| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced hepatocellular cancer (HCC) as result of hepatitis B and/or hepatitis C. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary liver cancer caused by a viral infection |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073071 |
| E.1.2 | Term | Hepatocellular carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036706 |
| E.1.2 | Term | Primary liver cancer non-resectable |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008910 |
| E.1.2 | Term | Chronic hepatitis B |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare Progression Free Survival (PFS) (i.e. the time between randomization until the 1st documented progression in the size of their tumour) of MTL-CEBPA in combination with sorafenib compared to sorafenib alone as determined by Blinded Independent Central Review (BICR) and assessed using RECIST v1.1 guidelines (standard guidelines for assessing the progression of tumours). |
|
| E.2.2 | Secondary objectives of the trial |
- To compare efficacy of MTL-CEBPA in combination with sorafenib compared to sorafenib alone as assessed by a blinded independent central assessor 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 Overall Survival of MTL-CEBPA in combination with sorafenib compared to sorafenib alone.
- To assess consistency in tumour-based efficacy endpoints between independent assessment 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-C30plus EORTC-QLQ-HCC18 QOL questionnaires. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
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 x 109/L.
15. Serum albumin ≥28 g/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 becoming post-menopausal unless permanently sterile. Permanent methods of sterilization include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause.
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.
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. |
|
| E.4 | Principal 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 ≥450 ms (males) and ≥460 ms (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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS) by RECIST V1.1 assessed by Blinded Independent Central Reviewer (BICR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS is defined as the time from randomization until the date of first documented progression (per RECIST v1.1) or death due to any cause in the absence of progression, whichever occurs first.
It will be analyzed by Intention to Treat (ITT), which will include all randomized participants. |
|
| E.5.2 | Secondary end point(s) |
1. Best Objective Response (BOR), Overall Response Rate (ORR), Duration of Response (DoR), Time to Response (TTR) and changes in tumour size by RECIST v1.1 assessed by BICR.
2. Overall Survival.
3. Progression Free Survival (PFS), BOR, ORR, DOR, TTR and changes in tumour size by RECIST v1.1 assessed by Investigator and BICR.
4. Incidence of AEs/serious AEs (SAE) and laboratory test results graded according to toxicity criteria (CTCAE v5.0 November 27, 2017), vital signs and ECG.
5. Change over time in scores from EORTC-QLQ-C30 and EORTC-QLQ-HCC18 QoL questionnaires. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
BOR is best response recorded from start of treatment until disease progression, last evaluable assessment in absence of progression, or start of new subsequent anti-cancer therapy.
ORR is calculated as number and % of participants with BOR response of Complete Response or Partial Response in the size of tumour
DoR is defined as time from date of first documented tumour response (CR/PR) until progression/death.
TTR is defined as the time from randomization to the date of the first documented tumour response (CR/PR). Time to response will be summarized descriptively by treatment arm.
Tumour size is defined as the sum of the diameters (SoDs) of the RECIST v1.1 target lesions.
OS is defined as the time between the date of randomization and the date of death from any cause. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Quality of Life as assessed by patient administered questionnaires.
|
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Germany |
| Hong Kong |
| Korea, Republic of |
| Netherlands |
| Singapore |
| Sweden |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study ends when the last participant completes the last study-related telephone-call or visit, withdraws study consent, is lost to follow-up and cannot be contacted. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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