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Evidence-Based Oncology January/February

From Bench to Bedside: Promising Colon Cancer Clinical Trials

Jill M. Comeau, PharmD, BCOP; and Brice Labruzzo Mohundro, PharmD, BCACP
Similar to most malignancies, the future of colon cancer research is focused on targeted and personalized therapy, with VEGF being the most commonly targeted pathway in current clinical trials. With the utilization of targeted therapy, the focus of treatment becomes the identification of patients who will benefit from this therapy. This is already seen in current practices, with the use of KRAS testing becoming the standard of care prior to initiating treatment for mCRC and utilization of EGFR inhibitors. Other pathways which are utilized or have been studied in other malignancies are also being studied in CRC, including HDAC, c-MET, and PARP. Along with traditional chemotherapy agents, new agents NKTR-102, EZN-2208, and ThermoDox are being created to improve the pharmacokinetics and delivery of the drug, which will hopefully improve both clinical benefit and patient tolerability. Immunomodulatory pathways, previously not found to be beneficial, have shown some promise in phase I and II trials. Currently, the main concern from a managed care perspective is the cost-benefit ratio of these medications. With 2 new agents approved in 2012, with only a 1.4-month OS benefit, the question that arises is the cost, both economic and quality of life. Past pharmacoeconomic studies have looked at the use of currently approved targeted therapies and the incremental cost-effectiveness ratio (ICER) per discounted life-year. Based upon 2008 Medicare reimbursements, the ICER in $/year, or the cost of saving a life-year, with targeted therapies (bevacizumab or cetuximab) added to conventional chemotherapy, was $170,896 per year compared with $102,336 per year for conventional chemotherapy. 54 With the approval of more targeted therapies, pharmacoeconomic studies are pivotal in assessing the effects on future healthcare costs. Future QOL studies would be also useful to demonstrate if the response or small survival gains are worth the toxicities, especially in non-curable diseases like CRC.

Author Affiliations: University of Louisiana at Monroe College of Pharmacy– Shreveport Campus (JMC), Shreveport, LA; University of Louisiana at Monroe College of Pharmacy–Baton Rouge Campus (BLM), Baton Rouge, LA.

Funding Source: None.

Author Disclosures: The authors (JMC, BLM) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (JMC, BLM); acquisition of data (JMC, BLM); analysis and interpretation of data (JMC, BLM); drafting of the manuscript (JMC, BLM); critical revision of the manuscript for important intellectual content (JMC, BLM); and administrative, technical, or logistic support (JMC, BLM).

Address correspondence to: Jill M. Comeau, PharmD, BCOP, Assistant Professor, University of Louisiana at Monroe College of Pharmacy–Shreveport Campus, 1725 Claiborne Ave, Shreveport, LA 71103. E-mail: comeau@ulm.edu.
1. American Cancer Society. Cancer Facts and Figures 2012. Atlanta: American Cancer Society; 2012.


2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2009_pops09/, based on November2011 SEER data submission, posted to the SEERwebsite, 2012.


3. Colon cancer. NCCN website. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed November 6, 2012.


4. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of afilbercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012; 30(28):3499-3506.


5. Van Custem E, Sobrero AF, Siena S, et al. Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC) [abstract]. J Clin Oncol. 2012;30(suppl):3502.


6. Irinotecan [package insert]. Schaumberg, IL: SAGENT Pharmaceuticals; 2012.


7. NKTR-102 and colon. Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/results?term= NKTR-102+colon&Search=Search. Accessed November 20, 2012.


8. EZN-2208 and colon cancer. Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/results?term=EZN-2208+colon&Search=Search. Accessed November 20, 2012.


9. Jameson GS, Hamm JT, Weiss GJ, et al. A multicenter, phase I, dose-escalation study to assess the safety, tolerability and pharmacokinetics
of etirinotecan pegol in patients with refractory tumors [published online November 7, 2012]. Clin Cancer Res. http://clincancerres.aacrjournals.org/content/early/2012/11/06/1078-0432.CCR-12-1201.long. Accessed November 11, 2012.


10. Goldberg RM, Garrett CR, Berkowitz NC, et al. Phase II study of EZN-2208 (PEG-SN38) with or without cetuximab in patients with metastatic colorectal cancer (CRC) [abstract]. J Clin Oncol. 2012;30(suppl 4):448.


11. Yoshino T, Mizunuma N, Yamazaki K, et al. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomized,
placebo-controlled phase 2 trial. Lancet Oncol. 2012;13(10):993-1001.


