E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Incurable/Non-metastatic Hepatocellular Carcinoma |
|
E.1.1.1 | Medical condition in easily understood language |
Incurable/Non-metastatic Hepatocellular Carcinoma |
|
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) |
|
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 |
1. To compare pembrolizumab plus lenvatinib in combination with transarterial chemoembolization (TACE) versus placebo plus TACE with regard to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) assessed by blinded, independent central review (BICR).
2. To compare pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE with regard to overall survival (OS).
|
|
E.2.2 | Secondary objectives of the trial |
1. To evaluate pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE with regard to PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by BICR.
2. To evaluate the safety and tolerability of pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE.
3. To evaluate pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE with regard to efficacy outcomes per RECIST 1.1 assessed by BICR.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Has a diagnosis of HCC confirmed by radiology, histology, or cytology. Has a radiologic diagnosis of HCC as per the AASLD guidelines, which requires: -liver cirrhosis and a liver mass confirmed by BICR that shows arterial phase hyperenhancement on triphasic CT or MRI, AND EITHER: Is ≥20 mm with either non-peripheral portal washout or an enhancing capsule OR Is 10-19 mm with non-peripheral portal venous washout AND an enhancing capsule. 2.Has HCC localized to the liver without portal vein thrombosis, and not amenable to curative treatment such as resection, ablation, or liver transplant. No extrahepatic HCC is permitted, confirmed by BICR. 3.Has at least one measurable HCC lesion based on RECIST 1.1, confirmed by BICR. 4.Has all lesions treatable with TACE in 1 or 2 sessions. 5.Is amenable, without any contraindications, to the TACE procedure and chemotherapy agent pre specified at the study site. 6.Has a CP class A liver score within 7 days prior to first dose of study intervention. 7.Has a predicted life expectancy of >3 months. 8.Has an ECOG PS of 0 to 1 within 7 days prior to first dose of study intervention. 9.Is male or female ≥ 18 years of age at the time of signing the informed consent. 10.Male participants are eligible to participate if they agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows: - Lenvatinib 7 days - TACE 95 days |
Refrain from donating sperm PLUS either: -Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR -Must agree to use contraception unless confirmed to be azoospermic. -Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. -Male participants must agree to refrain from donating sperm for 180 days after TACE. 11.A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: -Is not a WOCBP OR -Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows: - Pembrolizumab 120 days - Lenvatinib 30 days - Tace 180 days The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. -A WOCBP must have a negative highly sensitive pregnancy test within 24 hours for urine or 72 hours for serum before the first dose of study intervention. -If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. ·The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. ·Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 12.The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. 13.Participants with past or ongoing HCV infection will be eligible for the study. Treated participants must have completed their treatment at least 1 month prior to starting study intervention. 14.Participants with controlled HBV will be eligible as long as they meet the following criteria: -Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be <500 IU/mL prior to first dose of study interventions. Participants on active HBV therapy with viral loads <500 IU/mL should stay on the same therapy throughout study intervention. -Participants who are positive for HBc, negative for HBsAg, and negative or positive for HBs, and who have an undetectable HBV viral load, do not require HBV antiviral prophylaxis. -Participants not on HBV therapy with undetectable HBV viral load, but positive for HBsAg, may begin anti-viral prophylaxis at any time prior to first dose of study interventions. 15.Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg at screening and no change in antihypertensive medications within 1 week before Cycle 1 Day 1. 16.Has adequate organ function. Specimens must be collected within 7 days prior to the start of study intervention. |
|
E.4 | Principal exclusion criteria |
1.Has HCC lesion(s) measuring ≥10 cm in any dimension, has more than 10 lesions on radiographic evaluation or has HCC lesions occupying ≥50% of the liver volume, confirmed by BICR. 2.Has had esophageal or gastric variceal bleeding within the last 6 months. 3.Has bleeding or thrombotic disorders or is using anticoagulants requiring therapeutic INR monitoring, eg, warfarin or similar agents. Treatment with antiplatelet agents and low molecular weight heparin is permitted. 4.Has clinically apparent ascites on physical examination that is not controlled with medication. Ascites detectable on imaging studies only is allowed. 5.Has any macrovascular tumor thrombosis in the portal veins, confirmed by BICR. Microvascular tumor thrombosis detected on biopsy, but not radiographic scan, is permitted. 6.Has had clinically diagnosed hepatic encephalopathy in the last 6 months unresponsive to therapy. Participants on rifaximin or lactulose during screening to control their hepatic encephalopathy are excluded. 7.Has received any systemic chemotherapy, including anti-VEGF therapy, or any systemic investigational anticancer agents for HCC. 8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) 2. Overall Survival (OS)
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~43 months 2. Up to ~95 months
|
|
E.5.2 | Secondary end point(s) |
1. PFS per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) 2. Objective Response Rate (ORR) per mRECIST 3. Disease Control Rate (DCR) per mRECIST 4. Duration of Response (DOR) per mRECIST 5. Time to Progression (TTP) per mRECIST 6. Percentage of Participants Who Experience At Least One Adverse Event (AE) 7. Percentage of Participants Who Experience At Least One Serious Adverse Event (SAE) 8. Percentage of Participants Who Experience At Least One Hepatic Event of Clinical Interest (ECI) 9. Percentage of Participants Who Discontinue Study Drug Due to an AE 10. ORR per RECIST 1.1 11. DCR per RECIST 1.1 12. DOR per RECIST 1.1 13. TTP per RECIST 1.1
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~43 months 2. Up to ~95 months 3. Up to ~95 months 4. Up to ~95 months 5. Up to ~95 months 6. Up to ~95 months 7. Up to ~95 months 8. Up to ~95 months 9. Up to ~95 months 10. Up to ~95 months 11. Up to ~95 months 12. Up to ~95 months 13. Up to ~95 months
|
|
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 | 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 |
Health Utility Scores; anti-MK3475 antibody levels |
|
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.8.2 | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 48 |
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 |
Brazil |
Chile |
China |
Colombia |
Israel |
Japan |
New Zealand |
Thailand |
United States |
Turkey |
Ukraine |
Denmark |
France |
Germany |
Hungary |
Ireland |
Italy |
Netherlands |
Norway |
Portugal |
Spain |
Sweden |
Hong Kong |
Korea, Republic of |
Puerto Rico |
Taiwan |
United Kingdom |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |