Tivozanib in Treating Patients With Liver Cancer That Is Metastatic or Cannot Be Removed by Surgery
Primary Purpose
Advanced Adult Hepatocellular Carcinoma, Non-Resectable Hepatocellular Carcinoma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Tivozanib (1mg)
Tivozanib (1.5mg)
Sponsored by

About this trial
This is an interventional treatment trial for Advanced Adult Hepatocellular Carcinoma
Eligibility Criteria
Inclusion Criteria:
Advanced staged HCC (unresectable and not amenable to local or regional therapy; or metastatic HCC); the diagnosis of HCC should be based on at least one of the following:
- Magnetic resonance imaging (MRI) or computed tomography (CT) consistent with liver cirrhosis AND at least one solid liver lesion measuring >= 2 cm, with characteristics arterial enhancement and venous washout regardless of alpha-fetoprotein (AFP) levels
- AFP >= 400 ng/mL AND evidence of at least one solid liver lesion >= 2 cm regardless of specific imaging characteristics on CT or MRI
- Histological/cytology biopsy confirming HCC
- Patients must have measurable disease per RECIST 1.1 criteria defined as at least one lesion that can be accurately measured in at least one dimension, and that has not been the target of local or regional therapy including transarterial chemoembolization, intra-arterial chemotherapy, ethanol or radiofrequency ablation
- Life expectancy of greater than 3 months
- Child-Pugh liver function class A
- Aspartate aminotransferase (AST) =< 5 x institutional upper limits of normal (ULN)
- Total bilirubin =< 3 mg/dL
- International normalized ratio (INR) =< 2.0 (unless due to therapeutic warfarin use)
- Serum albumin > 2.8 g/dL
- Creatinine =< 1.5 x institutional ULN
- Absolute neutrophil count (ANC) >= 1200/mm^3
- Platelets >= 60,000/mm^3
- Hemoglobin (Hgb) >= 8.5 g/dL
- Patients must not have any evidence of bleeding diathesis or active gastrointestinal bleeding
- Patients must not be known to be human immunodeficiency virus (HIV) positive
- Patients must not have other uncontrolled intercurrent illnesses (excluding HBV or HCV); this includes (but is not limited to) ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Sexually active fertile patients (male and female), and their partners, must agree to use medically accepted methods of contraception during the course of the study and for 3 months after the last dose of the study drug
- Female patients of childbearing potential must have a negative pregnancy test at screening
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
- Subject or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
Exclusion Criteria:
- Patients who have had prior anti-angiogenic therapy, including but not limited to sorafenib, brivanib, bevacizumab, or sunitinib
- Patients who have had any prior line of systemic therapy including cytotoxic agents or molecularly targeted agents for advanced/unresectable disease; any number of prior regional therapies with transarterial chemoembolization (TACE), brachytherapy with yttrium-90 microsphere, intra-arterial chemotherapy, surgery, or ablative therapy are allowed
- Prior liver transplantation and on immunosuppression
- Known symptomatic or uncontrolled brain metastases or epidural disease
- Patient has a corrected QT interval (QTcF) > 500 ms at screening
- The patient is unable to swallow pills or diagnosed with a gastrointestinal disorder that are likely to interfere with the absorption of the study drug or with the patient's ability to take regular oral medication
- The patient is pregnant or breastfeeding
- Patients with second primary cancer (except adequately treated nonmelanoma skin cancer, curatively treated in-situ carcinoma of the cervix or superficial bladder cancer, or other solid tumors including lymphoma without bone marrow involvement curatively treated with no evidence of disease for >= 5 years)
- The patient has a previously-identified allergy or hypersensitivity to components of the study treatment formulation
- Patients receiving any medications or substances that are strong inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; moderate inducers of CYP3A4 should be used with caution
- Urine protein: creatinine ratio > 1
Sites / Locations
- Roswell Park Cancer Institute
- Case Western Reserve University
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Treatment (tivozanib - 1 mg)
Treatment (tivozanib - 1.5 mg)
Arm Description
Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Outcomes
Primary Outcome Measures
PFS, Assessed Using Standard RECIST Criteria
Will be descriptively analyzed using standard Kaplan-Meier estimation along with the corresponding descriptive statistics and 95% confidence intervals.
Secondary Outcome Measures
Clinical Benefit Rate (CR, PR, and SD) by RECIST
The number of patients achieving clinical benefit (CR, PR, or SD by RECIST).
