2017 EHA: DOSE-CONFIRMATION STUDY OF ORAL ASTX727, A COMBINATION OF ORAL DECITABINE WITH A CYTIDINE DEAMINASE INHIBITOR (CDAI) E7727, IN SUBJECTS WITH MYELODYSPLASTIC SYNDROMES (MDS): PRELIMINARY RESULTS

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Summary
An oral hypomethylatingagent which could be administered in a dose which would emulate parenteral pharmacokinetics would be more convenient and potentially enhance adherence to treatment. Heretofore, rapid clearance by cytidine deaminase (CDA) during first pass has prevented oral administration.1E7727, a novel CDAi, is orally bioavailable with a large safety margin and reproducible effectiveness in preclinical models.2A phase I dose finding study found that a fixed oral combination of 35 mg of decitabine and 100 mg of E7727 (ASTX727) should produce similar pharmacokinetics (PK) to decitabineadministered intravenously at 20 mg/m2 as a 1-hour infusion (DAC IV).3We tested this hypothesis in a randomized cross-over study of DAC IV vs ASTX727 and report the preliminary results here.

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ASTX727_Poster_EHA_abst-E1192_Garcia-Manero_final.pdf

2017 14th Intl. Symposium on MDS: Randomized Phase 2 Study of Guadecitabine in Patients with HMA-Naïve Higher Risk Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

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Summary
Guadecitabine (formerly SGI-110) is a next generation subcutaneous (SC) small volume dinucleotide HMA which results in prolonged in vivo exposure to active metabolite decitabine, and clinical activity reported in phase 1 in MDS and AML patients (Issa et al, Lancet Oncology 2015).

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2017 14th Int. Symposium in MDS: Randomized Phase 2 Study of Guadecitabine in Patients with HMA-Naïve Higher Risk Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

2017 ASCPT: Development of a Semi-Mechanistic PK/PD Model of an Oral Fixed Dose Combination (FDC) of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes.

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Summary

ASTX727 is an oral Fixed Dose Combination of a novel and potent oral CDA inhibitor, E7727 with decitabine for the treatment of patients with MDS. Decitabine is an approved IV treatment of MDS that is rapidly degraded by cytidine deaminase resulting in poor and variable oral bioavailability. Low doses of oral decitabine co-administered with E7727 were shown to produce exposures similar to IV decitabine with acceptable inter-patient variability.

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2017 ASCPT: Development of a Semi-Mechanistic PK/PD Model of an Oral Fixed Dose Combination (FDC) of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

2016 ASH: Successful Emulation of IV Decitabine Pharmacokinetics with an Oral Fixed-Dose Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine, in Subjects with Myelodysplastic Syndromes (MDS): Final Data of Phase 1 Study

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Summary

Patients with International Prognostic Scoring System (IPSS) intermediate 1 and 2 (Int) and high risk (HR) MOS benefit from therapy with hypomethylating agents (HMAs) decitabine (DAC) and azacitidine (AZA). Treatment requires 5 or 7 daily parenteral doses every month while the patient is benefitting. An oral HMA taken at home would provide patient convenience, and potentially enhance adherence to treatment particularly for long-term responders. Neither DAC nor AZA 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 in preclinical models. We report here the final results of a Phase 1 study including an extension arm of a PK-guided first in human dose escalation trial of ASTX727 (the combination of oral DAC and E7727).

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2016 ASH: Successful Emulation of IV Decitabine Pharmacokinetics with an Oral Fixed-Dose Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine, in Subjects with Myelodysplastic Syndromes (MDS): Final Data of Phase 1 Study

2016 ASH: Genetic Determinants of Response to Guadecitabine (SGI-110) in AML

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Summary

Guadecitabine is a next generation hypomethylating drug with improved pharmacokinetics and pharmacodynamics compared to decitabine and demonstrated clinical activity in both treatment naïve (tn) and relapsed-refractory (rr) AML. Previous studies reported similar response rates to guadecitabine in different cytogenetic subsets but it remains unknown whether this extends to genetic changes.

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2016 ASH: Genetic Determinants of Response to Guadecitabine (SGI-110) in AML

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