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

BackgroundColorectal 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/DesignNIKOLO 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.DiscussionThis 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 registrationThe study is registered with ClinicalTrials.gov (NCT02519582) and the European Clinical Trials Database (EudraCT 2014-005151-20).

Friend or Foe: S100 Proteins in Cancer

“…Furthermore, the U.S. Food and Drug Administration (FDA)-approved anthelmintic drug niclosamide was identified to inhibit S100A4-induced metastasis formation of colon cancer, by preventing β-catenin/T-cell factor (TCF) complex formation and therefore transcription of S100A4 [216]. Niclosamide tablets are currently being studied in a phase II clinical trial for the treatment of metastasised CRC [217]. Although these inhibitors seem to be very effective in pre-clinical studies, it is vital to notice that they are not selective inhibitors of S100A4, for example, the inhibition of β-catenin also results in downregulation of cyclin D1 and the proto-oncogene c-Myc [214], which might cause unfavourable side effects [247].…”

Wnt/β-catenin signaling as a useful therapeutic target in hepatoblastoma

“…An activation of Wnt/β-catenin signaling has also been associated with the development of colorectal cancer [66], glioblastoma [67] and bladder cancer [68] in patients. Considering the importance of this signaling in different cancers, a Phase II trial has been designed to investigate the safety and efficacy of oral niclosamide, Wnt/β-catenin signaling modulating drug, in colorectal cancer patients [69]. Moreover, it is suggested that the levels of endogenous negative regulators of Wnt/β-catenin including DKK1 and secreted frizzled-related protein-1 may be potentially employed as biomarkers for evaluating the beneficial effects of exercise on the metabolism and prognosis of breast cancer patients [70].…”

Larynx cancer: search for molecular markers

“…In cancer models, have been demonstrated efficacy of S100A4 and S100B transcriptional regulators 30,31 . Niclosamide, an FDA approved drug anthelminthic that blocks glucose uptake by intestinal tapeworm, is currently under evaluation for safety and efficacy in a phase II clinical trial for patients with metastatic colorectal cancer whose disease has progressed under previous therapy 32 . Ours findings corroborate and stimulate new studies on S100 proteins in head and neck cancer, including functional analysis as observed in others studies with specific genes in LSCC 33 , and animal models, as step to future clinical trials.…”