Pazopanib and ARQ 197 for Advanced Solid Tumors

Background:

- Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) signal
transduction pathways have synergistic effects on promoting angiogenesis and growth
factor expression. Hypoxia caused by treatment with VEGF inhibitors results in the
upregulation of c-MET, the receptor for HGF. In a mouse model, combined blockade of
VEGFR and c-Met significantly prolonged survival compared with inhibition of either
target alone.

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

Objectives:

- Establish the safety and tolerability of the combination of pazopanib with ARQ 197 in
patients with refractory advanced solid tumors.

- Establish the maximum tolerated dose (MTD) of the combination of pazopanib with ARQ 197
in patients with refractory advanced solid tumors.

- Evaluate changes in MET and phospho-MET following treatment with pazopanib and ARQ 197
in patients with refractory advanced solid tumors.

- Determine the pharmacokinetics (PK) of pazopanib and ARQ 197.

- Determine and compare levels of total MET, phospho MET, HIF-1 , and
epithelial-mesenchymal transition markers (e-cadherin, beta catenin) in tumor biopsy
samples prior to and following administration of the study drugs.

- Determine and compare levels of circulating levels of HGF, soluble MET (sMET), VEGF-A,
and soluble VEGFR2 (sVEGFR2) prior to and following administration of the study drugs.

- Determine polymorphisms in the CYP2C19 and correlate these with the observed toxicities,
and the PK of ARQ 197.

- Evaluate antitumor activity of the combination of pazopanib and ARQ 197 in patients with
refractory advanced solid tumors.

Eligibility:

-Adults with advanced, refractory solid tumors. Patients enrolling in the expansion cohorts
must have advanced sarcoma, gastric cancer, and MET-expressing malignancies, have disease
amenable to biopsy, and be willing to undergo pre-and post-treatment biopsies.

Study Design:

- ARQ 197 will be administered orally twice daily and pazopanib orally once daily, in
28-day cycles.

- Dose escalation will proceed using the traditional 3+3 design.

- Once the MTD is established, an additional cohort will be accrued for pharmacodynamic
(PD) studies in tumor biopsies (required in the expansion phase). For the first week,
patients will receive pazopanib alone to compare PK and PD results; combination therapy
will be given from week 2 onwards.

- ELIGIBILITY CRITERIA:

- Patients with histologically confirmed (by the Laboratory of Pathology, NIH) solid
tumors that have progressed following at least one line of standard therapy or for
whom no standard treatment options exist.

- Patients must have measurable or evaluable disease.

- Patients enrolling in the expansion cohorts must have disease amenable to biopsy, and
be willing to undergo pre-and post-treatment biopsies.

- Patients must have completed any chemotherapy, radiation therapy, or biologic therapy
greater than or equal to 4 weeks prior to entering the study (6 weeks for nitrosoureas
or mitomycin C). Patients must be greater than or equal to 2 weeks since any prior
administration of a study drug in a phase 0 or equivalent study. Patients must have
recovered to eligibility levels from prior toxicity or adverse events. Treatment with
bisphosphonates is permitted.

- Patients who have had prior treatment with any anti-angiogenic therapy and/or c-MET
inhibitor are eligible in the dose escalation phase unless the antiangiogenic therapy
and/or c-MET inhibitor were administered within the 4 weeks prior to entering the
study. In the expansion phase, prior c-MET inhibitor is not allowed, and
anti-angiogenic therapy is allowed unless it was administered within the 3 months
prior to entering the study.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of pazopanib in combination with ARQ 197 in patients
less than 18 years of age, children are excluded from this study.

- Life expectancy greater than 3 months.

- ECOG performance status 0 or 1.

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count greater than or equal to 1,500/microL

- Platelets greater than or equal to 100,000/microL

- Total bilirubin less than or equal to 1.5 X institutional ULN

- AST (SGOT)/ALT (SGPT) less than or equal to 2.5 X institutional ULN

- Creatinine less than or equal to 1.5 mg/dL (133 mcmol/L); OR

- Measured creatinine greater than or equal to 60 mL/minute for patients with
clearance creatinine levels greater than 1.5 mg/dL

- Urine protein/creatinine ratio less than 1 OR 24-hour urine protein less than 1
gram

- Subjects who have both bilirubin greater than ULN and AST/ALT greater than ULN are not
eligible.

- Subjects in the expansion cohort must have PT/INR/PTT less than or equal to 1.2 X
institutional ULN, except patients with confirmed positive lupus anticoagulant test.

- Subjects must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg
(diastolic) for eligibility. Initiation or adjustment of BP medication is permitted
prior to study entry provided that the average of three BP readings at a visit prior
to enrollment is less than 140/90 mmHg.

- The effects of study drugs on the developing human fetus are unknown. For this reason,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for at least 2 months after dosing with study
drugs ceases. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating physician
immediately. Women of child-bearing potential must have a negative pregnancy test
prior to entry.

