who have had prior treatment with any anti-angiogenic therapy and/or c-MET inhibitor are eligible in the dose escalation phase unless the antiangiogenic therapy and/or c-MET inhibitor were administered within the 4 weeks prior to entering the study. In the expansion phase, prior c-MET inhibitor is not allowed, and anti-angiogenic therapy is not allowed within the 3 months prior to entering the study.  
3.1.6 Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of pazopanib in combination with ARQ 197 in patients < 18 years of age, children are excluded from this study.  
3.1.7 Life expectancy > 3 months.  
3.1.8 ECOG performance status 0 or 1 (see Appendix A). 3.1.9 Patients must have normal organ and marrow function as defined below:  
| -   | Absolute neutrophil count      | ≥1,500/µL                       |
|-----|--------------------------------|---------------------------------|
| -   | Platelets                      | ≥100,000/µL                     |
| -   | Total bilirubin                | ≤1.5 X institutional ULN        |
| -   | AST (SGOT)/ALT (SGPT)          | ≤2.5 X institutional ULN        |
| -   | Creatinine                     | ≤1.5 mg/dL (133 mcmol/L); OR    |
| -   | Measured creatinine            | ≥60 mL/minute for patients with |
|     | clearance                      | creatinine levels >1.5 mg/dL    |
| -   | Urine protein/creatinine ratio | <1 OR                           |
|     | 24-hour urine protein <1 gram  |                                 |  
Subjects who have both bilirubin >ULN and AST/ALT >ULN are not eligible.  
3.1.10 Subjects in the expansion cohort must have PT/INR/PTT ≤ 1.2 X institutional ULN, except patients with confirmed positive lupus anticoagulant test.  
3.1.11 Subjects must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication is permitted prior to study entry provided that the average of three BP readings at a visit prior to enrollment is less than 140/90 mmHg.  
3.1.12 The effects of study drugs on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 2 months after dosing with study drugs ceases. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Women of child-bearing potential must have a negative pregnancy test prior to entry.  
3.1.13 Patients must be able to swallow whole tablets or capsules. Nasogastric or G-tube administration is not allowed.  
3.1.14 Ability to understand and the willingness to sign a written informed consent document.
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3.2 exclusion criteria

3.2.1 Patients who are receiving any other investigational agents.  
3.2.2 Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients whose brain metastatic disease status has remained stable for ≥ 4 weeks following treatment of the brain metastases are eligible to participate.  
3.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib or ARQ 197.  
3.2.4 Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of pazopanib or ARQ 197 will be determined following review of their cases by the Principal Investigator (see Sections 3.2.5-3.2.6 for further information). Efforts should be made to switch subjects with gliomas or brain metastases who are taking enzymeinducing anticonvulsant agents to other medications.  
3.2.5 Certain medications that act through the CYP450 system are specifically prohibited in subjects receiving pazopanib and ARQ 197 and others should be avoided or administered with extreme caution.  
- **Strong inhibitors of CYP3A4** such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinivir, retonavir, saquinavir, telithromycin, voriconazole may increase pazopanib concentrations and **are prohibited; although, in exceptional circumstances**
they may be administered in conjunction with **lowering the dose of**
pazopanib by 50% of what would otherwise be administered. Grapefruit juice is also an inhibitor of CYP450 and should not be taken with pazopanib.  
- **Strong inducers of CYP3A4,** such as rifampin, may decrease pazopanib concentrations, **are strictly prohibited.** (See Appendix B)
- Medications which have narrow therapeutic windows and are substrates of CYP3A4, CYP2D6, or CYP2C8 should be avoided and, if necessary, administered **with caution.** (See Appendix B)
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- inhibitors or inducers of

3.2.6 Cardiovascular baseline QTc ≥ 480 msec will exclude patients from entry on study. Medications that may cause QTc interval prolongation are listed in Appendix C, and should be avoided by patients entering on trial. Patients for whom a given medication that may cause QTc interval prolongation cannot be discontinued may be eligible at the discretion of the study PI. A comprehensive list of agents with the potential to cause QTc prolongation can be found at http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm. (Note: If subjects must take medications with a risk or possible risk of Torsades de Pointes, they should be watched carefully for symptoms of Torsades de Pointes, such as syncope. Performing additional EKGs on subjects who must take one or more of these medications is not required; however, additional investigations, including EKGs, may be performed as per the treating physician's judgment.)
3.2.7 Subjects with any of the following cardiovascular conditions within the past 6 months:
- cerebrovascular accident (CVA) or transient ischemic attack (TIA)
- clinically significant bradycardia or other uncontrolled cardiac arrhythmia - admission for unstable angina or myocardial infarction - cardiac angioplasty or stenting
- coronary artery bypass graft surgery - pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT
which has been treated with therapeutic anticoagulation for less than 6 weeks
- arterial thrombosis
- symptomatic peripheral vascular disease
- Class III or IV heart failure as defined by the NYHA functional classification system (see Appendix D). A subject who has a history of Class II heart failure and is asymptomatic on treatment may be considered eligible 3.2.8 History of serious or non-healing wound, ulcer, or bone fracture. 3.2.9 Patients who received major surgery within the past 4 weeks 3.2.10 Subjects with any condition that may impair the ability to swallow or absorb oral medications/investigational product including:
- any lesion, whether induced by tumor, radiation or other conditions, which makes it difficult to swallow capsules or pills
- prior surgical procedures affecting absorption including, but not limited to major resection of stomach or small bowel
- active peptic ulcer disease
- malabsorption syndrome 3.2.11 Subjects with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including
- active peptic ulcer disease
- known intraluminal metastatic lesions
- inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other gastrointestinal conditions which increase the risk of perforation
- history of abdominal fistula, gastrointestinal perforation or intraabdominal abscess within 28 days prior to beginning study treatment 3.2.12 History of hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to first dose of study drug.  
3.2.13 Urine protein/creatinine ratio should be screened by urine analysis. If protein is 1+ or higher, 24-hour urine protein should be obtained and the level should be < 1 g for patient enrollment. Patients with < 1+ proteinuria are eligible following initial determination by urinalysis within 1 week prior to enrollment and do not need the urinalysis repeated.  
3.2.14 Patients with clinically significant intercurrent illnesses, including but not limited to, life threatening infection, psychiatric illness/social situations that would limit compliance with study requirements will not be eligible to participate.  
3.2.15 Pregnant women are excluded from this study because the effects of the study drugs on the developing fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study drugs, breastfeeding should be discontinued prior to the first dose of study drug and women should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.  
3.2.16 HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions.  
3.2.17 Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted for prophylactic use, but not therapeutic use.
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3.3 inclusion of women and

Both men and women of all races and ethnic groups are eligible for this trial.
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3.4 screening evaluation

3.4.1 Histologic confirmation: By the Laboratory of Pathology, NIH. A block or stained slides of primary tumor tissue or of known recurrence will be required from each participant to confirm diagnosis.  
3.4.2 History and physical examination: Complete history and physical examination
(including height, weight, vital signs, performance score, EKG) will be conducted within 72 hours week prior to enrollment. Echocardiogram or MUGA scan for assessment of LV ejection fraction will be performed within 4 weeks prior to enrollment.
3.4.3 Imaging Studies (Baseline): Every participant should have an evaluation of known sites of disease as part of the baseline evaluation. All patients will be required to undergo a CT scan of the chest/abdomen/pelvis to evaluate sites of disease within 28 days prior to enrollment. MRI or CT scan with contrast of the brain, MRI liver, MRI for other disease sites, or bone scan may be done as clinically indicated.  
3.4.4 Laboratory Evaluation: Baseline laboratory data are to be obtained within 72 hours prior to enrollment:
- Hematological Profile: CBC with differential.  
- Biochemical Profile: albumin, alkaline phosphatase, total bilirubin, BUN,
calcium, creatinine, glucose, phosphorus, total protein, SGOT[AST], SGPT[ALT], magnesium, potassium, and sodium.  
- Coagulation Profile: PT, PTT, INR - Serum or urine pregnancy test for female participants of childbearing potential.  
- Urinalysis for urine protein/creatinine ratio or 24-hour urine for proteinuria if patients have 1+ or greater urine protein/creatinine ratio.  
- Serum liver tests (AST, ALT, serum bilirubin) will be performed as part of a risk mitigation plan before initiation of treatment with pazopanib.
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4 registration procedures

Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours of signing consent. A registration Eligibility Checklist from the Web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and faxed to
. After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release of any investigational agents. Verification of Registration will be forwarded electronically via email. Please note that it is very important for all registrars to acquire encrypted e-mail from NIH
Help Desk, since the verification of registration includes patient's information. A recorder is available during non-working hours.  
Off-Study Procedure: Authorized staff must notify the Central Registration Office (CRO) when a patient is taken off-study. An off-study form from the Web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and faxed to .
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5 treatment plan

This is an open-label Phase I trial evaluating the combination of pazopanib, an oral VEGFR
inhibitor, and ARQ 197, an oral MET inhibitor, in patients with refractory advanced solid tumors. Reported adverse events and potential risks for pazopanib and ARQ 197 are described in Section 7. Appropriate dose modifications for pazopanib and ARQ 197 are described in Section 6. No investigational or commercial agents or therapies other than pazopanib and ARQ 197 may be administered with the intent to treat the patient's malignancy. The study will be carried out in 2 phases, as described in Section 5.1. The drugs will be administered in 28-day cycles (± 1 day for scheduling). Pazopanib tablets should be administered orally without food (at least 1 hour before or 2 hours after eating) once a day. ARQ 197 tablets should be administered orally with food twice daily approximately every 12 hours. A missed or vomited dose should not be replaced. The patient should be instructed to take the next scheduled dose at the regularly scheduled time. Patients will be asked to maintain a Study Medication Diary (Appendix E) and record each dose of medication. Patients will be given instructions for completing the medication diary and will be asked to return it to the clinic staff at the end of each cycle.  
With Amendment H, dated 09/26/2013: For patients who have been on study for six or more cycles and are tolerating treatment well, two months worth of drug may be dispensed at a time; labs and blood pressure monitoring will only be performed once every 2 cycles (every 2 months). More frequent labs and assessment can be performed as clinically indicated.  
History and physical examination can be done up to 3 days before start of a new cycle. Patients will be examined on D1, D8 (only for patients who will have tumor biopsy), and D15 in the dose escalation phase, or D1 and D8 in the expansion phase, at the clinical center for the first cycle and prior to every new cycle. Blood pressure (BP) will be checked every 2 weeks during the first 2 cycles in the dose escalation phase and on D1 and D8 of cycle 1 in the expansion phase, and then at the beginning of subsequent cycles. Mid-cycle blood pressure monitoring can be performed by any healthcare provider. Labs (CBC with differential; serum chemistries, including glucose) will be performed as follows: − *Dose escalation phase*: every week for the first cycle, then every 2 weeks for cycle 2 and then at the start of each cycle (up to 3 days before start of a new cycle) for the remainder of the study. − *Expansion phase*: D1 and D8 of cycle 1, then at the start of each cycle (up to 3 days before start of a new cycle). EKG will be performed as follows:
− *Dose escalation phase*: at baseline, on C1D1 (3-6 hours after the first dose of ARQ 197) and on C1D15 (3-6 hours after the morning dose of ARQ 197) and as clinically indicated.  
− *Expansion phase*: at baseline, on C1D1 (3-6 hours after pazopanib), on C1D8 (3-6 hours after pazopanib), on C2D1 (3-6 hours after the morning dose of ARQ 197), and as clinically indicated. Evaluation of urine protein/creatinine ratio will be performed as follows:
− *Dose escalation phase*: at baseline, on C1D15, then at the start of each cycle.  
− *Expansion phase*: at baseline, on C1D8, then at the start of each cycle, and as clinically indicated.  
Echocardiogram or MUGA scan for assessment of LV ejection fraction will be performed at baseline and as clinically indicated. CT scans will be performed at baseline, and repeat imaging scans will be performed every 2 cycles. As part of a risk mitigation plan for possible hepatic failure, serum liver tests (AST, ALT, serum bilirubin) will be monitored before initiation of treatment with pazopanib and at weeks 3, 5, 7, and 9. Thereafter, monitoring will occur at months 3 and 4, and as clinically indicated. Periodic monitoring will continue after month 4.
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5.1 agent administration 5.1.1 dose

A primary objective of the trial is to establish the safety, tolerability, and MTD of the combination. Pazopanib will be administered QD, starting at 400 mg, and ARQ 197 will be administered BID, starting at 120 mg (dose level 1). The duration of a cycle will be 28 days (± 1 day for scheduling). Dose escalation will proceed in cohorts of 3 patients each (3+3 design) as outlined below (Table 2):  
| Dose Level                                                         | Pazopanib   | ARQ 197    |
|--------------------------------------------------------------------|-------------|------------|
| -2                                                                 | 200 mg QD   | 120 mg QD  |
| -1                                                                 | 400 mg QD   | 120 mg QD  |
| 1                                                                  |             |            |
| (starting dose)                                                    | 400 mg QD   | 120 mg BID |
| 2                                                                  | 600 mg QD   | 120 mg BID |
| 3                                                                  | 600 mg QD   | 240 mg BID |
| 4                                                                  | 800 mg QD   | 240 mg BID |
| 5                                                                  | 800 mg QD   | 360 mg BID |
| 6*                                                                 | 600 mg QD   | 360 mg BID |
| *If dose level 5 is above the MTD, dose level 6 will be evaluated. |             |            |  
Table 2: Dose Escalation Scheme Tumor biopsies will be optional during the escalation phase. For the escalation phase, 3 patients should have completed at least one cycle of therapy prior to considering dose escalation in the next cohort of patients. Dose escalation will proceed according to the following scheme. DLT is defined in Section 5.2. Determination of DLT will be based on toxicities observed in the first cycle of therapy. Patients are considered evaluable for toxicity for the purpose of cohort dose escalation decisions if they either 1) experienced DLT or 2) have received at least 80% of the planned 28-day doses of treatment in one cycle of therapy and have been followed for one full cycle without DLT. All toxicities will be reported for all patients who receive any amount of study drug on this study. Evaluation of toxicity will begin with study drug administration on cycle 1 day 1.  
| Number of Patients with DLT at  a Given Dose Level                        | Escalation Decision Rule                                                                                                                                                                                                                                                                                                                                                                                      |
|---------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0 out of 3                                                                | Enter 3 patients at the next dose level.                                                                                                                                                                                                                                                                                                                                                                      |
| ≥2                                                                        | Dose escalation will be stopped. This dose level will  be declared the maximally administered dose (highest  dose administered). Three (3) additional patients will  be entered at the next lowest dose level if only 3  patients were treated previously at that dose.                                                                                                                                       |
| 1 out of 3                                                                | Enter at least 3 more patients at this dose level. - If 0 of these 3 patients experience DLT, proceed to  the next dose level. - If 1 or more of this group suffer DLT, then dose  escalation is stopped, and this dose is declared the  maximally administered dose. Three (3)  additional patients will be entered at the next  lowest dose level if only 3 patients were treated  previously at that dose. |
| ≤1 out of 6 at highest dose level  below the maximally administered  dose | This is generally the recommended Phase II dose. At  least 6 patients must be entered at the recommended  Phase II dose.                                                                                                                                                                                                                                                                                      |
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5.1.2 expansion phase

Once the MTD is established, an additional cohort of patients will initially be treated with pazopanib alone, and tumor biopsies will be obtained to assess target inhibition, as outlined below. Tumor biopsies will be mandatory during the expansion phase of the study. Biopsies will be obtained at the time points outlined below. Depending on the results obtained from the tumor biopsies in the first few patients, the timing of the biopsy can be adjusted, but the number of tumor biopsies and the procedure will not change. Any change in the timing of the tumor biopsy will be discussed with the patient prior to obtaining informed consent.  
The cohort and dosing regimens after establishment of the MTD are described below. When administered as a single agent during the expansion phase, the dose of pazopanib will correspond to the dose determined for the combination MTD if the MTD is determined at dose level 5 (ARQ 197 360 mg BID/pazopanib 800 mg QD) or 6 (ARQ 197 360 mg BID/pazopanib 600 mg QD). Otherwise, the dose of pazopanib will be determined after discussion with CTEP. Once the MTD is established, the data will be discussed with CTEP prior to proceeding with accrual for the expansion phase.  
Cohort A (12 patients): Pazopanib will be given once daily as single agent from cycle 1 day 1 to day 7. Tumor biopsy will be done before drug administration on study
(baseline) and on cycle 1 day 8, 8-12 hours after pazopanib administration. **After** the tumor biopsy, patients will start to receive ARQ 197 in addition to pazopanib at the combination MTD. Twelve evaluable patients with both pre- and post-treatment biopsies will be treated initially in Cohort A. Mean increases in MET and pMET in these 12 patients will be measured to assess whether or not they are statistically significant. For the purposes of final analysis of the expansion phase, only patients with paired tumor biopsies will be considered evaluable. Patients with fewer than the 2 required biopsies will not be considered evaluable for the expansion phase and will need to be replaced in the accrual scheme of the expansion phase. If a patient has a dose-limiting toxicity (DLT) with the single lead-in agent pazopanib in the expansion cohort, the patient will be taken off treatment.
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5.2 definition of dose-limiting toxicity

