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expedited adverse event reporting

7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented in the "CTEP, NCI Guidelines: Adverse Event Reporting Requirements" which can  
Event Reporting System), accessed via the CTEP Web site be downloaded from the CTEP Web site ( http://ctep.cancer.gov ).  These requirements are briefly outlined in the table below (Section 7.3.2).
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to CTEP by telephone at Once Internet connectivity is restored, the 24-hour notification phoned in MUST be entered electronically into CTEP-AERS by the original submitter at the site.  
7.3.2 Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention 1, 2 .
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1). Death 2)
A life-threatening adverse event 3)
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
4)
A congenital anomaly/birth defect.  
5)
6)
(FDA, 21 CFR 312.32; ICH E2A and ICH E6).
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below.  
| Grade 3-5       |                                |            |
|-----------------|--------------------------------|------------|
| Hospitalization | Grade 1 and Grade 2 Timeframes | Timeframes |  
| Resulting in  Hospitalization     | 10 Calendar Days         |
|-----------------------------------|--------------------------|
| ≥ 24 hrs                          | 24-Hour 5 Calendar  Days |
| Not resulting in  Hospitalization | Not required             |
| ≥ 24 hrs                          |                          |  
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific  
  
  
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR.  
Expedited AE reporting timelines are defined as:
o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-   
o "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar  
  
  
- All Grade 3, 4, and Grade 5 AEs Expedited 10 calendar day reports for:
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above applies after this reporting period.  
Effective Date: May 5, 2011
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7.3.3 protocol-specific expedited adverse event

For this protocol only, certain AEs/grades are exceptions to the Expedited  
 Reporting Guidelines and do not require expedited reporting (i.e., CTEP-AERS). These are: any grade lymphopenia, grade 2 hypophosphatemia, grade 2 hyperglycemia, any grade alopecia, grade 2 anemia, grade 2 electrolytes (sodium, potassium, and magnesium), grade 2 albumin, grade 2 INR, grade 2 PTT, and grade 2 hyperuricemia will NOT be reported through CTEP-AERS but will be reported in the routine data submissions.
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7.3.4 pregnancy fetal death and

NOTE: When submitting CTEP-AERS reports for "Pregnancy", "Pregnancy loss", or "Neonatal loss", the Pregnancy Information Form should be completed and faxed along with any additional medical information to . The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) should be documented in the "Description of Event" section of the CTEP-AERS report. 7.3.4.1 Pregnancy
- Because patients who become pregnant on study risk intrauterine exposure  
of the fetus to agents which may be teratogenic. For this reason, pregnancy should be reported in an expedited manner via CTEP-AERS as Grade 3 "Pregnancy, puerperium and perinatal conditions - *Other*
(pregnancy)" under the *Pregnancy, puerperium and perinatal conditions* SOC.  
- The pregnancy outcome for patients on study should be reported via CTEP-AERS at the time the outcome becomes known, accompanied by the same Pregnancy Report Form used for the initial report.
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7.3.4.2 fetal death

- Fetal death is defined in CTCAE as "A disorder characterized by death in utero; failure of the product of conception to show evidence of respiration, heartbeat, or definite movement of a voluntary muscle after expulsion from the uterus, without possibility of resuscitation."
- Any fetal death should be reported expeditiously, as Grade 4 "Pregnancy, puerperium and perinatal conditions - Other (pregnancy loss)" under the Pregnancy, puerperium and perinatal conditions SOC.  
- A fetal death should NOT be reported as "Fetal death," a Grade 5 event under the Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS recognizes this event as a patient death.
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7.3.4.3 death neonatal

- Neonatal death, defined in CTCAE as "A disorder characterized by cessation of life occurring during the first 28 days of life" that is felt by the investigator to be at least possibly due to the investigational agent/intervention, should be reported expeditiously.  
- A neonatal death should be reported expeditiously as Grade 4 "General disorders and administration - Other (neonatal loss)" under the General disorders and administration SOC.  
- Neonatal death should NOT be reported as "Death neonatal" under the General disorders and administration SOC, a Grade 5 event. If reported as such, the CTEP-AERS interprets this as a death of the patient being treated.
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7.3.4 nci-irb expedited reporting of

An adverse event is defined as any reaction, side effect, or untoward event that occurs during the course of the clinical trial associated with the use of a drug in humans, whether or not the event is considered related to the treatment or  
clinically significant. For this study, AEs will include events reported by the patient, as well as clinically significant abnormal findings on physical examination or laboratory evaluation. A new illness, symptom, sign or clinically significant laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an AE. All AEs must be recorded on the AE case report form. All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until satisfactory resolution. AEs should be reported up to 30 days following the last dose of study drug. AEs that are considered treatment related, expected, continuing, but not resolvable by 30 days after treatment completion (e.g., alopecia) will not be followed after the 30-day period.
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suspected adverse reaction

Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 'reasonable possibility' means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.
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unexpected adverse reaction

An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application. "Unexpected" also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.
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serious

An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or others.
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serious adverse events

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following: - Death,  
- A life-threatening adverse drug experience - Inpatient hospitalization or prolongation of existing hospitalization  
- A persistent or significant disability/incapacity - A congenital anomaly/birth defect.  
- Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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disability

A substantial disruption of a person's ability to conduct normal life functions.
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life-threatening adverse drug experience

Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death.
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protocol deviation (nih definition)

Any change, divergence, or departure from the IRB approved research protocol.
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non-compliance (nih definition)

The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of human research subjects.
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unanticipated problem

Any incident, experience, or outcome that:
- Is unexpected in terms of nature, severity, or frequency in relation to
(a) the research risks that are described in the IRB-approved research protocol and informed consent document; Investigator's Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
- Is related or possibly related to participation in the research; AND  
- Places subjects or others at a g*reater risk of harm* (including physical, psychological, economic, or social harm) than was previously known or recognized.
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7.3.4.2 requirements

The NCI-IRB **requires** that the following language be used for reporting events to the NCI-IRB:
The Protocol PI will report to the NCI-IRB:  
- All deaths, except deaths due to progressive disease
- All Protocol Deviations - All Unanticipated Problems
- All serious non-compliance Reports must be received by the NCI-IRB within 7 working days of PI awareness via iRIS.
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7.3.4.3 nci-irb reporting of ind

Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NCI IRB.
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7.4 routine adverse event reporting

All Adverse Events **must** be reported in routine study data submissions. AEs reported through CTEP-AERS must also be reported in routine study data submissions.
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7.4.1 nci-irb requirements for pi

For reporting of adverse events at time of continuing review, the NCI-IRB requires a summary report of adverse events that have occurred on the protocol **since the previous**
continuing review and in aggregate. The method of presentation should provide the NCI-IRB with the information necessary to clearly identify risks to participants and to make a risk: benefit determination. Please sort the events by the system organ class and by grade. The summary report is based on the following guidance: any unexpected severity and/or unexpected frequency of expected events needs to be reported and interpreted in relation to the risk:benefit of study participants in the narrative.  
| System      | CTCAE   | Grade         | # of Events   | Total #   | Attribution to   | Serious?   | Unexpected?   |
|-------------|---------|---------------|---------------|-----------|------------------|------------|---------------|
| Organ Class | Term    | since last CR | of Events     | Research  |                  |            |               |  
Please use the following table for reporting adverse events at time of CR: The protocol PI will report to the NCI-IRB:
1.A summary of all protocol deviations in a tabular format to include the date the deviation occurred, a brief description of the deviation and any corrective action. 2.A summary of any instances of non-compliance 3.A tabular summary of the following adverse events:  
- All Grade 2 **unexpected** events that are possibly, probably or definitely related to the research;
- All Grade 3 and 4 events that are possibly, probably or definitely related to the research;
- All Grade 5 events regardless of attribution; - All Serious Events regardless of attribution.
NOTE: Grade 1 events are not required to be reported.
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7.5 secondary malignancy

A *secondary malignancy* is a cancer caused by treatment for a previous malignancy (e.g.,
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm. CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:
- Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])
- Myelodysplastic syndrome (MDS)
- Treatment-related secondary malignancy Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.
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7.6 second malignancy

A second malignancy is one unrelated to the treatment of a prior malignancy (and is **NOT** a metastasis from the initial malignancy). Second malignancies require **ONLY** routine reporting via CDUS unless otherwise specified.
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8 pharmaceutical information 8.1 pazopanib

Chemical Name: 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride  
Other Names: Pazopanib HCl, GW786034B (the suffix B denotes the  
monohydrochloride salt)  
Classification: VEGFR tyrosine kinase inhibitor Molecular Formula: C21H23N7O2S - HCl  
Molecular Weight: 474.0 g/mol (monohydrochloride salt)  
| 437.5 g/mol (free base)     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
|-----------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Physical Form:              | White to slightly colored solid                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| Solubility:                 | Very slightly soluble in 0.1M HCl (0.65 mg/mL); practically  insoluble in pH 7.0 phosphate buffer (0.00005 mg/mL) and in pH  11 piperidine buffer (0.0002 mg/mL).                                                                                                                                                                                                                                                                                                                                                                          |
| Mode of Action:             | Pazopanib is a highly potent inhibitor of vascular endothelial  growth factor (VEGF) receptor tyrosine kinases (VEGFR1,  VEGFR2, and VEGFR3). Vascular endothelial growth factor  receptor inhibition may block VEGF driven angiogenesis and, as a  consequence, constrain tumor growth.                                                                                                                                                                                                                                                   |
| How Supplied:               | Pazopanib monohydrochloride is supplied as a series of aqueous  film-coated tablets containing 200 mg and 400 mg of the free  base: - 200 mg, oval-shaped, white, packaged in bottles containing  34 tablets each - 400 mg, oval-shaped, white, packaged in bottles containing  68 tablets each Tablet excipients in all tablet sizes include microcrystalline  cellulose, povidone, sodium starch glycolate, and magnesium  stearate. The film-coat consists of titanium dioxide,  hypromellose, polyethylene glycol, and polysorbate 80. |
| Storage:                    | The intact bottles should be stored at controlled room temperature  [20°C-25°C, (68-77°F)]. Excursions are permitted between 15°C  and 30°C.                                                                                                                                                                                                                                                                                                                                                                                               |
| Stability:                  | Stability studies are ongoing.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Route of Administration:    | Oral pazopanib should be taken on an empty stomach either 1  hour before or 2 hours after meals. The tablets should be  swallowed whole and cannot be crushed or broken.                                                                                                                                                                                                                                                                                                                                                                   |
| Potential Drug Interaction: | See Section 5.3.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| Availability                | Pazopanib is an investigational agent supplied to investigators by  the Division of Cancer Treatment and Diagnosis (DCTD), NCI.  Pazopanib is provided to the NCI under a Collaborative  Agreement between GlaxoSmithKline and the DCTD, NCI (see  Section 12.3).                                                                                                                                                                                                                                                                          |
| 8.2                         | ARQ 197 (NSC 750832)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Chemical Name:              | (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4- (1H-indol-3-yl)pyrrolidine-2,5-dione                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Other Names:                | Tivantinib                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| CAS Registry Number         | 905854-02-06                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Classification:             | c-MET inhibitor                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |  
| Molecular Formula:          | C23H19N3O2                                                                                                                                                                                                                                                                                                                                                                                                                                          |
|-----------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Molecular Weight:           | 369.43                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| Solubility:                 | Soluble in DMSO                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Mode of Action:             | c-MET inhibitor ARQ 197 binds to the c-MET protein and  disrupts c-MET signal transduction pathways, which may induce  apoptosis in tumor cells overexpressing c-MET protein or  expressing constitutively activated c-MET protein.                                                                                                                                                                                                                 |
| Description:                | Off-white to light to dark orange powder.                                                                                                                                                                                                                                                                                                                                                                                                           |
| How Supplied:               | ArQule supplies and CTEP's Pharmaceutical Management  Branch distributes ARQ 197 in 120 mg tablets in 50 mL highdensity polyethylene bottles with polypropylene caps. ARQ 197  tablets are red orange film coated and round with a diameter of  9.2 mm. Inert ingredients include lactose monohydrate,  croscarmellose sodium, hydroxypropyl cellulose, purified water,  and magnesium stearate. The film coating contains purified  water, hypromellose, titanium dioxide, talc and ferric oxide.  Each bottle contains 100 tablets.                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Storage:                    | Store at controlled room temperature (20-25o C) with excursions  allowable to 15-30o C.                                                                                                                                                                                                                                                                                                                                                             |
| Stability:                  | Stability studies of the intact bottles are ongoing.                                                                                                                                                                                                                                                                                                                                                                                                |
| Route(s) of Administration: | Oral                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| Method of Administration:   | ARQ 197 tablets should be administered twice daily  approximately 12 hours apart. They should be taken with water,  swallowed whole and cannot be crushed or broken. ARQ 197 should be taken with food.                                                                                                                                                                                                                                             |
| Potential Drug Interaction: | ARQ 197 is metabolized via a drug metabolizing enzyme system  associated with cytochrome P450 (CYP2C19 and CYP3A4).  Interactions with drugs metabolized via the same enzyme system  are possible. Drugs which inhibit CYP2C19 may markedly  increase the plasma concentration of ARQ 197. Drugs and  substances which inhibit CYP3A4 may increase the plasma  concentrations of ARQ 197. (Refer to  http://medicine.iupui.edu/flockhart/table.htm) |
| Availability:               | ARQ 197 is an investigational agent supplied to investigators by  the Division of Cancer Treatment and Diagnosis (DCTD), NCI. ARQ 197 is provided to the NCI under a Collaborative  Agreement between the Pharmaceutical Collaborator and the  DCTD, NCI (see Section 12.3).                                                                                                                                                                        |
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8.3 agent ordering

