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Investigational New Drugs
Published in: Investigational New Drugs 3/2007

01-06-2007 | PHASE II STUDIES

A Phase II study of bosentan, a dual endothelin receptor antagonist, as monotherapy in patients with stage IV metastatic melanoma

Authors: Richard Kefford, Jane McNeil Beith, Guy Arthur Van Hazel, Michael Millward, James Marshall Trotter, David Keith Wyld, Rada Kusic, Revati Shreeniwas, Adele Morganti, Andrea Ballmer, Eleonor Segal, Oliver Nayler, Martine Clozel

Published in: Investigational New Drugs | Issue 3/2007

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Summary

There is no effective systemic therapy for disseminated metastatic melanoma. Data suggest that endothelin may play a role in pathophysiology of melanoma and that the dual endothelin receptor antagonist bosentan may have anti-tumor activity.
This multicenter, open-label, single-arm, prospective, proof-of-concept study assessed the effects of bosentan monotherapy (500 mg oral tablets, bid) on tumor response in patients with stage IV metastatic melanoma. Patients were treated until disease progression, death or serious adverse event leading to premature study drug discontinuation. Tumor response was assessed at 6-weekly intervals using the Response Evaluation Criteria in Solid Tumors (RECIST).
Among the 35 patients included in this study with stage IV metastatic melanoma, 21 (60%) were stage M1C, 10 (29%) stage M1B and 4 (11%) stage M1A (American Joint Committee on Cancer [AJCC] classification). Nine patients (26%) had received prior therapy for stage IV melanoma. Disease stabilization was observed in 6 of the 32 patients analyzed per protocol at week 6 with confirmatory evaluation at week 12, 5 of whom were still stable at ≥24 weeks. Of the 6 patients with disease stabilization, 2 were stage M1A, 1 was stage M1B and the remaining 3 were stage M1C. Partial or complete response was not observed. Progressive disease was observed in 17 (49%) patients at week 12 and in 25 (71%) patients at the end of the study (data base closure). The most frequent adverse events were typical for the underlying disease or known to be associated with bosentan: headache (43%), fatigue (34%), nausea (31%), back pain (23%) and abnormal hepatic function (23%).
Bosentan might have benefit in disease stabilization in certain patients with metastatic melanoma and deserves further investigation in combination with other anticancer drugs.
Literature
1.
Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton AJr, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF (2001) Final version of the American Joint Committee on cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648PubMed
2.
Thompson JF, Scolyer RA, Kefford RF (2005) Cutaneous melanoma. Lancet 365:687–701PubMed
3.
Eigentler TK, Caroli UM, Radny P, Garbe C (2003) Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. Lancet Oncol 4:748–759PubMedCrossRef
4.
Khayat D, Meric J-B, Rixe O (2004) Systemic chemotherapy and biochemotherapy for non-resected and metastatic melanoma. In: Thompson JF, Morton DL, Kroon BBR (eds) Textbook of Melanoma. Martin Dunitz, London, pp 586–601
5.
Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saiag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y (2004) Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a Phase III study. J Clin Oncol 22:1118–1125PubMedCrossRef
6.
Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N (2000) Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158–166PubMed
7.
Millward MJ, Bedikian AY, Conry RM, Gore ME, Pehamberger HE, Sterry W, Pavlick AC, De Conti RC, Gordon D, Itri LM (2004) Randomized multinational phase 3 trial of dacarbazine (DTIC) with or without Bcl-2 antisense (oblimersen sodium) in patients (pts) with advanced malignant melanoma (MM): Analysis of long-term survival. (Abstract 7505). In: Proceedings of the American Society of clinical oncology (ASCO), New Orleans, 2004 (Post-Meeting Edition) J Clin Oncol 22
8.
Baynash AG, Hosoda K, Giaid A, Richardson JA, Emoto N, Hammer RE, Yanagisawa M (1994) Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79:1277–1285PubMedCrossRef
9.
