Effect of Bosentan in Patients With Metastatic Melanoma Treated With Dacarbazine (DTIC)

A Multicenter, Randomized, Double-blind, Placebo-controlled Phase II Study to Evaluate the Effect of Bosentan in Patients With Stage IV Metastatic Melanoma Treated With Dacarbazine

The study is designed as a multicenter, double blind, parallel-group, placebo-controlled, randomized, event driven Phase II study of DTIC with or without bosentan as first-line treatment in patients with stage IV melanoma.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Drug: Placebo; Drug: Bosentan

Detailed Description

This is a randomized, double-blind (1:1 bosentan : placebo) trial to evaluate the effect of bosentan in combination with DTIC on TTP or death in patients with metastatic melanoma stage IV.

The patients will receive study medication (bosentan or placebo) and DTIC for 35 weeks to 105 weeks; the study will be completed when 66 events (tumor progression, death due to underlying disease, other/additional anti-tumor therapy) have been observed.

Study drug will be administered orally, 500 mg twice a day. DTIC will be given once every three weeks in a dosage of 1000 mg/m2 intravenously (i.v.) or in accordance with the Institution's DTIC treatment protocol.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Geelong, Australia, VIC 3220
    • Barwon Health - The Geelong Hospital
  • Hornsby, Australia, NSW
    • Sydney Haematology and Oncology Unit
  • Malvern, Australia, VIC 2144
    • Cabrini Hopsital - Oncology Department
  • Newcastle, Australia, NSW
    • New Castle Melanoma Unit
  • Perth, Australia, WA
    • Mount Medical Centre
  • Redcliffe, Australia, QLD 4020
    • Redcliffe Hospital - Dept Oncology & Palliative Care
  • South Brisbane, Australia, QLD 4001
    • Mater Adult Hospital
  • Southport, Australia, QLD 4215
    • Pacific Private Clinic
  • St Leonards, Australia, NSW
    • Royal North Shore Hospital
  • Sydney, Australia, NSW
    • Sydney Cancer Centre, Royal Prince Alfred Hospital
  • Westmead, Australia, NSW 2145
    • Westmead Hospital - Department of Oncology
  • Wollongong, Australia, NSW
    • Southern Medical Day Care Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female patients 18 years of age or older
2. Histologically proven malignant melanoma (Balch et al., J. Clin Oncol. 19(16): 3635-48, 2001) with stage IV measurable disease as defined by RECIST criteria (Therasse et al., J Natl Cancer Inst, 92(3): 205-16, 2000).
3. Patients with prior radiation therapy (> 30 days prior to study drug initiation) will be allowed provided the indicator lesion(s) used for this study was (were) outside the field of radiation or represent new lesions not previously irradiated.
4. Patients who had no prior therapy with DTIC.
5. Patients with cutaneous melanoma lesions must consent to having a biopsy obtained during the screening period and at the end of treatment for exploratory analysis of endothelin receptor expression. Biopsies obtained prior to the study that have been frozen in accordance with procedures specified for this protocol may be used.
6. ECOG performance status (≤ 2)
7. Life expectancy > 12 weeks
8. Female patients must be non-pregnant, non-breast feeding, and either post menopausal, surgically sterile, or practicing a reliable method of contraception (hormonal methods alone are not sufficient)
9. Provide written informed consent
10. Willing to return to study center for follow up

Exclusion Criteria:

1. ALT and/or AST > 3 × the upper limit of normal (ULN) at screening OR ALT and /or AST > 2 x ULN and total bilirubin > 2.0 mg/dl at screening
2. Lactate dehydrogenase > 1.5 x ULN
3. Hemoglobin >30% below the lower limit of normal
4. Systolic blood pressure < 85 mmHg
5. NYHA class III/IV congestive heart failure
6. Any prior chemotherapy, biological therapy or immunotherapy for stage IV metastatic disease.
7. Received immunotherapy < 30 days before treatment start (completed adjuvant immunotherapy for previous resected metastatic disease is allowed)
8. Concurrent use of calcineurin inhibitors (cyclosporine A, tacrolimus), sirolimus, fluconazole or glibenclamide (glyburide) or expected to receive any of these drugs during the study at inclusion and during the study.
9. History of other malignancy in the last 5 years, with the exception of squamous cell carcinoma of the skin treated with local resection and basal cell carcinoma
10. CNS metastases or carcinomatous meningitis
11. Ocular melanoma
12. Known hypersensitivity to any excipients of Tracleer™
13. Prior therapy with bosentan
14. Use of therapy with another investigational drug within 4 weeks of the start of dosing with bosentan or plan to receive such treatment during the study
15. Known drug or alcohol dependence or any other factor that will interfere with the conduct of the study
16. Any standard contraindications for the use of DTIC as per Australian package insert

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo
Experimental: Bosentan	Drug: Bosentan; Bosentan 500 mg bid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to tumor progression (TTP) or death (progression free survival) after initiation of treatment. Tumor progression is defined per RECIST criteria.	6 weekly

Secondary Outcome Measures

Outcome Measure	Time Frame
• Tumor response rate • Duration of overall response • Best overall response • Survival will be assessed at 12 months after initiation of study drug and every year thereafter for 5 years	6 weekly

Collaborators and Investigators

• Sponsor: Actelion
• Investigators: Study Director: Andjela Kusic-Pajic, MD, Actelion Pharmaceuticals Australia Pty. Ltd

Publications and helpful links

General Publications

• Kefford RF, Clingan PR, Brady B, Ballmer A, Morganti A, Hersey P. A randomized, double-blind, placebo-controlled study of high-dose bosentan in patients with stage IV metastatic melanoma receiving first-line dacarbazine chemotherapy. Mol Cancer. 2010 Mar 30;9:69. doi: 10.1186/1476-4598-9-69.

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2005
• Primary Completion (Actual): February 29, 2008
• Study Completion (Actual): February 29, 2008

Study Registration Dates

• First Submitted: October 14, 2009
• First Submitted That Met QC Criteria: November 5, 2009
• First Posted (Estimated): November 6, 2009

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Bosentan; Metastatic; Melanoma; DTIC
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplastic Processes; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Neoplasm Metastasis; Melanoma; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amides; Pyrimidines; Benzene Derivatives; Benzenesulfonamides; Sulfonamides; Sulfones; Bosentan
• Other Study ID Numbers: AC-052-281