NCI supplied agents may be requested by the Principal Investigator (or their authorized designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy requires that agent be shipped directly to the institution where the patient is to be treated.  PMB
does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained.)  The CTEP assigned protocol number must be used for ordering all CTEP supplied investigational agents.  The responsible investigator at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If there are several participating investigators at one institution, CTEP
supplied investigational agents for the study should be ordered under the name of one lead investigator at that institution. Active CTEP-registered investigators and investigator-designated shipping designees and ordering designees can submit agent requests through the PMB Online Agent Order Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP
requires the establishment of a CTEP Identity and Access Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an "active" account status and a
"current" password.  For questions about drug orders, transfers, returns, or accountability, call Monday through Friday between 8:30 am and 4:30 pm (ET) or e-mail anytime.
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8.4 agent accountability

Agent Inventory Records - The investigator, or a responsible party designated by the investigator, must maintain a careful record of the inventory and disposition of all agents received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See the CTEP Web site at http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage and to obtain a copy of the DARF and Clinical Drug Request form.) With Amendment H, dated 09/26/2013: For patient convenience, 2 months' worth of drug may be dispensed at a time to patients who have been on study for 6 cycles or more and who are tolerating treatment well.
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correlative/special studies 9

9.1 Pharmacodynamics Laboratory Contact 9.1.1 At least 24 hours prior to biopsy or blood sample collection, the research nurse will contact the NCI Phase I/II PK/PD Support Group in NIH Building 10: E-mail For biopsies, tubes pre-labeled with the information specified in Section 9.1.4, biopsy date, and site of tissue biopsy will be provided. Initial processing and shipping of the samples will be completed as described below.
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9.1.2 tumor biopsies 9.1.2.1 timing

Biopsies will be collected optionally during the escalation phase:
- before drug administration on study (baseline), and
- on cycle 1 day 8; 8-12 hours after the Day 7 evening dose of ARQ 197
(the morning dose of ARQ 197 will be taken 1 hour after pazopanib)
Biopsies will be mandatory during the expansion phase:
Cohort A
- before drug administration on study (baseline), and
- on cycle 1 day 8, 8-12 hours after pazopanib and before the first dose of ARQ 197
The C1D8 biopsy can be collected on C1D7 for scheduling reasons. Tumor biopsy requires fasting during at least 8 hours after food taken with ARQ 197.
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9.1.2.2 biopsy procedure

Serial tumor biopsies will be obtained through Interventional Radiology by a percutaneous approach. A maximum of 2 core biopsies 18-gauge in diameter and at least 1 cm in length will be obtained at each time point. Only percutaneous biopsies will be performed on patients with solid tumors. It is estimated that there will be between 2-5 million cells from each biopsy. If a site is deemed appropriate for biopsy with minimal risk to the participant by agreement between the investigators and Interventional Radiology, an attempt at biopsy will be made. Determination of a disease site amenable to biopsy will be determined on an individual case basis after discussion with an interventional radiologist. The biopsy procedure to be used in this protocol is described below; local anesthesia will be administered. Such biopsies can be safely performed as evidenced by literature reports [31] as well as our experience at the Clinical Center. Risks of the procedure include, but are not limited to, bleeding, infection, pain, and scarring. We will follow Clinical Center Interventional Radiology SOPs for coagulant panel and platelets.  
- All biopsies will be by percutaneous approach - No biopsy by an invasive (endoscopic, laparoscopic, or surgical) procedure will be performed.  
- Only cutaneous, subcutaneous, or easily accessible parenchymal lesion core biopsies will be performed.
•  
However, there will be no core biopsies of lung lesions.  Only fine needle aspiration (FNA) of a lung lesion may be performed at the discretion of the PI after discussion with an interventional radiologist.
The use of imaging to facilitate biopsies will be decided by members of the Interventional Radiology team and may include ultrasound, CT scan, or MRI.  
Should CT scan be needed for biopsy, the number of scans for each procedure will be limited to the minimum number needed to safely obtain a biopsy.  All cases will be carefully reviewed with the interventional radiologists at NIH who have extensive experience in performing such procedures.  Only if the procedure is considered to be low risk will we proceed with tumor biopsy in a given participant.  
Disease amenable to biopsy and willingness to undergo tumor biopsies is required for patients to enroll in the expansion phase.  Tumor biopsy is optional in the escalation phase.  Baseline biopsies will be performed following patient enrolling on study for Cohort A only.  If an initial attempt at percutaneous biopsy is unsuccessful, the patient will be given an option to proceed with a repeated attempt at percutaneous biopsy.  A separate consent form must be signed for each biopsy procedure, so patients may choose not to undergo subsequent biopsies.  If the baseline biopsy is unsuccessful or the patient refuses to undergo subsequent biopsies, no further biopsies will be performed but the patient will remain on study, receive study medication, and other correlative studies will be performed.  
However, for the purposes of final analysis of the expansion phase of Cohort A,
oly 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.
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9.1.2.3 solid tumor biopsy processing

Two tissue cores will be collected.  One sample will be immediately flash frozen in liquid nitrogen for alternate determination of MET PD biomarkers.  The second core will be immediately flash frozen in liquid nitrogen for determination of HIF-
1 α , pathology, MET gene sequencing, and epithelial-mesenchymal transition
(EMT) marker analysis.  The frozen biopsy specimens are transferred to PADIS, where the core biopsy sample is stored at -80°C.  Biopsy samples will be analyzed for total MET, p-MET, HIF-1 α, and EMT markers such as e-cadherin, beta catenin.  Sequencing for known mutations in the kinase and ligand binding domains will be performed in tumor biopsies.  
Biopsies for PD analysis will be shipped on dry ice to Dr. Kinders' laboratory for analysis:
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9.1.3 blood samples

Assays to be performed: sMET, HGF, VEGF-A, and sVEGFR2.  These research blood tests are mandatory and will be required for every patient. Samples will be obtained at the following time points:
Dose Escalation Phase
.  
.  
.  
.  
C2D1, before drug administration Expansion Phase
.  
.  
before drug administration on study (baseline)
C1D1: 2, 4, and 6 hours after pazopanib C1D8, before drug administration
.  
.  
C2D1, before drug administration
Blood samples should be obtained using EDTA as an anticoagulant (lavender top tubes);
the minimum volume of blood needed for analysis of all four markers is 3 mL.  
Plasma should be prepared from the blood samples within 1 hour (with interim storage and handling at 4°C); plasma should be transferred to new screw cap cryovial (silicon gasket), pre-labeled with bar code.  
Samples should be shipped to:  
  
9.1.4
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sample collection and processing

Biospecimens will be collected and processed using validated SOPs that will ensure both specimen quality and patient confidentiality pursuant to informed consent provisions.  
Information about each specimen (e.g., urine, blood, tumor biopsy, skin punch biopsy, before drug administration on study (baseline)
C1D1: 2, 4, and 6 hours after pazopanib C1D15, before drug administration circulating tumor cells, hair follicles, per specific protocol) will be recorded on a PK/PD collection worksheet included in Appendix H. Using a computerized inventory system and a backup hardcopy process, all specimen collection and processing steps will be documented and the specific location of each specimen will be tracked. Each new specimen collected will be assigned a unique barcode identifier that can be linked to the original specimen collected and other relevant information within the inventory system. To ensure patient confidentiality, only containers used for the initial specimen collections will be labeled with patient identifiers. Only the barcode identifier will be applied to all subsequent specimen containers. When specimens are processed and aliquoted, no patient information will be included on the new containers. Original specimen containers will be discarded. Only barcode-labeled specimens without patient identifiers will be shipped for analysis and/or storage. Specimen labels will indicate: CTEP protocol number, unique patient accession number, 3-digit sample number (see list below), collection time, and total volume collected, as appropriate. Samples from sets of at least three patients will be grouped for scientific analysis. Standardized 3-digit sample collection numbers: 100 series: urine for PK 200 series: blood for PK 300 series: blood for PD 400 series: blood for circulating tumor cells (CTCs) 500 series: tumor biopsies 600 series: skin punch biopsies 700 series: hair follicles 800 series: blood for pharmacogenomic analysis The inventory process contains other security provisions sufficient to safeguard patient privacy and confidentiality. Access to the inventory system and associated documents will be restricted to appropriate individuals. Requests to use specimens stored in the repository must be approved. The only patient information available in the inventory system will be the patient sex, diagnosis, and level of informed consent given. SOPs ensure that any changes in informed consent made by a patient and relayed to the PI will be reflected in the inventory system to ensure that specimens are destroyed as appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored for high-quality performance. Any new use of these samples will require prospective IRB review and approval. Access to these samples will only be granted following IRB approval of an additional protocol, granting the rights to use the material. If at any time, a patient withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the patient, if so requested), and reported as such to the IRB. Any samples lost (in transit or by a researcher) or destroyed  
due to unknown sample integrity (i.e., broken freezer allows for extensive sample thawing, etc.) will be reported as such to the IRB.
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9.2 pharmacokinetics 9.2.1 blood sample

