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01-08-2019 | PHASE I STUDIES

A phase I study of the vascular endothelial growth factor inhibitor Vatalanib in combination with Pemetrexed disodium in patients with advanced solid tumors

Authors: Fen Wang, Julian Molina, Daniel Satele, Jun Yin, Vun-Sin Lim, Alex A. Adjei

Published in: Investigational New Drugs | Issue 4/2019

Summary

Introduction Vatalanib is an oral receptor tyrosine kinase inhibitor that blocks all known VEGF, PDGF, and c-Kit receptors. This phase I study evaluated the safety, tolerability, and biologic activity of the combination of vatalanib with pemetrexed disodium in patients with advanced solid tumors. Methods Patients were administered escalating twice daily doses of vatalanib in combination with pemetrexed disodium in 21-day cycles. A dose expansion cohort was enrolled to further define the maximum tolerated dose (MTD) and further evaluate efficacy. Results A total of 29 patients were enrolled in the study (dose escalation, 9; dose expansion, 20). Dose-limiting toxicities included grade 4 thrombocytopenia (6.9%) and febrile neutropenia, anorexia, constipation, and dehydration. Other common adverse events were fatigue (75%), nausea (66%), vomiting (48%), oral mucositis (31%) and diarrhea (28%). The majority of these toxicities were Grade 1–2. The MTD was reached at vatalanib 250 mg twice daily continuously combined with pemetrexed disodium 500 mg/m² day 1. Overall, 2 patients (6.9%) had partial responses, 8 (27.6%) had stable disease for at least 4 cycles, 5 had progressive disease (17.2%) and 5 went off study before disease assessment. Conclusion The combination of vatalanib with pemetrexed disodium was feasible, but not well tolerated. The modest efficacy results are consistent with other results obtained from combinations of chemotherapy and a large number of VEGF tyrosine kinase inhibitors. This combination should not be developed further unless predictive biomarkers can be identified.

Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186. https://doi.org/10.1056/NEJM197111182852108 CrossRefPubMed

Folkman J (1995) Seminars in medicine of the Beth Israel hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 333(26):1757–1763. https://doi.org/10.1056/NEJM199512283332608 CrossRefPubMed

Hayes AJ, Li LY, Lippman ME (1999) Science, medicine, and the future. Antivascular therapy: a new approach to cancer treatment. BMJ 318(7187):853–856CrossRefPubMedPubMedCentral

Keshet E, Ben-Sasson SA (1999) Anticancer drug targets: approaching angiogenesis. J Clin Invest 104(11):1497–1501. https://doi.org/10.1172/JCI8849 CrossRefPubMedPubMedCentral

Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676. https://doi.org/10.1038/nm0603-669 CrossRefPubMed

Wood JM, Bold G, Buchdunger E, Cozens R, Ferrari S, Frei J, Hofmann F, Mestan J, Mett H, O'Reilly T, Persohn E, Rösel J, Schnell C, Stover D, Theuer A, Towbin H, Wenger F, Woods-Cook K, Menrad A, Siemeister G, Schirner M, Thierauch KH, Schneider MR, Drevs J, Martiny-Baron G, Totzke F (2000) PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 60(8):2178–2189PubMed

Drevs J, Müller-Driver R, Wittig C, Fuxius S, Esser N, Hugenschmidt H, Konerding MA, Allegrini PR, Wood J, Hennig J, Unger C, Marmé D (2002) PTK787/ZK 222584, a specific vascular endothelial growth factor-receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging. Cancer Res 62(14):4015–4022PubMed

Roboz GJ, Giles FJ, List AF, Cortes JE, Carlin R, Kowalski M, Bilic S, Masson E, Rosamilia M, Schuster MW, Laurent D, Feldman EJ (2006) Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. Leukemia 20(6):952–957. https://doi.org/10.1038/sj.leu.2404213 CrossRefPubMed

Langenberg MH, Witteveen PO, Lankheet NA, Roodhart JM, Rosing H, van den Heuvel IJ, Beijnen JH, Voest EE (2010) Phase 1 study of combination treatment with PTK 787/ZK 222584 and cetuximab for patients with advanced solid tumors: safety, pharmacokinetics, pharmacodynamics analysis. Neoplasia 12(2):206–213CrossRefPubMedPubMedCentral

10.

Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D (2011) Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol 29(15):1997–2003. https://doi.org/10.1200/JCO.2010.29.4496 CrossRefPubMed

11.

Van Cutsem E, Bajetta E, Valle J, Köhne CH, Hecht JR, Moore M, Germond C, Berg W, Chen BL, Jalava T, Lebwohl D, Meinhardt G, Laurent D, Lin E (2011) Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol 29(15):2004–2010. https://doi.org/10.1200/JCO.2010.29.5436 CrossRefPubMed

12.

Thomas AL, Morgan B, Horsfield MA, Higginson A, Kay A, Lee L, Masson E, Puccio-Pick M, Laurent D, Steward WP (2005) Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol 23(18):4162–4171. https://doi.org/10.1200/JCO.2005.09.034 CrossRefPubMed

13.

Hanauske AR, Chen V, Paoletti P, Niyikiza C (2001) Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors. Oncologist 6(4):363–373CrossRefPubMed

14.

Adjei AA (2004) Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent. Clin Cancer Res 10(12 Pt 2):4276s–4280s. https://doi.org/10.1158/1078-0432.CCR-040010 CrossRefPubMed

15.

Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21(14):2636–2644. https://doi.org/10.1200/JCO.2003.11.136 CrossRefPubMed

16.

Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26(21):3543–3551. https://doi.org/10.1200/JCO.2007.15.0375 CrossRefPubMed

17.

Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP (2009) Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 374(9699):1432–1440. https://doi.org/10.1016/S0140-6736(09)61497-5 CrossRefPubMed

18.

Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C (2012) Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 13(3):247–255. https://doi.org/10.1016/S1470-2045(12)70063-3 CrossRefPubMed

19.

Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C (2013) PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 31(23):2895–2902. https://doi.org/10.1200/JCO.2012.47.1102 CrossRefPubMed

20.

Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar MC, Paul S, Paoletti P, Einhorn L, Bunn PA (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22(9):1589–1597. https://doi.org/10.1200/JCO.2004.08.163 CrossRefPubMed

21.

Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, Simms L, Shepherd FA (2009) The differential efficacy of pemetrexed according to NSCLC histology: a review of two phase III studies. Oncologist 14(3):253–263. https://doi.org/10.1634/theoncologist.2008-0232 CrossRefPubMed

22.

Stinchcombe TE, Borghaei H, Barker SS, Treat JA, Obasaju C (2016) Pemetrexed with platinum combination as a backbone for targeted therapy in non-small-cell lung Cancer. Clin Lung Cancer 17(1):1–9. https://doi.org/10.1016/j.cllc.2015.07.002 CrossRefPubMed

23.

Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S, Brahmer JR, Ellis PM, Gajra A, Rackear N, Schiller JH, Smith TJ, Strawn JR, Trent D, Johnson DH, Practice ASCOC (2015) Systemic therapy for stage IV non-small-cell lung Cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 33(30):3488–3515. https://doi.org/10.1200/JCO.2015.62.1342 CrossRefPubMedPubMedCentral

24.

Paz-Ares LG, Altug S, Vaury AT, Jaime JC, Russo F, Visseren-Grul C (2010) Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. BMC Cancer 10:85. https://doi.org/10.1186/1471-2407-10-85 CrossRefPubMedPubMedCentral

25.

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol 5(6):649–655CrossRefPubMed

26.

Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB, E3200 ECOGS (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the eastern cooperative oncology group study E3200. J Clin Oncol 25(12):1539–1544. https://doi.org/10.1200/JCO.2006.09.6305 CrossRefPubMed

27.

Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12):2013–2019. https://doi.org/10.1200/JCO.2007.14.9930 CrossRefPubMed

28.

Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 27(8):1227–1234. https://doi.org/10.1200/JCO.2007.14.5466 CrossRefPubMed

29.

Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, van Hazel GA, Robinson B, Broad A, Ganju V, Ackland SP, Forgeson G, Cunningham D, Saunders MP, Stockler MR, Chua Y, Zalcberg JR, Simes RJ, Price TJ (2010) Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian gastrointestinal trials group randomized phase III MAX study. J Clin Oncol 28(19):3191–3198. https://doi.org/10.1200/JCO.2009.27.7723 CrossRefPubMed

30.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342. https://doi.org/10.1056/NEJMoa032691 CrossRefPubMed

31.

Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550. https://doi.org/10.1056/NEJMoa061884 CrossRefPubMed

32.

Tewari KS, Sill MW, Long HJ, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ (2014) Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370(8):734–743. https://doi.org/10.1056/NEJMoa1309748 CrossRefPubMedPubMedCentral

33.

Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX, Group GO (2011) Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365(26):2473–2483. https://doi.org/10.1056/NEJMoa1104390 CrossRefPubMed

34.

Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stähle A, Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, Stark D, Qian W, Parmar MK, Oza AM, Investigators I (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365(26):2484–2496. https://doi.org/10.1056/NEJMoa1103799 CrossRefPubMed

35.

Stark D, Nankivell M, Pujade-Lauraine E, Kristensen G, Elit L, Stockler M, Hilpert F, Cervantes A, Brown J, Lanceley A, Velikova G, Sabate E, Pfisterer J, Carey MS, Beale P, Qian W, Swart AM, Oza A, Perren T (2013) Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the international collaboration on ovarian neoplasms (ICON7) phase 3 randomised trial. Lancet Oncol 14(3):236–243. https://doi.org/10.1016/S1470-2045(12)70567-3 CrossRefPubMedPubMedCentral

36.

Della Pepa C, Tonini G, Pisano C, Di Napoli M, Cecere SC, Tambaro R, Facchini G, Pignata S (2015) Ovarian cancer standard of care: are there real alternatives? Chin J Cancer 34(1):17–27. https://doi.org/10.5732/cjc.014.10274 CrossRefPubMed

37.

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):205–216CrossRefPubMed

38.

Board R, Jayson GC (2005) Platelet-derived growth factor receptor (PDGFR): a target for anticancer therapeutics. Drug Resist Updat 8(1–2):75–83. https://doi.org/10.1016/j.drup.2005.03.004 CrossRefPubMed

39.

Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5):1011–1027. https://doi.org/10.1200/JCO.2005.06.081 CrossRefPubMed

40.

Chiorean EG, Malireddy S, Younger AE, Jones DR, Waddell MJ, Sloop MI, Yu M, Hall SD, Schneider B, Sweeney CJ (2010) A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 66(3):441–448. https://doi.org/10.1007/s00280-009-1179-2 CrossRefPubMed

41.

Sharma S, Freeman B, Turner J, Symanowski J, Manno P, Berg W, Vogelzang N (2009) A phase I trial of PTK787/ZK222584 in combination with pemetrexed and cisplatin in patients with advanced solid tumors. Investig New Drugs 27(1):63–65. https://doi.org/10.1007/s10637-008-9157-9 CrossRef

42.

Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, Hicklin DJ, Zhu Z, Bohlen P, Witte L, Hendrikx J, Hackett NR, Crystal RG, Moore MA, Werb Z, Lyden D, Rafii S (2002) Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8(8):841–849. https://doi.org/10.1038/nm740 CrossRefPubMedPubMedCentral

43.

Spigel DR, Hainsworth JD, Joseph MJ, Shipley DL, Hagan MK, Thompson DS, Burris HA, Greco FA (2018) Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an eastern cooperative oncology group performance status of 2. Cancer 124(9):1982–1991. https://doi.org/10.1002/cncr.30986 CrossRefPubMed

44.

Karayama M, Inui N, Fujisawa T, Enomoto N, Nakamura Y, Kuroishi S, Yokomura K, Koshimizu N, Sato M, Toyoshima M, Shirai T, Masuda M, Yamada T, Imokawa S, Suda T (2016) Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non small cell lung cancer. Eur J Cancer 58:30–37. https://doi.org/10.1016/j.ejca.2016.01.013 CrossRefPubMed

45.

Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S, Group L-LS (2014) Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 15(2):143–155. https://doi.org/10.1016/S1470-2045(13)70586-2 CrossRefPubMed

46.

Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH, group L-LS (2016) Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-lung 2): a randomized, double-blind, phase III trial. Lung Cancer 102:65–73. https://doi.org/10.1016/j.lungcan.2016.10.011 CrossRefPubMed

47.

Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE (2010) Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 11(7):619–626. https://doi.org/10.1016/S1470-2045(10)70132-7 CrossRefPubMedPubMedCentral

48.

de Boer RH, Arrieta Ó, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH, Langmuir P, Milenkova T, Read J, Vansteenkiste JF (2011) Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 29(8):1067–1074. https://doi.org/10.1200/JCO.2010.29.5717 CrossRefPubMed

49.

Lee JS, Hirsh V, Park K, Qin S, Blajman CR, Perng RP, Chen YM, Emerson L, Langmuir P, Manegold C (2012) Vandetanib versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol 30(10):1114–1121. https://doi.org/10.1200/JCO.2011.36.1709 CrossRefPubMed

50.

Laurie SA, Solomon BJ, Seymour L, Ellis PM, Goss GD, Shepherd FA, Boyer MJ, Arnold AM, Clingan P, Laberge F, Fenton D, Hirsh V, Zukin M, Stockler MR, Lee CW, Chen EX, Montenegro A, Ding K, Bradbury PA (2014) Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC clinical trials group study BR29. Eur J Cancer 50(4):706–712. https://doi.org/10.1016/j.ejca.2013.11.032 CrossRefPubMed

51.

Goss GD, Arnold A, Shepherd FA, Dediu M, Ciuleanu TE, Fenton D, Zukin M, Walde D, Laberge F, Vincent MD, Ellis PM, Laurie SA, Ding K, Frymire E, Gauthier I, Leighl NB, Ho C, Noble J, Lee CW, Seymour L (2010) Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study. J Clin Oncol 28(1):49–55. https://doi.org/10.1200/JCO.2009.22.9427 CrossRefPubMed

52.

Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, Abrão Miziara JE, Balint B, De Marinis F, Keller A, Arén 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. https://doi.org/10.1200/JCO.2009.26.1321 CrossRefPubMed

53.

Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S, Syrigos K, Le Marie E, Gottfried M, Vansteenkiste J, Alberola V, Strauss UP, Montegriffo E, Ong TJ, Santoro A, Group Nns-clcREUSNIS (2012) Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol 30(25):3084–3092. https://doi.org/10.1200/JCO.2011.39.7646 CrossRefPubMed

54.

Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu TE, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei YJ, Galimi F, Spigel DR (2012) International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol 30(23):2829–2836. https://doi.org/10.1200/JCO.2011.41.4987 CrossRefPubMed

55.

Scagliotti GV, Felip E, Besse B, von Pawel J, Mellemgaard A, Reck M, Bosquee L, Chouaid C, Lianes-Barragán P, Paul EM, Ruiz-Soto R, Sigal E, Ottesen LH, Lechevalier T (2013) An open-label, multicenter, randomized, phase II study of pazopanib in combination with pemetrexed in first-line treatment of patients with advanced-stage non-small-cell lung cancer. J Thorac Oncol 8(12):1529–1537. https://doi.org/10.1097/JTO.0000000000000005 CrossRefPubMed

56.

Aggarwal C, Somaiah N, Simon G (2012) Antiangiogenic agents in the management of non-small cell lung cancer: where do we stand now and where are we headed? Cancer Biol Ther 13(5):247–263. https://doi.org/10.4161/cbt.19594 CrossRefPubMedPubMedCentral

57.

Gasparini G, Longo R, Fanelli M, Teicher BA (2005) Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions. J Clin Oncol 23(6):1295–1311. https://doi.org/10.1200/JCO.2005.10.022 CrossRefPubMed

Title: A phase I study of the vascular endothelial growth factor inhibitor Vatalanib in combination with Pemetrexed disodium in patients with advanced solid tumors
Authors: Fen Wang
Julian Molina
Daniel Satele
Jun Yin
Vun-Sin Lim
Alex A. Adjei
Publication date: 01-08-2019
Publisher: Springer US
Published in: Investigational New Drugs / Issue 4/2019
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-018-0690-x

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Keynote webinar | Spotlight on antibody–drug conjugates in cancer