2021 Blood Virtual Congress: Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

/in , ,

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

Abstract:

Aim: Confirm fixed dose combination (FDC) of oral decitabine/cedazuridine produces similar clinical activity vs. IV decitabine. Background: An oral FDC of 35 mg decitabine and 100 mg of CDA inhibitor cedazuridine has shown 99% (90% CI 93% to 106%) equivalent exposure to 20 mg/m2 IV decitabine in a randomized cross-over study(1). If oral decitabine/cedazuridine treatment produces similar clinical results its use may decrease the burden associated with chronic parenteral hypomethylating agent (HMA) therapy in MDS and CMML.

Methods: Randomized cross over design: 133 subjects treated in US or Canada.
Primary PK endpoint: decitabine AUC equivalence over 5 days of dosing. Efficacy endpoints: best response per IWG 2006, transfusion independence, OS, and safety. AEs were graded by CTCAE v 4.03.

Results:  Patient Characteristics: median age 71.0 years; 65% male; 88%MDS/12%CMML; 43% either RBC or platelet baseline transfusion-dependent; 25% poor-risk cytogenetics, and 42% baseline BM blasts >5%. Best Response: CR in 29/133 patients (22%), mCR with HI:17% (without HI 16%), and HI: 7.5%, for an overall objective response (CR+mCR+HI) of 62%; 26% proceeded to transplant. With median follow up of 24.7 months, median OS had not been reached. Treatment-Emergent AEs (Grade ≥3 regardless of causality): thrombocytopenia (61%), neutropenia (58%), anemia (51%), febrile neutropenia (32%), leukopenia (25%), and pneumonia (18%), of patients treated with oral decitabine/cedazuridine (excluding IV decitabine cycle).

Conclusion: Efficacy and safety from oral decitabine 35 mg/ cedazuridine 100 mg daily for 5 days every 28 days are consistent with historical 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.

References:  Garcia-Manero, et al, Blood 2019; 134 (Supplement_1): 846. doi: https://doi.org/10.1182/blood-2019-122980

Heightman et al., “Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2”

/in , ,

Click link to view article

https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.1c00905

Abstract

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I–II clinical trial in patients with advanced solid tumors.

Munck et al., “ASTX029, a Novel Dual-Mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK”

/in , ,

Click link to view article

https://mct.aacrjournals.org/content/early/2021/07/30/1535-7163.MCT-20-0909#:~:text=ASTX029%20is%20a%20highly%20potent,not%20directly%20inhibiting%20MEK%20activity

Abstract

The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Due to its distinctive ERK binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual-mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, RSK, were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant anti-tumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human Phase I-II clinical trial in patients with advanced solid tumors (NCT03520075).

2021 AACR: A first-in-human, Phase 1 study of ASTX029, a dual-mechanism inhibitor of ERK1/2, in relapsed/refractory solid tumors

/in , ,

View Poster: A first-in-human, Phase 1 study of ASTX029, a dual-mechanism inhibitor of ERK1/2, in relapsed/refractory solid tumors Abstract: Background: The RAS-RAF-MEK-ERK pathway is commonly upregulated in human cancers. This is an open-label Phase 1 study of ASTX029, a dual-mechanism extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, in subjects with relapsed/refractory solid tumors (NCT03520075). Methods: The primary objectives are to identify a maximum tolerated dose and/or recommended Phase 2 dose. ASTX029 was administered orally daily of 21-day cycles as powder-in-bottle (PiB, Cohort 1/10mg) and tablet formulation (beginning with Cohort 6/80 mg) under fed conditions, and as tablet formulation under fasting conditions (beginning with Cohort 8/40 mg). Dose escalation occurred according to a “3+3 design” based on dose-limiting toxicity (DLT) events. Disease response was evaluated according to RECIST v1.1 and exploratory indicators, including tumor variant allele frequency changes detected by cell-free DNA (cfDNA) quantitation. Results: 56 subjects were treated with at least one dose of ASTX029 in Phase 1A (dose escalation). Of 46 subjects with data, 35 (76%) had any RAS mutations and 3 (9%) had BRAF mutations; 1 subject had both. At the 200 mg dose level (Cohort 5, PiB/fed), one of six evaluable subjects developed a DLT (grade 3 maculopapular rash). At the 280 mg dose level (Cohort 12, tablet/fasting), two subjects experienced grade 2 central serous retinopathy adverse events (CSR AEs) within a few days of dosing. These were the only CSR AEs noted and one event was declared a DLT. Both subjects recovered to baseline within days of dose interruption. One cohort level below this dose was expanded (Cohort 11/200 mg, tablet/fasting); this dose level was deemed safe (without a DLT or grade ≥2 visual AE in 7 subjects) and was selected for Phase 1B dose expansion. Mean pharmacokinetic (PK) exposure was 151% of target exposure, which is defined as the level expected to have biological activity based on animal studies. The most frequent grade ≥2 AEs assessed as drug-related included nausea (4 subjects, grade 2) and transaminitis (4 subjects: 3 grade 2, 1 grade 3). The grade 3 transaminitis occurred in a subject with metastatic sarcoma involving the liver. There was one serious AE of malaise considered related to study drug. Two subjects, one with KRAS-G12A and BRAF-D549N non-small cell lung cancer (120 mg) and one with KRAS-G12D metastatic pancreatic cancer (200 mg), achieved partial responses (cycle 15/ongoing and cycle 3/ongoing, respectively). In 2 subjects with stable disease as the best response, longitudinal cfDNA sequencing showed a decrease of tumor variant allele frequencies after 2 cycles of ASTX029, followed by a return to baseline levels before disease progression. The most common reason for ASTX029 discontinuation was disease progression. Conclusions: This Phase 1A study of the ERK1/2 inhibitor ASTX029 has identified a dose level of 200 mg daily of a 21-day cycle for investigation in the Phase 1B portion of the study. Pharmacokinetic and pharmacodynamic data suggest target exposures are achieved with preliminary clinical activity.