Blood samples for PK analysis will be collected prior to drug administration and at multiple time points after drug administration beginning on D1 and D15 of cycle 1 only. Pazopanib will be taken on an empty stomach 1 hour before a meal and ARQ 197 will be taken with food. D1: pre-dose, and 1, 2, 4, 6, and 12 hours after administration of pazopanib, with the morning dose of ARQ 197 administered 1 hour after pazopanib and the evening dose of ARQ 197 administered after the 12hour time point (corresponding to 1, 3, 5, and 11 hours after administration of ARQ 197). The actual time of collection will be noted for each sample. D15: pre-dose, and 1, 2, 4, and 6 hours after administration of pazopanib, with the morning dose of ARQ 197 administered 1 hour after pazopanib (corresponding to 1, 3, and 5 hours after administration of ARQ 197). The actual time of collection will be noted for each sample.
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9.2.1.2 expansion phase

Blood samples for PK analysis will be collected prior to drug administration and at multiple time points after drug administration beginning on D1 and D7 of cycle 1 only. Pazopanib will be taken on an empty stomach 1 hour before a meal and ARQ 197 will be taken with food. 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.  
The PK studies are mandatory and will be required for every patient. The total volume of blood collected for PK studies during the initial treatment cycle is expected to be < 70 mL per patient. Based on results from initial measurements, sampling times may be adjusted, but neither the total number of samples nor the total amount of blood drawn per patient will be increased. Samples will be collected in lavender-top (EDTA) tubes with 6 mL (3 mL for day 1 in Cohort A of the expansion phase) of blood per sample. It is important to fill the Vacutainer tubes to the specified collection volume. The tube containing blood for plasma preparation will be gently inverted 10 times to ensure  
thorough mixing of anticoagulant and blood, then placed in a cool box containing crushed ice and/or water.
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9.2.2 blood sample preparation

All samples will be centrifuged within 45 min of collection, at 1,500 x g for 10 min at 4°C. Immediately following centrifugation, the separated plasma for each sample will be divided into three aliquots at the following volume: 1. Aliquot \#1 (for pazopanib assay): 1.0 mL 2. Aliquot \#2 (for ARQ 197 assay): 0.5 mL 3. Aliquot \#3 (Back up sample): Remaining volume Note: For samples from day 1 in Cohort A of the expansion phase, Aliquot \#1 will be taken for analysis of single agent pazopanib. Aliquot \#1 of plasma should be transferred with a plastic pipette into a 1.8 mL Nunc Cryovial tube (provided by GlaxoSmithKline), and Aliquots \#2 and \#3 should be each pipetted into polypropylene cryogenic sample storage vials (with screw-cap) (provided by Daiichi Sankyo Pharma Development, Department of Drug Metabolism and Pharmacokinetics [DMPK]), designated Set 1 and Set 2. Then, they should be maintained being chilled before being transferred to freezer. Within 90 min after blood draw, the sample storage vials will be stored, still in upright position, in a -70°C freezer. PPD and Covance Inc., respectively will analyze the parent drug molecules and possibly metabolites of pazopanib and ARQ 197 in plasma. These facilities have extensive experience in the measurement of drugs and metabolites in body fluids.
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9.2.3 shipment of samples

Specimens will be labeled with the following information: Sample type, ID number (CTEP protocol number + unique patient accession number + 3digit sample number), and collection time. The shipment must contain a complete sample manifest (electronic or paper) containing the sample type, ID number (CTEP protocol number + unique patient accession number + 3-digit sample number), and collection time, along with the name and address, including the telephone and fax numbers of the person responsible for sending the samples. No personally identifiable information will be sent with samples. A phone call or fax communication should precede all sample shipments. A phone or fax communication must precede all HIV positive or other known infections sample shipments. Detailed sample inventory information must accompany the samples. Lack of paperwork or illegible information will delay sample login and project initiation. Samples that are unclearly or incompletely labeled may be subject to additional handling fees. PPD encourages submission of sample inventory information in electronic form.  
Plasma samples will be shipped on dry ice via prepaid overnight mail (e.g., UPS or FedEx), Monday through Wednesday (please ensure that wherever possible samples are transported so as to arrive between the hours of 09:00 and 16:00):
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9.3 pharmacogenetics (pg)

As emerging information regarding the safety and efficacy of ARQ 197 may become available in the future, samples will be retained for possible future research if the patient gives permission.  
The sample will be retained until the DNA has been exhausted or until the Sponsor instructs the genotyping contractor to destroy the sample in accordance with laboratory procedures.  During this time, the DNA sample will not be immortalized or sold to anyone.  Subjects will have the right to withdraw consent and have their sample destroyed at any time as long as there is DNA
remaining.  The PG test for CYP2C19 is mandatory and will be required for every patient.
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blood sample collection 9.3.1

As part of this study, a blood sample (1 x 10 mL) will be taken at baseline to evaluate the CYP2C19 genotype of subjects.  Samples will be collected into a 10 mL EDTA
polypropylene (lavender-top) blood collection tube.  It is very important to collect a full tube.  The sample should be stored at -70 °C until shipment.
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shipment of samples 9.3.2

Samples will be shipped on dry ice at a regular interval to:  
Covance Inc
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10 study calendar

Baseline history and physical exam are to be conducted within 72 hours prior to start of protocol therapy; laboratory evaluations (including serum liver tests) and EKG must also be done within 72 hours. Scans, x-rays, and echocardiogram or MUGA scan must be done ≤ 4 weeks prior to the start of therapy. In the event that the patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. The duration of a cycle will be 28 days (± 1 day for scheduling). Start of next cycle may be delayed for up to 1 week to accommodate scheduling conflicts. History and physical examination and laboratory evaluations can be performed up to 3 days before the start of the next cycle.
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10.1 dose escalation phase

| C1  W2 (D8- 14)                                                                                              | C1  W3 (D15- 21)                                                                                | C1  W4 (D22- 28)                                                      | C2  W2 (D8- 14)   | C2  W3 (D15- 21)   | C2  W4 (D22- 28)   |    |    |    |    |
|--------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------|-------------------|--------------------|--------------------|----|----|----|----|
| C1                                                                                                           |                                                                                                 |                                                                       |                   |                    |                    |    |    |    |    |
| PreStudy                                                                                                              | W1 (D1-7)                                                                                       | C2  W1 (D1-7)                                                         | C3  W1  on        | Off                |                    |    |    |    |    |
| Treatment                                                                                                    |                                                                                                 |                                                                       |                   |                    |                    |    |    |    |    |
| Pazopaniba                                                                                                   | X                                                                                               | X                                                                     | X                 | X                  | X                  | X  | X  | X  | X  |
| ARQ 197a                                                                                                     | X                                                                                               | X                                                                     | X                 | X                  | X                  | X  | X  | X  | X  |
| Informed consent                                                                                             | X                                                                                               |                                                                       |                   |                    |                    |    |    |    |    |
| Demographics                                                                                                 | X                                                                                               |                                                                       |                   |                    |                    |    |    |    |    |
| Medical history                                                                                              | X                                                                                               |                                                                       |                   |                    |                    |    |    |    |    |
| Concurrent meds                                                                                              | X                                                                                               | X-------------------------------------------------------------------X |                   |                    |                    |    |    |    |    |
| Physical examb                                                                                               | X                                                                                               | X                                                                     | X                 | X                  | X                  |    |    |    |    |
| Vital signsc                                                                                                 | X                                                                                               | X                                                                     | X                 | X                  | X                  | X  |    |    |    |
| Height                                                                                                       | X                                                                                               |                                                                       |                   |                    |                    |    |    |    |    |
| Weight                                                                                                       | X                                                                                               | X                                                                     | X                 | X                  |                    |    |    |    |    |
| Performance status                                                                                           | X                                                                                               | X                                                                     | X                 | X                  |                    |    |    |    |    |
| CBC w/diff, pltsd                                                                                            | X                                                                                               | X                                                                     | X                 | X                  | X                  | X  | X  | X  |    |
| Serum chemistryd                                                                                             | X                                                                                               | X                                                                     | X                 | X                  | X                  | X  | X  | X  |    |
| Coagulation                                                                                                  | X                                                                                               |                                                                       |                   |                    |                    |    |    |    |    |
| Urine protein/creatinine  ratio or 24-hour urine                                                             | X                                                                                               | X                                                                     | X                 | X                  | X                  |    |    |    |    |
| proteine EKGf                                                                                                | X                                                                                               | X                                                                     |                   |                    |                    |    |    |    |    |
| Echocardiogram/MUGA                                                                                          | X                                                                                               |                                                                       |                   |                    |                    |    |    |    |    |
| Adverse event evaluation                                                                                     | X------------------------------------------------------------------X                            | X                                                                     |                   |                    |                    |    |    |    |    |
| Tumor measurements                                                                                           | Tumor measurements are repeated every 2 cycles.                                                 |                                                                       |                   |                    |                    |    |    |    |    |
| X                                                                                                            | Documentation (radiologic) must be provided for patients                                        | X                                                                     |                   |                    |                    |    |    |    |    |
| removed from study for progressive disease.                                                                  |                                                                                                 |                                                                       |                   |                    |                    |    |    |    |    |
| B-HCGg                                                                                                       | X                                                                                               |                                                                       |                   |                    |                    |    |    |    |    |
| Tumor biopsiesh                                                                                              | X                                                                                               | X                                                                     |                   |                    |                    |    |    |    |    |
| PD blood samplingi                                                                                           | X                                                                                               | X                                                                     | X                 | X                  |                    |    |    |    |    |
| PG blood samplingj                                                                                           | X                                                                                               |                                                                       |                   |                    |                    |    |    |    |    |
| PK blood samplingk                                                                                           | X                                                                                               | X                                                                     | X                 |                    |                    |    |    |    |    |
| a:                                                                                                           | Pazopanib once daily (empty stomach) and ARQ 197 twice daily (with meals) at the assigned dose. |                                                                       |                   |                    |                    |    |    |    |    |
| b: Physical examination at Clinical Center should be performed on day 1 and day 15, and then at the start of |                                                                                                 |                                                                       |                   |                    |                    |    |    |    |    |  
B-HCGg X  
Tumor biopsiesh X X  
PD blood samplingi X X X X PG blood samplingj X  
PK blood samplingk X X X  
a: Pazopanib once daily (empty stomach) and ARQ 197 twice daily (with meals) at the assigned dose.  
b: Physical examination at Clinical Center should be performed on day 1 and day 15, and then at the start of  
each cycle (up to 3 days before start of new cycle). For patients who have been on study for 6 or more cycles and are tolerating treatment well, physical exams may be performed once every 2 cycles (every 2 months).  
c: BP monitoring by a health care provider should be performed every 2 weeks during the first 2 cycles and  
then at the beginning of subsequent cycles. For patients who have been on study for 6 or more cycles and  
are tolerating treatment well, BP monitoring may be performed once every 2 cycles (every 2 months).  
Mid-cycle BP check can be performed by any health care professional. Patients should measure and  
record their blood pressure at home at least once per day for the duration of the study.  
d: Serum chemistry (albumin, alkaline phosphatase, total bilirubin, BUN, calcium, creatinine, glucose,  
phosphorus, magnesium, potassium, total protein, SGOT [AST], SGPT [ALT], sodium) and CBC w/diff,  
platelets should be performed within 72 hours of enrollment (pre-study) and weekly during cycle 1 (D8,  
D15 and D22 ± 1 day for scheduling conflicts), every 2 weeks during cycle 2 (± 1 day for scheduling  
conflicts), and at the start of each cycle (up to 3 days before start of new cycle). For patients who have been on study for 6 or more cycles and are tolerating treatment well, lab tests may be performed once every 2 cycles (every 2 months). Serum liver tests (AST, ALT, serum bilirubin) will also be performed during 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.  
e: Evaluation of urine protein/creatinine ratio should occur at baseline (within 72 hours of enrollment), on C1D15 (± 1 day for scheduling conflicts), then at the start of each cycle, and as clinically indicated. If patient has urine protein/creatinine ratio >1+, obtain a 24 hour urine for protein and creatinine clearance.  
f: EKG will be performed at baseline, on C1D1 (3-6 hours after the first dose of ARQ 197) and on C1D15 (36 hours after the morning dose of ARQ 197) and as clinically indicated.  
g: Serum or urine pregnancy test (women of childbearing potential) within 1 week prior to enrollment.  
h: Tumor biopsies are optional in the escalation phase: at baseline and on C1D8, 8-12 hours after the Day 7 evening dose of ARQ 197 (taken 1 hour after pazopanib).  
i: Samples will be obtained at the following time points: at baseline, on C1D1 2, 4, and 6 hours after pazopanib), on C1D15 (pre-drugs), and on C2D1 (pre-drugs).  
j: A sample for PG study will be obtained at baseline.  
k: Blood samples for PK will be collected from all patients during cycle 1 only:
D1: pre-dose, and 1, 2, 4, 6, and 12 hours after administration of pazopanib. D15: pre-dose, and 1, 2, 4, and 6 hours after administration of pazopanib.
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10.2 expansion phase

