Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand Up 2 cancer study

Abstract

PurposeTherapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies.Experimental DesignWe conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10. An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease. A 2nd cohort with added eligibility restrictions was accrued: prior therapies were limited to no more than 2 or 3 (KRAS-mutated and KRAS-wildtype cancers, respectively) and <30% of liver involvement. The primary endpoint was RECIST response. Serial biopsies were performed at baseline and after 2 cycles of therapy.ResultsForty-seven patients were enrolled (24:Cohort 1, 23:Cohort 2). Patients were heavily pre-treated (median prior therapies 4: Cohort 1 and 2.5: cohort 2). No responses were observed. Median progression-free survival was 1.9 months; overall survival was 5.6 and 8.3 months in Cohorts 1 and 2, respectively. Toxicity was tolerable and as expected. Unsupervised cluster analysis of serial tumor biopsies suggested greater DNA demethylation in patients with PFS above the median.ConclusionIn this first trial of CRC patients with combination epigenetic therapy, we show tolerable therapy without significant clinical activity as determined by RECIST responses. Reversal of hypermethylation was seen in a subset of patients and correlated with improved PFS.

Colorectal cancer: epigenetic alterations and their clinical implications

“…Unfortunately, two subsequent and more recent studies have not found any clinical activity. The first study investigated the combination of 5-Aza-CR and CAPOX (capecitabine + oxaliplatin) in CIMP-high CRC patients (101), and the second study evaluated the combination of 5-Aza-CR and entinostat, a histone deacetylase inhibitor (102). …”

Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells

“…In the clinic, these inhibitors (DNMTi’s)—when combined other epigenetic modulators like histone deacetylase inhibitors (HDACi’s)—may yield enhanced effects, in part through augmenting re-expression of genes abnormally silenced in association with promoter hypermethylation. In this regard, there are signs in clinical trials in small subsets of patients employing epigenetic compounds for treating solid tumors (including lung and breast cancers) of improved overall survival [17–19]. Experience with these agents for treating hematologic neoplasms has primarily shown efficacy to the point that DNMTi's and HDACi's are FDA approved for myelodysplasia/acute myeloid leukemia (MDS/AML, and T-cell cutaneous lymphoma respectively [12, 20, 21].…”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…The treatment induced severe toxicity resulting in poor tolerability. [122] A number of promising chromatin destabilizing compounds have been reported, such as curaxin, a molecule targeting the facilitates chromatin transcription (FACT) complex, that is, a heterodimeric protein complex regulating eukaryotic transcription elongation, causing nucleosome destabilization without damaging the DNA primary structure. No objective response was observed during and after the treatment.…”

“…[126,127] A phase II clinical study of pembrolizumab for the treatment of advanced colorectal carcinoma led to the FDA approval of this drug. [121,122] Even more interesting are promising results on drug applications of combination treatments of chemotherapeutic platinum and ruthenium complexes with the immune checkpoint inhibitors programmed death (ligand)-1 (PD-L1) and CTLA-4 ( Figure 3B). Therefore, it would be interesting to see whether the impact of this genotype on the immune system abrogates as well ruthenium-based drug treatment.…”