Adjuvant Therapy with Pembrolizumab Versus Placebo in Participants with Hepatocellular Carcinoma and Complete Radiological Response after Surgical Resection or Local Ablatio
- Conditions
- Adjuvant treatment of HCCMedDRA version: 20.0Level: PTClassification code 10073071Term: Hepatocellular carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2018-004800-20-BG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 950
1. Has a diagnosis of HCC documented radiologically by AASLD criteria (participants undergoing ablation without a prior biopsy) and/or pathologically (participants undergoing ablation and not meeting AASLD criteria, and participants undergoing surgical resection); fibrolamellar, sarcomatoid and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible and:
A. Has a complete radiological response after surgical resection (R0 resection) and an intermediate risk (Stage I), high risk (Stage II, IIIA) or very high risk of recurrence (subtypes of Stage IIIB as described below) as per American Joint Committee on Cancer (AJCC) 8th edition with adaptations based on tumor characteristics as established by the pathology report
- Intermediate risk of recurrence: solitary tumor =2 cm without microvascular invasion and not histologic grade 3 or 4
- High risk of recurrence: solitary tumor =2 with microvascular invasion or same size and histologic grade 3 or 4, or multiple tumors regardless of microvascular invasion or histologic grade
- Very high risk of recurrence: single tumor or multiple tumors of any size with macrovascular invasion. Stage IIIB tumor(s) with direct invasion of adjacent organs or with perforation of visceral peritoneum will not be eligible
OR
B. Has a complete radiological response after local ablation (only radiofrequency or microwave ablation are allowed) and intermediate, high risk of recurrence or very high-risk group
- Intermediate risk of recurrence: Solitary tumor =2 cm and =3 cm
- High risk of recurrence: 2-4 tumors, with all =3 cm or one solitary tumor >3 cm and =5 cm.
- Very high-risk group: 2-4 tumors with at least one >3 cm and all =5 cm.
2. No more than 12 weeks must have elapsed between the date of the staging and the date of surgical resection or local ablation.
3. Has an eligibility scan (CT of the chest, triphasic CT scan or MRI of the abdomen, and CT or MRI of the pelvis) confirming complete radiological response =4 weeks after complete surgical resection or local ablation. Randomization needs to occur within 12 weeks of the date of surgical resection or local ablation
4. Has no radiologic evidence of disease prior to enrollment as per investigator assessment
5. Has an ECOG performance status of 0 or 1 within 7 days prior to C1D1
6. Has a Child-Pugh class A liver score (5 to 6 points) within 7 days prior to C1D1
7. Has AFP concentration lower than 400 ng/mL within 28 days prior to C1D1 (if there are several AFP values available within 28 days prior to C1D1, the closest AFP value to C1D1 should be below 400 ng/mL)
8. Has AFP concentration at initial diagnosis prior to resection or ablation available
9. Participant may have a past or ongoing HCV infection. Participants must have completed their treatment at least 1 month prior to C1D1 or have received at least 1 month of DAA HCV therapy with no DAA-related safety events and stable LFTs. For participants not on anti HCV therapy at the time of randomization, DAAs for treatment of HCV infection can be initiated per Investigator’s discretion, if LFTs are stable after 3-6 months of study intervention upon sponsor consultation.
10. Participant may have controlled hepatitis B, 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 less than 500 IU/mL prior to first dose of study intervention. Participants on active HBV therapy with viral loads under 500 IU/mL should stay on the same
1. Has a known additional malignancy that is progressing or has required active antineoplastic treatment (including hormonal) or surgery within the past 3 years
2. Has had esophageal or gastric variceal bleeding within the last 6 months. All cirrhotic participants will be screened for esophageal varices with an upper endoscopy, unless such assessment has been performed in the past 12 months before C1D1. If varices are present, they should be treated according to institutional standards before starting study intervention
3. Has clinically apparent ascites on physical examination
4. Has had clinically diagnosed hepatic encephalopathy in the last 6 months. Participants on rifaximin or lactulose to control their hepatic encephalopathy regardless of when the diagnosis of hepatic encephalopathy occurred are not eligible
5. Has received local therapy to liver ablation other than with radiofrequency or microwave ablation (ie alcohol ablation, transcatheter chemoembolization [TACE], transcatheter embolization [TAE], hepatic arterial infusion [HAI], local radiation/Stereotactic Body Radiation Therapy [SBRT] or radioembolization)
6. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
7. Has an active infection requiring systemic therapy
8. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry
9. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
10. Has known active tuberculosis (TB; Bacillus tuberculosis)
11. 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)
12. Has received prior systemic anti-cancer therapy for HCC including investigational agents
13. Is receiving any of the following prohibited concomitant therapies:
- Antineoplastic systemic chemotherapy or biological therapy
- Immunotherapy not specified in this protocol
- Investigational agents other than pembrolizumab
- Received prior radiotherapy within 2 weeks of start of study
intervention
- Oncological surgical therapy
- Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE that is suspected to have an immunologic etiology. Inhaled or topical steroids are allowed, and systemic steroids at doses =10 mg/day prednisone or equivalent are allowed. Exception: steroids may be used for premedication prior to imaging
14. Has received a live vaccine within 30 days prior to the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®, [Influenza Vaccine Live, AstraZeneca]) are live attenuated vaccines and are not allowed
15. 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 C1D1
16. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: 1. To compare Recurrence-Free Survival (RFS)<br>2. To compare Overall Survival (OS);Secondary Objective: 1. To evaluate the safety and tolerability<br>2. To compare score change from baseline in global quality of life (QoL) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) global health status/QoL scale and EORTC QLQ-HCC18<br>3. To characterize health utilities using the EuroQoL-5 Dimension Questionnaire, 5-Level (EQ-5D-5L) health utility scores;Primary end point(s): 1.Recurrence-Free Survival (RFS)<br>2.Overall Survival (OS)<br>;Timepoint(s) of evaluation of this end point: 1.Up to ~4 years<br>2.Up to ~6 years
- Secondary Outcome Measures
Name Time Method Secondary end point(s): 1.Percentage of participants who experience an adverse event (AE)<br>2.Percentage of participants who discontinue study treatment due to an AE<br>3.Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Overall Scores and Subscale Scores<br>4.Change from Baseline in EORTC QLQ-Hepatocellular Carcinoma Module (EORTC QLQ-HCC18) Scale Score<br>5.Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Health Utility Score<br>;Timepoint(s) of evaluation of this end point: 1.Up to ~6 years<br>2.Up to ~1 year<br>3.Baseline, time of last patient reported outcome (PRO) assessment (up to ~7 years)<br>4.Baseline, time of last PRO assessment (up to ~7 years)<br>5.Baseline, time of last PRO assessment (up to ~7 years)<br>