Didemnin B is a cyclic peptide isolated from the marine tunicate Trididemnin cyanophorum. It is a known potent inhibitor of RNA, DNA and protein synthesis, with activity against the murine B16 melanoma. Fourteen patients with disseminated malignant melanoma were evaluated in a Southwest Oncology Group phase II trial of didemnin B at 4.2 mg/m2 by 30 min i.v. infusion every 28 days (SWOG-8754). Only patients with no prior chemotherapy were eligible; prior radiation therapy, surgery and at most one prior biologic regimen were allowed. Patients with brain metastasis were eligible only if the disease in the brain had been treated and controlled. All patients had to have normal renal and hepatic function and adequate granulocyte and platelet counts, a performance status of 0-2, and bidimensionally measurable disease. Fourteen patients were entered on the study; five received one and nine received two courses of didemnin B. No responses were noted among the 11 patients evaluable for response. Five patients developed unusual but reversible hypersensitivity reactions during the second course of therapy. Other toxicity in this trial was nausea and vomiting and diarrhea, none of severity greater than grade 3. Given the lack of antitumor efficacy and the unusual toxicity, further evaluation of didemnin B in this dose and schedule in malignant melanoma is not warranted.