E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable hepatocellular carcinoma (HCC) |
|
E.1.1.1 | Medical condition in easily understood language |
Unresectable hepatocellular carcinoma (HCC) |
|
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) |
|
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. |
|
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. |
|
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. |
|
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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint is Time to Progression (TTP). |
|
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 |
|
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 |
|
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.
|
|
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.8.2.4 | 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 | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
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 |
|
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
|
|
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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |