guadecitabine (SGI-110)

P2, N=32, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2025 --> Jun 2025 | Trial primary completion date: Jan 2025 --> Jun 2025

P2, N=55, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed

P1, N=28, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Jul 2024 --> Jul 2025

P2, N=100, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | N=71 --> 100 | Trial completion date: Nov 2024 --> Jul 2024 | Trial primary completion date: Nov 2024 --> Jul 2024

P1, N=55, Active, not recruiting, University of Southern California | Trial completion date: Jun 2024 --> Dec 2024

P2, N=32, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P1/2, N=75, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

P1, N=34, Recruiting, Royal Marsden NHS Foundation Trust | Active, not recruiting --> Recruiting

P2, N=45, Completed, Northwestern University | Active, not recruiting --> Completed | Trial completion date: Mar 2022 --> Mar 2023

P1/2, N=33, Active, not recruiting, University of Southern California | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Nov 2024

P1, N=55, Active, not recruiting, University of Southern California | Trial completion date: Mar 2024 --> Jun 2024

P2, N=32, Suspended, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=24, Completed, Shadia Jalal, MD | Active, not recruiting --> Completed

in 2022, patients with MDS and CMML previously exposed to HMA were treated with a combination of atezolizumab, an immune checkpoint inhibitor (ICI), and guadecitabine, an HMA. We obtained peripheral blood samples from eight patients with ASXL1 mutated myeloid neoplasms detected by commercial NGS testing; aspirate was also obtained from a diagnostic BM biopsy in one patient. Table 1 shows patient demographics, characteristics and mutational analyses in both T and myeloid cells. Most patients were treatment-naïve, but one had been treated with HMA until 6 months prior to sample collection, and one patient had received cyclosporine for over 20 years for an undiagnosed autoimmune condition.

P2, N=71, Active, not recruiting, M.D. Anderson Cancer Center | N=107 --> 71 | Trial completion date: Nov 2023 --> Nov 2024 | Trial primary completion date: Nov 2023 --> Nov 2024

From 2014 to 2018, 82 patients with MDS and 18 patients with CMML were enrolled and treated. Median age was 69 (IQR 62.5 – 75), 62% were male, 38.4% had complex karyotype, 86.6% were categorized as IPSS-M high or very-high risk. Additionally, 33.7% were TP53mut, 21.4% were TP53multi-hit.

Herein we report long-term follow-up of this cohort of patients, along with T cell programmed death-1 (PD-1) expression analyzed based on mutational status. Significant upregulation of PD-1 was noted in T lymphocytes from both wild-type and co-mutated patients. The effect of mutant ASXL1 on T cell responsiveness to ICI deserves further investigation; patients with ASXL1-mutated HMA-refractory myeloid malignancies may benefit from ICI.

Background Our phase Ib NIBIT Foundation M4 study firstly reported that administration of the hypomethylating agent (DHA) guadecitabine (guade), a prodrug of decitabine (D), followed by I in metastatic melanoma (MM) patients (pts) is safe and has promising clinical and tumor immune-modulating activity (Di Giacomo, CCR 2019). Conclusions Treatment with ASTX727 plus I and N is feasible in PD-1/PD-L1 refractory MM and NSCLC pts. The Stage 1 of the NIBIT-ML1 study is recruiting.

P1, N=34, Active, not recruiting, Royal Marsden NHS Foundation Trust | Trial completion date: Sep 2024 --> Sep 2026 | Trial primary completion date: Sep 2024 --> Sep 2026

Integration of a genetic immunoediting index with an adaptive immunity signature stratifies patients/lesions into four distinct subsets and discriminates 5-year overall survival and progression free survival. These results suggest that coupling genetic immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.

P2, N=55, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

This phase 3 study evaluated the efficacy and safety of the new hypomethylating agent guadecitabine (n = 408) vs a preselected treatment choice (TC; n = 407) of azacitidine, decitabine, or low-dose cytarabine in patients with acute myeloid leukemia unfit to receive intensive induction chemotherapy. In conclusion, there was no significant difference in efficacy between guadecitabine and TC in the overall population. This trial was registered at www.clinicaltrials.gov as #NCT02348489.

gDEC did not impact the expression of androgen receptor (AR) or AR-variant 7 (AR-V7) nor sensitize the prostate cancer cells to the anti-androgen enzalutamide in vitro. Moreover, gDEC treatment increased global histone 3 lysine 4 mono-and di-methylation (H3K4me1 and H3K4me2). In sum, gDEC, in addition to directly depleting the corepressor DNMT1, upregulated KMT activating epigenetic enzymes, activating terminal epithelial program activation, and prostate cancer cell cycling exits independent of apoptosis.