Dose-limiting toxicity (DLT) is defined as an adverse event that is related (possibly, probably, or definitely) to administration of study drugs and fulfills one of the following criteria:
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5.2.1 grade >= 3 non-hematological

Grade ≥ 3 non-hematological toxicity felt to be related to study medications will be considered dose-limiting with the following clarifications:  
5.2.1.1 Diarrhea Grade 3 will only be considered dose-limiting if it is refractory to treatment as outlined in Section 5.3.2, Supportive Care Guidelines, and unable to be corrected to Grade 2 or less within 24 hours. Bloody or Grade 4 diarrhea will be dose-limiting.  
5.2.1.2 Nausea and vomiting Grade 3 will only be considered dose-limiting if it is refractory to anti-emetic therapy and unable to be corrected to Grade 1 or less within 24 hours (Section 5.3.1).  
5.2.1.3 Rise in creatinine to Grade 3, not corrected to Grade 1 or less within 48 hours with IV fluids will be considered dose-limiting. All Grade 4 rises in creatinine will be dose limiting.
5.2.1.4 Grade ≥ 3 metabolic toxicities unable to be corrected to Grade 2 or less within 48 hours (such as glucose changes, hypocalcemia or hypercalcemia, hypomagnesemia or hypermagnesemia, hyperuricemia, hypophosphatemia, and hyponatremia) will be considered dose limiting. For hypokalemia or hyperkalemia, grade ≥ 2 toxicities unable to be corrected to grade 1 or less within 48 hours will be considered dose limiting. Grade 4 metabolic toxicities that are symptomatic will be considered dose-limiting regardless of duration or ability to correct.  
5.2.1.5 QTc prolongation to ≥ 500 msec on at least two separate EKGs (refer to Section 5.3) will be dose limiting.  
5.2.1.6 AST/ALT > 8 X ULN or AST/ALT > 3 X ULN and concurrent bilirubin elevation > 2 X ULN will be dose limiting.  
5.2.1.7 Grade ≥ 3 bleeding in any sites or grade ≥ 2 pulmonary bleeding will be dose limiting.  
5.2.1.8 Grade 4 venous thrombosis, pulmonary embolism, or any grade of arterial thrombosis will be dose limiting.  
5.2.2 Grade 4 thrombocytopenia.  
5.2.3 Grade 4 neutropenia ≥ 3 days or febrile neutropenia.  
5.2.4 Any degree of anemia, leucopenia in the absence of grade 4 neutropenia ≥ 3 days, or lymphopenia will not be considered dose limiting.
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5.3 general concomitant medication and

All patients will be provided with the best available supportive care. All concurrent medications should be documented prior to initiation of treatment, and be periodically reviewed with the patient. Particular attention must be paid to medications which may prolong the QTc interval (Appendix C) and agents that interact with CYP450 isoenzymes (Appendix B).
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qtc prolongation

Caution should be exercised when administering pazopanib to patients with a history of QTc interval prolongation, in patients taking anti-arrhythmics or other medications that may prolong the QTc interval, and those with relevant pre-existing cardiac disease. A list of medications that may cause QTc interval prolongation are listed in Appendix C, and should be avoided by patients on this study. EKG will be performed as described in Section 5. If the QTc interval on followup EKG is > 500 msec, the EKG should be repeated within 7 days and, if the QTc interval remains > 500 msec, the subject should be removed from the study. Additionally, if the QTc interval is increased by 60 msec or more from baseline but the QTc interval remains at <500 msec, the EKG should be repeated within 7 days. If the repeat EKG again shows a > 60 msec increase in the QTc interval from baseline, consideration should be given to removing  
the subject from the study or increasing monitoring, after discussion with the principal investigator.
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cyp450 interactions

In vitro and in vivo animal data indicate that the metabolism of pazopanib is primarily mediated by CYP3A4. In vitro data indicate that pazopanib is a potential inhibitor for CYP2C9, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. In addition, one in vitro study suggested that pazopanib may induce CYP3A4 at high concentrations. Potent CYP3A4 inhibitors and inducers are prohibited on pazopanib trials. In exceptional circumstances, medications which strongly inhibit CYP3A4 may be administered, with caution, if the dose of pazopanib is decreased to 50% of the dose which would otherwise be administered.
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medications that strongly inhibit cyp3a4

- Antibiotics: clarithromycin, telithromycin, troleandomycin
- HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir)
- Antifungals: itraconazole, ketoconazole, voriconazole
- Antidepressant: nefazodone Grapefruit juice is also an inhibitor of CYP450 and should not be taken with pazopanib.
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medications that strongly induce cyp3a4

- Glucocorticoids: cortisone (>50 mg), hydrocortisone (>40 mg), prednisone (>10 mg),
methylprednisolone (>8 mg), dexamethasone (>1.5 mg)
- Anticonvulsants: phenytoin, carbamezepine, phenobarbital, oxcarbazepine
- HIV antivirals: efavirenz, nevirapine
- Antibiotics: rifampin (rifampicin), rifabutin, rifapentene
- Miscellaneous: St. John's Wort, modafinil, pioglitazone, troglitazone Pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6. Drugs that have narrow therapeutic windows and are substrates for these enzymes should be avoided and, if necessary, administered with caution (see Appendix B). Because of pazopanib's long half-life, caution should continue to be exercised for at least 7 days and up to 15 days after the last dose of pazopanib when administering these medications.
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medications that are substrates for

- Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine (potential increased risk for developing ergot toxicity that includes severe vasospasm leading to peripheral as well as cerebral ischemia)
- Neuroleptics: pimozide (potential increased risk for QT interval prolongation, ventricular arrhythmia, and sudden death)
- Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine, propafenone (potential increased risk for QT interval prolongation and Torsade de Pointes)
- Immune modulators: cyclosporine, tacrolimus, sirolimus (potential increased risk for nephrotoxicity and neurotoxicity)
- Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine In vitro studies indicate ARQ 197 is metabolized by CYP2C19, and to a lesser extent CYP3A4. The metabolism and consequently overall pharmacokinetics of ARQ 197 could be altered by inhibitors and/or inducers or other substrates of CYP2C19 and CYP3A4. In patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 or CYP2C19, every attempt should be made to change the medications to another agent that does not affect the CYP pathway (see Appendix B).
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specific recommendations regarding other oral

Co-administration of pazopanib with some oral hypoglycemics, including glipizide, glyburide, (glibenclamide), glimerpiride, nateglinide, repaglinide, gliclazide, acetohexamide, carbutamide, glibornuride, glymidine, metahexamide, and tolazmide, (but not including tolbutamide and chlorpropamide, which are prohibited) may result in an increase in plasma concentrations of the oral hypoglycemic agents, leading to hypoglycemia. Therefore, reducing the doses of these oral hypoglycemic agents should be considered when pazopanib administration starts. The blood glucose should be monitored closely and patients should be instructed to measure their blood glucose if they experience symptoms of hypoglycemia and inform their physicians if their blood glucose concentrations are low. After at least 14 days of pazopanib administration, the doses of oral hypoglycemic agents may be increased **as necessary** to maintain adequate blood glucose control.
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specific recommendations regarding non-dihydropyridine calcium

Co-administration of pazopanib with calcium channel blockers may result in increased plasma concentrations of the latter. The non-dihydropyridine calcium channel blockers verapamil and diltiazem have potential depressive effects on cardiac conduction and contractility. When pazopanib therapy is initiated, the administration of an anti-hypertensive or anti-anginal agent other than verapamil and diltiazem is recommended in the setting of a PR interval > 200 msec, sinus bradycardia (< 60 beats per minute), or second or third degree heart block, unless the patient has a permanent pacemaker.
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5.3.1 nausea/vomiting

Anti-emetics will not be administered routinely prior to pazopanib or ARQ 197. However, if a patient develops nausea/vomiting, anti-emetics such as but not limited to prochlorperazine, metoclopramide, 5-HT3 antagonists, or aprepitant may be given. In addition, if a patient develops nausea and/or vomiting that is Grade 2 or greater, antiemetics may be instituted prophylactically at the discretion of the investigator. Nausea and vomiting will be considered refractory if it does not resolve to ≤ Grade 1 with treatment with a combination of at least 2 of the antiemetics within 24 hours.
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5.3.2 diarrhea

