Study of Milciclib in Patients With Unresectable/Metastatic Hepatocellular Carcinoma

Inclusion Criteria:

• Patients with diagnosis of HCC, confirmed by histology or radiology according toAmerican Association for the Study of Liver Diseases/European Association for theStudy of the Liver (AASLD/EASL) criteria prior to the start of the investigationalproduct. Imaging characteristics should be retrieved from at least a 3-phase liverprotocol CT or MRI with target tumor lesion(s) demonstrating arterialhyper-enhancement and wash-out in the venous phase;
• Tumor stages eligible for the study are defined as:

1. HCC within the Barcelona Clinic Liver Cancer (BCLC) stage C. In case of portalvein thrombosis (PVT) an associated target lesion in the liver parenchyma shouldbe clearly defined. PVT without associated target lesion are not eligible to thestudy;
2. Untreatable post-chemoembolization (TACE) or post-radioembolization (TARE)progression defined as BCLC stage B or C with radiographic progression accordingto mRECIST after TACE or TARE not eligible for further surgical or loco-regionaltherapy;
3. Recurring HCC non eligible for pre-transplant downstaging protocols or forresection;

• Patients must have failed sorafenib treatment or be intolerant to sorafenib oractively refusing sorafenib

1. Failing sorafenib treatment is defined if after ≥ 14 days of therapy (notnecessarily consecutive) radiology progression is ascertained according tomRECIST;
2. Intolerant to sorafenib treatment is defined as a sorafenib related Grade 2 orgreater adverse event (CTC-AE) that continues or recurs after sorafenib treatmentinterruption for 7 days or dose reduction;
3. Active refusal should be documented by a written and signed patient declarationto be filed in the clinical records;

• Child-Pugh score ≤ 6 (class A);
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
• Local or loco-regional therapy (i.e., surgery, radiation therapy, hepatic arterialembolization, chemoembolization, radioembolization, radiofrequency ablation,percutaneous ethanol injection, or cryoablation) must have been completed ≥4 weeksprior to study entry with documentation of progressive or recurrent disease;
• Signed and dated Investigational Review Board/Independent Ethics Committee (IRB/IEC)approved Informed Consent/Genetic Consent.

Exclusion Criteria:

• Prior use of any systemic anti-cancer therapy (including experimental agents andimmunotherapy) except for sorafenib and second line treatment with regorafenibdiscontinued for intolerance within 14 days;
• Known fibrolamellar HCC or mixed hepato-cholangiocarcinoma;
• Grade 3 oesophageal varices, regardless of previous bleeding episodes on endoscopyperformed no more than in the last 12 months;
• Clinical meaningful ascites defined as CTCAE Grade≥2. Patient who have been on astable medication regimen for at least 2 months to manage ascites are eligible if theyshow no ascites at the clinical examination. Patients with clinically undetectableascites who are Child A with detectable ascites at CT/MRI are eligible to theprotocol;