Safety, Pharmacokinetics, and Efficacy of CPX-1 Liposome Injection in Patients with Advanced Solid Tumors

• Published in: Clinical cancer research Vol. 15; no. 2; pp. 692 - 700
• Main Authors: BATIST, Gerald, GELMON, Karen A, CHI, Kim N, MILLER, Wilson H, CHIA, Stephen K. L, MAYER, Lawrence D, SWENSON, Christine E, JANOFF, Andrew S, LOUIE, Arthur C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.01.2009
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Area Under Curve; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cohort Studies; combination chemotherapy; Dose-Response Relationship, Drug; Female; Floxuridine - administration & dosage; Floxuridine - pharmacology; Humans; Liposomes - chemistry; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; molar ratios; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - therapy; Pharmacology. Drug treatments; Phase 1; Treatment Outcome; Tumors; Human; Solid tumor; Toxicity; Treatment efficiency; Liposome; Patient; Advanced stage; Drug carrier; Malignant tumor; Safety; Pharmacokinetics; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0515

Purpose: CPX-1 is a novel, liposome-encapsulated formulation of irinotecan and floxuridine designed to prolong in vitro optimized synergistic molar ratios of both drugs postinfusion. This open-label, single-arm, dose-escalating phase I study was designed to determine the maximum tolerated dose and pharmacokinetics of CPX-1 in patients with advanced solid tumors. Experimental Design: Patients received CPX-1 at 30, 60, 100, 150, 210, or 270 units/m 2 (1 unit = 1 mg irinotecan + 0.36 mg floxuridine) infused over 90 minutes every 14 days in 28-day cycles. Pharmacokinetic samples were collected on days 1 and 15 of cycle 1. Results: Thirty-three patients were enrolled, treated, and evaluated for safety; 30 patients were evaluated for response. A 1:1 plasma irinotecan to floxuridine molar ratio was maintained for 8 to 12 hours. Grade 3/4 toxicities included diarrhea (24.2%), neutropenia (12.1%), and hypokalemia (12.1%); 1 patient (270 units/m 2 ) died of persistent diarrhea, which led to dehydration and renal failure (grade 5). Partial response occurred in 3 (12%) of the 25 subjects evaluated through Response Evaluation Criteria in Solid Tumors. Progression-free survival lasting >6 months occurred in 9 patients, 6 with colorectal cancer. Among 15 colorectal cancer patients (10 with prior irinotecan), the calculated median progression-free survival was 5.4 months; 11 patients (72.7%) achieved disease control and 2 patients (13%) had partial response. Conclusions: Outpatient CPX-1 was well tolerated and antitumor activity was shown in patients with advanced solid tumors. The recommended dose for future studies is 210 units/m 2 . This is the first clinical evaluation of fixed drug ratio dosing designed to maintain synergistic molar ratios for enhanced therapeutic benefit.