| 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] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| 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 |
Primary Objective:
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 |
Secondary Objectives:
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 population
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 (patients must have received at least 4 weeks of prior therapy). Antiangiogenic agents include sorafenib, bevacizumab and brivanib. 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 treatment discontinuation.
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 ascites/hepatic encephalopathy must be 1; for the determination of the Child-Pugh Class
5. At least 2 weeks since the last dose of prior systemic treatment, radiotherapy, or surgical procedure. 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 eligible.
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 urine
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 systemic therapy.
2. Any prior local therapy (such as surgery, radiation therapy, hepatic arterial embolization, TACE, hepatic arterial infusion, radiofrequency ablation, percutaneous ethanol injection or cryoablation) within 2 weeks of study screening.
3. Prior history of liver transplant.
4. Presence of hepatic encephalopathy and/or clinically relevant ascites (e.g., that can be classified as Child-Pugh encephalopathy or ascites of 2 or 3 points).
5. Presence of main portal vein invasion by HCC.
6. NCI CTCAE grade ≥ 3 hemorrhage within 4 weeks of starting study treatment, or
variceal hemorrhage of any grade within 12 months of study screening.
7. 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 non-healing wound/ulcer.
8. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of study screening.9. 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, portal vein thrombosis, deep vein thrombosis or pulmonary embolism.
10. History of or known active seizure disorder, brain metastases, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.
11. Alcohol intake within 7 days of study screening and anticipated alcohol intake during the study.
12. Current use or anticipated need for treatment with botanical formulation having an approved indication for cancer treatment, such as “Xiao Chai Hu Tang”, “Kanglaite”, etc
13. Current use or anticipated need for treatment with drugs that are known potent
cytochrome P450 (CYP) 3A4/5 inhibitors (e.g., grapefruit juice, verapamil, ketoconazole, nefazodone, itraconazole, miconazole, erythromycin, telithromycin, clarithromycin,indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine).
14. 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 wort).
15. 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.
16. Gastrointestinal abnormalities including:
inability to take oral medication;
requirement for intravenous alimentation;
prior surgical procedures affecting absorption including total gastric resection;
treatment for active peptic ulcer disease in the past 6 months;
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.
17. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
18. 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.
19. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
20. 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 designated associate.21.
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality
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 |
RandomizedPortion:
Overall Survival evaluated for 3 years after the last subject is randomized.
Non-randomized Portion
• 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) |
PFS
TTP
ORR
DR
CBR
Type, incidence, severity (graded by the National Cancer Institute [NCI] Common
Terminology Criteria for Adverse Events [CTCAE], version 3.0), timing, seriousness,
and relatedness of adverse events and laboratory abnormalities
Axitinib population PK analysis
Patient Reported Outcome (PRO) of health-related quality of life and disease-related
symptoms as measured by the Functional Assessment of Cancer Therapy –
Hepatobiliary questionnaire (FACT-Hep) and health status measured by the EuroQol
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 growth. |
|
| 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 follow-up visit.
• 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.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | 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.7.1.3 | Other | No |
| E.7.1.3.1 | 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 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| 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.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 |
| Bulgaria |
| China |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Singapore |
| Slovakia |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
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 | 1 |
| 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 |
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