Dp. Ryan et al., Phase I and pharmacokinetic study of esteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies, CLIN CANC R, 7(2), 2001, pp. 231-242
Ecteinascidin 743 (ET-743) is a cytotoxic tetrahydroisoquinoline alkaloid t
hat covalently binds to DNA in the minor groove. The ill vitro chemosensiti
vity of cancer cells to ET-743 is markedly enhanced by prolonging the durat
ion of exposure to the drug. A Phase I study of ET-743 given as a 72-h cont
inuous i.v. infusion every 21 days was performed. Characteristics of the 21
adult patients with refractory solid tumors enrolled in the study were as
follows: (a) 12 men; (b) 9 women; (c) median age, 59 years; (d) Eastern Coo
perative Oncology Group performance status less than or equal to1, 20 patie
nts; and (e) two prior regimens of chemotherapy, 7 patients. Dose limiting
toxicity (DLT) was defined by typical criteria, except that grade 3 transam
initis did not constitute a DLT, There were no DLTs in the six patients eva
luated at the first two dose levels of 600 and 900 mug/m(2), Reversible gra
de 4 transaminitis occurred in two of nine patients after treatment with th
e first cycle of therapy at the third dose level of 1200 mug/m(2). Another
patient experienced grade 4 rhabdomyolysis, renal failure requiring hemodia
lysis, grade 4 neutropenia, and grade 3 thrombocytopenia during the second
cycle of therapy with this dose. The maximum tolerated dose was 1200 mug/m(
2), and an additional six patients were enrolled at an intermediate dose le
vel of 1050 mug/m(2). This well-tolerated dose was established as the recom
mended Phase II dose. The disposition of ET-743 was distinctly biexponentia
l, and a departure from linear pharmacokinetic behavior was evident at the
1200-mug/m(2) dose level. Pharmacokinetic parameters determined at 1050 mug
/m(2) were (mean +/- SD): maximum plasma concentration, 318 +/- 147 pg/ml;
initial disposition phase half-life, 9.0 +/- 10.3 min; terminal phase half-
life, 69.0 +/- 56.7 h; and total plasma clearance, 28.4 +/- 22.5 liters/h/m
(2). Prolonged systemic exposure to concentrations of the agent that are cy
totoxic in vitro were achieved. Toxicity of the drug is clearly schedule-de
pendent, because increasing the duration of infusion from 3 or 24 h to 72 h
results in decreased myelosuppression and comparable hepatotoxicity, Altho
ugh there were no objective responses to therapy, clear evidence of antitum
or activity was observed in a patient with epithelioid mesothelioma, as con
firmed by positron emission tomography studies. A Phase II trial to assess
the efficacy of ET-743 against this highly refractory neoplasm has been ini
tiated on the basis of this observation. The therapeutically optimal admini
stration schedule remains to be established, inasmuch as there have been in
dications of activity against a variety of tumors during Phase I studies wh
en the drug was infused over times ranging from 1 to 72 h, Characterizing t
he pharmacokinetics of ET-743 during the course of Phase II trials and Phas
e I combination studies is recommended to assure that this promising new an
ticancer drug can be used with an acceptable margin of safety.