Contributions to TSC1 & 2 Gene Variation Databases TSC1 N=820 entries TSC2 N*=2064 entries Published data 73% Unpublished data Total = 27% Published data

Contributions to TSC1 & 2 Gene Variation Databases

Published(Journals/old DBs)One Diagnostic Lab

Other DiagnosticLabs2 US Clinics

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TSC1N=820 entries

TSC2N*=2064 entries

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Database curators: Dr Rosemary Ekong and Prof Sue Povey

A phase II trial of the mTOR inhibitor sirolimus in patients with TSC or sporadic LAM (TESSTAL trial)

Julian Sampson, Institute of Medical Genetics, Cardiff, UK

See Davies DM et al. Clin Cancer Res 2011; 17:4071-4081

TRIAL LOCATION NPRIMARY

OUTCOME DRUG PHASE

1 Cincinnati 25 AML sirolimus II

2 Cincinnati 25 SEGA everolimus II

3 UK/Switz (MC) 16 AML sirolimus II

4 Cincinnati 30 AML everolimus II

5 USA (MC) 36 AML sirolimus II

6 International 99 AML everolimus III

7 International 99 SEGA everolimus III

Current and Completed Clinical Trials of mTOR inhibition in TSC

10 Boston/Cincinnati 20 Neurocognition everolimus II

8 Barcelona 18 AML sirolimus II

9 Cincinnati/Houston 20 Seizures everolimus II

11 Cincinnati 99* LAM everolimus II

TESSTAL: Design

• Non-randomised, Open label• Multicentre (Brighton, Cardiff, Nottingham,

Zurich)• Primary outcome = angiomyolipoma size• Oct 2005 – Sept 2009• Fleming’s single stage design• P1 0.1, P2 0.4, α 0.05, β 0.1 (N ≥ 15)• Sample size: 16 recruited• Intention to treat

Treatment

• Oral sirolimus as liquid, once daily for 2 years

• Dose adjusted to obtain:

- Starting drug level 3-6 ng/ml

- Escalation to 6-10 ng/ml at 2 months (first MRI on treatment) unless all target AML reduced by ≥ 10% (4 of 16 patients)

• Sirolimus levels lower than in previous trial (Bissler et al.)

Major Inclusion Criteria• TSC (Roach criteria, 1998) or LAM (CT/Bx)• 1 or more AML of ≥ 2cm • 18 – 65 yrs of age• GFR ≥ 40 mL/min

Major Exclusion Criteria• IQ < 70• AML bleed last 12 months• AML embolization last 6 months• Continuous O2 requirement

• Proteinuria >1g/day• Pregnancy/intention• Breast-feeding• Change in AED in last 3 months

Assessments: Primary Outcome

• AML size by serial MRI scan• Un-enhanced transaxial scans, 1.5 Tesla systems• Scans at baseline, 2, 6,12, 24 months• Up to 5 target AMLs per kidney• Sum Longest Diameters (SLD)• RECIST criteria i.e. response is ≥ 30% reduction

in SLD and no new lesions

Assessments: Secondary Outcomes

• Pulmonary Function• FEV1, FVC, DLCO at baseline,4, 6, 12, 24 months• Expressed as % predicted values

• Neurocognition• IQ for inclusion by NART• Immediate recall memory - AIMBP• Immediate recognition memory - CANTAB• Executive function - CANTAB

3 were not enrolled 2 were ineligible 1 declined to participate

19 patients with tuberous sclerosis or lymphangiomeiomatosis (LAM) screened

SIROLIMUS THERAPY, 16 started

10 had angiomyolipomas measured at 24 months

11 had neurocognitive assessment at 12 months



13 had angiomyolipomas measured at 6 months*

12 had angipomyolipomas measured at 12 months

9 with LAM had pulmonary function assessed at baseline

8 had pulmonary function assessed at 4 months

6 had pulmonary function assessed at 6 months#



16 had angiomyolipomas measured at baseline

14 had neurocognitive assessment at baseline

16 patients enrolled 6 had LAM only 3 had tuberous sclerosis and LAM 7 had tuberous sclerosis only

1 withdrew

1 withdrew

1 withdrew1 died

1 withdrew

1 withdrew


















1 withdrew

1 withdrew

1 withdrew1 died

1 withdrew

1 withdrew


















1 withdrew

1 withdrew

1 withdrew1 died

1 withdrew

1 withdrew


















1 withdrew

1 withdrew

1 withdrew1 died

1 withdrew

1 withdrew

Angiomyolipoma Response sum of longest diameters

• Reduction AML burden in all patients• 8/16 patients respond by RECIST criteria• 8/10 in per-protocol group• 25% diameter reduction ≡ 60% in volume

