This is an open-label, multi-center, dose escalation Phase 1/2a study to establish the recommended dose for Phase 2 (RP2D) from Phase 1a and Phase 1b, as well as evaluating the preliminary efficacy of the RP2D in expansion cohorts (Phase 2a) in patients with liver related cancers.

Phase 1

Conditions: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or, metastatic liver disease
MedDRA version: 20.0Level: PTClassification code 10073071Term: Hepatocellular carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: LLTClassification code 10073077Term: Intrahepatic cholangiocarcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: LLTClassification code 10027479Term: Metastatic liver carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2018-000995-14-BE

Lead Sponsor: Medivir AB

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 102

Inclusion Criteria

Unless otherwise stated, inclusion criteria apply to all phases and cohorts in the study.
1. Male or female = 18 years of age on the day of signing informed consent.
2. Able to understand and voluntarily sign a written informed consent and is willing, and able, to comply with the protocol requirements.
3. Must have measurable disease based on RECIST v1.1 as determined by the site study team. Must have at least 1 target lesion in the liver. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
4. Must have a Child-Pugh A status for Phase 1a and Phase 1b. SRC discretion to expand to include Child-Pugh B status for Phase 1a and Phase 1b. Must have a Child Pugh A or B status for Phase 2a. SRC discretion to restrict to Child Pugh A status for Phase 2a.
5. Must have an ECOG performance status of 0 or 1 at Screening.
6. Must have life expectancy of > 12 weeks in the investigator’s opinion.
7. Must have ALT and AST = 5.0 × upper limit of normal (ULN) at Screening.
8. Must have total bilirubin (TBil) = 3.0 mg/dL at Screening.
9. Must have platelets = 75,000/mL at Screening.
10. Must have International Normalized Ratio (INR) = 1.7 at Screening.
11. Female who is postmenopausal,
OR
Female who is of childbearing potential who agrees to use a highly efficient method of contraception (ie, a method with less than 1% failure rate [eg, sterilization, hormone implants, hormone injections, intrauterine devices, or vasectomized partner or combined birth control pills]) from Screening until 90 days after the final dose of MIV-818.
OR
Male who agrees to use condoms from Screening until 90 days after the final dose of MIV-818.
OR
Male with a female partner of childbearing potential (WOCBP) who is using a highly efficient method of contraception as described above.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
12. WOCBP must have a negative serum pregnancy test at Screening and negative (serum or urine) pregnancy test within 72 h before the first study drug dose. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the patient to be eligible.

Phase 1a- and Phase 1b-specific Inclusion Criteria
1. Must have progressed on or are intolerant of standard therapy with:
- Histologically or cytologically confirmed HCC; including fibrolamellar HCC, patients with HCC that received their diagnosis according to the agreed international radiological guideline are also admissible upon agreement between the investigator and the medical monitor, or
- Histologically or cytologically confirmed iCCA, or
- Liver metastases from solid tumors comprising, but not limited to, renal, colon, pancreatic, breast, lung, and gastric tumors, with limited extrahepatic tumor burden.

Phase 2a-specific Inclusion Criteria
1. Must have:
- Histologically or cytologically confirmed HCC (patients with HCC that received their diagnosis according to the agreed international radiological guideline are also admissible upon agreement between the investigator and the medical monitor) with limited extrahepatic tumor burden who have progressed or are intolerant of standard therapy, or
- Histologically or cytologically confirmed iCCA with limited extrahepatic tumor burden who have progressed or are intolerant of standard the

Exclusion Criteria

Patients are excluded from this study if any 1 or more of the following criteria is met:
1. Tumor volume exceeding 50% of liver.
2. History of previous malignancy within the last 5 years except basal cell carcinoma or carcinoma in situ in solid organ.
3. Known CNS or brain metastases, unless previously treated and stable for 3 months.
4. Ongoing significant disease other than target disease as judged by the investigator to compromise the patients’ ability to complete this study.
5. History of solid organ transplant or bone marrow transplant.
6. Receiving immunosuppressive therapy including oral corticosteroids exceeding 15 mg daily of prednisone, 2 mg daily of dexamethasone or equivalent.
7. Positive hepatitis B surface antigen (HBsAg) screen, and/or a positive HCV antibody screen. A positive total hepatitis B core antibody test, in conjunction with a negative antibody to HBsAg test. Patients with active hepatitis are to be excluded.
8. Positive human immunodeficiency virus (HIV) infection.
9. Poorly controlled ascites and/or requirement for therapeutic paracentesis more frequently than once every 3 months.
10. Symptomatic encephalopathy within 3 months prior to Screening and/or requirement for medication for encephalopathy.
11. Esophageal variceal bleeding within 2 weeks prior to Screening.
12. Receiving prior anticancer therapy within 4 weeks prior to Screening.
13. Receiving any other investigational agent within 4 weeks prior to Screening
14. Enrolled in another clinical study with an investigational drug.
15. Presence of residual toxicities of CTCAE Grade > 1 after prior anticancer therapy within 2 weeks of first treatment with MIV-818, except for alopecia.
16. History of allergic reactions attributed to compounds of similar chemical or biological composition to MIV-818.
17. HCC of diffuse infiltrative type.

Phase 2a-specific Exclusion Criteria

Patients are excluded from Phase 2a of this study if the following criterion is met:

1. Patients with a diagnosis of fibrolamellar HCC.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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