Phase I–II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma

BACKGROUND: This phase I–II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma. METHODS: The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m(−2) (n=20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m(−2) on days 1, 8 and 15 q4wk combined with DTIC 800 mg m(−2) q4wk (n=38). RESULTS: The overall response rate with plitidepsin/DTIC was 21.4% all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ⩽1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug–drug pharmacokinetic interactions were found. CONCLUSION: This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m(−2) fortnightly and DTIC 800 mg m(−2) q4wk is recommended.