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Phase I Study of Tivantinib Plus Bevacizumab

Phase 1
18 Years
Open (Enrolling)
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I Study of Tivantinib Plus Bevacizumab


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


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 2C19 (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

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)

- 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 hr

- The effects of tivantinib on the developing human fetus are unknown; for this reason
and because tyrosine kinase inhibitors as well as other therapeutic agents used in
this trial are known to be teratogenic, 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 not recovered from adverse events due to agents administered
more than 4 weeks earlier

- Major hemorrhagic or thrombotic event within 6 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 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

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

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

- 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 because tivantinib is a tyrosine kinase
inhibitor with the potential for teratogenic or abortifacient effects; because there
is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with tivantinib, breastfeeding should be discontinued if the
mother is treated with tivantinib; these potential risks may also apply to

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
tivantinib; in addition, these patients are at increased risk of lethal infections
when treated with marrow-suppressive therapy; appropriate studies will be undertaken
in patients receiving combination antiretroviral therapy when indicated

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase II recommended dose (RP2D) of the combination of tivantinib and bevacizumab, defined as the dose level at which the DLT rate is closest to 1/6 graded according to the National Cancer Institute (NCI) CTCAE v4.0

Outcome Time Frame:

Up to 28 days

Safety Issue:


Principal Investigator

Leonard Appleman

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Pittsburgh


United States: Food and Drug Administration

Study ID:




Start Date:

December 2012

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific



University of PittsburghPittsburgh, Pennsylvania  15261