We compare the efficacy and safety of the new medication MTL-CEBPA in combination with sorafenib with the efficacy and safety of sorafenib alone. Sorafenib is already being used for the treatment of HCC.
ID
Source
Brief title
Condition
- Viral infectious disorders
- Hepatobiliary neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To compare PFS of MTL-CEBPA in combination with sorafenib compared to sorafenib
alone as determined by BICR and assessed using RECIST v1.1 guidelines.
Secondary outcome
To compare efficacy of MTL-CEBPA in combination with sorafenib compared to
sorafenib alone as assessed by BICR for the following: Best Objective Response
(BOR), Objective Response Rate (ORR), Duration of Response (DoR), Time to
Response (TTR), and changes in tumour size.
To compare OS of MTL-CEBPA in combination with sorafenib compared to sorafenib
alone.
To assess consistency in tumour-based efficacy endpoints between BICR and
Investigator assessment.
To evaluate the safety and tolerability profile of MTL-CEBPA when administered
in combination with sorafenib and compared to sorafenib alone.
To compare the health-related quality of life (HRQoL) of MTL-CEBPA in
combination with sorafenib compared to sorafenib alone as assessed by
EORTC-QLQ-C30 plus EORTC-QLQ-HCC18 QOL questionnaires.
Background summary
MTL-CEBPA is made of two strands of ribonucleic acid (RNA). RNA is a substance
that carries and gives information to genes, which are structures that carry
the information needed to make the different parts of our cells. The drug
MTL-CEBPA sends a message to a particular gene to work harder to produce the
proteins necessary to make sure the liver works properly.
Previous research has shown that MTL-CEBPA was safe to give in humans and can
have an anti-cancer effect by slowing down tumour growth. The current thinking
is that MTL-CEBPA works in combination with other anti-cancer drugs. In this
study, called OUTREACH2, MTL-CEBPA is combined with another drug sorafenib.
Sorafenib is a type of targeted therapy approved for the treatment of liver
cancer. Sorafenib*s category of drug is called a multi kinase inhibitor.
Sorafenib works by blocking signals in the cancer cells that make them grow.
Blocking the signals causes the cells to die. Sorafenib can also stop cancer
cells developing new blood vessels. This reduces their supply of oxygen and
nutrients, so the tumour shrinks or stops growing.
Study objective
We compare the efficacy and safety of the new medication MTL-CEBPA in
combination with sorafenib with the efficacy and safety of sorafenib alone.
Sorafenib is already being used for the treatment of HCC.
Study design
Phase II, randomised, open label, two-arm, comparative study. This is an
interventional, parallel study with active control, run across multiple
centres.
Randomisation: Participants will be randomised in a 2:1 ratio in 2 groups
between MTLCEBPA + sorafenib (100 participants) and sorafenib alone (50
participants).
Intervention
Participants will be assigned to two groups to receive MTL-CEBPA + sorafenib or
sorafenib monotherapy in a 2:1 randomisation scheme.
Stratification: ALBI (albumin-bilirubin) grade (1 vs >1) and geographic region
(Asia vs Rest of World).
MTL-CEBPA will be administered once a week (QW) at a dose of 130 mg/m2 by i.v.
infusion over 60 minutes for 3 weeks followed by a rest period of 1 week (4
weeks = one cycle) and continued until study treatment discontinuation criteria
are met.
Sorafenib will be administered orally starting on Cycle 1 Day 1 for
participants in the sorafenib monotherapy group and on Day 8 for participants
in the MTL-CEBPA + sorafenib group, at the approved dose of 400*mg (2 x 200 mg
tablets) twice daily (BID). Sorafenib will be administered following MTL-CEBPA
administration on days when both drugs are administered and continued until
study treatment discontinuation criteria are met.
Study burden and risks
Subject will visit the hospital for screening visit and during cycle 1 visits
on day 1,2,8,15 and for additional cycles on day 1.8.15. and 22.
per cycle weekly infusion with MTL-CEBPA the first 3 weeks and sorafenib daily
dose as of day 8 of first cycle.
or if sorafenib alone group dialy dose of sorafenib from day 1.
every three weeks completion of questionnaires estimated 10 to 15 minutes but
subject should take as long as needed.
every 8 weeks CT scan
blood samples taken at all visits
subject can consent to optional tumor biopsies at screening and during
treatment.
Wood lane 84
London W12 0BZ
GB
Wood lane 84
London W12 0BZ
GB
Listed location countries
Age
Inclusion criteria
1. Written informed consent obtained prior to any specific trial-related
procedure.
