apaziquone and Proteinuria

In a phase II trial, the activity of EO9, a new bioreductive alkylating agent, was assessed. EO9 was used as second-line chemotherapy in breast cancer patients and as first-line chemotherapy for patients with gastric, pancreatic and colorectal cancer. EO9 was given as a 5 min i.v. infusion at a weekly dose of 12 mg/m2. 92 patients were entered; 22 with breast cancer, 26 with colon cancer, 24 with pancreatic cancer and 20 with gastric cancer. In general, the drug was well tolerated with nausea and vomiting occurring in 26.42 and 13.3% of courses, respectively. Reversible proteinuria was the main toxicity occurring in 45% of courses. Antitumour activity was not observed. At this dose and schedule, EO9 is not an active drug in the type of tumour studied.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Aziridines; Breast Neoplasms; Colorectal Neoplasms; Digestive System Neoplasms; Female; Follow-Up Studies; Humans; Indolequinones; Indoles; Male; Middle Aged; Pancreatic Neoplasms; Proteinuria; Stomach Neoplasms

EO9 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)-prop-be ta- en-alpha-ol] is a new bioreductive alkylating indoloquinone with a distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, and lack of bone marrow toxicity in preclinical models. Clinical phase I studies were performed to determine the toxicities, maximally tolerated dose, and pharmacology of EO9. The drug was administered as a 5-min IV infusion at intervals of 3 weeks or weekly to 59 patients with solid tumors. The starting dose of 2.7 mg/m2 was one-tenth of the mouse-equivalent dose lethal to 10% of mice. Doses were escalated according to a Fibonacci-like schedule. The pharmacokinetics of EO9 and its aziridine ring-opened metabolite EO5A were determined using a new high performance liquid chromatography method and noncompartmental calculation of kinetic parameters. The sigmoid maximal effects (Emax) model was used to fit pharmacokinetic parameters to toxicities. The 59 patients received in total 150 evaluable courses of EO9. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. With the 3-weekly schedule, all symptoms were reversible on day 15 except in 2 patients, who developed acute renal failure. The renal function and proteinuria were quantitated and further evaluated by determining renal clearance ratios of immunoglobulin G/albumin and pancreatic/salivary amylase. The immunogobuline G/albumin and pancreatic/salivary amylase ratios pointed to a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The maximum tolerated dose was 27 mg/m2, the recommended dose 22 mg/m2. The pharmacokinetics showed rapid elimination from the central compartment and wide interpatient variation in disposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Agents; Aziridines; Drug Administration Schedule; Female; Humans; Indolequinones; Indoles; Male; Middle Aged; Neoplasms; Proteinuria

A novel bioreductive alkylating indoloquinone compound, E09 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)- prop-F128b-en-alpha-ol], has been shown to have distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, but no notable bone marrow toxicity in preclinical models.. A phase I study was carried out to determine the toxicity, maximum tolerated dose (MTD), pharmacology, and antitumor response of E09.. E09 was administered as a 5-minute intravenous infusion once every 3 weeks to 32 patients with solid tumors. The starting dose of 2.7 mg/m2 was one tenth of the mouse equivalent of lethal dose to 10% of animals (MELD10). Dose was escalated by 100% until the area under the curve (AUC) at the MELD10 was reached, following a Fibonacci-like schedule. The pharmacokinetics of E09 and its metabolite E05A with an open aziridine ring was determined using a new high-pressure liquid chromatographic method and noncompartmental calculation of kinetic parameters. The sigmoid Emax model was used to fit pharmacokinetic parameters to toxicity. The renal function and proteinuria were quantitated and were further evaluated by determining renal clearance ratios of immunoglobulin G (IgG) to albumin and pancreatic amylase to salivary amylase.. The 32 patients were treated with a total of 85 assessable courses of E09. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. All symptoms were reversible on day 15 except in two patients, who developed acute renal failure. The ratios of IgG to albumin and pancreatic amylase to salivary amylase suggested a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The pharmacokinetics of E09 showed its rapid elimination from the central compartment but with wide interpatient variation in the overall disposition of the drug. Total plasma clearance of E09 ranged from 3.2 to 24 L/min. The AUC of E09 was linearly related to the administered dose. The relationship between the AUC and proteinuria was best fitted by the sigmoid Emax model (r = .98). In two patients with adenocarcinoma of unknown primary site and in a third patient with bile duct cancer, a partial response was observed.. The MTD of E09 was determined to be 27 mg/m2. The standard approach of drug administration is considered unsuitable because of potential renal toxicity and wide variability in the pharmacokinetics of E09. Individual dose adjustments based on plasma concentration measurements are recommended to combine maximally achievable exposure with tolerable toxicity.

Topics: Adult; Aged; Antineoplastic Agents; Aziridines; Female; Humans; Indolequinones; Indoles; Male; Metabolic Clearance Rate; Middle Aged; Proteinuria