If diarrhea develops and does not have an identifiable cause other than study drug administration, anti-diarrheals such as Lomotil (diphenoxylate HCl 2.5 mg + atropine sulfate 0.025 mg/tablet) dosed according to package insert or loperamide 4 mg po after the first unformed stool with 2 mg po with every 2 hours (4 mg every 4 hours while asleep), till resolution of episode of at least 12 hours (no more than 16 mg of loperamide  
during a 24-hour period). This regimen can be repeated for each diarrheal episode. Diarrhea will be considered refractory if it does not resolve within 24 hours to ≤ Grade 2 with the above regimen (maximum of 16 mg of loperamide in a 24-hour period). If the patient develops blood or mucus in the stool, dehydration, or hemodynamic instability, or fever along with the diarrhea, anti-diarrheals will be discontinued and the patient will be treated with IV fluids and antibiotics as medically indicated.
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5.3.3 neutropenia

To reduce the risk of severe myelosuppression events, a complete blood count (CBC) should be performed weekly during cycle 1, every 2 weeks during cycle 2, and at the start of each subsequent cycle (up to 3 days before start of new cycle) in the dose escalation phase. In the expansion phase, CBC will be performed on D1 and D8 of cycle 1, then at the start of each cycle (up to 3 days before start of new cycle). Febrile neutropenia is a life-threatening complication requiring hospitalization and urgent broadspectrum antibiotics, as well as an aggressive search for the source and microbial cause of the episode. Growth factors to prevent neutropenia will not be administered prophylactically. If necessary, they may be administered according to accepted American Society of Clinical Oncology (ASCO) guidelines to allow re-treatment.
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5.3.4 anemia

Symptomatic anemia should be treated with red blood cell transfusion and is recommended if the hemoglobin falls below 8 g/dL. The initiation of erythropoietic therapy for the management of chemotherapy-induced anemia follows the American Society of Hematology/ASCO clinical practice guidelines (http://www.asco.org/).
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5.3.5 thrombocytopenia

Thrombocytopenia will be treated conservatively. In the absence of bleeding, or a necessary invasive procedure, platelet transfusions should be given for a platelet count
≤10,000/mm3. If invasive procedure(s) is (are) planned, or the patient develops bleeding, platelet transfusions should be administered in accordance with the standard of practice, usually maintaining a platelet count above 50,000/mm3.
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5.3.6 reflux/gastritis

Antacids and other anti-ulcer medications such as histamine H2-receptor antagonists may be used if clinically indicated. To avoid significantly altering gastric pH, when needed, these medications should be used 4 hours after study drug administration. Proton pump inhibitors such as omeprazole and lansoprazole, which have a potential for interaction with ARQ 197, should be avoided.
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5.4 duration of therapy

In the absence of treatment delays due to adverse events, treatment may continue until one of the following criteria applies:
- Disease progression
- Intercurrent illness that prevents further administration of treatment  
- Significant toxicity occurs despite 2 dose reductions as described in Section 6 or no lower dose level exists
- Pregnancy
- Patient decides to withdraw from the study, or
- General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.
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5.5 duration of follow up

Patients will be followed for 30 days after the last dose is administered or until one of the following occurs: patient enrolls on another protocol, patient receives standard of care, or death, whichever comes first. The follow-up will consist of a phone call between Days 27-30 after the last dose to evaluate adverse events that were ongoing and any new events that might be deemed related to the therapy. Toxicities felt to be possibly, probably, or definitely related to the study drugs that have not resolved or stabilized by Day 30 post-treatment will be followed until stabilization or resolution via biweekly phone calls.
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5.6 criteria for removal from

Patients will be removed from study for one of the following reasons: completed 30-day followup period or toxicities are unresolved but stabilized. The reason for study removal and the date the patient was removed must be documented in the medical record and communicated by fax to Central Registration per Section 4.
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6 dosing delays/dose modifications

Toxicities (hematologic and non-hematologic; except any grade lymphopenia, anemia, or alopecia) should have resolved to ≤ Grade 2 prior to starting the next cycle or receiving the next dose of pazopanib or ARQ 197 within a cycle. Study drugs should be held for hypokalemia or hyperkalemia ≥ grade 2; hypocalcemia or hypercalcemia ≥ grade 3; hypophosphatemia ≥ grade 3; hypomagnesemia or hypermagnesemia ≥ grade 3. These laboratory values should be corrected as soon as possible in a manner consistent with good medical judgment. Study drugs may be readministered when hypokalemia or hyperkalemia is grade 1 or within institutional limits; hypocalcemia or hypercalcemia is ≤ grade 2; hypophosphatemia is ≤ grade 2; and hypomagnesemia or hypermagnesemia is ≤ grade 2. Even though study drug administration is allowed at these lower grades, every effort should be made to correct the abnormal lab values to normal if possible. If the potassium level is grade 2 or greater and/or if the calcium, magnesium, and/or phosphate are grade 3 or higher, an EKG must be performed and appropriate action taken based on the results. Treatment may be delayed for a maximum of 2 weeks for toxicities. In case toxicities do not resolve as stated, the patient will not receive further therapy on this protocol and will be followed for resolution of toxicities. Start of next cycle may be delayed for up to 1 week to accommodate scheduling conflicts. Dose modifications are intended for within-cycle and start-of-next-cycle changes. If administration of study drug is interrupted for any reason, it will not be made up, and  
counting of the cycle days continues (i.e., if a patient stops pazopanib and ARQ 197 on day 15 and resumes 2 days later, they will be considered day 17). A maximum of 2 dose reductions will be allowed before patient is taken off treatment. Patients who require a dose reduction will not have the dose re-escalated. Dose reductions may occur to a single compound independent of the other compound if toxicity necessitating a dose reduction is attributed to a single agent in the opinion of the study Principal Investigator. One dose level reduction due to pazopanib-associated toxicities such as hypertension means that pazopanib dose should be reduced to 400 mg if an original dose is 600 mg or to 600 mg if it is 800 mg. Similarly, one dose level reduction due to ARQ 197-associated toxicities means that ARQ 197 dose should be reduced to 120 mg bid if an original dose is 240 mg bid, or to 240 mg bid if it is 360 mg bid.
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6.1 dose reduction 6.1.1 doses

- Doses will not be modified for electrolyte abnormalities, unless these are not correctable within 48 hours, or for alopecia.  
- Dose of study drugs will not be reduced for nausea, vomiting, or diarrhea unless these are considered refractory as defined in Section 5.3.  
- Dose reductions may occur to a single compound, independent of the other compound. Doses of ARQ 197 will not be reduced for any grade hypertension or proteinuria.
- For uncontrolled hypertension (as defined in Section 6.1.5), only the dose of pazopanib will be reduced to the next lower dose level.  
- For proteinuria, only the dose of pazopanib will be reduced to the next lower dose level (Section 6.1.6).  
6.1.2 **Grade 2 drug-related toxicity:** No changes will be made to the dose of either study drug for Grade 2 toxicities, and therapy will not be interrupted, except as otherwise noted (e.g., hypokalemia or hyperkalemia as described above, Grade 2 hemorrhage or thrombosis as described in Section 6.1.10). However, for persistent symptomatic skin rash or hand foot syndrome limiting instrumental activities of daily living that do not improve to grade 1 or less within 2 weeks with optimal management, doses of both pazopanib and ARQ 197 will be held until toxicities have resolved to ≤ Grade 1 prior to re-starting study treatment. Therapy will be re-initiated at the next lower dose level.  
6.1.3 **Grade 3 drug-related neutropenia and/or thrombocytopenia:** Doses of both pazopanib and ARQ 197 will be held until toxicities have resolved to ≤ Grade 2 prior to re-starting study treatment. Therapy will be re-initiated at the same dose level at the first occurrence of either event. In the case of second occurrence of either event, therapy will be re-initiated at the next lower dose level. Therapy will not be interrupted or doses modified for any grade lymphopenia, anemia, or leucopenia in the absence of grade 3 or 4 neutropenia.
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6.1.4 grade 4 drug-related neutropenia

of both pazopanib and ARQ 197 will be held until toxicities have resolved to ≤ Grade 2 prior to re-starting study treatment. Therapy will be re-initiated at the next lower dose level.
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6.1.5 hypertension toxicity

