TY - JOUR
T1 - A phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II)in patients with advanced malignancies
AU - Kim, Noe Kyeong
AU - Kim, Tae You
AU - Shin, Sang Goo
AU - Park, Young Iee
AU - Lee, Jung Ae
AU - Cho, Yong Baik
AU - Kim, Key H.
AU - Kim, Dae Kee
AU - Heo, Dae Seog
AU - Bang, Yung Jue
PY - 2001/4/15
Y1 - 2001/4/15
N2 - BACKGROUND. A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-l,3-dioxolane] platinum(II) (SKI 2053R), a new platinum derivative, was performed to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetic profile of SKI 2053R in patients with advanced, refractory malignancies. METHODS. Twenty-one patients were entered into the study. SKI 2053R was administered with an intravenous infusion over 1 hour every 4 weeks. The SKI 2053R dose was escalated from 40 mg/m2 up to 480 mg/m2 using a modified Fibonacci scheme. Pharmacokinetic analysis was done in all patients to determine the total and ultrafiltrable platinum concentrations in both the plasma and the urine. RESULTS. All patients were evaluable for toxicity and response. There was no significant toxicity with dosages up to 360 mg/m2. At 480 mg/m2, two of three patients developed Grade 4 hepatotoxicity, Grade 3 leukopenia and thrombocytopenia, and Grade 2 azotemia and proteinuria. Other toxicity included nausea and emesis, but it was controlled with antiemetics. SKI 2053R did not cause significant neurotoxicity or mucositis. There were 4 patients with stable disease among the 21 patients. Plasma decay of the total and free platinum concentrations was best fitted by using a two-compartment, open model. The terminal plasma half-life of the total platinum after SKI 2053R administration ranged from 63.4 hours to 114.1 hours in dosages ranging from 40 mg/m2 to 480 mg/m2 without significant dose dependency. However, the terminal plasma half-life of the free platinum concentration showed a significant dose dependent, incremental pattern. The renal excretion of SKI 2053R measured as platinum ranged from 49% to 75% of the administered dose. CONCLUSIONS. The MTD of SKI 2053R was 480 mg/m2. The major DLTs were hepatotoxicity, nephrotoxicity, and myelosuppression. The recommended starting dose for a subsequent Phase II study is 360 mg/m2 once every 4 weeks.
AB - BACKGROUND. A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-l,3-dioxolane] platinum(II) (SKI 2053R), a new platinum derivative, was performed to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetic profile of SKI 2053R in patients with advanced, refractory malignancies. METHODS. Twenty-one patients were entered into the study. SKI 2053R was administered with an intravenous infusion over 1 hour every 4 weeks. The SKI 2053R dose was escalated from 40 mg/m2 up to 480 mg/m2 using a modified Fibonacci scheme. Pharmacokinetic analysis was done in all patients to determine the total and ultrafiltrable platinum concentrations in both the plasma and the urine. RESULTS. All patients were evaluable for toxicity and response. There was no significant toxicity with dosages up to 360 mg/m2. At 480 mg/m2, two of three patients developed Grade 4 hepatotoxicity, Grade 3 leukopenia and thrombocytopenia, and Grade 2 azotemia and proteinuria. Other toxicity included nausea and emesis, but it was controlled with antiemetics. SKI 2053R did not cause significant neurotoxicity or mucositis. There were 4 patients with stable disease among the 21 patients. Plasma decay of the total and free platinum concentrations was best fitted by using a two-compartment, open model. The terminal plasma half-life of the total platinum after SKI 2053R administration ranged from 63.4 hours to 114.1 hours in dosages ranging from 40 mg/m2 to 480 mg/m2 without significant dose dependency. However, the terminal plasma half-life of the free platinum concentration showed a significant dose dependent, incremental pattern. The renal excretion of SKI 2053R measured as platinum ranged from 49% to 75% of the administered dose. CONCLUSIONS. The MTD of SKI 2053R was 480 mg/m2. The major DLTs were hepatotoxicity, nephrotoxicity, and myelosuppression. The recommended starting dose for a subsequent Phase II study is 360 mg/m2 once every 4 weeks.
KW - Dose limiting toxicity
KW - Maximum tolerated dose
KW - Pharmacokinetics
KW - Platinum derivative
UR - http://www.scopus.com/inward/record.url?scp=0035871359&partnerID=8YFLogxK
U2 - 10.1002/1097-0142(20010415)91:8<1549::AID-CNCR1164>3.0.CO;2-2
DO - 10.1002/1097-0142(20010415)91:8<1549::AID-CNCR1164>3.0.CO;2-2
M3 - Article
C2 - 11301404
AN - SCOPUS:0035871359
SN - 0008-543X
VL - 91
SP - 1549
EP - 1556
JO - Cancer
JF - Cancer
IS - 8
ER -
