Solid Tumor
Conditions
Keywords
Pazopanib, Tivantinib, MET Inhibitor, Advanced Cancer, Anti-Angiogenesis, Cancer, Solid Tumor, Sarcoma
Brief summary
Background: \- Pazopanib is an anticancer drug that blocks the growth of new blood vessels in tumors. It has been approved to treat renal cell cancer and soft tissue sarcomas in patients who have received prior chemotherapy. ARQ 197 (Tivantinib) is an experimental drug that blocks a protein called mesenchymal-epithelial transition factor (c-MET), which cancer cells need to grow. Studies suggest that some drugs that block blood vessel growth can increase the production of c-MET in tumors, which helps cancer cells keep growing. Blocking both blood vessel growth and c-MET with pazopanib and ARQ 197 may help kill cancer cells faster. This study will use these drugs to treat solid tumors that have not responded to earlier treatments. Objectives: \- To test the safety and effectiveness of pazopanib and ARQ 197 for advanced solid tumors. Eligibility: \- Individuals at least 18 years of age who have advanced solid tumors that have not responded to earlier treatments. Design: * Participants will be screened with a physical exam and medical history. They will also have blood and urine tests, and imaging studies. * The study drugs will be given in 4-week cycles of treatment. Participants will take pazopanib once a day and ARQ 197 twice a day by mouth. Some participants will start with pazopanib or ARQ 197 alone for the first week. Then they will take both drugs together for the rest of the study. * Participants will be monitored with frequent blood tests and imaging studies. Optional tumor samples may be collected during different treatment cycles.
Detailed description
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 mesenchymal-epithelial transition factor (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 putative hepatocyte growth factor receptor (MET) inhibitor ARQ 197 (Tivantinib) 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, Hypoxia-Inducible Factor (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 hepatocyte growth factor (HGF), soluble MET (sMET), vascular endothelial growth factor A (VEGF-A), and soluble vascular endothelial growth factor receptor 2 (VEGFR2) (sVEGFR2) prior to and following administration of the study drugs. * Determine polymorphisms in the cytochrome P450 2C19 (CYP2C19) and correlate these with the observed toxicities, and the pharmacokinetics (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 maximum tolerated dose (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.
Interventions
DRUGPazopanib
Vascular endothelial growth factor (VEGFR) inhibitor
DRUGARQ 197
Hepatocyte growth factor receptor (mesenchymal-epithelial transition factor \[c-MET\]) inhibitor
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* ELIGIBILITY CRITERIA: * Patients with histologically confirmed (by the Laboratory of Pathology, National Institutes of Health (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 mesenchymal epithelial transition factor (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 (Tivantinib) in patients less than 18 years of age, children are excluded from this study. * Life expectancy greater than 3 months. * Eastern Cooperative Oncology Group (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 upper limit of normal (ULN) * Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase(SGOT)/alanine transaminase (ALT) serum glutamic pyruvic transaminase(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 prothrombin time (PT)/ international normalized ratio (INR)/partial thromboplastin time (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 enzyme inducing anticonvulsant agents to other medications. * Certain medications that act through the cytochromes P450 (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 cytochrome P450 3A4 (CYP3A4) such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, 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 Cytochrome P450 Family 3 Subfamily A Member 4 (CYP3A4), such as rifampin, may decrease pazopanib concentrations, are strictly prohibited. * Medications which have narrow therapeutic windows and are substrates of CYP3A4, cytochrome P450 2D6 CYP2D6), or cytochrome P₄₅₀2C8 (CYP2C8) should be avoided and, if necessary, administered with caution. * Inhibitors or inducers of cytochrome P450 2C19 (CYP2C19) should be avoided and, if necessary, administered with caution. * Cardiovascular baseline corrected QT Interval (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 principal investigator (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 electrocardiograms (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 physicians 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 New York Heart Association (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. * Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic (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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Time receiving study drug, up to 22 cycles | The highest Grade 3 or 4 adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe, and Grade 4 is life threatening. |
| Changes in MET and Phospho-MET Levels | MET and phospho-MET levels were measured on Cycle 1 Day 1 and Cycle 1 Day 8. | MET or phospho-MET levels (in fmol) normalized to the amount of total protein in a sample (in mg). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | Date treatment consent signed to date off study, approx 22m (month)/2 days(d); 13m/20 d; 5m/23 d; 17m./24 d; 7 m/5 d; 5m/5 d; 5m/13 d; and 23m/21d for DL1, DL2, DL3, DL3 foll/by DL2, DL4, DL4 foll/by DL3, DL 4 foll/by DL 3 foll/by DL2; & DL5 respectively. | Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
| Pazopanib-induced Changes to Epithelial-mesenchymal Phenotype in Human Tumors | Pre-treatment and day 8 post administration | Core tumor biopsies were collected from participants with advanced malignancies. Analyses was performed by epithelial-mesenchymal transition immunofluorescence assay (EMT-IFA) for changes in E-cadherin (E+), vimentin(V+), and mixed V+E+ phenotypes. The small imaging pixel size (0.25 µm\^2)of the IFA relative to the dimensions of the cross sectional areas of tumor (ranging from 75 to 500 µm\^2 in parotid, prostate, colon, and ovarian cancers) allowed us to quantify individual areas of V+ and E+ staining as well as areas of colocalized E+V+ staining within single cells. The assay reports the change in log10(V/E) vratios. The log10(V/E) ratio was determined pre-treatment and in day 8 biopsies and the reported values indicate the change between the two time points. Each value in the table as currently written reflects the change in log10(V/E) ratios between pre- and post-treatment E-cadherin and vimentin values. The full range values indicate the range of changes observed for individual pt. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level (DL) 1: Pazopanib (Paz): 400 mg & ARQ 197: 120 mg Cycle=28 days,Pazopanib: 400 mg by mouth (PO) every day (QD) ,ARQ 197: 120 mg PO twice a day (BID) | 3 |
| Dose Level 2: Pazopanib: 600 mg & ARQ 197: 120 mg Cycle=28 days,Pazopanib: 600 mg by mouth (PO) every day (QD),ARQ 197: 120 mg by mouth (PO) twice a day (BID) | 3 |
| Dose Level 3: Pazopanib: 600 mg & ARQ 197: 240 mg Cycle=28 days,Pazopanib: 600 mg by mouth (PO) every day (QD),ARQ 197: 240 mg by mouth (PO) twice a day (BID) | 2 |
| DL 3 Followed by DL 2: Pazopanib: 600 mg & ARQ 197: 240 mg Foll/by Pazopanib: 600 mg/ARQ 197:120 mg Cycle=28 days,Pazopanib: 600 mg by mouth (PO) every day (QD),ARQ 197: 240 mg by mouth (PO) twice a day (BID) foll/by Cycle=28 days,Pazopanib: 600 mg by mouth (PO) every day (QD),ARQ 197: 120 mg by mouth (PO) twice a day (BID) | 1 |
| Dose Level 4: Pazopanib: 800 mg & ARQ 197: 240 mg Cycle=28 days,Pazopanib: 800 mg by mouth (PO) every day (QD),ARQ 197: 240 mg by mouth (PO) twice a day (BID) | 4 |
