Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors.
OBJECTIVE
The DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (decitabine) induces DNA demethylation and re-expression of epigenetically silenced genes, and increases carboplatin sensitivity of tumor xenograft models. We designed a clinical study to determine the feasibility of delivering a dose of decitabine, combined with carboplatin, that would be capable of producing equivalent biologic effects in patients with solid tumors.


METHODS
In a two-stage design, 33 patients received escalating doses of decitabine administered as a 6-hour infusion on day 1 followed by carboplatin, area under the concentration-time curve (AUC) 5 (cohort 1) and AUC 6 (cohort 2), on day 8 of a 28-day cycle. Pharmacodynamic analyses included 5-methyl-2'-deoxycytidine levels, MAGE1A CpG island methylation, and fetal hemoglobin (HbF) expression.


RESULTS
The major toxicity was myelosuppression. Dose limiting toxicities, prolonged grade 4 neutropenia (one patient), and sepsis and grade 3 anorexia/fatigue (one patient), were seen in two of four patients treated with decitabine 135 mg/m2 and carboplatin AUC 5. Dose limiting toxicity comprising neutropenic sepsis (one patient) and grade 3 fatigue (one patient) was seen in two of 10 patients treated at decitabine 90 mg/m2 and carboplatin AUC 6. Decitabine induced dose-dependent, reversible demethylation in peripheral-blood cells (PBCs) maximally at day 10. Furthermore, decitabine 90 mg/m2 induced demethylation of the MAGE1A CpG island in PBCs, buccal cells, and tumor biopsies, as well as elevation of HbF expression.


CONCLUSIONS
Decitabine can be combined safely with carboplatin at a dose and schedule that causes epigenetic changes equivalent to or greater than that observed in mice with carboplatin-sensitized xenografts. The recommended dose/schedule for phase II trials is decitabine 90 mg/m2 (day 1) followed by carboplatin AUC 6 (day 8) every 28 days.
Appleton
Kim
K
Centre for Oncology and Applied Pharmacology, Glasgow University, Cancer Research UK Beatson Laboratories, Glasgow, United Kingdom.
Mackay
Helen J
HJ
Judson
Ian
I
Plumb
Jane A
JA
McCormick
Carol
C
Strathdee
Gordon
G
Lee
Chooi
C
Barrett
Sophie
S
Reade
Sarah
S
Jadayel
Dalal
D
Tang
Adrian
A
Bellenger
Katharine
K
Mackay
Lynsay
L
Setanoians
Albert
A
Schätzlein
Andreas
A
Twelves
Chris
C
Kaye
Stanley B
SB
Brown
Robert
R
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000077209:Decitabine; D016190:Carboplatin; D015254:DNA Modification Methylases; D001374:Azacitidine