Phase I trial of intravenous thymidine and carboplatin in patients with advanced cancer.
OBJECTIVE
To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m(2) in a phase I trial.


METHODS
Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone. Carboplatin was administered over 20 minutes at hour 20 of the 24-hour thymidine infusion. The carboplatin dose was escalated in patient groups: 200 mg/m(2) (n = 3); 300 mg/m(2) (n = 7); 350 mg/m(2) (n = 4); 400 mg/m(2) (n = 3); 480 mg/m(2) (n = 10); and 576 mg/m(2) (n = 5). At the maximum-tolerated dose (480 mg/m(2)), five patients received combined therapy first and carboplatin alone second, and five patients received carboplatin first and combined therapy second. Maintenance therapy for stable or responding patients was combined therapy.


RESULTS
Evaluation demonstrated a trend toward thymidine protection of carboplatin-induced treatment-limiting thrombocytopenia. Neutropenia with carboplatin alone or in combination was negligible. Thymidine alone had no myelosuppressive effects and produced reversible grade 1 or 2 nausea and vomiting (57%), headache (25%), and grade 1 neurotoxicity (22%). Thymidine did not enhance expected carboplatin toxicities. There was no therapy-related infection or bleeding. Analysis of platinum in plasma ultrafiltrate and urine showed no effect by thymidine. Similarly, thymidine pharmacokinetics was not affected by carboplatin. As predicted, nicotinamide adenine dinucleotide levels in peripheral lymphocytes were increased during exposure to carboplatin and/or thymidine but were decreased by carboplatin alone. In three patients with high-grade glioma, responses included one complete remission (21 months) and one partial remission (14 months) at the 480-mg/m(2)-dose level, and disease stabilization (7 months) at the 400-mg/m(2-dose) level. A minor response was observed in a patient with metastatic colon cancer (5 months) at the 480-mg/m(2)-dose level.


CONCLUSIONS
The combination of carboplatin and thymidine as described is well tolerated. The data presented have resulted in a phase II study by the North American Brain Tumor Consortium.
Robins
H I
HI
University of Wisconsin Comprehensive Cancer Center, Madison, WI 53792, USA. hirobins@facstaff.wisc.edu
Tutsch
K
K
Katschinski
D M
DM
Jacobson
E
E
Mehta
M
M
Olsen
M
M
Cohen
J D
JD
Tiggelaar
C L
CL
Arzoomanian
R Z
RZ
Alberti
D
D
Feierabend
C
C
Wilding
G
G
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009243:NAD / Q000097:blood; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D013921:Thrombocytopenia / Q000139:chemically induced; D013936:Thymidine / Q000008:administration & dosage*; D013941:Thymine / Q000097:blood; D014839:Vomiting / Q000139:chemically induced
D000970:Antineoplastic Agents; D009243:NAD; D016190:Carboplatin; D013941:Thymine; D013936:Thymidine