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

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ClinicalTrials.gov Identifier: NCT02716012
Recruitment Status : Active, not recruiting
First Posted : March 22, 2016
Last Update Posted : January 20, 2021
Sponsor:
Information provided by (Responsible Party):
Mina Alpha Limited

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.


Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Liver Cancer Drug: MTL-CEBPA Drug: Sorafenib 200mg Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 51 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 1, 2016
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Liver Cancer
Drug Information available for: Sorafenib

Arm Intervention/treatment
Experimental: MTL-CEBPA Monotherapy
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
Intravenous administration

Experimental: MTL-CEBPA & Sorafenib (combination)
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
Intravenous administration

Drug: Sorafenib 200mg
Sorafenib tablets

Experimental: MTL-CEBPA & Sorafenib (sequential)
MTL-CEBPA is administered weekly or twice weekly for 2 cycles (28-day cycle) followed by 2 cycles of sorafenib
Drug: MTL-CEBPA
Intravenous administration

Drug: Sorafenib 200mg
Sorafenib tablets




Primary Outcome Measures :
  1. Part 1- Incidence of Grade 3 or 4 drug related adverse events [ Time Frame: During cycle 1 (28 days) of treatment assessed over 15 months ]
    Frequency of adverse events graded according to NCI CTCAE v5.0

  2. Part 2 - Change in tumour size from baseline using RECIST 1.1 and mRECIST in patients treated with MTL-CEBPA in combination with sorafenib [ Time Frame: Eight weekly intervals until death assessed for 100 weeks ]
    Increase or decrease in tumour measurement using Response Evaluation Criteria in Solid Tumours (RECIST) reports


Secondary Outcome Measures :
  1. 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 [ Time Frame: At the end of every cycle (28 days) of treatment assessed over 15 months ]
    Frequency of treatment-related adverse events graded according to NCI CTCAE v5.0



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02716012


Locations
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Singapore
National University Hospital
Singapore, Singapore
Taiwan
National Taiwan University Hospital
Taipei, Taiwan
United Kingdom
University Hospitals Birmingham NHS Foundation Trust
Birmingham, United Kingdom
Cambridge University Hospitals NHS Trust
Cambridge, United Kingdom
The Beatson West of Scotland Cancer Centre
Glasgow, United Kingdom
Clatterbridge Cancer Centre NHS Foundation Trust
Liverpool, United Kingdom
Guy's and St. Thomas' NHS Foundation Trust
London, United Kingdom
Imperial College Healthcare NHS Trust
London, United Kingdom
The Royal Free London NHS Foundation Trust
London, United Kingdom
University College London Hospitals NHS Foundation Trust
London, United Kingdom
Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle, United Kingdom
Sponsors and Collaborators
Mina Alpha Limited
Investigators
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Principal Investigator: Dr Debashis Sarker, MBChB, MRCP Guy's and St Thomas' NHS Foundation Trust and King's College London
Study Director: Professor Nagy Habib, FRCS Mina Alpha Limited
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Mina Alpha Limited
ClinicalTrials.gov Identifier: NCT02716012    
Other Study ID Numbers: MNA-3521-011
2015-003051-21 ( EudraCT Number )
20332 ( Other Identifier: UK NIHR CRN )
First Posted: March 22, 2016    Key Record Dates
Last Update Posted: January 20, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Mina Alpha Limited:
Oligonucleotide
RNA
saRNA
Sorafenib
Myeloid
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Liver Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Sorafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action