Pazopanib and ARQ 197 for Advanced Solid Tumors
Condition: Solid Tumor
MeSH terms: Neoplasms
Intervention: Pazopanib; ARQ 197
Intervention description: Vascular endothelial growth factor (VEGFR) inhibitor; Hepatocyte growth factor receptor (mesenchymal-epithelial transition factor [c-MET]) inhibitor
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Maximum age: 120 Years
Healthy volunteers: No
Keywords: Pazopanib; Tivantinib; MET Inhibitor; Advanced Cancer; Anti-Angiogenesis; Cancer; Solid Tumor; Sarcoma

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.
    

Eligibility 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.