Clinical studies with EO9, a new indoloquinone bioreductive alkylating cytotoxic agent. EORTC Early Clinical Trials Group.
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)
Verweij
J
J
Department of Medical Oncology, Rotterdam Cancer Institute, Dr. Daniel den Hoed Kliniek, The Netherlands.
Aamdal
S
S
Schellens
J
J
Koier
I
I
Lund
B
B
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001388:Aziridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine; D011507:Proteinuria / Q000139:chemically induced
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; C060817:apaziquone