|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|Hepatocellular carcinoma (HCC)
|E.1.1.1||Medical condition in easily understood language ||
|E.1.1.2||Therapeutic area ||Diseases [C] - Cancer [C04]
|E.1.2 Medical condition or disease under investigation
|E.1.2||Classification code ||10019829
|E.1.2||Term ||Hepatocellular carcinoma recurrent
|E.1.2||System Organ Class ||10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
|E.1.3||Condition being studied is a rare disease || No
|E.2 Objective of the trial
|E.2.1||Main objective of the trial ||
To compare the OS of patients with advanced HCC receiving axtitinib +
best supportive care (BSC) versus (vs) placebo + BSC following failure of
one prior antiangiogenic therapy.
|E.2.2||Secondary objectives of the trial ||
To compare PFS between both arms
To compare TTP between both arms
To compare overall response rate (ORR) between both arms
To evaluate DR within each treatment arm
To compare CBR between both arms
To evaluate the safety and tolerability of axitinib in this patient
To evaluate the pharmacokinetics of axitinib in this patient population.
To compare patients' health-related quality of life (HRQoL) and health
status between both arms.
To evaluate baseline blood VEGF-C level as a potential predictive
biomarker of axitinib efficacy.
To evaluate blood soluble protein concentrations and RNA transcripts
associated with angiogenesis or tumor growth.
|E.2.3||Trial contains a sub-study || No
|E.3||Principal inclusion criteria ||
|1. Locally advanced or metastatic HCC confirmed by histology or cytology
(diagnosis of HCC obtained from a prior tumor biopsy specimen is
acceptable) or liver mass confirmed as HCC by one or more imaging
modalities, including triphasic contrastenhanced helical CT, triphasic
dynamic contrast-enhanced MRI and contrast-enhanced
ultrasonography, and not amenable to local therapy.
2. Failure of one prior antiangiogenic therapy. Antiangiogenic agents
include sorafenib, bevacizumab and brivanib only. Failure is defined as
either a) documented progressive disease (per RECIST version 1.1)
while receiving prior therapy or after the last dose of prior therapy; or b)
intolerance to the prior antiangiogenic therapy. Intolerance to prior
antiangiogenic therapy (at any dose and/or duration) is defined as
documented treatment-related grade 3 or 4 adverse events that led to
3. Presence of either measurable or non-measurable disease according
to RECIST (version 1.1).
4. Child-Pugh Class A (score 5-6) or B (score 7 only) disease. Score for
hepatic encephalopathy must be 1; the score for ascites must be no
greater than 2 and clinically irrelevant; for the determination of the
Child-Pugh Class see Appendix 6 of the protocol.
5. At least 2 weeks since the last dose of prior systemic treatment,
radiotherapy, or surgical procedure (4 weeks for major surgery). All
treatment-related toxicities must have resolved to NCI CTCAE Version
3.0 grade ≤1 or back to baseline except for alopecia or hypothyroidism.
6. No evidence of preexisting uncontrolled hypertension as documented
by 2 baseline blood pressure readings taken at least 1 hour apart. The
baseline systolic blood pressure readings must be ≤140 mm Hg, and the
baseline diastolic blood pressure readings must be ≤90 mm Hg. Patients
whose hypertension is controlled by antihypertensive therapies are
7. Eighteen years of age or older.
8. ECOG performance status 0 or 1.
9. Life expectancy of ≥ 8 weeks.
10. Required baseline laboratory data within the following parameters:
• Neutrophils ≥ 1,500/≥L
• Platelets ≥ 75,000/≥L
• Hemoglobin ≥ 9.0 g/dL
• Serum aspartate aminotransferase (AST; serum glutamate-oxalate
transferase [SGOT]) and serum alanine aminotransferase (ALT; serum
glutamate-pyruvate transferase [SGPT]) ≤ 5 x ULN
• Serum creatinine ≤ 1.5 x ULN
• INR <1.7 or prothrombin time (PT)< 4 seconds above ULN (i.e. Child-
Pugh Score is
no greater than 1)
• Serum albumin ≥ 2.8 g/dL (i.e. Child-Pugh Score is no greater than 2)
• Total bilirubin ≤ 3 mg/dL (i.e. Child-Pugh Score is no greater than 2)
• Urinary protein <2+ by urine dipstick. If dipstick is ≥2+ then a 24 hour
collection should be done and the patient may enter only if urinary
protein is <2.0 g per 24 hours.
