Abstract
BackgroundPatients 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/designTropomysin 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.DiscussionInterventions 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 registrationInternational Standard Randomised Controlled Trial Number Registry, ISRCTN75715723. Registered on 22 October 2014.
Highlights
Patients with germline mutations in a tumour suppressor gene called Cylindromatosis protein (CYLD) develop multiple, disfiguring, hair follicle tumours on the head and neck
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
We demonstrated that CYLD defective tumour primary cell culture models on three-dimensional tissue culture scaffolds were highly sensitive to nanomolar levels of tropomyosin receptor kinase (TRK) inhibition
Summary
Germline mutations in CYLD develop multiple primary tumours in the skin. We report a trial design which allows within-patient placebo controls, allowing for an unbiased preliminary assessment of TRK inhibition in skin tumours from these patients. This design allows the number of tumours required in each arm to achieve statistical robustness despite the small number of participants typically seen in rare disease. (PDF 140 kb) Additional file 6: SPIRIT figure showing schedule of events in cohort 2 of the trial.
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