12. TAS-102. Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/results?term=TASwww.clinicaltrials.gov/ct2/show/NCT01075048?term=tivantinib+colon&rank=1. Accessed November 22, 2012. 102&Search=Search. Accessed November 20, 2012.


13. ThermoDox. Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/results?term=thermodox&Search=Search. Accessed November 15, 2012.


14. Landon CD, Park J, Needham D, Dewhirst MW. Nanoscale drug delivery and hyperthermia: the materials design and preclinical and clinical testing of low temperature-sensitive liposomes used in combination with mild hyperthermia in the treatment of local cancer. The Open Nanomedicine Journal. 2011;3:38-64.


15. Spratlin JL, Cohen RB, Eadens M, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28(5):780-787.


16. Chu E. An update on the current and emerging targeted agents in metastatic colorectal cancer. Clin Colorectal Cancer. 2012;11(1):1-13.


17. A study of IMC-1121B or IMC-18F1 in colorectal cancer. http://clinicaltrials.gov/ct2/show?term=ramucirumab+colon&rank=4. Accessed November 22, 2012.


18. Icrucumab (IMC-18F1). www.lillyoncologypipeline.com/Pages/vegfr1-antibody.aspx. Accessed November 22, 2012.


19. A study in second line metastatic colorectalcancer. http://clinicaltrials.gov/ct2/show?term=ramucirumab+colon&rank=5. Accessed November 22, 2012.


20. Garrett CR, Siu LL, El-Khoueiry A, et al. Phase I dose-escalation study to determine the safety, pharmacokinetics, and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. Br J Cancer. 2011;105(1):44-52.


21. Mekhail T, Masson E, Fischer BS, et al. Metabolism, excretion, and pharmacokinetics of oral brivanib in patients with advanced or metastatic solid tumors [published online July 29, 2010]. Drug Metab Dispos. 2010;38(11):1962- 1966.


22. Cetuximab with or without brivanib in treating patients with K-Ras wild type tumours and metastatic colorectal cancer. http://clinicaltrials.gov/ct2/show/NCT00640471?term=brivanib+colon&rank=1. Accessed November 22, 2012.


23. Sattler M, Reddy MM, Hasina R, Gangadhar T, Salgia R. The role of the c-Met pathway in lung cancer and the potential for targeted therapy. Ther Adv Med Oncol. 2011;3(4):171-184.


24. Neklason DW, Done MW, Sargent NR, et al. Activating mutation in MET oncogene in familial colorectal cancer. BMC Cancer. 2011;11:424.


25. Sharma N, Adjei AA. In the clinic: ongoing clinical trials evaluating c-MET-inhibiting drugs. Ther Adv Med Oncol. 2011;3(1, suppl):S37-S50.


26. Rosen LS, Senzer N, Mekhail T, et al. A phase I dose-escalation study of Tivantinib (ARQ197) in adult patients with metastatic solid tumors. Clin Cancer Res. 2011;17(24):7754-7764.


27. ARQ197 in combination with chemotherapy in patients with metastatic colorectal cancer. www. clinicaltrials.gov/ct2/show/NCT01075048?term=tivantinib+colon&rank=1. Accessed November 22, 2012.


28. Spigel DR, Ervin TJ, Ramlau R, et al. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC [abstract]. J Clin Oncol. 2011;29(suppl):7505.


29. FOLFOX/Bevacizumab with onartuzumab (MetMab) versus placebo as first-line treatment in patients with metastatic colorectal cancer. www.clinicaltrials.gov/ct2/show/NCT01418222?term=metmab+colon&rank=1. Accessed November 23, 2012.


30. Frank D, Jumonville A, LoConte NK, et al. A phase II study of capecitabine and lapatinib in advanced refractory colorectal adenocarcinoma: a Wisconsin Oncology Network study. J Gastrointest Oncol. 2012;3(2):90-96.


31. Lapatinib and colon cancer. Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/results?te rm=lapatinib+colon&Search=Search. Accessed November 16, 2012.


32. Gore L, Rothenberg ML, O’Bryant CL, et al. A phase I and pharmokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas. Clin Cancer Res. 2008;14:4517-4525.


33. Entinostat and colon cancer. Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/result s?term=entinostat+colon&Search=Search. Accessed November 16, 2012.


