Tivantinib and Bevacizumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
|ClinicalTrials.gov Identifier: NCT01749384|
Recruitment Status : Completed
First Posted : December 13, 2012
Last Update Posted : October 12, 2017
|Condition or disease||Intervention/treatment||Phase|
|Solid Neoplasm||Biological: Bevacizumab Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Tivantinib||Phase 1|
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.
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Study of Tivantinib Plus Bevacizumab|
|Actual Study Start Date :||December 6, 2012|
|Actual Primary Completion Date :||May 24, 2016|
|Actual Study Completion Date :||May 24, 2016|
Experimental: Treatment (bevacizumab, tivantinib)
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.
Other Names:Other: Laboratory Biomarker Analysis
Correlative studiesOther: Pharmacological Study
Correlative studiesDrug: Tivantinib
- 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 ]
- Change in HGF, HGFA, VEGF, and PIGF in plasma by enzyme-linked immunosorbent assay [ Time Frame: Baseline to up to day 15 of course 1 ]Plasma before and after the treatment will be measured and compared by Wilcoxon signed rank test.
- Change in MET, FAK, AKT, STAT3 in skin tissue by immunohistochemistry [ Time Frame: Baseline to up to day 15 of course 1 ]Skin biomarkers before and after the treatment will be measured and compared by Wilcoxon signed rank test.
- Clinical response rate as evaluated by RECIST [ Time Frame: Up to 4 weeks after completion of study treatment ]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.
- Incidence of adverse events graded according to NCI CTCAE v4.0 that are possibly, probably, or definitely related to treatment [ Time Frame: Up to 4 weeks after completion of study 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.
- Pharmacokinetics (PK) of tivantinib when administered in combination with bevacizumab [ Time Frame: At days 1, 2, and 15 of course 1 ]PK outcomes for CYP2C19 mutant carriers will be summarized and compared to non-carriers by exact tests when sample size permits.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01749384
|United States, Pennsylvania|
|Penn State Milton S Hershey Medical Center|
|Hershey, Pennsylvania, United States, 17033-0850|
|University of Pittsburgh Cancer Institute (UPCI)|
|Pittsburgh, Pennsylvania, United States, 15232|
|Principal Investigator:||Leonard Appleman||University of Pittsburgh Cancer Institute (UPCI)|