Phase I and pharmacokinetic trial of AP5346, a DACH-platinum-polymer conjugate, administered weekly for three out of every 4 weeks to advanced solid tumor patients.

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Campone M, Rademaker-Lakhai JM, Bennouna J, Howell SB, Nowotnik DP, Beijnen JH, Schellens JH

Phase I and pharmacokinetic trial of AP5346, a DACH-platinum-polymer conjugate, administered weekly for three out of every 4 weeks to advanced solid tumor patients.

Cancer Chemother Pharmacol. 2007 Sep;60(4):523-33. Epub 2007 Feb 17.

PubMed ID
17308894 [ View in PubMed
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Abstract

PURPOSE: To determine the maximum tolerated dose (MTD) safety and pharmacokinetics of AP5346, a copolymer-linked 1,2-diaminocyclohexane(DACH)-platinum compound, in advanced solid tumor patients. EXPERIMENTAL DESIGN: AP5346 was administered as a 1-hour IV infusion on days 1, 8, 15 of a 28-day cycle. Seven dose levels (DL) were explored: DL1: 40 mg platinum (Pt)/m2 (1 patient); DL2: 80 (1); DL3: 160 (3); DL4: 320 (3); DL5: 640 (6); DL6: 850 (6); DL7: 1280 (6) mg Pt/m2. Dose-limiting toxicity (DLT) included infusion omission and cycle delay >2 weeks. RESULTS: Twenty-six patients received 41 cycles (median 1/patient, range 1-4). No DLT occurred in DL 1-4; 1 DLT in DL5 (RD; renal insufficiency), two in DL6 (MTD; vomiting; fatigue) and 5 in DL7 (neutropenic infection with diarrhea; neutropenia with vomiting; vomiting with fatigue; renal insufficiency; and fatigue). Two deaths occurred due to renal insufficiency (DL5); in both cases patients had disease in or surrounding genitourinary tract whose contribution could not be accurately discerned. Grade 1-2 creatinine abnormalities occurred in seven patients. Nausea/emesis was frequent (92%), reaching grade 3-4 (23%), but controlled by antiemetics. Grade 2-4 allergic reactions occurred in 4 patients. Cmax and AUC increased linearly with dose for total plasma platinum and ultrafiltrate platinum. Antitumor activity included two partial responses in metastatic melanoma and ovarian cancer, and an additional CA-125 normalization (from 133 IU/l) in a suspected ovarian cancer. CONCLUSIONS: AP5346 administered weekly for 3 weeks out of every four is tolerated up to a dose of 640 mg Pt/m2 on the first cycle when given with antiemetic prophylaxis. The pharmacokinetics of AP5346 indicates a prolonged half-life, and evidence of antitumor activity was observed at this dose level.

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