- Patients must be able to swallow whole tablets or capsules. Nasogastric or G-tube
administration is not allowed.

- Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents.

- Patients with active brain metastases or carcinomatous meningitis are excluded from
this clinical trial. Patients whose brain metastatic disease status has remained
stable for greater than or equal to 4 weeks following treatment of the brain
metastases are eligible to participate.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pazopanib or ARQ 197.

- Eligibility of subjects receiving any medications or substances known to affect or
with the potential to affect the activity or pharmacokinetics of pazopanib or ARQ 197
will be determined following review of their cases by the Principal Investigator.
Efforts should be made to switch subjects with gliomas or brain metastases who are
taking enzymeinducing anticonvulsant agents to other medications.

- Certain medications that act through the CYP450 system are specifically prohibited in
subjects receiving pazopanib and ARQ 197 and others should be avoided or administered
with extreme caution.

- Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin,
atazanavir, indinavir, nefazodone, nelfinivir, retonavir, saquinavir,
telithromycin, voriconazole may increase pazopanib concentrations and are
prohibited; although, in exceptional circumstances they may be administered in
conjunction with lowering the dose of pazopanib by 50% of what would otherwise be
administered. Grapefruit juice is also an inhibitor of CYP450 and should not be
taken with pazopanib.

- Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib
concentrations, are strictly prohibited.

- Medications which have narrow therapeutic windows and are substrates of CYP3A4,
CYP2D6, or CYP2C8 should be avoided and, if necessary, administered with caution.

- Inhibitors or inducers of CYP2C19 should be avoided and, if necessary,
administered with caution.

- Cardiovascular baseline QTc greater than or equal to 480 msec will exclude patients
from entry on study. Medications that may cause QTc interval prolongation are listed,
and should be avoided by patients entering on trial. Patients for whom a given
medication that may cause QTc interval prolongation cannot be discontinued may be
eligible at the discretion of the study PI. A comprehensive list of agents with the
potential to cause QTc prolongation can be found at
http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm. (Note: If subjects must
take medications with a risk or possible risk of Torsades de Pointes, they should be
watched carefully for symptoms of Torsades de Pointes, such as syncope. Performing
additional EKGs on subjects who must take one or more of these medications is not
required; however, additional investigations, including EKGs, may be performed as per
the treating physician s judgment.)

- Subjects with any of the following cardiovascular conditions within the past 6

months:

- cerebrovascular accident (CVA) or transient ischemic attack (TIA)

- clinically significant bradycardia or other uncontrolled cardiac arrhythmia

- admission for unstable angina or myocardial infarction

- cardiac angioplasty or stenting

- coronary artery bypass graft surgery

- pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been
treated with therapeutic anticoagulation for less than 6 weeks

- arterial thrombosis

- symptomatic peripheral vascular disease

- Class III or IV heart failure as defined by the NYHA functional classification system.
A subject who has a history of Class II heart failure and is asymptomatic on treatment
may be considered eligible

- History of serious or non-healing wound, ulcer, or bone fracture.

- Patients who received major surgery within the past 4 weeks

- Subjects with any condition that may impair the ability to swallow or absorb oral
medications/investigational product including:

- any lesion, whether induced by tumor, radiation or other conditions, which makes it
difficult to swallow capsules or pills

- prior surgical procedures affecting absorption including, but not limited to major
resection of stomach or small bowel

- active peptic ulcer disease

- malabsorption syndrome

-Subjects with any condition that may increase the risk of gastrointestinal bleeding
or gastrointestinal perforation, including

- active peptic ulcer disease

- known intraluminal metastatic lesions

- inflammatory bowel disease (e.g., ulcerative colitis, Crohn s disease) or other
gastrointestinal conditions which increase the risk of perforation

- history of abdominal fistula, gastrointestinal perforation or intraabdominal abscess
within 28 days prior to beginning study treatment

- History of hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to
first dose of study drug.

- Urine protein/creatinine ratio should be screened by urine analysis. If protein
is 1+ or higher, 24-hour urine protein should be obtained and the level should be
less than 1g for patient enrollment. Patients with less than 1+ proteinuria are
eligible following initial determination by urinalysis within 1 week prior to
enrollment and do not need the urinalysis repeated.

- Patients with clinically significant intercurrent illnesses, including but not
limited to, life threatening infection, psychiatric illness/social situations
that would limit compliance with study requirements will not be eligible to
participate.

- Pregnant women are excluded from this study because the effects of the study
drugs on the developing fetus are unknown. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of
the mother with the study drugs, breastfeeding should be discontinued prior to
the first dose of study drug and women should refrain from nursing throughout the
treatment period and for 14 days following the last dose of study drug.

- HIV-positive patients on combination antiretroviral therapy are ineligible
because of the potential for PK interactions.

- Patients who require use of coumarin-derivative anticoagulants such as warfarin
are excluded. Low molecular weight heparin is permitted for prophylactic use, but
not therapeutic use.

INCLUSION OF WOMEN AND MINORITIES:

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