Study Investigating the Association of NP137 With Atezolizumab-Bevacizumab Combination in First Line in Unresectable HCC

The study is a multicentric, prospective, single arm phase 1b trial. This study will enroll 43 to 52 patients and consists of 2 parts: Safety Lead-in Phase and Expansion Phase. Initially, 3 to 12 patients will be enrolled into a Safety Lead-in Phase based on a 3 + 3 design, with the possibility of dose de-escalation, to confirm the recommended dose of NP137.

The Expansion Phase will start after completion of Safety Lead-in Phase at the confirmed dose and will include 40 patients. Patients will be assigned to the experimental single arm (NP137+ Atezolizumab-Bevacizumab).

Inclusion criteria

• Males or females ≥ 18 years of age
• Histologically confirmed (liver biopsy within 24 previous weeks) and documented unresectable hepatocellular carcinoma
• Patients with a BCLC C or BCLC B status ineligible for or in failure of locoregional treatment, as per the Barcelona Clinic Liver Cancer (BCLC) staging system
• No prior systemic therapy for advanced HCC
• Liver tumor burden < 50% of the liver (per Investigator judgment)
• Child-Pugh A (≤ 6) without any history of cirrhotic decompensation within the past 6 months
• Antiviral therapy required in hepatitis B virus patients (Hepatitis B antigen positive)
• Willing to have liver biopsy between C4 and C5
• Presence of a measurable tumor per RECIST v1.1 criteria
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Life expectancy ≥ 12 weeks
• Absence of previous liver decompensation
• In case of cirrhosis, last esophageal varices detection by esogastroduodenal endoscopy have to be performed within last the 6 months before inclusion
• Adequate hematologic function prior to the first dose of NP137, defined as:

Absolute neutrophils count ≥ 1500 cells/μL 14.2. Hemoglobin ≥ 9 g/dL with no transfusion within 4 weeks prior to first planned dose of NP137 14.3. Platelet count > 50,000/μL with no transfusion within 2 weeks prior to first planned dose of NP137

• Adequate renal function prior to first dose, defined as:

15.1. Serum creatinine < 1.5 × Upper limit of normal (ULN ) 15.2. Creatinine clearance ≥ 30 mL/min/m2 (by Cockroft-Gault equation of 24-hour urine) if creatinine ≥ 1.5 × ULN

• Adequate hepatic function prior first dose, defined as AST/ALT ≤ 5 × ULN
• Women patients of childbearing potential must have a negative serum pregnancy test at screening and baseline, and be willing to use a highly effective contraception. The patient should be advised to continue the contraception for at least 6 months following the completion of dosing. Women with cessation for > 24 months of previously occurring menses, or women of any age who have had a hysterectomy, or have had both ovaries removed will be considered to be of non-childbearing potential.
• Male patients of reproductive potential must be willing to use one acceptable method of contraception, as judged by Investigator and Sponsor and/or to refrain from donating sperm from the time of screening through at least 6 months following the completion of dose administration.
• Amenable to computed tomography (CT) with 3 or 4 phase liver or magnetic resonance imaging (MRI) of abdomen and pelvis, and CT of chest, or MRI of whole body, for initial tumor size measurements and subsequent follow-up.
• Absence of other clinically relevant abnormalities for any screening laboratory test results as judged by the Investigator and Sponsor.
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
• Able to understand and provide written informed consent
• Patients covered by Health Insurance System

Exclusion criteria

• Any known history of encephalopathy within 6 months prior to first planned dose of treatment
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
• Known esophageal varices with recent history of bleeding (within previous 6 months)
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• Chronic treatment with immunosuppressive agents (like steroids) ≤ 6 weeks prior to first planned dose of treatment.
• Major surgical procedures, open biopsy or significant traumatic injury ≤ 4 weeks prior to first dose of treatment or anticipation of major surgical procedure during the course of the trial, minor surgical procedures ≤ 1 week of first planned dose (the surgical wound must be fully healed)
• Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure
• Any clinically significant cardiovascular condition as judged by the Investigator (such as New York Heart Association Class II or greater cardiac failure, myocardial infarction, or cerebrovascular accident within 3 months prior to Day 1 of Cycle 1, uncontrolled arterial hypertension, unstable arrhythmia, or unstable angina)
• Severe or uncontrolled renal condition
• Untreated chronic hepatitis B
• Co-infection of HBV and HCV
• Use of any prohibited concomitant medications within 14 days of the Baseline/Day 1 visit
• Contraindication to additionnal liver biopsy planned between C4 and C5
• Contraindication to iodinated contrast agent infusion
• Known current alcohol (> 20g/ Day in women and > 30g/ Day in men) or substance abuse
• History of leptomeningeal disease
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
• Known active tuberculosis
• History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 6 months after the last dose of treatment
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
• Uncontrolled tumor-related pain
• Uncontrolled or symptomatic hypercalcemia
• Treatment with systemic immunostimulatory agents
• Inadequately controlled arterial hypertension
• Prior history of hypertensive crisis or hypertensive encephalopathy
• Evidence of bleeding diathesis or significant coagulopathy
• History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration
• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
• Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses
• Known clinically significant or life threatening organ or systemic disease such that in the opinion of the Investigator, the significance of the disease will compromise the patient's participation in the trial
• Known intolerance or hypersensitivity to the active ingredient or to one of the components of the study drug
• Persistent toxicities related to prior treatment of grade greater than 1
• Subjects with active infection
• History of bone marrow allograft or solid organ transplant
• Subjects requiring corticosteroid therapy at a dose equivalent to more than 10 mg of prednisone equivalent dose per day (corticosteroid administration is permitted by a route resulting in minimal systemic exposure [cutaneous, rectal, articular, ocular or inhalation] is authorized).
• Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
• History of gastrointestinal perforations and fistulae
• Uncontrolled or symptomatic proteinuria
• Active aneurysm considered as unstable and/or at high risk of complication
• Patients who experienced immune-mediated pericardial disorders during previous treatment by immune checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1 therapeutic antibodies
• Subject who participate or plan to participate in another interventional clinical trial or who is in exclusion period for another study,
• Subject who cannot be contacted in case of emergency
• Persons referred to in Articles L1121-5 to L1121-8 of the French code of public health (this corresponds to all persons protected: pregnant or parturient women, breastfeeding mothers, persons deprived of liberty by judicial or administrative decision, persons subject to a legal protection measure).