11. Signed and dated informed consent indicating that the patient (or
legally acceptable representative if applicable by local laws) has been
informed of all the pertinent aspects of the trial prior to enrollment.
12. Willingness and ability to comply with scheduled visits, treatment
plans, laboratory tests, and other study procedures, including
completion of patient-reported outcome (PRO) questionnaires.
|E.4||Principal exclusion criteria||
|1. Prior treatment of advanced HCC with more than one prior first-line
2. Any prior local therapy (such as radiation therapy, hepatic arterial
embolization, TACE, hepatic arterial infusion, radiofrequency ablation,
percutaneous ethanol injection or cryoablation) within 2 weeks of
starting the study treatment; major surgery within 4 weeks of starting
the stugy treatment.
3. Presence of hepatic encephalopathy (i.e. Child-Pugh score of 2 or 3)
and/or clinically relevant ascites (i.e. Child-Pugh score of 3).
4. Presence of main portal vein invasion by HCC (invasion to 1st or 2nd
branch of portal vein is acceptable).
5. NCI CTCAE grade ≥ 3 hemorrhage within 4 weeks of starting study
variceal hemorrhage of any grade within 12 months of study screening.
6. Presence of esophageal varices of greater than grade 2 according to
Paquet classification (grade 2 allowed only if on prophylactic treatment)
or esophageal varices in the presence of any red signs and/or serious or
7. History of abdominal fistula, gastrointestinal perforation, or intraabdominal
abscess within 28 days of study screening.
8. Any of the following within the 12 months prior to study drug
administration: severe/unstable angina, myocardial infarction, coronary
artery bypass graft, symptomatic congestive heart failure,
cerebrovascular accident, transient ischemic attack, deep vein
thrombosis or pulmonary embolism.
9. History of or known active seizure disorder, brain metastases, spinal
cord compression, or carcinomatous meningitis, or new evidence of brain
or leptomeningeal disease.
10. Alcohol intake within 7 days of study screening and anticipated
alcohol intake during the study.
11. Current use or anticipated need for treatment with botanical
formulation having an approved indication for liver cancer treatment,
such as "Kanglaite", etc
12. Current use or anticipated need for treatment with drugs that are
cytochrome P450 (CYP) 3A4/5 inhibitors (e.g., grapefruit juice,
ketoconazole, nefazodone, itraconazole, miconazole, erythromycin,
telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir,
lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine).
13. Current use or anticipated need for treatment with drugs that are
known CYP3A4/5 or CYP1A2 inducers (e.g., carbamazepine,
dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin,
amobarbital, nevirapine, primidone, rifabutin, rifampin, and St. John's
14. Requirement of anticoagulant therapy with oral vitamin K
antagonists. Low-dose anticoagulants for maintenance of patency of
central venous access devise or prevention of deep venous thrombosis is
allowed. Therapeutic use of low molecular weight heparin is allowed.
15. Gastrointestinal abnormalities including:
• inability to take oral medication;
• requirement for intravenous alimentation;
• prior surgical procedures affecting absorption including total gastric
• treatment for active peptic ulcer disease in the past 6 months unless
the ulcer is completely healed confirmed by endoscopy prior to study
• active gastrointestinal bleeding, unrelated to cancer, as evidenced by
hematemesis, hematochezia or melena in the past 3 months without
evidence of resolution documented by endoscopy or colonoscopy;
• malabsorption syndromes.
16. Known human immunodeficiency virus (HIV) or acquired
immunodeficiency syndrome (AIDS)-related illness.
17. History of a malignancy (other than HCC) except those treated with
curative intent for skin cancer (other than melanoma), in situ breast or
in situ cervical cancer, or those treated with curative intent for any other
cancer with no evidence of disease for 2 years.
18. Dementia or significantly altered mental status that would prohibit
the understanding or rendering of informed consent and compliance with
the requirements of this protocol.
