A phase II trial of didemnin B in myeloma

Abstract

Didemnin B is a member of a class of compounds, derived from a marine source, undergoing phase II study. Twenty-two patients with relapsed myeloma were treated with didemnin B at an initial dose of 4.9 mg/m2, given once every 28 days. All were evaluable for toxicity, and 15 were evaluable for myeloma response. No tumor regressions occurred in the 15 patients evaluable for response. Vomiting was the major toxicity, occurring in 73% of patients despite vigorous pre- and post-treatment medication with at least three intravenous antiemetics. Two instances of grade 4 hypersensitivity reaction occurred. We conclude that didemnin B has no activity at this dose and schedule in myeloma that has relapsed after one or two prior therapeutic regimens.

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 mild toxicities such as nausea, vomiting, and anemia were still found when didemnin B 176 was tested on advanced epithelial ovarian cancer. No activity was found in the phase II trial of didemnin B 176 for myeloma, a cancer, and leukemia group B (CALGB study) (4.9 mg/m 2 , every 28 days) [203]. Taylor et al [197] showed that didemnin B 176 was toxic but inactive in patients with renal cell cancer treated at dose 3.47 mg/m 2 i.v.…”

Mechanism of Protein Synthesis Inhibition by Didemnin B in Vitro

“…Didemnin B (Figure 1) displays encouraging antineoplastic and antiviral activity in vitro•, for example, it inhibits cell growth in human tumor stem-cell assays at concentrations from 1 to 100 nM (Jiang et al, 1983;Rinehart et al, 1983;Rinehart, 1985). However, results from phase II clinical trials indicate that this compound has little or no activity against cancer in humans, possibly due to its rapid conversion to an inactive metabolite (Malfetano et al, 1993;Jones et al, 1992; Dorr et al, 1988;Shin et al, 1991;Weiss et al, 1994;Sondak et al, 1994). Inhibition of T-cell proliferation by didemnin B has led to its evaluation as an immunosuppressive agent (Montgomery et al, 1985;Teunissen et al, 1992).…”

Scalable synthesis of the unusual amino acid segment (ADMOA unit) of marine anti-inflammatory peptide: solomonamide A

“…[α] 25 D = +18.51 (c = 0.55, CHCl 3 ); IR (neat): ν max 2930, 2858, 2107, 1466, 1255, 1107, 833, 701, 614 cm −1 ; 1 H NMR (CDCl 3 , 500 MHz): δ 7.68-7.63 (m, 4H), 7.44-7.34 (m, 6H), 4.15-4.12 (dd, J = 3.0, 6.4 Hz, 1H), 3.90 (t, J = 4.2 Hz, 1H), 3.85 (d, J = 2.9 Hz, 1H), 3.80-3.76 (dd, J = 5.2, 10.2 1H), 3.74-3.71 (dd, J = 4.2, 6.4 Hz, 1H), 3.60-3.55 (dd, J = 7.0, 10.2 Hz, 1H), 2.71-2.58 (m, 4H), 2.05-1.95 (m, 1H), 1.24 (t, J = 7.3 Hz, 3H), 1.18 (t, J = 7.4 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H), 1.06 (s, 9H), 0.95 (s, 9H), 0.82 (s, 9H), 0.22 (s, 3H), 0.18 (s, 3H), 0.09 (s, 3H), 0.02 (s, 3H); 13 Benzyl (5R,6S,7R,8R)-5-(bis(ethylthio)methyl)-7-(tert-butyldimethylsilyloxy)-2,2,3,3,8,12,12-heptamethyl-11,11-diphenyl-4,10-dioxa-3,11-disilatridecan-6-ylcarbamate (5). To a stirred solution of azide 14 (1.8 g, 2.3 mmol) and ammonium chloride (0.3 g, 5.8 mmol) in ethyl alcohol (18 mL) and water (6 mL), zinc powder (0.2 g, 3.0 mmol) was added and the mixture was stirred vigorously at room temperature.…”

“…3 A good number of marine peptides have been taken into chemical development viz. dolastatin, 4 didemnins, 5 auristatin, 6 ecteinascidin 743. 7 Zampella's group has isolated two cyclic peptides, namely solomonamides A and B (Fig.…”