Incidence of Adverse Events and Toxicities, Assessed Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4
Toxicity frequency will be tabulated by grade across all dose levels and cycles for all patients in the safety sample and for the subset treated at the recommended phase 2 dose.
Overall Survival Rate
Overall survival is defined as the time from treatment until death or last follow-up.
Full Information
NCT ID
NCT01835223
First Posted
April 15, 2013
Last Updated
October 6, 2020
Sponsor
Roswell Park Cancer Institute
Collaborators
National Comprehensive Cancer Network, AVEO Pharmaceuticals, Inc., National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT01835223
Brief Title
Tivozanib in Treating Patients With Liver Cancer That Is Metastatic or Cannot Be Removed by Surgery
Official Title
Multicenter Phase 1b/2 Study of Tivozanib in Patients With Advanced Inoperable Hepatocellular Carcinoma
Study Type
Interventional
2. Study Status
Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
July 11, 2013 (Actual)
Primary Completion Date
December 24, 2018 (Actual)
Study Completion Date
November 8, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Roswell Park Cancer Institute
Collaborators
National Comprehensive Cancer Network, AVEO Pharmaceuticals, Inc., National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase I/II trial studies the side effects and best dose of tivozanib and to see how well it works in treating patients with liver cancer that has spread to other parts of the body or cannot be removed by surgery. Tivozanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES:
I. Progression free survival (PFS) at 24 weeks in patients with advanced hepatocellular carcinoma (HCC).
SECONDARY OBJECTIVES:
I. To determine the safety of tivozanib in HCC. II. To determine the overall survival (OS) and clinical benefit rate (complete response [CR], partial response [PR] and stable disease [SD]) by Response Evaluation Criteria in Solid Tumors (RECIST).
III. To determine the steady state pharmacokinetics (PK) and soluble vascular endothelial growth factor receptor 2 (VEGFR-2) baseline/change with tivozanib and use modeling to correlate exposure with biomarker change and the primary outcome measure of PFS.
IV. To determine the change in viral load (hepatitis B virus [HBV] and hepatitis C virus [HCV]) during therapy in patients with HBV or HCV associated HCC.
V. To determine the change in tumor marker (alfa fetoprotein) with tivozanib therapy is in the effect of tivozanib on several tumor-associated immune response markers.
OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.
Patients receive tivozanib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Adult Hepatocellular Carcinoma, Non-Resectable Hepatocellular Carcinoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
33 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment (tivozanib - 1 mg)
Arm Type
Experimental
Arm Description
Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm Title
Treatment (tivozanib - 1.5 mg)
Arm Type
Experimental
Arm Description
Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Tivozanib (1mg)
Other Intervention Name(s)
AV-951, TIVOZANIB
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Tivozanib (1.5mg)
Other Intervention Name(s)
AV-951, TIVOZANIB
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
PFS, Assessed Using Standard RECIST Criteria
Description
Will be descriptively analyzed using standard Kaplan-Meier estimation along with the corresponding descriptive statistics and 95% confidence intervals.
Time Frame
24 weeks
Secondary Outcome Measure Information:
Title
Clinical Benefit Rate (CR, PR, and SD) by RECIST
Description
The number of patients achieving clinical benefit (CR, PR, or SD by RECIST).
Time Frame
Up to 3 years
Title
Incidence of Adverse Events and Toxicities, Assessed Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4
Description
Toxicity frequency will be tabulated by grade across all dose levels and cycles for all patients in the safety sample and for the subset treated at the recommended phase 2 dose.
Time Frame
Up to 3 years
Title
Overall Survival Rate
Description
Overall survival is defined as the time from treatment until death or last follow-up.
Time Frame
Up to 3 years
Other Pre-specified Outcome Measures:
Title
AFP Response
Description
Defined as an AFP decrease greater than 50%.
Time Frame
Up to 3 years
Title
Antiviral Effects (if Any in Those With HBV or HCV Associated HCC)
Time Frame
Up to 3 years
Title
Drug Exposure, as Assessed by Steady State PK
Description
Associations between drug exposure and response/survival and toxicity by quartiles of drug exposure.