19. Female patients who are pregnant or lactating, or men and women of
reproductive potential not willing or not able to employ an effective
method of birth control/contraception to prevent pregnancy during
treatment and for 6 months after discontinuing study treatment. The
definition of effective contraception should be in agreement with local
regulation and based on the judgment of the principal investigator or a
20. Other severe acute or chronic medical or psychiatric condition or
that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study
results, and in the judgment of the investigator would make the patient
inappropriate for entry into this study.
|E.5 End points
|E.5.1||Primary end point(s)||
|E.5.1.1||Timepoint(s) of evaluation of this end point||
Overall Survival evaluated for 3 years after the last subject is
• Plasma PK (Cmax, AUCinf, AUClast, Tmax, t1/2, CL/F, Vz/F) and
tolerability of single-agent axitinib following continuous dosing.
Assessed Cycle 1 Day 15
• First-cycle DLT (Child-Pugh Class B, Score 7 population only).
• Type, incidence, severity, timing, seriousness, and relatedness of
adverse events, laboratory abnormalities based upon the National
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) version 3.0. will be assessed throughout the study.
|E.5.2||Secondary end point(s)||
Type, incidence, severity (graded by the National Cancer Institute
Terminology Criteria for Adverse Events [CTCAE], version 3.0), timing,
and relatedness of adverse events and laboratory abnormalities
Axitinib population PK analysis
Patient Reported Outcome (PRO) of health-related quality of life and
symptoms as measured by the Functional Assessment of Cancer Therapy
Hepatobiliary questionnaire (FACT-Hep) and health status measured by
EQ-5D Self-Report Questionnaire (EQ-5D).
Plasma soluble proteins [including but not limited to AFP, VEGF-A,
VEGF-C, sVEGFR, HGF, sHGFR]
Plasma RNA transcripts associated with angiogenesis and tumor
|E.5.2.1||Timepoint(s) of evaluation of this end point||
|• Tumor assessment including CT/MRI will be required at baseline and
every 8 weeks. Response (CR/PR) requires confirmation at least 4
weeks after the response is noted.
• Safety assessment (for adverse events) will be carried out throughout
the study and at the 28 day follow-up visit.
• Axitinib Population PK analysis - assessed Day 1 of Cycle 1, 2 and 3
• Patient Reported Outcome (PRO) of health-related quality of life and
disease-related symptoms as well as Health status will be assessed
every 4 weeks during the study, end of treatment and at the 28 day
• Plasma soluble proteins will be assessed, at baseline, Cycle 2 Day 1
and end of treatment.
• Plasma RNA transcripts will be assessed, at baseline, Cycle 2 Day 1 and
end of treatment.
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| No
|E.7||Trial type and phase
|E.7.1||Human pharmacology (Phase I)|| No
|E.7.1.1||First administration to humans|| No
|E.7.1.2||Bioequivalence study|| No
|E.184.108.40.206||Other trial type description||
|E.7.2||Therapeutic exploratory (Phase II)|| Yes
|E.7.3||Therapeutic confirmatory (Phase III)|| No
|E.7.4||Therapeutic use (Phase IV)|| No
|E.8 Design of the trial
|E.8.1.3||Single blind|| No
|E.8.1.4||Double blind || Yes
|E.8.1.5||Parallel group|| Yes
|E.8.1.6||Cross over || No
|E.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || Yes
|E.8.2.4||Number of treatment arms in the trial||2
The trial involves single site in the Member State concerned
|E.8.4|| The trial involves multiple sites in the Member State concerned || Yes
|E.8.4.1||Number of sites anticipated in Member State concerned||4
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||21
|E.8.6 Trial involving sites outside the EEA
|E.8.6.1||Trial being conducted both within and outside the EEA|| Yes
|E.8.6.2||Trial being conducted completely outside of the EEA|| No
|E.8.6.3||If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned||
|Korea, Republic of
|E.8.7||Trial has a data monitoring committee|| Yes
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|End of Trial in all participating countries is defined as the time at which:
Enrolment is completed according to protocol planned sample size, and assessments and requirements are completed as per protocol.
The stated objectives of the trial are achieved.
Recommendation by DMC.
|E.8.9 Initial estimate of the duration of the trial
|E.8.9.1||In the Member State concerned years||1
|E.8.9.1||In the Member State concerned months||7
|E.8.9.1||In the Member State concerned days||0
|E.8.9.2||In all countries concerned by the trial years||1
|E.8.9.2||In all countries concerned by the trial months||7
|E.8.9.2||In all countries concerned by the trial days||0