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ASH 2020: Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

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Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Abstract:

Introduction:
Hypomethylating agents (HMAs) or DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine are established standard of care for the treatment of MDS and CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver, hence requiring intravenous infusion or subcutaneous injections daily for 5-7 days every month (m). This parenteral administration requirement adds significant burden to older cancer patients due to daily time commitment and travel to treatment centers. It also increases exposure to and infection risk with SARS-CoV-2 during the COVID-19 pandemic. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination drug of decitabine and the CDA inhibitor cedazuridine that have shown 99% (90% CI 93% to 106%) equivalent exposure to standard dose IV decitabine 20 mg/m2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present the clinical efficacy and safety results of oral decitabine/cedazuridine from 133 patient study in MDS and CMML (ASTX727-02 ASCERTAIN study).

 Methods:
We used a randomized cross over design where patients were randomized in the first 2 cycles 1:1 to either Sequence A: decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m2 in Cycle 2, or Sequence B: IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2 to do an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days. All patients received oral decitabine/cedazuridine in all subsequent cycles from Cycle 3 onwards until disease progression or unacceptable toxicity. Patients were eligible as per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response as assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.

Results:

138 subjects were randomized, of whom 133 were treated on study. The median age was 71.0 years (range 44-88), 65% were male, 88% MDS and 12% CMML, 43% were either red blood cells (RBCs) or platelets transfusion-dependent at baseline, 25% had poor-risk cytogenetics, and 42% had baseline bone marrow blasts >5%. At the data cutoff for the response analysis, the median duration of follow up was 12.6 m (range 9.3 to 20.5 m) with median number of treatment cycles of 8 (range 1 to 18). Of the 133 treated patients the best response was complete response (CR) in 28 patients (21%; 95% CI 15-29%), marrow (m)CR with hematological improvement (HI) in 20 patients (15%), mCR without HI in 23 patients (17.3%), and HI in 10 patients (7.5%) for an overall objective response (CR+mCR+HI) in 81 patients (61%; 95% CI 52-69%). Median duration of CR was 7.5 m (range 1.6 to 17.5 m), and median time to CR was 4.3 m (range 2.1 to 15.2 m). Of the 133 treated patients 27 (20%) went on to receive allogeneic hematopoietic cell transplant. Of the 57 patients who were either RBCs or platelets transfusion-dependent at baseline, 30 (53%) became transfusion independent for both RBCs and platelets for at least 8 consecutive weeks, and 19 (33%) were both RBCs and platelets transfusion independent for at least 16 consecutive weeks. Median survival has not been reached. Most common Treatment-Emergent AEs of Grade ≥3 regardless of causality were neutropenia in 51.5%, thrombocytopenia in 50%, anemia in 40%, febrile neutropenia in 26%, leukopenia in 21%, pneumonia in 12%, and sepsis in 7% of patients treated with oral decitabine/cedazuridine (excluding the IV decitabine cycle).

Summary/Conclusions: Efficacy and safety from oral decitabine 35 mg/ cedazuridine 100 mg daily for 5 days every 28 days are consistent with clinical data from standard IV decitabine 20 mg/m2 daily for 5 days. Oral decitabine/cedazuridine is the only oral HMA with systemic exposure equivalent to its injectable drug. Further investigation of oral decitabine/cedazuridine in all-oral combination studies is warranted and underway.

 

2020 EORTC-NCI-AACR: The non-peptidomimetic cIAP1/2 and XIAP antagonist tolinapant promotes an anti-tumour immune response in T-cell lymphoma

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The non-peptidomimetic cIAP1/2 and XIAP antagonist tolinapant promotes an anti-tumour immune response in T-cell lymphoma

Summary

Tolinapant (ASTX660) is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP) [1], which is currently being tested in a first in human phase I-II clinical trial in patients with advanced solid tumours and lymphomas (NCT02503423) [2]. IAP antagonists have been reported to exhibit broad immuno-modulatory effects on both the innate and adaptive immune systems. We have investigated the profile of tolinapant in preclinical T cell lymphoma models and evaluated tolinapant’s ability to enhance immune mediated killing of T cell lymphoma cells, both in vitro and in vivo.

References:

  1. G Ward et al., 2018, Mol Cancer Therapeutics Jul;17(7):1381-1391
  2. A Hollebecque et al., 2019, AACR-NCI-EORTC International Conference on Molecular
    Targets and Cancer Therapeutics

Combined inhibition of SHP2 and ERK enhances anti-tumor effects in preclinical models

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Combined inhibition of SHP2 and ERK enhances anti-tumor effects in preclinical models

Summary

MAPK signalling is frequently dysregulated in cancer. The pathway can Panel composition and the number of responding cell lines Examples of dose-response curves Anti-tumor activity of SHP2i, ASTX029 and combination in MIA PaCa-2 xenograft be targeted by inhibition of different nodes and is tightly regulated by feedback mechanisms. Resistance to single-agent therapies frequently occurs through several different mechanisms including upregulation of receptor tyrosine kinases (RTKs), therefore, combination therapies are of interest.

The Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is a key regulator of MAPK pathway downstream of RTKs and upstream of RAS, whilst ERK acts at the bottom of the pathway phosphorylating multiple substrates.

We investigated the potential of targeting the MAPK pathway through a combination of SHP2 and ERK inhibition in preclinical models. Using a SHP2 inhibitor (SHP2i) discovered by our structure-based drug discovery programme and ASTX029, an ERK inhibitor in a Phase I-II clinical trial (NCT03520075), we tested panels of cell lines representing various indications and genetic backgrounds in vitro and confirmed enhanced tumor growth inhibition by the combination in a xenograft model.

The clinical candidate, ASTX029, is a novel, dual mechanism ERK1/2 Inhibitor and has potent activity in MAPK-activated cancer cell lines and in vivo tumor models

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The clinical candidate, ASTX029, is a novel, dual mechanism ERK1/2 Inhibitor and has potent activity in MAPK-activated cancer cell lines and in vivo tumor models

Summary

  • The MAPK signaling pathway is commonly upregulated in human cancers due to oncogenic mutations of upstream
    components such as BRAF or KRAS.
  • MAPK pathway inhibition has been clinically validated by BRAF and MEK inhibitors.
  • As the final node in the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers, including those resistant to upstream inhibition.
  • Previously we described the fragment-based discovery of a chemical series targeting ERK[1]. Here we disclose for the first time the structure of the clinical candidate, ASTX029.

References:

  1. Heightman et al., (2018). J Med Chem 61; 4978

2020 AACR: ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, promotes an anti-tumor immune response in pre-clinical models of T-cell lymphoma

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ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, promotes an anti-tumor immune response in pre-clinical models of T-cell lymphoma

Summary

  • ASTX660 is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first in human phase I-II study in patients with advanced solid tumors and lymphomas (NCT02503423) where preliminary activity has been described in a group of T-cell lymphomas (1)
  • Herein, together with its well-characterized pro-apoptotic effect (2), we describe a new role for ASTX660 as an immunomodulatory molecule capable of promoting an anti-tumor immune response in pre-clinical models of T-cell lymphoma. These data add to the description of ASTX660’s mode of action and our ongoing understanding of the preliminary clinical efficacy that has been reported.

References:
1. Samaniego F, et al., Hematological Oncology. 2019;37(S2):527.
2.Ward GA et al., Mol Can Ther. 2018;17(7):1381-91

2020 EHA: Characterization of ASTX660, an antagonist of cIAP1/2 and XIAP, in mouse models of T cell lymphoma

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Characterization of ASTX660, an antagonist of cIAP1/2 and XIAP, in mouse models of T cell lymphoma

Abstract:

Background:  ASTX660 is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first in human phase I-II study in patients with advanced solid tumor and lymphomas (NCT02503423). IAP antagonists have been reported to exhibit broad immuno-modulatory effects on both the innate and adaptive immune systems .

Aims:  We have investigated the profile of ASTX660 in preclinical T cell lymphoma models and evaluated ASTX660’s ability to enhance immune mediated killing of T cell lymphoma cells, both in vitro and in vivo.

Methods:  ASTX660 was tested in a panel of human and mouse tumor cell lines, assessing apoptosis, necroptosis and immunogenic cell death (ICD). ASTX660 was tested in vitro alone or with recombinant death receptor ligands (TNFa, FASL or TRAIL) and with or without caspase-8/RIPK inhibitors to demonstrate mechanism of action. Target engagement along with induction of apoptosis, necroptosis and ICD markers were analysed by Western blotting, and flow cytometry. Murine tumor models in immunocompetent and immunocompromised mice were utilised to evaluate the efficacy of ASTX660 in the presence or absence of an effective immune response. The Nanostring IO360 panel was used to assess immune cell recruitment.

Results:  ASTX660 antagonised IAPs in cell lines, as indicated by a decrease in cIAP1 protein levels and disruption of the XIAP:SMAC protein complex. In murine T cell lymphoma cell lines (BW5147, EL4 and L5178Y), ASTX660 treatment was associated with an increase in apoptosis or necroptosis and ICD biomarkers. In immunocompetent mice, administration of ASTX660 delivered a complete regression of BW5147 tumor growth, which was not seen in mice deficient in T and B cells. These mice remained refractory to subsequent rechallenge after initial complete regression. Biomarker evaluation from this model indicated a potent immunogenic/necroptotic response after ASTX660 dosing and upregulation of immune effector cells.

