E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
advanced or inoperable hepatocellular carcinoma |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
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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 |
The primary objective is to determine the efficacy of AMG 386 in combination with sorafenib as measured by the time to progression event rate at 4-months in subjects with advanced or inoperable hepatocellular carcinoma (HCC). |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of AMG 386 in combination with sorafenib in subjects with advanced or inoperable hepatocellular carcinoma and Child Pugh A liver function score • To estimate the efficacy (as measured by objective response rate [ORR], disease control rate [DCR], time to progression [TTP], progression free survival [PFS], and overall survival [OS]) of AMG 386 10 mg/kg IV QW in combination with sorafenib 400 mg PO BID in subjects with advanced or inoperable hepatocellular carcinoma • To evaluate the pharmacokinetics (PK) of AMG 386 and sorafenib when used in combination (only in a sub-group of subjects at selected sites outside of Europe for sorafenib) • To determine the incidence of occurrence of anti-AMG386 antibody formation |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease Related • Subjects must have histologically confirmed advanced or inoperable HCC • Child-Pugh liver function class A (see Appendix G) • Measurable disease with at least one unidimensionally measurable lesion per RECIST (see Appendix E). Demographic • Men or women ≥ 18 years old • Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less • Subjects of child-bearing potential and sexually active must consent to the use of an accepted and effective non-hormonal method of contraception (ie, double barrier method [eg, condom plus diaphragm]) from signing the informed consent through 6 months following last administration of study drug Laboratory • Adequate organ and hematological function as evidenced by the following laboratory studies within 14 days prior to enrollment: o Hematological function, as follows: • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L • Platelet count ≥ 75 x 109/L • Hemoglobin ≥ 8.5 g/dL o Renal function, as follows: • Calculated creatinine clearance > 50 mL/min according to the Cockcroft-Gault formula • Urinary protein quantitative value of ≤ 30 mg in urinalysis or ≥ 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample o Hepatic function, as follows: • Aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN) • Alanine aminotransferase (ALT) ≤ 5 x ULN • Alkaline phosphatase ≤ 2.0 x ULN (if bone metastases are present, ≤ 5 x ULN) • Albumin ≥ 2.8 g/dL • Bilirubin ≤ 2.0 mg/dL o Hemostatic function, as follows: • International Normalized Ratio (INR) ≤ 1.7 • Partial thromboplastin time (PTT) or activated partial thromboplastin (aPTT) ≤ 1.5 x ULN per institutional laboratory range General • Able to tolerate infusions and self-administer oral medications • Competent to comprehend, sign, and date an institutional review board (IRB)/Independent Ethics Committee (IEC) -approved informed consent form • Life expectancy ≥ 3 months (per investigator opinion) • Subject plans to begin protocol directed therapy within 7 days of enrollment |
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E.4 | Principal exclusion criteria |
Disease Related • Any previous systemic chemotherapy for HCC (chemotherapy or targeted therapies) • Previous surgical resections are allowed if ≥ 30 days elapsed prior to enrollment • Locoregional therapies (eg, TACE) are allowed if ≥ 30 days elapsed prior to enrollment provided that subjects either have a target lesion which has not been subjected to local therapy and/or the target lesions(s) within the field of the local therapy has shown an increase of ≥ 20% in size • History of arterial or venous thromboembolism within 12 months prior to enrollment • History of clinically significant bleeding within 6 months prior to enrollment (including pulmonary hemorrhage, gastroesophageal varices or gross hemoptysis (≥ 1/2 teaspoon or 2.5 mL of bright red blood) • Known history of central nervous system metastases. An MRI or CT scan of the brain or head will be performed within 30 days prior to enrollment. • Patients with fibrolamellar hepatocellular carcinoma • Radiation therapy ≤ 14 days prior to enrollment. Subjects who received radiation therapy must have recovered from all radiation induced toxicities prior to enrollment Medications • Currently or previously treated with sorafenib or other small molecule inhibitors of VEGF including, but not limited to AMG 706 (motesanib), SU11248 (sunitinib), PTK787 (vatalanib), AZD 2171 (cediranib), AEE-788 • Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor including but not limited to, XL-820, XL-184, or CVX-060/PF-4856884 • Concomitant or use within 30 days prior to enrollment of any strong inducer of CYP3A4 including, but not limited to, rifampin, St. John’s wort, phenytoin, carbamazepine, phenobarbital and dexamethasone • Concomitant anti-viral therapy is allowed with the exception of interferon alfa or pegylated interferon alfa therapy • Current or within 30 days prior to enrollment treatment with immune modulators such as cyclosporine and tacrolimus • Enrolled in or has not yet completed at least 30 days since ending other investigational device or drug trials, or currently receiving other investigational treatments General Medical • Known ongoing pancreatitis • Clinically significant cardiovascular disease within 12 months prior to enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent • Major surgery within 4 weeks before enrollment or still recovering from prior surgery • History of allergic reactions to bacterially produced proteins • Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding • Exclude subjects with a history of prior malignancy, except: - Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by treating physician - Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease - Adequately treated cervical carcinoma in situ without evidence of disease - Prostatic intraepithelial neoplasia without evidence of prostate cancer - Other primary solid tumor with no known active disease present that in the opinion of the investigator will not affect patient outcome in the setting of current hepatocellular carcinoma diagnosis • Minor surgical procedures, placement of central venous access device (except PICC or peripherally inserted central catheter), or fine needle aspiration within 7 days prior to enrollment • Uncontrolled hypertension as defined as diastolic > 90 mmHg OR systolic > 150 mmHg. The use of anti-hypertensive medications to control hypertension is permitted. • Known active or ongoing infection (except uncomplicated urinary tract infection [UTI]) within 14 days before enrollment • Subject known positive test(s) for human immunodeficiency virus (HIV) infection, • Anticoagulation therapy must be stopped 1 week prior to enrollment except: - aspirin and anti-platelet agents - low dose warfarin (ie. ≤ 1mg daily) • Non-healing wound, ulcer (including gastrointestinal) or fracture Other • Any condition which in the investigator’s opinion makes the subject unsuitable for study participation • Other investigational procedures are excluded. • Subject will not be available for follow-up assessment • Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the TTP event rate at 4 months. The 4-month TTP event rate is defined as the proportion of subjects with radiologic disease progression per the RECIST criteria 4 months after the initiation of the study. Subjects who do not meet the criteria for disease progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Historical comparator data |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
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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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The end of study is when all subjects have completed the treatment period or safety follow-up or long-term follow-up (maximum 48 months from the date the last subject was enrolled), whichever is later. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |