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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 : April 5, 2022
Sponsor:
Information provided by (Responsible Party):
Mina Alpha Limited

Tracking Information
First Submitted Date  ICMJE March 11, 2016
First Posted Date  ICMJE March 22, 2016
Last Update Posted Date April 5, 2022
Actual Study Start Date  ICMJE March 1, 2016
Estimated Primary Completion Date November 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 16, 2021)
  • 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
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: March 21, 2016)
Incidence of Grade 3 or 4 drug related adverse events and clinical lab abnormalities defined as Dose Limiting Toxicities (DLTs) using NCI CTCAE v 4.03 [ Time Frame: During cycle 1 (28 days) of treatment ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 16, 2021)
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
Original Secondary Outcome Measures  ICMJE
 (submitted: March 21, 2016)
  • Recommended Phase 2 Dose (RP2D) of MTL-CEBPA defined as the most appropriate dose to maximise a favourable risk/benefit reward for the participant population [ Time Frame: After completion of all Cycle 1 (28 days) of treatment for participant enrolled in part 1 ]
  • Total Active Pharmaceutical Ingredient (API) levels in plasma. [ Time Frame: The pharmacokinetics profile will be assessed by blood collection during Cycle 1 (28 days) of treatment ]
  • Preliminary evidence of liver function improvement [ Time Frame: Liver function will be assessed by blood collection twice weekly at every cycle (28 days) of treatment ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE First-in-Human Safety, Tolerability and Antitumour Activity Study of MTL-CEBPA in Patients With Advanced Liver Cancer
Official Title  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hepatocellular Carcinoma
  • Liver Cancer
Intervention  ICMJE
  • Drug: MTL-CEBPA
    Intravenous administration
  • Drug: Sorafenib 200mg
    Sorafenib tablets
Study Arms  ICMJE
  • 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.
    Intervention: Drug: MTL-CEBPA
  • 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.
    Interventions:
    • Drug: MTL-CEBPA
    • Drug: Sorafenib 200mg
  • 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
    Interventions:
    • Drug: MTL-CEBPA
    • Drug: Sorafenib 200mg
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: March 21, 2016)
51
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2023
Estimated Primary Completion Date November 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Singapore,   Taiwan,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02716012
Other Study ID Numbers  ICMJE MNA-3521-011
2015-003051-21 ( EudraCT Number )
20332 ( Other Identifier: UK NIHR CRN )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Mina Alpha Limited
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Mina Alpha Limited
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account Mina Alpha Limited
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP