Phase I and pharmacokinetic study of ecteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies.
Ecteinascidin 743 (ET-743) is a cytotoxic tetrahydroisoquinoline alkaloid that covalently binds to DNA in the minor groove. The in vitro chemosensitivity of cancer cells to ET-743 is markedly enhanced by prolonging the duration of exposure to the drug. A Phase I study of ET-743 given as a 72-h continuous 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 Cooperative Oncology Group performance status < or = 1, 20 patients; and (e) two prior regimens of chemotherapy, 7 patients. Dose limiting toxicity (DLT) was defined by typical criteria, except that grade 3 transaminitis did not constitute a DLT. There were no DLTs in the six patients evaluated at the first two dose levels of 600 and 900 microg/m2. Reversible grade 4 transaminitis occurred in two of nine patients after treatment with the first cycle of therapy at the third dose level of 1200 microg/m2. Another patient experienced grade 4 rhabdomyolysis, renal failure requiring hemodialysis, grade 4 neutropenia, and grade 3 thrombocytopenia during the second cycle of therapy with this dose. The maximum tolerated dose was 1200 microg/m2, and an additional six patients were enrolled at an intermediate dose level of 1050 microg/m2. This well-tolerated dose was established as the recommended Phase II dose. The disposition of ET-743 was distinctly biexponential, and a departure from linear pharmacokinetic behavior was evident at the 1200-microg/m2 dose level. Pharmacokinetic parameters determined at 1050 microg/m2 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/m2. Prolonged systemic exposure to concentrations of the agent that are cytotoxic in vitro were achieved. Toxicity of the drug is clearly schedule-dependent, because increasing the duration of infusion from 3 or 24 h to 72 h results in decreased myelosuppression and comparable hepatotoxicity. Although there were no objective responses to therapy, clear evidence of antitumor activity was observed in a patient with epithelioid mesothelioma, as confirmed by positron emission tomography studies. A Phase II trial to assess the efficacy of ET-743 against this highly refractory neoplasm has been initiated on the basis of this observation. The therapeutically optimal administration schedule remains to be established, inasmuch as there have been indications of activity against a variety of tumors during Phase I studies when the drug was infused over times ranging from 1 to 72 h. Characterizing the pharmacokinetics of ET-743 during the course of Phase II trials and Phase I combination studies is recommended to assure that this promising new anticancer drug can be used with an acceptable margin of safety.
Ryan
D P
DP
Massachusetts General Hospital, Boston, Massachusetts 02114, USA. dpryan@partners.org
Supko
J G
JG
Eder
J P
JP
Seiden
M V
MV
Demetri
G
G
Lynch
T J
TJ
Fischman
A J
AJ
Davis
J
J
Jimeno
J
J
Clark
J W
JW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004149:Dioxoles / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000378:metabolism*; D044005:Tetrahydroisoquinolines; D013997:Time Factors; D018675:Toxicity Tests; D000077606:Trabectedin
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077606:Trabectedin