Top

Published in:

01-10-2010 | Original Article

A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer

Authors: A. Sabharwal, P. G. Corrie, R. S. Midgley, C. Palmer, J. Brady, P. Mortimer, A. J. Watson, G. P. Margison, M. R. Middleton

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2010

Abstract

Background

Expression of the DNA repair protein O ⁶-methylguanine-DNA methyltransferase (MGMT) correlates with resistance to irinotecan in colorectal cancer cell lines. This phase I study evaluated the maximum tolerated dose (MTD) of lomeguatrib, an inactivating pseudosubstrate of MGMT, in combination with irinotecan in patients with metastatic colorectal cancer and assessed the safety, toxicity and clinical pharmacology of combination treatment.

Patients and methods

Patients with metastatic colorectal cancer received lomeguatrib (10–80 mg PO) on days 1–5 with irinotecan (250–350 mg/m² IV) on day 4 of a 21-day cycle.

Results

Twenty-four patients, pre-treated with a median of 2 lines of chemotherapy, received 104 cycles of treatment. The MTD was defined as 80 mg/day lomeguatrib with 300 mg/m² irinotecan. The main toxicities observed were neutropaenia and diarrhoea. Lomeguatrib of 80 mg/day produced complete MGMT depletion in all available peripheral blood mononuclear cells (PBMCs) and paired tumour biopsies (one patient). There was no pharmacokinetic interaction between the drugs. In 22 patients assessable for tumour response, one achieved a partial response and 16 had stable disease.

Conclusion

This study defined a tolerable dose of irinotecan in combination with lomeguatrib in patients with metastatic colorectal cancer. Combination treatment gave a similar response rate to irinotecan monotherapy in this heavily pre-treated patient group.

Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P et al (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355(9209):1041–1047CrossRefPubMed

Kohne CH, van Cutsem E, Wils J, Bokemeyer C, El-Serafi M, Lutz MP et al (2005) Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol 23(22):4856–4865CrossRefPubMed

Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343(13):905–914CrossRefPubMed

Rowland KM, Pitot HC, Sargent DJ, Philip PA, Mitchell EP, Mailliard JA, et al. (2005) Results of 3rd line therapy on N9841: a randomized phase III trial of oxaliplatin/5-fluorouracil (5FU)/leucovorin (FOLFOX4) versus irinotecan (CPT-11) in patients (pts) with advanced colorectal cancer (CRC) previously treated with prior 5FU chemotherapy. In: ASCO annual meeting proceedings, 1 June 2005, J Clin Onco, p. Abstr no. 3519

Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22(2):229–237CrossRefPubMed

Okamoto R, Takano H, Okamura T, Park JS, Tanimoto K, Sekikawa T et al (2002) O(6)-methylguanine-DNA methyltransferase (MGMT) as a determinant of resistance to camptothecin derivatives. Jpn J Cancer Res 93(1):93–102PubMed

Ranson M, Hersey P, Thompson D, Beith J, McArthur GA, Haydon A et al (2007) Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma. J Clin Oncol 25(18):2540–2545CrossRefPubMed

Khan OA, Ranson M, Michael M, Olver I, Levitt NC, Mortimer P et al (2008) A phase II trial of lomeguatrib and temozolomide in metastatic colorectal cancer. Br J Cancer 98(10):1614–1618CrossRefPubMed

Ranson M, Middleton MR, Bridgewater J, Lee SM, Dawson M, Jowle D et al (2006) Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 12(5):1577–1584CrossRefPubMed

10.

Watson AJ, Margison GP (2000) O6-alkylguanine-DNA alkyltransferase assay. Methods Mol Biol 152:49–61PubMed

11.

Sabharwal A (2008) Inhibition of O6-methylguanine DNA methyltransferase (MGMT) in solid tumors by lomeguatrib. In: ASCO annual meeting, 20 May 2008, Chicago, J Clin Oncol, p. abstr 3597

12.

Pitot HC, Goldberg RM, Reid JM, Sloan JA, Skaff PA, Erlichman C et al (2000) Phase I dose-finding and pharmacokinetic trial of irinotecan hydrochloride (CPT-11) using a once-every-three-week dosing schedule for patients with advanced solid tumor malignancy. Clin Cancer Res 6(6):2236–2244PubMed

13.

Mathijssen RH, Verweij J, Loos WJ, de Bruijn P, Nooter K, Sparreboom A (2002) Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38. Br J Cancer 87(2):144–150CrossRefPubMed

14.

Cunningham D, Pyrhonen S, James RD, Punt CJ, Hickish TF, Heikkila R et al (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352(9138):1413–1418CrossRefPubMed

15.

Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R et al (1998) Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352(9138):1407–1412CrossRefPubMed

16.

Kefford RF, Thomas NP, Corrie PG, Palmer C, Abdi E, Kotasek D et al (2009) A phase I study of extended dosing with lomeguatrib with temozolomide in patients with advanced melanoma. Br J Cancer 100(8):1245–1249CrossRefPubMed

17.

Pourquier P, Waltman JL, Urasaki Y, Loktionova NA, Pegg AE, Nitiss JL et al (2001) Topoisomerase I-mediated cytotoxicity of N-methyl-N′-nitro-N-nitrosoguanidine: trapping of topoisomerase I by the O6-methylguanine. Cancer Res 61(1):53–58PubMed

18.

Houghton PJ, Stewart CF, Cheshire PJ, Richmond LB, Kirstein MN, Poquette CA et al (2000) Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models. Clin Cancer Res 6(10):4110–4118PubMed

19.

Friedman HS, Keir S, Pegg AE, Houghton PJ, Colvin OM, Moschel RC et al (2002) O6-benzylguanine-mediated enhancement of chemotherapy. Mol Cancer Ther 1(11):943–948PubMed

20.

Quinn JA, Reardon DA, Friedman AH, Rich JN, Sampson JH, Vredenburgh J et al (2004) Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma. Neuro oncol 6(2):145–153CrossRefPubMed

21.

Reardon DA, Quinn JA, Rich JN, Gururangan S, Vredenburgh J, Sampson JH et al (2004) Phase 2 trial of BCNU plus irinotecan in adults with malignant glioma. Neuro oncol 6(2):134–144CrossRefPubMed

22.

Gruber ML, Buster WP (2004) Temozolomide in combination with irinotecan for treatment of recurrent malignant glioma. Am J Clin Oncol 27(1):33–38CrossRefPubMed

23.

Phillips GL, Fay JW, Herzig GP, Herzig RH, Weiner RS, Wolff SN et al (1983) Intensive 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU), NSC #4366650 and cryopreserved autologous marrow transplantation for refractory cancer. A phase I-II study. Cancer 52(10):1792–1802CrossRefPubMed

Title: A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer
Authors: A. Sabharwal
P. G. Corrie
R. S. Midgley
C. Palmer
J. Brady
P. Mortimer
A. J. Watson
G. P. Margison
M. R. Middleton
Publication date: 01-10-2010
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1225-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Patients and methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 5/2010

Enhancement of cisplatin sensitivity by NSC109268 in budding yeast and human cancer cells is associated with inhibition of S-phase progression

Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study

Phase II study of S-1 and docetaxel for previously treated patients with locally advanced or metastatic non-small cell lung cancer

Relationship among pharmacokinetics and pharmacodynamics of fenretinide and plasma retinol reduction in neuroblastoma patients

C6 ceramide potentiates curcumin-induced cell death and apoptosis in melanoma cell lines in vitro

A phase II study of combination therapy with irinotecan and S-1 (IRIS) in patients with advanced colorectal cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer