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Cancer Chemotherapy and Pharmacology

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01.02.2012 | Original Article

Phase IB study of sorafenib in combination with gemcitabine and cisplatin in patients with refractory solid tumors

verfasst von: B. Schultheis, G. Kummer, M. Zeth, E. Brendel, C. Xia, M. Kornacker, D. Strumberg

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2012

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Abstract

Purpose

Sorafenib (BAY 43-9006), a multikinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. This study investigated the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with gemcitabine and cisplatin.

Methods

Patients with advanced solid tumors were treated with 75 mg/m² cisplatin on day 1 and 1,250 mg/m² gemcitabine on days 1 and 8 of each 21-day cycle. On day 5 of cycle 1, sorafenib 400 mg twice daily was started and continued throughout the complete treatment cycles without interruption.

Results

Nineteen patients were valid for safety analysis. The most frequent toxicities related to the cytotoxic agents were hematological disorders. Sorafenib-related toxicities were skin-related, gastrointestinal, and constitutional symptoms. No clinically relevant pharmacokinetic drug–drug interaction between sorafenib, cisplatin, and gemcitabine was detected. AUC_0-72 and C _max of total and unbound platinum were only marginally changed by concomitant sorafenib. Concomitant sorafenib increased mean AUC and C _max of gemcitabine by 12 and 21%.

Conclusions

Sorafenib as continuous oral treatment in combination with gemcitabine and cisplatin demonstrated an acceptable safety profile. No clinically relevant pharmacokinetic interaction was detected. Preliminary antitumor activity, pharmacokinetic, and safety data support the recommendation of 400 mg sorafenib twice daily in combination with cisplatin and gemcitabine to be further evaluated in clinical studies.

Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109. doi:10.1158/0008-5472.CAN-04-1443 PubMedCrossRef

Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J, Johnson DH, Laskin JL, Masters G, Milton D, Nordquist L, Pfister DG, Piantadosi S, Schiller JH, Smith R, Smith TJ, Strawn JR, Trent D, Giaccone G (2009) American society of clinical oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 27(36):6251–6266. doi:10.1200/JCO.2009.23.5622 PubMedCrossRef

D’Addario G, Fruh M, Reck M, Baumann P, Klepetko W, Felip E (2010) Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v116–v119. doi:10.1093/annonc/mdq189 PubMedCrossRef

Cardenal F, Lopez-Cabrerizo MP, Anton A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, Garcia M, Lianes P, Montalar J, Vadell C, Gonzalez-Larriba JL, Nguyen B, Artal A, Rosell R (1999) Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 17(1):12–18PubMed

Crino L, Scagliotti GV, Ricci S, De Marinis F, Rinaldi M, Gridelli C, Ceribelli A, Bianco R, Marangolo M, Di Costanzo F, Sassi M, Barni S, Ravaioli A, Adamo V, Portalone L, Cruciani G, Masotti A, Ferrara G, Gozzelino F, Tonato M (1999) Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: a randomized phase III study of the Italian lung cancer project. J Clin Oncol 17(11):3522–3530PubMed

Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schonekas H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R (2006) Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 24(24):3946–3952. doi:10.1200/JCO.2005.05.1490 PubMedCrossRef

Sun S, Schiller JH, Spinola M, Minna JD (2007) New molecularly targeted therapies for lung cancer. J Clin Invest 117(10):2740–2750. doi:10.1172/JCI31809 PubMedCrossRef

Flaherty KT, Schiller J, Schuchter LM, Liu G, Tuveson DA, Redlinger M, Lathia C, Xia C, Petrenciuc O, Hingorani SR, Jacobetz MA, Van Belle PA, Elder D, Brose MS, Weber BL, Albertini MR, O’Dwyer PJ (2008) A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel. Clin Cancer Res 14(15):4836–4842. doi:10.1158/1078-0432.CCR-07-4123 PubMedCrossRef

Kupsch P, Henning BF, Passarge K, Richly H, Wiesemann K, Hilger RA, Scheulen ME, Christensen O, Brendel E, Schwartz B, Hofstra E, Voigtmann R, Seeber S, Strumberg D (2005) Results of a phase I trial of sorafenib (BAY 43–9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin Colorectal Cancer 5(3):188–196PubMedCrossRef

10.

