Patient case: 26-year-old female with Cervical cancer. Genetic variant: STK11. Other conditions: None.

Clinical trial: Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM

Summary: The purpose of this study is to determine the safety and efficacy of the mTOR inhibitor sirolimus as a treatment for renal angiomyolipomas in patients with tyberous sclerosis complex or sporadic lymphangioleiomyomatosis.

Detailed description: Inherited mutations of the TSC1 or TSC2 gene cause tuberous sclerosis while acquired (somatic) mutations of either gene are associated with sporadic lymphangioleiomyomatosis (LAM). Renal angiomyolipomas are a feature of both disorders. TSC1 and TSC2 regulate signalling through the mammalian target of rapamycin (mTOR) pathway. Inhibition of mTOR may result in a decrease in size of TSC 1/2 assciated lesions. We are treating patients with tuberous sclerosis or sporadic LAM with the mTOR inhibitor rapamycin in a non-randomised, open label pilot study of safety and efficacy. Change in size of renal angiomyolipomas is the primary end point

Eligibility: Inclusion Criteria:
  -  If female, documentation of negative pregnancy test prior to enrolment.
  -  Participants, including males, must use an effective form of contraception, whilst taking sirolimus and for twelve weeks after stopping the drug
  -  One or more renal angiomyolipomata of at least two centimetres or greater in largest diameter
  -  Adequate renal function :glomerular filtration rate > 40 ml/min
  -  Clinically definite diagnosis of tuberous sclerosis (modified Gomez criteria) or sporadic LAM (biopsy-proven or compatible high resolution chest CT scan and respiratory function tests.)
  -  Signed and dated informed consent
  Exclusion Criteria:
  -  History of non-compliance or inability to give informed consent
  -  Significant haematological or hepatic abnormality (i.e. transaminase levels > 150 i.u./L serum albumin < 30 g/L, haematocrit< 30%, platelets < 100,000/ mm3, adjusted absolute neutrophil count < 1,500/mm3, total WBC < 3,000/ mm3)
  -  Greater than 1 g proteinuria daily
  -  Multiple bilateral AMLs, where individual lesions cannot be distinguished
  -  Renal haemorrhage within preceding year
  -  In those who have had a renal haemorrhage, known conservatively managed renal aneurysm(s) greater than 10mm
  -  Patients who have had embolisation for AML(s) within the preceding 6 months
  -  Patients who are unable to walk 100 metres on the flat
  -  Continuous requirement for supplemental oxygen
  -  Patients who have had or are being considered for organ transplant
  -  Uncontrolled hyperlipidaemia
  -  Intercurrent infection at initiation of Sirolimus
  -  Surgery within last 2 months
  -  Pregnant or lactating women
  -  Use of an investigational drug within the last 30 days
  -  Change in anti epileptic drug medication within the last 3 months
  -  Likely to need vaccination e.g. for travel during the course of the trial (except for influenza vaccine in patients with LAM)
  -  Current usage of strong inhibitors of CYP3AE ( such as ketoconazole, voriconazole, itraconazole, tilithromycin or clarithromycin) or strong inducers (such as rifampicin or rifabutin)

Relevance to patient case: not relevant