Therapeutic BP monitoring by a health care provider will occur every 2 weeks during the first 2 cycles then at least every cycle for the duration of treatment in the dose escalation phase, and on D1 and D8 of cycle 1 then at least every cycle in the expansion phase. All patients will be required to monitor their BP at least once a day (preferably BID) throughout the treatment and record the readings in the study diary (Appendix E). Table 3 will be used for the grading of pazopanib-associated hypertension, for immediate and long-term management, and for the determination of pazopanib dose modification. Suggested antihypertensive medications are listed in Table 4.  
| Table 3: Recommended Hypertension Monitoring and Management (BP in mmHg) Grade Antihypertensive Blood Pressure  Pazopanib                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                            |                                                                     |                                          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|------------------------------------------|
| (CTCAE v4)                                                                                                                                                                                                                                                                                                                                                                                                                             | Therapy                                                                                                                                                                                    | Monitoring                                                          | Dose Modification                        |
| Persistent Grade 1 Pre-hypertension Systolic 120-139 Diastolic 80-90                                                                                                                                                                                                                                                                                                                                                                   | Standard                                                                                                                                                                                   | No Change                                                           |                                          |
| Persistent Grade 2- Moderate Systolic 140-159  Diastolic 90-99                                                                                                                                                                                                                                                                                                                                                                         | Step 1) Initiate BP treatment  and if needed, after 24-48 hr of  treatment, increase dose in  stepwise fashion every 24-48  hours until BP is controlled or  at maximum dose of medication | BP should be  monitored as  recommended by  the treating  physician | No change except as described  in step 4 |
| Step 2) If BP still not controlled,  add another anti-hypertensive  medication, a LA DHP CCB,  ACE1, ARB, or ABB; increase  dose of this drug as described in  step 1  Step 3) If BP still not controlled,  add 3rd drug from the list of  antihypertensives in step 2;  increase dose of this drug as  described in step 1 Step 4) If BP still not controlled,  consider either 1 dose reduction  of pazopanib or stopping  pazopanib |                                                                                                                                                                                            |                                                                     |                                          |  
| Clinical Center Protocol #: 12-C-0009 Grade Antihypertensive                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Blood Pressure                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Pazopanib                                                                                                                                                                                               |                   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|
| (CTCAE v4)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Therapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Monitoring                                                                                                                                                                                              | Dose Modification |
| NOTE: Stopping or reducing  the dose of pazopanib is  expected to cause a decrease in  BP. The treating physician  should monitor the subject for  hypotension and adjust the  number and dose of  antihypertensive  medication(s) accordingly                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                         |                   |
| Persistent Grade 3  Severe  Systolic ≥160 Diastolic ≥100                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | HOLD pazopanib until systolic  BP ≤159 and diastolic BP ≤99.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | BP should be  monitored as  recommended by  the treating  physician unless  the subject is  symptomatic with  systolic BP >180  or diastolic BP  >110 in which  case, monitoring  should be  intensive. | HOLD pazopanib until systolic  BP ≤159 and diastolic BP ≤99.  After this, pazopanib may be readministered. If BP is still  grade 2, manage as described  above for grade 2 hypertenison.                   |
| BP management is identical to  that for Grade 2 (see steps 1-4  above) with 2 major  exceptions:  1) If systolic BP >180 or  diastolic BP >110 and the  subject is symptomatic:  optimal management with  intensive IV support in ICU;  STOP pazopanib and notify  hospital staff that stopping  pazopanib may result in a  decrease in BP and  2) If systolic BP >180 or  diastolic BP >110 and the  subject is asymptomatic, 2 new antihypertensives must  be given together in step 1  (and dose escalated  appropriately as in step 1). | In most circumstances, if BP  cannot be controlled after an  optimal trial of antihypertensive  medications, consider either 1  dose reduction of pazopanib  when systolic BP ≤159 and diastolic BP ≤99 or stopping  pazopanib. HOWEVER, If the subject requires  hospitalization for  management of symptomatic systolic BP >180 or diastolic  BP >110, permanently  discontinue pazopanib or if BP  is controlled to systolic BP  ≤159 and diastolic BP ≤99,  consider re-starting pazopanib  at 1 lower dose level after  consultation with the study  Principal Investigator |                                                                                                                                                                                                         |                   |
| NOTE: Stopping or reducing  the dose of pazopanib is  expected to cause a decrease in  BP. The treating physician  should monitor the subject for  hypotension and adjust the  number and dose of  antihypertensive  medication(s) accordingly                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                         |                   |
| Grade 4 Life-threatening  consequences of  hypertension                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Intensive                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Permanently discontinue  pazopanib or if systolic BP  ≤159 and diastolic BP ≤99, consider re-starting pazopanib  at 1 lower dose level after  consultation with the study  Principal Investigator       |                   |
| Abbreviations: Dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), Angiotensin Converting  Enzyme Inhibitors (ACEI), Angiotensin II Receptor Blockers (ARB), alpha beta blocker (ABB) - *See table below for suggested antihypertensive medications by classOptimal management with  intensive IV support in ICU;  STOP pazopanib and notify  hospital staff that stopping  pazopanib may result in a  decrease in BP                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                         |                   |  
| Grade      | Antihypertensive                                                                                        | Blood Pressure   | Pazopanib         |
|------------|---------------------------------------------------------------------------------------------------------|------------------|-------------------|
| (CTCAE v4) | Therapy                                                                                                 | Monitoring       | Dose Modification |
| -          | If subjects require a delay of >2 weeks for management of hypertension, discontinue protocol therapy    |                  |                   |
| -          | If subjects require >2 dose reductions, discontinue protocol therapy                                    |                  |                   |
| -          | Subjects may have up to 2 drugs for management of hypertension prior to any dose reduction in pazopanib |                  |                   |
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notes

- While patients are receiving treatment with pazopanib, the early initiation of antihypertensive treatment for grade 1 or 2 hypertension to minimize more severe or persistent hypertension is not considered a grade 3 adverse event.  
- Decisions to hold or decrease the pazopanib dose during treatment must be based on BP
readings taken in the clinic by a medical professional.  
- Based on prior clinical experience with pazopanib, the use of calcium channel blockers
(dihydropyridine category) and ACE inhibitors as first-line and second-line therapy is recommended.  
Table 4: Oral Antihypertensive Medications: Agents in bold characters are suggested as optimal choices to avoid or minimize potential drug-interactions with pazopanib through CYP450.  
| Agent                                                | Initial            | Intermediate      | Maximum            | Hepatic                          |                   |
|------------------------------------------------------|--------------------|-------------------|--------------------|----------------------------------|-------------------|
| class                                                | Agent              | dose              | dose               | dose                             | metabolism        |
| Dihydro-pyridine Calcium-Channel  Blockers (DHP CCB) | nifedipine XL      | 30 mg daily       | 60 mg daily        | 90 mg daily                      | CYP 3A4 substrate |
| amlodipine                                           | 2.5 mg daily       | 5 mg daily        | 10 mg daily        | CYP 3A4 substrate                |                   |
| felodipine                                           | 2.5 mg daily       | 5 mg daily        | 10 mg daily        | CYP 3A4 substrate  and inhibitor |                   |
| metoprolol                                           | 25 mg twice daily  | 50 mg twice daily | 100 mg twice daily | CYP 2D6 substrate                |                   |
| atenolol                                             | 25 mg daily        | 50 mg daily       | 100 mg daily       | No                               |                   |
| acebutolol                                           | 100 mg twice daily | 200-300 mg twice  | 400 mg             | Yes (CYP450                      |                   |
| daily                                                | twice daily        | unknown)          |                    |                                  |                   |
| bisoprolol                                           | 2.5 mg daily       | 5-10 mg daily     | 20 mg daily        | Yes (CYP450  unknown)            |                   |
| Selective β Blockers (BB)                            | captopril          | 12.5 mg 3x daily  | 25 mg 3x daily     | 50 mg 3x daily                   | CYP 2D6 substrate |
| enalapril                                            | 5 mg daily         | 10-20 mg daily    | 40 mg daily        | CYP 3A4 substrate                |                   |
| ramipril                                             | 2.5 mg daily       | 5 mg daily        | 10 mg daily        | Yes (CYP450  unknown)            |                   |
| lisinopril                                           | 5 mg daily         | 10-20 mg daily    | 40 mg daily        | No                               |                   |
| fosinopril                                           | 10 mg daily        | 20 mg daily       | 40 mg daily        | Yes (CYP450  unknown)            |                   |
| Rarely used:                                         | 4 mg daily         | none              | 8 mg daily         | Yes, but not                     |                   |
| perindopril                                          | CYP450             |                   |                    |                                  |                   |
| Angiotensin Converting Enzyme Inhibitors (ACEIs)     | Rarely used:       | 10 mg daily       | 20 mg daily        | 40 mg daily                      | No                |
| quinapril                                            |                    |                   |                    |                                  |                   |
| Angiotensin II                                       | losartan           | 25 mg daily       | 50 mg daily        | 100 mg daily                     | CYP 3A4 substrate |  
| Agent                    | Initial       | Intermediate       | Maximum            | Hepatic              |                   |
|--------------------------|---------------|--------------------|--------------------|----------------------|-------------------|
| class                    | Agent         | dose               | dose               | dose                 | metabolism        |
| Receptor Blockers (ARBs) | candesartan   | 4 mg daily         | 8-16 mg daily      | 32 mg daily          | CYP 2C9 substrate |
| irbesartan               | 75 mg daily   | 150 mg daily       | 300 mg daily       | CYP 2C9 substrate    |                   |
| telmisartan              | 40 mg daily   | none               | 80 mg daily        | Yes, but not  CYP450 |                   |
| valsartan                | 80 mg daily   | none               | 160 mg daily       | Yes, but not  CYP450 |                   |
| α and β                  | labetolol     | 100 mg twice daily | 200 mg twice daily | 400 mg twice daily   | CYP 2D6 substrate |
| Blocker                  | and inhibitor |                    |                    |                      |                   |
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6.1.6 proteinuria toxicity

