VISUGROMAB for Hepatocellular carcinoma (unresectable or metastatic) | Compensated liver disease (Child-Pugh A)

Inclusion criteria

• {"criterion_text":"- 1. Histologically confirmed diagnosis of unresectable or metastatic HCC, not amenable to a curative treatment approach. For participants with cirrhosis, clinical diagnosis by the American Association for the Study of Liver Diseases (AASLD) criteria is sufficient.\n- 10. All toxicities attributable to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 or below (according to National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0) or to baseline Grade before start of treatment.\n- 11. Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to receiving the first dose of IMP. Definition of females of childbearing potential: A female is considered fertile following menarche and until becoming post-menopausal unless permanently or surgically sterile. Surgical sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.A postmenopausal state is defined as no menses for at least 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.\n- 12. Female participants of childbearing potential must be willing to use an adequate, highly effective method of contraception for the course of the trial until 180 days after the last dose of IMP administration (visugromab/nivolumab/lenvatinib/placebo). If hormonal contraception is used an additional barrier method must be used as it is unknown if lenvatinib may impact the effectiveness of hormonal contraception.\n- 13. Male participants with a female partner(s) of childbearing potential, must agree to use an adequate method of contraception starting with the first dose of IMP until 180 days after the last dose of IMP administration (visugromab/nivolumab/lenvatinib/placebo). Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.\n- 14. Ability to understand the purpose of the trial, provide signed and dated informed consent prior to performing any protocol-related procedures (including Screening evaluations), and able to comply with the trial procedures (including completion of the electronic questionnaire on patient-reported outcomes). Note: The participant may also provide consent for Future Biomedical Research. However, the participant may participate in the main trial without participating in Future Biomedical Research.\n- 2. Measurable disease as per the local reading provided to the Investigator by a qualified radiologist based on an assessment per RECIST v1.1. Participants who received prior local therapy to the liver (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization, etc.) are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST v1.1.\n- 3. Must have failed one line of prior systemic treatment for unresectable or metastatic HCC containing an approved anti-PD-(L)1 CPI. The minimum treatment duration on this regimen must have been 12 weeks exposure for the CPI with no documented progression in this period. Failure of the prior line of systemic treatment for unresectable or metastatic HCC must have occurred under ongoing CPI treatment. Discontinuation of the prior CPI and line of treatment due to AEs, or any other reason than progression/relapse does not permit enrollment.\n- 4. Be ≥ 18 years of age on the day of signing informed consent.\n- 5. Life expectancy of at least 3 months as assessed by the Investigator.\n- 6. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.\n- 7. Child-Pugh score of A6 or better.\n- 8. Adequate organ function, defined as: •\tBone marrow function o\tAbsolute neutrophil count (ANC) ≥ 1.500 /μL. o\tPlatelets ≥ 75,000 /μL without transfusions. o\tHemoglobin ≥ 9.0 g/dL after ≥ 4 weeks without transfusions. •\tRenal o\tCreatinine clearance (CrCl) ≥ 50 mL/min 1.73m2. Note: CrCl will be assessed as estimated GFR (eGFR) following the CKD-EPIcr-cr equation. •\tHepatic o\tSerum bilirubin ≤ 2× upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 2 and ≤3× ULN. o\tSerum aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 5× ULN. •\tEndocrine o\tThyroid stimulating hormone (TSH) within normal range including participants with thyroid hormone substitution. If TSH is not within normal range at baseline, the participant will still be eligible if total T3 or free T3 and free T4 are within the normal limits.•\tCoagulation o\tAdequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤2.3 o\tNo evidence for clinically relevant hypo- or hypercoagulability or presence of clinically relevant thrombosis/thrombotic event. Note: All laboratory values relevant for inclusion criterion 8 need to be obtained within 14 days prior to enrollment.\n- 9. Documented virology status of hepatitis must be available."}

