2019 EORTC: Preliminary results of ASTX660, a novel non-peptidomimetic cIAP1/2 and XIAP antagonist, in 118 patients with solid tumors or lymphoma

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Preliminary results of ASTX660, a novel non-peptidomimetic cIAP1/2 and XIAP antagonist, in 118 patients with solid tumors or lymphoma

Abstract
Background:
ASTX660 is an oral, novel nonpeptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first-in-human phase 1‒2 study in patients (pts) with advanced solid tumors or lymphoma (ClinicalTrials.gov NCT02503423). In the ongoing phase 2, ASTX660 has demonstrated preliminary evidence of clinical activity in the relapsed/refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) cohorts (Mehta et al, presented at the EHA Conference 2019, abs PS1073). Here, we report overall efficacy and safety data from the solid tumors (head and neck squamous cell carcinoma [HNSCC]; cervical carcinoma and other solid tumors) and lymphoma (diffuse large B-cell lymphoma [DLBCL], PTCL, CTCL,) phase 2 cohorts.

Method:
Pts received treatment with ASTX660 orally at the RP2D 180mg/day on days 1 to 7, and 15 to 22 in a 28-day cycle. In the first stage 14 evaluable pts were enrolled in each of the 6 phase 2 cohorts with the option to expand the cohort if activity was observed. The primary endpoint was response rate as assessed by the investigator according to the Lugano criteria (DLBCL and PTCL), Global Assessment (CTCL), or RECIST 1.1 (solid tumors). Adverse events (AEs) were assessed per CTCAE V4.03.

Result:
As of June 4, 2019, a total of 107 pts have received ASTX660 in the solid tumors and lymphoma phase 2 cohorts (HNSCC n=14; DLBCL n=16; PTCL n=26; CTCL n=23; cervical carcinoma n=14; other solid tumors n= 14). Median age (range) was 61 (23-84) years and median number (range) of prior anticancer regimens was 3 (0-12). Among all pts, the most common related AEs of any grade (≥ 10%) were rash (35%), lipase elevation (34%), amylase elevation (29%), diarrhea (14%), fatigue (14%), AST elevation (13%), nausea (13%), and anemia (11%). Related AEs ≥ Grade 3 occurring in ≥ 5% of pts were rash (18%), lipase elevation (16%) and amylase elevation (9%). As of 4 June 2019, 86 pts (80%) discontinued study treatment: 64 (60%) due to progressive disease, 13 (12%) due to AE, 4 (4%) due to death, 4 (4%) due to withdrawal by participant and 1 (1%) for investigator’s decision. At the time of analysis, the ORR was 36% in the PTCL cohort and 15% in the CTCL cohort. One PR was reported in a pt with metastatic melanoma after 12 cycles of treatment. No objective responses were reported in the HNSCC, DLBCL or cervical cohorts. Accrual in the PTCL and CTCL continues; updated efficacy and safety data will be presented at the meeting.

Conclusion: In the phase 2 part of the study ASTX660 monotherapy has demonstrated a manageable safety profile and encouraging activity in PTCL and CTCL warranting cohort expansion. Future plans include evaluation of ASXT660 both as mono- or combination therapy in selected malignancies.

2019 EHA: ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, induces apoptosis in T cell lymphoma by enhancing immune mediated and death receptor dependent killing

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ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, induces apoptosis in T cell lymphoma by enhancing immune mediated and death receptor dependent killing

 

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 tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor (TNF) receptor superfamily mediated apoptosis and are potent anti-tumor immune enhancers.

Aim: Herein, we describe the profile of ASTX660 in a range of T cell lymphoma (TCL) cell lines and evaluate ASTX660’s ability to enhance immune mediated killing of tumor cells.

Methods: A panel of human and mouse T-cell lymphoma cell lines were tested in proliferation (Alamar blue or CellTiterGlo) or apoptosis assays (activated caspase-3 substrate assays by IncuCyte or FACS) for sensitivity to ASTX660 alone or in combination with recombinant Death Receptor ligands (TNFa, FASL or TRAIL). Additionally, we used a novel co-culture system of tumor cell lines with anti-CD3 activated human peripheral blood mononuclear cells (PBMC) to assess ASTX660 effects on immune mediated cell killing. Target engagement and induction of apoptosis markers were analysed by Western blotting.

