| Eligibility |
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. 21.International Normalized Ratio (INR) <1.5.
22.Calculated creatinine clearance =50 mL/min (Cockcroft & Gault). 23.AEs due to prior
therapy must have resolved to Grade =1 (except alopecia or endocrinopathies that are
adequately managed through hormone replacement treatment).
24.Negative blood pregnancy test for women of childbearing potential (within 10 days prior
to first drug administration). Note: a woman is considered of child-bearing potential
following menarche and until becomingpost-menopausal unless permanently sterile. Permanent
methods of sterilisation include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy. A post-menopausal state is defined as no menses for 12 months without an
alternative medical
cause.https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG
/2014_09_HMA_CTFG_Contraception.pdf(see additional information / requirements in Section
5.1.) 25.Female participants of childbearing potential must use highly effective*
contraceptive measures adequate to prevent a new pregnancy for the duration of the study
treatment with MTL-CEBPA and sorafenib and, in addition, for at least six months after the
last dose of MTL-CEBPA and six months beyond the last dose of sorafenib, as recommended in
sorafenib's U.S. Package Insert (USPI). For women with reproductive potential who use a
hormonal method of contraception, concurrent use of a second (barrier) method is
recommended. * Highly effective methods of birth control are defined as those that result
in a low failure rate (i.e. less than 1% per year) when used consistently and correctly
(e.g. implants, injectables, oral contraceptives, some intrauterine devices, bilateral
tubal occlusion, true sexual abstinence in line with the preferred and usual lifestyle of
the participant, or vasectomised partner). (See additional information / requirements
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_
09_ HMA_CTFG_Contraception.pdf) 26.Male participants with partners of child-bearing
potential must use highly effective contraception and are required to use barrier
contraception plus an additional contraceptive method that together result in a failure
rate of <1% per year during the treatment period and for at least three months after the
last dose of MTL-CEBPA. Male participants will also be advised to abstain from sexual
intercourse with pregnant or lactating women, or to use condoms. Male participants with
partners of child-bearing potential must use highly effective contraception during
treatment with sorafenib and for 3 months beyond the last dose of sorafenib, as recommended
in sorafenib's USPI.
27.Abstinence is only acceptable if it is line with the preferred and usual lifestyle of
the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods), declaration of abstinence for the duration of exposure to IMP, and
withdrawal are not acceptable methods of contraception.
28.Able to comply with all the requirements of the protocol. Exclusion Criteria
Participants should not enter the study if any of the following exclusion criteria are
fulfilled.
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
<350cells/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
vaccinesfor 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 5years 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.
21. Participants with sepsis, ineffective biliary drainage with or without cholangitis,
obstructive jaundice, or encephalopathy at screening visit or within the last 2 weeks
prior to study treatment initiation.
22. Evidence of spontaneous bacterial peritonitis or renal failure, or allergic reaction
at screening visit or within the last two weeks prior to study treatment initiation,
whichever is earlier.
23. Pregnant or lactating women.
24. Known hypersensitivity to the active substance or to any of the excipients of both
MTL-CEBPA and sorafenib.
25. History or evidence of any other condition or therapy, including a known psychiatric
or substance abuse disorder that, in the judgment of the investigator, may interfere
with the study conduct or confound the results, pose a risk to the participant, is not
in their best interest to take part, or may affect their ability to follow the
protocol specific procedures for the duration of the study.
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