34. Shacham-Shmueli E, Geva R, Figer A, et al. Phase I trial of sorafenib in combination with 5-fluorouracil/leucovorin in advanced solid tumors. J Clin Pharmacol. 2012;52:656-669.


35. Sorafenib and colon cancer. Clinicaltrials.gov. www.clinicaltrials.gov/ct2/results?term=sorafenib+colon+cancer&Search=Search. Accessed November 20, 2012.


36. Pishvaian MJ, Slack R, Witkiewicz A, et al. A phase II study of the PARP inhibitor, ABT-888 plus temozolomide in patients with heavily pretreated, metastatic colorectal cancer [abstract]. J Clin Oncol. 2011;29(suppl):3502.


37. Veliparib and colon cancer. Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/results?term=veliparib+colon+cancer&Search=Search. Accessed November 28, 2012.


38. Bardou M, Barkun A, Martel M. Effect of statin therapy on colorectal cancer. Gut. 2010; 59(11):1572-1585.


39. Lee J, Jung KH, Park YS, et al. Simvastatin plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as first-line chemotherapy in metastatic colorectal patients: a multicenter phase II study. Cancer Chemother Pharmacol. 2009;64(4):657-663.


40. Simvastatin plus colon cancer.Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/results?term=simvastatin+colon&recr=Open. AccessedNovember 24, 2012.


41. Simvastatin + cetuximab/irinotecan in K-ras mutant colorectal cancer (CRC). www.clinicaltrials. gov/ct2/show/NCT01281761?term=simva statin+colon&rank=5. Accessed November 24, 2012.


42. Rosuvastatin in treating patients with stage I or stage II colon cancer that was removed by surgery. www.clinicaltrials.gov/ct2/show/NC T01011478?term=rosuvastatin+colon&rank=1. Accessed November 24, 2012.


43. Baker A, Chang J, Erler J. Emerging role of lysyl oxidases in promoting tumour metastasis. Oncology News Online. www.oncologynews.biz/pdf/sep_oct_11/128-131_ONSO11_feature%20art.pdf. Accessed November 23, 2012.


44. Rodriguez HM, Vaysberg M, Mikels A, et al. Modulation of lysyl oxidase-like 2 enzymatic activity by an allosteric antibody inhibitor. J Biol Chem. 2010;285(27):20964-20974.


45. Gilead Sciences to acquire Areesto Biosciences for $255 million [press release]. Gilead website. www.gilead.com/pr_1509319. Accessed November 23, 2012.


46. First-in-human study of AB0024 to evaluate safety and tolerability in adults with advanced solid tumors. www.clinicaltrials.gov/ct2/show/ NCT01323933?term=ab0024&rank=1. Accessed November 23, 2012.


47. Efficacy and safety of GS-6624 with FOLFIRI as second line treatment in colorectal adenocarcinoma.http://clinicaltrials.gov/ct2/show/ NCT01479465?term=GS-6624+colon&rank=1. Accessed November 23, 2012.


48. Imprime PGG and colon cancer. Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/results?term=Imprime+PGG+colon&Search=Search. Accessed November 19, 2012.


49. Tamayo MB, Cornelio GH, Bautista ML, et al. A Phase Ib/II, dose-escalating, safety, and efficacy study of imprime PGG and cetuximab in patients with advanced colorectal cancer (CRC) [abstract]. J Clin Oncol. 2010;(suppl):e14103.


50. Phase I trial of “bi-shRNAifurin/GMCSF DNA/autologous tumor cell” vaccine (FANG) in advanced cancer. Molecular Therapy. 2012;20:679- 686.


51. Fang vaccine and colon cancer. Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/results?term=Fang+vaccine+colon&Search=Search. Accessed November 19, 2012.


52. Marshall J, Hwang JJ, Pishvaian MJ, et al. A pilot trial of a combination of therapeutic vaccines (GI-4000 and GI-6207) as adjunctive therapy with first-line therapy with bevacizumab plus either FOLFOX or FOLFIRI in stage IV patients with newly diagnosed ras-mutant positive or negative metastatic colorectal cancer [abstract]. J Clin Oncol. 2012;(suppl):TPS3638.


53. GI-4000 and colon cancer. Clinicaltrials.gov website. www.clinicaltrials.gov/ct2/results? term=GI-4000+colon&Search=Search. Accessed November 19, 2012.


54. Wong Y, Meropol NJ, Speier W, et al. Cost implications of new treatments for advanced colorectal cancer. Cancer. 2009;115(10):2081- 2091.
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