First-in-Human Safety, Tolerability and Antitumour Activity Study of MTL-CEBPA in Patients With Advanced Liver Cancer

Study Overview
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Brief Summary
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MNA-3521-011 study is a multi-centre, open-label, first-in-human, phase 1a/b clinical study dose/dose frequency escalation followed by a cohort expansion part. MTL-CEBPA is administered as monotherapy or in combination with sorafenib to patients with advanced hepatocellular carcinoma and cirrhosis of the liver. All participants will be considered unsuitable for liver tumour resection and/or is refractory to radiotherapy and other loco-regional therapies. MTL-CEBPA consists of a double stranded RNA formulated into a SMARTICLES® liposomal nanoparticle and is designed to activate the CEBPA gene.

Official Title
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A First-in-Human, Multi-centre, Open-label, Phase 1a/b Clinical Study With RNA Oligonucleotide Drug MTL-CEBPA to Investigate Its Safety, Tolerability, and Antitumour Activity in Patients With Advanced Liver Cancer

Conditions
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Hepatocellular Carcinoma, Liver Cancer

Intervention / Treatment
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* Drug: MTL-CEBPA
* Drug: Sorafenib 200mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed advanced HCC with cirrhosis resulting from hepatitis B, hepatitis C, alcohol-related liver disease or any other aetiology OR Histologically confirmed advanced HCC resulting from NASH with or without cirrhosis Patient is considered unsuitable for liver tumour resection and/or is refractory to radiotherapy and other loco-regional therapies At least one measurable lesion with target lesion size ≥ 1.0 cm as measured by MRI or CT Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Child-Pugh class A or B (up to B7) Eligible to undergo pre and post treatment mandated biopsies Acceptable laboratory parameters, as demonstrated by: Platelets ≥ 70 x 10^9/L Serum albumin > 26 g/L ALT and AST ≤ 5 x ULN Bilirubin ≤ 50 µmol /L WBC ≥ 2.0 x 10^9/L, Absolute neutrophil count ≥ 1.5 x 109/L Haemoglobin ≥ 9.0 g/dL Prothrombin time (PT) <20 seconds Acceptable renal function as demonstrated by: Serum creatinine ≤ 1.5 x ULN Calculated creatinine clearance ≥ 60 mL/min Exclusion Criteria: Patients who have been treated with TACE or chemotherapy within the last 28 days Prior investigational drugs within the last 30 days Grade > 1 prior treatment-related toxicities (excluding alopecia) at the time of screening Patients with clinically significant cancer ascites Any episode of bleeding from oesophageal varices or other uncontrolled bleeding within the last 3 months prior to study treatment initiation Patients with history of haemorrhage or gastrointestinal perforation Patients administered with serum albumin within the last 7 days prior to the first study drug administration Known infection with human immunodeficiency virus (HIV) Patients with central nervous system (CNS), bone or peritoneal metastasis Patients presenting with marked baseline prolongation of QT/QTc interval defined as repeated demonstration of a QTc interval ≥450 ms (males) and ≥460 ms (females) using Fridericia's correction formula Signs and symptoms of heart failure characterised as greater than the New York Heart Association (NYHA) Class I or other clinically significant cardiac abnormalities (including history of myocardial infarction) including stable abnormalities. Major surgery within the last 30 days prior to study treatment initiation Patients with history of organ transplantation or cardiac surgery Patients with sepsis, ineffective biliary drainage with or without cholangitis, obstructive jaundice or encephalopathy at screening visit or within the last two weeks prior to study treatment initiation, whichever earlier Evidence of spontaneous bacterial peritonitis or renal failure or allergic reactions to the agent or excipient at screening visit or within the last two weeks prior to study treatment initiation, whichever earlier Known hypersensitivity to the active sorafenib or to any of the excipients Occurrence of a grade 3 or higher sorafenib or lenvatinib related toxicity during any sorafenib / lenvatinib treatment received prior to study enrolment, according to toxicity criteria (NCI CTCAE v 5.0) Pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MTL-CEBPA Monotherapy<br>MTL-CEBPA administered weekly, twice weekly or thrice weekly over 3 weeks followed by 1 week of rest defining a 28-day cycle. | Drug: MTL-CEBPA<br>* Intravenous administration<br>|
| Experimental: MTL-CEBPA & Sorafenib (combination)<br>MTL-CEBPA is administered weekly or twice weekly in combination with sorafenib over 3 weeks followed by 1 week of rest defining a 28-day cycle. | Drug: MTL-CEBPA<br>* Intravenous administration<br>Drug: Sorafenib 200mg<br>* Sorafenib tablets<br>|
| Experimental: MTL-CEBPA & Sorafenib (sequential)<br>MTL-CEBPA is administered weekly or twice weekly for 2 cycles (28-day cycle) followed by 2 cycles of sorafenib | Drug: MTL-CEBPA<br>* Intravenous administration<br>Drug: Sorafenib 200mg<br>* Sorafenib tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1- Incidence of Grade 3 or 4 drug related adverse events | Frequency of adverse events graded according to NCI CTCAE v5.0 | During cycle 1 (28 days) of treatment assessed over 15 months | 
| Part 2 - Change in tumour size from baseline using RECIST 1.1 and mRECIST in patients treated with MTL-CEBPA in combination with sorafenib | Increase or decrease in tumour measurement using Response Evaluation Criteria in Solid Tumours (RECIST) reports | Eight weekly intervals until death assessed for 100 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2 - Safety and tolerability of co-administering MTL-CEBPA with sorafenib assessed using frequency of adverse events graded according to toxicity criteria (NCI CTCAE v 5.0) and categorised by body system | Frequency of treatment-related adverse events graded according to NCI CTCAE v5.0 | At the end of every cycle (28 days) of treatment assessed over 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oligonucleotide, RNA, saRNA, Sorafenib, Myeloid