Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers
- 109 Downloads
Background: Pancreaticobiliary malignancies respond poorly to conventional chemotherapy, and novel agents are needed. Dolatstatin-10 is a potent antimitotic pentapeptide isolated from the marine mollusk Dolabella auricularia that inhibits microtubule assembly. We conducted 2 parallel phase II trials of dolastatin-10 in patients with advanced hepatobiliary cancers and pancreatic adenocarcinoma. Patients and methods: Eligible patients had histologically-confirmed metastatic pancreatic adenocarcinoma or metastatic, locally advanced or recurrent cancer of the liver, bile duct or gallbladder, and had received no prior chemotherapy for advanced disease. Dolastatin-10 400 μg/m2 was administered intravenously by bolus every 21 days. Restaging CT scans were obtained every 2 cycles. Results: Twenty-eight patients (16 hepatobiliary, including 7 hepatomas, 6 cholangiocarcinomas, 2 gallbladder carcinomas, and 12 pancreatic carcinomas) enrolled; 27 were evaluable for response. There were no objective responses. Grade 3/4 neutropenia occurred in 59% of patients and neutropenic fever in 18%. Median and 1-year survival were 5.0 months and 17% for the pancreatic cancer patients, and 3.0 months and 29% for the hepatobiliary patients. Median time to progression was 1.3 months for the pancreatic cancer patients and 1.6 months for the hepatobiliary patients. Conclusions: Dolastatin-10 is inactive against hepatobiliary and pancreatic carcinomas.
Keywordsdolastatin-10 hepatobiliary cancer hepatocellular carcinoma cholangiocarcinoma gallbladder carcinoma pancreatic adenocarcinoma
Unable to display preview. Download preview PDF.
- 1.Burris HA 3rd, Moore MJ, Andersen J, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15: 2403–2413, 1997PubMedGoogle Scholar
- 6.Bai R, Pettit GR, Hamel E: Dolastatin-10, a powerful cytostatic peptide derived from a marine animal. Inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain. Biochem Pharmacol 39: 1941–1949, 1990Google Scholar
- 12.Madden T, Tran HT, Beck D, Huie R, Newman RA, Pusztai L, Wright JJ, Abbruzzese JL: Novel marine-derived anticancer agents: A phase I clinical, pharmacological, and pharmacodynamic study of dolostatin-10 (NSC 376128) in patients with advanced solid tumors. Clin Cancer Res 6: 1293–1301, 2000PubMedGoogle Scholar
- 18.Vaishampayan U, Glode M, Du W, Kraft A, Hudes G, Wright J, Hussain M: Phase II study of dolastatin-10 in patients with hormone-refractory metastatic prostate adenocarcinoma. Clin Cancer Research 6: 4205–4208, 2000Google Scholar
- 20.Singh DA, Kindler HL, Eng C, Skoog L, Lenz H-J, Taber D, Vokes EE: Phase II trial of the epothilone B analog BMS-247550 in patients with hepatobiliary cancer. Proc Am Soc Clin Oncol 22: 281, 2003Google Scholar
- 21.Whitehead RP, McCoy SA, Rivkin SE, Gross HM, Conrad ME, Abbruzzese JL: A phase II trial of epothilone B analogue BMS-247550 (NSC #710428) in patients with advanced pancreas cancer: A Southwest Oncology Group Study. Proc Am Soc Clin Oncol 23: 315, 2004Google Scholar