Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease

Sandra L Dabora, David Neal Franz, Stephen Ashwal, Arthur Sagalowsky, Francis J DiMario Jr, Daniel Miles, Drew Cutler, Darcy Krueger, Raul N Uppot, Rahmin Rabenou, Susana Camposano, Jan Paolini, Fiona Fennessy, Nancy Lee, Chelsey Woodrum, Judith Manola, Judy Garber, Elizabeth A Thiele, Sandra L Dabora, David Neal Franz, Stephen Ashwal, Arthur Sagalowsky, Francis J DiMario Jr, Daniel Miles, Drew Cutler, Darcy Krueger, Raul N Uppot, Rahmin Rabenou, Susana Camposano, Jan Paolini, Fiona Fennessy, Nancy Lee, Chelsey Woodrum, Judith Manola, Judy Garber, Elizabeth A Thiele

Abstract

Background: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.

Methods: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.

Results: 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).

Conclusions: Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.

Trial registration: Clinicaltrials.gov NCT00126672.

Conflict of interest statement

Competing Interests: Wyeth/Pfizer supplied study drug at no charge per an investigator originated proposal written by SD. SD has been a consultant to Novartis. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Enrollment Chart.
Figure 1. Enrollment Chart.
Figure 2. Kidney angiomyolipoma regression with sirolimus…
Figure 2. Kidney angiomyolipoma regression with sirolimus treatment.
Panel A) percent change in kidney tumor size (sum LD) for individual cases (black bars-best response during year one on study; adjacent white bars-week 52 response for same subject). All subjects were treated with sirolimus from weeks 0 to 52. Panels B and C) percent change in kidney tumor size compared with baseline for kidney tumors at each time point. After week 52, a subset (Panel B) was observed off treatment (black, OFF SIROLIMUS AFTER WK 52 group, n = 15). Another subset (Panel C) received additional study drug treatment after week 52 (red, ON SIROLIMUS AFTER WK 52 group, n = 13). Panel D) percent change in kidney tumor size at 24 months (104 weeks) for indicated groups. Panel E) kidney tumor size at week 0 and week 104 (month 24) for the OFF SIROLIMUS AFTER WK 52 group. Panel F) kidney tumor size at week 0 and week 104 (month 24) for ON SIROLIMUS AFTER WK 52 group.
Figure 3. Brain tumors (SEGAs), liver angiomyolipomas,…
Figure 3. Brain tumors (SEGAs), liver angiomyolipomas, skin lesions, and lung function.
Panel A shows the diameter (cm) of brain tumors (SEGAs) at baseline and week 52 in 11 participants. T1 post gadolinium MR images (courtesy of Dr. Nathaniel D. Wycliffe, Department of Radiology, Loma Linda University School of Medicine) in panels B–E show a SEGA near the right foramen of Monroe that measured 1.8 cm maximal diameter at baseline (B,D) with near complete resolution of the lesion after sirolimus treatment (C,E).. Panel F is a graph of liver angiomyolipoma size for all cases (longest diameter in cm) at baseline and at best response. Panel G shows changes in TSC skin lesions with sirolimus treatment. Panels H–J show pulmonary function data (FVC, FEV1, DLCO) at week 0 and week 52 for female participants with TSC/LAM (n = 15). See Tables S6, S7 and Figures S5, S6, S7 for data on LAM subsets.
Figure 4. Serum VEGF-D levels are elevated…
Figure 4. Serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size.
Panel A shows baseline serum VEGF-D levels for all subjects and indicated subgroups (women, men, TSC/LAM and TSC). According to other studies , , mean serum VEGF-D levels in control female populations are 300–657 ng/ml (indicated by gray box, see additional details in Table S4, mean VEGF-D levels in control males is not available). Panel B shows that serum VEGF-D levels decrease after 52 weeks of sirolimus treatment. Panels C and D show the correlation between kidney tumor size (sum LD in cm) and serum VEGF-D levels (pg/ml) at baseline (Panel C) and week 52 (Panel D).

