Phase II trial to investigate the safety and efficacy of orally applied niclosamide in patients with metachronous or sychronous metastases of a colorectal cancer progressing after therapy: the NIKOLO trial

Abstract

Background: Colorectal cancer (CRC) is the second most common cause of all cancer deaths in Europe and the Western world with a lifetime risk of approximately 5%. Despite several improvements in the treatment of patients with unresectable CRC prognosis is poor and there is the need of developing new treatment strategies for patients with metastatic chemorefractory disease. The S100 calcium binding protein A4 (S100A4) predicts metastasis formation and reduced CRC patient survival. S100A4 was previously identified as transcriptional target of the Wnt/β-catenin signaling pathway. The Food and Drug Administration (FDA)-approved anti-helminthic drug niclosamide is known to intervene in the Wnt/β-catenin pathway signaling, leading to reduced expression of S100A4 linked to restricted in vivo metastasis formation. Thus, we aim at translation of our findings on restricting S100A4-driven metastasis into clinical practice for treating metastasized CRC patients progressing after standard therapy.

Methods/design: NIKOLO is a phase II, single center, one-arm open-label clinical trial to investigate the safety and efficacy of niclosamide tablets in patients with metastasized CRC progressing under standard therapy. Eligible patients will receive 2 g of orally applied niclosamide once a day and will continue with the treatment once daily till disease progression or toxicity. Toxicities will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. The primary objective of this trial is to assess the progression free survival after 4 months, secondary objectives are overall survival, time to progression, disease control rate (remission + partial remission + stable disease), and safety. Furthermore, pharmacokinetic analysis will be conducted to evaluate niclosamide plasma concentration.

Discussion: This study is expected to provide evidence of the feasibility, toxicity and efficacy of niclosamide in the treatment of patients with metastasized CRC and could help to establish a new treatment option.

Trial registration: The study is registered with ClinicalTrials.gov (NCT02519582) and the European Clinical Trials Database (EudraCT 2014-005151-20).

Keywords: Colorectal cancer; Niclosamide; S100A4.

Conflict of interest statement

Authors’ information

Susen Burock: Charité Comprehensive Cancer Center, Invalidenstraße 80, 10117 Berlin, Germany.

Severin Daum: Department of Medicine I, Gastroenterology, Rheumatology and Infectious Diseases, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.

Ulrich Keilholz: Charité Comprehensive Cancer Center, Invalidenstraße 80, 10117 Berlin, Germany and German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

Konrad Neumann: Charité Comprehensive Cancer Center, Invalidenstraße 80, 10117 Berlin, Germany, Department for Biostatistics and Clinical Epidemiology, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.

Wolfgang Walter: Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany.

Ulrike Stein: Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany and German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

Ethics approval and consent to participate

The final protocol was approved by the ethics committee of the Landesamt für Gesundheit und Soziales (LAGeSo), Berlin, Germany and the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) and is registered at EudraCT database (EudraCT 2014-005151-20) and at Clinicaltrials.gov (NCT02519582).

This study complies with the Declaration of Helsinki in its recent version, the Medical Association’s professional code of conduct, the principles of the International Conference on Harmonisation about Good Clinical Practice guidelines (ICH-GCP) and the Federal Data Protection Act. The trial will also be carried out in keeping with local legal and regulatory requirements. The medical secrecy and the Federal Data Protection Act will be followed.

Written informed consent is obtained from each patient in oral and written form before inclusion in the trial and the nature, scope, and possible consequences of the trial have been explained by a physician. The investigator will not undertake any measures specifically required only for the clinical trial until valid consent has been obtained.

Competing interests

The authors declare that they have no competing interests, besides the following patent applications:

Stein U, Walther W, Sack U, Scudiero D, Schlag PM, Shoemaker RH. Niclosamide for treatment of cancer metastasis. US 14/112,521(12.11.2013), EP2012/057049 (18.4.2012).

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