Exclusion criteria

• {"criterion_text":"- 1. Known fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma.\n- 21. Comedication with metformin in participants with type II diabetes. This includes combination products containing metformin. Note: For trial participation metformin must be replaced by other antidiabetic(s) prior to start of IMP administration (at minimum 7 days prior to trial baseline GDF-15 measurement) and for the whole duration of IMP administration as metformin induces GDF-15 production/serum levels significantly and would interfere with pharmacodynamic analyses.\n- 22. Chronic systemic corticosteroid treatment for other reasons. Participants with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections are not excluded from participation.\n- 2. Currently participating in a clinical trial or receiving any investigational therapy or has participated in a trial of an investigational agent in the past 4 weeks or used an investigational device within 4 weeks prior to administration of any IMP for any disease.\n- 23. Presence of active infection requiring systemic therapy.\n- 24. Known history of Human Immunodeficiency Virus (HIV) infection (known HIV 1/2 antibodies positive).\n- 25. Active HBV infection. Note: Active HBV infection is defined as having a positive HBV DNA or HBsAg test at Screening. Participants with a history of HBV infection who are negative for HBsAg and HBV-DNA by polymerase chain reaction will be considered non-infected with HBV. Note: Participants with active HBV can be enrolled if o\tHBV DNA < 1000 IU/mL obtained within 28 days prior to initiation of trial treatment AND, o\tAnti-HBV treatment (with effective antiviral therapy according to local SoC) for a minimum of 14 days prior to trial entry and willingness to continue treatment for the length of the trial.\n- 26. Coinfection of HBV and HCV OR HBV and hepatitis D virus (HDV). Note: Active HCV infection is defined as having a positive HCV ribonucleic acid (RNA) test at Screening. Management of the HCV infection must follow local institutional practice. Participants with a history of HCV infection who are negative for HCV-RNA by PCR will be considered non-infected with HCV. Note: Active HDV infection is defined as having a positive HDV RNA test at Screening. Participants with a history of HDV infection who are negative for HDV-RNA by PCR will be considered non-infected with HDV.\n- 27. Known history of allogeneic tissue/solid organ transplant.\n- 28. History of or ongoing hepatic encephalopathy.\n- 29. Active variceal hemorrhage within 3 weeks prior to Cycle 1 Day 1. Note: Patients at risk of variceal bleeding or history of variceal bleeding should be screened and treated for gastric and esophageal varices as per institutional guidelines prior to initiating lenvatinib treatment.\n- 10. Clinically active inflammatory bowel disease, active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, peritoneal carcinomatosis.\n- 30. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s participation for the full duration of the trial, or make it not in the best interest of the participant to participate, in the opinion of the treating Investigator.\n- 31. Symptomatic pleural effusion. A participant who is clinically stable following treatment for this condition (including therapeutic thoraco- or paracentesis) is eligible.\n- 32. Interstitial lung disease or a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.\n- 3. Prior exposure to visugromab or another anti-GDF-15 antibody. •\tParticipants having received additional anti-PD-(L)1 therapy before 1L systemic treatment of unresectable or metastatic HCC, e.g., in the context of local therapy, are ineligible\n- 33. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial.\n- 34. Known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial (including illicit drugs or severe alcoholism) or had a recent history (within the last 6 months before planned treatment start) of such abuse, or any other condition that as per Investigator view does not permit trial participation.\n- 35. Participant is under legal guardianship.\n- 4. More than 1 line of prior systemic treatment for unresectable or metastatic HCC.\n- 5. Any acute or chronic major tissue injury that may require maintained GDF-15 function for tissue protection as per Investigator assessment (e.g., diagnosed with liver, kidney, myocardial infarction, or other major organ failure, all within < 3 months prior to planned treatment start).\n- 6. Major surgery (e.g., surgery which requires general anesthetic and/or involves opening of body cavities) within 3 weeks prior to randomization (during Safety Run-In: initiation of treatment).\n- 11. Gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib in the opinion of the investigator.\n- 7. Received or completed any palliative radiotherapy within 28 days of the first dose of IMP.\n- 8. Expected to require any other form of antineoplastic therapy while on trial.\n- 9. Received a live or live-attenuated vaccination within 30 days of planned treatment start.\n- 12. Preexisting Grade ≥3 gastrointestinal or non-gastrointestinal fistula.\n- 13. Proteinuria ≥ 1 g /24 h. Note: Patients with > 1+ proteinuria on urine dipstick testing must undergo 24 h urine collection for quantitative assessment of proteinuria.\n- 14. Known history of other prior malignancy except if the participant has undergone potentially curative therapy with a minimum of 5 years of complete remission prior to randomization (during Safety Run-In: initiation of treatment), no evidence of disease recurrence and no further required therapy. Note: Not applicable if participants underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers and are considered to be cured.\n- 15. Known or detected clinically active central nervous system (CNS) involvement by HCC or other tumors.\n- 16. Has one of the following cardiovascular risk factors: •\tMyocardial infarction in the past 3 months before planned treatment start. •\tUncontrolled heart failure. •\tUncontrolled ventricular arrhythmia. •\tQT interval corrected for heart rate using Fridericia’s formula interval ≥ 470 ms regardless of sex. •\tPeri- or myocarditis in the past 3 months before planned treatment start. •\tA history of ischemic stroke in the past 3 months before planned treatment start. •\tA history of aneurysm if associated with an elevated risk of bleeding. •\tUncontrolled hypertension (≥ 160/100 mmHg) despite optimal antihypertensive therapy. Note: Stable atrial fibrillation with or without anticoagulation is exempted if there was no cardiac decompensation in the past 3 months before planned treatment start.\n- 17. Prior severe sensitivity reaction to treatment with another monoclonal antibody (mAb).\n- 18. Known sensitivity to visugromab and/or nivolumab and/or lenvatinib, or any component of these drug products.\n- 19. Known contraindication to lenvatinib and/or nivolumab treatment.\n- 20. Active autoimmune disease that has required systemic treatment in past 3 months before planned treatment start (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Not considered systemic treatment in this context are local corticosteroid treatment or replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.)."}

