2016 ASCO: Epigenetic resensitization in recurrent, platinum-resistant OC using SGI-110: Phase 2 results

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Summary

  • In the past 20 years there has been little change in the 1-, 3-, and 5-year survival rates for patients with ovarian cancer.
  • 5-year survival is ~25% for patients diagnosed with advanced stage disease
  • Recurrence is common and patients develop resistance to chemotherapy
  • Platinum resistant ovarian cancer is uniformly fatal and epigenetic changes have been implicated in the development of platinum resistance
  • Previous experience with decitabine, a hypomethylatingagent, in combination with carboplatin demonstrated activity in recurrent platinum resistant ovarian cancer patients (Matei et al. Cancer Research 2012)
  • Guadecitabine is a dinucleotide of decitabine and deoxyguanosine, affords increased in vivo exposure of decitabine by protecting it from deamination due to slow release upon SQinjection
  • In Phase 1 studies, guadecitabine provides longer exposure and more potent hypomethylationcompared to decitabine. Combining guadecitabine with carboplatin in this population may improve upon the encouraging preliminary results and an acceptable dose for phase 2 was previously established (Fleming, et al AACR 2014)

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Epigenetic resensitization in recurrent, platinum-resistant OC using SGI-110: Phase 2 results

2016 AACR: Immune checkpoint(s) expression in AML pts enrolled in phase 1-2 study with guadecitabine

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Summary

Immune checkpoint(s) blockade is becoming the therapeutic mainstay in melanoma and lung cancer. Based on these important clinical achievements, immunotherapy with immunomodulating monoclonal antibodies (mAb) is being explored as a new therapeutic modality in most human malignancies, either alone or in combination with other immunomodulating agents. We have provided extensive evidence that the second generation DNA hypomethylating agent (DHA), guadecitabine (SGI-110), plays a promising role in potentiating the immunogenicity
and the immune recognition of human malignancies through the up-regulation of the expression of different immune molecules on cancer cells. These findings led us to hypothesize that DHA could represent ideal partners for immune checkpoint(s) blocking agents to improve their therapeutic efficacy. Here, we studied the expression of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), and 2 (PD-L2), and cytotoxic T lymphocyteassociated antigen 4 (CTLA-4) in peripheral blood mononuclear cells of acute myeloid leukemia (AML) patients (N=23), enrolled in a phase 1-2 study with guadecitabine. Patients included in this preliminary analysis were selected based on their responsiveness to therapy. Quantitative RT-PCR analyses showed a constitutive expression
(gene/β-actin molecules >7.5E-05) of PD1, PD-L1, PD-L2 and CTLA-4 in 82.6%, 100%, 47.8% and 8.7% patients, respectively.

Guadecitabine therapy up-regulated (≥2 fold) the expression of PD1, PD-L1, PD-L2 and CTLA-4 in 57.9%, 56.5%, 18.2% and 0% patients, respectively, at any of the time-points investigated during treatment. De novo expression of PD1, PD-L2 and CTLA-4 was observed in 100%, 41.6% and 38.1% of the immune checkpoint(s)-negative patients, respectively.
Though preliminary, these results further support the strong link between epigenetics/DNA methylation and immune response, in cancer patients, and strengthen the therapeutic potential of igenetic immunomodulation, with “consolidated” and emerging immune checkpoint(s) blocking mAb.

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2016 AACR: Immune checkpoint(s) expression in AML pts enrolled in phase 1-2 study with guadecitabine

2016 ESH-MDS: Results of a P2 study of SGI-110 in pts with r/r intermediate or high risk MDS or CMML

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Summary

Guadecitabine (SGI-110) is a next generation hypomethylating agent (HMA) designed as a dinucleotide of decitabine and deoxyguanosine that is resistant to deamination by cytidine deaminase CDA).
This results in a prolonged in vivo exposure to decitabine following small volume subcutaneous (SC) administration of guadecitabine.

Safety and clinical activity in resistant MDS and AML have been shown in a Phase 1 trial (Issa et al, Lancet Oncology, 2015).

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2016 ESH-MDS: Results of a P2 study of SGI-110 in pts with r/r intermediate or high risk MDS or CMML

2016 TAT: Guadecitabine (SGI-110), a novel partner in immunotherapy

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Summary

  • Guadecitabine(SGI-110) is a novel hypomethylatingdinucleotide of decitabine(DAC) and deoxyguanosinethat is resistant to degradation by cytidine deaminase and results in prolonged in vivo exposure to its active metabolite DAC. The differentiated pharmacokinetic profile offers the potential of improved biological and clinical activity and safety over currently available hypomethylatingagents (HMA).
  • We reported previously results from the Phase 1 dose-escalation study in AML and MDS1and the Phase 2 randomized dose-response study in r/r AML patients of SGI-110 given SC at 2 doses (60 and 90 mg/m2) in a 5-day regimen2or at 60 mg/m2in a 10-day regimen.
  • Rationale for guadecitabinecombination with immunomodulating agents
    • Tumor Associated Antigens (TAAs) including Cancer Testis Antigens (CTAs) e.g. NY-ESO-1 and MAGE-A are often silenced by hypermethylation
    • Guadecitabine demethylates and induces CTA re-expression rendering the tumor more immunogenic
    • Guadecitabine induces better tumor recognition by immune system (cytotoxic CD8+ T lymphocytes)
    • Clinical correlation between hypermethylationand poor survival reported in Melanoma and Liver Cancer
    • Anecdotal clinical data from patients treated with HMA and immunotherapy
  • Guadecitabineimmunomodulatory data
    • Preclinical In vitro Data:
      • Guadecitabine demethylates the promoters and induces the expression of CTAs MAGE-A3, NY-ESO-1 in cancer cell lines
      • Guadecitabine induces tumor recognition by cytotoxic T lymphocytes
    • Preclinical In vivo Data
      • Synergy when guadecitabineis combined with CTLA-4 antibody
    • Clinical Data
      • Guadecitabine achieves dose-dependent demethylation and induction of CTAs (NY-ESO-1; MAGE-A1 and A3) in AML and MDS patients