| C1  W3  (D15- 21)                                | C1  W4  (D22- 28)                                                                                                                                                                                  | C2  W2  (D8- 14)                                                     | C2  W3  (D15- 21)   | C2  W4  (D22- 28)   |     |    |    |    |    |
|--------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------|---------------------|---------------------|-----|----|----|----|----|
| C1                                               |                                                                                                                                                                                                    |                                                                      |                     |                     |     |    |    |    |    |
| PreStudy                                                  | W1  (D1-7)                                                                                                                                                                                         | C1  W2  (D8-14)                                                      | C2  W1  (D1-7)      | C3  W1  on          | Off |    |    |    |    |
| Treatment                                        |                                                                                                                                                                                                    |                                                                      |                     |                     |     |    |    |    |    |
| Pazopaniba                                       | X                                                                                                                                                                                                  | X                                                                    | X                   | X                   | X   | X  | X  | X  | X  |
| ARQ 197a                                         | X                                                                                                                                                                                                  | X                                                                    | X                   | X                   | X   | X  | X  | X  | X  |
| Informed consent                                 | X                                                                                                                                                                                                  |                                                                      |                     |                     |     |    |    |    |    |
| Demographics                                     | X                                                                                                                                                                                                  |                                                                      |                     |                     |     |    |    |    |    |
| Medical history                                  | X                                                                                                                                                                                                  |                                                                      |                     |                     |     |    |    |    |    |
| Concurrent meds                                  | X                                                                                                                                                                                                  | X------------------------------------------------------------------X |                     |                     |     |    |    |    |    |
| Physical examb                                   | X                                                                                                                                                                                                  | X                                                                    | X                   | X                   | X   |    |    |    |    |
| Vital signsc                                     | X                                                                                                                                                                                                  | X                                                                    | X                   | X                   | X   |    |    |    |    |
| Height                                           | X                                                                                                                                                                                                  |                                                                      |                     |                     |     |    |    |    |    |
| Weight                                           | X                                                                                                                                                                                                  | X                                                                    | X                   | X                   |     |    |    |    |    |
| Performance status                               | X                                                                                                                                                                                                  | X                                                                    | X                   | X                   |     |    |    |    |    |
| CBC w/diff, pltsd                                | X                                                                                                                                                                                                  | X                                                                    | X                   | X                   | X   |    |    |    |    |
| Serum chemistryd                                 | X                                                                                                                                                                                                  | X                                                                    | X                   | X                   | X*  | X  | X  |    |    |
| Coagulation                                      | X                                                                                                                                                                                                  |                                                                      |                     |                     |     |    |    |    |    |
| Urine protein/creatinine  ratio or 24-hour urine | X                                                                                                                                                                                                  | X                                                                    | X                   | X                   | X   |    |    |    |    |
| proteine EKGf                                    | X                                                                                                                                                                                                  | X                                                                    | X*                  |                     |     |    |    |    |    |
| Echocardiogram/MUGA                              | X                                                                                                                                                                                                  |                                                                      |                     |                     |     |    |    |    |    |
| Adverse event evaluation                         | X------------------------------------------------------------------X                                                                                                                               | X                                                                    |                     |                     |     |    |    |    |    |
| Tumor measurements                               | Tumor measurements are repeated every 2 cycles.                                                                                                                                                    |                                                                      |                     |                     |     |    |    |    |    |
| X                                                | Documentation (radiologic) must be provided for patients                                                                                                                                           | X                                                                    |                     |                     |     |    |    |    |    |
| removed from study for progressive disease.      |                                                                                                                                                                                                    |                                                                      |                     |                     |     |    |    |    |    |
| B-HCGg                                           | X                                                                                                                                                                                                  |                                                                      |                     |                     |     |    |    |    |    |
| Tumor biopsiesh                                  | X                                                                                                                                                                                                  | X                                                                    |                     |                     |     |    |    |    |    |
| PD blood samplingi                               | X                                                                                                                                                                                                  | X                                                                    | X                   | X                   |     |    |    |    |    |
| PG blood samplingj                               | X                                                                                                                                                                                                  |                                                                      |                     |                     |     |    |    |    |    |
| PK blood samplingk                               | X                                                                                                                                                                                                  | X                                                                    |                     |                     |     |    |    |    |    |
| a:                                               | Pazopanib once daily (empty stomach) and ARQ 197 twice daily (with meals) at MTD dose. Single-agent  pazopanib from C1D1 to D7 then the combination of ARQ 197 and pazopanib from C1D8 in Cohort A |                                                                      |                     |                     |     |    |    |    |    |  
B-HCGg X  
Tumor biopsiesh X X  
PD blood samplingi X X X X  
PG blood samplingj X  
PK blood samplingk X X  
a: Pazopanib once daily (empty stomach) and ARQ 197 twice daily (with meals) at MTD dose. Single-agent  
pazopanib from C1D1 to D7 then the combination of ARQ 197 and pazopanib from C1D8 in Cohort A  
b: Physical examination at Clinical Center should be performed on D1 and D8 and then at the start of each  
cycle (up to 3 days before start of new cycle). For patients who have been on study for 6 or more cycles  
and are tolerating treatment well, physical exams may be performed once every 2 cycles (every 2  
months).  
c: BP monitoring by a health care provider should be performed on D1 and D8 of cycle 1 and then at the  
beginning of subsequent cycles. For patients who have been on study for 6 or more cycles and are  
tolerating treatment well, BP monitoring may be performed once every 2 cycles (every 2 months).  
Patients should measure and record their blood pressure at home at least once per day for the duration of the  
study.  
d: Serum chemistry (albumin, alkaline phosphatase, total bilirubin, BUN, calcium, creatinine, glucose,  
phosphorus, magnesium, potassium, total protein, SGOT [AST], SGPT [ALT], sodium) and CBC w/diff, platelets should be performed within 72 hours of enrollment (pre-study) and again on D18 of cycle 1, and  
at the start of each cycle (± 1 day for scheduling conflicts). For patients who have been on study for 6 or more cycles and are tolerating treatment well, lab tests may be performed once every 2 cycles (every 2 months). Serum liver tests (AST, ALT, serum bilirubin) will also be performed during weeks 3, 5, 7 (*can be collected by patients' local physician), and 9; thereafter, monitoring will occur at months 3 and 4, and as clinically indicated. Periodic monitoring will continue after month 4.  
e: Evaluation of urine protein/creatinine ratio should occur at baseline, on C1D8, then at the start of each cycle
(± 1 day for scheduling conflicts), and as clinically indicated. If patient has urine protein/creatinine ratio >1+, obtain a 24 hour urine for protein and creatinine clearance.  
f: EKG will be performed at baseline, on C1D1 (3-6 hours after the morning dose of pazopanib), on C1D8 (36 hours after pazopanib), on *C2D1 (3-6 hours after the morning dose of ARQ 197), and as clinically indicated.  
g: Serum or urine pregnancy test (women of childbearing potential) within 1 week prior to enrollment.  
h: Tumor biopsies are mandatory in the expansion phase: at baseline and on C1D8, 8-12 hours after pazopanib before the first dose of ARQ 197.  
i: Samples will be obtained at the following time points: at baseline, on C1D1 (2, 4, and 6 hours after pazopanib ), on C1D8 (pre-drugs), and on C2D1 (pre-drugs).  
j: A sample for the PG study will be obtained at baseline.  
k: Blood samples for PK will be collected from all patients during cycle 1 only on D1 and D7 as specified in Section 9.2.1.2.
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11 measurement of effect 11.1

For the purposes of this study, patients should be re-evaluated for response every 2 cycles. In addition to a baseline scan, confirmatory scans should also be obtained at least 4 weeks following initial documentation of objective response. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline
(version 1.1) [*Eur J Ca* 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
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11.1.1 definitions

Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first treatment with study agents. Evaluable for objective response. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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11.1.2 disease parameters

Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Note: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable. *If the investigator thinks it appropriate to include them, the* conditions under which such lesions should be considered must be defined in the protocol. Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice  
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if noncystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target** lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for nonnodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.
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11.2 methods for evaluation of

All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the  
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Tumor markers Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published
[*JNCI* 96:487-488, 2004; *J Clin Oncol* 17, 3461-3467, 1999; *J Clin Oncol* 26:1148-1159, 2008]. In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer [*JNCI* 92:1534-1535, 2000].  
FDG-PET While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDGPET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.
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11.3 response criteria 11.3.1 evaluation

Response and progression will be evaluated using RECIST version 1.1. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria per Section 11.1.  
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, which is based on the long axis for non-nodal lesions and the short axis for nodal lesions of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, which is based on the long axis for non-nodal lesions and the short axis for nodal lesions of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
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11.3.2 evaluation of non-target lesions

Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD):Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. *Unequivocal progression* should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).
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11.3.3 evaluation of best overall

