Tivozanib in Treating Patients With Liver Cancer That Is Metastatic or Cannot Be Removed by Surgery

Multicenter Phase 1b/2 Study of Tivozanib in Patients With Advanced Inoperable Hepatocellular Carcinoma

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.

Study Overview

• Status: Completed
• Conditions: Advanced Adult Hepatocellular Carcinoma; Non-Resectable Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Tivozanib (1mg); Drug: Tivozanib (1.5mg)

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.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (tivozanib - 1 mg); Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Tivozanib (1mg); Given PO; Other Names: AV-951; TIVOZANIB
Experimental: Treatment (tivozanib - 1.5 mg); Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Tivozanib (1.5mg); Given PO; Other Names: AV-951; TIVOZANIB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Benefit Rate (CR, PR, and SD) by RECIST	The number of patients achieving clinical benefit (CR, PR, or SD by RECIST).	Up to 3 years
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.	Up to 3 years
Overall Survival Rate	Overall survival is defined as the time from treatment until death or last follow-up.	Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
AFP Response	Defined as an AFP decrease greater than 50%.	Up to 3 years
Antiviral Effects (if Any in Those With HBV or HCV Associated HCC)		Up to 3 years
Drug Exposure, as Assessed by Steady State PK	Associations between drug exposure and response/survival and toxicity by quartiles of drug exposure.	Up to 3 years

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Collaborators: National Cancer Institute (NCI); National Comprehensive Cancer Network; AVEO Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 11, 2013
• Primary Completion (Actual): December 24, 2018
• Study Completion (Actual): November 8, 2019

Study Registration Dates

• First Submitted: April 15, 2013
• First Submitted That Met QC Criteria: April 15, 2013
• First Posted (Estimate): April 18, 2013

Study Record Updates

• Last Update Posted (Actual): October 28, 2020
• Last Update Submitted That Met QC Criteria: October 6, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: I 229112 (Other Identifier: Roswell Park Cancer Institute); P30CA016056 (U.S. NIH Grant/Contract); NCI-2013-00756 (Registry Identifier: CTRP (Clinical Trial Reporting Program))