Advanced hepatocellular carcinoma MedDRA version: 20.0 Level: PT Classification code 10073071 Term: Hepatocellular carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: PEMBROLIZUMAB
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEMBROLIZUMAB
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Concentration uni
Sponsors
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Have a HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible) 2. Have BCLC Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach 3. Have a Child-Pugh class A liver score within 7 days prior to first dose of study intervention 4. Have a predicted life expectancy of >3 months 5. Have at least one measurable HCC lesion based on RECIST 1.1 as confirmed by the BICR vendor 6. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1 within 7 days prior to first dose of study intervention 7. Participant is male or female 8. Participant is =18 years of age, at the time of signing the informed consent 9. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 30 days after the last dose of lenvatinib: •Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) • Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials. Please note that 30 days after lenvatinib is stopped, if the participant is on pembrolizumab/placebo only, no male contraception measures are needed. 10. A female participant is eligible to participate if she is not pregnant not breastfeeding, and at least 1 of the following conditions applies: - Is not a woman of childbearing potential (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 120 days post pembrolizumab/placebo or 30 days post lenvatinib, whichever occurs last. A WOCBP must have a negative highly selective pregnancy test (urine or serum as required by local regulations) within 24 hours 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. 11. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study 12. Participants with past or ongoing HCV infection will be eligible for the study. The treated participants must have completed their treatment at least 1 month prior to starting study intervention 13. Participants with controlled hepatitis B will be eligible as long as they meet the following criteria: a) Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Participants on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study treatment b) Participants who are positive for anti-hepatitis B core antibody HBc, negative for hepatitis B surface antigen (HBsAg), and negative or positive for anti-hepatitis B surface antibody (HBs), and who have
Exclusion criteria
Exclusion criteria: 1.Has had esophageal or gastric variceal bleeding within the last 6 months. All participants will be screened for esophageal or gastric varices unless such screening has been performed in the past 3 months before first dose of treatment 2.Bleeding or thrombotic disorders or use of factor X inhibitors or anticoagulants requiring therapeutic international normalized ratio (INR). Treatment with low molecular weight heparin is permitted. 3.Has clinically apparent ascites on physical examination that is not controlled with medication 4.Portal vein invasion (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging 5.Has had clinically diagnosed hepatic encephalopathy in the last 6 months unresponsive to therapy within 3 days. Participants on rifaximin or lactulose to control their hepatic encephalopathy are not allowed 6.Has medical contraindications that preclude all forms of contrast enhanced imaging(CT or MRI) 7.Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib 8.Has a preexisting Grade =3 gastrointestinal or non-gastrointestinal fistula 9.Clinically significant hemoptysis from any source or tumor bleeding within 2 weeks prior to the first dose of study drug 10.Has significant cardiovascular impairment within 12 months of the first dose of study intervention such as history of congestive heart failure greater than New York Heart Association Class II, unstable angina, myocardial infarction or cerebrovascular accident stroke, or cardiac arrhythmia associated with hemodynamic instability 11.Has had major surgery to the liver within 4 weeks prior to the first dose of study intervention 12.Has had a minor surgery within 7 days prior to the first dose of study intervention (Cycle1 Day1) 13.Has serious nonhealing wound, ulcer, or bone fracture 14.Has received any systemic chemotherapy, including anti-VEGF therapy, or any systemic investigational anticancer agents for advanced/unresectable HCC 15.Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PDL2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor 16.Has received locoregional therapy to liver within 4 weeks prior to the first dose of study intervention 17.Has received prior radiotherapy to a non-liver region within 2 weeks of start of study intervention 18.Has received a live vaccine within 30 days prior to the first dose of study intervention 19.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 intervention 20.Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention 21.Has a known additional malignancy that is progressing or has required active treatment within the past 3 years 22.Has a known history of, or any evidence of, CNS metastases and/or carcinomatous meningitis as assessed by local site investigator 23.Has severe hypersensitivity (=Grade 3) to study intervention and/or any of their excipients 24.Has an active autoimmune disease that has required systemic treatment in past 2 years 25.Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis 26.Participants with proteinuria >1+ on urine dipstick testing will undergo 24-hour urine collection for quan
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1) To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by Blinded Independent Central Review (BICR) modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ 2) To compare overall survival (OS);Secondary Objective: 1) To compare objective response rate (ORR) per RECIST 1.1 as assessed by BICR 2) To evaluate duration of response (DOR), and disease control rate (DCR) per RECIST 1.1 as assessed by BICR 3) To evaluate the safety and tolerability of pembrolizumab plus lenvatinib versus placebo plus lenvatinib 4) To characterize the population pharmacokinetics (PK) of lenvatinib when co-administered with pembrolizumab 5) To evaluate TTP per RECIST 1.1 assessed by BICR 6) To evaluate efficacy outcomes per modified RECIST 1.1 (mRECIST) assessed by BICR;Primary end point(s): 1) PFS, defined as the time from randomization to the first documented disease progression per RECIST1.1 (by blinded central vendor) or death due to any cause, whichever occurs first 2) OS, defined as the time from randomization to death due to any cause;Timepoint(s) of evaluation of this end point: To be performed when approximately 335 OS events (63% of expected total OS events) are observed. With 21 months enrollment, the IA1 is expected approximately at Month 27, at which time approximately 474 PFS events are expected to have been accumulated. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) Objective Response (OR): Complete response (CR) or partial response (PR). 2) Duration of Response (DOR) defined as the time from the first documented evidence of CR or PR until the first documented disease progression or death due to any cause, whichever occurs first. - Disease Control (DC), defined as a best overall response of CR, PR, or stable disease (SD). SD must be achieved at =6 weeks after randomization to be considered best overall response. 4) Adverse events (AEs), serious AEs (SAEs), immune-related (irAEs), and hepatic AEs. 5) Study intervention discontinuations due to AEs. 6) Plasma concentration of lenvatinib versus time 7) TTP defined as the time from randomization to the first documented disease progression. 8) PFS, OR, DOR, DCR, and time to disease progression (TTP) ;Timepoint(s) of evaluation of this end point: To be performed when approximately 452 OS events (85% of expected total OS events) have been observed, projected to occur at approximately Month 36, at which time approximately 571 PFS events are expected to have been accumulated. | — |
Countries
Australia, Canada, Chile, China, Colombia, France, Germany, Ireland, Italy, Japan, Korea, Republic of, Mexico, New Zealand, Poland, Russian Federation, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States
Contacts
Public ContactGlobal Clinical Trial Operations
Merck Sharp & Dohme (UK) Ltd.
Outcome results
None listed