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
Overview
- Phase
- Phase 2
- Intervention
- Bosentan
- Conditions
- Melanoma
- Sponsor
- Actelion
- Enrollment
- 80
- Primary Endpoint
- Time to tumor progression (TTP) or death (progression free survival) after initiation of treatment. Tumor progression is defined per RECIST criteria.
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
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.
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female patients 18 years of age or older
- •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).
- •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.
- •Patients who had no prior therapy with DTIC.
- •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.
- •ECOG performance status (≤ 2)
- •Life expectancy \> 12 weeks
- •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)
- •Provide written informed consent
- •Willing to return to study center for follow up
Exclusion Criteria
- •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
- •Lactate dehydrogenase \> 1.5 x ULN
- •Hemoglobin \>30% below the lower limit of normal
- •Systolic blood pressure \< 85 mmHg
- •NYHA class III/IV congestive heart failure
- •Any prior chemotherapy, biological therapy or immunotherapy for stage IV metastatic disease.
- •Received immunotherapy \< 30 days before treatment start (completed adjuvant immunotherapy for previous resected metastatic disease is allowed)
- •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.
- •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
- •CNS metastases or carcinomatous meningitis
Arms & Interventions
Bosentan
Intervention: Bosentan
Placebo
Intervention: Placebo
Outcomes
Primary Outcomes
Time to tumor progression (TTP) or death (progression free survival) after initiation of treatment. Tumor progression is defined per RECIST criteria.
Time Frame: 6 weekly
Secondary Outcomes
- • 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)