Unresectable hepatocellular carcinoma (HCC) MedDRA version: 14.0 Level: LLT Classification code 10019828 Term: Hepatocellular carcinoma non-resectable System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: ARQ 197
Product Code: ARQ 197
Pharmaceutical Form: Capsule
INN or Proposed INN: (-)-trans-3-(5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-1yl)-4(1H-indo-3-yl)pyrrolidine-2, 5-dione
CAS Num
Sponsors
ArQule, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 90 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 9
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Secondary Objective: 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.;Main Objective: Evaluate time to progression (TTP) among all patients treated with ARQ 197 compared to placebo.;Primary end point(s): Primary endpoint is Time to Progression (TTP).;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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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. ;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 | — |
Countries
Belgium, Canada, Germany, Italy
Contacts
Public ContactJennifer Vineyard
ICON Clinical Research
Outcome results
None listed