hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or, metastatic liver disease MedDRA version: 20.0 Level: PT Classification code 10073071 Term: Hepatocellular carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: LLT Classification code 10073077 T
Conditions
Interventions
Product Name: MIV-818
Product Code: MIV-818
Pharmaceutical Form: Capsule
INN or Proposed INN: Troxacitabine based prodrug
Current Sponso
Sponsors
Medivir AB
Eligibility
Sex/Gender
All
Inclusion criteria
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 a Child-Pugh A or B status Phase 1b and 2a. SRC discretion to restrict to Child- Pugh A status for Phase 1b and 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 adequate renal function with estimated creatinine clearance = 60 mL/min (based on Cockcroft and Gault formula or similar) at Screening 10. Must have platelets = 75,000/mL at Screening. 11. Must have International Normalized Ratio (INR) = 1.7 at Screening. 12. Female who is postmenopausal, OR Female who is of childbearing potential (postmenarchal) 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. 13. 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 14. Must have progressed on or are intolerant of standard therapy with: a. 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 b. Histologically or cytologically confirmed iCCA, or c. Liver metastases from colon, rectal or gastric solid tumors, with limited extrahepatic tumor burden. (any extrahepatic metastases should be limited to 1 other site and a maximum of 1 target lesi
Exclusion criteria
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 2 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.Active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) and patients with active hepatitis C (eg, hepatitis C RNA is [qualitative] detected). 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 anticancer therapy within 4 weeks prior to first dose of MIV-818. 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. 18. Receiving drugs that are extensively metabolized by cytochrome P450 (CYP) 3A4. Drugs that are extensively metabolized by CYP3A4 must be discontinued 5 half-lives before first dose of MIV-818. 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: If not specified otherwise, all study objectives apply to all phases of the study. The primary objectives of this study are: • To determine the Recommended Phase 2 Dose (RP2D) by evaluating the safety and tolerability of escalating doses of MIV-818 in patients with HCC, iCCA, or metastatic liver disease (Phase 1a and Phase 1b) • To evaluate the Objective Response Rate (ORR) measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in Phase 2a expansion cohorts of patients with HCC and iCCA treated with the established RP2D of MIV-818 ; Secondary Objective: If not specified otherwise, all study objectives apply to all phases of the study. The secondary objectives of this study are: • To evaluate the ORR measured by Modified Response Evaluation Criteria in Solid Tumors (mRECIST) in patients treated with MIV-818 • To evaluate the ORR measured by RECIST v1.1 in liver lesions only in patients treated with MIV-818 • To evaluate the ORR based on RECIST v1.1 in patients treated with escalating doses of MIV-818 (Phase 1a and Phase 1b) • To assess the effects of MIV-818 on plasma levels of AFP • Phase 2a cohorts (HCC or iCCA): - To evaluate the safety and tolerability of MIV-818 RP2D - To assess duration of Progression Free Survival (PFS) - To assess Clinical Benefit Rate (CBR) defined as complete response plus partial response plus SD (CR+PR+SD) - To assess Duration of Response (DOR) - To assess OS (Overall Survival) - To assess Time to Response (TTR) ; Primary end point(s): Phase 1a and Phase 1b Safety and tolerability in escalating doses of MIV-818 will be assessed by monitoring: • Incidence and severity of AEs | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Throughout the study as per schedule of assessments in the protocol ie by evaluable RECIST assessment; Secondary end point(s): Phase 1a and Phase 1b • ORR (objective response rate) will be assessed by monitoring tumor response and progression using RECIST v1.1 • ORR will be assessed by monitoring tumor response and progression using mRECIST • ORR will be assessed by monitoring tumor response and progression using RECIST v1.1 in liver lesions only • Plasma levels of AFP (a-fetoprotein) Phase 2a • ORR will be assessed by monitoring tumor response and progression using mRECIST • ORR will be assessed by monitoring tumor response and progression using RECIST v1.1 in liver lesions only • Plasma levels of AFP • PFS (progression free survival) • CBR clinical benefit rate (CR+PR+SD) • DOR (duration of response) • OS (overall survival) • TTR (time to response) Safety and tolerability will be assessed by monitoring: • Incidence and severity of AEs. • Incidence and magnitude of clinically significant changes in clinical laboratory parameters or overall pattern of shifts by treatment group in individual laboratory values suggestive of possible trends, but not necessarily establishing clinical abnormality. • Incidence and severity of clinically significant adverse findings in vital signs, ECG, and other physical examination parameters. | — |
Countries
Belgium, Korea, Republic of, United Kingdom, United States
Contacts
Public ContactProject Manager
Worldwide Clinical Trials
Outcome results
None listed