E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable hepatocellular carcinoma (HCC) |
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E.1.1.1 | Medical condition in easily understood language |
Unresectable hepatocellular carcinoma (HCC) |
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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 | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Evaluate time to progression (TTP) among all patients treated with ARQ 197 compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
Evaluate progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate among all patients treated with ARQ 197 compared to placebo.
Evaluate ORR in crossover population following radiographic disease progression on placebo.
Further characterize the safety of ARQ 197 in patients with unresectable HCC.
Further evaluate pharmacokinetics of ARQ 197
Exploratory Objectives:
Evaluate time to new lesion among all patients treated with ARQ 197 compared to placebo.
Evaluate the association between hepatitis viral status and tumor markers of the c-Met signaling pathway, blood HGF, vascular endothelial growth factor (VEGF),
soluble c-Met levels, other relevant signaling pathways such as PTEN, EGFR, VEGFR, KRAS, IGFR, CYP2C19, UGT1A1, pharmacokinetics, and key clinical endpoints including TTP, PFS, ORR and OS. The key efficacy endpoints in subgroups of patients will also be explored. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Each prospective subject must meet ALL of the following inclusion criteria in order to be eligible for this study:
1. Written informed consent granted prior to initiation of any study-specific screening procedures
2. 18 year of age or older
3. Histologically or cytologically confirmed HCC
4. Archival, fresh core needle biopsy or fine needle aspiration (FNA) tumor samples
5. Received at least one cycle of prior systemic therapy (at least 3 weeks for continuously administered drugs) and experienced radiographic disease progression or was unable to tolerate therapy. If intolerance was manifested by a Grade 3 or 4 event of such nature that re-challenge is not acceptable, less than 3 weeks of continuous administration will be allowed.
6. Discontinued prior treatment for at least 4 weeks, or at least 2 weeks (14 days) if drug was administered continuously and orally (e.g. sorafenib or sunitinib), prior to the study randomization
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1 (Appendix 2)
8. Local or loco-regional therapy (i.e., surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed ≥4 weeks prior to randomization.
9. Measurable disease as defined by a modified version of the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. (See Section 9) Tumor lesions previously treated with local therapy should demonstrate clear dimensional increase by radiographic assessment in order to be selected as target lesion(s) at baseline. (Radiological assessment needs to be redone within 7 days prior to randomization if the pre-study AFP levels has increased by more than 30% since the last AFP level taken one to four months prior to randomization).
10. Adequate bone marrow, liver, and renal functions at Pre-Study Visit, defined as:
- Platelet count ≥ 60 × 109/L
- Hemoglobin ≥ 9.0 g/dL
- Absolute neutrophil count (ANC) ≥1.5 × 109/L
- Total bilirubin ≤ 2 mg/dL
- Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 5 × upper limit of normal (ULN)
- Serum creatinine ≤1.5 × ULN
- International normalized ratio (INR) 0.8 to 1.4 or ≤3 for patients receiving anticoagulant such as coumadin or heparin. Patients who are therapeutically anticoagulated are allowed to participate provided that no prior evidence of underlying abnormality exists in these parameters
- Albumin ≥ 2.8 g/dL
11. Women of childbearing potential must have a negative pregnancy test performed within ten days prior to the start of study drug.
12. Male and female subjects of child-bearing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received. |
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E.4 | Principal exclusion criteria |
Potential subjects who meet ANY of the following exclusion criteria are not eligible for enrollment into this study:
1. More than 1 prior systemic regimen.
2. Child-Pugh Class B-C cirrhotic status (See Appendix 4 for Child-Pugh Classification)
3. Previous or concurrent cancer that is distinct from HCC in primary site or histology, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated >3 years prior to enrollment is permitted.
4. History of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification within 6 months prior to study entry; active coronary artery disease (CAD); clinically significant bradycardia or other uncontrolled cardiac arrhythmia defined as ≥ Grade 3 according to NCI CTCAE, version 4.0, or uncontrolled hypertension; myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring > 6 months prior to study entry is permitted).
5. Active clinically serious infections defined as ≥ Grade 3 according to NCI CTCAE, version 4.0.
6. Substance abuse, medical, psychological or social conditions that may, in the opinion of the Investigator, interfere with the patient’s participation in the study or evaluation of the study results
7. Any condition that is unstable or which could jeopardize the safety of the patient and his/her protocol compliance
8. Known human immunodeficiency virus (HIV) infection
9. Pregnancy or breast-feeding.
10. History of liver transplant
11. Inability to swallow oral medications
12. Clinically significant gastrointestinal bleeding occurring ≤4 weeks prior to randomization. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint is Time to Progression (TTP). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
TTP will be calculated as the time from randomization until disease progression per a modified version of the revised RECIST 1.1 criteria |
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E.5.2 | Secondary end point(s) |
Evaluate progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate among all patients treated with ARQ 197 compared to placebo.
Evaluate ORR in crossover population following radiographic disease progression on placebo.
Further characterize the safety of ARQ 197 in patients with unresectable HCC.
Further evaluate pharmacokinetics of ARQ 197.
Exploratory:
Evaluate time to new lesion among all patients treated with ARQ 197 compared to placebo.
Evaluate the association between hepatitis viral status and tumor markers of the c-Met signaling pathway, blood HGF, vascular endothelial growth factor (VEGF), soluble c-Met levels, other relevant signaling pathways such as PTEN, EGFR, VEGFR, KRAS, IGFR, CYP2C19, UGT1A1, pharmacokinetics, and key clinical endpoints including TTP, PFS, ORR and OS. The key efficacy endpoints in subgroups of patients will also be explored. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS calculated as time from randomization until disease progression per RECIST/death from any cause. OS calculated from date of randomization until death. If no recorded date of death in the database -censored at the time of last study contact.
ORR = patients with a confirmed complete or partial response divided by the total number of patients
The number and percent of patients in each RECIST response category (CR, PR, SD, and PD) and the disease control rate (CR, PR and SD combined).
The time to new lesion will be calculated as the time from randomization until the first new lesion is detected per RECIST criteria. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 | Information not present in EudraCT |
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 |
Belgium |
Canada |
Germany |
Italy |
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E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |