A phase I and pharmacokinetic study of VNP40101M, a new alkylating agent, in patients with advanced or metastatic cancer.
OBJECTIVE
VNP40101M is a new alkylating agent that demonstrated broad anti-tumor activity in murine tumor models. A phase I trial was initiated to determine the toxicities, maximum tolerated dose, and pharmacokinetics of VNP40101M by short IV infusion.


METHODS
The starting dose was 3 mg/m(2) every four weeks, and was escalated in successive cohorts as follows: 6, 12, 24, 40, 60, 80, and 100 mg/m(2). Beyond 100 mg/m(2), dose increments were 25%. Initially, 1-2 patients were assigned to a dose level. Intra-patient dose escalation was permitted. With the first instance of a drug-related > or = grade 2 adverse event, all dose levels required assessment of 3-6 patients. Pharmacokinetic parameters were assessed in the first cycle and any cycle with a change in dose.


RESULTS
Twenty-six patients in 13 dose levels ranging from 3-305 mg/m(2) were evaluated. Dose-related thrombocytopenia was the major toxicity, with the nadir occurring at a median of day 27. At 305 mg/m(2), six of eight patients developed grade 3 thrombocytopenia, including one event that met the definition for DLT. Other dose-related toxicities included moderate granulocytopenia, anemia, and a mild infusion-related syndrome consisting of acute headache and facial flushing. The granulocyte nadir occurred at a median of day 34, and recovery of both thrombocytopenia and neutropenia to < grade 2 occurred at a median of day 43. VNP40101M peak plasma concentrations and AUC were linear with dose. The elimination half-life was short and estimated to be approximately 15 minutes.


CONCLUSIONS
The MTD and recommended dose for phase II trials is 305 mg/m(2) every six weeks. Phase II trials in less heavily pre-treated patient populations are warranted.
Murren
John
J
Yale-New Haven Cancer Center, New Haven, CT, USA.
Modiano
Manuel
M
Kummar
Shivaani
S
Clairmont
Caroline
C
Egorin
Merrill
M
Chu
Edward
E
Sznol
Mario
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D006834:Hydrazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced
D000970:Antineoplastic Agents; D006834:Hydrazines; D013449:Sulfonamides; C483604:laromustine
Cancer Res. 2002 May 15;62(10):2731-5
12019144
Int J Toxicol. 2002 Jan-Feb;21(1):23-38
11936896
Adv Enzyme Regul. 1993;33:19-26
8356908
Cancer Res. 2001 Apr 1;61(7):3033-8
11306484
J Med Chem. 1996 Feb 2;39(3):796-801
8576923
Biochem Pharmacol. 1979 May 15;28(10):1631-8
383080
J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
10655437
Clin Cancer Res. 2004 May 1;10(9):2908-17
15131024
Biochem Pharmacol. 1988 Mar 15;37(6):1061-6
3355582
Cancer Res. 1997 Sep 15;57(18):3895-8
9307267
Biochem Pharmacol. 2000 Feb 1;59(3):283-91
10609557
Cancer Biochem Biophys. 1989 Oct;10(4):365-75
2620294
J Med Chem. 1987 Nov;30(11):2157-61
3669023
Anticancer Drugs. 2002 Jun;13(5):511-9
12045463