A Cancer Research UK Randomised, Multicentre, Phase II Trial of the DNAhypomethylating Agent, 5-Aza-2'-Deoxycytidine (Decitabine) Given Intravenously in Combination With Carboplatin, Versus Carboplatin Alone Given 4 Weekly in Patients With Progressive, Advanced Ovarian Cancer
- To compare the response rate in patients with progressive, advanced ovarian epithelial
cancer, fallopian tube cancer, or primary peritoneal cancer who have methylated hMLH1
DNA in plasma treated with carboplatin with vs without decitabine.
- To compare the response rate in all patients (regardless of methylation status) treated
with these regimens.
- To compare the progression-free survival and overall survival of patients treated with
- To compare the safety and tolerability of these regimens.
- To determine the feasibility of combining decitabine with carboplatin.
- To determine the incidence of hypersensitivity reactions to carboplatin.
- To study the relationship between peak plasma levels of decitabine and global or CpG
island specific methylation.
- To study the relationship between global and gene specific methylation in peripheral
blood mononuclear cells and response.
- To correlate the methylation status of genes associated with drug resistance detected
in plasma DNA with response.
- To determine the sensitivity and specificity of methylation of genes associated with
drug resistance detected in plasma DNA as a predictor of methylation status in tumor
cells isolated from ascites or tumor biopsy.
- To study methylation and expression of genes in tumor cells isolated from ascites or
tumor biopsy before and after treatment with decitabine and/or carboplatin.
- To investigate any correlation between methylation and expression of genes in surrogate
tissues, body fluids, or tumor cells and response or progression-free survival.
- To examine markers of cell death in plasma.
- To compare the methylation in tumor taken at the time of presentation vs at the time of
OUTLINE: This is a multicenter study. Patients are stratified according to prior first-line
treatment (platinum alone vs platinum and taxane vs platinum and other combination), WHO
performance status (0 vs 1 vs 2), measurable disease criteria (RECIST criteria vs CA-125
criteria vs both), participating center, and the number of prior platinum-based regimens (1
vs 2). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive carboplatin IV over 30-60 minutes on day 1.
- Arm II: Patients receive decitabine IV over 6 hours on day 1 and carboplatin IV over
30-60 minutes on day 8.
In both arms, treatment repeats every 28 days for up to 8 courses in the absence of disease
progression or unacceptable toxicity.
Patients undergo blood sample collection periodically for pharmacodynamic studies. Samples
are assessed for methylation of hMLH1 by methylation-specific PCR; global DNA methylation by
high performance liquid chromatography (HPLC) ; methylation of the MAGE-1A gene promoter by
methylation-specific PCR or bisulfite pyrosequencing; and markers of apoptosis by ELISA.
Pharmacokinetic studies of decitabine are also performed using blood samples from patients
randomized to arm II. Ascitic fluid and/or tumor tissue samples may also be collected for
After completion of study treatment, patients are followed at 28 days and then every 2
Peer Reviewed and Funded or Endorsed by Cancer Research UK.
Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment
Response rate (partial response [PR] or complete response [CR]) in patients with methylated hMLH1 DNA in plasma as measured by RECIST criteria or CA-125 criteria
Stanley B. Kaye, MD, FRCP
Royal Marsden NHS Foundation Trust