Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM

Condition(s) targeted: Tuberous Sclerosis; Lymphangioleiomyomatosis

Intervention: sirolimus (Drug)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: Cardiff University

Official(s) and/or principal investigator(s):
Julian R Sampson, DM, Principal Investigator, Affiliation: Cardiff Univeristy

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.

Official title: A Trial of the Efficacy and Safety of Sirolimus(Rapamycin)Therapy for Renal Angiomyolipmoas in Patients With Tuberous Sclerosis Complex and Sporadic Lymphangioleiomyomatosis

Study design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Primary outcome:

longest diameter of renal angiomyolipomas assessed by MRI scan, toxicity graded by National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0

toxicity graded by National Cancer Institute's Common Terminology Criteria for Adverse Events

Secondary outcome: respiratory function tests (FEV1, FVC, DLCO), cognitive function (memory, executive skills)

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

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

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)

City Hospital, Nottingham NG5 1PB, United Kingdom

Royal Sussex County Hospital, Brighton BN2 5BE, United Kingdom

University Hospital of Wales, Cardiff, Wales CF14 4XN, United Kingdom

Starting date: October 2005
Ending date: September 2009
Last updated: April 29, 2008