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Sirolimus Therapy for Angiomyolipoma in Tuberous Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 trial
Davies, D.M., de Vries, P.J., Johnson, S.R., McCartney, D.L., Cox, J.A., Serra, A.L., WATSON, P.C., Howe, C.J., Doyle, T., Pointon, K., Cross, J.J., Tattersfield, A.E., Kingswood, C. and Sampson, J.R.
Clinical Cancer Research, 17, 4071-4081
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PURPOSE Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis. These disorders are associated with mutations of TSC1 or TSC2 that lead to over-activation of mammalian target of rapamycin complex 1 (mTORC1), suggesting an opportunity for targeted therapy using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders. EXPERIMENTAL DESIGN In this multicenter phase 2 non-randomized open label trial sixteen patients with tuberous sclerosis or sporadic lymphangioleiomyomatosis and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady state blood levels were 3-10ng/ml. The primary outcome was change in size of renal angiomyolipomas measured by magnetic resonance imaging and assessed by RECIST criteria. Secondary outcomes included safety, neurocognitive function and pulmonary function. RESULTS The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in 8 (all from the per-protocol group of 10). Forty one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in 7 of 8 patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus. CONCLUSIONS This study demonstrated sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic lymphangioleiomyomatosis receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation.