Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer

Summary

This phase I trial studies the sides effects and best dose of hydroxychloroquine when given together with trametinib in treating patients with pancreatic cancer that has spread to nearby tissue, lymph nodes or other places in the body and cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as hydroxychloroquine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving trametinib together with hydroxychloroquine may work better in treating patients with pancreatic cancer.

Timeline

Start

2019-01-30

Primary completion

2025-01-15

Completion

2025-08-03

Publications

• Background Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017 Jan;67(1):7-30. doi: 10.3322/caac.21387. Epub 2017 Jan 5.
• Background Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, Neale RE, Tempero M, Tuveson DA, Hruban RH, Neoptolemos JP. Pancreatic cancer. Nat Rev Dis Primers. 2016 Apr 21;2:16022. doi: 10.1038/nrdp.2016.22.
• Background Hidalgo M, Cascinu S, Kleeff J, Labianca R, Lohr JM, Neoptolemos J, Real FX, Van Laethem JL, Heinemann V. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology. 2015 Jan-Feb;15(1):8-18. doi: 10.1016/j.pan.2014.10.001. Epub 2014 Oct 17.
• Background Collisson EA, Trejo CL, Silva JM, Gu S, Korkola JE, Heiser LM, Charles RP, Rabinovich BA, Hann B, Dankort D, Spellman PT, Phillips WA, Gray JW, McMahon M. A central role for RAF-->MEK-->ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2012 Aug;2(8):685-93. doi: 10.1158/2159-8290.CD-11-0347. Epub 2012 May 24.
• Background Infante JR, Somer BG, Park JO, Li CP, Scheulen ME, Kasubhai SM, Oh DY, Liu Y, Redhu S, Steplewski K, Le N. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer. 2014 Aug;50(12):2072-81. doi: 10.1016/j.ejca.2014.04.024. Epub 2014 Jun 7.
• Background Kasuga A, Nakagawa K, Nagashima F, Shimizu T, Naruge D, Nishina S, Kitamura H, Kurata T, Takasu A, Fujisaka Y, Okamoto W, Nishimura Y, Mukaiyama A, Matsushita H, Furuse J. A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors. Invest New Drugs. 2015 Oct;33(5):1058-67. doi: 10.1007/s10637-015-0270-2. Epub 2015 Aug 12.
• Background Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, Schuman SS, Shea JE, Seipp MT, Yap JT, Burrell LD, Lum DH, Whisenant JR, Gilcrease GW 3rd, Cavalieri CC, Rehbein KM, Cutler SL, Affolter KE, Welm AL, Welm BE, Scaife CL, Snyder EL, McMahon M. Protective autophagy elicited by RAF-->MEK-->ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019 Apr;25(4):620-627. doi: 10.1038/s41591-019-0367-9. Epub 2019 Mar 4.
• Background Rodriguez-Viciana P, Tetsu O, Oda K, Okada J, Rauen K, McCormick F. Cancer targets in the Ras pathway. Cold Spring Harb Symp Quant Biol. 2005;70:461-7. doi: 10.1101/sqb.2005.70.044.
• Background Young A, Lyons J, Miller AL, Phan VT, Alarcon IR, McCormick F. Ras signaling and therapies. Adv Cancer Res. 2009;102:1-17. doi: 10.1016/S0065-230X(09)02001-6.
• Background Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013 Feb 1;31(4):482-9. doi: 10.1200/JCO.2012.43.5966. Epub 2012 Dec 17.
• Background Gysin S, Lee SH, Dean NM, McMahon M. Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res. 2005 Jun 1;65(11):4870-80. doi: 10.1158/0008-5472.CAN-04-2848.
• Background Gysin S, Paquette J, McMahon M. Analysis of mRNA profiles after MEK1/2 inhibition in human pancreatic cancer cell lines reveals pathways involved in drug sensitivity. Mol Cancer Res. 2012 Dec;10(12):1607-19. doi: 10.1158/1541-7786.MCR-12-0188. Epub 2012 Jul 25.
• Background Awasthi N, Zhang C, Schwarz AM, Hinz S, Wang C, Williams NS, Schwarz MA, Schwarz RE. Comparative benefits of Nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer. Carcinogenesis. 2013 Oct;34(10):2361-9. doi: 10.1093/carcin/bgt227. Epub 2013 Jun 26.
• Background Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006 Feb 27;166(4):458-64. doi: 10.1001/archinte.166.4.458.
• Background Larsen AC, Dabrowski T, Frokjaer JB, Fisker RV, Iyer VV, Moller BK, Kristensen SR, Thorlacius-Ussing O. Prevalence of venous thromboembolism at diagnosis of upper gastrointestinal cancer. Br J Surg. 2014 Feb;101(3):246-53. doi: 10.1002/bjs.9353. Epub 2014 Jan 20.
• Background Blom JW, Osanto S, Rosendaal FR. High risk of venous thrombosis in patients with pancreatic cancer: a cohort study of 202 patients. Eur J Cancer. 2006 Feb;42(3):410-4. doi: 10.1016/j.ejca.2005.09.013.
• Background Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, Sgouros J, Gardiner E, Wedgwood K, Ettelaie C, Bozas G. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer. 2012 Jun;48(9):1283-92. doi: 10.1016/j.ejca.2011.10.017. Epub 2011 Nov 17.
• Background Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer. 2011 Apr 1;117(7):1334-49. doi: 10.1002/cncr.25714. Epub 2010 Nov 8.
• Background Khorana AA, Dalal M, Lin J, Connolly GC. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer. 2013 Feb 1;119(3):648-55. doi: 10.1002/cncr.27772. Epub 2012 Aug 14.
• Background Lyman GH, Bohlke K, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, Kakkar AK, Key NS, Levine MN, Liebman HA, Tempero MA, Wong SL, Somerfield MR, Falanga A; American Society of Clinical Oncology. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update 2014. J Clin Oncol. 2015 Feb 20;33(6):654-6. doi: 10.1200/JCO.2014.59.7351. Epub 2015 Jan 20.
• Background Khorana AA, Otten HM, Zwicker JI, Connolly GC, Bancel DF, Pabinger I; Subcommittee on Haemostasis and Malignancy of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH. J Thromb Haemost. 2014 Nov;12(11):1928-31. doi: 10.1111/jth.12725. Epub 2014 Sep 30. No abstract available.
• Background Balaban EP, Mangu PB, Yee NS. Locally Advanced Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. 2017 Apr;13(4):265-269. doi: 10.1200/JOP.2016.017376. Epub 2016 Oct 31. No abstract available.
• Background Sohal DP, Mangu PB, Khorana AA, Shah MA, Philip PA, O'Reilly EM, Uronis HE, Ramanathan RK, Crane CH, Engebretson A, Ruggiero JT, Copur MS, Lau M, Urba S, Laheru D. Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016 Aug 10;34(23):2784-96. doi: 10.1200/JCO.2016.67.1412. Epub 2016 May 31.
• Background Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008 May 15;111(10):4902-7. doi: 10.1182/blood-2007-10-116327. Epub 2008 Jan 23.

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Indications