This is a Phase 2b, randomized, blinded clinical trial investigating the efficacy and safety of visugromab in combination with nivolumab and Lenvatinib compared to double placebo and Lenvatinib in participants with unresectable or metastatic HCC and compensated liver function (Child-Pugh A) after failure of 1L treatment that included an anti-PD-(L)1 compound. The trial consists of 2 Parts: a non-randomized Safety-run-in part (Part 1) and the subsequent randomized part (Part 2) with 2 treatment arms (A and B). Randomization of participants into Treatment Arm A and B will continue until 40 efficacy-evaluable participants are enrolled into each Treatment Arm.
Histologically confirmed diagnosis of unresectable or metastatic HCC, not amenable to a curative treatment approach.
Measurable disease as per RECIST v1.1 as determined by the Investigator based upon local radiologist assessment.
Must have failed one line of prior systemic treatment for unresectable or metastatic HCC containing an approved anti PD (L)-1 checkpoint inhibitor (CPI) with a minimum treatment duration of 12 weeks exposure for the CPI with no documented progression in this period.
Age ≥ 18 years on the day of signing the informed consent.
Known fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma.
More than 1 line of prior systemic treatment for unresectable or metastatic HCC.
Received or completed any palliative radiotherapy for symptoms within 28 days of the first dose of IMP.
Expected to require any other form of antineoplastic therapy during the trial.
Parallel
Visugromab RDE (recommended dose for expansion)
Biological/VaccineParticipants receive visugromab (RDE) intravenous (IV) on Day 1 of every 21-day cycle (every 3 weeks, or Q3W) for up to 35 treatments
Nivolumab
Biological/VaccineParticipants receive Nivolumab 360mg intravenous (IV) on Day 1 of every 21-day cycle (every 3 weeks, or Q3W) for up to 35 treatments after visugromab infusion
Lenvatinib
DrugParticipants receive Lenvatinib per os (PO) once daily according to body weight (\> 60kg: 12mg; \< 60kg: 8mg)
Placebo Saline Infusion
Other interventionSaline (0.9%NaCl) intravenous (2x IV) on Day 1 of every 21-day cycle every 3 weeks (Q3W) for up to 35 treatments
Progression-free survival (PFS)
Investigator assessed Progression-free survival (PFS) time from randomization (during Safety Run-In: initiation of treatment) to first documented disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurred first.
Independently assessed PFS by Blinded Independent Central Review (BICR)
CR (Complete Response) rate
PR (Partial Response) rate
ORR (Overall Response) rate
Overall response rate, defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) per RECIST v1.1 as assessed by the Investigator
Maximum concentration (Cmax) of visugromab
Cmax is the maximum observed serum concentration of visugromab
Minimum concentration (Cmin) of visugromab
Cmin is the minimum observed serum concentration of visugromab
Functional Assessment of the Anorexia and Cachexia Therapy questionnaire (FAACT-A/CS)
FAACT-ACS consists of 12 items assessing anorexia/cachexia-related symptoms. Each item is scored individually from 0 ("Not at all") to 4 ("Very much"), with some requiring reverse scoring as in the FAACT Scoring Guideline. The FAACT-ACS subscale score is calculated by summing item scores (reversals performed as applicable); multiplied by the total number of items and divided by the number of items answered. The total score ranges from 0-48, with higher scores indicating better anorexia/cachexia-related quality of life.
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