Hepatitis B, Hepatitis C, Hepatocellular Carcinoma
Conditions
Keywords
saRNA, MTL-CEBPA, Sorafenib
Brief summary
This is a Phase II study in patients with advanced liver cancer (hepatocellular carcinoma) as a result of hepatitis B and/or C infection. Participants will be dosed with either MTL-CEBPA (an experimental treatment) and sorafenib or sorafenib alone. The MTL-CEBPA is administered once every 3 weeks via intravenous infusion. Sorafenib is taken orally from Day 8 for the combination group or Day 1 for the sorafenib alone group at a dose of 400 mg twice a day. Participants will receive 3 week cycles of treatment until disease progression, unacceptable toxicity, withdrawal of consent or death occurs. The combination of MTL-CEBA and sorafenib combination of treatment was tested in a previous Phase I study (OUTREACH) which showed anti-tumour activity along with a good safety and toxicity profile.
Detailed description
After a participant has signed the consent form to confirm they wish to participate in the study a number of assessments (screening) will be completed to determine whether they are suitable to be enrolled in the study. Prior to the the first dose of experimental drug (MTL-CEBPA) a 2:1 randomisation programme will allocate to which arm the person will be allocated. For participants allocated to the combination treatment arm, MTL-CEBPA will be given via infusion on the first day (Cycle 1 Day 1) of the study. It will subsequently be administered every 21 days. Sorafenib tablets (a drug which is already used to treat liver cancer) will be started on the eighth day of the study and taken daily whilst the participant is in the study. If the participant is tolerating the combination of drugs and there is no evidence that the cancer is advancing they will continue to receive cycles (21 days in length) of treatment. For participants allocated to the single treatment arm, sorafenib tablets will be started on Day 1. All participants will have contrast-enhanced CT scans of the chest, abdomen and pelvis at the beginning of the study and then every 8 weeks whilst in the study. Assessments will be completed throughout the study to ensure the combination of drugs is safe. These will include recording any adverse events (untoward medical occurrences), vital signs (such as blood pressure, pulse, body temperature, and breathing rates), ECG, and completing blood tests. Blood samples, analysed in both local (hospital/clinic site) and central laboratories (ie, facilities independent of hospital/clinic labs) will be taken throughout the study. The maximum amount of blood taken in any 28-day treatment cycle is approximately 182 mL. A patient questionnaire will be used to assess changes in health-related quality of life for participants. The questionnaire will be used for all participants in the study and will be completed every 3 weeks. All participants will be offered an optional liver tumour biopsy prior to being administered study treatment and again if clinically feasible during treatment.
Interventions
DRUGMTL-CEBPA
Administered once every 3 weeks on Day 1 of each 3 week cycle.
DRUGSorafenib
Oral adminstration twice a day
Sponsors
Mina Alpha Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will be randomised 2:1 to receive either both the experimental drug, MTL-CEBPA, and sorafenib tablets or sorafenib tablets alone
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival (PFS) | From baseline CT scan until end of documented progression or date of death from any cause assessed up o 100 weeks | Change from baseline CT scan using blinded central review of Response Evaluation Criteria in Solid Tumours v.1.1 and compare between the two arms |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Health-related quality of life (HRQoL) questionnaires | From first cycle of treatment to end of study approximately one year | 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. |
| Overall survival (OS) | From first dose of MTL-CEBPA and sorafenib or sorafenib alone to end of treatment | To compare overall survival (OS) between the two arms using statistical analysis |
| Adverse events | From first dose of MTL-CEBPA and sorafenib or sorafenib alone to end of treatment | Compare the incidence of AEs/serious AEs (SAE) graded according to toxicity criteria (CTCAE v5.0 between the two arms |
Countries
Singapore, United States
Outcome results
None listed