| DL 4 Followed by DL 3: Pazopanib: 800 mg & ARQ 197: 240 mg Foll/by Pazopanib: 600 mg/ARQ 197: 240 mg Cycle=28 days,Pazopanib: 800 mg by mouth (PO) every day (QD),ARQ 197: 240 mg by mouth (PO) twice a day (BID) foll/by Cycle=28 days,Pazopanib: 600 mg by mouth (PO) every day (QD),ARQ 197: 240 mg by mouth (PO) twice a day (BID) | 1 |
| DL4 Foll/by DL3 Foll/by DL2 Paz800mg/ARQ240mg Foll/by Paz600 mg/ARQ240mg Foll/by Paz600 mg/ARQ120 mg Cycle=28 days,Pazopanib: 800 mg by mouth (PO) every day (QD),ARQ 197: 240 mg by mouth (PO) twice a day (BID) foll/by Cycle=28 days,Pazopanib: 600 mg by mouth (PO) every day (QD),ARQ 197: 240 mg by mouth (PO) twice a day (BID) foll/by Cycle=28 days,Pazopanib: 600 mg by mouth (PO) every day (QD),ARQ 197: 120 mg by mouth (PO) twice a day (BID) | 1 |
| Dose Level 5: Pazopanib: 800 mg & ARQ 197: 360 mg Cycle=28 days,Pazopanib: 800 mg by mouth (PO) every day (QD),ARQ 197: 360 mg by mouth (PO) twice a day (BID) | 16 |
| Enrolled But Not Treated Enrolled but failed screening and was not treated. | 1 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Enrolled on new protocol | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Infection of blood | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Patient choice - surgery | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Per patient choice | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Refused further treatment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Screening failure | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Switched to alternative treatment | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose Level 2: Pazopanib: 600 mg & ARQ 197: 120 mg | Dose Level 3: Pazopanib: 600 mg & ARQ 197: 240 mg | DL 3 Followed by DL 2: Pazopanib: 600 mg & ARQ 197: 240 mg Foll/by Pazopanib: 600 mg/ARQ 197:120 mg | Dose Level 4: Pazopanib: 800 mg & ARQ 197: 240 mg | DL 4 Followed by DL 3: Pazopanib: 800 mg & ARQ 197: 240 mg Foll/by Pazopanib: 600 mg/ARQ 197: 240 mg | DL4 Foll/by DL3 Foll/by DL2 Paz800mg/ARQ240mg Foll/by Paz600 mg/ARQ240mg Foll/by Paz600 mg/ARQ120 mg | Dose Level 5: Pazopanib: 800 mg & ARQ 197: 360 mg | Dose Level (DL) 1: Pazopanib (Paz): 400 mg & ARQ 197: 120 mg | Enrolled But Not Treated | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 1 Participants | 1 Participants | 4 Participants | 1 Participants | 1 Participants | 15 Participants | 2 Participants | 1 Participants | 29 Participants |
| Age, Continuous | 50.9 years STANDARD_DEVIATION 11.92 | 60.3 years STANDARD_DEVIATION 7.21 | 27.6 years STANDARD_DEVIATION 0 | 56.38 years STANDARD_DEVIATION 8.42 | 20.5 years STANDARD_DEVIATION 0 | 61.9 years STANDARD_DEVIATION 0 | 50.04 years STANDARD_DEVIATION 13.45 | 40.7 years STANDARD_DEVIATION 23.95 | 44.4 years STANDARD_DEVIATION 0 | 49.25 years STANDARD_DEVIATION 14.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 0 Participants | 4 Participants | 0 Participants | 1 Participants | 14 Participants | 3 Participants | 1 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 3 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 8 Participants | 3 Participants | 1 Participants | 20 Participants |
| Region of Enrollment United States | 3 participants | 2 participants | 1 participants | 4 participants | 1 participants | 1 participants | 16 participants | 3 participants | 1 participants | 32 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 9 Participants | 0 Participants | 1 Participants | 14 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 7 Participants | 3 Participants | 0 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 3 | 1 / 2 | 0 / 1 | 0 / 4 | 0 / 1 | 0 / 1 | 0 / 16 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 2 / 2 | 1 / 1 | 4 / 4 | 1 / 1 | 1 / 1 | 16 / 16 |
| serious Total, serious adverse events | 1 / 3 | 2 / 3 | 1 / 2 | 0 / 1 | 1 / 4 | 0 / 1 | 0 / 1 | 6 / 16 |
Outcome results
Primary
Changes in MET and Phospho-MET Levels
MET or phospho-MET levels (in fmol) normalized to the amount of total protein in a sample (in mg).
