Phase II study of didemnin B in advanced colorectal cancer

Abstract

Didemnin B is a depsipeptide derived from a Caribbean tunicate (sea squirt) that has demonstrated antineoplastic activity against a variety of murine tumor models, including the L1210 and P388 leukemia, the B16 melanoma, and M5076 sarcoma cell lines. Based on these data, we designed a phase II trial in which 15 patients with measurable, unresectable colorectal cancer were treated with Didemnin B at an initial dosage of 3.47 mg/m2 over 30 minutes administered by intravenous infusion every 28 days; the dosage was altered in accordance with the toxicity observed, with only one patient requiring a dosage reduction for pronounced nausea and vomiting. No hematologic or nonhematologic toxicity developed. No complete or partial responses were observed. These results do not compare favorably with results of treatments using other single agents or combinations that are currently available for the treatment of advanced colorectal cancers. However, because of the tolerable levels of toxicity experienced by in our patients, it is possible that an insufficient dose of the medication was delivered. We concluded that Didemnin B is not active against of colorectal cancers at the dosage and schedule at which it was administered in this study.

Fate of tritiated didemnin B in mice: excretion and tissue concentrations after an intraperitoneal dose

“…These high concentrations of [ 3 H]didemnin B in the digestive tract may help to explain the previously noted gastrointestinal upset in anticancer trials [10,11,[24][25][26][27] as well as gastrointestinal lesions in rats and dogs [3,4]. Liver residues of [ 3 H]didemnin B in mice of Study 2 at 6-12 h were in the range that damaged cancer cells in vitro [28,29]. High concentrations in the liver may help to explain the acute hepatotoxicity noted in cancer patients as well as in rats and dogs in toxicity studies [3,4,24,30,31].…”

“…Liver residues of [ 3 H]didemnin B in mice of Study 2 at 6-12 h were in the range that damaged cancer cells in vitro [28,29]. High concentrations in the liver may help to explain the acute hepatotoxicity noted in cancer patients as well as in rats and dogs in toxicity studies [3,4,24,30,31].…”

“…every 28 days at 0.14-4.51 mg/m 2 provided no significant antitumor response; but one of four patients with pancreatic adenocarcinoma was stable through 12 courses of treatment and worsened after discontinuation [24]. The results were disappointing in cancer patients with myeloma [25], metastatic malignant melanoma [26], epithelial ovarian cancer [27,28], colorectal cancer [29], metastatic, advanced, or recurrent squamous carcinoma of the cervix [30,31], metastatic breast cancer [32] and advanced adenocarcinoma of the kidney [33].…”

Macrocyclic N-Methylated Cyclic Peptides and Depsipeptides

“…One partial response was achieved (5%) in 21 patients [193]. Some phase II clinical trials were also undertaken by other groups [122,[195][196][197][198][199][200][201][202][203]. From the data analysis, didemnin B 176 is not recommended in the treatment of renal cell carcinoma.…”

“…The toxicity was mild (nausea and vomiting), there were no objective responses and 43% had a stable disease state for at least 3 months. No complete or partial response was found in the phase II study of didemnin B 176 in advanced colocteral cancer [200]. Some phase II clinical trials were also undertaken by other groups [122,[195][196][197][198][199][200][201][202][203].…”