Publication | Closed Access
A phase II study of decitabine and carboplatin in recurrent platinum (Pt)-resistant ovarian cancer (OC).
14
Citations
0
References
2011
Year
Pbmc DnaCancer ManagementAberrant Dna MethylationGynecologyPathologyPhase Ii StudyTumor BiologyOvarian CancerAnti-cancer AgentMolecular DiagnosticsCancer ResearchMolecular OncologyMedicineRecurrent OcCancer TreatmentCancer GeneticsPharmacologyRecurrent PlatinumCancer GenomicsOncology
5011 Background: Aberrant DNA methylation is a hallmark of cancer. Preclinical studies showed that hypomethylating agents reverse Pt resistance, supporting testing low dose decitabine (D) combined with carboplatin (Cp), in recurrent Pt-resistant OC. Methods: Key eligibility included recurrent OC, Pt-resistant or Pt-refractory, measurable (RECIST) or detectable (GCIC), normal organ function, no limit on prior therapy. Treatment was D 10mg/m2 d1-5 prior to Cb (AUC 5, d8), based on phase I results. Primary endpoint was response rate (RR). Secondary endpoints were clinical benefit rate (CBR), progression free survival (PFS), safety, and overall survival (OS). PBMCs, plasma, and tumor biopsies were collected on d1 and d8 for assessment of biomarkers correlating with PFS. Genome-wide DNA methylation and gene expression profiling of tumors used Infinium and Affymetrix U133A arrays. Global (LINE-1) and gene-specific DNA methylation and expression levels were measured by pyrosequencing and qRT-PCR. Data analysis included linear mixed-effects models, statistical analysis for microarrays (SAM), clustering, functional pathway prediction, and gene ontology. Results: 17 patients were enrolled. Median age was 60 (45-83), median number of prior regimens was 5 (1-10). 15 patients had Pt-resistant and 2 Pt-refractory OC; 16 had measurable, 1, detectable OC. 1CR (GCIC) and 5 PRs (RECIST) were observed (RR=35%, 95% CI: 14%-62%). 6 other patients had stable disease. CBR was 70% and median PFS was 309 days. 9 patients (53%) were free of progression at 6 mos. Most common grade 3-4 AEs were neutropenia (23%), thrombocytopenia, leukopenia, anemia (11% each). LINE-1 methylation was decreased on d8 vs. d1 in PBMC DNA (P<0.05). Demethylation of OC-associated genes MLH1, RASSF1a, HOXA10, and HOXA11,in tumors from d1 to d8 is positively correlated with PFS (P<0.05). Inflammatory response genes were altered in tumors on d8 vs. d1, and expression of pathways involved in proliferation, transformation, survival, and DNA repair were reduced on d1, correlating with PFS (P<0.01). Conclusions: Low-dose D alters DNA methylation restoring sensitivity to Cp in patients with heavily pre-treated OC, resulting in a high RR and prolonged PFS.