Tivantinib and Bevacizumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
Tivantinib and Bevacizumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
This phase I trial studies the side effects of and best dose of tivantinib when given
 together with bevacizumab in treating patients with solid tumors that have spread to other
 areas of the body or cannot be removed by surgery. Tivantinib may stop the growth of tumor
 cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as
 bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab
 may also stop the growth of cancer by blocking blood flow to the tumor. Giving tivantinib
 together with bevacizumab may work better in treating tumor cells.
PRIMARY OBJECTIVES:

 I. Determine the recommended phase II dose (RP2D) of the vascular endothelial growth factor
 (VEGF) monoclonal antibody, bevacizumab in combination with the allosteric met proto-oncogene
 (MET) inhibitor, tivantinib, in patients with advanced solid tumors.

 SECONDARY OBJECTIVES:

 I. Describe the dose-limiting toxicity (DLT) and other toxicities associated with bevacizumab
 in combination with tivantinib as assessed by Common Terminology Criteria for Adverse Events
 (CTCAE) version (v) 4.0.

 II. Document anti-tumor activity of bevacizumab in combination with tivantinib in patients
 with advanced solid tumors.

 III. Determine the pharmacokinetics of tivantinib when administered in combination with
 bevacizumab in patients with advanced solid tumors.

 IV. Perform cytochrome P450 family 2, subfamily C, polypeptide 19 (CYP2C19) genotyping on all
 subjects and correlate with pharmacokinetics and toxicity.

 V. Assess the effect of bevacizumab plus tivantinib on plasma components of the
 hepatocellular growth factor (HGF)-MET signaling pathway (HGF, HGF activator [HGFA]) and VEGF
 signaling pathway (VEGF A, B, C, D and placental growth factor [PIGF]).

 VI. Assess tissue (tumor and skin) protein biomarkers before and after study treatment
 including MET, phospho-MET^tyrosine (Tyr)1349 and phosphor-focal adhesion kinase
 (FAK)^Tyr861.

 VII. Assess early therapy response by quantitative biomarker imaging fludeoxyglucose F 18
 (F-18 FDG) positron emission tomography (PET) and magnetic imaging resonance (MRI) on a
 smaller sample (n up to 15) of subjects willing to participate in the imaging assessment
 through UPCI 12-096.

 OUTLINE: This is a dose-escalation study of tivantinib.

 Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days -15, 1, and 15
 (day -15 of course 1 only) and tivantinib orally (PO) twice daily (BID) on days 1-28. Courses
 repeat every 28 days in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up for 4 weeks.
Inclusion Criteria:

 -  Patients must have histologically confirmed solid tumor malignancy (excluding squamous
 cell carcinoma of lung) that is metastatic or unresectable and for which standard
 curative or palliative measures do not exist or are no longer effective

 -  Patients must have measurable or evaluable disease by Response Evaluation Criteria in
 Solid Tumors (RECIST) (version 1.1)

 -  Current diagnosis of type II diabetes mellitus is eligible as long as patient glucose
 levels are well-controlled (fasting =< 150 mg/dL) with anti-diabetic medication

 -  Patients must be able to swallow pills and no significant impairment in
 gastrointestinal absorption

 -  There are no restrictions on prior therapy:

 -  Prior bevacizumab is allowed

 -  Prior therapy with inhibitors of MET or HGF is allowed

 -  Eastern Cooperative Oncology Group (ECOG) performance status must be =< 2 (Karnofsky
 >= 60%)

 -  Life expectancy must be greater than 3 months

 -  Hemoglobin >= 9.0 g/dL

 -  Leukocytes >= 3,000/mcL

 -  Absolute neutrophil count >= 1,500/mcL

 -  Platelets >= 100,000/mcL

 -  Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
 alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
 institutional ULN

 -  Serum or plasma creatinine =< 1.5 X institutional ULN OR creatinine clearance >= 60
 mL/min for patients with creatinine levels > 1.5 X institutional ULN

 -  Urine protein =< +1 on spot urinalysis/urine dipstick; if urine dipstick > +1, a
 24-hour urine for protein must be =< 1 G/24 hour (hr)

 -  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 and for
 the duration of study participation; 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; men treated or enrolled on this protocol must also
 agree to use adequate contraception prior to the study, for the duration of study
 participation, and 4 months after completion of tivantinib administration

 -  Negative urine or serum pregnancy test within 7 days of start of protocol therapy (for
 female patients who have not undergone bilateral oophorectomy or hysterectomy)

 -  Patients must have the ability to understand and the willingness to sign a written
 informed consent document

 -  Patients must have available archival tumor tissue (formalin-fixed, paraffin-embedded)
 for submission of blocks or unstained slides

 Exclusion Criteria:

 -  Patients who have had chemotherapy, monoclonal antibody therapy or radiotherapy within
 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to start of study drugs or
 those who have adverse events not resolved to a grade 1 or neuropathy not resolved to
 =< grade 2 due to agents administered more than 4 weeks earlier

 -  Major hemorrhagic or thrombotic event within 3 months of start of protocol therapy

 -  Major surgery within 6 weeks or non-healing wounds

 -  Patients who have received kinase inhibitor therapy within 2 weeks of start of
 protocol therapy

 -  Patients who are receiving any other investigational agents

 -  Known central nervous system (CNS) disease except for treated brain metastasis;
 treated brain metastases are defined as having no ongoing requirement for steroids and
 no evidence of progression or hemorrhage after treatment for at least 3 months, as
 ascertained by clinical examination and brain imaging (magnetic resonance imaging
 [MRI] or computed tomography [CT]); (stable dose of non-enzyme-inducing
 anticonvulsants are allowed); treatment for brain metastases may include whole brain
 radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or
 equivalent) or a combination as deemed appropriate by the treating physician; patients
 with CNS metastases treated by neurosurgical resection or brain biopsy performed
 within 3 months prior to day 1 will be excluded

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to tivantinib or bevacizumab, or to Chinese hamster ovary cells

 -  Tivantinib is metabolized by CYP2C19, and to a lesser extent cytochrome P450, family
 3, subfamily A, polypeptide 4 (CYP3A4); the metabolism and consequently overall
 pharmacokinetics of tivantinib could be altered by inhibitors and/or inducers or other
 substrates of CYP2C19 and CYP3A4; while inhibitors/inducers of these cytochrome P450
 isoenzymes are not specifically excluded, investigators should be aware that
 tivantinib exposure may be altered by the concomitant administration of these drugs;
 as part of the enrollment/informed consent procedures, the patient will be counseled
 on the risk of interactions with other agents, and what to do if new medications need
 to be prescribed or if the patient is considering a new over-the-counter medicine or
 herbal product

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Patients with clinically significant cardiovascular disease, including any of the
 following, are excluded:

 -  Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] > 160
 mmHg and/or diastolic blood pressure [DBP] > 90 mmHg despite antihypertensive
 medication)

 -  History of cerebrovascular accident (CVA) within 6 months of start of protocol
 therapy

 -  Myocardial infarction or unstable angina within 6 months of start of protocol
 therapy

 -  New York Heart Association grade II or greater congestive heart failure

 -  Serious and inadequately controlled cardiac arrhythmia

 -  Significant vascular disease (e.g. significant aortic aneurysm, history of aortic
 dissection)

 -  Clinically significant peripheral vascular disease

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

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

 -  Pregnant women are excluded from this study, and breastfeeding should be discontinued
 if the mother is treated with tivantinib; these potential risks may also apply to
 bevacizumab

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy are ineligible