2017 ASH: Predictors of Response and Survival in 206 AML Patients Treated with Guadecitabine in a Phase 2 Study

Summary
Background: Guadecitabine is a next generation hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a prospective phase 2 study testing different schedules of guadecitabine in 206 AML patients. We present here the results of multiple logistic regression, and Cox regression analyses of predictors of composite Complete Response or CRc (CR+CRp+CRi) and overall survival (OS).

Methods: Multiple logistic regression analysis of response (CRc), and Cox regression analysis of OS were conducted with inclusion of the following baseline variables: disease state (relapsed/refractory (r/r) vs. treatment naïve (TN) AML); guadecitabine schedule (10day vs. 5day); age (<75 vs. ≥75); ECOG PS (01 vs. ≥2); Cytogenetics (others vs. poor risk); baseline BM blasts (≤40% vs. >40%); baseline Peripheral blood (PB) blasts (≤30% vs. >30%); baseline WBCs count (<20,000/μL vs. ≥20,000/μL); Flt3 ITD, NPM, and TP53 mutations (each present vs. not detected). Cutoff values for blasts % for BM and PB were chosen based on the median or mean values respectively, and cutoff value for WBCs count was chosen as a common cutoff used for proliferative AML. Backward elimination method with alpha =0.05 was used to reach the final models.

Results: We treated 206 AML patients (103 patients each for TN or r/r AML); 101 with 5day schedule and 105 with 10day schedule. There were 91 patients (44%) ≥75 y; 53 (26%) with ECOG PS≥2; 85 (41%) with poor risk cytogenetics; 99 (48%) with baseline BM blasts >40%; 65 (32%) with baseline PB blasts >30%; 20 (9.7%) with WBCs ≥20,000/μL. Flt3, NPM, and TP53 mutations were present in 8%, 9%, and 4% of patients respectively. The final logistic regression model indicated that patients with ECOG PS 01 and those with baseline PB blasts ≤ 30% have twofold higher odds of response than those with ECOG PS ≥2 and PB blasts >30% (Odds ratio 2.18; and 2.03 respectively; p<0.05 for both). Patients with TN AML had fivefold higher odds of response to guadecitabine than r/r AML (Odds ratio of response for r/r AML 0.22; p <0.0001). The final Cox regression model showed that both ECOG PS 01 and PB blasts ≤30% retained their significance for OS (HR 0.69 with p=0.03; and 0.61 with p=0.004 respectively). However disease state (r/r AML vs TN AML) lost significance for OS while cytogenetics risk level (others vs poor risk) became significant with a HR for OS of 0.68, p=0.016.

Summary/Conclusions: In a prospective series of AML patients treated with guadecitabine in a phase 2 study, better ECOG PS 01 and lower baseline PB blasts ≤30% were associated with a significantly higher likelihood of response and a longer OS. Patients with TN AML had significantly higher likelihood of response than those with r/r AML but this was not a significant factor for OS when other factors are present in the model such as ECOG PS, cytogenetics risk and PB blasts. On the other hand, the presence of poor risk cytogenetics did not alter the likelihood of response to guadecitabine but still had shorter survival compared to patients with other cytogenetics risk levels. Other variables such as age, baseline BM blasts %, and baseline WBCs count did not significantly impact response or OS in AML patients treated with guadecitabine when all other factors are present in the models. The analysis of genetic mutations was limited by the small number of patients where these mutations were present. The analysis of the treatment schedule is limited by the different effect of the schedule on r/r AML compared to TN AML where the 10day schedule did better than the 5day schedule in r/r AML but not in TN AML patients.

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Predictors of Response and Survival in 206 AML Patients Treated with Guadecitabine in a Phase 2 Study

2017 ESH-AML: LINE-1 and P15 Demethylation May Predict Response to Guadecitabine

Summary
Guadecitabine (formerly known as SGI-110) is a next-generation hypomethylating agent (HMA) composed of a dinucleotide of decitabine and deoxyguanosine (Figure 1). Guadecitabine is a dinucleotide resistant to degradation by cytidine deaminase (CDA) resulting in longer in vivo exposure to its active metabolite, decitabine, after a small volume ( ~ 1 mL) subcutaneous (SC) administration. A prospective phase 2 trial in 103 patients with relapsed or refractory AML (r/r AML) investigated 60 mg/m2 and 90mg/m2 doses in a 5-day regimen, and 60 mg/m2 in a 10-day regimen given every 28 days. In that trial, LINE-1 was used to measure general DNA demethylation and P15 gene promotor methylation was used to measure a specific tumor suppressor gene demethylation during Cycle 1 as potential markers of biological activity that may predict clinical response (See Trial Design in Figure 2).

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2017 ESH-AML: LINE-1 and P15 Demethylation May Predict Response to Guadecitabine

2017 ACCP: Population Pharmacokinetics Analysis for Guadecitabine (SGI-110) and Decitabine after Subcutaneous Dosing with SGI-110 in Patients with Relapsed/Refractory AML and MDS

Summary
Guadecitabine is next-generation HMA formulated as a dinucleotide of decitabine and deoxyguanosine delivered as a low volume and pharmaceutically stable subcutaneous (SC) injection. In vivo conversion to active metabolite decitabine results in longer effective half-life and more extended decitabine exposure window than decitabine IV infusion. The differentiated PK profile may lead to improved biological and clinical activity and safety over currently available HMAs (Issa et al. Lancet Oncology 2015).
SGI-110-01 (NCT01261312) was a phase 1-2, dose escalation, multicenter study of subcutaneous regimens of SGI-110 in subjects with intermediate or high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Several dosing regimens were tested. In regimen 1 and its phase 2 expansion, guadecitabine was administered daily for 5 days of a 28-day cycle. In regimens 2a and 2b, it was administered weekly or twice-weekly, respectively, for 3 weeks of a 28-day cycle. In another part of the phase 2 expansion, it was administered daily for 10 days (1-5 and 8-12) of a 28-day cycle.
The PK data included full concentration-time profiles of parent SGI-110 and its active metabolite, decitabine obtained after the first dose and after dose on day 5 (for regimen 1 and expansion), day 8 (for regimen 2a) or day 12 (for expansion 10-day regimen) of cycle 1.
The abstract reported results of the population PK analysis of data from 98 patients. Since the time the abstract was submitted, more data became available, and the model was updated. This poster describes the population PK modeling of data using an updated dataset from 124 patients.

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2017 ACCP: Population Pharmacokinetics Analysis for Guadecitabine (SGI-110) and Decitabine after Subcutaneous Dosing with SGI-110 in Patients with Relapsed/Refractory AML and MDS

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)

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)

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

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

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

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

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

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

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