2. Male or female 18 years or older.
3. Histologically confirmed advanced HCC with cirrhosis in a participant with a
history of hepatitis B and/or C. Participants with past or ongoing HCV
infection will be eligible for the study. Participants must have completed
their treatment at least 1 month prior to starting study intervention and their
HCV viral load below the limit of quantification. Participants who are HCV Ab
positive but HCV RNA negative due to prior treatment or natural resolution will
be eligible. Participants with past or controlled ongoing hepatitis B will be
eligible as long as their HBV viral load is less than 500 IU/mL prior to first
dose of study drug. Participants on active HBV therapy with viral loads under
100 IU/mL should stay on the same therapy throughout study intervention.
4. Child-Pugh classification A.
5. Unsuitable for liver tumour resection and/or refractory to loco-regional
therapy.
6. Not eligible for liver transplantation.
7. Had progression or recurrence of HCC following previous treatment with
atezolizumab in combination with bevacizumab. Participants with progression or
recurrence of HCC on non-atezolizumab anti-PD-1/PD-L1 inhibitors and non
bevacizumab anti-VEGF agent in combination or as any as single agents, and no
prior treatment with atezolizumab and bevacizumab, are eligible.
8. Naïve to tyrosine kinase inhibitors, including sorafenib, regorafenib,
cabozantinib, and lenvatinib.
9. Participants with BCLC stage C disease. BCLC Stage B will be allowed if not
amenable to locoregional therapy or refractory to locoregional therapy, and not
amenable to a curative treatment approach (Appendix B).
10. Eastern Cooperative Oncology Group performance status of 0 or 1.
11. Has the ability to swallow and retain oral medication.
12. Life expectancy greater than 3 months at time of recruitment.
13. At least one measurable liver lesion (RECIST v1.1) assessed by the
investigator.
14. Platelet count >70 x109/L.
15. Serum albumin >=28g/L.
16. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=5 x
the upper limit of normal (ULN).
17. Bilirubin <=50 µmol /L.
18. White Blood Cell (WBC) >=2.0 x 109/L.
19. Absolute neutrophil count >=1.5 x 109/L.
20. Haemoglobin >=9.0 g/dL.
Exclusion criteria
1. Child-Pugh classification B and C.
2. Participants without a history of hepatitis B and/or hepatitis C.
3. Participants with fibrolamellar and mixed hepatocellular/cholangiocarcinoma
subtype HCC.
4. Participants with no prior therapy who are eligible for first-line treatment
with atezolizumab in combination with bevacizumab.
5. Participants who received investigational drug(s) within the last 30 days
prior to study treatment initiation.
6. Participants with clinically significant ascites.
7. Any episode of bleeding from oesophageal varices or other uncontrolled
bleeding including
clinically meaningful epistaxis within the last 3 months prior to study
treatment initiation.
8. Clinically diagnosed hepatic encephalopathy in the last 6 months
unresponsive to therapy.
9. Participants with a history of gastrointestinal haemorrhage or perforation.
10. Has known active CNS metastases and/or carcinomatous meningitis.
Participants with previously treated such metastases
may participate provided they are radiologically stable for at least 4
weeks by repeat imaging performed during study
screening, clinically stable and without requirement of steroid
treatment for at least 28 days prior to first dose of study
intervention. MRI brain scan are required for all participants with
stable brain metastases at screening (CT scan will be
allowed if MRI is contraindicated).
11. Participants administered with serum albumin within the last 7 days prior
to the first study treatment administration.
12. Known infection with human immunodeficiency virus (HIV) with CD4+ T-cell
counts <350 cells/µL or with a history of AIDS-defining opportunistic
infection. No HIV testing is required unless mandated by local health authority.
13. Received a live vaccine within 30 days prior to the first dose of study
treatment. Live vaccines include, but are not limited to: measles, mumps,
rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid
vaccine. Seasonal influenza vaccines for injection are generally killed virus
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®)
are live attenuated vaccines and are not allowed.
14. Known other malignancy that is progressing or has required active treatment
in the last 5 years prior to screening, with the exception of malignancies with
a negligible risk of metastasis or death such as early-stage cancers treated
with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma
of the skin, in situ cervical cancer, or in situ breast cancer that has
undergone potentially curative therapy.
15. Participants presenting with a baseline prolongation of QT/QTc interval
defined as repeated demonstration of a QTc interval >=450ms (males) and >=460ms
(females) using Fridericia*s correction formula.
16. Participants with a screening diastolic blood pressure >90 mm Hg.
17. Clinically significant cardiovascular disease within 12 months from first
dose of study intervention, including New York Heart Association Class III or
IV congestive heart failure, unstable angina, myocardial infarction, cerebral
vascular accident, or cardiac arrhythmia associated with hemodynamic
instability.
Note: Medically controlled arrhythmia would be permitted.
18. Major surgery within the last 30 days prior to study treatment initiation.
If the participant had major surgery, the participant must have recovered
adequately from the procedure and/or any complications from the surgery prior
to starting study intervention.
19. Participants with a history of organ transplantation
20. Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-005431-23-NL |
| CCMO | NL80197.000.22 |