Part A is a phase I study investigating the safety of DKN-01 administered as mono- as well as
combination therapy with sorafenib in a 2 step dose escalation. Up to 20 patients with
advanced HCC will be included in Part A. Tumor assessment will be performed every 8 weeks.The
first 10 patients (cohort 1) will start with IV infusion of 300 mg DKN-01 on day 1 and 15
(monotherapy for 28 days). DLTs will be determined. After cycle 2 of monotherapy patients of
cohort 1 will continue with combination of 300 mg DKN-01 IV on day 1 and 15 and sorafenib
(recommended dose 800 mg per day or at discretion of the investigator) until disease
progression. After 2 cycles of combination therapy and prior to the start of the next cohort
DLTs will be determined. Part B is a phase II study to investigate the anti-tumor activity
and safety of DKN-01 in patients with advanced HCC. DKN-01 is administered at the recommend
phase II dose (RP2D) for monotherapy and at the recommend phase II dose for combination
therapy established in Part A. Depending on the tolerability, the doses may be different for
monotherapy and for combination therapy. Up to 50 additional patients with advanced HCC may
be enrolled in Part B. Every 8 weeks tumor assessment will be performed. If progression of
disease (PD1) is observed with DKN-01 monotherapy, patients will continue on study receiving
DKN-01 at the recommend phase II dose for combination therapy.
- Patients must have histologically confirmed diagnosis (by either primary surgical
specimen or biopsy for recurrence) of advanced stage or recurrent diagnosis of HCC
based 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 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 (fine needle aspiration and bone metastasis samples are not
acceptable).
- 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 v5.0) 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. (like bone
metastases 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 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:
- 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.
- HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV RNA or
antibody
- Acceptable liver function:
- Total bilirubin ≤2.0 × upper limit of normal (ULN).
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 at
least a year) or permanently sterilized (e.g. bilateral oophorectomy, hysterectomy,
bilateral salpingectomy) can participate in the trial and are not required to use any
contraception.
- Women of child bearing potential (WOCBP, a woman is considered of childbearing
potential i.e. fertile, following menarche and until becoming post-menopausal) 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) when used consistently and
correctly such as:
- combined (estrogen and progestogen containing) hormonal contraception associated
with 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 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.
Exclusion Criteria:
- 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.
- 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 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
1. Phase I: Adverse Events (Time Frame - assessment period is 2 cycles for monotherapy (each cycle is 28 days)): Absolute and relative incidences of treatment-emergent adverse events.
2. Phase I: Adverse Events (Time Frame - assessment period is 2 cycles for combination therapy (each cycle is 28 days)): Absolute and relative incidences of treatment-emergent adverse events.
3. Phase II: Time to progression (TTP2) (Time Frame - time from the first DKN-01 intake until PD2, assessed up to 2 years): The TTP2 is defined as the time from the first DKN-01 intake until PD2. Tumor progression is assessed by mRECIST criteria (modified Response Evaluation Criteria in Solid Tumors).
Secondary outcome:
1. Phase I: pharmacokinetics of DKN-01 (Time Frame - monotherapy for 8 weeks and in combination with sorafenib for 8 weeks): Serum DKN-01 levels 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
2. Phase II: Overall survival (OS) (Time Frame - time from first DKN-01 intake until death from any cause, assessed up to 2 years): Overall survival is defined as the time from first DKN-01 intake until death from any cause, assessed up to 2 years
3. Phase II: progression free survival (PFS1, PFS2) (Time Frame - time from first DKN- 01 intake until death or PD1 or PD2 respectively whichever comes first, assessed up to 2 years): Progression free survival (PFS1, PFS2) is defined as the time from first DKN-
01 intake until death or PD1 or PD2 respectively whichever comes first, assessed up to 2 years
4. Phase II:objective response rate (ORR) (Time Frame - 2, 4 and 6 months after first DKN- 01 intake): ORR (CR or PR), binary measurement
5. Phase II: disease control rate (DCR) (Time Frame - 2, 4 and 6 months after first DKN- 01 intake): DCR (CR, PR or SD), binary measurement (CR, PR or SD) after 2, 4 and 6 months will be analyzed by absolute and relative frequencies.
6. Phase II: Duration of disease control with DKN-01 (Time Frame - time from first to the last disease control (CR, PR, or SD), assessed up to 2 years): Duration of disease control is defined as the time from the first to the last occurrence of disease control (CR, PR, or SD), assessed up to 2 years
7. Phase II: Adverse Events (Time Frame - assessment period is during mono- and combination therapy with sorafenib (through study completion, estimated 2 years)): Absolute and relative incidences of treatment-emergent adverse events as assessed by NCI CTCAE v5.0
Experimental: DKN-01 300 mg Phase I Study treatment will be started as monotherapy with DKN-01 for up to 8 weeks or until unacceptable toxicity occurs. The study will be continued as combination therapy of DKN-01 and sorafenib until objective disease progression (PD) or unacceptable toxicity occurs. The dose of DKN-01 for cohort 1 will be 300 mg , depending on the results of the safety assessment. Phase II The dose of DKN-01 will be the recommended phase II dose (RP2D) determined from Part A. Study treatment will be started as monotherapy with DKN-01 until objective disease progression (PD1) or unacceptable toxicity occurs. After PD1, study treatment will be continued as combination therapy of DKN-01 and sorafenib until disease progression (PD2) or unacceptable toxicity occurs.
Experimental: DKN-01 600 mg Phase I Study treatment will be started as monotherapy with DKN-01 for up to 8 weeks or until unacceptable toxicity occurs. The study will be continued as combination therapy of DKN-01 and sorafenib until objective disease progression (PD) or unacceptable toxicity occurs. The dose of DKN-01 for cohort 2 will be 600 mg or 150 mg, depending on the results of the safety assessment. Phase II The dose of DKN-01 will be the recommended phase II dose (RP2D) determined from Part A. Study treatment will be started as monotherapy with DKN-01 until objective disease progression (PD1) or unacceptable toxicity occurs. After PD1, study treatment will be continued as combination therapy of DKN-01 and sorafenib until disease progression (PD2) or unacceptable toxicity occurs.
DKN-01 300 mg: DKN-01 will be administered intravenous (IV) over a minimum of 30 minutes and up to a maximum of 2 hours given on days 1 and 15 of each 28 day cycle.
DKN-01 600 mg: DKN-01 will be administered intravenous (IV) over a minimum of 30 minutes and up to a maximum of 2 hours given on days 1 and 15 of each 28 day cycle.
Sorafenib: For combination with DKN-01, sorafenib will be administrated according to standard clinical practice. Part A: After 8 weeks monotherapy with DKN-01, the study will be continued as combination therapy of DKN-01 and sorafenib until objective disease progression (PD) or unacceptable toxicity occurs. Part B:After PD1, study treatment will be continued as combination therapy of DKN-01 and sorafenib until disease progression (PD2) or unacceptable toxicity occurs.
Quelle: ClinicalTrials.gov
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