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Advanced Adult Hepatocellular CarcinomaPhase 1/2NCT01835223

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

A Phase 1/2 study testing Tivozanib (1mg) and Tivozanib (1.5mg) in people with Advanced Adult Hepatocellular Carcinoma and Non-Resectable Hepatocellular Carcinoma, run by Roswell Park Cancer Institute 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/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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Tivozanib (1mg) and Tivozanib (1.5mg)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
33 participants
Where
2 sitesUnited States
Study dates
11 Jul 2013to 8 Nov 2019
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Roswell Park Cancer Institute

    Buffalo, New York, 14263

  • Case Western Reserve University

    Cleveland, Ohio, 44106

Other trials in United States

About this study

Official title: 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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. Progression free survival (PFS) at 24 weeks in patients with advanced hepatocellular carcinoma (HCC).

SECONDARY OBJECTIVES:

  1. 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.

  1. 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.

Being tested
Tivozanib (1mg), Tivozanib (1.5mg)

What participants receive

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

  • Tivozanib (1mg)Drug

    Also called AV-951, TIVOZANIB

    Given PO

  • Tivozanib (1.5mg)Drug

    Also called AV-951, TIVOZANIB

    Given PO

Study groups in NCT01835223
Study groupRoleWhat they receive
Treatment (tivozanib - 1 mg)ExperimentalPatients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Tivozanib (1mg)
Treatment (tivozanib - 1.5 mg)ExperimentalPatients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Tivozanib (1.5mg)

What is being measured

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

  1. 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.

    Measured: 24 weeks

Secondary outcomes (3)

  1. Clinical Benefit Rate (CR, PR, and SD) by RECIST

    The number of patients achieving clinical benefit (CR, PR, or SD by RECIST).

    Measured: Up to 3 years

  2. 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.

    Measured: Up to 3 years

  3. Overall Survival Rate

    Overall survival is defined as the time from treatment until death or last follow-up.

    Measured: Up to 3 years

Timeline

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

  1. First posted18 Apr 2013 (estimated)
  2. Study start11 Jul 2013
  3. Primary completion24 Dec 2018
  4. Study completion8 Nov 2019

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 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
33 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01835223
Sponsor's protocol ID
I 229112
Other IDs
NCI-2013-00756, I 229112, P30CA016056
Status last verified
Oct 2020
First submitted
15 Apr 2013
Last updated
28 Oct 2020
Data monitoring committee
Yes

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.

    PubMed 34071188

  • 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.

    PubMed 33445053

  • 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.

    PubMed 33101775

  • 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.

    PubMed 32037403

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Tivozanib (1mg) and Tivozanib (1.5mg) in people with Advanced Adult Hepatocellular Carcinoma and Non-Resectable Hepatocellular Carcinoma, run by Roswell Park Cancer Institute 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 22 inclusion and 11 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 28 Oct 2020. 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 combined 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.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

PFS, Assessed Using Standard RECIST Criteria (time frame: 24 weeks). 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 NCT01835223, which also lists 4 linked publications.

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 28 Oct 2020.

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