Time frame: MET and phospho-MET levels were measured on Cycle 1 Day 1 and Cycle 1 Day 8.
Population: Biopsies were not collected for this assay from all participants, and not all biopsies yielded quantifiable data. While biopsies were collected from 8 patients at Dose Level 5, not every biopsy pair yielded a quantifiable signal in these assays. There were 5 pairs averaged for the intact MET and 2 pairs each for the pY1234/1235-MET and pY1356-MET. Unquantifiable biopsy pairs (either at one or both time points) were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Level (DL) 1: Pazopanib (Paz): 400 mg & ARQ 197: 120 mg | Changes in MET and Phospho-MET Levels | Intact MET | -52.66 fmol/mg | — |
| Dose Level (DL) 1: Pazopanib (Paz): 400 mg & ARQ 197: 120 mg | Changes in MET and Phospho-MET Levels | pY1234/1235-MET | NA fmol/mg | — |
| Dose Level (DL) 1: Pazopanib (Paz): 400 mg & ARQ 197: 120 mg | Changes in MET and Phospho-MET Levels | pY1356-MET | NA fmol/mg | — |
| Dose Level 5: Pazopanib: 800 mg & ARQ 197: 360 mg | Changes in MET and Phospho-MET Levels | Intact MET | -195.4 fmol/mg | Standard Deviation 218.9 |
| Dose Level 5: Pazopanib: 800 mg & ARQ 197: 360 mg | Changes in MET and Phospho-MET Levels | pY1234/1235-MET | -130.3 fmol/mg | Standard Deviation 40.2 |
| Dose Level 5: Pazopanib: 800 mg & ARQ 197: 360 mg | Changes in MET and Phospho-MET Levels | pY1356-MET | -51.5 fmol/mg | Standard Deviation 1.8 |
Primary
Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant
The highest Grade 3 or 4 adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe, and Grade 4 is life threatening.
Time frame: Time receiving study drug, up to 22 cycles
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Level (DL) 1: Pazopanib (Paz): 400 mg & ARQ 197: 120 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 4 | 0 Adverse events |
| Dose Level (DL) 1: Pazopanib (Paz): 400 mg & ARQ 197: 120 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 3 | 1 Adverse events |
| Dose Level 2: Pazopanib: 600 mg & ARQ 197: 120 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 4 | 0 Adverse events |
| Dose Level 2: Pazopanib: 600 mg & ARQ 197: 120 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 3 | 0 Adverse events |
| Dose Level 3: Pazopanib: 600 mg & ARQ 197: 240 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 3 | 0 Adverse events |
| Dose Level 3: Pazopanib: 600 mg & ARQ 197: 240 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 4 | 0 Adverse events |
| DL 3 Followed by DL 2: Pazopanib: 600 mg & ARQ 197: 240 mg Foll/by Pazopanib: 600 mg/ARQ 197:120 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 3 | 0 Adverse events |
| DL 3 Followed by DL 2: Pazopanib: 600 mg & ARQ 197: 240 mg Foll/by Pazopanib: 600 mg/ARQ 197:120 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 4 | 0 Adverse events |
| Dose Level 4: Pazopanib: 800 mg & ARQ 197: 240 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 3 | 3 Adverse events |
| Dose Level 4: Pazopanib: 800 mg & ARQ 197: 240 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 4 | 0 Adverse events |
| DL 4 Followed by DL 3: Pazopanib: 800 mg & ARQ 197: 240 mg Foll/by Pazopanib: 600 mg/ARQ 197: 240 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 4 | 0 Adverse events |
| DL 4 Followed by DL 3: Pazopanib: 800 mg & ARQ 197: 240 mg Foll/by Pazopanib: 600 mg/ARQ 197: 240 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 3 | 5 Adverse events |
| DL4 Foll/by DL3 Foll/by DL2 Paz800mg/ARQ240mg Foll/by Paz600 mg/ARQ240mg Foll/by Paz600 mg/ARQ120 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 3 | 1 Adverse events |