 

Chessari at al. Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction; Med Chem 2021

/in , , , , ,

Chessari at al., “Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction”; Med Chem 2021

https://doi.org/10.1021/acs.jmedchem.0c02188

2020 ASH: Anti-tumor Activity of ASTX029, a Dual Mechanism Inhibitor of ERK1/2, in Preclinical AML Models

/in , ,

View Poster:
Anti-tumor Activity of ASTX029, a Dual Mechanism Inhibitor of ERK1/2, in Preclinical AML Models

Abstract:

Oncogenic mutations in genes such as the RAS family (KRAS, NRAS or HRAS) or receptor tyrosine kinases (RTKs) drive tumor growth through aberrant activation of the mitogen activated protein kinase (MAPK) signaling pathway. Acute myeloid leukemia (AML) patients frequently exhibit activating mutations in MAPK pathway members, such as NRAS and KRAS, suggesting that these malignancies may be driven by aberrant activation of the MAPK pathway. Targeting of the MAPK pathway has been clinically validated in solid tumors, with agents targeting BRAF and MEK approved for the treatment of BRAF-mutant melanoma. However, there is currently no approved therapy directly targeting activated RAS family members and resistance to MAPK pathway inhibitors is frequently associated with reactivation of MAPK signaling. ERK1/2 (ERK) is a downstream node in the MAPK pathway and therefore represents an attractive therapeutic target for inhibition of MAPK signaling in these settings.

We have recently described in vivo anti-tumor activity in MAPK-activated solid tumor models following treatment with ASTX029, a highly potent ERK inhibitor developed using fragment-based drug design. ASTX029 has a distinctive ERK binding mode which confers dual mechanism inhibition of ERK, inhibiting both the catalytic activity of ERK and its phosphorylation by MEK. Here, we demonstrate that ASTX029 is also active in AML models and potently inhibits in vitro and in vivo MAPK signaling and growth in these models.

Using a panel of 15 AML cell lines, we investigated sensitivity to ASTX029 in vitro. We observed that 8 cell lines bearing mutations leading to increased MAPK pathway signaling were sensitive to treatment with ASTX029 with an average IC50 value of 47 nM, in contrast to an average IC50 value of 1800 nM for cell lines without activating mutations. The phosphorylation of RSK, a direct substrate of ERK, was suppressed for up to 24 h following treatment with ASTX029 in vitro. We have previously demonstrated good oral bioavailability for ASTX029 and once daily dosing resulted in significant tumor growth inhibition in AML cell line xenograft models. To confirm target engagement in vivo, we examined MAPK signaling in xenograft tissue and observed inhibition of the phosphorylation of RSK and of ERK itself, consistent with the dual mechanism of action proposed for ASTX029.

In summary, the ERK inhibitor, ASTX029, has potent activity against MAPK-activated tumor models, including AML models, and is now being tested in a Phase 1/2 clinical trial in advanced solid tumors (NCT03520075). These data highlight its therapeutic potential for the treatment of AML in patients with mutations leading to MAPK pathway activation and support further investigation in these patient populations.