References:
1. Michie J. et al., The Immuno-Modulatory Effects of Inhibitor of Apoptosis Proteins Antagonists, Cells, 2020, 9(1), 207.
2. A. Hollebecque et al., AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2019.

 

2020 EHA: ASTX295, a novel small molecule MDM2 antagonist, demonstrates potent activity in AML in combination with decitabine

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ASTX295, a novel small molecule MDM2 antagonist, demonstrates potent activity in AML in combination with decitabine

Abstract:

Background: The tumour suppressor p53 is activated in response to various stress signals to induce transcriptional changes leading to cellular responses such as cell cycle arrest and apoptosis. Activity of p53 is tightly regulated by the E3 ubiquitin ligase MDM2, which inhibits p53 function by, for example, targeting it for proteasomal degradation. Targeting the MDM2-p53 interaction to restore p53 function, is therefore, a promising strategy for cancer therapy and a number of these compounds are in clinical development including ASTX295 (NCT03975387). ASTX295 is a novel, orally bioavailable MDM2 antagonist developed through structure-based drug design that has demonstrated potent activity in a range of p53 wild-type pre-clinical models.

Aims: We investigated the therapeutic potential of ASTX295 alone and in combination with decitabine, a DNA- hypomethylating agent, in AML.

Methods: Primary blasts were isolated from AML patient samples using a combination of antibodies against CD34, CD33, CD45 and CD117. A panel of AML cell lines and primary AML blasts were treated with decitabine and ASTX295 at a range of concentrations, alone and in combination. After treatment, viability was assessed by Alamar blue assay or induction of apoptosis by flow cytometry using a fluorescent caspase substrate or Annexin V.

Effects of drug combinations were analysed using the Combenefit software based on different mathematical models (Loewe, bliss & HSA). Target engagement was confirmed by western blotting.

Results: When tested in a panel of p53 wild-type AML cell lines, ASTX295 exerted a strong anti-proliferative effect in which GI50 <30 nM was observed in 9 out of 11 cell lines. Additionally, p53 activation by ASTX295 triggered apoptosis in both AML cell lines, and primary AML blasts isolated from patients.

Activity of ASTX295 was further enhanced by combining with decitabine. Treatment of AML cell lines with ASTX295 and decitabine showed an increase in growth inhibitory effect and apoptosis compared to respective single agent treatments. This combinatory effect, as assessed by Combenefit, was also observed in primary AML blasts in which 7 of 12 samples tested demonstrated increased apoptosis at or above 300 nM ASTX295 and 100 nM decitabine. Target engagement of ASTX295 and decitabine was confirmed by upregulation of p53 transcriptional targets and decreased DNMT-1 expression.

Summary/Conclusion: Our findings demonstrate that the combination of ASTX295 with decitabine exhibits potent activity against p53 wild-type AML cells, and thus merits further investigation.

2020 EHA: Comparative results of azacitidine and decitabine from a large prospective Phase 3 study in treatment naïve acute myeloid leukemia (TN-AML) not eligible for intensive chemotherapy

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Comparative results of azacitidine and decitabine from a large prospective Phase 3 study in treatment naïve acute myeloid leukemia (TN-AML) not eligible for intensive chemotherapy

 

Abstract:

Background: Older patients with TN-AML who are ineligible for intensive chemotherapy have limited therapeutic options and poor outcomes. Hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) have been the standard of care in this population for more than a decade and were approved in Europe for patients not candidates for intensive chemotherapy or patients not candidates for hematopoietic cell transplant. However, there is no direct efficacy and safety comparative data of AZA and DEC from a prospective large randomzied study. We took advantage of the largest randomized trial for patients with TN-AML who were not eligible for intensive chemotherapy, ASTRAL-1, to compare efficacy and safety of AZA vs DEC in patients randomized to these 2 treatments

Aims: To compare clinical outcomes between AZA and DEC in TN-AML patients not eligible for intensive chemotherapy

Methods: ASTRAL-1 is a global randomized Phase 3 trial which enrolled 815 patients with TN AML who were not eligible for intensive chemotherapy using stringent criteria including age ≥ 75 year or comorbidities including ECOG PS 3. Patients were randomized 1:1 to either Guadecitabine (G), a next generation HMA (60 mg/m2/d SC days 1-5) or a preselected Treatment Choice (TC) of AZA (75 mg/m2/d IV or SC days 1-7), DEC (20 mg/m2/d IV days 1-5), or low dose Ara-C (LDAC) (20 mg SC BID days 1-10). AML diagnosis and responses were assessed by an independent central pathologist blinded to randomization assignment. Responses were recorded using IWG 2003 criteria. Rates of Complete Response (CR) and Overall Survival (OS) were co-primary endpoints.

Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs were DEC (43%), AZA (42%), or LDAC (15%). Of 407 patients randomized to TC, 338 (83%) were treated with either AZA (171 patients) or DEC (167 patients). Baseline variables were well balanced between AZA and DEC patients with no statistically significant differences in baseline characteristics: median age 76 y for both treatments, with poor PS 2-3 in 47.4% vs 53.9%, poor risk cytogenetics 38% vs 33.5%, secondary AML 38% vs 36.5%, BM blasts > 30% in 63.7% vs 71.3%, and TP53 mutations in 12.9% vs 11.3% for AZA vs DEC respectively. Median follow up was 25.5 months and median number of treatment cycles was 6 for AZA (range 1,31), and 5 for DEC (range 1,34). The ITT analyses showed a CR rate of 17.5% vs 19.2% (p= 0.70); and overall CR (CR+CRp+CRi) of 22.2% vs 25.1% (p= 0.53) for AZA vs DEC respectively. Median OS was 8.7 vs 8.2 months for AZA vs DEC respectively with Hazard Ratio of 0.97 (95% CI 0.77, 1.23; log rank p= 0.8). Additional subgroup analyses by baseline characteristics and molecular genetic mutations will be presented at the meeting. There was no statistically significant difference in the incidence of Grade ≥ 3 AEs (88.9% vs 87.4%), serious AEs (81.9% vs 76.0%), or 30-day all-cause mortality (11.7% vs 7.8%) for AZA vs DEC respectively. There was a trend of higher 60-day all-cause mortality on AZA (20.5%) vs DEC (13.2%) (p= 0.07).

Conclusions/Summary: This is the largest comparison of clinical outcomes associated with AZA and DEC for patients with TN AML not eligible for intensive chemotherapy who were treated in the same prospective study. While patients were randomized between G and each of AZA and DEC separately with no direct randomization of AZA vs DEC, the patients’ characteristics were well balanced in patients randomized to the two HMA treatments. There were no significant differences in CR, overall CR, OS, or safety between AZA and DEC.

Ramsey, et al., Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model

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Ramsey, H.E., Oganesian, A., Gorska, A.E. et al. Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model. Targ Oncol 15, 231–240 (2020). https://doi.org/10.1007/s11523-020-00709-x

Abstract:

Background: DNA methyltransferase inhibitors (DNMTis) improve survival for patients with myelodysplastic syndromes (MDS) and those with acute myeloid leukemia (AML) unable to receive standard cytotoxic chemotherapy and are, accordingly, the backbone of standard-of-care treatment for these conditions. Standard regimens with DNMTIs, decitabine (DEC) or azacitidine (AZA) include daily subcutaneous (s.c.) or intravenous (i.v.) administration for 5–7 consecutive days. Attempts to provide the therapy orally have been limited given rapid clearance of the agents by the enzyme cytidine deaminase (CDA), which is ubiquitous in the gut and liver as part of first-pass metabolism. Recently, cedazuridine (CDZ), an oral inhibitor of CDA, was successfully combined with DEC to approximate the pharmacokinetics of i.v. DEC in patients.

Objective: To determine if an oral dosing strategy might be feasible in the clinic with AZA, we attempted to increase the bioavailability of oral AZA through the use of CDZ, in a murine model.

Methods: Following pharmacokinetic and pharmacodynamic assessment of oral AZA dosed with CDZ in murine and monkey models, we tested this regimen in vivo with a human cell line-derived xenograft transplantation experiment (CDX). Following this we combined the regimen with venetoclax (VEN) to test the efficacy of an all-oral regimen in a patient-derived xenograft (PDX) model.

Results: Parenteral AZA and oral AZA + CDZ exhibited similar pharmacokinetic profiles, and efficacy against human AML cells. Tumor regression was seen with AZA + CDZ in MOLM-13 CDX and PDX models.

Conclusions: We conclude that oral AZA when combined with CDZ achieves successful tumor regression in both CDX and PDX models. Furthermore, the combination of AZA + CDZ with VEN in a PDX model emulated responses seen with VEN + AZA in the clinic, implying a potential all-oral VEN-based therapy opportunity in myeloid diseases.

Garcia-Manero et al., Oral cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML

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Garcia-Manero et al, “Oral cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML”. Blood. 2020 Apr 13. pii: blood.2019004143. doi: 10.1182/blood.2019004143. [Epub ahead of print]

Abstract:

This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with
cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-
1/2- or high-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral
cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral
cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage
and then as a single fixed-dose combination (FDC) tablet. Primary endpoints: mean decitabine systemic exposure (geometric least-squares
mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), % long interspersed nuclear element 1
(LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and
treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1%, 106.5%) and 97.6% (80.5%, 118.3%)
for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical
responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events
regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35
mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar
efficacy. ClinicalTrials.gov NCT02103478.