Clinical trial NCT02716012: First-in-Human Safety, Tolerability and Antitumour Activity Study of MTL-CEBPA in Patients With Advanced Liver Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Hepatocellular Carcinoma
Liver Cancer
Keywords: Oligonucleotide
RNA
saRNA
Sorafenib
Myeloid
Lead sponsor: Mina Alpha Limited
Sponsor class: INDUSTRY
First posted: 2016-03-22
Enrollment: 75
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Part 1- Incidence of Grade 3 or 4 drug related adverse events
timeFrame: During cycle 1 (28 days) of treatment assessed over 15 months
measure: Part 2 - Change in tumour size from baseline using RECIST 1.1 and mRECIST in patients treated with MTL-CEBPA in combination with sorafenib
timeFrame: Eight weekly intervals until death assessed for 100 weeks
Secondary outcomes:
measure: 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
timeFrame: At the end of every cycle (28 days) of treatment assessed over 15 months
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: National University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Trust
city: Glasgow
country: United Kingdom
facility: The Beatson West of Scotland Cancer Centre
city: Liverpool
country: United Kingdom
facility: Clatterbridge Cancer Centre NHS Foundation Trust
city: London
country: United Kingdom
facility: Guy's and St. Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: London
country: United Kingdom
facility: The Royal Free London NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Newcastle
country: United Kingdom
facility: Newcastle upon Tyne Hospitals NHS Foundation Trust
Study officials:
affiliation: Guy's and St Thomas' NHS Foundation Trust and King's College London
name: Dr Debashis Sarker, MBChB, MRCP
role: PRINCIPAL_INVESTIGATOR
affiliation: Mina Alpha Limited
name: Professor Nagy Habib, FRCS
role: STUDY_DIRECTOR
References:
citation: Sarker D, Plummer R, Meyer T, Sodergren MH, Basu B, Chee CE, Huang KW, Palmer DH, Ma YT, Evans TRJ, Spalding DRC, Pai M, Sharma R, Pinato DJ, Spicer J, Hunter S, Kwatra V, Nicholls JP, Collin D, Nutbrown R, Glenny H, Fairbairn S, Reebye V, Voutila J, Dorman S, Andrikakou P, Lloyd P, Felstead S, Vasara J, Habib R, Wood C, Saetrom P, Huber HE, Blakey DC, Rossi JJ, Habib N. MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-alpha, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial. Clin Cancer Res. 2020 Aug 1;26(15):3936-3946. doi: 10.1158/1078-0432.CCR-20-0414. Epub 2020 May 1.