Summary

• Hepatocellular Carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer death worldwide (1)
• Sorafenib treatment improves survival in advanced disease, but no therapy has demonstrated significant activity after progression on sorafenib (2)
• SGI-110, a dinucleotide of decitabine and deoxyguanosine (Fig 1), affords increased in vivo exposure of decitabine by protecting it from deamination due to slow release upon SQ injection
• In Phase 1 AML/MDS studies, SGI-110 provides longer exposure and more potent hypomethylation compared to decitabine (3)
•  Preclinical studies demonstrated:
  • In vitro, SGI-110 induced significant hypomethylation of tumor suppressor genes RASSF1A, SOCS1 and DAB2IP in human HCC cell lines HuH7 an HepG2 and resulted in a potent reduction in colony formation at low nanomolar concentrations of SGI-110 (4)
  • SGI-110 efficiently sensitizes HCC cells and xenografts to oxaliplatin by inhibiting distinct signaling pathways, allowing for high antitumor activity without systemic toxicity (Kuang et al., AACR 2015, Abst 2533)
  • Numerous epigenetic alterations accumulate during hepatocarcinogenesis, leading to activation of oncogenes or loss of tumor suppressor genes in HCC. Specifically, increased methylation of genes implicated in HCC tumorigenesis has been associated with pathogenesis and poor outcome
• In this study, we evaluated therapeutic and biologic effects of SGI-110, a hypomethylating agent (HMA)in patients with HCC. PK and PD results of this open-label, phase 2 study in patients with HCC are presented here

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2015: AACR PD and PK Results of SGI-110 in Patients with HCC after Progression on Sorafenib

Summary

SGI-110 (guadecitabine) is a dinucleotide of decitabine and deoxyguanosine and a novel subcutaneous (SQ) hypomethylating agent. In a previous Phase 1 (dose escalation) study, we found in relapsed/refractory (r/r) AML patients who were treated with SGI-110 (36 mg/m2-125 mg/m2) subcutaneously (SQ) daily for 5 days a correlation between low LINE-1 demethylation induction, a three gene expression classifier score (low CDA, low P15 and high DNMT3B) and resistance to SGI-110. Here, we analyzed r/r AML patients (n=122) from Phase 1/2 studies treated at harmacologically effective doses of SGI-110 looking for determinants of hypomethylation and response. Phase 1 patients with r/r AML (n=27) who were treated at a therapeutic dose range of SGI-110 (36 mg/m2 – 125 mg/m2) by SQ daily for 5 days. Phase 2 study r/r AML patients received 60 mg/m2 SQ daily for 5 days (n=22), 90 mg/m2 SQ daily for 5 days (n=25) and 60 mg/m2 SQ daily for 10 days (n=48). Global DNA methylation at pre/post treatment was estimated by bisulfite-pyrosequencing for the LINE-1 repetitive sequence. We also examined expression of a panel of genes (CDA, P15, P21, DNMT3B, DNMT3A, DNMT1, and CTCF) at baseline by quantitative RT-PCR.

We analyzed samples from 122 patients with r/r AML. Median age was 59.6 (range, 23–86), 75 were males (61.5%). Overall, peak LINE-1 demethylation generally occurred on day 8 after daily x 5 treatment, or on day 8 or 15 after daily x 10 treatment(Fig.1). In individual patients, peak LINE-1 demethylation ranged from +4.9% to -56.3%. In 122 r/r AML patients, 28 showed overall remission (23.0 %, 15 CR and 13 CRi/CRp). Unsupervised clustering by expression of a panel of genes at baseline grouped the patients into two clusters: A (N=95, response rate = 29.5 %) and B (N=27, response rate = 0 %).

Cluster B is characterized by high DNMT3b expression, low P15 expression, low CDA expression (average Z-score 1.44 ± 0.26 in cluster B compared to -1.26 ± 0.14 in clusters A, p<0.0001) and reduced demethylation (demethylation average -14.2 ± 1.90 % in cluster B compared to -26.1 ± 1.38 % in clusters A, p<0.0001)(Fig. 2). Peak LINE-1 demethylation was significantly higher in responders than non-responders (average demethylation -32.33 ± 1.91 % in responders compared to -21.25 ± 1.42 % in non-responders, p=0.0001). (Fig.3) A three gene classifier score (low CDA, low P15 and high DNMT3B) was associated with low LINE-1 demethylation (R=0.27, p=0.0034) as well as resistance to SGI-110 (mean Z-score -0.75 in non-responders compared to -1.67
in responders, p=0.014)(Fig.4).

In a phase 1/2 study of SGI-110, we identified in r/r AML patients a gene expression signature (high DNMT3B, low P15, and low CDA) associated with reduced demethylation and resistance to SGI-110 and we found strong trends for associations between demethylation and response.

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2015 AACR: Determinants of hypomethylation and clinical response in r/r AML pts treated with SGI-110

Summary

Acute myeloid leukemia (AML) is a tumor associated with myeloid line of blood cells, characterized by the abnormal rapid proliferation of white blood cells in the bone marrow. The most common approach for AML treatment is the reduction of abnormal cell proliferation rate which can be achieved by targeting the key stages of the cell cycle.

Decitabine is a well characterized hypomethylating agent (HMA), which is incorporated into DNA during the S-phase of cell cycle, inhibits methylation of antitumor genes and induces G2/M arrest. However, it has a very short half-life (15-35 min) after IV infusion due to rapid degradation by cytidine deaminase. SGI-110, a 2nd generation HMA was designed to increase the in vivo exposure/potential efficacy of its active metabolite decitabine. The aim of this effort was to explore how changes in exposure window of decitabine affect DNA demethylation and tumor cell proliferation in AML patients.

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2015 ASCPT: Systems Pharmacology Modeling of Decitabine and SGI-110

Summary

SGI-110 is a second generation hypomethylating agent (HMA) formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine that prolongs the in vivo exposure of decitabine by protecting it from deamination. It gets injected subcutaneously as a small volume, allowing longer half-life and more extended decitabine exposure than DAC IV infusion. SGI-110’s differentiated pharmacokinetic profile resulted in potent hypomethylation and clinical responses in previously treated MDS and AML patients in a phase 1 trial (Kantarjian H et al. 2012).
Here, we have identified novel DNA-methylation biomarker candidates that may be predictive of response to SGI-110 using Differential Methylation Hybridisation (DMH) profiling of the NCI-60 cell line panel (Fassbender A et al, 2010). Cell lines were stratified based on SGI-110 EC50 values from Colony Forming Assays and the degree of LINE-1 (Long Interspersed Nucleotide Elements) demethylation post-SGI-110 treatment. Both stratification data sets were used to classify cell lines into either SGI-110 sensitive or resistant, and to generate 249 genomic methylation sites as candidate biomarkers of response to SGI-110. Fifty genomic fragments that characterized sensitivity and resistance to SGI-110 in cancer cell lines were selected for further validation. These candidate markers were tested in DNA samples from whole blood from 44 treatment naïve and relapsed/refractory AML patients that were classified into responders and non-responders following treatment with SGI-110 in our phase 2 clinical study.
We have identified DNA methylation patterns associated with sensitivity and resistance to SGI-110 in vitro. The validated methylation biomarker discovery process based on DMH and DBS approaches may help to identify and characterise specific subgroups of AML patients that could preferentially respond to SGI-110.

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2014:ASH Identification of Methylation Biomarkers to Predict Clinical Response to SGI-110 in AML pts