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The  
patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Target Lesions                                                                                                           | Non-Target                                                                         | New Lesions               | Overall                                           | Best Overall Response when   |
|--------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|---------------------------|---------------------------------------------------|------------------------------|
| Lesions                                                                                                                  | Response                                                                           | Confirmation is Required* |                                                   |                              |
| CR                                                                                                                       | CR                                                                                 | No                        | CR                                                | >4 wks. Confirmation**       |
| CR                                                                                                                       | Non-CR/Non-PD                                                                      | No                        | PR                                                |                              |
| CR                                                                                                                       | Not evaluated                                                                      | No                        | PR                                                | >4 wks. Confirmation**       |
| PR                                                                                                                       | Non-CR/Non                                                                                    |                           |                                                   |                              |
| PD/not evaluated                                                                                                         | No                                                                                 | PR                        |                                                   |                              |
| SD                                                                                                                       | Non-CR/Non                                                                                    |                           |                                                   |                              |
| PD/not evaluated                                                                                                         | No                                                                                 | SD                        | documented at least once >4  wks. from baseline** |                              |
| PD                                                                                                                       | Any                                                                                | Yes or No                 | PD                                                |                              |
| Any                                                                                                                      | PD***                                                                              | Yes or No                 | PD                                                | no prior SD, PR or CR        |
| Any                                                                                                                      | Any                                                                                | Yes                       | PD                                                |                              |
| *                                                                                                                        | See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. |                           |                                                   |                              |
| **                                                                                                                       | Only for non-randomized trials with response as primary endpoint.                  |                           |                                                   |                              |
| *** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as  disease progression. |                                                                                    |                           |                                                   |                              |  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "symptomatic deterioration." Every effort should be made to document the objective progression even after discontinuation of treatment.
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for patients with non-measurable disease

| Non-Target Lesions                                                                                                                                                                                     | New Lesions   | Overall Response   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------------|
| CR                                                                                                                                                                                                     | No            | CR                 |
| Non-CR/non-PD                                                                                                                                                                                          | No            | Non-CR/non-PD*     |
| Not all evaluated                                                                                                                                                                                      | No            | not evaluated      |
| Unequivocal PD                                                                                                                                                                                         | Yes or No     | PD                 |
| Any                                                                                                                                                                                                    | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is increasingly  used as an endpoint for assessment of efficacy in some trials so to assign this category when no |               |                    |
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11.4 duration of response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).  
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.
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11.5 confirmatory measurement

To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat assessments that should be performed at least 4 weeks after the criteria for response are first met. In the case of SD, follow-up measurements must have met the SD criteria at leastonce after study entry for a minimum interval of 8 weeks.
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12 data reporting / regulatory

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements).
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12.1 data reporting 12.1.1 method

Data will be collected in the Center for Cancer Research C3D database. This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application. Reports are due January 31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html).  
Note: All adverse events that have occurred on the study, including those reported through CTEP-AERS, must be reported via the monitoring method identified above. 12.1.2 **Responsibility for Data Submission** N/A
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12.3 collaborative agreements language

The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer  
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the "Intellectual Property Option to Collaborator" (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms of award, apply to the use of the Agent(s) in this study:
12.3.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient's family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov.  
12.3.2 For a clinical protocol where there is an investigational Agent used in combination with (an)other Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by each Collaborator shall be as follows
(data pertaining to such combination use shall hereinafter be referred to as "MultiParty Data"):
a. NCI will provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NCI, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol.  
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own Agent.  
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own Agent.  
12.3.3 Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order as described in the IP Option to Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all Clinical Data and Results and Raw Data will be collected , used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.  
12.3.4 When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them.  
12.3.5 Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.
12.3.6 Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group office for Cooperative Group studies or by the principal investigator for non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in addition to Collaborator(s)'s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: E-mail: The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator's confidential/ proprietary information.
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13 statistical considerations 13.1 study

A primary objective of the trial is to establish the safety, tolerability, and MTD of the combination. Another primary objective is to evaluate changes in MET and phospho-MET following treatment with pazopanib and ARQ 197. Twelve patients 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 it is statistically significant.
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13.2 sample size/accrual rate

The study is designed to have 5 dose escalation cohorts, with a standard design using 3 patients per cohort, unless DLT is noted, in which case up to 6 patients may be enrolled in a cohort. With 6 dose levels, up to 36 patients may be enrolled for determination of the MTD. In addition, to  
characterizing the pharmacodynamics of the combination, up to an additional 12 patients will be enrolled in the expansion phase, for a total of 54 patients. Only patients with paired tumor biopsies will be considered evaluable in the expansion phase. To allow for a few patients who may not be evaluable, the accrual ceiling will be set at 56 patients. It is anticipated that 2-3 patients per month may be enrolled onto this trial. Thus, depending on the number of patients needed to reach the MTD, it is expected that 18 to 27 months will be required to accrue the number of patients necessary to complete the trial.
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13.3 analysis of secondary endpoints

We will assess pMET (1235/1356) reduction, MET reduction, VEGF reduction, TSP-1 increase, HIF1α increase, and change in EMT markers, descriptively (magnitude of change, with 2-sided 90% CI), in blood and tumor assays (where paired samples are available), for the various dose combinations in the escalation and expansion phases.
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13.4 reporting and exclusions

13.4.1 Evaluation of toxicity - All patients will be evaluable for toxicity from the time of their first treatment with study agents.  
13.4.2 Evaluation of response - All patients included in the study will be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 9 usually designates the "unknown" status of any type of data in a clinical database.]
All of the patients who met the eligibility criteria (with the possible exception of those who received no study medication) will be included in the main analysis of the response rate. Patients in response categories 4-9 will be considered to have a treatment failure (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be protocol specific. All conclusions will be based on all eligible patients. Subanalyses may then be performed on the basis of a subset of patients, excluding those for whom major protocol deviations have been identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis will be clearly reported. The 95% confidence intervals will also be provided.
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14 human subjects protections 14.1

This study will be open to all individuals regardless of gender, ethnicity, or race, provided that the aforementioned inclusion and exclusion criteria are met. Patients for this study will be recruited through internal referral, our physician referral base, and through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer). To date, there is no information that suggests that differences in drug metabolism or effect on tumor would be expected in one ethnic group compared to another. Efforts will be made to extend accrual to each representative population, but a balance must be struck between participant safety considerations and limitations on the number of individuals exposed to potentially ineffective treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to ethnic identity are noted, a follow-up study may be written to investigate those differences more fully. Due to lack of knowledge of the effects of pazopanib and ARQ 197 on the fetus or infants, as well as the possibility of teratogenic effects, pregnant and nursing women will be excluded from this trial. Patients with unstable or serious medical conditions are excluded due to the possibility that pazopanib and/or ARQ 197 may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events with respect to pazopanib and/or ARQ 197. HIV-positive patients on combination antiretroviral therapy are excluded from the study because of possible PK interactions with pazopanib and/or ARQ 197.
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14.1.1 participation of children

This study includes patients 18 years of age and older. Because insufficient dosing or adverse event data are currently available on the use of pazopanib and ARQ 197 in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials. Studies will be performed in patients <18 years of age when it is appropriate to do so.
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14.2 evaluation of benefits and

There may or may not be any clinical benefit to a patient from participation in this trial. Their participation will benefit future cancer patients. Potential risks include the possible occurrence of any of a range of side effects that are listed in the consent document. The procedure for protecting against or minimizing risks will be to medically evaluate patients as described in Sections 5 and 6. Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which participants are entitled under applicable regulations.
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14.3 consent and assent process

An associate or principal investigator on the trial will inform patients of the purpose, alternatives, drug administration plan, research objectives, and follow-up of this trial. The patient will be provided an IRB-approved consent for review and signature and his/her questions will be  
answered. After a decision is made to enroll into the study, a signature will be obtained from the patient. The original signed consent goes to Medical Records; a copy will be placed in the research record. All patients must have a signed informed consent form and an on-study (confirmation of eligibility) form filled out and signed by a participating investigator before entering on study.
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14.4 procedure for protecting against

All care will be taken to minimize side effects, but they can be unpredictable in nature and severity. This study may involve risks to patients, which are currently unforeseeable. All patients will be monitored for side effects from taking study medication. This research represents a greater than minimal risk to participants, but presents the prospect of direct benefit to individual subjects. The research component of this study required to obtain 2 CT tumor biopsies confers radiation exposure at an effective dose of 0.29 rem. This dose is below NIH RSC guidelines and represents a slightly greater than minimal risk to patients.
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14.5 patient advocate

The patients' rights representative is available to patients receiving treatment on this protocol at the NIH Clinical Center at
, on the Bethesda NIH campus. Patients will be informed that they can contact the study PI or RN at any time with questions about their medical care, and that the patients' rights representative is also available to answer non-medical questions about the study.
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references

