A Phase I and Pharmacokinetic Study of Squalamine, a Novel Antiangiogenic Agent, in Patients with Advanced Cancers
Purpose: A Phase I study of squalamine, a novel antiangiogenic agent originally isolated from the dogfish shark Squalus acanthias , was conducted in patients with advanced cancers to: ( a ) determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of squalamine la...
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Veröffentlicht in: | Clinical cancer research 2001-12, Vol.7 (12), p.3912-3919 |
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Zusammenfassung: | Purpose: A Phase I study of squalamine, a novel antiangiogenic agent originally isolated from the dogfish shark Squalus acanthias , was conducted in patients with advanced cancers to: ( a ) determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of squalamine lactate when
given as a 120-h continuous i.v. infusion every two weeks; and ( b ) to obtain information on prolonged (>120-h) continuous i.v. infusions in patients who have tolerated 120-h infusions.
Experimental Design: A rapid dose escalation scheme was used that permitted intrapatient dose escalation. Three or more patients were treated
at each dose, of which at least one patient started treatment de novo at that dose. Once DLT was encountered, the dose was decreased by one dose level, and the duration of infusion was prolonged
from 10 up to 30 days in 5-day increments.
Results: Nineteen patients were treated at eight squalamine dose levels; the number of patients/dose level who received 120-h infusions
were [expressed as dose in mg/m 2 /day (number of patients initiated de novo at that dose/total number of patients treated at that dose)]: 6 (3/3), 12 (3/6), 24 (1/5), 48 (2/6), 96 (4/10), 192 (2/6),
384 (3/8), and 538 (1/5). DLT was encountered at 384 mg/m 2 /day (1/3 de novo patients, 5/8 total patients) and 538 mg/m 2 /day (1/1 de novo patients, 4/5 total patients) and consisted of hepatotoxicity, characterized by grade 3 transaminase elevations that resolved
3–11 days after ceasing squalamine infusion. Three patients did not experience hepatotoxicity when first treated at 384 mg/m 2 /day but developed DLT at the same dose when de-escalated from 538 mg/m 2 /day. Other toxicities included grade 1–3 fatigue, grade 1–2 nausea, anorexia, and neuromuscular symptoms. The maximum duration
of continuous i.v. infusion was 20 days at a dose rate of 192 mg/m 2 /day in one patient without adverse effects. Pharmacokinetic calculations revealed a linear relationship between area under
the curve or Cmax and squalamine dose rate up to 384 mg/m 2 /day, with a prolonged terminal squalamine persistence in patient plasma (median t 1/2 = 18 h; range, 8–48 h). Transient tumor responses were observed in a patient with synovial cell sarcoma and a patient with
breast carcinoma with cutaneous metastases.
Conclusions: The best tolerated dose rate of squalamine when administered as a 120-h continuous i.v. infusion was 192 mg/m 2 /day; however, patients without prior exposure to squalami |
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ISSN: | 1078-0432 1557-3265 |