Evaluation of urine protein/creatinine ratio (UPC) should occur as follows: − *Dose escalation phase*: at baseline, on C1D15, then at the start of each cycle − *Expansion phase*: at baseline, on C1D8, then at the start of each cycle. If, at any time, a subject has a urine protein/creatinine ratio greater than 1, a 24 hour urine collection must be performed. If a subject develops the nephrotic syndrome, treatment must be discontinued. Although subjects with ≥1+ proteinuria at entry are ineligible, increases in proteinuria may occur during treatment and should be managed as Table 5:  
| UPC > 1and < 3        | Obtain 24-hr urine protein and if <3 g, continue at current dose and monitor as  clinically indicated                                                                                                                                                                                                                                                                                       |
|-----------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| UPC ≥ 3 or 24-h urine | Step 1. Interrupt pazopanib.                                                                                                                                                                                                                                                                                                                                                                |
| protein ≥ 3 g         | 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 dose can no  longer be reduced, discontinue pazopanib and remove subject from study. |
| Nephrotic syndrome    | Permanently discontinue pazopanib and remove subject from study                                                                                                                                                                                                                                                                                                                             |  
Table 5: Pazopanib Dose Modifications for Proteinuria Toxicity
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6.1.7 cardiac toxicity

1. Discontinue pazopanib in patients who develop symptomatic heart failure. 2. Modify the pazopanib dose using the table presented in Appendix F in patients who develop compromised symptomatic LVEF. The NCI developed the table in Appendix F using the NSABP-B31 and NCCTG9831 monitoring guidelines for adjuvant trastuzumab in patients with breast cancer. These studies enrolled populations considered most likely to be cured; thus, the investigators used the most stringent and conservative monitoring.  
3. Discontinue ARQ 197 in patients who develop symptomatic bradycardia.  
4. Patients with asymptomatic bradycardia will not have drug held or dose modified.  
Bradycardic patients with a heart rate < 50 beats per minute should have an EKG done on day 1 of every cycle, or as clinically indicated.  
5. QTc Prolongation, see Table 6.  
| If EKG reveals an increase in the QTc to ≥500 msec  or an increase in the QTc by at least 60 msec from  baseline   | Repeat EKG before re-administration of pazopanib and/or  ARQ 197   |
|--------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| If repeat EKG shows QTc interval is >500 msec                                                                      | Remove subject from study                                          |
| If on repeat EKG, QTc remains at least 60 msec                                                                     | Consider removing subject from study                               |
| longer than baseline but is less than 500 msec                                                                     |                                                                    |
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6.1.8 management of subjects with

Table 7: Management of Liver Function Test Abnormality  
| AST, ALT and/or Bilirubin Isolated AST/ALT elevations                                                    | Continue pazopanib, but monitor weekly until AST/ALT returns to < 2.5 or                                                                                                                                                                                                                                                                                                                                                                                      |
|----------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| between 3X ULN and 8X ULN                                                                                | baseline                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| AST/ALT >8 X ULN                                                                                         | Hold pazopanib until AST/ALT returns to < 2.5 X ULN or baseline.  If the potential benefit of reinitiating pazopanib treatment is considered to  outweigh the risk for hepatotoxicity, then consider reintroducing pazopanib at  a reduced dose of 400 mg once daily and measure serum liver tests weekly for  8 weeks only after discussion with the PI and CTEP.  If AST/ALT elevations >3 X ULN recur, then pazopanib should be  permanently discontinued. |
| AST/ALT >3 X ULN and  concurrent bilirubin elevations  >2 X ULN                                          | Permanently discontinue pazopanib.                                                                                                                                                                                                                                                                                                                                                                                                                            |
| Mild indirect hyperbilirubinemia, known or  suspected Gilbert's syndrome,  and elevation in ALT >3 X ULN | Continue pazopanib, but monitor weekly until ALT returns to grade 1 (NCI  CTCAE) or baseline.                                                                                                                                                                                                                                                                                                                                                                 |
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6.1.9 reversible posterior leukoencephalopathy syndrome

RPLS or clinical syndromes related to vasogenic edema of the white matter have been rarely reported in association with pazopanib therapy (<3%). Clinical presentations are variable and may include altered mental status, seizure, and cortical visual deficit. Hypertension is a common risk factor in patients who develop RPLS. MRI scans are key to diagnosis and typically demonstrate vasogenic edema (hyperintensity in T2 and FLAIR images and hypointensity in T1 images) predominantly in the white matter of the posterior parietal and occipital lobes; less frequently, the anterior distributions and the  
gray matter may also be involved. RPLS should be in the differential diagnosis in patients presenting with unexplained mental status changes, visual disturbance, seizure or other CNS findings. RPLS is potentially reversible, but timely correction of the underlying causes, including control of blood pressure and interruption of the offending drug, is important in order to prevent progression to irreversible tissue damage. Pazopanib should be held in patients with symptoms/signs suggestive of RPLS, pending work-up and management, including control of blood pressure. Pazopanib should be discontinued upon diagnosis of RPLS. After consultation with the study PI and CTEP, NCI, consideration of restarting the study drugs may be evaluated in light of any clinical benefit.  
| Adverse  Event                           | Grade                                                                                                                                                                                                                                                                                              | Treatment Modification                               |
|------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------|
| Grade 1                                  | No interruption in treatment until hemoptysis. If hemoptysis, contact PI to  determine if it is appropriate to continue pazopanib.  Maintain current dose. For non-pulmonary bleeding, hold pazopanib unless resolved to ≤ grade 1;  reduce dose to next lower dose level, and continue treatment. |                                                      |
| Hemorrhage/ Bleeding                     | For pulmonary bleeding, permanently discontinue pazopanib and remove  subject from study.                                                                                                                                                                                                          |                                                      |
| Grade 2                                  | If grade 2 or greater hemorrhage/ bleeding recurs following dose reduction,  stop pazopanib and remove subject from study.                                                                                                                                                                         |                                                      |
| Grades 3 or 4                            | Discontinue treatment and withdraw subject from study.                                                                                                                                                                                                                                             |                                                      |
| Grade 1                                  | No interruption in treatment; maintain current dose. Hold pazopanib until subject is receiving a stable dose of Low Molecular  Weight Heparin (LMWH). Treatment may resume during the period of full-dose anticoagulation if all of  the following criteria are met: - The subject must have been treated with an anticoagulant at the desired  level for at least one week. - The subject must not have had a grade 3 or 4 or significant grade 2  hemorrhagic event while on anticoagulant. 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 pazopanib dosing (e.g., re-initiating, escalating/deescalating, or discontinuing pazopanib), 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 or pulmonary  embolus Grade 2, 3 |                                                                                                                                                                                                                                                                                                    |                                                      |
| Vascular/ Thrombosis                     | Discontinue treatment and remove subject from study.                                                                                                                                                                                                                                               |                                                      |
| Arterial                                 |                                                                                                                                                                                                                                                                                                    |                                                      |
| Thrombosis/ ischemia                     | All grades                                                                                                                                                                                                                                                                                         | Discontinue pazopanib and remove subject from study. |
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6.1.10 management of other adverse

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following lists of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires expedited reporting (via CTEP-AERS) in addition to routine reporting.
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7.1 comprehensive adverse events and