Time Frame
Up to 3 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Advanced staged HCC (unresectable and not amenable to local or regional therapy; or metastatic HCC); the diagnosis of HCC should be based on at least one of the following:
Magnetic resonance imaging (MRI) or computed tomography (CT) consistent with liver cirrhosis AND at least one solid liver lesion measuring >= 2 cm, with characteristics arterial enhancement and venous washout regardless of alpha-fetoprotein (AFP) levels
AFP >= 400 ng/mL AND evidence of at least one solid liver lesion >= 2 cm regardless of specific imaging characteristics on CT or MRI
Histological/cytology biopsy confirming HCC
Patients must have measurable disease per RECIST 1.1 criteria defined as at least one lesion that can be accurately measured in at least one dimension, and that has not been the target of local or regional therapy including transarterial chemoembolization, intra-arterial chemotherapy, ethanol or radiofrequency ablation
Life expectancy of greater than 3 months
Child-Pugh liver function class A
Aspartate aminotransferase (AST) =< 5 x institutional upper limits of normal (ULN)
Total bilirubin =< 3 mg/dL
International normalized ratio (INR) =< 2.0 (unless due to therapeutic warfarin use)
Serum albumin > 2.8 g/dL
Creatinine =< 1.5 x institutional ULN
Absolute neutrophil count (ANC) >= 1200/mm^3
Platelets >= 60,000/mm^3
Hemoglobin (Hgb) >= 8.5 g/dL
Patients must not have any evidence of bleeding diathesis or active gastrointestinal bleeding
Patients must not be known to be human immunodeficiency virus (HIV) positive
Patients must not have other uncontrolled intercurrent illnesses (excluding HBV or HCV); this includes (but is not limited to) ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Sexually active fertile patients (male and female), and their partners, must agree to use medically accepted methods of contraception during the course of the study and for 3 months after the last dose of the study drug
Female patients of childbearing potential must have a negative pregnancy test at screening
Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
Subject or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
Exclusion Criteria:
Patients who have had prior anti-angiogenic therapy, including but not limited to sorafenib, brivanib, bevacizumab, or sunitinib
Patients who have had any prior line of systemic therapy including cytotoxic agents or molecularly targeted agents for advanced/unresectable disease; any number of prior regional therapies with transarterial chemoembolization (TACE), brachytherapy with yttrium-90 microsphere, intra-arterial chemotherapy, surgery, or ablative therapy are allowed
Prior liver transplantation and on immunosuppression
Known symptomatic or uncontrolled brain metastases or epidural disease
Patient has a corrected QT interval (QTcF) > 500 ms at screening
The patient is unable to swallow pills or diagnosed with a gastrointestinal disorder that are likely to interfere with the absorption of the study drug or with the patient's ability to take regular oral medication
The patient is pregnant or breastfeeding
Patients with second primary cancer (except adequately treated nonmelanoma skin cancer, curatively treated in-situ carcinoma of the cervix or superficial bladder cancer, or other solid tumors including lymphoma without bone marrow involvement curatively treated with no evidence of disease for >= 5 years)
The patient has a previously-identified allergy or hypersensitivity to components of the study treatment formulation
Patients receiving any medications or substances that are strong inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; moderate inducers of CYP3A4 should be used with caution
Urine protein: creatinine ratio > 1
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Renuka Iyer
Organizational Affiliation
Roswell Park Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Case Western Reserve University
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
34071188
Citation
Kalathil SG, Thanavala Y. Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches. Cells. 2021 May 28;10(6):1332. doi: 10.3390/cells10061332.
Results Reference
derived
PubMed Identifier
33445053
Citation
Kalathil SG, Thanavala Y. Importance of myeloid derived suppressor cells in cancer from a biomarker perspective. Cell Immunol. 2021 Mar;361:104280. doi: 10.1016/j.cellimm.2020.104280. Epub 2020 Dec 31.
Results Reference
derived
PubMed Identifier
33101775
Citation
Kalathil SG, Wang K, Hutson A, Iyer R, Thanavala Y. Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients. Oncoimmunology. 2020 Sep 30;9(1):1824863. doi: 10.1080/2162402X.2020.1824863.
Results Reference
derived
PubMed Identifier
32037403
Citation
Fountzilas C, Gupta M, Lee S, Krishnamurthi S, Estfan B, Wang K, Attwood K, Wilton J, Bies R, Bshara W, Iyer R. A multicentre phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma. Br J Cancer. 2020 Mar;122(7):963-970. doi: 10.1038/s41416-020-0737-6. Epub 2020 Feb 10.
Results Reference
derived
Learn more about this trial
Tivozanib in Treating Patients With Liver Cancer That Is Metastatic or Cannot Be Removed by Surgery
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