Weekly 24 h infusion of aviscumine (rViscumin): a phase I study in patients with solid tumours.

Aviscumine is a ribosome-inactivating protein with potent antitumour activity in vitro and in vivo and is an Escherichia coli-derived recombinant counterpart of natural mistletoe lectin-I. The current study was performed to determine the safety profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a prolonged infusion of aviscumine in cancer patients. Aviscumine was given once weekly as a 24 h central intravenous infusion in patients with advanced, refractory progressive solid malignant tumours. Fourteen fully eligible patients (11 male, 3 female) with a median age 58 yrs (range 41-77) were enrolled. They had histologically verified disease, were 18 yrs old, had an ECOG PS 2 and adequate bone marrow, liver and renal function. DLT was defined as any non-haematological grade 3-4 toxicity (Common Toxicity Criteria [CTC] version 2.0), neutrophil count <500/ microl for 7 days, febrile neutropenia or thrombocytopenia grade 4. The MTD was defined as the dose level below the dose at which 2 patients per dose level experienced a DLT during the first treatment cycle. Colorectal cancer, soft tissue sarcoma and pancreatic cancer were the most common tumour types. Dose levels of aviscumine ranged from 4 to 6 microg/kg. The median number of cycles was 2.8 (range, 2-8). Common side effects in cycle 1 were fatigue, fever, nocturia, urticaria, erythema and pruritus. DLTs occurred in 2/3 patients on the 6 microg/kg dose level and consisted of increases in ASAT grade 3, ALAT grade 3, gammaGT grade 3/4, hypokalemia grade 3 and fatigue grade 3. No DLTs were observed on dose levels 4 and 5 microg/kg. The best response (RECIST) was stable disease in 4 pts, lasting for 4-8 cycles. Pharmacokinetics indicated that potentially active plasma levels of the compound were maintained during the entire infusion. We conclude that the recommended dose for weekly 24 h infusions of Aviscumine should be 5 microg/kg.

Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group.

BACKGROUND: Aviscumine is an Escherichia coli-derived recombinant type II ribosome-inactivating protein with potent antitumor activity in vitro and in vivo. It is the recombinant counterpart of natural mistletoe lectin-I. The current study was performed to determine the safety profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the intravenous (i.v.) administration of aviscumine in cancer patients. Translational research included the evaluation of pharmacokinetics and monitoring of plasma cytokine and anti-aviscumine antibody induction after administration of the drug. PATIENTS AND METHODS: Aviscumine was given twice weekly as a 1 h central i.v. infusion in patients with advanced, refractory progressive, solid malignant tumors who had not been previously exposed to natural mistletoe preparations. They had histologically or cytologically verified disease, were > or =18 years old, had an Eastern Cooperative Oncology Group performance status < or =2 and adequate bone marrow, liver and renal function. DLT was defined as any non-hematological grade 3-4 toxicity (National Cancer Institute Common Toxicity Criteria version 2.0), neutrophil count <500/microl for > or =7 days, febrile neutropenia or thrombocytopenia grade 4. The MTD was defined as the dose at which >20% of patients experienced DLT during the first treatment cycle. The Continual Reassessment Method was used to determine the number of patients required per dose level. RESULTS: Forty-one fully eligible patients (19 male, 22 female) with a median age of 56 years (range 37-74) were enrolled. Colorectal, ovarian, renal cell and breast cancer were the most common tumor types. Dose levels of aviscumine ranged from 10 to 6400 ng/kg. The median number of cycles was two (range one to eight). Common clinical toxicities in cycle 1 were fatigue, fever, nausea, vomiting and allergic reactions. Fatigue grade 3 was dose limiting in one of six patients at 4000 ng/kg and reversible grade 3 liver toxicity (elevation in alkaline phosphatase, transaminases and/or gamma-glutamyltransferase) occurred in one of 10 patients at 4800 ng/kg and in two of five patients at 6400 ng/kg. The best response (RECIST criteria) was stable disease in 11 patients, lasting for two to eight cycles. The pharmacokinetic evaluation revealed a short alpha half-life of 13 min and linear kinetics on dose levels > or =1600 ng/kg. Aviscumine stimulated the immune system with a release of cytokines such as interleukin (IL)-1beta, IL-6 and interferon-gamma, and induced immunoglobulin (Ig) G- and/or IgM-anti-aviscumine antibodies of uncertain clinical relevance. CONCLUSIONS: The recommended dose for further clinical trials is 5600 ng/kg twice weekly. Based on the short half-life of the recombinant protein observed in this trial, the exploration of prolonged infusion schedules of aviscumine is warranted.

Phase I and pharmacokinetic study of TZT-1027, a novel synthetic dolastatin 10 derivative, administered as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory cancer.

BACKGROUND: 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 AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Experiences with primary fascia closure of the abdomen in gastroschisis--a 16 year review]. / Erfahrungen mit dem primären Faszienverschluss des Abdomens bei Gastroschisis--ein 16-Jahresüberblick.

47 children with gastroschisis were operated at the Hannover Medical School between 1980 and 1995. The average gestation period was the 36th week of pregnancy with an average birthweight of 2370 gr. A primary layered closure of the abdominal wall was performed on 46 children. A multi-sided closure of the abdominal wall defect using Gore-Tex was necessary in only one case. Post-operative intubation lasted for an average of 56 hours. The children were fed by parenteral nutrition for an average of 32 days, with oral feeding starting on the 15th post-operative day. The average weight on discharge was 3035 gr. 18% of the children had post-operative problems such as sepsis, necrotic enterocolitis and ileus. A death rate of only 2% is proof of the progress that has been made in prenatal care of the newborn child suffering from gastroschisis and suggests that primary closure of the abdomen is the operative method to be aimed for.