The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system.  In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. Frequency is provided based on 2383 patients.  Below is the CAEPR for Pazopanib (GW786034)
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses nxt to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| Version 2.6¹, January 21, 2015       |                                 |                        |
|--------------------------------------|---------------------------------|------------------------|
| Adverse Events with Possible         |                                 |                        |
| Relationship to Pazopanib (GW786034) | Specific Protocol Exceptions to |                        |
| (CTCAE 4.0 Term)                     | Expedited Reporting (SPEER)     |                        |
| [n= 2383]                            |                                 |                        |
| Likely (>20%)                        | Less Likely (<=20%)             | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS | Anemia (Gr 3)                   |                        |
| Anemia                               | Hemolytic uremic syndrome*      |                        |
| Thrombotic thrombocytopenic          |                                 |                        |
| purpura 2                            |                                 |                        |
| CARDIAC DISORDERS                    | Left ventricular systolic       |                        |
| dysfunction                          |                                 |                        |
| Myocardial infarction                |                                 |                        |
| Sinus bradycardia                    |                                 |                        |
| ENDOCRINE DISORDERS                  | Hypothyroidism                  |                        |
| GASTROINTESTINAL DISORDERS           |                                 |                        |
| Abdominal pain                       | Abdominal pain (Gr 3)           |                        |  
CTEP Protocol \#880  
| Clinical Center Protocol #: 12-C-0009                |                                             |                                       |
|------------------------------------------------------|---------------------------------------------|---------------------------------------|
| Adverse Events with Possible                         |                                             |                                       |
| Relationship to Pazopanib (GW786034)                 | Specific Protocol Exceptions to             |                                       |
| (CTCAE 4.0 Term)                                     | Expedited Reporting (SPEER)                 |                                       |
| [n= 2383]                                            |                                             |                                       |
| Likely (>20%)                                        | Less Likely (<=20%)                         | Rare but Serious (<3%)                |
| Constipation                                         | Constipation (Gr 2)                         |                                       |
| Diarrhea                                             | Diarrhea (Gr 2)                             |                                       |
| Dyspepsia                                            | Gastrointestinal fistula 3                  | Gastrointestinal fistula 3 (Gr 2)     |
| Gastrointestinal hemorrhage 4                        |                                             |                                       |
| Gastrointestinal perforation 5                       | Gastrointestinal perforation 2 (Gr 2)       |                                       |
| Mucositis oral                                       |                                             |                                       |
| Nausea                                               | Nausea (Gr 3)                               |                                       |
| Vomiting                                             | Vomiting (Gr 2)                             |                                       |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS |                                             |                                       |
| Edema limbs                                          |                                             |                                       |
| Fatigue                                              | Fatigue (Gr 3)                              |                                       |
| Fever                                                |                                             |                                       |
| HEPATOBILIARY DISORDERS                              | Hepatic failure                             |                                       |
| INVESTIGATIONS                                       | Activated partial                           |                                       |
| thromboplastin time.                                 |                                             |                                       |
| prolonged                                            |                                             |                                       |
| Alanine aminotransferase                             | Alanine aminotransferase increased (Gr 3)   |                                       |
| increased                                            | Alkaline phosphatase                        | Alkaline phosphatase increased (Gr 2) |
| increased                                            |                                             |                                       |
| Aspartate aminotransferase                           | Aspartate aminotransferase increased (Gr 3) |                                       |
| increased                                            | Blood bilirubin increased (Gr 3)            |                                       |
| Blood bilirubin increased                            | Creatinine increased                        | Creatinine increased (Gr 2)           |
| Electrocardiogram QT corrected                       |                                             |                                       |
| interval prolonged                                   |                                             |                                       |
| Lymphocyte count decreased                           | Lymphocyte count decreased (Gr 3)           |                                       |
| Neutrophil count decreased                           | Neutrophil count decreased (Gr 3)           |                                       |
| Platelet count decreased                             | Platelet count decreased (Gr 4)             |                                       |
| Weight loss                                          | Weight loss (Gr 2)                          |                                       |
| White blood cell decreased                           | White blood cell decreased (Gr 2)           |                                       |
| METABOLISM AND NUTRITION DISORDERS                   |                                             |                                       |
| Anorexia                                             | Anorexia (Gr 2)                             |                                       |
| Dehydration                                          | Dehydration (Gr 2)                          |                                       |
| Hypercalcemia                                        |                                             |                                       |
| Hyperglycemia                                        | Hyperglycemia (Gr 2)                        |                                       |
| Hyperkalemia                                         | Hyperkalemia (Gr 2)                         |                                       |
| Hypermagnesemia                                      |                                             |                                       |
| Hypematremia                                         |                                             |                                       |
| Hypoalbuminemia                                      | Hypoalbuminemia (Gr 2)                      |                                       |
| Hypocalcemia                                         | Hypocalcemia (Gr 2)                         |                                       |
| Hypoglycemia                                         | Hypoglycemia (Gr 2)                         |                                       |
| Hypokalemia                                          |                                             |                                       |
| Hypomagnesemia                                       |                                             |                                       |
| Hyponatremia                                         | Hyponatremia (Gr 2)                         |                                       |  
CTEP Protocol \#880  
| Clinical Center Protocol #: 12-C-0009                       |                                          |                        |
|-------------------------------------------------------------|------------------------------------------|------------------------|
| Adverse Events with Possible                                |                                          |                        |
| Relationship to Pazopanib (GW786034)                        | Specific Protocol Exceptions to          |                        |
| (CTCAE 4.0 Term)                                            | Expedited Reporting (SPEER)              |                        |
| [n= 2383]                                                   |                                          |                        |
| Likely (>20%)                                               | Less Likely (<=20%)                      | Rare but Serious (<3%) |
| Hypophosphatemia                                            | Hypophosphatemia (Gr 2)                  |                        |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS             |                                          |                        |
| Arthralgia                                                  | Arthralgia (Gr 2)                        |                        |
| Back pain                                                   |                                          |                        |
| Myalgia                                                     | Myalgia (Gr 2)                           |                        |
| Pain in extremity                                           |                                          |                        |
| NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND |                                          |                        |
| POLYPS)                                                     | Tumor pain                               |                        |
| NERVOUS SYSTEM DISORDERS                                    |                                          |                        |
| Dizziness                                                   | Dizziness (Gr 2)                         |                        |
| Dysgeusia                                                   | Dysgeusia (Gr 3)                         |                        |
| Headache                                                    | Headache (Gr 2)                          |                        |
| Reversible posterior                                        |                                          |                        |
| leukoencephalopathy syndrome                                |                                          |                        |
| RENAL AND URINARY DISORDERS                                 | Acute kidney injury                      |                        |
| Proteinuria                                                 | Proteinuria (Gr 2)                       |                        |
| Urinary fistula                                             | Urinary fistula (Gr 2)                   |                        |
| REPRODUCTIVE SYSTEM AND BREAST DISORDERS                    |                                          |                        |
| Female genital tract fistula                                | Female genital tract fistula (Gr 2)      |                        |
| Uterine fistula                                             | Uterine fistula (Gr 2)                   |                        |
| Vaginal fistula                                             | Vaginal fistula (Gr 2)                   |                        |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS             |                                          |                        |
| Cough                                                       |                                          |                        |
| Dyspnea                                                     |                                          |                        |
| Respiratory hemorrhage 6                                    | Respiratory hemorrhage 6 (Gr 2)          |                        |
| Respiratory, thoracic and                                   |                                          |                        |
| mediastinal disorders - Other                               |                                          |                        |
| (interstitial lung disease) 7                               |                                          |                        |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS                      |                                          |                        |
| Alopecia                                                    | Alopecia (Gr 2)                          |                        |
| Palmar-plantary                                             |                                          |                        |
| erythrodysesthesia                                          |                                          |                        |
| syndrome                                                    |                                          |                        |
| Rash maculo-papular                                         | Rash maculo-papular (Gr 2)               |                        |
| Skin and subcutaneous tissue                                | Skin and subcutaneous tissue disorders - |                        |
| disorders - Other (hair color:                              | Other (hair color change/hair            |                        |
| change/hair depigmentation)                                 | depigmentation) (Gr 2)                   |                        |
| Skin hypopigmentation                                       | Skin hypopigmentation (Gr 2)             |                        |
| VASCULAR DISORDERS                                          |                                          |                        |
| Hypertension                                                | Hypertension (Gr 3)                      |                        |
| Thromboembolic event 8                                      |                                          |                        |
| Vascular disorders - Other                                  |                                          |                        |
| (arterial thromboembolic event) 8                           |                                          |                        |  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Thrombotic microangiopathy (TMA) which includes both Hemolytic uremic syndrome (HUS) and Thrombotic thrombocytopenic purpura (TTP) has been reported in clinical trials of GW786034.  
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Enterovesical fistula, Esophageal fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL
DISORDERS SOC.  
4Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC.  
5Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC.  
6Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY,
THORACIC AND MEDIASTINAL DISORDERS SOC.  
7Interstitial lung disease may include, Adult respiratory distress syndrome, Pneumonitis, Pulmonary fibrosis, Respiratory, thoracic and mediastinal disorders - Other (Acute respiratory distress syndrome), Respiratory, thoracic and mediastinal disorders - Other (Aveolitis), Respiratory, thoracic and mediastinal disorders - Other (Bronchiolitis obliterans), Respiratory, thoracic and mediastinal disorders - Other (Interstitial fibrosis), Respiratory, thoracic and mediastinal disorders - Other (Interstitial pneumonia), Respiratory, thoracic and mediastinal disorders - Other (Interstitial pneumonitis), Respiratory, thoracic and mediastinal disorders - Other (Organizing pneumonia), Respiratory, thoracic and mediastinal disorders - Other (Pulmonary infiltrates), Respiratory, thoracic and mediastinal disorders - Other (Toxic pneumonitis).  
8These events can result in life-threatening pulmonary, cardiac, cerebral, and other complications. 9Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.  
Adverse events also reported on Pazopanib (GW786034) trials but with the relationship to Pazopanib (GW786034) still undetermined:
untitled h1
blood and lymphatic system disorders

CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac disorders - Other
(sinus arrest); Cardiac disorders - Other (supraventricular extrasystoles); Cardiac disorders - Other (Takotsubo [Broken Heart Syndrome]); Cardiac disorders - Other (Torsades de Pointes); Chest pain -
cardiac; Pericardial effusion; Supraventricular tachycardia ENDOCRINE DISORDERS - Adrenal insufficiency EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (asthenopia); Eye disorders - Other
(eye/retinal hemorrhage); Eye disorders - Other (foreign body sensation in eyes); Eye pain; Floaters; Glaucoma; Photophobia; Retinal tear GASTROINTESTINAL DISORDERS - Abdominal distension; Dry mouth; Duodenal obstruction; Dysphagia; Esophagitis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (hyperactive bowel); Gastrointestinal disorders - Other (oropharyngeal pain); Gastrointestinal disorders - Other (pneumatosis intestinalis); Gastrointestinal pain; Oral pain; Pancreatitis; Periodontal disease; Proctitis; Small intestinal obstruction GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Malaise; Non-cardiac chest pain; Pain INFECTIONS AND INFESTATIONS - Infection9 INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising INVESTIGATIONS - Cardiac troponin T increased; Cholesterol high; Ejection fraction decreased; GGT
increased; INR increased; Investigations - Other (blood lactate dehydrogenase increased); Investigations - Other (blood TSH increased); Lipase increased; Serum amylase increased; Weight gain METABOLISM AND NUTRITION DISORDERS - Hypertriglyceridemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest wall pain; Generalized muscle weakness; Head soft tissue necrosis; Muscle weakness lower limb; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other (muscle spasms); Neck pain NERVOUS SYSTEM DISORDERS - Extrapyramidal disorder; Intracranial hemorrhage; Ischemia cerebrovascular; Memory impairment; Paresthesia; Peripheral sensory neuropathy; Stroke; Syncope; Transient ischemic attacks PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Suicide attempt RENAL AND URINARY DISORDERS - Hematuria; Urinary frequency REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Reproductive system and breast disorders - Other (vaginal necrosis); Vaginal discharge; Vaginal hemorrhage RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Laryngeal edema; Pharyngolaryngeal pain; Pleural effusion; Pleuritic pain; Pneumothorax; Postnasal drip; Sore throat; Voice alteration SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Pruritus; Purpura; Skin hyperpigmentation; Skin ulceration VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Vasculitis Note: Pazopanib (GW786034) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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7.1.2 caepr for arq 197

The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for CTEP Protocol \#880 further clarification.  Frequency is provided based on 579 patients.  Below is the CAEPR for AQ 197 (tivantinib).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| Version 2.1, June 17, 2013¹                                                                   |                                   |                        |
|-----------------------------------------------------------------------------------------------|-----------------------------------|------------------------|
| Adverse Events with Possible                                                                  | Specific Protocol Exceptions to   |                        |
| Relationship to ARQ 197 (tivantinib)                                                          | Expedited Reporting (SPEER)       |                        |
| (CTCAE 4.0 Term)                                                                              | (formerly known as ASAEL)         |                        |
| [n= 579]                                                                                      |                                   |                        |
| Likely (>20%)                                                                                 | Less Likely (<=20%)               | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS                                                          |                                   |                        |
| Anemia                                                                                        | Anemia (Gr 2)                     |                        |
| CARDIAC DISORDERS                                                                             | Sinus bradycardia                 |                        |
| GASTROINTESTINAL DISORDERS                                                                    |                                   |                        |
| Diarrhea                                                                                      | Diarrhea (Gr 2)                   |                        |
| Nausea                                                                                        | Nausea (Gr 2)                     |                        |
| Vomiting                                                                                      | Vomiting (Gr 2)                   |                        |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS                                          |                                   |                        |
| Fatigue                                                                                       | Fatigue (Gr 2)                    |                        |
| INVESTIGATIONS                                                                                | Lymphocyte count decreased        |                        |
| Neutrophil count decreased                                                                    | Neutrophil count decreased (Gr 2) |                        |
| White blood cell decreased                                                                    |                                   |                        |
| METABOLISM AND NUTRITION DISORDERS                                                            |                                   |                        |
| Anorexia                                                                                      | Anorexia (Gr 2)                   |                        |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS                                                        | Palmar-plantar                    |                        |
| erythrodysesthesia syndrome                                                                   |                                   |                        |
| Rash maculo-papular                                                                           | Rash maculo-papular (Gr 2)        |                        |
| 1This table will be updated as the toxicity profile of the agent is revised.  Updates will be |                                   |                        |  
distributed to all Principal Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
²Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS
SOC.  
Also reported on ARQ 197 (tivantinib) trials but with the relationship to ARQ 197 (tivantinib) still undetermined:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Lymph node pin CARDIAC DISORDERS - Cardiac arrest EYE DISORDERS - Dry eye; Eye disorders - Other (blindness unilateral)
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Ascites; Constipation; Dry mouth; Duodenal ulcer; Dyspepsia; Flatulence; Gastrointestinal disorders -  
Other (eructation [belching]); Gastrointestinal disorders - Other (peritoneal hemorrhage); Mucositis oral; Oral pain; Small intestinal obstruction GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Fever; Flu like symptoms; Gait disturbance; Malaise; Non-cardiac chest pain; Pain HEPATOBILIARY DISORDERS - Bile duct stenosis; Hepatic failure Infections and infestations - Infection2 Injury, poisoning and procedural complications - Fracture INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin increased; Electrocardiogram QT corrected interval prolonged; GGT increased; INR increased; Investigations - Other (pancytopenia); Platelet count decreased; Weight loss METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hyponatremia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Flank pain; Generalized muscle weakness; Musculoskeletal and connective tissue disorder - Other (muscle spasms); Neck pain; Pain in extremity Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Treatment related secondary malignancy NERVOUS SYSTEM DISORDERS - Dizziness; Dysgeusia; Headache; Nervous system disorders - Other (spinal cord compression); Peripheral motor neuropathy; Seizure; Stroke; Syncope; Transient ischemic attacks PSYCHIATRIC DISORDERS - Anxiety; Confusion; Insomnia RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders -
Other (hydronephrosis); Urinary retention; Urinary tract obstruction Reproductive system and breast disorders - Pelvic pain RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Bronchospasm; Cough; Dyspnea; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (oropharyngeal pain)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (skin fissures); Skin hyperpigmentation VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event Note: ARQ 197 (tivantinib) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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7.2 adverse event characteristics

- **CTCAE term (AE description) and grade:** The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
'Expectedness': AEs can be 'Unexpected' or 'Expected' (see Section 7.1 above) for
.  
expedited reporting purposes only.  'Expected' AEs (the ASAEL) are bold and italicized in the CAEPR (Section 7.1).  
.  
Attribution of the AE:
lal st 2 3.  
4.  
5.  
Definite - The AE is clearly related to the study treatment.  
Probable - The AE is likely related to the study treatment.  
Possible - The AE may be related to the study treatment.  
Unlikely - The AE is doubtfully related to the study treatment.  
Unrelated - The AE is clearly NOT related to the study treatment.
7.3