1. Gerritsen, M.E., et al., *Using gene expression profiling to identify the molecular basis of* the synergistic actions of hepatocyte growth factor and vascular endothelial growth factor in human endothelial cells. British Journal of Pharmacology, 2003. 140(4): p. 595610.  
2. Xin, X., et al., *Hepatocyte Growth Factor Enhances Vascular Endothelial Growth* Factor-Induced Angiogenesis in Vitro and in Vivo. Am J Pathol, 2001. 158(3): p. 11111120.  
3. Van Belle, E., et al., Potentiated Angiogenic Effect of Scatter Factor/Hepatocyte Growth Factor via Induction of Vascular Endothelial Growth Factor : The Case for Paracrine Amplification of Angiogenesis. Circulation, 1998. 97(4): p. 381-390.  
4. Zhang, Y.-W., et al., *Hepatocyte growth factor/scatter factor mediates angiogenesis* through positive VEGF and negative thrombospondin 1 regulation. Proceedings of the National Academy of Sciences of the United States of America, 2003. 100(22): p. 1271812723.  
5. Yamashita, J.-i., et al., *Immunoreactive Hepatocyte Growth Factor Is a Strong and* Independent Predictor of Recurrence and Survival in Human Breast Cancer. Cancer Research, 1994. 54(7): p. 1630-1633.  
6. Eder, J.P., et al., *A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and* Vascular Endothelial Growth Factor Receptor 2. Clinical Cancer Research. 16(13): p.  
3507-3516.  
7. Yap, T.A. and J.S. de Bono, *Targeting the HGF/c-Met Axis: State of Play.* Molecular Cancer Therapeutics. 9(5): p. 1077-1079.  
8. Sennino, B., et al., *Reduction of tumor invasiveness and metastasis and prolongation of* survival of RIP-Tag2 mice after inhibition of VEGFR plus c-Met by XL184 Molecular Cancer Therapeutics, 2009. 8(12 (suppl)).  
9. Pàez-Ribes, M., et al., *Antiangiogenic Therapy Elicits Malignant Progression of Tumors* to Increased Local Invasion and Distant Metastasis. Cancer Cell, 2009. 15(3): p. 220231.  
10. Ebos, J.M.L., et al., Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis. Cancer Cell, 2009. 15(3): p. 232-239.  
11. Loges, S., et al., Silencing or Fueling Metastasis with VEGF Inhibitors: Antiangiogenesis Revisited. Cancer Cell, 2009. 15(3): p. 167-170.
12. Pennacchietti, S., et al., *Hypoxia promotes invasive growth by transcriptional activation* of the met protooncogene. Cancer Cell, 2003. 3(4): p. 347-361.  
13. Comoglio, P.M., S. Giordano, and L. Trusolino, Drug development of MET inhibitors:
targeting oncogene addiction and expedience. Nat Rev Drug Discov, 2008. 7(6): p. 504516.  
14. Wang, R., et al., Activation of the Met Receptor by Cell Attachment Induces and Sustains Hepatocellular Carcinomas in Transgenic Mice. The Journal of Cell Biology, 2001. 153(5): p. 1023-1034.  
15. Nakagawa, T., et al., *E7050: A dual c-Met and VEGFR-2 tyrosine kinase inhibitor* promotes tumor regression and prolongs survival in mouse xenograft models. Cancer Science. 101(1): p. 210-215.  
16. Qian, F., et al., Inhibition of Tumor Cell Growth, Invasion, and Metastasis by EXEL-2880
(XL880, GSK1363089), a Novel Inhibitor of HGF and VEGF Receptor Tyrosine Kinases.  
Cancer Research, 2009. 69(20): p. 8009-8016.  
17. Kumar, R., et al., *Pharmacokinetic-pharmacodynamic correlation from mouse to human* with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther, 2007. 6(7): p. 2012-21.  
18. Sonpavde, G., T.E. Hutson, and C.N. Sternberg, Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opinion on Investigational Drugs, 2008. 17(2): p. 253-261.  
19. Podar, K., et al., *The small-molecule VEGF receptor inhibitor pazopanib (GW786034B)*
targets both tumor and endothelial cells in multiple myeloma. Proceedings of the National Academy of Sciences, 2006. 103(51): p. 19478-19483.  
20. Levy, C., M. Khaled, and D.E. Fisher, MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med, 2006. 12(9): p. 406-14.  
21. McGill, G.G., et al., *c-Met expression is regulated by Mitf in the melanocyte lineage.* J
Biol Chem, 2006. 281(15): p. 10365-73.  
22. Munshi, N., et al., ARQ 197, a Novel and Selective Inhibitor of the Human c-Met Receptor Tyrosine Kinase with Antitumor Activity. Molecular Cancer Therapeutics. 9(6):
p. 1544-1553.  
23. Bagai, R., W. Fan, and P.C. Ma, *ARQ-197, an oral small-molecule inhibitor of c-Met for* the treatment of solid tumors. IDrugs. 13(6): p. 404 - 414.  
24. Eathiraj, S., et al., Discovery of a Novel Mode of Protein Kinase Inhibition Characterized by the Mechanism of Inhibition of Human Mesenchymal-epithelial Transition Factor (c-  
Met) Protein Autophosphorylation by ARQ 197. Journal of Biological Chemistry, 2011. 286(23): p. 20666-20676.  
25. Yap, T.A., et al., *Phase I Trial of a Selective c-MET Inhibitor ARQ 197 Incorporating* Proof of Mechanism Pharmacodynamic Studies. Journal of Clinical Oncology, 2011. 29(10): p. 1271-1279.  
26. Srivastava, A.K., et al. Preclinical assessment of MET modulation by a VEGFR
inhibitor/MET inhibitor combination that shows additive anti-tumor efficacy. in *AACR* Annual Meeting Abstract 3672. Chicago.  
27. Sennino, B., et al., *Suppression of Tumor Invasion and Metastasis by Concurrent* Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors. Cancer Discovery, 2012.  
28. Knudsen, B.S., et al., *A novel multipurpose monoclonal antibody for evaluating human cMet expression in preclinical and clinical settings.* Appl Immunohistochem Mol Morphol, 2009. 17(1): p. 57-67.  
29. Athauda, G., et al., *c-Met Ectodomain Shedding Rate Correlates with Malignant* Potential. Clinical Cancer Research, 2006. 12(14): p. 4154-4162.  
30. Cecchi, F., D.C. Rabe, and D.P. Bottaro, Targeting the HGF/Met signalling pathway in cancer. European Journal of Cancer. 46(7): p. 1260-1270.  
31. Dowlati, A., et al., *Sequential tumor biopsies in early phase clinical trials of anticancer* agents for pharmacodynamic evaluation. Clin Cancer Res, 2001. 7(10): p. 2971-6.
appendix a performance status criteria
references

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

| CYP2C19 Inhibitors Amiodarone Amitriptyline Amprenavir Aprepitant Azelastine Bortezomib Buprenorphine Cholecalciferol/Vitamin D3 Cimetidine Citalopram Clotrimazole Clozapine Delavirdine Diazepam Dimethyl sulfoxide Drospirenone Efavirenz Entacapone Ethinyl estradiol Ethotoin   | Felbamate Fenofibrate Fluconazole Fluoxetine Fluvoxamine Fosamprenavir Gefitinib Gemfibrozil Imipramine Indinavir Indomethacin Isoniazid Ketoconazole Lansoprazole Letrozole Loratadine Losartan Mephobarbital Mestranol Methimazole   | Methoxsalen Methsuximide Miconazole Moclobemide Modafinil Nelfinavir Nicardipine Nilutamide Olanzapine Omeprazole Orphenadrine Oxcarbazepine Paroxetine Pentamidine Pimozide Pioglitazone Probenecid Progesterone Propofol Rabeprazole   | Ritonavir Rosiglitazone  Saquinavir Selegiline Sertraline Sildenafil Sulconazole Telmisartan Ticlopidine Tioconazole Topiramate Torsemide Tranylcypromine Valdecoxib Valproic acid Voriconazole Warfarin Zafirlukast   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CYP2C19 Inducers Aminoglutethimide                                                                                                                                                                                                                                                   | Fosphenytoin                                                                                                                                                                                                                           | Rifampin                                                                                                                                                                                                                                 | St. John's wort (1)                                                                                                                                                                                                    |
| Carbamazepine                                                                                                                                                                                                                                                                        | Phenytoin                                                                                                                                                                                                                              |                                                                                                                                                                                                                                          |                                                                                                                                                                                                                        |
| CYP2C19 Substrates Carisoprodol Cilostazol Citalopram Clobazam Clomipramine Desogestrel Diazepam                                                                                                                                                                                     | Escitalopram  Esomeprazole  Fosphenytoin Imipramine Lansoprazole Mephenytoin Mephobarbital                                                                                                                                             | Methsuximide Moclobemide  Nelfinavir  Nilutamide Omeprazole Pantoprazole Pentamidine                                                                                                                                                     | Phenobarbital Phenytoin Progesterone  Rabeprazole Sertraline Trimipramine Voriconazole                                                                                                                                 |
| When ARQ 197 is co-administered with compounds classified as 'inhibitors', increased plasma                                                                                                                                                                                          |                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                          |                                                                                                                                                                                                                        |  
When ARQ 197 is co-administered with compounds classified as 'inhibitors', increased plasma concentrations of ARQ 197 is the potential outcome. The co-administration of 'inducers' would potentially lower plasma ARQ 197 concentrations. When drugs classified as 'substrates' are coadministered with ARQ 197, there is the potential for higher concentrations of the 'substrate'.  
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF,
Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH;
LexiComp Inc. 2007: 1899-1912.  
Only major substrates and effective inducers are listed.  
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/. (1) Wang *et al*. (2004). *Clin Pharmacol Ther*. 75:191-197  