Primary endpoints

• {"endpoint_text":"- 1. Progression-free survival (PFS) as assessed by the local site. PFS is defined as time from randomization (during Safety Run-In: initiation of treatment) to first documented disease progression per RECIST v1.1 or death due to any cause, whichever occurred first.","definition_or_measurement_approach":"PFS defined as time from randomization (during Safety Run-In: initiation of treatment) to first documented disease progression per RECIST v1.1 or death due to any cause; assessed by the local site."}

Secondary endpoints

• {"endpoint_text":"- 1. Independently assessed Progression-free survival by Blinded Independent Central Review\n- 2. Overall survival.\n- 3. Objective response rate, defined as the percentage of participants with best overall response of complete response or partial response per RECIST v1.1 as assessed by the Investigator.\n- 4. Participant weight course over time.\n- 5. Complete response rate.\n- 6. Partial response rate.\n- 7. Objective response rate.\n- 8. Time to response.\n- 9. Duration of response.\n- 10. Progression-free survival rate.\n- 11. Overall survival rate.\n- 12. Incidence, type, and severity of adverse events (AEs), recorded as treatment-emergent AEs (TEAEs), treatment-related AEs (including immune mediated Adverse Events [imAEs], reported as AEs of Special Interest [AESIs]), and serious AEs (SAEs).\n- 13. Participants’ subjective wellbeing as assessed via the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for cancer (EORTC QLQ–C30).","definition_or_measurement_approach":"Independently assessed PFS: by Blinded Independent Central Review. Overall survival: time to death from any cause. Objective response rate: percentage with best overall response of complete or partial response per RECIST v1.1 as assessed by Investigator. Participant weight: serial weight measurements over time. Complete/partial response rates and ORR per RECIST v1.1. Time to response and duration of response per RECIST v1.1 definitions. PFS rate and OS rate are standard survival metrics. AEs: incidence, type, severity recorded as TEAEs, treatment-related AEs (including imAEs/AESIs) and SAEs. Subjective wellbeing: measured using EORTC QLQ–C30 questionnaire."}

France

Earliest CTIS Part Ii Submission Date

25-11-2025

Latest Decision Or Authorization Date

05-01-2026

Processing Time Days

41

Number Of Sites

4

Number Of Participants

16

Germany

Earliest CTIS Part Ii Submission Date

27-11-2025

Latest Decision Or Authorization Date

23-12-2025

Processing Time Days

26

Number Of Sites

4

Number Of Participants

15

Italy

Earliest CTIS Part Ii Submission Date

28-11-2025

Latest Decision Or Authorization Date

08-01-2026

Processing Time Days

41

Number Of Sites

3

Number Of Participants

14

Spain

Earliest CTIS Part Ii Submission Date

24-11-2025

Latest Decision Or Authorization Date

09-01-2026

Processing Time Days

46

Number Of Sites

5

Number Of Participants

14

Primary sponsor

Full Name

CatalYm GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Contract research organisations

Name

Psi Cro AG

Name

Metronomia Clinical Research GmbH

Name

Suvoda LLC

Name

Primevigilance Limited

Responsibilities

Safety Reporting

Third parties

• {"country":"Switzerland","full_name":"Lonza AG","duties_or_roles":"Drug Substance: Release testing (Polysorbate), Stability testing (Polysorbate); Drug Product: Release testing, Stability testing, Stability storage","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Alderley Analytical Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Bioreliance Limited","duties_or_roles":"Drug Substance: Testing cell banks for viruses","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Fisher Clinical Services GmbH (Allschwil)","duties_or_roles":"Drug Product: Secondary packaging, Labelling","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH (Rheinfelden)","duties_or_roles":"Drug Product: QP Release, Distribution","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"France","full_name":"Solvias France","duties_or_roles":"Drug Product: Stability testing (sterility), Release testing(sterility)","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Lonza Biologics PLC","duties_or_roles":"Drug Substance: Cell bank storage, Manufacturing, Release testing, Stability testing; Drug Product: Stability testing (potency)","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Mlm Medical Labs GmbH","duties_or_roles":"Laboratory Kit Supply, Sample Management & Triage","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH (Weil Am Rhein)","duties_or_roles":"Decomissioning","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Lonza AG (Stein Ag)","duties_or_roles":"Drug Product: Manufacturing, Primary Packaging, Release testing (microbiologic), Stability storage","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Median Technologies","duties_or_roles":"Central Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Discovery Life Sciences LLC","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Bioreliance Corp.","duties_or_roles":"Drug Substance: Testing cell banks for viruses, mycoplasmas and sterility","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Primevigilance Limited","duties_or_roles":"Safety Reporting","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Metronomia Clinical Research GmbH","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Nuvisan GmbH","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Bioreliance Limited (Glasgow)","duties_or_roles":"Drug Substance: Testing cell banks for viruses and non-viral adventitious agents, Identity testing unprocessed bulk for viruses and mycoplasmas","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Metabolon Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Lonza Biologics Inc.","duties_or_roles":"Drug Substance: Cell bank storage","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Fisher Clinical Services Inc.","duties_or_roles":"Drug Product: Secondary packaging, Labelling","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Psi Cro AG","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Eurofins Adme Bioanalyses","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Lonza Biologics PLC (Bath Road)","duties_or_roles":"","organisation_type":"Pharmaceutical company"}