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Open Access 01-12-2016 | Study protocol

Lapatinib-capecitabine versus capecitabine alone as radiosensitizers in RAS wild-type resectable rectal cancer, an adaptive randomized phase II trial (LaRRC trial): study protocol for a randomized controlled trial

Authors: Nuno Sousa, Olga Sousa, Lúcio Lara Santos, Rui Henrique, Manuel R. Teixeira, Mário Dinis-Ribeiro, Armando Teixeira-Pinto

Published in: Trials | Issue 1/2016

Abstract

Background

Preoperative radiochemotherapy followed by surgical removal of the rectum with total mesorectum excision is the preferred treatment option for stages II and III rectal cancer. However, development of metastatic disease is the main cause of death for these patients with 5-year disease-free survival rates of 56 %. Anti-epidermal growth factor receptor (EGFR) targeted therapy is effective in metastatic rectal cancer, and human epidermal growth factor receptor 2 (HER-2) signaling may mediate resistance to EGFR inhibitors. Moreover, preclinical data support a synergistic effect of EGFR inhibition with radiation therapy.

Methods/design

This Bayesian phase II trial with adaptive randomization was designed to assess the efficacy of adding lapatinib, a dual inhibitor of EGFR and HER-2, to standard radiochemotherapy with capecitabine in stages II and III rectal cancer.

Discussion

The results of this trial will provide evidence of the feasibility and efficacy of the combination of lapatinib-capecitabine as radiosensitizers and explore potential predictive biomarkers for response to this novel neoadjuvant approach to resectable rectal cancer.

Trial registration

EudraCT 2013-001203-36. Registered on 13 December 2013.

Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007;18(3):581–92. doi:10.1093/annonc/mdl498.CrossRefPubMed

Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, Boyle P, editors. Cancer incidence in five continents, vol. IX. IARC scientific publications. Lyon: IARC (International Agency for Research on Cancer); 2009.

Coleman MP, Quaresma M, Berrino F, Lutz JM, De Angelis R, Capocaccia R, et al. Cancer survival in five continents: a worldwide population-based study (CONCORD). Lancet Oncol. 2008;9(8):730–56. doi:10.1016/S1470-2045(08)70179-7.CrossRefPubMed

Kapiteijn E, Putter H, van de Velde CJ. Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in The Netherlands. Br J Surg. 2002;89(9):1142–9. doi:10.1046/j.1365-2168.2002.02196.x.CrossRefPubMed

Wong RK, Tandan V, De Silva S, Figueredo A. Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma. Cochrane Database Syst Rev. 2007;2:CD002102. doi:10.1002/14651858.CD002102.pub2.PubMed

Ceelen WP, Van Nieuwenhove Y, Fierens K. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database Syst Rev. 2009;1:CD006041. doi:10.1002/14651858.CD006041.pub2.PubMed

Collette L, Bosset JF, den Dulk M, Nguyen F, Mineur L, Maingon P, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol. 2007;25(28):4379–86. doi:10.1200/JCO.2007.11.9685.CrossRefPubMed

Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355(11):1114–23. doi:10.1056/NEJMoa060829.CrossRefPubMed

Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24(28):4620–5. doi:10.1200/JCO.2006.06.7629.CrossRefPubMed

10.

Capecitabine, summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000316/WC500058151.pdf.

11.

Ballonoff A, Kavanagh B, McCarter M, Kane M, Pearlman N, Nash R, et al. Preoperative capecitabine and accelerated intensity-modulated radiotherapy in locally advanced rectal cancer: a phase II trial. Am J Clin Oncol. 2008;31(3):264–70. doi:10.1097/COC.0b013e318161dbd3.CrossRefPubMed

12.

De Paoli A, Chiara S, Luppi G, Friso ML, Beretta GD, Del Prete S, et al. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol. 2006;17(2):246–51. doi:10.1093/annonc/mdj041.CrossRefPubMed

13.

Dunst J, Debus J, Rudat V, Wulf J, Budach W, Hoelscher T, et al. Neoadjuvant capecitabine combined with standard radiotherapy in patients with locally advanced rectal cancer: mature results of a phase II trial. Strahlenther Onkol. 2008;184(9):450–6. doi:10.1007/s00066-008-1751-4.CrossRefPubMed

14.

Marsh Rde W, George TJ, Siddiqui T, Mendenhall WM, Zlotecki RA, Grobmyer S, et al. A phase II trial of neoadjuvant capecitabine combined with hyperfractionated accelerated radiation therapy in locally advanced rectal cancer. Am J Clin Oncol. 2010;33(3):251–6. doi:10.1097/COC.0b013e3181a650e8.PubMed

15.

Velenik V, Anderluh F, Oblak I, Strojan P, Zakotnik B. Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced resectable rectal cancer: prospective phase II trial. Croat Med J. 2006;47(5):693–700.PubMedPubMedCentral

16.

Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, et al. Capecitabine (Cape) versus 5-fluorouracil (5-FU)-based (neo-)adjuvant chemo-radiotherapy (CRT) for locally advanced rectal cancer (LARC): long-term results of a randomized, phase III trial. Onkologie. 2011;34:199.CrossRef

17.

Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19(3):183–232.CrossRefPubMed

18.

Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA. Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med. 2011;154(1):37–49. doi:10.1059/0003-4819-154-1-201101040-00006.CrossRefPubMed

19.

Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697–705. doi:10.1200/JCO.2009.27.4860.CrossRefPubMed

20.

Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65. doi:10.1056/NEJMoa0804385.CrossRefPubMed

21.

Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706–13. doi:10.1200/JCO.2009.27.6055.CrossRefPubMed

22.

Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–17. doi:10.1056/NEJMoa0805019.CrossRefPubMed

23.

Van Cutsem E, Lenz HJ, Kohne CH, Heinemann V, Tejpar S, Melezinek I, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33(7):692–700. doi:10.1200/JCO.2014.59.4812.CrossRefPubMed

24.

Quesnelle KM, Grandis JR. Dual kinase inhibition of EGFR and HER2 overcomes resistance to cetuximab in a novel in vivo model of acquired cetuximab resistance. Clin Cancer Res. 2011;17(18):5935–44. doi:10.1158/1078-0432.ccr-11-0370.CrossRefPubMedPubMedCentral

25.

Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3(99):99ra86. doi:10.1126/scitranslmed.3002442.CrossRefPubMedPubMedCentral

26.

Magne N, Chargari C, Castadot P, Ghalibafian M, Soria JC, Haie-Meder C, et al. The efficacy and toxicity of EGFR in the settings of radiotherapy: focus on published clinical trials. Eur J Cancer. 2008;44(15):2133–43. doi:10.1016/j.ejca.2008.06.029.CrossRefPubMed

27.

Milano G, Magne N. Anti-EGFR and radiotherapy. Cancer Radiother. 2004;8(6):380–2. doi:10.1016/j.canrad.2004.09.002.CrossRefPubMed

28.

Czito BG, Willett CG, Bendell JC, Morse MA, Tyler DS, Fernando NH, et al. Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results. J Clin Oncol. 2006;24(4):656–62. doi:10.1200/JCO.2005.04.1749.CrossRefPubMed

29.

Marquardt F, Rodel F, Capalbo G, Weiss C, Rodel C. Molecular targeted treatment and radiation therapy for rectal cancer. Strahlenther Onkol. 2009;185(6):371–8. doi:10.1007/s00066-009-1936-5.CrossRefPubMed

30.

Valentini V, De Paoli A, Gambacorta MA, Mantini G, Ratto C, Vecchio FM, et al. Infusional 5-fluorouracil and ZD1839 (gefitinib-Iressa) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: a phase I and II trial (1839IL/0092). Int J Radiat Oncol Biol Phys. 2008;72(3):644–9. doi:10.1016/j.ijrobp.2008.01.046.CrossRefPubMed

31.

Giannopoulou E, Antonacopoulou A, Floratou K, Papavassiliou AG, Kalofonos HP. Dual targeting of EGFR and HER-2 in colon cancer cell lines. Cancer Chemother Pharmacol. 2009;63(6):973–81. doi:10.1007/s00280-008-0820-9.CrossRefPubMed

32.

Zhou Y, Li S, Hu YP, Wang J, Hauser J, Conway AN, et al. Blockade of EGFR and ErbB2 by the novel dual EGFR and ErbB2 tyrosine kinase inhibitor GW572016 sensitizes human colon carcinoma GEO cells to apoptosis. Cancer Res. 2006;66(1):404–11. doi:10.1158/0008-5472.CAN-05-2506.CrossRefPubMed

33.

Sambade MJ, Camp JT, Kimple RJ, Sartor CI, Shields JM. Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf > MEK > ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK. Radiother Oncol. 2009;93(3):639–44. doi:10.1016/j.radonc.2009.09.006.CrossRefPubMedPubMedCentral

34.

Sambade MJ, Kimple RJ, Camp JT, Peters E, Livasy CA, Sartor CI, et al. Lapatinib in combination with radiation diminishes tumor regrowth in HER2+ and basal-like/EGFR+ breast tumor xenografts. Int J Radiat Oncol Biol Phys. 2010;77(2):575–81. doi:10.1016/j.ijrobp.2009.12.063.CrossRefPubMedPubMedCentral

35.

Fields ALA, Rinaldi DA, Henderson CA, Germond CJ, Chu L, Brill KJ, et al. An open-label multicenter phase II study of oral lapatinib (GW572016) as single agent, second-line therapy in patients with metastatic colorectal cancer. J Clin Oncol (Meeting Abstracts). 2005;23(16_suppl):3583.

36.

