DKN-01 Inhibition in Advanced Liver Cancer

NCT03645980 | Unknown Phase 1 DMC

• 3 other identifiers: Dial-12017-002468-41AIO-HEP-0318
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 6

Brief Summary

This clinical trial is a prospective, open label, single arm oncological phase I/II trial in patients with hepatocellular carcinoma and WNT signaling alterations. The trial consists of two parts: 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.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.

Conditions

Hepatocellular Carcinoma

Keywords

DKN-01; Hepatocellular Carcinoma; WNT signaling

Outcome Measures

Primary Outcomes (3)

• Phase I: Adverse Events

  Absolute and relative incidences of treatment-emergent adverse events.

  assessment period is 2 cycles for monotherapy (each cycle is 28 days)

• Phase I: Adverse Events

  Absolute and relative incidences of treatment-emergent adverse events.

  assessment period is 2 cycles for combination therapy (each cycle is 28 days)

• Phase II: Time to progression (TTP2)

  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).

  time from the first DKN-01 intake until PD2, assessed up to 2 years

Secondary Outcomes (7)

• Phase I: pharmacokinetics of DKN-01

  monotherapy for 8 weeks and in combination with sorafenib for 8 weeks

• Phase II: Overall survival (OS)

  time from first DKN-01 intake until death from any cause, assessed up to 2 years

• Phase II: progression free survival (PFS1, PFS2)

  time from first DKN- 01 intake until death or PD1 or PD2 respectively whichever comes first, assessed up to 2 years

• Phase II:objective response rate (ORR)

  2, 4 and 6 months after first DKN- 01 intake

• Phase II: disease control rate (DCR)

  2, 4 and 6 months after first DKN- 01 intake

Study Arms (2)

DKN-01 300 mg

EXPERIMENTAL

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.

Drug: DKN-01 300 mg; Drug: Sorafenib

DKN-01 600 mg

EXPERIMENTAL

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.

Drug: DKN-01 600 mg; Drug: Sorafenib

Interventions

DKN-01 300 mg DRUG

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-01 300 mg

DKN-01 600 mg DRUG

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

Sorafenib DRUG

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.

DKN-01 300 mg; DKN-01 600 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ambulatory male or female patients ≥ 18 years
• 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

You may not qualify if:

• 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)
• 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

Sponsors & Collaborators

• Johannes Gutenberg University Mainz: lead
• Leap Therapeutics, Inc.: collaborator

Study Sites (6)

Universitätsklinikum Köln

Cologne, 50937, Germany

RECRUITING

Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

RECRUITING

Med. Hochschule Hannover

Hanover, 30625, Germany

RECRUITING

Universitätsklinikum Schleswig Holstein Campus Lübeck

Lübeck, 23538, Germany

RECRUITING

Universitätsmedizin Mainz, I. Med. Klinik und Poliklinik

Mainz, 55131, Germany

RECRUITING

II. Medizinische Universitätsklinik Gastroenterologie, Hepatologie, Infektiologie

Mannheim, 68167, Germany

RECRUITING

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Sorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Jens U Marquardt, Dr med

  Universitätsklinikum Schleswig Holstein Campus Lübeck

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jens U Marquardt, Dr med

CONTACT

++49 451 500; Jens.Marquardt@uksh.de

Markus Möhler, Dr.med

CONTACT

+49 6131 17; markus.möhler@unimedizin-mainz.de

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Jun. Prof. Dr. J. U. Marquardt

Study Record Dates

• First Submitted: August 17, 2018
• First Posted: August 24, 2018
• Study Start: October 10, 2018
• Primary Completion: August 31, 2021
• Study Completion: August 31, 2022
• Last Updated: October 22, 2020

Record last verified: 2020-10

Locations

DE (6)