| CYP3A4 Inhibitors  Acetaminophen Acetazolamide Amiodarone Amlodipine Amprenavir Anastrozole Aprepitant Atazanavir Atorvastatin Azelastine Azithromycin Betamethasone Bortezomib Bromocriptine Caffeine Cerivastatin Chloramphenicol Chlorzoxazone Cimetidine Ciprofloxacin Cisapride Clarithromycin  Clemastine Clofazimine Clotrimazole Clozapine Cocaine Conivaptan Cyclophosphamide Cyclosporine Danazol Dasatinib (1) Delavirdine Desipramine Dexmedetomidine Diazepam  Diclofenac  Dihydroergotamine  Diltiazem Disulfiram Docetaxel Doxorubicin Doxycycline Drospirenone Efavirenz Enoxacin Entacapone Ergotamine Erythromycin Ethinyl estradiol Etoposide Felodipine Fentanyl Fluconazole Fluoxetine Fluvastatin Fluvoxamine Fosamprenavir   | Glyburide Grapefruit juice (2) Haloperidol Hydralazine Ifosfamide Imatinib Indinavir Irbesartan Isoniazid Isradipine Itraconazole Ketoconazole Lansoprazole Lidocaine  Lomustine Losartan  Lovastatin Mefloquine Mestranol Methadone Methimazole Methoxsalen Methylprednisolone Metronidazole Miconazole Midazolam Mifepristone Mirtazapine Mitoxantrone   | Modafinil Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nisoldipine Nizatidine Norfloxacin Olanzapine Omeprazole Orphenadrine Oxybutynin Paroxetine Pentamidine Pergolide Phencyclidine Pilocarpine Pimozide Pravastatin Prednisolone  Primaquine Progesterone Propofol  Propoxyphene Quinidine Quinine Quinupristin Rabeprazole   | Ranolazine Risperidone Ritonavir Saquinavir Selegiline Sertraline Sildenafil Sirolimus Sulconazole Tacrolimus Tamoxifen Telithromycin Teniposide Testosterone Tetracycline Ticlopidine Tranylcypromine Trazodone Troleandomycin Valproic acid Venlafaxine Verapamil Vinblastine Vincristine Vinorelbine Voriconazole Zafirlukast Ziprasidone   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CYP3A4 Inducers Aminoglutethimide Carbamazepine Fosphenytoin Nafcillin  Nevirapine Oxcarbazepine                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Pentobarbital Phenobarbital Phenytoin                                                                                                                                                                                                                                                                                                                      | Primidone Rifabutin Rifampin                                                                                                                                                                                                                                                                                                                 | Rifapentine St. John's wort (3)                                                                                                                                                                                                                                                                                                                |
| CYP3A4 Substrates  Albuterol Alfentanil Alprazolam Amlodipine Amprenavir Aprepitant Aripiprazole Atazanavir Atorvastatin Benzphetamine Bisoprolol Bortezomib Bosentan Bromazepam Bromocriptine Buprenorphine Buspirone                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Docetaxel Doxepin Doxorubicin Doxycycline Efavirenz Eletriptan Enalapril Eplerenone Ergoloid mesylates Ergonovine Ergotamine Erythromycin Escitalopram Estradiol Estrogens, conj., synthetic Estrogens, conj., equine Estrogens, conj., esterified                                                                                                         | Ketoconazole Lansoprazole Letrozole Levomethadyl acetate  hydrochloride Levonorgestrel Lidocaine Losartan Lovastatin Medroxyprogesterone  Mefloquine Mestranol Methadone Methylergonovine Methysergide Miconazole Midazolam                                                                                                                  | Quetiapine Quinidine Rabeprazole Repaglinide Rifabutin Rifampin Ritonavir Saquinavir Sertraline Sibutramine Sildenafil Simvastatin Sirolimus Sufentanil Tacrolimus Tamoxifen Tamsulosin                                                                                                                                                        |  
| Busulfan Carbamazapine Cerivastatin Chlordiazepoxide Chloroquine Chlorpheniramine Cisapride Citalopram Clarithromycin Clobazam Clonazepam Clorazepate Cocaine Colchicine Cyclophosphamide Cyclosporine Dantrolene Dapsone Delavirdine Diazepam Digitoxin Dihydroergotamine Diltiazem Disopyramide   | Estrone Estropipate Ethinyl estradiol Ethosuximide Etoposide Felbamate Felodipine Fentanyl Flurazepam Flutamide Fosamprenavir Fulvestrant Gefitinib Halofantrine Haloperidol Ifosfamide Imatinib Indinavir Irinotecan Isosorbide dinitrate Isosorbide mononitrate Isradipine Itraconazole Ketamine   | Miglustat Mirtazapine Modafinil Montelukast Moricizine Nateglinide Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nimodipine Nisoldipine Nitrendipine Norethindrone Norgestrel Ondansetron Paclitaxel Pergolide Phencyclidine Pimozide Pioglitazone Primaquine Progesterone   | Telithromycin Teniposide Terbinafine Tetracycline Theophylline Tiagabine Ticlopidine Tolterodine Toremifene Trazodone Triazolam Trimethoprim Trimipramine Troleandomycin Vardenafil Venlafaxine Verapamil Vinblastine Vincristine Vinorelbine Zolpidem Zonisamide Zopiclone   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
When pazopanib and ARQ 197 are co-administered with compounds classified as 'inhibitors', increased plasma concentrations of pazopanib and ARQ 197 are the potential outcomes. The co-administration of
'inducers' would potentially lower plasma concentrations of both study drugs. When drugs classified as 'substrates' are co-administered with pazopanib or ARQ 197, there is the potential for higher concentrations of the 'substrate'. Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF,
Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH;
LexiComp Inc. 2007: 1899-1912. Only major substrates and effective inducers are listed. Additional information for drug interactions with cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/. (1) Investigator's Brochure: Pazopanib. GlaxoSmithKline. February 2009.  
(2) Malhotra *et al*. (2001). Clin Pharmacol Ther. 69:14-23. (3) Mathijssen *et al*. (2002). J Natl Cancer Inst. 94:1247-1249; Frye et al. (2004). Clin Pharmacol Ther.  
76:323-329.  
| CYP2C8/9 Inhibitors Amiodarone Amitryptiline Amlodipine Anastrozole Aprepitant Atazanavir Azelastine Bortezomib Candesartan Chloramphenicol Cholecalciferol (Vitamin D3)  Cimetidine Clopidogrel Clotrimazole Clozapine Cyclosporine Delavirdine Dexmedetomidine Diclofenac Diltiazem Dimethyl sulfoxide Disulfiram Drospirenone Efavirenz Entacapone Eprosartan Etoposide   | Felodipine Fluconazole Fluoxetine Fluphenazine Flurbiprofen Fluvastatin Fluvoxamine Gemfibrozil Ibuprofen Imatinib Indinavir Indomethacin Irbesartan Isoniazid Ketoconazole Ketoprofen Lansoprazole Leflunomide Losartan Lovastatin Mefenamic acid Meloxicam Methimazole Methoxsalen Metronidazole Miconazole Midazolam   | Modafinil Montelukast Nateglinide Nelfinavir Nicardipine Nifedipine Olanzapine Omeprazole Ondansetron Orphenadrine Pantoprazole Paroxetine Pentamidine Pioglitizone Piroxicam Pravastatin Progesterone Propafenone Propofol Propoxyphene Pyrimethamine Quinidine Quinine Ritonavir Rosiglitazone Saquinavir Selegiline   | Sertraline Sildenafil Simvastatin Sulconazole Sulfadiazine Sulfamethoxazole Sulfinpyrazone Sulfisoxazole Tamoxifen Teniposide Thioridazine Ticlopidine Tioconazole Tolbutamide Tolcapone Tranylcypromine Tretinoin Triazolam Trimethoprim Valdecoxib Valproic acid Valsartan Verapamil Voriconazole Warfarin Zafirlukast   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CYP2C8/9 Inducers Carbamazepine                                                                                                                                                                                                                                                                                                                                              | Phenobarbital                                                                                                                                                                                                                                                                                                             | Primidone                                                                                                                                                                                                                                                                                                                | Rifapentine                                                                                                                                                                                                                                                                                                                |
| Fosphenytoin                                                                                                                                                                                                                                                                                                                                                                 | Phenytoin                                                                                                                                                                                                                                                                                                                 | Rifampin                                                                                                                                                                                                                                                                                                                 | Secobarbital                                                                                                                                                                                                                                                                                                               |
| CYP2C8/9 Substrates Alosetron Amiodarone Bosentan Carvedilol Fluoxetine Fosphenytoin Glimepiride Glipizide Ketamine                                                                                                                                                                                                                                                          | Losartan Mephenytoin Mestranol Montelukast Nateglinide Paclitaxel Phenytoin Pioglitazone Propofol                                                                                                                                                                                                                         | Rifampin Rosiglitazone Selegiline Sertraline Sulfadiazine Sulfamethoxazole Sulfinpyrazone Sulfisoxazole Tamoxifen                                                                                                                                                                                                        | Tolbutamide Torsemide Trimethoprim Voriconazole Warfarin Zafirlukast Zopiclone                                                                                                                                                                                                                                             |
| When drugs classified as 'substrates' are co-administered with pazopanib, there is the potential for higher  concentrations of the 'substrate'. When pazopanib is co-administered with compounds classified as                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                            |  
When drugs classified as 'substrates' are co-administered with pazopanib, there is the potential for higher concentrations of the 'substrate'. When pazopanib is co-administered with compounds classified as 'inhibitors', increased plasma concentrations of pazopanib is the potential outcome. The coadministration of 'inducers' would potentially lower plasma pazopanib concentrations.  
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP,
Lance LL eds. Drug Information Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.)
appendix a performance status criteria
appendix b potential drug interactions

