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Solid NeoplasmPhase 1NCT01749384

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

A Phase 1 study testing Bevacizumab, Laboratory Biomarker Analysis and Pharmacological Study in people with Solid Neoplasm, run by National Cancer Institute (NCI) at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Solid Neoplasm
What is being tested?
Bevacizumab, Laboratory Biomarker Analysis and Pharmacological Study
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
2 sitesUnited States
Study dates
6 Dec 2012to 24 May 2016
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Penn State Milton S Hershey Medical Center

    Hershey, Pennsylvania, 17033-0850

  • University of Pittsburgh Cancer Institute (UPCI)

    Pittsburgh, Pennsylvania, 15232

Other trials in United States

About this study

Official title: Phase I Study of Tivantinib Plus Bevacizumab

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

  1. 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.

Conditions
Solid Neoplasm
Being tested
Bevacizumab, Laboratory Biomarker Analysis, Pharmacological Study, Tivantinib

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BevacizumabBiological

    Also called Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Pharmacological StudyOther

    Correlative studies

  • TivantinibDrug

    Also called ARQ 197, ARQ-197, c-Met Inhibitor ARQ 197

    Given PO

Study groups in NCT01749384
Study groupRoleWhat they receive
Treatment (bevacizumab, tivantinib)ExperimentalPatients 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.
Receives: Biological: Bevacizumab; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Tivantinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: Up to 28 days

Secondary outcomes (5)

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

    Plasma before and after the treatment will be measured and compared by Wilcoxon signed rank test.

    Measured: Baseline to up to day 15 of course 1

  2. Change in MET, FAK, AKT, STAT3 in skin tissue by immunohistochemistry

    Skin biomarkers before and after the treatment will be measured and compared by Wilcoxon signed rank test.

    Measured: Baseline to up to day 15 of course 1

  3. Clinical response rate as evaluated by RECIST

    The clinical response rate will be calculated and corresponding 95% exact confidence interval will be provided. The percent changes in tumor sized from the baseline will be presented by the waterfall plot.

    Measured: Up to 4 weeks after completion of study treatment

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

    The maximum grade of toxicity for each category of interest will be recorded for each patient and the summary results will be tabulated by category and grade. All DLTs and other serious (grade 3 or greater) toxicity events on a patient-by-patient basis will be described; descriptions will include dose level and any relevant baseline data. Statistics on the number of cycles received by patients and any dose reductions will be tabulated. Toxicity profile for CYP2C19 mutant carriers will be summarized and compared to non-carriers by exact tests when sample size permits.

    Measured: Up to 4 weeks after completion of study treatment

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

    PK outcomes for CYP2C19 mutant carriers will be summarized and compared to non-carriers by exact tests when sample size permits.

    Measured: At days 1, 2, and 15 of course 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Dec 2012 (estimated)
  2. Study start6 Dec 2012
  3. Primary completion24 May 2016
  4. Study completion24 May 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01749384
Sponsor's protocol ID
NCI-2012-02765
Other IDs
NCI-2012-02765, UPCI 12-085, UPCI# 12-085, 9153, 9153, P30CA047904, U01CA099168, UM1CA186690
Status last verified
Oct 2017
First submitted
11 Dec 2012
Last updated
12 Oct 2017
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 34164713

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Bevacizumab, Laboratory Biomarker Analysis and Pharmacological Study in people with Solid Neoplasm, run by National Cancer Institute (NCI) at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: Up to 28 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01749384, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Oct 2017.

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