Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors: a pediatric brain tumor consortium study.
OBJECTIVE
VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain tumors.


METHODS
VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently in patients stratified based on intensity of prior therapy (moderately pretreated, stratum I; heavily pretreated, stratum II). Correlative studies included pharmacokinetics and measurement of O(6)-alkylguanine-DNA alkyl transferase levels in peripheral blood mononuclear cells before and after treatment.


RESULTS
Forty-one eligible patients (stratum I, 19; stratum II, 22) were enrolled on this study. The dose-limiting toxicity in 35 evaluable patients was myelosuppression, which occurred in 4 of 16 patients in stratum I and 3 of 19 patients in stratum II. Pharmacokinetic studies showed a median terminal half-life of 30 min (range, 14-39.5). The maximum tolerated dose in stratum I and II were 45 and 30 mg/m(2)/d daily for 5 days every 6 weeks, respectively. Peripheral blood mononuclear cells alkylguanine alkyl transferase levels did not decrease significantly after VNP40101M treatment. Central imaging review confirmed that three patients had stable disease for a median of 45 weeks (range, 37-61+) after therapy.


CONCLUSIONS
The recommended dose of VNP40101M for phase II studies in children with brain tumors is 45 mg/m(2)/d in moderately pretreated and 30 mg/m(2)/d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.
Gururangan
Sridharan
S
The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA. gurur002@mc.duke.edu
Turner
Christopher D
CD
Stewart
Clinton F
CF
O'Shaughnessy
Melinda
M
Kocak
Mehmet
M
Poussaint
Tina Young
TY
Phillips
Peter C
PC
Goldman
Stewart
S
Packer
Roger
R
Pollack
Ian F
IF
Blaney
Susan M
SM
Karsten
Verena
V
Gerson
Stanton L
SL
Boyett
James M
JM
Friedman
Henry S
HS
Kun
Larry E
LE
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007223:Infant; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D006834:Hydrazines; D013449:Sulfonamides; C483604:laromustine