2016 ASH: Long Term Survival and Clinical Complete Responses of Various Prognostic Subgroups in 103 Relapsed/Refractory Acute Myeloid Leukemia (r/r AML) Patients Treated with Guadecitabine (SGI-110) in Phase 2 Studies

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Summary

Guadecitabine (SGI-110) is a novel next-generation hypomethylating agent (HMA) administered as a small volume subcutaneous (SC) injection which results in extended decitabine exposure. Phase 2 study has been conducted in r/r AML patients using two different doses and schedules of guadecitabine. We report here long term survival and clinical complete response rates in various prognostic subgroups of r/r AML patients

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2016 ASH: Long Term Survival and Clinical Complete Responses of Various Prognostic Subgroups in 103 Relapsed/Refractory Acute Myeloid Leukemia (r/r AML) Patients Treated with Guadecitabine (SGI-110) in Phase 2 Studies

2016 EHA: OS and subgroup results from randomized Phase 2 study of SGI-110 in previously treated MDS

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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.

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2016 EHA: OS and subgroup results from randomized Phase 2 study of SGI-110 in previously treated MDS

2016: Addition of onalespib to crizotinib prior to progression in pts with ALK-pos NSCLC: P2 Results

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Summary

  • Hsp90 is required for proper ALK function
  • Onalespib (AT13387) is a second generation Hsp90 inhibitor
  • Onalespib in ALK-driven pre-clinical models:
    • Displays potent antitumor activity
    • Delays the onset of resistance
  • In the clinic, onalespib
    •  Has a safety profile consistent with the class
    • (diarrhea, mild transient visual changes)
    • PK & PD results support weekly dosing
    • – Has antitumor activity (PR) at a dose of 220 mg/m2 (D1,8,15 of 28 Day cycle)
  • Crizotinib (CZT) has demonstrated clinical activity in ALK-pos NSCLC
  • AT13387-05 is a 3-part, Phase 1-2 study in ALK-pos NSCLC
    • Part A (Phase 1 of the study demonstrated the safety of Onalespib/CZT in combination with some activity in progressing patients
    • Results are presented for Part B of the study, randomization to combination of Onalespib added to CZT vs CZT alone prior to development of resistance (Fig 2)

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Addition of onalespib to crizotinib prior to progression in pts with ALK-pos NSCLC: P2 Results

2016 AACR: Dual IAP Antagonist, ASTX660, Increases Anti-tumor Activity of Paclitaxel in TNBC Models

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Summary

Paclitaxel-mediated secretion of inflammatory mediators, including TNFα, potentially creates paracrine and autocrine loops that can contribute to survival and reduction of paclitaxel-induced apoptosis in cancer cells.

One of the mechanisms of cancer cell survival is the expression of inhibitor of apoptosis proteins (IAPs). Cellular IAP (cIAP) is involved in inflammatory pro-survival NF-B activation, blocking the activation of the effector caspases 3 and 7, while X-linked IAP (XIAP) directly binds the effector caspases 3, 7 and 9, inhibiting the full activation of the apoptosis pathway.

ASTX660, a fragment-derived small molecule that is orally bioavailable, is a dual antagonist of cIAP and XIAP (Chessari 2014). Its inhibitory activity has been demonstrated in preclinical models of melanoma and other types of cancer, in which inflammation was present. It is currently being investigated in a single-agent Phase I/II clinical trial in patients with advanced solid tumors and lymphomas (NCT02503423).

Here, we characterize the activity of ASTX660 in preclinical models of triple-negative breast cancer (TNBC) as a single agent and in combination with paclitaxel whose inflammatory properties are hypothesized to sensitize the cells to ASTX660.

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AACR: Dual IAP Antagonist, ASTX660, Increases Anti-tumor Activity of Paclitaxel in TNBC Models

2016 EHA: Phase 1 dose-escalation study of ASTX727: comparable variability in pharmacokinetics

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Summary

Hypomethylating agents (HMA) are typically administered parenterally and adjusted to body surface area (BSA) in order to achieve target pharmacokinetic (PK) parameters associated with response. Much of the variation associated with administration of HMAs is related to the intrinsic activity of cytidine deaminase (CDA) an enzyme which rapidly metabolizes HMAs and is highest in the gut and liver. We report here intra-and inter-patient pharmacokinetic variation in patients from a study aiming to match PK parameters of BSA adjusted dosing with IV decitabine (DAC) with a novel fixed-dose oral combination (ASTX727), of DAC and E7727, a CDA inhibitor. Preliminary safety and clinical activity were previously reported and are updated here.

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EHA: Phase 1 dose-escalation study of ASTX727: comparable variability in pharmacokinetics

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