Tropomyosin Receptor Antagonism in Cylindromatosis (TRAC), an early phase trial of a topical tropomyosin kinase inhibitor as a treatment for inherited CYLD defective skin tumours: study protocol for a randomised controlled trial

Trials. 2017 Mar 7;18(1):111. doi: 10.1186/s13063-017-1812-z.


Background: Patients with germline mutations in a tumour suppressor gene called CYLD develop multiple, disfiguring, hair follicle tumours on the head and neck. The prognosis is poor, with up to one in four mutation carriers requiring complete surgical removal of the scalp. There are no effective medical alternatives to treat this condition. Whole genome molecular profiling experiments led to the discovery of an attractive molecular target in these skin tumour cells, named tropomyosin receptor kinase (TRK), upon which these cells demonstrate an oncogenic dependency in preclinical studies. Recently, the development of an ointment containing a TRK inhibitor (pegcantratinib - previously CT327 - from Creabilis SA) allowed for the assessment of TRK inhibition in tumours from patients with inherited CYLD mutations.

Methods/design: Tropomysin Receptor Antagonism in Cylindromatosis (TRAC) is a two-part, exploratory, early phase, single-centre trial. Cohort 1 is a phase 1b open-labelled trial, and cohort 2 is a phase 2a randomised double-blinded exploratory placebo-controlled trial. Cohort 1 will determine the safety and acceptability of applying pegcantratinib for 4 weeks to a single tumour on a CYLD mutation carrier that is scheduled for a routine lesion excision (n = 8 patients). Cohort 2 will investigate if CYLD defective tumours respond following 12 weeks of treatment with pegcantratinib. As patients have multiple tumours, we intend to treat 10 tumours in each patient, 5 with active treatment and 5 with placebo. Patients will be allocated both active and placebo treatments to be applied randomly to tumours on the left or right side. The target is to treat 150 tumours in a maximum of 20 patients. Tumour volume will be measured at baseline and at 4 and 12 weeks. The primary outcome measure is the proportion of tumours responding to treatment by 12 weeks, based on change in tumour volume, with secondary measures based on adverse event profile, treatment compliance and acceptability, changes in tumour volume and surface area, patient quality of life and pain.

Discussion: Interventions for rare genetic skin diseases are often difficult to assess in an unbiased way due to small patient numbers and the challenges of incorporating adequate controls into trial design. Here we present a single-centre, randomised, placebo-controlled trial design that leverages the multiplicity of tumours seen in an inherited skin tumour syndrome that may inform the design of other studies in similar genetic diseases.

Trial registration: International Standard Randomised Controlled Trial Number Registry, ISRCTN75715723 . Registered on 22 October 2014.

Keywords: CYLD; CYLD defective tumours; Cylindromatosis; Pegcantratinib; TRK inhibition; Tropomyosin receptor kinase (TRK) inhibitor.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Biomarkers, Tumor / genetics*
  • Chemotherapy, Adjuvant
  • Clinical Protocols
  • DNA Mutational Analysis
  • Deubiquitinating Enzyme CYLD / genetics*
  • Drug Administration Schedule
  • England
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Heterocyclic Compounds, 4 or More Rings / administration & dosage*
  • Heterocyclic Compounds, 4 or More Rings / adverse effects
  • Humans
  • Neoplastic Syndromes, Hereditary / drug therapy*
  • Neoplastic Syndromes, Hereditary / enzymology
  • Neoplastic Syndromes, Hereditary / genetics
  • Neoplastic Syndromes, Hereditary / surgery
  • Phenotype
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Research Design
  • Skin / drug effects*
  • Skin / enzymology
  • Skin / pathology
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics
  • Skin Neoplasms / surgery
  • Time Factors
  • Treatment Outcome


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Heterocyclic Compounds, 4 or More Rings
  • Protein Kinase Inhibitors
  • pegcantratinib
  • Receptor Protein-Tyrosine Kinases
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD

Supplementary concepts

  • Familial cylindromatosis

Associated data

  • ISRCTN/ISRCTN75715723