Paclitaxel and TAK-228 in Urothelial Carcinoma

Summary

Phase II Multicentre, single arm, open label study of Paclitaxel and TAK-228 in metastatic urothelial carcinoma (UC) and the impact of PI3K-mTOR pathway genomic alterations

Timeline

Start

2018-05-04

Primary completion

2020-11

Completion

2020-11

Publications

• Background Iyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV, Kim PH, Lin O, Weinhold N, Sander C, Zabor EC, Janakiraman M, Garcia-Grossman IR, Heguy A, Viale A, Bochner BH, Reuter VE, Bajorin DF, Milowsky MI, Taylor BS, Solit DB. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol. 2013 Sep 1;31(25):3133-40. doi: 10.1200/JCO.2012.46.5740. Epub 2013 Jul 29.
• Background Guo Y, Chekaluk Y, Zhang J, Du J, Gray NS, Wu CL, Kwiatkowski DJ. TSC1 involvement in bladder cancer: diverse effects and therapeutic implications. J Pathol. 2013 May;230(1):17-27. doi: 10.1002/path.4176. Epub 2013 Mar 21.
• Background Wagle N, Grabiner BC, Van Allen EM, Hodis E, Jacobus S, Supko JG, Stewart M, Choueiri TK, Gandhi L, Cleary JM, Elfiky AA, Taplin ME, Stack EC, Signoretti S, Loda M, Shapiro GI, Sabatini DM, Lander ES, Gabriel SB, Kantoff PW, Garraway LA, Rosenberg JE. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 2014 May;4(5):546-53. doi: 10.1158/2159-8290.CD-13-0353. Epub 2014 Mar 13.
• Background Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 Jan;63(1):11-30. doi: 10.3322/caac.21166. Epub 2013 Jan 17.
• Background Ortmann CA, Mazhar D. Second-line systemic therapy for metastatic urothelial carcinoma of the bladder. Future Oncol. 2013 Nov;9(11):1637-51. doi: 10.2217/fon.13.139.
• Background Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. doi: 10.1200/JCO.2002.20.4.937.
• Background von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. doi: 10.1200/JCO.2005.07.757.
• Background Verdoorn BP, Kessler ER, Flaig TW. Targeted therapy in advanced urothelial carcinoma. Oncology (Williston Park). 2013 Mar;27(3):219-26.
• Background Ching CB, Hansel DE. Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway. Lab Invest. 2010 Oct;90(10):1406-14. doi: 10.1038/labinvest.2010.133. Epub 2010 Jul 26.
• Background Platt FM, Hurst CD, Taylor CF, Gregory WM, Harnden P, Knowles MA. Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res. 2009 Oct 1;15(19):6008-17. doi: 10.1158/1078-0432.CCR-09-0898. Epub 2009 Sep 29.
• Background Bowles DW, Diamond JR, Lam ET, Weekes CD, Astling DP, Anderson RT, Leong S, Gore L, Varella-Garcia M, Vogler BW, Keysar SB, Freas E, Aisner DL, Ren C, Tan AC, Wilhelm F, Maniar M, Eckhardt SG, Messersmith WA, Jimeno A. Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies. Clin Cancer Res. 2014 Mar 15;20(6):1656-65. doi: 10.1158/1078-0432.CCR-13-2506. Epub 2014 Feb 3.
• Background Bowles DW, Ma WW, Senzer N, Brahmer JR, Adjei AA, Davies M, Lazar AJ, Vo A, Peterson S, Walker L, Hausman D, Rudin CM, Jimeno A. A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br J Cancer. 2013 Sep 3;109(5):1085-92. doi: 10.1038/bjc.2013.474. Epub 2013 Aug 13.
• Background Gomez-Pinillos A, Ferrari AC. mTOR signaling pathway and mTOR inhibitors in cancer therapy. Hematol Oncol Clin North Am. 2012 Jun;26(3):483-505, vii. doi: 10.1016/j.hoc.2012.02.014. Epub 2012 Mar 31.
• Background Seront E, Rottey S, Sautois B, Kerger J, D'Hondt LA, Verschaeve V, Canon JL, Dopchie C, Vandenbulcke JM, Whenham N, Goeminne JC, Clausse M, Verhoeven D, Glorieux P, Branders S, Dupont P, Schoonjans J, Feron O, Machiels JP. Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers. Ann Oncol. 2012 Oct;23(10):2663-2670. doi: 10.1093/annonc/mds057. Epub 2012 Apr 3.