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2016 TAT: Guadecitabine (SGI-110), a novel partner in immunotherapy

2015 ASH:Comparison of Efficacy & Safety Results in 103 TN-AML Pts using 5 & 10 day regimens SGI-110

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2015 ASH:Comparison of Efficacy & Safety Results in 103 TN-AML Pts using 5 & 10 day regimens SGI-110

2015_ESH-AML: Baseline biomarkers and DNA demethylation correlate w. clinical responses in SGI-110

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Summary

Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine (DAC) and deoxyguanosine that is resistant to degradation by cytidine deaminase and results in prolonged in vivo exposure to its active moiety DAC. The differentiated pharmacokinetic profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. We reported previously results from the Phase 1 dose-escalation study in AML and MDS1 and the Phase 2 randomized dose-response study in r/r AML patients of SGI-110 given SC at 2 doses (60 and 90 mg/m2) in a 5-day regimen2 or at 60 mg/m2 in a 10-day regimen3. Here we report an overall assessment of the association between clinical responses, global DNA demethylation assessed by LINE1 assay and baseline expression of a panel of 7 genes (CDA, P15, P21, DNMT3B, DNMT3A, DNMT1 and CTCF) assessed by qRT-PCR.

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2015_ESH-AML: Baseline biomarkers and DNA demethylation correlate w. clinical responses in SGI-110

2015 AACR: Onalespib delays the emergence of resistance to erlotinig in EGFR-driven xenograft model

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Summary

Kinase inhibitors have been used successfully in the clinic, but relapse is common due to the emergence of resistance. Inhibition of HSP90 leads to the depletion of oncogenic ‘client’ proteins and
the simultaneous inhibition of many signalling pathways. As such, the use of HSP90 inhibitors to overcome resistance has been widely investigated.

Onalespib (AT13387) is a potent, second generation HSP90 inhibitor, which has been studied in many preclinical models of kinase inhibitor resistance. Recent findings indicate that an upfront
combination of onalespib and either vemurafenib or crizotinib, in models of mutant BRAF melanoma or ALK-translocated non-small cell lung cancer (NSCLC), can delay the emergence of resistance
to these therapies (Smyth et al 2014, Wallis et al 2014). Here we have extended this work to a combination of onalespib and erlotinib in an EGFR-driven NSCLC model.

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2015 AACR: Onalespib delays the emergence of resistance to erlotinig in EGFR-driven xenograft model

2015 ASH: Results of FIH P1 PK Guided Dose-Escalation Study of ASTX727 in Subjects with MDS

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Summary

Treatment of MDS patients with parenteral hypomethylating agents (HMA) such as decitabine (DAC) requires frequent visits to the physician. An orally administered HMA would provide significant patient convenience, potentially enhance adherence to treatment, and permit the exploration of extended treatment schedules with lower doses of DAC. Neither DAC nor azacitidine is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin and reproducible effectiveness in preclinical models. We report here the first in human Phase 1 results of a PK-guided dose escalation trial of ASTX727 (the orally administered combination of DAC
and E7727).

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2015 ASH: Results of FIH P1 PK Guided Dose-Escalation Study of ASTX727 in Subjects with MDS

2015 ASH: Correlations Between Biomarkers and Clinical Responses in Phase 1/2 Study of Guadecitabine

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Summary

  • Guadecitabine (SGI-110) is a novel subcutaneous (SC) next generation hypomethylating agent (HMA) designed as a dinucleotide of decitabine (DAC) and deoxyguanosine that is resistant to degradation by cytidine deaminase (CDA) and results in prolonged in vivo exposure to its active moiety DAC. The differentiated pharmacokinetic profile offers the potential of improved biological and clinical activity and safety over currently available HMAs.
  • In the Phase 1 study, patients with r/r AML were treated at escalating doses of guadecitabine. In the Phase 2 study, r/r AML patients were randomized to receive guadecitabine at 60 mg/m2 or 90 mg/m2 SC daily for 5 days (dailyx5). In a separate cohort, patients were treated with 60 mg/m2 SC daily for 10 days (dailyx10: days 1-5 and 8-12) for up to 4 cycles followed by subsequent cycles of the dailyx5 regimen. All regimens were dosed with a 28 day treatment cycle.
  • We have reported the clinical efficacy and safety results from the Phase 1 dose-escalation study in AML and MDS (Issa et al, Lancet Oncology 2015) and the Phase 2 randomized dose-response study in r/r AML at 2 doses (60 and 90 mg/m2) in a 5-day regimen (Kantarjian et al, ASH 2013) and 60 mg/m2 in the 10-day regimen (Griffiths et al, ASCO 2014).

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2015 ASH: Correlations Between Biomarkers and Clinical Responses in Phase 1/2 Study of Guadecitabine

2015 EHA: Late response & OS long term follow up of randomized P2 Study of SGI-110 in elderly AML

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Summary

  • We previously reported results from a multicenter study of guadecitabine randomized to a 5-day regimen at either 60 or 90 mg/m2 in 51 treatment naïve elderly AML patients not eligible for intensive chemotherapy
  • There were no significant differences in overall composite complete response (CRc: CR+CRp+CRi) or safety between the two doses; however 14 patients were still on treatment at the time of the prior analysis
  • We present here current results on these patients with a median follow-up of 24 months (20.2-33) during which 38 death events occurred in the 51 patients treated (75%)

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2015 EHA: Late response & OS long term follow up of randomized P2 Study of SGI-110 in elderly AML