| DL4 Foll/by DL3 Foll/by DL2 Paz800mg/ARQ240mg Foll/by Paz600 mg/ARQ240mg Foll/by Paz600 mg/ARQ120 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 4 | 1 Adverse events |
| Dose Level 5: Pazopanib: 800 mg & ARQ 197: 360 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 3 | 7 Adverse events |
| Dose Level 5: Pazopanib: 800 mg & ARQ 197: 360 mg | Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant | Grade 4 | 10 Adverse events |
Other Pre-specified
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: Date treatment consent signed to date off study, approx 22m (month)/2 days(d); 13m/20 d; 5m/23 d; 17m./24 d; 7 m/5 d; 5m/5 d; 5m/13 d; and 23m/21d for DL1, DL2, DL3, DL3 foll/by DL2, DL4, DL4 foll/by DL3, DL 4 foll/by DL 3 foll/by DL2; & DL5 respectively.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level (DL) 1: Pazopanib (Paz): 400 mg & ARQ 197: 120 mg | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 3 Participants |
| Dose Level 2: Pazopanib: 600 mg & ARQ 197: 120 mg | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 3 Participants |
| Dose Level 3: Pazopanib: 600 mg & ARQ 197: 240 mg | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 2 Participants |
| DL 3 Followed by DL 2: Pazopanib: 600 mg & ARQ 197: 240 mg Foll/by Pazopanib: 600 mg/ARQ 197:120 mg | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 1 Participants |
| Dose Level 4: Pazopanib: 800 mg & ARQ 197: 240 mg | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 4 Participants |
| DL 4 Followed by DL 3: Pazopanib: 800 mg & ARQ 197: 240 mg Foll/by Pazopanib: 600 mg/ARQ 197: 240 mg | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 1 Participants |
| DL4 Foll/by DL3 Foll/by DL2 Paz800mg/ARQ240mg Foll/by Paz600 mg/ARQ240mg Foll/by Paz600 mg/ARQ120 mg | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 1 Participants |
| Dose Level 5: Pazopanib: 800 mg & ARQ 197: 360 mg | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 16 Participants |
Other Pre-specified
Pazopanib-induced Changes to Epithelial-mesenchymal Phenotype in Human Tumors
Core tumor biopsies were collected from participants with advanced malignancies. Analyses was performed by epithelial-mesenchymal transition immunofluorescence assay (EMT-IFA) for changes in E-cadherin (E+), vimentin(V+), and mixed V+E+ phenotypes. The small imaging pixel size (0.25 µm\^2)of the IFA relative to the dimensions of the cross sectional areas of tumor (ranging from 75 to 500 µm\^2 in parotid, prostate, colon, and ovarian cancers) allowed us to quantify individual areas of V+ and E+ staining as well as areas of colocalized E+V+ staining within single cells. The assay reports the change in log10(V/E) vratios. The log10(V/E) ratio was determined pre-treatment and in day 8 biopsies and the reported values indicate the change between the two time points. Each value in the table as currently written reflects the change in log10(V/E) ratios between pre- and post-treatment E-cadherin and vimentin values. The full range values indicate the range of changes observed for individual pt.
Time frame: Pre-treatment and day 8 post administration
Population: This analysis was only performed on biopsy pairs from participants at Dose Level 5, so no biopsy pairs were collected at other Dose Levels (which is why the other levels indicate 0 participants analyzed) and analysis of the changes at those Dose Levels was not applicable (N/A) since no samples were collected.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Level 5: Pazopanib: 800 mg & ARQ 197: 360 mg | Pazopanib-induced Changes to Epithelial-mesenchymal Phenotype in Human Tumors | 0.332 Change in log10(V/E) Ratios |