Ward, et al; “Epigenetic priming by hypomethylation enhances the immunogenic potential of tolinapant in T-cell lymphoma”; Cancer Research Communications, 2024
Click link to view article:
https://doi.org/10.1158/2767-9764.CRC-23-0415
Abstract:
Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion of and resistance to apoptosis are significant factors in tumorigenesis and drug resistance. Bypassing apoptotic pathways and eliciting another form of regulated cell death, namely necroptosis, an immunogenic cell death (ICD), may override apoptotic resistance. Here, we present the mechanistic rationale for combining tolinapant, an antagonist of the inhibitor of apoptosis proteins (IAP), with decitabine, a hypomethylating agent (HMA), in T-cell lymphoma (TCL). Tolinapant treatment alone of TCL cells in vitro and in syngeneic in vivo models demonstrated that ICD markers can be upregulated, and we have shown that epigenetic priming with decitabine further enhances this effect. The clinical relevance of ICD markers was confirmed by the direct measurement of plasma proteins from peripheral TCL patients treated with tolinapant. We showed increased levels of necroptosis in TCL lines, along with the expression of cancer-specific antigens (such as cancer testis antigens) and increases in genes involved in interferon signaling induced by HMA treatment, together deliver a strong adaptive immune response to the tumor. These results highlight the potential of a decitabine and tolinapant combination for TCL and could lead to clinical evaluation.
2023 SOHO: Randomized Phase 1-2 Study to Assess Safety and Efficacy of Low-Dose (LD) Oral Decitabine/Cedazuridine (ASTX727) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients: Interim Safety Analysis
Abstract:
Background: Cedazuridine (CED), a cytidine deaminase (CDA) inhibitor allows oral availability of decitabine (DEC); 5 daily doses of the fixed-dose combination (FDC) of 35 mg DEC/100 mg CED standard dose (SD) provides equivalent exposure to an IV DEC regimen of 20 mg/m2 D1-5 (Garcia-Manero et al, 2020). Attenuated HMA regimens (e.g., 3 days IV DEC) have shown activity in LR-MDS (Jabbour, et al. 2017).
Aims: This Phase 1/2 study explores lower dose oral DEC/CED regimens in LR-MDS patients.
Methods: Phase 1/2 study in lower-risk-MDS (IPSS low risk and lntermediate-1) subjects requiring treatment. Phase 1: explored 28-day regimens, dose ranges 5-20 mg DEC/100mg CED; duration ranges 5-10 days. Primary endpoints: recommended Phase 2 dose (RP2D) based on safety and dose-limiting toxicity (DLT). Secondary endpoints: clinical activity per 2006 IWG (transfusion independence [TI], LFS, OS). Phase 2: randomized 81 LR-MDS 1:1 to receive Phase 1 RP2D vs. 35 mg DEC/100 mg CED (SD) for 3days (SD-3Day) (reflecting attenuated HMA regimen for LR-MDS). Similar efficacy and safety endpoints as Phase 1.
Results: Phase 1: 47 patients treated with five different DEC/CED regimens. DLT (myelosuppression-associated) increased with higher treatment doses and longer duration. Hematologic Improvement (HI) % across dosing regimens: 30% (14/47), 8-week RBC transfusion-independent rate: 33% (7/21); mOS: 31 months (95%Cl:19,NE); mLFS 23 months (95%Cl:14,32). Based on clinical efficacy and safety, 10mg DEC/100mgCED D1-5 every 28D (LD-5Day) was selected as RP2D.
Phase 2: Baseline: Int-1 (65-73%), 48% prior MDS treatment (21%ESA, 26% luspatercept), 46% RBC transfusion-dependent (TD); 14% platelet TD. At cutoff, 80 subjects had received a median of 4.5 treatment cycles, ~10 patients received subsequent transplant. PK data showed LD-5Day exposure about half SD-3Day exposure. Reported adverse event terms with LD-5Day were similar to SD-5day, with most common grade ≥3 from myelosuppression. By cycle 8, average neutrophil counts were higher in LD-5Day regimen vs. SD-3Day regimen; platelet changes were similar. Of 8 all-cause deaths at data cutoff, only 1 was within 30days (in SD-3Day group).
Conclusion: This Phase 1/2 study suggests LD-5Day regimen is tolerable (less neutropenia) and potentially an optimal regimen for LR-MDS (longer term efficacy analysis vs. SD-3Day regimen pending).
2023 SOHO: Efficacy and Safety of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subpopulation from Phase 2 and ASCERTAIN Phase 3 Studies
View Presentation: Efficacy and Safety of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subpopulation from Phase 2 and ASCERTAIN Phase 3 Studies
Abstract:
Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disease characterized by persistent monocytosis, splenomegaly, and both dysplastic and myeloproliferative changes in the bone marrow. Hypomethylating agents (HMAs) are approved for CMML treatment. ASTX727 (DEC/CED), an orally available fixed dose combination (FDC) of 35 mg decitabine (DEC) and 100 mg cedazuridine (CED), a cytidine deaminase inhibitor, produces comparable PK AUC exposure compared to IV DEC (Garcia-Manero, et al, 2019).
Aims: We present the combined clinical experience of CMML patients in studies leading to FDA approval of oral DEC/CED (ClinicalTrilas.gov NCT02103478 and NCT03306264, respectively) including genetic profiles.
Methods: 33 CMML candidates for parenteral decitabine with PS 0-2 were enrolled and received standard oral decitabine/cedazuridine (DEC/CED) regimen. Clinical endpoints were best response by International Working Group (IWG) 2006, transfusion independence (TI), transformation-free survival (TFS), overall survival (OS), and safety. Molecular profiling used an NGS panel, including somatic mutations affecting CMML prognosis and response to HMA therapy. Cox-regression analysis on various factors (eg binary mutational status, CR, etc.) was used for analyses of risk-factors for OS.
Results: Patients: Median age 71 years, 55% patients ECOG PS of 1, 85% no prior anticancer therapy for CMML, one-third RBC transfusion-dependent at baseline, 70% CMML-1 (2022 WHO classification), 76% MD-CMML. Patients received a median of 10 cycles of therapy (range 2-36).
Efficacy: 7 (21.2%) Complete Responses (CR), 14 (42.4%) marrow CR (mCR), including 5 (15.2%) with hematologic improvement (HI); overall response rate (ORR) [CR + PR+ mCR + HI] 75.8%. Of those RBC transfusion-dependent at baseline, 63.6% became TI for at least 8 weeks. mTFS was 28.3 months; mOS 35.7 months. Safety: profile was consistent with decitabine; most grade ≥3 events from myelosuppression. Given the advanced age, only 3(9%) went on to transplant. Cox regression analysis only associated post-treatment RBC TI with survival with no observed effect on OS for other baseline or response-related factors; the sensitivity of these analyses is limited by patient number.
Conclusions/Summary: DEC/CED has clinical benefit in CMML patients with a well-tolerated safety profile. TI may be associated with longer survival.
© Astex Pharmaceuticals
All rights reserved