• Background Milowsky, M.I., Final results of a multicenter, open-label phase II trial of dovitinib (TKI258) in patients with advanced urothelial carcinoma with either mutated or nonmutated FGFR3. 2013, J Clin Oncol 2013; 31(Suppl 6) [abstract: 255].
• Background Bajorin DF. Paclitaxel in the treatment of advanced urothelial cancer. Oncology (Williston Park). 2000 Jan;14(1):43-52, 57; discussion 58, 61-2.
• Background Raghavan D. Progress in the chemotherapy of metastatic cancer of the urinary tract. Cancer. 2003 Apr 15;97(8 Suppl):2050-5. doi: 10.1002/cncr.11280.
• Background Rossi JF. Phase I study of atacicept in relapsed/refractory multiple myeloma (MM) and Waldenstrom's macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):136-8. doi: 10.3816/CLML.2011.n.031.
• Background Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends Mol Med. 2007 Oct;13(10):433-42. doi: 10.1016/j.molmed.2007.08.001. Epub 2007 Oct 1.
• Background Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006 Sep;6(9):729-34. doi: 10.1038/nrc1974. Epub 2006 Aug 17.
• Background Jessen K, Wang S, Kessler L, et al. INK128 is a potent and selective TORC1/2 inhibitor with broad oral antitumor activity. Mol Cancer Ther. 2009;8(12 Suppl) Abstract B148
• Background Kessler L, Wang S, Xin G, Kucharski J, Staunton J, Lan L, et al. INK128, an orally active TORC1/2 kinase inhibitor, shows broad antitumor activity and enhances efficacy of cytotoxic as well as targeted agents. Cancer Res 2010;70(8; Supplement 1 Abstract 4496).
• Background Hassan B, Akcakanat A, Takafumi S, Evans K, Adkins F, Meric-Bernstam F. Inhibitor MLN0128 Has Antitumor Efficacy In Cell Lines With Intrinsic And Acquired Rapamycin-Resistance. Academic Surgical Congress 2013(Abstract ASC20130420).
• Background Shafer A, Zhou C, Gehrig PA, Boggess JF, Bae-Jump VL. Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction of apoptosis. Int J Cancer. 2010 Mar 1;126(5):1144-54. doi: 10.1002/ijc.24837.
• Background Shu CH, Yang WK, Shih YL, Kuo ML, Huang TS. Cell cycle G2/M arrest and activation of cyclin-dependent kinases associated with low-dose paclitaxel-induced sub-G1 apoptosis. Apoptosis. 1997;2(5):463-70. doi: 10.1023/a:1026422111457.
• Background Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, Mills GB, Meric-Bernstam F. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res. 2004 Oct 15;10(20):7031-42. doi: 10.1158/1078-0432.CCR-04-0361.
• Background Voss M, Gordon MS, Mita M, Rini B, Makker V, Macarulla T, et al. Phase I study of investigational oral mTORC1/2 inhibitor TAK-228 (formerly MLN0128): expansion phase in patients with renal, endometrial, or bladder cancer. ESMO poster Sept 2015
• Background Ghobrial IM, Siegel DS, Vij R, Berdeja JG, Richardson PG, Neuwirth R, Patel CG, Zohren F, Wolf JL. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenstrom's macroglobulinemia. Am J Hematol. 2016 Jun;91(4):400-5. doi: 10.1002/ajh.24300.
• Background TAK-228 Investigator Brochure Edition 10. 22 March 2017
• Background PACLITAXEL - paclitaxel injection, solution [package insert]. Princeton, NJ. Sandoz; 2011
• Hernandez-Prat A, Rodriguez-Vida A, Juanpere-Rodero N, Arpi O, Menendez S, Soria-Jimenez L, Martinez A, Iarchouk N, Rojo F, Albanell J, Brake R, Rovira A, Bellmunt J. Novel Oral mTORC1/2 Inhibitor TAK-228 Has Synergistic Antitumor Effects When Combined with Paclitaxel or PI3Kalpha Inhibitor TAK-117 in Preclinical Bladder Cancer Models. Mol Cancer Res. 2019 Sep;17(9):1931-1944. doi: 10.1158/1541-7786.MCR-18-0923. Epub 2019 Jun 3.

Drugs

Indications