Hosoda K, Hammer RE, Richardson JA, Baynash AG, Cheung JC, Giaid A, Yanagisawa M (1994) Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79:1267–1276PubMedCrossRef
10.
Ceccherini I, Zhang AL, Matera I, Yang G, Devoto M, Romeo G, Cass DT (1995) Interstitial deletion of the endothelin-B receptor gene in the spotting lethal (sl) rat. Hum Mol Genet 4:2089–2096PubMedCrossRef
11.
Lahav R, Ziller C, Dupin E, Le Douarin NM (1996) Endothelin 3 promotes neural crest cell proliferation and mediates a vast increase in melanocyte number in culture. Proc Natl Acad Sci USA 93:3892–3897PubMedCrossRef
12.
Imokawa G, Miyagishi M, Yada Y (1995) Endothelin-1 as a new melanogen: coordinated expression of its gene and the tyrosinase gene in UVB-exposed human epidermis. J Invest Dermatol 105:32–37PubMedCrossRef
13.
Jamal S, Schneider RJ (2002) UV-induction of keratinocyte endothelin-1 downregulates E-cadherin in melanocytes and melanoma cells. J Clin Invest 110:443–452PubMedCrossRef
14.
Mangahas CR, dela Cruz GV, Schneider RJ, Jamal S (2004) Endothelin-1 upregulates MCAM in melanocytes. J Invest Dermatol 123:1135–1139PubMedCrossRef
15.
Demunter A, De Wolf-Peeters C, Degreef H, Stas M, Van Den Oord JJ (2001) Expression of the endothelin-B receptor in pigment cell lesions of the skin. Evidence for its role as tumor progression marker in malignant melanoma. Virchows Arch 438:485–491PubMedCrossRef
16.
Lahav R, Heffner G, Patterson PH (1999) An endothelin receptor B antagonist inhibits growth and induces cell death in human melanoma cells in vitro and in vivo. Proc Natl Acad Sci USA 96:11496–11500PubMedCrossRef
17.
Bagnato A, Rosano L, Spinella F, Di Castro V, Tecce R, Natali PG (2004) Endothelin B receptor blockade inhibits dynamics of cell interactions and communications in melanoma cell progression. Cancer Res 64:1436–1443PubMedCrossRef
18.
Sekulic A, Suresh P, Pittelkow M, Markovic S (2002) Bosentan, a novel endothelin-A and -B receptor antagonist inhibits proliferation of malignant melanoma cells (Abstract) Meeting of the American Association for Cancer Research. Mayo Clinic, Rochester, MN, USA
19.
Berger Y, Chapuis Bernasconi C, Juillerat-Jeanneret L (2006) Targeting the endothelin axis in human melanoma: combination of endothelin receptor antagonism and alkylating agents. Exp Biol Med 231:in press
20.
Egidy G, Peduto Eberl L, Valdenaire O, Irmler M, Majdi R, Diserens AC, Fontana A, Janzer RC, Pinet F, Juillerat-Jeanneret L (2000) The endothelin system in human glioblastoma. Lab Invest 80:1681–1689PubMedCrossRef
21.
Eberl L, Valdenaire O, Saintgiorgio V, Jeannin J, Juillerat-Jeanneret L (2000) Endothelin receptor blockade potentiates FasL-induced apoptosis in rat colon carcinoma cells. Int J Cancer 86:182–187PubMedCrossRef
22.
Cruz A, Parnot C, Ribatti D, Corvol P, Gasc JM (2001) Endothelin-1, a regulator of angiogenesis in the chick chorioallantoic membrane. J Vasc Res 38:536–545PubMedCrossRef
23.
Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, Olschewski H, Peacock A, Pietra G, Rubin LJ, Simonneau G, Priori SG, Garcia MA, Blanc JJ, Budaj A, Cowie M, Dean V, Deckers J, Burgos EF, Lekakis J, Lindahl B, Mazzotta G, McGregor K, Morais J, Oto A, Smiseth OA, Barbera JA, Gibbs S, Hoeper M, Humbert M, Naeije R, Pepke-Zaba J (2004) Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 25:2243–2278PubMedCrossRef
24.
Packer M, McMurray J, Massie BM, Caspi A, Charlon V, Cohen-Solal A, Kiowski W, Kostuk W, Krum H, Levine B, Rizzon P, Soler J, Swedberg K, Anderson S, Demets DL (2005) Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study. J Card Fail 11:12–20PubMedCrossRef
25.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRef
Metadata
Title
A Phase II study of bosentan, a dual endothelin receptor antagonist, as monotherapy in patients with stage IV metastatic melanoma
Authors
Richard Kefford
Jane McNeil Beith
Guy Arthur Van Hazel
Michael Millward
James Marshall Trotter
David Keith Wyld
Rada Kusic
Revati Shreeniwas
Adele Morganti
Andrea Ballmer
Eleonor Segal
Oliver Nayler
Martine Clozel
Publication date
01-06-2007
Published in
Investigational New Drugs / Issue 3/2007
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-006-9014-7

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