E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced or metastatic and/or unresectable HCC |
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E.1.1.1 | Medical condition in easily understood language |
Locally advanced or metastatic and/or unresectable HCC |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 assess the Time-on-Treatment with cabozantinib in lenvatinib (lenvatinib monotherapy or lenvatinib-IO combination therapy) pre-treated patients with locally advanced and/or metastatic and/or unresectable Hepatocellular Carcinoma (HCC). |
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E.2.2 | Secondary objectives of the trial |
Secondary efficacy objectives are overall survival, progression free survival, objective response rate, duration of response and treatment exposure (time on treatment/dose intensity/dose reductions). Changes in ECOG performance status, ALBI score and Child-Pugh score over the course of treatment are also determined. Furthermore, safety and tolerability are being evaluated including the assessment of treatment-related adverse events (TRAEs) that lead to treatment interruptions, modification or discontinuations.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Fully-informed written consent. 2. Males and females ≥ 18 years of age. *There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently. 3. Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/ cytology or clinically by guideline criteria in cirrhotic patients 4. Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and /or locoregional therapies. 5. Patients who have shown progressive disease during or after first line therapy OR patients must have had their treatment interrupted due to the level of toxicities AND cabozantinib therapy is intended as second line therapy. 6. ECOG performance status ≤ 2. 7. Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade 1 prior to study entry, with the exception of alopecia. 8. For women of childbearing potential and men who are sexually active with women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods. |
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E.4 | Principal exclusion criteria |
1. Unwillingness to give informed consent for participation in the study. 2. Prior sorafenib treatment. 3. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 5 months after last dose of study treatment. 4. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment. 5. Significant portal hypertension (moderate or severe ascites). 6. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. 7. Liver cirrhosis Child-Pugh B with > 7 points and Child-Pugh C. 8. Severely impaired kidney function. 9. History of encephalopathy in past 12 months, if not completely regressive or more than one episode within the last 6 months. 10. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina. 11. Baseline QTcF >500 ms. 12. Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study. 13. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. 14. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications. 15. Elevations of AST/ALT exceeding 5 X ULN. 16. Treatment with investigational systemic therapy within 28 days prior to initiation of study treatment. 17. Prior cabozantinib use. 18. Is currently participating or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. 19. Patients who have been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG. 20. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is: • Time-on-Treatment
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoints will include: • Overall survival (OS) • Progression free survival (PFS) • Objective response rate (ORR) according to RECIST 1.1 • Duration of response (DOR) • Treatment exposure (time on treatment/dose intensity/dose reductions) • Toxicity: o Treatment-related adverse events (TRAEs) o TRAE related treatment interruptions o TRAE related treatment modifications o TRAE related treatment discontinuations • Change in ECOG Performance Status during treatment • Change in ALBI Grade during treatment • Change in Child Pugh Score during treatment • Translational research: correlation of biomarkers potentially associated with clinical efficacy (OS, PFS and ORR) of cabozantinib by o NGS Oncopanel analysis o VEGF module expression analysis.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | |