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

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. AP5346 was administered as a 1-hour IV infusion on days 1, 8, 15 of a 28-day cycle. Seven dose levels (DL) were ex...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2007-09, Vol.60 (4), p.523-533
Main Authors: CAMPONE, Mario, RADEMAKER-LAKHAI, Jeany M, BENNOUNA, Jaafar, HOWELL, Stephen B, NOWOTNIK, David P, BEIJNEN, Jos H, SCHELLENS, Jan H. M
Format: Article
Language:English
Subjects:
Abnormalities
Adult
Aged
Allergic reactions
Anticancer properties
Antiemetics
Antineoplastic Agents
Antitumor activity
Biological and medical sciences
Cancer
Chemotherapy
Copolymers
Creatinine
Design of experiments
Diarrhea
Drug Administration Schedule
Drug Evaluation
Experimental design
Fatigue
Female
Genitourinary tract
Humans
Hypersensitivity
Kidneys
Male
Maximum Tolerated Dose
Medical sciences
Melanoma
Metastases
Middle Aged
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Nausea
Neoplasms
Neutropenia
Organoplatinum Compounds - administration & dosage
Organoplatinum Compounds - adverse effects
Organoplatinum Compounds - chemistry
Organoplatinum Compounds - pharmacokinetics
Ovarian cancer
Patients
Pharmacokinetics
Pharmacology
Pharmacology. Drug treatments
Platinum
Platinum - administration & dosage
Platinum - blood
Platinum compounds
Polymers
Polymers - administration & dosage
Prophylaxis
Renal insufficiency
Solid tumors
Toxicity
Tumors
Vomiting
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Summary: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. 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. 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. 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.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-006-0397-0