DKN-01 Inhibition in Advanced Liver Cancer

Inclusion Criteria:

• Ambulatory male or female patients ≥ 18 years

• Patients must have histologically confirmed diagnosis (by either primary surgicalspecimen or biopsy for recurrence) of advanced stage or recurrent diagnosis of HCCbased on histopathologic findings.

• Tumor tissue is mandatory for pre-treatment evaluation (baseline) (fresh biopsy during 4-weeks screening time preferred. Archived specimen is only acceptable, if ≤ 6 monthsold. Baseline tumor biopsy samples must be available prior to the first dose ofDKN-01.

• Tumor tissue (FFPE) must be received by central histopathology laboratory forcorrelative studies (fine needle aspiration and bone metastasis samples are notacceptable).

• Patients with activated WNT/β-catenin signaling identified by glutamine synthetasestaining (high positive staining in tumor tissue) by an approved lab. Positivestaining must be confirmed prior to first dose of DKN-01.

• Child-Pugh score <7 (Child-Pugh Class A).

• Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease notamenable to resection, locoregional therapy or refractory to locoregional therapy.

• At least one tumor lesion measurable on radiographic imaging as defined by mRECIST forHCC that has not been previously treated by locoregional therapies.

• Locoregional therapies or radiation therapy must be completed at least 4 weeks priorto baseline scan. All toxic effects > grade 1 (NCI CTCAE v5.0) related to any priorHCC treatment must be resolved. Palliative radiotherapy for symptomic control isacceptable and no additional radiotherapy for the same lesion is planned. (like bonemetastases should not be targets for RECIST).

• ECOG performance status (PS) of 0 or 1.

• Estimated life expectancy of at least 3 months, in the judgment of the Investigator.

• Disease-free of active second/secondary or prior malignancies for ≥2 years with theexception of currently treated basal cell, squamous cell carcinoma of the skin, orcarcinoma in-situ of the cervix or breast.

• Patients are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC,or HCV-HCC defined as follows:

• HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface antibody,detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV surfaceantigen) or chronic HBV infection (as evidenced by detectable HBV surface antigenor HBV DNA). Patients with chronic HBV infection must have HBV DNA < 2000 IU/mLand must be on antiviral therapy.

• HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV RNA orantibody

• Acceptable liver function:

• Total bilirubin ≤2.0 × upper limit of normal (ULN).

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × ULN.

• Acceptable renal function: o Calculated creatinine clearance ≥50 mL/min using the Cockcroft and Gault Method (Cockroft and Gault 1976).

• Acceptable hematologic status:

• Neutrophil Granulocyte ≥1500 cells/μl.

• Hemoglobin ≥ 8,5 g/dL (transfusion permitted within 30 days of study entry).

• Platelet count ≥75,000 cells/μl.

• Acceptable coagulation status: o INR ≤ 1.7 and no active bleeding, (i.e., no clinically significant bleeding within 14 days prior to first dose of study therapy

• Female subjects who are post-menopausal (defined as spontaneous amenorrhea for atleast a year) or permanently sterilized (e.g. bilateral oophorectomy, hysterectomy,bilateral salpingectomy) can participate in the trial and are not required to use anycontraception.

• Women of child bearing potential (WOCBP, a woman is considered of childbearingpotential i.e. fertile, following menarche and until becoming post-menopausal) musthave a negative serum or urine pregnancy test within 7 days prior to first dose ofDKN- 01. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalentunits of HCG.

• Women of childbearing potential must be willing to practice a highly effective andmedically accepted contraception method during trial and for 18 months after last doseof study drug. A highly effective method of birth control is defined as one whichresults in a low failure rate (i.e. less than 1% per year) when used consistently andcorrectly such as:

• combined (estrogen and progestogen containing) hormonal contraception associatedwith inhibition of ovulation: oral, intravaginal, transdermal

• progestogen-only hormonal contraception associated with inhibition of ovulation:oral, injectable, implantable

• intrauterine device (IUD)

• intrauterine hormone-releasing system ( IUS)

• bilateral tubal occlusion

• vasectomised partner (medical assessment must be present and done)

• sexual abstinence when this is in line with the preferred and usual lifestyle ofthe subject

• Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) arenot acceptable methods of contraception. Female condom and male condom should not beused together.

• Sexually-active male subjects must be willing to use contraception (condom,contraception for non-pregnant WOCBP partner) with their partners throughout the studyand for 18 months after last dose of study drug and agree to inform the Investigatorif the respective partner becomes pregnant during this time

• Provided written informed consent prior to any study-specific procedures.

• Ability of patient to understand nature, importance and individual consequences ofclinical trial.

Exclusion Criteria:

• Patients with the following histology of hepatocellular cancer are not eligible forenrollment: fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.

• New York Heart Association Class III or IV cardiac disease, myocardial infarctionwithin the past 6 months, or unstable arrhythmia.

• Specific cardiac preconditions : Fridericia-corrected QT interval (QTcF) >470 msec (female) or >450 msec (male), or history of congenital long QT syndrome. Any ECGabnormality that in the opinion of the Investigator would preclude safe participationin the study; patients with pacemakers where QTc is not a reliable measure willrequire an evaluation by a cardiologist to exclude co-existing cardiac conditionswhich would prohibit safe participation in the study.

• Active, uncontrolled bacterial, viral, or fungal infections, within 7 days of studyentry requiring systemic therapy.

• Known to be human immunodeficiency virus (HIV) positive,

• History of major organ transplant (i.e., heart, lungs, liver, or kidney).

• History of autologous/allogenic bone marrow transplant.

• Serious non-malignant disease that could compromise protocol objectives in the opinionof the Investigator and/or Sponsor.

• Pregnancy or nursing.

• Major surgical procedures, open biopsy or significant traumatic injury within 4 weeksprior to treatment start (minor procedures within 1 week)

• History of osteonecrosis of the hip or evidence of structural bone abnormalities inthe proximal femur on magnetic resonance imaging (MRI) scan that are symptomatic andclinically significant. Degenerative changes of the hip joint are not exclusionary.Screening of asymptomatic patients is not required.

• Symptomatic central nervous system (CNS) malignancy or metastasis. Patients withtreated CNS metastases are eligible provided their disease is radiographically stable,asymptomatic, and they are not currently receiving corticosteroids and/oranticonvulsants. Screening of asymptomatic patients without a history of CNSmetastases is not required.

• Known osteoblastic bone metastasis. Screening of asymptomatic patients without ahistory of metastatic bone lesions is not required.

• Medical or psychological conditions that would jeopardise an adequate and orderlycompletion of the trial.

• Thrombotic or embolic events (except HCC tumor thrombus <pVT4) within the past 6months (including cerebrovascular accidents)

• Evidence of portal hypertension with bleeding esophageal or gastric varices within thepast 6 months

• Patients with portal vein thrombosis = pVT4