ASH 2020: Comparative Results of Azacitidine and Decitabine from a Large Prospective Phase 3 Study in Treatment Naive Patients with Acute Myeloid Leukemia Not Eligible for Intensive Chemotherapy

/in , ,

View Video Poster: Comparative Results of Azacitidine and Decitabine from a Large Prospective Phase 3 Study in Treatment Naive Patients with Acute Myeloid Leukemia Not Eligible for Intensive Chemotherapy

Abstract:

Background:
Background: Prognosis of elderly (≥65 years of age) patients (pts) with acute myeloid leukemia (AML) remains dismal with a substantial proportion being deemed unfit for intensive chemotherapy. Monotherapy with the hypomethylating agents azacitidine (AZA) or decitabine (DEC) has been the de facto standard of  care for the treatment of chemotherapy-ineligible AML pts although both AZA and DEC did not improve median OS compared to low-dose cytarabine (LDAC) or physician choice, respectively, in phase III trials. No clinical trials comparing AZA and DEC head-to-head in AML exist. Here, we present a subgroup analysis of pts enrolled in the phase III ASTRAL-1 trial (NCT02348489) who were randomized to the AZA or DEC control arm.

Methods:
ASTRAL-1 randomized 815 treatment-naïve AML pts ineligible for intensive chemotherapy in a 1:1 ratio to either guadecitabine or treatment-choice (TC) of AZA, DEC, LDAC (NCT02348489). Study protocol and results have been presented previously (Fenaux, EHA 2019). Briefly, adult (≥18 years of age) pts with newly-diagnosed AML ineligible for intensive chemotherapy based on age of 75 years or older, major organ comorbidities, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-3 were eligible for enrollment. Exclusion criteria included prior treatment with AZA or DEC, extramedullary central nervous system AML, inability to tolerate treatment in the TC arm, or refractory congestive heart failure, uncontrolled active infection, or advanced pulmonary disease. Pts were pre-selected to receive either AZA, DEC, or LDAC with subsequent 1:1 randomization to either guadecitabine or TC in the respective arm. Patients treated with standard doses and schedules of AZA or DEC within the TC arm were included in the subgroup analysis presented here. Co-primary outcomes were rates of complete response (CR) and median, 1-year, and 2-year overall survival (OS) as defined by the International Working Group response criteria for AML. Composite CR (CRc) was defined as the composite of CR, CR with incomplete platelet count recovery (CRp), and CR with incomplete cell count recovery (CRi).

Rates of CR among pts treated with AZA and DEC were compared using Fisher’s exact test. Survival outcomes were compared using log-rank tests to compare the hazard ratio for death among the AZA and DEC treated pts. Subgroup analyses for OS stratified by patient and disease characteristics were performed.

Results:

815 patients were enrolled in the ASTRAL-1 trial across 144 sites in 24 countries with 171 and 167 pts being randomized to and treated with AZA and DEC in the TC arm of the trial, respectively. Baseline patient and disease characteristics were well-balanced between the AZA and DEC-treated pts (Table 1). The median number of treatment cycles was 6 (range [R]: 1-31) in the AZA arm and 5 (R: 1-34) in the DEC arm. There was no statistically significant difference in the co-primary endpoint of CR with 30 pts (17.5%) in the AZA and 32 pts (19.2%) in the DEC arm achieving CR (p=0.78). The rate of CRc (CR + CRp + CRi) was comparable among AZA and DEC-treated patients with 22.2% (38 out of 171 pts) and 25.1% (42 out of 167 pts), respectively (Table 2). Median OS between AZA and DEC-treated pts was similar with 8.7 months and 8.2 months in the two arms, respectively (hazard ratio [HR] for death: 0.97; 95% CI: 0.77-1.23; p=0.81). One-year and 2-year OS was comparable in both groups with 39% and 15% in the AZA arm and 32% and 14% in the DEC arm, respectively. Median OS estimates in clinically or genetically-defined patient subgroups were similar between AZA and DEC-treated pts. Serious adverse events leading to death occurred more frequently in the AZA arm compared with DEC (AZA: 38% vs 26% with DEC; p=0.02).

Conclusion:

Outcomes in treatment-naïve AML pts ineligible for intensive chemotherapy treated with AZA or DEC in the randomized phase III ASTRAL-1 trial are comparable with CR rates of 17.5% and 19.2% and median OS of 8.7 months and 8.2 months, respectively. No patient, disease, or molecular characteristics predicted a higher likelihood of response to either AZA or DEC. Safety in this frail patient population was comparable to prior trails of HMAs in AML and no major safety differences between AZA and DEC were detected although fatal serious adverse events tended to be higher in the AZA-treated cohort.

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

/in , ,

View Poster:
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

/in , , , , ,

View Poster:

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