A Non-Randomised, Open Label, Pilot Trial of Sirolimus Therapy for Segmental Overgrowth Due to PIK3CA Related Overgrowth

Research summary

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.

Main inclusion criteria

To be included in the trial the participant must:

  1. Have given, or their guardian has given, written informed consent to participate

  2. Aged 3 to 65 years inclusive

  3. Male or female

  4. Post-zygotic PIK3CA mutation

  5. Clinically stable in the opinion of the investigator

  6. Measurably progressive overgrowth, in current progression or with clinical history of overgrowth progression

  7. An MRI/DXA baseline scan performed six months prior to enrolment in the trial for which data is available for review

  8. Participant Pregnancy and contraception:

    1. Female participants of child bearing potential must use an effective method of contraception during treatment and for at least 12 weeks after the final dose of sirolimus. Acceptable methods are:

      1. True abstinence (this must be the participant’s usual and preferred lifestyle, not just for the duration of the trial)

      2. Oral contraceptive (either combined or progestogen alone)

      3. Contraceptive implant, injections or patches

      4. Vaginal ring

      5. Intrauterine device (IUD, coil or intrauterine system)

      6. Condom and cap

      7. Diaphragm plus spermicide

    2. A female patient of child bearing potential is defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 12 consecutive months if aged 55 years or older.

    3. Men must use one of the following, reliable forms to contraception for the entire duration of treatment and for 12 weeks after the final dose of sirolimus:

      1. Condom plus spermicide even if female partner is using another method of contraception (Men should also use a condom to protect male partners, or female partners who are pregnant or breast feeding, from exposure to the Trial medicine in semen).

      2. True abstinence (this must be the participant’s usual and preferred lifestyle,
        not just for the duration of the Trial)

Main exclusion criteria

  1. The participant elects to withdraw from the trial

  2. Severe/grade III side-effects on treatment

  3. Neutropenia (neutrophils < 1.0 10^9)

  4. Heavy proteinuria

  5. Deterioration in renal function (GFR<70mls/min/1.73 m2)

  6. Deterioration in liver function (ALT>3 times upper limit of normal)

  7. Pneumonitis/ decline in respiratory reserve

  8. Severe, recurrent infections or septicaemia

  9. QTc prolongation >500ms (women), >490ms (men)

  10. Malignancy or investigation for malignancy

  11. Inability or failure to attend trial visits

  12. Decision of independent drug surveillance committee

  13. Pregnancy

Chief investigator

Dr Robert Semple

Contact details

Clinical Trials ManagerDr Paula Kareclas

Telephone: 01223 596473 | Email: [email protected]