| CYP2D6 Substrates Amitriptyline Atomoxetine Carvedilol Chlorpheniramine Chlorpromazine Clomipramine Codeine Desipramine Dextromethorphan Dihydrocodeine   | Diphenhydramine Dolasetron Doxepin Duloxetine Flecainide  Fluoxetine Fluvoxamine Haloperidol Hydrocodone Imipramine   | Maprotiline Metoclopramide Metoprolol Mexiletine Nortriptyline Palonosetron Paroxetine Perhexiline Promethazine Propafenone   | Propranolol Protriptyline Risperidone Tamoxifen Thioridazine Timolol Tolterodine Tramadol Trazodone Venlafaxine   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|  
When drugs classified as 'substrates' are co-administered with pazopanib, there is the potential for higher concentrations of the 'substrate'.
appendix a performance status criteria
appendix c medications that may

The following table presents a list of drugs that prolong, may prolong, or are unlikely to prolong the QTc. Please note that this list is frequently updated. For the most current list of medications, users should be directed to the following website: *http://www.azcert.org/medical-pros/drug-lists/druglists.cfm.*  
| Drugs that are generally  accepted to have a risk of  causing Torsades de Pointes   | Drugs that in some reports have been  associated with Torsades de Pointes  and/or QTc prolongation but at this  time lack substantial evidence for  causing Torsades de Pointes   | Drugs that, in some reports, have been  weakly associated with Torsades de  Pointes and/or QTc prolongation but that  are unlikely to be a risk for Torsades de  Pointes when used in usual recommended  dosages and in subjects without other risk  factors (e.g., concomitant QTc prolonging  drugs, bradycardia, electrolyte  disturbances, congenital long QTc  syndrome, concomitant drugs that inhibit  metabolism)   |
|-------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Generic/Brand Name                                                                  | Generic/Brand Name                                                                                                                                                                | Generic/Brand Name                                                                                                                                                                                                                                                                                                                                                                                                          |
| Amiodarone /Cordarone®                                                              | Alfuzosin /Uroxatral®                                                                                                                                                             | Amitriptyline /Elavil®                                                                                                                                                                                                                                                                                                                                                                                                      |
| Amiodarone /Pacerone®                                                               | Amantadine /Symmetrel®                                                                                                                                                            | Ciprofloxacin /Cipro®                                                                                                                                                                                                                                                                                                                                                                                                       |
| Arsenic trioxide /Trisenox®                                                         | Atazanavir /Reyataz®                                                                                                                                                              | Citalopram /Celexa®                                                                                                                                                                                                                                                                                                                                                                                                         |
| Astemizole /Hismanal®                                                               | Azithromycin /Zithromax®                                                                                                                                                          | Clomipramine /Anafranil®                                                                                                                                                                                                                                                                                                                                                                                                    |
| Bepridil /Vascor®                                                                   | Chloral hydrate /Noctec®                                                                                                                                                          | Desipramine /Pertofrane®                                                                                                                                                                                                                                                                                                                                                                                                    |
| Chloroquine /Aralen®                                                                | Clozapine /Clozaril®                                                                                                                                                              | Diphenhydramine /Benadryl®                                                                                                                                                                                                                                                                                                                                                                                                  |
| Chlorpromazine /Thorazine®                                                          | Dolasetron /Anzemet®                                                                                                                                                              | Diphenhydramine /Nytol®                                                                                                                                                                                                                                                                                                                                                                                                     |
| Cisapride /Propulsid®                                                               | Dronedarone /Multaq®                                                                                                                                                              | Doxepin /Sinequan®                                                                                                                                                                                                                                                                                                                                                                                                          |
| Clarithromycin /Biaxin®                                                             | Felbamate /Felbatrol®                                                                                                                                                             | Fluconazole /Diflucan®                                                                                                                                                                                                                                                                                                                                                                                                      |
| Disopyramide /Norpace®                                                              | Flecainide /Tambocor®                                                                                                                                                             | Fluoxetine /Sarafem®                                                                                                                                                                                                                                                                                                                                                                                                        |
| Dofetilide /Tikosyn®                                                                | Foscarnet /Foscavir®                                                                                                                                                              | Fluoxetine /Prozac®                                                                                                                                                                                                                                                                                                                                                                                                         |
| Domperidone /Motilium®                                                              | Fosphenytoin /Cerebyx®                                                                                                                                                            | Galantamine /Reminyl®                                                                                                                                                                                                                                                                                                                                                                                                       |
| Droperidol /Inapsine®                                                               | Gatifloxacin /Tequin®                                                                                                                                                             | Imipramine /Norfranil®                                                                                                                                                                                                                                                                                                                                                                                                      |
| Erythromycin /Erythrocin®                                                           | Gemifloxacin /Factive®                                                                                                                                                            | Itraconazole /Sporanox®                                                                                                                                                                                                                                                                                                                                                                                                     |
| Erythromycin /E.E.S.®                                                               | Granisetron /Kytril®                                                                                                                                                              | Ketoconazole /Nizoral®                                                                                                                                                                                                                                                                                                                                                                                                      |
| Halofantrine /Halfan®                                                               | Indapamide /Lozol®                                                                                                                                                                | Mexiletine /Mexitil®                                                                                                                                                                                                                                                                                                                                                                                                        |
| Haloperidol /Haldol®                                                                | Isradipine /Dynacirc®                                                                                                                                                             | Nortriptyline /Pamelor®                                                                                                                                                                                                                                                                                                                                                                                                     |
| Ibutilide /Corvert®                                                                 | Lapatinib /Tykerb®                                                                                                                                                                | Paroxetine /Paxil®                                                                                                                                                                                                                                                                                                                                                                                                          |
| Levomethadyl /Orlaam®                                                               | Lapatinib /Tyverb®                                                                                                                                                                | Protriptyline /Vivactil®                                                                                                                                                                                                                                                                                                                                                                                                    |
| Mesoridazine /Serentil®                                                             | Levofloxacin /Levaquin®                                                                                                                                                           | Sertraline /Zoloft®                                                                                                                                                                                                                                                                                                                                                                                                         |  
| Drugs that are generally  accepted to have a risk of  causing Torsades de Pointes   | Drugs that, in some reports, have been  weakly associated with Torsades de  Pointes and/or QTc prolongation but that  are unlikely to be a risk for Torsades de  Pointes when used in usual recommended  dosages and in subjects without other risk  factors (e.g., concomitant QTc prolonging  drugs, bradycardia, electrolyte  disturbances, congenital long QTc  syndrome, concomitant drugs that inhibit  metabolism)   |                              |
|-------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|
| Generic/Brand Name                                                                  | Generic/Brand Name                                                                                                                                                                                                                                                                                                                                                                                                          | Generic/Brand Name           |
| Methadone /Dolophine®                                                               | Lithium /Lithobid®                                                                                                                                                                                                                                                                                                                                                                                                          | Solifenacin /VESIcare®       |
| Methadone /Methadose®                                                               | Lithium /Eskalith®                                                                                                                                                                                                                                                                                                                                                                                                          | Trimethoprim-Sulfa /Sulfa®   |
| Pentamidine /Pentam®                                                                | Moexipril/HCTZ /Uniretic®                                                                                                                                                                                                                                                                                                                                                                                                   | Trimethoprim-Sulfa /Bactrim® |
| Pentamidine /NebuPent®                                                              | Moxifloxacin /Avelox®                                                                                                                                                                                                                                                                                                                                                                                                       | Trimipramine /Surmontil®     |
| Pimozide /Orap®                                                                     | Nicardipine /Cardene®                                                                                                                                                                                                                                                                                                                                                                                                       |                              |
| Probucol /Lorelco®                                                                  | Nilotinib /Tasigna®                                                                                                                                                                                                                                                                                                                                                                                                         |                              |
| Procainamide /Pronestyl®                                                            | Octreotide /Sandostatin®                                                                                                                                                                                                                                                                                                                                                                                                    |                              |
| Procainamide /Procan®                                                               | Ofloxacin /Floxin®                                                                                                                                                                                                                                                                                                                                                                                                          |                              |
| Quinidine /Cardioquin®                                                              | Ondansetron /Zofran®                                                                                                                                                                                                                                                                                                                                                                                                        |                              |
| Quinidine /Quinaglute®                                                              | Oxytocin /Pitocin®                                                                                                                                                                                                                                                                                                                                                                                                          |                              |
| Sotalol /Betapace®                                                                  | Paliperidone /Invega® Drugs that in some reports have been  associated with Torsades de Pointes  and/or QTc prolongation but at this  time lack substantial evidence for  causing Torsades de Pointes Perflutren lipid microspheres                                                                                                                                                                                         |                              |
| Sparfloxacin /Zagam®                                                                | /Definity®                                                                                                                                                                                                                                                                                                                                                                                                                  |                              |
| Terfenadine /Seldane®                                                               | Quetiapine /Seroquel®                                                                                                                                                                                                                                                                                                                                                                                                       |                              |
| Thioridazine /Mellaril®                                                             | Ranolazine /Ranexa® Risperidone /Risperdal® Roxithromycin* /Rulide® Sertindole /Serlect® Sertindole /Serdolect® Sunitinib /Sutent® Tacrolimus /Prograf® Tamoxifen /Nolvadex® Telithromycin /Ketek® Tizanidine /Zanaflex® Vardenafil /Levitra® Venlafaxine /Effexor® Voriconazole /VFend® Ziprasidone /Geodon®                                                                                                               |                              |
| References:                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                             |                              |  
APPENDIX D: NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC
DISEASE  
| Class   | Functional Capacity                                                                                                                                                                                                                                           | Objective Assessment                                              |
|---------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|
| I       | Subjects with cardiac disease but without resulting limitations of  physical activity. Ordinary physical activity does not cause undue  fatigue, palpitation, dyspnea, or anginal pain.                                                                       | No objective evidence of  cardiovascular disease.                 |
| II      | Subjects with cardiac disease resulting in slight limitation of  physical activity. They are comfortable at rest. Ordinary physical  activity results in fatigue, palpitation, dyspnea, or anginal pain.                                                      | Objective evidence of  minimal cardiovascular  disease.           |
| III     | Subjects with cardiac disease resulting in marked limitation of  physical activity. They are comfortable at rest. Less than ordinary  activity causes fatigue, palpitation, dyspnea, or anginal pain.                                                         | Objective evidence of  moderately severe  cardiovascular disease. |
| IV      | Subjects with cardiac disease resulting in inability to carry on any  physical activity without discomfort. Symptoms of heart failure or  the anginal syndrome may be present even at rest. If any physical  activity is undertaken, discomfort is increased. | Objective evidence of  severe cardiovascular  disease.            |
appendix e patient's medication diary
appendix c medications that may

EXPANSION PHASE, COHORT A, CYCLE 1  
  
Today's date ____________________ Agent: Pazopanib, ARQ 197 Patient Name_____________________*______* **Patient Study ID** __________________
INSTRUCTIONS TO THE PATIENT:
1. Complete one form for each cycle of treatment.  
2. **Starting on day 1**, you will take **pazopanib** once each day in the morning either 1 hour before or 2 hours after a meal with 1 cup of water.  
Dose: ___________. Take ___ 200 mg tablets and ___ 400 mg tablets every day. You should swallow the tablets whole. Do not chew, crush, or break the tablets.  
3. **Starting on day 8**, you will take **ARQ 197** twice each day, about 12 hours apart, with food. You should swallow the tablets whole. Do not chew, crush, or break the tablets.  
You will not take ARQ 197 on days 1-7 of cycle 1.  
Morning dose: ___________. Take ___ 120 mg tablets. Evening dose: ___________.  
Take ___ 120 mg tablets.  
4. Record the date, the number of tablets of each size you took, and when you took them. 5. If you have any comments or notice any side effects, please record them in the Comments column.  
6. Please bring this form and your bottles of **pazopanib and ARQ 197** tablets when you return for each appointment.  
7. You should measure your own blood pressure at home at least once a day (preferably twice a day). If your systolic pressure (top number) is greater than 150 or your diastolic blood pressure (bottom number) is greater than 90, re-measure your blood pressure 1 to 4 hours later. If your systolic pressure is still greater than 150 or your diastolic blood pressure is still greater than 90, please contact your study team for instructions. You should also call the research team if you experience any symptoms of high blood pressure, such as chest pain, shortness of breath, headache, blood in the urine, or double vision.
CTEP-assigned Protocol \#8880 Local Protocol \# ___________________  
Today's date _____________________ Agent: Pazopanib, ARQ 197 Patient Name_____________________*______________* **Patient Study ID** ___________________  
| Patient Name___________________________________                                               | Patient Study ID ___________________   |                      |                        |                     |          |
|-----------------------------------------------------------------------------------------------|----------------------------------------|----------------------|------------------------|---------------------|----------|
| Pazopanib                                                                                     | ARQ 197                                | Blood  Pressure  AM  |                        |                     |          |
| # of  tablets  taken                                                                          |                                        |                      |                        |                     |          |
| 200 mg                                                                                        | 400 mg                                 | 120 mg               | 120 mg                 |                     |          |
| 1                                                                                             | --------                               | --------             | --------               | --------            |          |
| 2                                                                                             | --------                               | --------             | --------               | --------            |          |
| 3                                                                                             | --------                               | --------             | --------               | --------            |          |
| 4                                                                                             | --------                               | --------             | --------               | --------            |          |
| 5                                                                                             | --------                               | --------             | --------               | --------            |          |
| 6                                                                                             | --------                               | --------             | --------               | --------            |          |
| 7                                                                                             | --------                               | --------             | --------               | --------            |          |
| 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28                                  | Time of  morning  dose                 | # of  tablets  taken | Time of  evening  dose | Blood  Pressure  PM | Comments |
| # of tablets  taken                                                                           |                                        |                      |                        |                     |          |
| Day                                                                                           | Date                                   | Time  of dose        |                        |                     |          |
| Patient's signature _________________________________________________________________________ |                                        |                      |                        |                     |          |
appendix f lvef dose modification
appendix c medications that may

Asymptomatic Decrease in LVEF The decision to continue or hold STUDY DRUG is based on the LVEF as it relates to the institutions's lower limit of normal (LLN)
and change in ejection fraction from screening (LVEF as measured at registration) according to the following table:  
| Relationship of  LVEF to institution's  LLN   | LVEF Decrease  < 10%                              | LVEF Decrease  10-15%                                                                           | LVEF Decrease  ≥ 16%                              |
|-----------------------------------------------|---------------------------------------------------|-------------------------------------------------------------------------------------------------|---------------------------------------------------|
| Normal                                        | Continue                                          | Continue                                                                                        | Continue and repeat  MUGA/ECHO within  1-2 cycles |
| 1-5% below LLN                                | Continue and repeat  MUGA/ECHO within  1-2 cycles | HOLD and repeat  MUGA/ECHO within  1-2 cycles                                                   |                                                   |
| ≥ 6% below LLN                                | Continue and repeat  MUGA/ECHO within  1-2 cycles | Continue and repeat  MUGA/ECHO within  1-2 cycles HOLD and repeat  MUGA/ECHO within  1-2 cycles | HOLD and repeat  MUGA/ECHO within  1-2 cycles     |  
Discontinue STUDY DRUG if:
- Two consecutive HOLD catagories occur.  
- Three intermittant HOLD catagories occur (at the discretion of the investigator, STUDY DRUG may also be permanently discontinued prior to the occurance of 3 intermittant HOLD catagories).
If LVEF is maintained at a "Continue and repeat MUGA/ECHO" or improves from a HOLD to a "Continue and repeat MUGA/ECHO" category, additonal MUGA scans/echocardiograms prior to the next scheduled MUGA/ECHO will be at the discretion of the investigator.
appendix f lvef dose modification
symptomatic cardiac events

Discontinue STUDY DRUG if:
- A patient has symptoms of congestive heart failure (CHF) and a diagnosis of CHF is confirmed. - A patient has a myocardial infarction.
appendix g facsimile transmission form
symptomatic cardiac events

Please use this form to send notification of shipment  
| From:   | Telephone:   |
|---------|--------------|
| Date:   | Fax:         |  
To: PPD Fax:  
| Protocol Number: Number of samples shipped: Date Shipped: Expected date of arrival: Courier: Airway Bill No.: Number of packages: On dry ice:   | Yes / No (Circle one)   |
|-------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|
| Associated hazards: Shipped by: (Study Centre Number)                                                                                           |                         |  
Please use this form to send notification of shipment  
| From:   | Telephone:   |
|---------|--------------|
| Date:   | Fax:         |
appendix g facsimile transmission form
to covance inc. fax

| Protocol Number: Number of samples shipped: Date Shipped: Expected date of arrival: Courier: Airway Bill No.: Number of packages: On dry ice:   | Yes / No (Circle one)   |
|-------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|
| Associated hazards: Shipped by: (Study Centre Number)                                                                                           |                         |