Chu QS, Schwartz G, de Bono J, Smith DA, Koch KM, Versola MJ, et al. Phase I and pharmacokinetic study of lapatinib in combination with capecitabine in patients with advanced solid malignancies. J Clin Oncol. 2007;25(24):3753–8. doi:10.1200/JCO.2007.11.1765.CrossRefPubMed

37.

Midgley RS, Kerr DJ, Flaherty KT, Stevenson JP, Pratap SE, Koch KM, et al. A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan. Ann Oncol. 2007;18(12):2025–9. doi:10.1093/annonc/mdm366.CrossRefPubMed

38.

Siegel-Lakhai WS, Beijnen JH, Vervenne WL, Boot H, Keessen M, Versola M, et al. Phase I pharmacokinetic study of the safety and tolerability of lapatinib (GW572016) in combination with oxaliplatin/fluorouracil/leucovorin (FOLFOX4) in patients with solid tumors. Clin Cancer Res. 2007;13(15 Pt 1):4495–502. doi:10.1158/1078-0432.CCR-07-0004.CrossRefPubMed

39.

Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34. doi:10.1056/NEJMoa1305275.CrossRefPubMed

40.

Edge SB, American Joint Committee on Cancer. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.

41.

Drzymala M, Hawkins MA, Henrys AJ, Bedford J, Norman A, Tait DM. The effect of treatment position, prone or supine, on dose-volume histograms for pelvic radiotherapy in patients with rectal cancer. Br J Radiol. 2009;82(976):321–7. doi:10.1259/bjr/57848689.CrossRefPubMed

42.

Bosset JF, Servagi-Vernat S, Crehange G, Azria D, Gerard JP, Hennequin C. Rectal cancer: the radiation basis of radiotherapy, target volume. Cancer Radiother. 2011;15(6-7):431–5. doi:10.1016/j.canrad.2011.07.236.CrossRefPubMed

43.

Myerson RJ, Garofalo MC, El Naqa I, Abrams RA, Apte A, Bosch WR, et al. Elective clinical target volumes for conformal therapy in anorectal cancer: a radiation therapy oncology group consensus panel contouring atlas. Int J Radiat Oncol Biol Phys. 2009;74(3):824–30. doi:10.1016/j.ijrobp.2008.08.070.CrossRefPubMed

44.

Roels S, Duthoy W, Haustermans K, Penninckx F, Vandecaveye V, Boterberg T, et al. Definition and delineation of the clinical target volume for rectal cancer. Int J Radiat Oncol Biol Phys. 2006;65(4):1129–42. doi:10.1016/j.ijrobp.2006.02.050.CrossRefPubMed

45.

Kavanagh BD, Pan CC, Dawson LA, Das SK, Li XA, Ten Haken RK, et al. Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S101–7. doi:10.1016/j.ijrobp.2009.05.071.CrossRefPubMed

46.

Spalding AC, Jee KW, Vineberg K, Jablonowski M, Fraass BA, Pan CC, et al. Potential for dose-escalation and reduction of risk in pancreatic cancer using IMRT optimization with lexicographic ordering and gEUD-based cost functions. Med Phys. 2007;34(2):521–9.CrossRefPubMed

47.

Viswanathan AN, Yorke ED, Marks LB, Eifel PJ, Shipley WU. Radiation dose-volume effects of the urinary bladder. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S116–22. doi:10.1016/j.ijrobp.2009.02.090.CrossRefPubMedPubMedCentral

48.

Bentzen SM, Joiner MC. The linear-quadratic approach in clinical practice. In: Joiner M, van der Kogel A, editors. Basic clinical radiobiology. 4th ed. London: Hodder Arnold; 2009. p. 120–34.CrossRef

49.

Valentini V, Aristei C, Glimelius B, Minsky BD, Beets-Tan R, Borras JM, et al. Multidisciplinary Rectal Cancer Management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2). Radiother Oncol. 2009;92(2):148–63. doi:10.1016/j.radonc.2009.06.027.CrossRefPubMed

50.

Berry DA. Bayesian clinical trials. Nat Rev Drug Discov. 2006;5(1):27–36. doi:10.1038/nrd1927.CrossRefPubMed

51.

Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin Trials. 2008;5:93–106. doi:10.1177/1740774508089279.CrossRefPubMed

Title: Lapatinib-capecitabine versus capecitabine alone as radiosensitizers in RAS wild-type resectable rectal cancer, an adaptive randomized phase II trial (LaRRC trial): study protocol for a randomized controlled trial
Authors: Nuno Sousa
Olga Sousa
Lúcio Lara Santos
Rui Henrique
Manuel R. Teixeira
Mário Dinis-Ribeiro
Armando Teixeira-Pinto
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Trials / Issue 1/2016
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-016-1583-y

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Lapatinib-capecitabine versus capecitabine alone as radiosensitizers in RAS wild-type resectable rectal cancer, an adaptive randomized phase II trial (LaRRC trial): study protocol for a randomized controlled trial

Abstract

Background

Methods/design

Discussion

Trial registration

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods/design

Discussion

Trial registration

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