E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with Hepatocellular Carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Subjects with cancer of the hepatocytes in the liver |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073071 |
E.1.2 | Term | Hepatocellular carcinoma |
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 |
The objective of this study is to evaluate the effect of cabozantinib compared with placebo on overall survival in subjects with advanced HCC previously treated with sorafenib. |
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histological or cytological diagnosis of HCC (results of a previous biopsy will be accepted)
2. The subject has disease that is not amenable to a curative treatment approach (eg, transplant, surgery, radiofrequency ablation)
3. Received prior sorafenib
4. Progression following at least 1 prior systemic treatment for HCC
5. Recovery to ≤ Grade 1 from toxicities related to any prior treatments, unless the adverse events are clinically nonsignificant and/or stable on supportive therapy
6. Age ≥ 18 years old on the day of consent
7. ECOG performance status of 0 or 1
8. Adequate hematologic function, based upon meeting the following laboratory criteria within 7 days before randomization:
a. absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 109/L)
b. platelets ≥ 60,000/mm3 (≥ 60 x 109/L)
c. hemoglobin ≥ 8 g/dL (≥ 80 g/L)
9. Adequate renal function, based upon meeting the following laboratory criteria within 7 days before randomization:
a. serum creatinine ≤ 1.5 x upper limit of normal or calculated creatinine clearance ≥ 40 mL/min (using the Cockroft-Gault equation: (140 – age) x weight (kg)/(serum creatinine × 72 [mg/dL]) for males. (For females multiply by 0.85.) AND
b. urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1g
10. Child-Pugh Score of A
11. Total bilirubin ≤ 2 mg/dL (≤ 34.2 μmol/L) within 7 days before randomization
12. Serum albumin ≥ 2.8 g/dL (≥ 28 g/L) within 7 days before randomization
13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5.0 upper limit of normal (ULN) within 7 days before randomization
14. Hemoglobin A1c (HbA1c) ≤ 8% within 7 days before randomization (if HbA1c results are unavailable [eg, hemoglobin variant], a fasting serum glucose ≤ 160 mg/dL)
15. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection
16. Capable of understanding and complying with the protocol requirements and signed informed consent
17. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment
18. Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression, low body weight, or other reasons. |
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E.4 | Principal exclusion criteria |
1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma
2. Receipt of more than 2 prior systemic therapies for advanced HCC. Additional prior systemic therapies used as adjuvant or local therapy are allowed.
3. Any type of anticancer agent (including investigational) within 2 weeks before randomization
4. Radiation therapy within 4 weeks (2 weeks for radiation for bone metastases) or radionuclide treatment (eg, I-131 or Y-90) within 6 weeks of randomization. Subject is excluded if there are any clinically relevant ongoing complications from prior radiation therapy.
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization,
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to randomization
5. Prior cabozantinib treatment
6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before randomization. Eligible subjects must be without corticosteroid treatment at the time of randomization.
7. Concomitant anticoagulation, at therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, low molecular weight heparin (LMWH), thrombin or coagulation factor X (FXa) inhibitors, or antiplatelet agents (eg, clopidogrel). Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (≤ 1 mg/day), and low-dose LMWH are permitted.
8. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
a. Cardiovascular disorders including
i. Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment
iii. Stroke (including TIA), myocardial infarction, or other ischemic event within 6 months before randomization
iv. Thromboembolic event within 3 months before randomization. Subjects with thromboses of portal/hepatic vasculature attributed to underlying liver disease and/or liver tumor are eligible
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization,
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to randomization
c. Major surgery within 2 months before randomization. Complete healing from major surgery must have occurred 1 month before randomization. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before randomization. Subjects with clinically relevant complications from prior surgery are not eligible
d. Cavitating pulmonary lesion(s) or endobronchial disease
e. Lesion invading a major blood vessel including but not limited to: inferior vena pulmonary artery or aorta). Subjects with lesions invading the portal
vasculature are eligible.
f. Clinically significant bleeding risk including the following within 3 months of randomization: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors
g. Other clinically significant disorders such as:
i. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)-related illness. Subjects with active
hepatitis virus infection controlled with antiviral therapy are eligible.
ii. Serious non-healing wound/ulcer/bone fracture
iii. Malabsorption syndrome
iv. Uncompensated/symptomatic hypothyroidism
v. Requirement for hemodialysis or peritoneal dialysis
vi. History of solid organ transplantation
(Please see page 43 of the protocol for the remaining criteria)
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis of OS is event-driven and will be conducted after at least 621 deaths have been observed.
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E.5.2 | Secondary end point(s) |
Objective response rate (ORR) per RECIST 1.1
Progression-free survival (PFS) per RECIST 1.1 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The testing of the secondary endpoints (PFS and ORR) will occur only if the result of either an interim analysis or the final analysis of OS achieves statistical significance. |
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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 | No |
E.6.10 | Pharmacogenetic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.7 | Other | No |
E.8.1.7.1 | Other trial design description |
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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 | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
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 |
Australia |
Belgium |
Canada |
France |
Germany |
Hong Kong |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Poland |
Romania |
Singapore |
Spain |
Taiwan |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
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 | 5 |