| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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) |
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| 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 |
Part A:
Evaluation of safety and tolerability using frequency and severity of adverse events to establish the recommended phase II dose (RP2D) of DKN-01 when administered as monotherapy for 8 weeks and in combination with sorafenib for 8 weeks in adult patients with HCC.
Part B:
To assess the time to progression (TTP1, TTP2) in treatment naïve patients with advanced HCC after treatment with DKN-01 monotherapy until PD1 and in combination with sorafenib until PD2. TTP1 and TTP2 will be determined according to mRECIST
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| E.2.2 | Secondary objectives of the trial |
Part A:
- To assess safety of the doses of 300 mg and 600 mg DKN-01 given as mono- and as combination therapy
- To characterize the pharmacokinetics of DKN-01 when administered at the dose of 300 mg and 600 mg as monotherapy and in combination with sorafenib
Part B:
- To assess tumor response with DKN-01 monotherapy and in combination with sorafenib
- To assess the clinical safety of DKN-01 monotherapy and in combination with sorafenib at the dose used for part B
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients meeting all of the following criteria will be considered for enrollment to the trial:
- Ambulatory male or female patients ≥ 18 years
- Patients must have histologically confirmed diagnosis
- Tumor tissue is mandatory for pre-treatment evaluation (baseline) (fresh biopsy during
4-weeks screening time preferred. Archived specimen is only acceptable, if ≤ 6 months
old. Baseline tumor biopsy samples must be available prior to the first dose of DKN-01.
- Tumor tissue (FFPE) must be received by central histopathology laboratory for correlative studies
- Patients with activated WNT/β-catenin signaling identified by glutamine synthetase staining (high positive staining in tumor tissue) by an approved lab. Positive staining 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 not amenable to resection, locoregional therapy or refractory to locoregional therapy.
- At least one tumor lesion measurable on radiographic imaging as defined by mRECIST for HCC that has not been previously treated by locoregional therapies.
- Locoregional therapies or radiation therapy must be completed at least 4 weeks prior to baseline scan. All toxic effects > grade 1 (NCI CTCAE v4.03) related to any prior HCC treatment must be resolved. Palliative radiotherapy for symptomic control is acceptable and no additional radiotherapy for the same lesion is planned.
- 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 the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma 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:
o HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV surface antigen) or chronic HBV infection (as evidenced by detectable HBV surface antigen or HBV DNA). Patients with chronic HBV infection must have HBV DNA < 2000 IU/mL and must be on antiviral therapy.
o HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV RNA or antibody
- Acceptable liver function:
o Total bilirubin ≤2.0 × upper limit of normal (ULN).
o 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:
o Neutrophil Granulocyte ≥1500 cells/µl.
o Hemoglobin ≥ 8,5 g/dL (= 5,28 mmol/l)(transfusion permitted within 30 days of study entry).
o 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 at least a year) or permanently sterilized (e.g. bilateral oophorectomy, hysterectomy, bilateral salpingectomy) can participate in the trial
- Women of child bearing potential must have a negative serum or urine pregnancy test within 7 days prior to first dose of DKN-01. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG.
- Women of childbearing potential must be willing to practice a highly effective and medically accepted contraception method during trial and for 18 months after last dose of study drug. A highly effective method of birth control is defined as one which results in a low failure rate (i.e. less than 1% per year):
o combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
o progestogen-only hormonal contraception associated with inhibition of ovulation:
o intrauterine device (IUD)
o intrauterine hormone-releasing system ( IUS)
o bilateral tubal occlusion
o vasectomised partner
o sexual abstinence when this is in line with the preferred and usual lifestyle of the subject
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.
- Sexually-active male subjects must be willing to use contraception (condom, contraception for non-pregnant WOCBP partner) with their partners throughout the study and for 18 months after last dose of study drug and agree to inform the Investigator if 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 of clinical trial.
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| E.4 | Principal exclusion criteria |
Patients presenting at least one of the following criteria will not be enrolled in the trial:
- - Patients with the following histology of hepatocellular cancer are not eligible for enrollment: fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
- New York Heart Association Class III or IV cardiac disease, myocardial infarction within 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 ECG abnormality that in the opinion of the Investigator would preclude safe participation in the study; patients with pacemakers where QTc is not a reliable measure will require an evaluation by a cardiologist to exclude co-existing cardiac conditions which would prohibit safe participation in the study.
- Active, uncontrolled bacterial, viral, or fungal infections, within 7 days of study entry requiring systemic therapy.
- 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 opinion of the Investigator and/or Sponsor.
- Pregnancy or nursing.
- Major surgical procedures, open biopsy or significant traumatic injury within 4 weeks prior to treatment start (minor procedures within 1 week)
- History of osteonecrosis of the hip or evidence of structural bone abnormalities in the proximal femur on magnetic resonance imaging (MRI) scan that are symptomatic and clinically 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 with treated CNS metastases are eligible provided their disease is radiographically stable, asymptomatic, and they are not currently receiving corticosteroids and/or anticonvulsants. Screening of asymptomatic patients without a history of CNS metastases is not required.
- Known osteoblastic bone metastasis. Screening of asymptomatic patients without a history of metastatic bone lesions is not required.
- Medical or psychological conditions that would jeopardise an adequate and orderly completion of the trial.
- Thrombotic or embolic events (except HCC tumor thrombus <pVT4) within the past 6 months (including cerebrovascular accidents)
- Evidence of portal hypertension with bleeding esophageal or gastric varices within the past 6 months
- Patients with portal thrombosis = pVT4
Medication Related
- prior systemic therapy for HCC
- Currently receiving any other investigational agent or received an investigational agent
within last 30 days prior to first dose or within 5 times the half-life of this agent before
the first dose of study treatment.
- Previously treated with an anti-DKK1 therapy.
- Treatment with strong inducers of CYP3A4 within 7 days prior to first dose (including
Cyclosporin, Erythromycin, Ketoconazole, Itraconazole, Quinidine, Phenobarbital salt
with Quinidine, Ritonavir, Valspodar, Verapamil, St John's wort, rifampicin).
- Significant allergy to a pharmaceutical therapy that, in the opinion of the Investigator,
poses an increased risk to the patient.
- History of hypersensitivity to the investigational medicinal product or to any drug with
similar chemical structure or to any excipient present in the pharmaceutical form of the
investigational medicinal product.
Lifestyle-Related
- Active substance abuse (including active alcohol abuse).
- Involuntary incarcerated patients
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A: Primary variables are the absolute and relative frequencies of adverse events.
Part B: Time to progression (TTP2). The TTP2 is defined as the time from the first dosing until PD2. Tumor progression is assessed by mRECIST criteria (modified Response Evaluation Criteria in Solid Tumors). TTP1 i.e. the time from the first dosing until PD1 (objective progression with DKN-01 monotherapy) will also be evaluated.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: after 2 cycles of monotherapy and 2 cycles of combination therapy with sorafenib
Part B: at time of PD1 and PD2 |
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| E.5.2 | Secondary end point(s) |
Part A: Serum DKN-01 levels in patients
Part B:
- To assess overall survival (OS), progression free survival (PFS1, PFS2), the objective response rate (ORR), and the disease control rate (DCR) with DKN-01 as a monotherapy and in combination with sorafenib at end of study
- Duration of disease control with DKN-01
- Adverse Events as assessed by NCI CTCAE v5.0
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: after 2 cycles of monotherapy and 2 cycles of combinationtherapy with sorafenib
Part B: at time of PD1 and PD2 |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| dose-finding, testing for tolerability |
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| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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