A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor sonidegib (LDE225) in patients with advanced solid tumors

Clinical Cancer Research

Volumn 20, Issue 7, 2014, Pages 1900-1909

  Rodon, Jordi ^a   Tawbi, Hussein A ^b   Thomas, Anne L ^c   Stoller, Ronald G ^b   Turtschi, Christian P ^d   Baselga, Jose ^e   Sarantopoulos, John ^f   Mahalingam, Devalingam ^f   Shou, Yaping ^g   Moles, Melissa A ^g   Yang, Lin ^g   Granvil, Camille ^h   Hurh, Eunju ^g   Rose, Kristine L ^h   Amakye, Dereck D ^h   Dummer, Reinhard ^d   Mita, Alain C ^f  

^a UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^b UNIVERSITY OF PITTSBURGH CANCER INSTITUTE   (United States)

^c UNIVERSITY OF LEICESTER   (United Kingdom)

^d UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^e MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^f UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

^g NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^h NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; CREATINE KINASE; MESSENGER RNA; MYOGLOBIN; SONIDEGIB; TRANSCRIPTION FACTOR GLI1; BIPHENYL DERIVATIVE; G PROTEIN COUPLED RECEPTOR; GLI1 PROTEIN, HUMAN; PYRIDINE DERIVATIVE; SMO PROTEIN, HUMAN; TRANSCRIPTION FACTOR;

ADENOCARCINOMA; ADULT; ADVANCED CANCER; AGED; ALOPECIA; ANOREXIA; AREA UNDER THE CURVE; ARTICLE; ASTHENIA; BASAL CELL CARCINOMA; CILIARY BODY TUMOR; COLORECTAL CANCER; CONSTIPATION; CREATINE KINASE BLOOD LEVEL; CUTANEOUS MELANOMA; DIARRHEA; DIZZINESS; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSGEUSIA; FATIGUE; FEMALE; GASTROINTESTINAL TOXICITY; GASTROINTESTINAL TUMOR; GERM CELL TUMOR; HUMAN; HUMAN TISSUE; HYPERBILIRUBINEMIA; KIDNEY DYSFUNCTION; LEIOMYOSARCOMA; LETHARGY; LUNG CANCER; MAJOR CLINICAL STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MEDULLOBLASTOMA; MERKEL CELL TUMOR; MESOTHELIOMA; MULTICENTER STUDY; MUSCLE SPASM; MUSCLE WEAKNESS; MYALGIA; MYOSITIS; NAUSEA; OSTEOSARCOMA; PANCREAS CANCER; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; SINGLE DRUG DOSE; SKIN BIOPSY; SOLID TUMOR; SPINDLE CELL CARCINOMA; TIME TO MAXIMUM PLASMA CONCENTRATION; TUMOR BIOPSY; UNSPECIFIED SIDE EFFECT; UROGENITAL TRACT TUMOR; VOMITING; WEIGHT REDUCTION; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; CANCER STAGING; CARCINOMA, BASAL CELL; CLINICAL TRIAL; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; MIDDLE AGED; ORAL DRUG ADMINISTRATION; PATHOLOGY; SIGNAL TRANSDUCTION; VERY ELDERLY;

ADMINISTRATION, ORAL; ADULT; AGED; AGED, 80 AND OVER; BIPHENYL COMPOUNDS; CARCINOMA, BASAL CELL; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MALE; MAXIMUM TOLERATED DOSE; MEDULLOBLASTOMA; MIDDLE AGED; NEOPLASM STAGING; PYRIDINES; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS;

EID: 84898721363     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-13-1710     Document Type: Article

References (33)

1. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003;3:903-11. (Pubitemid 37500175)
2. Teglund S, Toftgard R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta 2010;1805:181-208.
3. Lorusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, et al. Phase I trial of hedgehog pathway inhibitor GDC-0449 in patients with refractory, locally-advanced or metastatic solid tumors. Clin Cancer Res 2011;17:2502-11.
4. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012;366:2171-9.
5. Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012;366:2180-8.
6. Erivedge prescribing information. 2012 [cited 2013 May 14] Available from: http://www.accessdata.fda.gov/drugsatfda-docs/label/2012/203388lbl.pdf.
7. Siu LL, Papadopoulos K, Alberts SR, Kirchoff-Ross R, Vakkalagadda B, Lang L, et al. A first-in-human, phase I study of an oral hedgehog (HH) pathway antagonist, BMS-833923 (XL139), in subjects with advanced or metastatic solid tumors. J Clin Oncol 2010 ASCO Ann Mtg Proc 2010;28:abstr 2501.
8. Jimeno A, Weiss GJ, Miller WHJr, Gettinger S, Eigl BJ, Chang AL, et al. Phase I study of the hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res 2013;19:2766-74.
9. Jamieson C,Cortes JE,Oehler V,Baccarani M,KantarjianHM,Papayannidis C, et al. Phase I dose-escalation study of PF-04449913, an oral hedgehog (Hh) inhibitor, in patients with select hematologic malignancies. Blood ASH Ann Mtg Proc 2011;118:abstr 424.
10. Pan S,WuX, Jiang J, Gao W, Wan Y, Cheng D, et al. Discovery of NVP-LDE225, a potent and selective smoothened antagonist. Am Cancer Soc Med Chem Lett 2010;1:130-4.
11. Buonamici S, Williams J, Morrissey M, Wang A, Guo R, Vattay A, et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med 2010;2:51ra70.
12. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. 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;92:205-16.
13. Macdonald DR, Cascino TL, Schold SCJr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277-80. (Pubitemid 20195640)
14. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010;28:1963-72.
15. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med 1998;17:1103-20. (Pubitemid 28221028)
16. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med 2008;27:2420-39. (Pubitemid 351802902)
17. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-81. (Pubitemid 36962641)
18. Shou Y, Robinson D, Amakye D, Rose K, Cho Y, Ligon KL, et al. A five-gene Hedgehog signature developed as a patient preselection tool for Hedgehog inhibitor therapy in medulloblastoma. Clin Cancer Res. In press.
19. Amakye D, Robinson D, Rose K, Cho J, Ligon KL, Sharp T, et al. The predictive value of a 5-gene signature as a patient pre-selection tool in medulloblastoma for Hedgehog pathway inhibitor therapy. Am Assoc Cancer Res Congress 2012;72:abstr 4818.
20. Weber WA, Petersen V, Schmidt B, Tyndale-Hines L, Link T, Peschel C, et al. Positron emission tomography in non-small-cell lung cancer: prediction of response to chemotherapy by quantitative assessment of glucose use. J Clin Oncol 2003;21:2651-7. (Pubitemid 46606307)
21. Rittie L, Stoll SW, Kang S, Voorhees JJ, Fisher GJ. Hedgehog signaling maintains hair follicle stem cell phenotype in young and aged human skin. Aging Cell 2009;8:738-51.
22. Liu HX, Maccallum DK, Edwards C, Gaffield W, Mistretta CM. Sonic hedgehog exerts distinct, stage-specific effects on tongue and taste papilla development. Dev Biol 2004;276:280-300. (Pubitemid 39592394)
23. Teperino R, Amann S, Bayer M, McGee SL, Loipetzberger A, Connor T, et al. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell 2012;151:414-26.
24. Pasternak RC, Smith SCJr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40:567-72.
25. Graham RA, Lum BL, Cheeti S, Jin JY, Jorga K, Von Hoff DD, et al. Pharmacokinetics of hedgehog pathway inhibitor GDC-0449 in patients with locally-advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. Clin Cancer Res 2011;17:2512-20.
26. Geoerger B, Aerts I, Casanova M, Chisholm J, Hargrave D, Leary SES, et al. Updated results from a phase I study of LDE225, a smoothened antagonist, in pediatric patients with recurrent medulloblastoma or other solid tumors. International Society of Paediatric Oncology meeting abstracts 2012:abstr O037.
27. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009;361:1173-8.
28. Gajjar AJ, Gururangan S, Qaddoumi IA, Packer R, Goldman S, Prados M, et al. A prospective phase II study to determine the efficacy of GDC 0449 (vismodegib) in adults with recurrent medulloblastoma (MB): a pediatric brain tumor consortium study (PBTC 25B). J Clin Oncol 2013 ASCO Ann Mtg Proc 2013;31:abstr 2035.
29. Gajjar A, Stewart CF, Ellison DW, Kaste S, Kun LE, Packer RJ, et al. Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a pediatric brain tumor consortium study. Clin Cancer Res 2013;19:6305-12.
30. ClinicalTrials.gov. A phase II study of efficacy and safety in patients with locally advanced or metastatic basal cell carcinoma (BOLT). 2011 [cited 2013 May 14]. Available from: http://ClinicalTrials.gov/show/NCT01327053.
31. ClinicalTrials.gov. Efficacy, safety and pharmacokinetics of oral LDE225 in treatment of patients with nevoid basal cell carcinoma syndrome (NBCCS BCC). 2011 [cited 2013 May 14]. Available from: http://clinicaltrials.gov/ct2/show/ NCT01350115.
32. ClinicalTrials.gov. A dose finding and safety study of oral LDE225 in children. 2010 [cited 2013 May 14]. Available from: http://ClinicalTrials.gov/ show/NCT01125800.
33. ClinicalTrials.gov. A phase III study of oral LDE225 versus (vs) temozolomide (TMZ) in patients with hedgehog (Hh)-pathway activated relapsed medulloblastoma (MB). 2012 [cited 2013 May 14]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01708174.