No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival.

No abstract available

P2, N=107, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2022 --> Nov 2023 | Trial primary completion date: Nov 2022 --> Nov 2023

While there are limited studies using decitabine as a hypomethylating agent (HMA) in PTCL, a recent guadecitabine prospective study showed 40% ORR (Wong et al., Leukemia, 2022)...Subjects with CD30-positive disease must have received or be ineligible for brentuximab vedotin... The Study opened in June 2022 with primary completion estimated to be December 2025. Pharmacokinetic, Oral, Peripheral T-cell lymphoma

Targeted sequencing of 263 genes was performed in 604 patients enrolled in the randomized, multi-center phase 3 'ASTRAL-1' trial (NCT02348489) evaluating the second-generation hypomethylating agent guadecitabine (SGI- 110) in treatment-naïve AML pts not eligible for intensive chemotherapy in comparison to a treatment choice of decitabine, azacitidine, or low-dose cytarabine. Using different modelling algorithms, our comprehensive analysis of the so far largest study in older, treatmentnaïve AML patients identified distinct trajectories of leukemia development, provided support for AML with mutated DDX41 as a new clinico-pathologic entity and a basis for the development of a risk stratification that may be applicable for the numerous older patients receiving less intensive therapies. Tumorigenesis, Age, AML, Prognostic groups

Twenty-nine percent were treated with azacitidine, 26% with decitabine, 12% with HMA with immunotherapy combinations (12%), azacitidine + anti-CD47 therapy (5%) SGI-110 (8%), ASTX727 (7%), or azacitidine with venetoclax (4%), or decitabine with venetoclax (1%). This study documents that IPSS-M is not accurate at risk stratifying patients with MDS at the time of HMA failure. Despite the inclusion of molecular variables and patient stratification, the risk of death may be too high to be adequately captured.Figure 1. Kaplan-Meier survival function for overall survival of patients with HMA failure by IPSS-M categories with p-value for log-rank test.

P1/2, N=75, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2023 --> Mar 2024 | Trial primary completion date: Mar 2023 --> Mar 2024

P2, N=55, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2022 --> Dec 2023 | Trial primary completion date: Aug 2022 --> Dec 2023

These results indicate Guadecitabine as a promising epigenetic drug to be added to ICBs therapy.

Interestingly, the ICR/GIE classification discriminated 5-year OS and PFS while the classification based on response groups did not. Moreover, patients with a “high ICR/non-GIE” (i.e., without immunoediting) showed lower expression of antigen presentation and processing-related genes associated with defective HLA-class I expression in the lesions, in spite of high CD8+ content.

Guadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.

Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. While 4/9 patients had prolonged stable disease there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, though signs of biologic activity were noted.

Epigenetic priming using a hypomethylating agent with an immune check point inhibitor was feasible and induced durable clinical benefit associated to immune responses in selected patients with recurrent ovarian cancer.

Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.

P1, N=34, Active, not recruiting, Royal Marsden NHS Foundation Trust | Trial completion date: Jun 2021 --> Sep 2024 | Trial primary completion date: Jun 2021 --> Sep 2024

To solve this problem, several clinical trials, such as irinotecan plus cetuximab vs. cetuximab monotherapy, have been conducted. Another clinical trial on irinotecan plus guadecitabine, a DNA-methyltransferase inhibitor, has also been conducted.

Background Guadecitabine (G) is a next-generation hypomethylating agent (HMA), administered as a small-volume subcutaneous (SC) injection, designed with the potential to overcome pharmacokinetic resistance to first-generation HMAs (decitabine and azacitidine)...Aims Compare overall survival of guadecitabine to that of TC consisting of low-dose cytarabine (LDAC), intensive chemotherapy (IC), or best supportive care (BSC)...The AEs with the highest incidence in subjects who received guadecitabine were febrile neutropenia (38.5 vs 18.9% for TC), pneumonia (34.4% vs 18.9% for TC), neutropenia (34.1% vs 15.6% for TC), and thrombocytopenia (32.2% vs 21.3% for TC). Conclusion This large, global, randomized phase 3 study did not demonstrate superiority of guadecitabine over Standard TC in MDS/CMML patients who were refractory or relapsed following full course of prior HMA treatment.

P2, N=55, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=90 --> 55 | Trial completion date: Jun 2021 --> Aug 2022 | Trial primary completion date: Jun 2021 --> Aug 2022