Results: ASTX660 antagonises IAPs in TCL cell lines, as indicated by a decrease in cIAP1 protein levels. This ASTX660-dependent decrease in cIAP was associated with an increase in TNFa-dependent apoptosis in the EL4 and L5178 TCL cell lines. Several T-cell lymphoma models, including HuT-78, HH and My-La expressed low levels of TNFR1 and therefore did not respond to ASTX660 in the presence of TNFa. However, in these cell lines, ASTX660 conferred a significant increase in FASL or TRAIL-dependent apoptosis, indicating that ASTX660 sensitises TCL cells to various death receptor ligands and response correlates with receptor expression levels. In addition to this direct effect on TCL cell lines, ASTX660 also enhances anti-CD3 stimulated PBMC-dependent killing of multiple tumour cell lines, including TCL lines, via induction of caspase activity. Additional preclinical experiments (both in vitro and in vivo) are underway to further characterise the mode of action of ASTX660 in TCL.

Conclusion: The combination of both direct and indirect effects of ASTX660 on TCL lines, described here, supports the ongoing clinical testing of ASTX660 in TCL (NCT02503423). Preliminary clinical efficacy and safety data of ASTX660 in relapsed/refractory (r/r) peripheral T cell lymphoma and cutaneous T cell lymphoma is the subject of a separate abstract.

 

2019 EHA: Preliminary Results of ASTX660, a Novel Non-Peptidomimetic cIAP1/2 and XIAP Antagonist, in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

Background: ASTX660 is an oral, novel nonpeptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first-in-human phase 1‒2 study in patients (pts) with advanced solid tumors and lymphoma (ClinicalTrials.gov NCT02503423). In the phase 1 part of the study, the recommended phase 2 dose (RP2D) was identified with a favorable safety profile and initial evidence of clinical activity in a pt with mycoses fungoides (Mita et al, presented at the AACR-NCI-EORTC Conference 2017, abs #A091).

AIMS: Herein we report preliminary efficacy and safety data from the relapsed/refractory (r/r) peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) Phase 2 cohorts.

Methods: Pts receive treatment with ASXT660 at the RP2D 180mg/day on Days 1 to 7, and 15 to 22 in a 28-day cycle. The primary endpoint is response rate as assessed by the investigator according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Adverse events (AEs) are assessed per CTCAE V4.03.

Results: As of 15 January 2019, 16 PTCL pts and 13 CTCL pts have received ASTX660. Pt characteristics: median (range) age: PTCL: 59 (39-81) years and CTCL: 57 (23-75) years; median prior therapies: PTCL: 3 (1-7) and CTCL: 3 (1-9). In the PTCL cohort the ORR is 28% (4/14); 2 pts have yet to reach their first assessment. Three responding pts remain on study drug for 7-10 months. Responses have been observed in pts with AITL and PTCL-NOS. In the CTCL cohort the global response is 25% (3/12); 1 pt has yet to reach their first assessment. Two responding pts remain on study drug for 4-6 months. Responses have been seen in pts with large cell transformation, sezary syndrome and visceral metastases. Among all pts, the most common related AEs of any grade (≥ 15%) were lipase elevation (38%), amylase elevation (34%), ALT elevation (28%), elevation (24%) and rash (24%). Related AEs ≥ Grade 3 occurring in ≥3 pts were rash (n=5) and lipase elevation (n=4). Accrual continues; updated efficacy and safety data will be presented at the meeting.

Conclusion: In ongoing Phase 2 cohorts ASTX660 has shown activity against PTCL and CTCL with manageable safety profile. These early data support continued development of ASXT660 for the treatment of r/r PTCL and CTCL. Correlative studies are aimed at identifying predictors of response.

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Preliminary Results of ASTX660, a Novel Non-Peptidomimetic cIAP1/2 and XIAP Antagonist, in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

2018: ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth.

Abstract

Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. ASTX660 is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells, and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue, direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of noncanonical NF-κB signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNFα-dependent induction of apoptosis in various cancer cell lines in vitro, whereas dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase I–II clinical trial (NCT02503423), and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective. Mol Cancer Ther; 17(7); 1–11. ©2018 AACR.

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Ward et al. “ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth.” Mol Cancer Ther. June 14, 2018, doi: 10.1158/1535-7163.MCT-17-0848

2017 EORTC: Phase 1 study of the IAP inhibitor ASTX660 in adults with advanced cancers and lymphomas

Summary
Due to their roles in the evasion of apoptosis, Inhibitor of Apoptosis Proteins (IAPs) are considered attractive targets for anti-cancer therapy. ASTX660 is a potent, next generation, non-peptidomimetic, dual antagonist of both XIAP and cIAP1, discovered using fragment-based drug design (1-3). We report here the results of the first-in-human phase 1 dose escalation and dose expansion study of ASTX660 administered orally to adults with advanced solid tumors and lymphoma.

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Phase 1 study of the IAP inhibitor ASTX660 in adults with advanced cancers and lymphomas

2016 AACR: Dual IAP Antagonist, ASTX660, Increases Anti-tumor Activity of Paclitaxel in TNBC Models

Summary

Paclitaxel-mediated secretion of inflammatory mediators, including TNFα, potentially creates paracrine and autocrine loops that can contribute to survival and reduction of paclitaxel-induced apoptosis in cancer cells.

