Clinical trial NCT01835223: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Adult Hepatocellular Carcinoma
Non-Resectable Hepatocellular Carcinoma
Lead sponsor: Roswell Park Cancer Institute
Sponsor class: OTHER
Collaborators: name: National Comprehensive Cancer Network
name: AVEO Pharmaceuticals, Inc.
name: National Cancer Institute (NCI)
First posted: 2013-04-18
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: PFS, Assessed Using Standard RECIST Criteria
timeFrame: 24 weeks
Secondary outcomes:
measure: Clinical Benefit Rate (CR, PR, and SD) by RECIST
timeFrame: Up to 3 years
measure: Incidence of Adverse Events and Toxicities, Assessed Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4
timeFrame: Up to 3 years
measure: Overall Survival Rate
timeFrame: Up to 3 years
Other outcomes:
measure: AFP Response
timeFrame: Up to 3 years
measure: Antiviral Effects (if Any in Those With HBV or HCV Associated HCC)
timeFrame: Up to 3 years
measure: Drug Exposure, as Assessed by Steady State PK
timeFrame: Up to 3 years
Locations:
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
Study officials:
affiliation: Roswell Park Cancer Institute
name: Renuka Iyer
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.