| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced stage hepatocellular carcinoma (HCC) |
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| E.1.1.1 | Medical condition in easily understood language |
| advanced stage hepatocellular carcinoma (HCC) |
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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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019828 |
| E.1.2 | Term | Hepatocellular carcinoma non-resectable |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077738 |
| E.1.2 | Term | Hepatocellular carcinoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 efficacy of the combination of lenvatinib and nivolumab in the first line treatment of patients with multinodular, advanced stage hepatocellular carcinoma (HCC) in terms of the objective response rate (according to RECIST 1.1).
Furthermore, safety and tolerability of combination treatment will be evaluated.
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| E.2.2 | Secondary objectives of the trial |
| Secondary efficacy objectives are to determine ORR according to iRECIST, time-to-progression (TTP), progression free survival (PFS) and overall survival (OS). In addition, tissue and blood samples will be analyzed for molecular parameters and immune cell composition to identify biomarkers associated with clinical efficacy of the experimental regimen. |
|
| 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. Unresectable, multinodular tumour, not eligible for resection or local ablation
4. Histologically confirmed diagnosis of hepatocellular carcinoma
5. Has a Child-Pugh Classification score ≤ 6 for assessed liver function within 7 days before allocation (Appendix 4: Child-Pugh Score)
6. At least one measurable site of disease as defined by RECIST 1.1 criteria with spiral CT scan or MRI.
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
8. Life expectancy of at least 12 weeks.
9. Adequate bone marrow, hepatic and renal function including the following:
- Haemoglobin ≥ 10.0 g/dL, absolute neutrophil count ≥ 1,500 /µL, platelets ≥70,000 /µL;
- Total bilirubin ≤ 3.0 mg/dL upper normal limit;
- AST (SGOT), ALT (SGPT) ≤ 5 x upper normal limit;
- International normalized ratio (INR) ≤1.25;
- Albumin ≥ 30 g/dL;
- Creatinine ≤ 1.5 x upper normal limit
OR
measured or calculated creatinine clearance (according to Cockcroft-Gault) ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
(GFR can also be used in place of creatinine or CrCl)
10. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial. Women must not be breastfeeding.
11. If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection, meets the following criteria:
- Patients with HBV or HCV infection should be monitored for viral levels during study participation.
- Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should have HBV DNA < 100 IU/ml and should be managed per local treatment guidelines.
Controlled (treated) hepatitis B subjects will be allowed if they started treatment at the time point of enrollment into the study by the latest and treatment is continued during study participation and for ≥ 6 months after end of study treatment.
- HCV patients with advanced HCC are mostly not treated for their HCV infection. However, patients treated for HCV are considered suitable for inclusion if antiviral therapy has been completed ≥ 30 days prior to first administration of study drug.
12. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
13. WOCBP must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo 5 half-lives. The terminal half-lives of nivolumab is approximately 25 days. WOCBP should use an adequate method to avoid pregnancy for approximately 5 months (30 days plus the time required for nivolumab to undergo 5 half-lives) after the last dose of investigational drug.
14. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo 5 half-lives. The terminal half-lives of nivolumab is approximately 25 days. Males who are sexually active with WOCBP must continue contraception for approximately 7 months (90 days plus the time required for nivolumab to undergo 5 half-lives) after the last dose of investigational drug. In addition, male subjects must be willing to refrain from sperm donation during this time.
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| E.4 | Principal exclusion criteria |
1. Previous systemic therapy in the first-line setting.
2. Patients on a liver transplantation list or with advanced liver disease as defined below:
• Encephalopathy
• Untreatable Ascites.
3. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
4. Prior organ allograft or allogeneic bone marrow transplantation.
5. Local therapies ongoing or completed <4 weeks prior to the baseline scan.
6. Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months prior to the first dose of study drug with the exception of thrombosis of a segmental portal vein.
7. Prior, systemic anti-cancer chemotherapy, radiotherapy administered <4 weeks prior to study entry, endocrine- or immunotherapy or use of other investigational agents.
8. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
9. Major surgery within 4 weeks of starting the study. Patients must have recovered from effects of major surgery.
10. Malignancies other than disease under study within 5 years prior to inclusion, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
11. Uncontrolled hypertension.
12. Clinically significant cardiovascular disease.
13. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive study drug.
14. Proteinuria (≥2g/24h)
15. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or compliance with the study protocol.
16. Subjects with a history of or current CNS metastases. A scan to confirm the absence of brain metastases is not required. Patients with unknown CNS metastatic status and any clinical signs indicative of CNS metastases are eligible if CNS metastases are excluded using CT and/or MRI scans.
17. Pregnant or breast-feeding women.
18. Immunocompromised patients, e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV).
19. Subjects with active, known, or suspected autoimmune disease. Subjects with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll. For any cases of uncertainty, it is recommended that the medical monitor be consulted prior to signing informed consent.
20. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
21. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
22. All toxicities attributed to prior anti-cancer therapy other than hearing loss, alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 4.03) or baseline before administration of study drug.
23. > Grade 1 peripheral neuropathy according to CTCAE version 4.03
24. Patients who have received a live vaccine within 30 days prior to enrolment.
25. History of allergy or hypersensitivity to study drugs or any constituent of the products
26. Is currently participating in 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.
27. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
28. 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:
• Objective response rate (ORR) according to RECIST 1.1 based on the ITT population
The primary safety endpoint is:
• Safety (according to NCI-CTCAE V 4.03) and tolerability
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary efficacy endpoint objective response rate will be evaluated as best overall response. Therefore, timepoint of evalutation is at end of treatment of last patient (LPO).
Safety events according to CTCAE 4.0 will be analyzed at the end of study. |
|
| E.5.2 | Secondary end point(s) |
• ORR according to iRECIST
• Time-to-progression (TTP)
• Progression free survival (PFS)
• Overall survival (OS)
• Translational research: correlation of biomarkers potentially associated with clinical efficacy (OS, PFS and ORR) from lenvatinib plus nivolumab by molecular quantitation of mRNA expression of PD-1, PD-L1 and PD-L2, immune cell infiltrates (IGHM, CD3, CD8, FOXP3, CD68, CD205), chemokines (CXCL9, CXCL10, CXCL13) and invasion markers (MMP7, MMP9).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR, TTP, PFS, OS will be evaluated at the end of study.
Translational research endpoints will be evaluated as soon as necessary data for correlation analysis is available. |
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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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Translational research on the MoA of the combination treatment |
|
| 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.8.3 |
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 | 15 |
| 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 | 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
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