References

    1. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355:1345–1356.
    1. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol. 1998;13:624–628.
    1. Henske EP, Wessner LL, Golden J, Scheithauer BW, Vortmeyer AO, et al. Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am J Pathol. 1997;151:1639–1647.
    1. Nie D, Di Nardo A, Han JM, Baharanyi H, Kramvis I, et al. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat Neurosci. 2010;13:163–172.
    1. Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, et al. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med. 2008;14:843–848.
    1. Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, et al. Mutational Analysis in a Cohort of 224 Tuberous Sclerosis Patients Indicates Increased Severity of TSC2, Compared with TSC1, Disease in Multiple Organs. Am J Hum Genet. 2001;68:64–80.
    1. Franz DN, Brody A, Meyer C, Leonard J, Chuck G, et al. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med. 2001;164:661–668.
    1. Gomez M, Sampson J, Whittemore V, , editors. The tuberous sclerosis complex. Third Ed. ed. Oxford, England: Oxford University Press; 1999.
    1. Gao X, Pan D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev. 2001;15:1383–1392.
    1. Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2005;37:19–24.
    1. Potter CJ, Huang H, Xu T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell. 2001;105:357–368.
    1. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–2281.
    1. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–456.
    1. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–523.
    1. Lee L, Sudentas P, Donohue B, Asrican K, Worku A, et al. Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer. 2005;42:213–227.
    1. Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci. 2008;28:5422–5432.
    1. Woodrum C, Nobil A, Dabora SL. Comparison of three rapamycin dosing schedules in A/J Tsc2+/− mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors. Journal of Translational Medicine. 2010;8:14.
    1. Zeng LH, Xu L, Gutmann DH, Wong M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008;63:444–453.
    1. Chan JA, Zhang H, Roberts PS, Jozwiak S, Wieslawa G, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol. 2004;63:1236–1242.
    1. El-Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet. 2003;361:1348–1349.
    1. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem. 2002;277:30958–30967.
    1. Ewalt DH, Sheffield E, Sparagana SP, Delgado MR, Roach ES. Renal lesion growth in children with tuberous sclerosis complex. J Urol. 1998;160:141–145.
    1. Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc. 1991;66:792–796.
    1. Casper KA, Donnelly LF, Chen B, Bissler JJ. Tuberous sclerosis complex: renal imaging findings. Radiology. 2002;225:451–456.
    1. Sooriakumaran P, Gibbs P, Coughlin G, Attard V, Elmslie F, et al. Angiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treated. BJU Int. 2009;105:101–106.
    1. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials. 1989;10:1–10.
    1. Therasse P. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216.
    1. Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clinical Pharmacokinetics. 2001;40:573–585.
    1. Schubert M, Venkataramanan R, Holt DW, Shaw LM, McGhee W, et al. Pharmacokinetics of sirolimus and tacrolimus in pediatric transplant patients. Am J Transplant. 2004;4:767–773.
    1. Motulsky H. Fitting Models to Biological Data using Linear and Nonlinear Regression. San Diego, , CA: GraphPad Software, Inc; 2003.
    1. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008;358:140–151.
    1. Rodriguez-Moreno A, Ridao N, Garcia-Ledesma P, Calvo N, Perez-Flores I, et al. Sirolimus and everolimus induced pneumonitis in adult renal allograft recipients: experience in a center. Transplant Proc. 2009;41:2163–2165.
    1. Sancak O, Nellist M, Goedbloed M, Elfferich P, Wouters C, et al. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype–phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. Eur J Hum Genet. 2005;13:731–741.
    1. Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc. 2000;75:591–594.
    1. Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, et al. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med. 2001;164:669–671.
    1. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21:154–165.
    1. Lohela M, Saaristo A, Veikkola T, Alitalo K. Lymphangiogenic growth factors, receptors and therapies. Thromb Haemost. 2003;90:167–184.
    1. Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A. 2000;97:6085–6090.
    1. Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J. Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement. Chest. 2009;135:1293–1300.
    1. Seyama K, Kumasaka T, Souma S, Sato T, Kurihara M, et al. Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol. 2006;4:143–152.
    1. Young LR, Inoue Y, McCormack FX. Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N Engl J Med. 2008;358:199–200.
    1. Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest. 2010;138:674–681.
    1. Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, et al. Sirolimus Therapy for Angiomyolipoma in Tuberous Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 trial. Clin Cancer Res 2011
    1. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. New England Journal of Medicine. 2010;363:1801–1811.
    1. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem. 2002;277:30958–30967.
    1. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, et al. Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis. N Engl J Med 2011
    1. White DA, Camus P, Endo M, Escudier B, Calvo E, et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med. 2010;182:396–403.
    1. Au KS, Williams AT, Roach ES, Batchelor L, Sparagana SP, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. 2007;9:88–100.
    1. Peces R, Peces C, Cuesta-Lopez E, Perez-Duenas V, Vega-Cabrera C, et al. Low-dose rapamycin reduces kidney volume angiomyolipomas and prevents the loss of renal function in a patient with tuberous sclerosis complex. Nephrol Dial Transplant 2010
    1. Haemel AK, O'Brian AL, Teng JM. Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol. 2010;146:715–718.
    1. Hofbauer GF, Marcollo-Pini A, Corsenca A, Kistler AD, French LE, et al. The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. Br J Dermatol. 2008;159:473–475.
    1. Rauktys A, Lee N, Lee L, Dabora SL. Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model. BMC Dermatol. 2008;8:1.
    1. Lee L, Sudentas P, Dabora SL. Combination of a rapamycin analog (CCI-779) and interferon-gamma is more effective than single agents in treating a mouse model of tuberous sclerosis complex. Genes Chromosomes Cancer. 2006;45:933–944.
    1. Lee N, Woodrum C, Nobil A, Rauktys A, Messina MP, et al. Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. BMC Pharmacol. 2009;9:8.
    1. Watson MS, Epstein C, Howell RR, Jones MC, Korf BR, et al. Developing a national collaborative study system for rare genetic diseases. Genet Med. 2008;10:325–329.
    1. Johnson SR, Tattersfield AE. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med. 1999;160:628–633.
    1. Taveira-DaSilva AM, Stylianou MP, Hedin CJ, Hathaway O, Moss J. Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone. Chest. 2004;126:1867–1874.

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