One of the mechanisms of cancer cell survival is the expression of inhibitor of apoptosis proteins (IAPs). Cellular IAP (cIAP) is involved in inflammatory pro-survival NF-B activation, blocking the activation of the effector caspases 3 and 7, while X-linked IAP (XIAP) directly binds the effector caspases 3, 7 and 9, inhibiting the full activation of the apoptosis pathway.

ASTX660, a fragment-derived small molecule that is orally bioavailable, is a dual antagonist of cIAP and XIAP (Chessari 2014). Its inhibitory activity has been demonstrated in preclinical models of melanoma and other types of cancer, in which inflammation was present. It is currently being investigated in a single-agent Phase I/II clinical trial in patients with advanced solid tumors and lymphomas (NCT02503423).

Here, we characterize the activity of ASTX660 in preclinical models of triple-negative breast cancer (TNBC) as a single agent and in combination with paclitaxel whose inflammatory properties are hypothesized to sensitize the cells to ASTX660.

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AACR: Dual IAP Antagonist, ASTX660, Increases Anti-tumor Activity of Paclitaxel in TNBC Models

2014 EORTC: Induction of apoptosis with a novel dual cIAP1/XIAP antagonist in models of melanoma

Summary

Inhibitor of apoptosis (IAP) antagonists are being tested in the clinic for the treatment of cancer as they can switch cancer cell TNFα signalling from being pro-survival to being pro-apoptotic, and
relieve the block on effector caspase activation (1,2). Astex has used fragment based-drug discovery to develop a first-in-class, dual XIAP/cIAP1 antagonist (ASTX660), which is non-peptidomimetic,
does not contain an alanine as a warhead and demonstrates prolonged antagonism of both XIAP and cIAP1 in vivo.

Melanoma is a highly aggressive malignancy with an exceptional ability to develop resistance to targeted therapies. Targeting IAP proteins in melanoma is a promising strategy to overcome this
resistance (3), and ASTX660 represents a novel approach because of the enhanced potency against XIAP (4).

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2014 EORTC: Induction of apoptosis with a novel dual cIAP1/XIAP antagonist in models of melanoma

2014 BACR: Characterisation of the Activity of Potent XIAP/cIAP1 Dual Antagonists in Melanoma Models

Summary

The inhibitor of apoptosis proteins (IAPs) are widely de-regulated in many tumours and contribute to cancer drug resistance. The targeted inhibition of IAPs can switch TNF-alpha
signaling in cancer cells from pro-survival to pro-apoptotic. Therefore, IAPs represent an attractive target for cancer therapy.
The IAP family member cellular IAP1 (cIAP1) is involved in the regulation of TNF-alpha signaling and X-linked IAP (XIAP) directly interacts with and inhibits caspases. IAP family members are
characterized by BIR (baculoviral IAP repeat) domains, to which the endogenous inhibitor of IAPs SMAC (second mitochondria derived activator of caspases) binds. Peptidomimetic compounds
based on the SMAC sequence have been developed, but they show high selectivity for cIAP1. We used our fragment based-drug discovery approach to generate a non-alanine, nonpeptidomimetic
IAP antagonist, which has dual potency for XIAP and cIAP1. Here we describe the characterization of this compound in in vitro and in vivo models of melanoma and breast cancer.
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2014 BACR: Characterisation of the Activity of Potent XIAP/cIAP1 Dual Antagonists in Melanoma Models

2014 CPTT. Novel Small Molecule Antagonists of XIAP and cIAP Generated by Fragment-based Drug Discovery

Summary

The inhibitor of apoptosis proteins (IAPs) are widely de-regulated in many tumours and contribute to cancer drug resistance. The targeted inhibition of IAPs can switch TNF-alpha
signaling in cancer cells from pro-survival to pro-apoptotic. Therefore, IAPs represent an attractive target for cancer therapy.
The IAP family member cellular IAP1 (cIAP1) is involved in the regulation of TNF-alpha signaling and X-linked IAP (XIAP) directly interacts with and inhibits caspases. IAP family members are
characterized by BIR (baculoviral IAP repeat) domains, to which the endogenous inhibitor of IAPs SMAC (second mitochondria derived activator of caspases) binds. Peptidomimetic compounds
based on the SMAC sequence have been developed, but they show high selectivity for cIAP1. We used our fragment based-drug discovery approach to generate a non-alanine, nonpeptidomimetic
IAP antagonist, which has dual potency for XIAP and cIAP1. Here we describe the characterization of this compound in in vitro and in vivo models of melanoma and breast cancer.

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2014 CPTT. Novel Small Molecule Antagonists of XIAP and cIAP Generated by Fragment-based Drug Discovery