(for spherical lesions)

Angiomyolipoma Response: Percent Reduction in Sum of Longest Diameters

2 months 6 months 12 months 24 months

LAM1 10 ND 13 Deceased

LAM2 6 31 42 50

LAM3 14 14 14 41

LAM4 8 8 23 38

LAM5 4 Withdrew

LAM6 37 Withdrew

TSC1 (L) 28 28 30 28

TSC2 (L) 13 27 27 Withdrew

TSC3 9 14 Withdrew

TSC4 2 2 Withdrew

TSC5 16 32 32 34

TSC6 ND 5 29 26

TSC7 22 23 30 28

TSC8 (L) 34 24 18 17

TSC9 16 11 18 21

TSC10 2 6 14 17

AML Response

• 41 / 48 AMLs smaller at last measurement than baseline• 2 unchanged• 5 larger:

TSC3 - 1 of 5 AMLs increased by 1mm. Others shrank by 20-30%

TSC4 - 4 of 9 AMLs grew (by up to 30%) while 5 shrank (by up to 25%)

• Most shrinkage in first year – mean LD of AMLs measured at 0,12 and 24 months were 2.92, 2.19 and 2.11cm respectively

FEV1

0 4 8 12 16 20 240

20

40

60

80

100

120LAM1LAM2LAM3LAM4LAM5LAM6TSC1(L)TSC2(L)TSC8(L)

% p

redi

cted

FVC

0 4 8 12 16 20 240

20

40

60

80

100

120

% p

redi

cted

DLCO

0 4 8 12 16 20 240

20

40

60

80

100

120

Months

% p

redi

cted

Lung Function in Patients with LAM

Mean rate of decline in FEV1 = 49 ml/yr over 12/12 (N=7) = 76 ml/yr over 24/12 (N = 5)

TSC* N S-LAM N

IQ (SD) 105 (+/-15) 8 107 (+/-12) 6

Deficits on Tests(< 5th Percentile)

At Baseline 9/88 (10.2%) 8 2/63 (3.2%) 6

At 4 months 6/88 (6.8%) 8 1/45 (2.2%) 5

At 12 months 7/77 (9.1%) 7 0/44 (0%) 5

IQ and Neurocognitive Deficits

* No patient with TSC had seizures in the year prior to or during the study

Immediate Recall MemoryTSC mean change + 2S-LAM +1.6

Immediate Recognition MemoryTSC mean change -1.625 S-LAM - 0.6

Executive FunctionTSC mean change + 1.5S-LAM + 3.0

Neurocognitive Tests: Summary Scores by Domain

Adverse Events• Reported in all patients. Majority CTCAE grade 1 or 2

• All patients had some time off therapy (days to months)

• Drug discontinued in 2 patients because of toxicity (peripheral oedema, proteinuria)

• One death (deemed unrelated to treatment)

• Frequent AEs:Respiratory infections, 5/16 – all LAM3 serious and possibly sirolimus-related

Mouth ulcers, 6/16

Proteinuria, 5/16

Summary

• Sirolimus therapy (3-10ng/ml) reduced size of most AMLs in patients with TSC or S-LAM

• AML burden reduced in all patients• Most shrinkage in first year of therapy• Response sustained at 2 years• Side effects acceptable to most patients – but care in LAM• Neurocognitive function – similar changes in TSC and

S-LAM patients• Lung function in LAM – little change, decline slowed ?

Acknowledgements

TESSTAL team:D Mark Davies, Petrus de Vries, Simon Johnson,

Deborah McCartney, Jane Cox, Andreas Serra, Peter Watson, Christopher Howe, Tim Doyle, Kate Pointon, Justin cross, Anne

Tattersfield, Chris Kingswood.

J Bissler, D Franz, D Kruger, F McCormack (Cincinnati)

A Hunt

TSA, James Tudor Trust, Wyeth (Pfizer)

TRON: UK Trial of Everolimus for neurocognitive problems in TSC

TRON• Randomized control (2:1) trial, single UK centre• Recruitment target 48• Age 16 - 60 yrs• IQ ≥ 60 and deficit (-2 SD or more) in a 1º outcome

measure• 6 months treatment, blood levels 3-10ng/ml• Determine effect sizes on recall memory and executive

function in TSC• Secondary outcomes: seizures, QOL, wider aspects of

neurocognition, safety• Protocol developed with Novartis and TSA (GB)• Recruitment planned to open end 2011

Documents

Contributions to TSC1 & 2 Gene Variation Databases TSC1 N=820 entries TSC2 N*=2064 entries Published data 73% Unpublished data Total = 27% Published data