PROMISE

Segmental overgrowth disorders are rare conditions characterised by abnormal growth which is usually asymmetric and confined to discrete parts of the body. We and others have recently identified mosaic activating mutations in the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K; encoded by the PIK3CA gene) in a subset of overgrowth disorders1234. The PI3K-AKT-mTOR is a critical signalling pathway, which regulates cellular growth, proliferation and survival. Activating mutations in PIK3CA lead to increased activation of the AKT-mTORC1 axis5, which in turn promotes excessive growth in affected tissue.

The PIK3CA-related overgrowth spectrum is wide, and depends upon the timing of the founder mutation in embryogenesis, and potentially upon the exact mutation. Clinical presentation ranges from isolated enlargement of a digit, to extensive overgrowth of limbs, abdomen and in some cases the brain, and may be accompanied by vascular or lymphatic malformations. Associated morbidity can be profound, with functional impairment, debilitating haemorrhages and thromboses, coupled with neurological sequelae and, in some cases, death. At present, serial debulking surgery is the only available therapeutic option. The identification of gain-of-function mutations in PI3K has raised the possibility of treatment with drugs that inhibit components of the PI3K-AKT signalling pathway; mTOR lies downstream from PI3K, and is a key determinant of cellular growth, and is therefore a putative druggable target in PIK3CA-related overgrowth.

Although a randomised controlled trial is optimal for therapeutic studies, a number of complexities unique to this condition have been identified that suggest that an open label non-randomised proof-of-concept trial is necessary in the first instance to determine the effect size of treatment, and enable future trial planning. PROMISE is an open-label, phase II, non-randomised, pilot trial which will involve treating 10 participants with PIK3CA-related overgrowth with low dose sirolimus therapy for six months. This is a single centre trial, which will run in parallel with two separately sponsored, independent trials in France and the USA. The protocol design, documentation and methodologies for measuring primary and secondary end-points will be identical across all trials to facilitate pooling of results at the end of the trial under a data sharing agreement. The toxicity information from the other trials will be part of the annual review.

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