CTCAE (2006) National Cancer Institute Common Terminology of Adverse Events v3.0. http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf

11.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) 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 92(3):205–216PubMedCrossRef

12.

Gatzemeier U, Eisen T, Santoro M, Pazzola A, Bennouna J, Liao M, Strauss UP, Montegriffo E, Ong TJ, Biesma B (2010) Sorafenib (S) + gemcitabine/cisplatin (GC) vs GC alone in the first-line treatment of advanced non-small cell lung cancer (NSCLC): phase III NSCLC research EXperience Utilizing Sorafenib (NExUS) trial. 35th ESMO Congress, Milan, Italy. Ann Oncol 21(Supplement 8):viii7 (abstract)

13.

Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, Abrao Miziara JE, Balint B, De Marinis F, Keller A, Aren O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, Dimatteo S, Hanna N (2010) Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 28(11):1835–1842. doi:10.1200/JCO.2009.26.1321 PubMedCrossRef

14.

Scagliotti G, Govindan R (2010) Targeting angiogenesis with multitargeted tyrosine kinase inhibitors in the treatment of non-small cell lung cancer. Oncologist 15(5):436–446. doi:10.1634/theoncologist.2009-0225 PubMedCrossRef

15.

Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Stahel R, Sabatier L, Pignon JP, Tursz T, Le Chevalier T, Soria JC (2006) DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355(10):983–991. doi:10.1056/NEJMoa060570 PubMedCrossRef

16.

Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957. doi:10.1056/NEJMoa0810699 PubMedCrossRef

17.

Kim ES, Herbst RS, Lee JJ, Blumenschein Jr GR, Tsao A, Alden CM, Tang X, Liu S, Stewart DJ, Heymach JV, Tran HT, Hicks ME, Erasmus J Jr, Gupta S, Powis G, Lippman SM, Wistuba II, Hong WK (2010) The BATTLE trial (biomarker-integrated approaches of targeted therapy for lung cancer elimination): personalizing therapy for lung cancer. Oral presentation at the plenary session of the AACR 101st Annual Meeting, Washington, USA

18.

Smit EF, Dingemans AM, Thunnissen FB, Hochstenbach MM, van Suylen RJ, Postmus PE (2010) Sorafenib in patients with advanced non-small cell lung cancer that harbor K-ras mutations: a brief report. J Thorac Oncol 5(5):719–720. doi:10.1097/JTO.0b013e3181d86ebf01243894-201005000-00021[pii] PubMedCrossRef

19.

Kelly RJ, Rajan A, Force J, Keen C, Cao L, Yu Y, Choyke PL, Turkbey B, Raffeld M, Xi L, Steinberg SM, Wright JJ, Lopez-Chavez A, Kummar S, Guttierrez M, Giaccone G (2011) Evaluation of KRAS mutations, angiogenic biomarkers and DCE-MRI in patients with advanced non-small cell lung cancer receiving sorafenib. Clin Cancer Res. doi:10.1158/1078-0432.CCR-10-2331

Titel: Phase IB study of sorafenib in combination with gemcitabine and cisplatin in patients with refractory solid tumors
verfasst von: B. Schultheis
G. Kummer
M. Zeth
E. Brendel
C. Xia
M. Kornacker
D. Strumberg
Publikationsdatum: 01.02.2012
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2012
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1685-x

Springer Medizin

Phase IB study of sorafenib in combination with gemcitabine and cisplatin in patients with refractory solid tumors

Abstract

Purpose

Methods

Results

Conclusions

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Update Onkologie

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

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