| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049010 |
| E.1.2 | Term | Carcinoma hepatocellular |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
Phase Ib: To determine the MTD/recommended Phase II dose and characterize the pharmacokinetics (PK) of E7050 when administered in combination with sorafenib in patients with locally advanced or metastatic hepatocellular carcinoma (HCC);
Phase II: To evaluate the safety and tolerability of E7050 when administered in combination with sorafenib as compared with sorafenib alone in patients with locally advanced or metastatic HCC. |
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| E.2.2 | Secondary objectives of the trial |
| Phase II: To make a preliminary assessment of the efficacy of E7050 when administered in combination with sorafenib compared with sorafenib alone in patients with locally advanced or metastatic HCC. Efficacy will be evaluated by median time to progression (TTP), median progression-free survival (PFS), proportion of PFS at Week 12, overall survival (OS), and overall response rate (ORR). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients may be entered in the study only if they meet all of the following criteria:
1. Male or female patient ≥ 18 years of age;
2. Histologically or cytologically confirmed, unresectable locally advanced or metastatic HCC. Patients with HCC may be enrolled without histological confirmation of disease so long as they meet the following criteria for diagnosis of HCC (and all other protocol eligibility criteria):
Lesion >2 cm in diameter, AND
Serum α-fetoprotein (AFP) ≥400 ng/mL (if serum AFP is <400 ng/mL,
a biopsy is required to confirm HCC); AND
Radiological appearance of mass is suggestive of HCC (ie, contrast
enhanced CT or MRI with arterial hypervascularity AND venous or
delayed phase washout);
3. No previous prior systemic anti-cancer therapy (1 prior systemic anti-cancer regimen is allowed in Phase 1b);
4. At least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v. 1.1) criteria. 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;
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1;
6. Child-Pugh Cirrhotic Status A or B with a score of 7;
7. For patients with hypertension, it must be well controlled. If a patient presents with poorly controlled hypertension, defined as a mean systolic blood pressure ≥140 mm Hg or mean diastolic blood pressure ≥90 mm Hg, antihypertensive medication(s) should be initiated or adjusted with a goal to control the blood pressure <140/90 mm Hg. Blood pressure must be reassessed on 2 occasions, consecutively, that are separated by a minimum of 24 hours;
8. Patients must have adequate liver function as evidenced by bilirubin ≤2.0 mg/dL and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤5 times the upper limit of the normal range (ULN). If there are bone metastases, liver-specific alkaline phosphatase (gamma-glutamyltransferase) may be separated from the total and used to assess liver function instead of total alkaline phosphatase;
9. International normalized ratio (INR) 0.8 to 1.4 or ≤3 for patients receiving vitamin K antagonists;
10. Patients must have adequate renal function as evidenced by:
Serum creatinine ≤1.5 X ULN and creatinine clearance >50 mL/min
per the Cockcroft and Gault formula;
Urine protein creatinine (UPC) ratio of <1 on a spot urine or <1.0 g
of protein determined by 24-hour urine protein analysis. If the UPC
ratio is ≥1, 24-hour urine protein must be assessed and the 24-
hour urine protein must be <1.0 g of protein for the patient to be
eligible;
11. Patients must have adequate bone marrow function as evidenced by an absolute neutrophil count (ANC) ≥1.5 X 109/L, hemoglobin ≥9.0 g/dL (a hemoglobin <9.0 g/dL at Screening is acceptable if it is corrected to ≥9 g/dL by growth factor or transfusion prior to the first dose), and platelet count ≥60 X 109/L;
12. Male or female patients of childbearing potential must agree to use double barrier contraception, oral contraceptives, or avoidance of pregnancy measures during the study and for 90 days after the last day of treatment;
13. Females of childbearing potential must have a negative serum pregnancy test at Screening;
14. Females may not be breastfeeding;
15. Ability to understand and willingness to sign a written informed consent. |
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| E.4 | Principal exclusion criteria |
Patients will not be entered in the study for any of the following reasons:
1. Prior treatment with E7050, its chemical derivatives or prior anti-c-Met therapy;
2. Prior anti-angiogenic therapy (permitted in Phase Ib);
3. Prior systemic anti-cancer therapy (two prior systemic anti-cancer regimens are allowed for the Phase 1b portion of the study, must not be within 4 weeks prior to first day of study-defined treatment);
4. Prior external beam radiation to the primary site;
5. Prior central thoracic radiation therapy, including to the heart;
6. Previous chemoembolization, radioembolization, radiofrequency ablation, or other local ablative therapies within 6 weeks prior to the first day of study-defined treatment;
7. Child-Pugh Cirrhotic Status >7;
8. History of other malignancies except: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated, a) in situ carcinoma of the uterine cervix, or b) prostate cancer, or c) superficial bladder cancer; or (3) other curatively treated solid tumor with no evidence of disease for ≥3 years;
9. Presence of brain metastases, unless the patient has received adequate treatment at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 4 weeks prior to randomization;
10. Received treatment in another clinical study within the 30 days prior to commencing study treatment or patients who have not recovered from side effects of an investigational drug to Grade ≤1, except for peripheral neuropathy (Grade 1 and Grade 2 are permitted) and alopecia;
11. Palliative radiotherapy is not permitted throughout the study period;
12. Common Terminology Criteria (CTC) Grade ≥3 peripheral neuropathy (Grade 1 and Grade 2 are permitted);
13. Active clinically serious infections defined as Grade ≥3 according to CTCAE v. 4.0;
14. Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within the 28 days prior to commencing study treatment. Minor surgery such as core biopsy or Portacath placement or skin biopsy is permitted if ≥7 days have passed;
15. History of bleeding diathesis or coagulopathy other than due to anti-coagulation therapy;
16. History of bleeding varices;
17. Active hemoptysis (defined as bright red blood of ½ teaspoon or more) within the 30 days prior to study entry;
18. Clinically significant gastrointestinal bleeding (bleeding requiring procedural intervention, eg. variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial embolization, topical coagulation therapy) within 6 months prior to first dose;
19. History of untreated deep venous thrombosis within the past 6 months (eg, calf vein thrombosis);
20. Refractory nausea and vomiting, malabsorption, significant bowel resection with clinical evidence of malabsorption, or any other medical condition that would preclude adequate absorption or result in the inability to take oral medication;
21. Significant cardiovascular impairment (history of congestive heart failure New York Heart Association [NYHA] Grade >2, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia);
22. Known positive human immunodeficiency virus (HIV);
23. Have anymedical condition that would interfere with the conduct of the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary exploratory efficacy endpoint will be the median time-to-progression (TTP), within treatment group, defined as time from the date of randomization of a patient until the date of first documented progression of such patient’s disease based on independent assessments (Phase II) according to RECIST (version 1.1). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Date of first documented progression of such patient's disease based on Investigator assessments according to RECIST or (2) the date of such patient's death due to any cause. |
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| E.5.2 | Secondary end point(s) |
| Secondary exploratory efficacy endpoints include median progression-free survival (PFS), proportion of PFS at Week 12, overall survival (OS), and overall response rate (ORR), within treatment group. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 12 for proportion of PFS |
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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 | 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Belgium |
| Italy |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
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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 | 2 |
| 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 | 3 |
| 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 |
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