Tivantinib and Bevacizumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

NCT01749384 | Completed Phase 1

• 7 other identifiers: NCI-2012-02765UPCI 12-085UPCI# 12-0859153P30CA047904U01CA099168UM1CA186690
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Solid Neoplasm

Outcome Measures

Primary Outcomes (1)

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

  Up to 28 days

Secondary Outcomes (5)

• Change in HGF, HGFA, VEGF, and PIGF in plasma by enzyme-linked immunosorbent assay

  Baseline to up to day 15 of course 1

• Change in MET, FAK, AKT, STAT3 in skin tissue by immunohistochemistry

  Baseline to up to day 15 of course 1

• Clinical response rate as evaluated by RECIST

  Up to 4 weeks after completion of study treatment

• Incidence of adverse events graded according to NCI CTCAE v4.0 that are possibly, probably, or definitely related to treatment

  Up to 4 weeks after completion of study treatment

• Pharmacokinetics (PK) of tivantinib when administered in combination with bevacizumab

  At days 1, 2, and 15 of course 1

Study Arms (1)

Treatment (bevacizumab, tivantinib)

EXPERIMENTAL

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

Biological: Bevacizumab; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Tivantinib

Interventions

Bevacizumab BIOLOGICAL

Given IV

Also known as: Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar FKB238, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF

Treatment (bevacizumab, tivantinib)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (bevacizumab, tivantinib)

Pharmacological Study OTHER

Correlative studies

Treatment (bevacizumab, tivantinib)

Tivantinib DRUG

Given PO

Also known as: ARQ 197, ARQ-197, c-Met Inhibitor ARQ 197

Treatment (bevacizumab, tivantinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

Penn State Milton S Hershey Medical Center

Hershey, Pennsylvania, 17033-0850, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

Related Publications (1)

• Maguire WF, Schmitz JC, Scemama J, Czambel K, Lin Y, Green AG, Wu S, Lin H, Puhalla S, Rhee J, Stoller R, Tawbi H, Lee JJ, Wright JJ, Beumer JH, Chu E, Appleman LJ; ETCTN-9153 Study Team. Phase 1 study of safety, pharmacokinetics, and pharmacodynamics of tivantinib in combination with bevacizumab in adult patients with advanced solid tumors. Cancer Chemother Pharmacol. 2021 Oct;88(4):643-654. doi: 10.1007/s00280-021-04317-y. Epub 2021 Jun 23.

  PMID: 34164713 DERIVED

MeSH Terms

Interventions

Bevacizumab; Immunoglobulin G; Disulfides; ARQ 197

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunoglobulin Isotypes; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals

Study Officials

• Leonard Appleman

  University of Pittsburgh Cancer Institute (UPCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 11, 2012
• First Posted: December 13, 2012
• Study Start: December 6, 2012
• Primary Completion: May 24, 2016
• Study Completion: May 24, 2016
• Last Updated: October 12, 2017

Record last verified: 2017-10

Locations

US (2)