dolastatin-10 and Neutropenia

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.. 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 microg/m(2) was administered intravenously by bolus every 21 days. Restaging CT scans were obtained every 2 cycles.. 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.. Dolastatin-10 is inactive against hepatobiliary and pancreatic carcinomas.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bile Duct Neoplasms; Carcinoma, Hepatocellular; Cholangiocarcinoma; Depsipeptides; Female; Gallbladder Neoplasms; Humans; Liver Neoplasms; Male; Middle Aged; Neutropenia; Oligopeptides; Pancreatic Neoplasms

TZT-1027 is a synthetic dolastatin 10 analog with antineoplastic properties in various cell lines and tumor xenografts. The purpose of this phase I study was to evaluate the safety and toxicity, maximum tolerated dose, pharmacokinetics and pharmacodynamics, clinical and metabolic antitumor activity of TZT-1027 when given as a 1-h intravenous infusion every 3 weeks in patients with refractory solid tumors.. Patients had a histologically verified refractory tumor with measurable disease, were > or = 18 years old, had an Eastern Cooperative Oncology Group performance status <2 and adequate bone marrow, liver, renal and cardiac function. Dose-limiting toxicity was defined as platelets <25 x 10(9)/l, neutrophils <0.5 x 10(9)/l for >5 days, febrile neutropenia > or = 38.5 degrees C with grade 4 (National Cancer Institute-common toxicity criteria) neutropenia, or grade 3/4 non-hematological toxicity excluding nausea and vomiting. The last dose was the dose where > or = 2 out of six patients experienced dose-limiting toxicity in cycle one. The maximum tolerated dose was one dose level below with less than two of six patients with dose-limiting events.. Twenty-one non-selected, fully evaluable patients were enrolled. The majority were male (19) and the median age was 55 years (range 39-67). Dose levels of TZT-1027 ranged from 1.35 to 3.0 mg/m(2). The median number of cycles was two (range 1-4). Dose-limiting toxicities were observed in three patients at the 3.0 mg/m(2) dose level, including neutropenia, fatigue and a short lasting, reversible peripheral neurotoxic syndrome. The most common toxicities per patient were fatigue, anorexia, alopecia, nausea, constipation, leukopenia and neutropenia. Based on RECIST criteria, the best response was stable disease in seven patients. The pharmacokinetic evaluation revealed a T(1/2) of approximately 7 h and linear kinetics.. The recommended dose of TZT-1027 for the 3-weekly administration is 2.7 mg/m(2). Neutropenia, fatigue and a reversible peripheral neurotoxic syndrome are dose-limiting with this schedule. TZT-1027 may be associated with neurological side-effects in patients previously exposed to neurotoxic compounds such as oxaliplatin.

Topics: Adult; Aged; Alopecia; Anorexia; Antineoplastic Agents; Area Under Curve; Constipation; Depsipeptides; Dose-Response Relationship, Drug; Fatigue; Female; Humans; Infusions, Intravenous; Leukopenia; Male; Middle Aged; Nausea; Neoplasms; Neutropenia; Oligopeptides

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Depsipeptides; Heart; Humans; Hypertension; Neutropenia; Oligopeptides; Structure-Activity Relationship