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Decitabine

Decitabine and cedazuridine drug combination

Antimetabolites

Enzyme Inhibitors

ASTX660 once daily (Days 1-7 and 15-21 per 28-day cycle) + ASTX727 FDC once daily (Days 1-5 per 28-day cycle)

ASTX660 once daily (Days 1-7 and 15-21 per 28-day cycle) as a single agent or in combination with ASTX727 FDC once daily (Days 1-5 per 28-day cycle)

ASTX660 at the recommended dose for expansion identified in Part 2 + ASTX727 FDC once daily (Days 1-5 per 28-day cycle)

ASTX660

ASTX727

To evaluate the safety, pharmacokinetics (PK), and efficacy of ASTX660 when given alone and in combination with ASTX727 in participants with relapsed/refractory (R/R) acute myeloid leukemia (AML). The duration of the study is expected to be approximately 30 months.

This is a three-part dose escalation and dose expansion Phase 1 study of ASTX660 alone and in combination with ASTX727 in adults with R/R AML.

Part 1 is an open-label, single arm, dose escalation with ASTX660 in combination with ASTX727 at the standard fixed dose combination (FDC).

Part 2 is an open-label, randomized, dose escalation intended to evaluate ASTX660 as a monotherapy and ASTX660 in combination with ASTX727 FDC.

Part 3 is an exploratory single arm dose expansion to further expand the number of participants treated with ASTX660 in combination with ASTX727 FDC.

A Study of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)

A Phase 1, Parallel, Open-Label Study of the Safety and Tolerability, Pharmacokinetics, and Antileukemic Activity of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Astex Pharmaceuticals, Inc.

Immune System Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Lymphoma

Uterine Cervical Neoplasms

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Dose-escalation stage to identify the MTD and the RP2D, defined as either the MTD or a dose below the MTD that the Data and Safety Review Committee (DSRC) agree shows adequate pharmacological evidence of target engagement and/or clinical activity. Subjects will receive ASTX660 once a day for 7 consecutive days every other week of each 28-day cycle (ie, \[7 days on/ 7 days off\] ×2; daily dosing on Days 1-7 and 15-21). The starting dose will be escalated stepwise in successive cohorts of 3 to 6 evaluable subjects each (standard 3+3 study design), until the RP2D is determined.

Dose-expansion stage to confirm tolerability of ASTX660 at the RP2D using the every-other-week daily dosing regimen. Up to a total of 12 subjects (including the 3 or 6 subjects treated at the RP2D in Part 1) will be treated at the RP2D.

The purpose of the optional Part 3 is to allow for exploration of an alternative dosing regimen of ASTX660 based on emerging safety, PK, and pharmacodynamic (PD) data from Parts 1 and 2 (using the original every-other-week dosing regimen), with agreement of the DSRC. If Part 3 is conducted, the plan is to enroll up to 18 evaluable subjects in 1 or more cohorts using a standard 3+3 study design.

Treatment with ASTX660 for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) not responsive or relapsed after standard therapy.

Treatment with ASTX660 for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Treatment with ASTX660 for progressive or relapsed peripheral T-cell lymphoma (PTCL).

Treatment with ASTX660 for relapsed or refractory cutaneous T-cell lymphoma (CTCL).

Treatment with ASTX660 for other tumor types that are characterized by a molecular feature that may confer sensitivity to ASTX660 (eg, oncogenic activation of the NF-κB pathway or documented amplification of the gene loci encoding c-IAP1 or c-IAP2), pending confirmation in writing by the Astex medical monitor.

Treatment with ASTX660 for cervical carcinoma not responsive or relapsed after standard therapy.

This is an open-label, dose-escalation Phase 1/2 study to assess the safety of ASTX660, determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and recommended dosing regimen, and to obtain preliminary efficacy, pharmacokinetic (PK), and target engagement data, in subjects with advanced solid tumors or lymphoma for whom standard life-prolonging measures are not available.

ASTX660 is a synthetic small molecule dual antagonist of cellular inhibitor of apoptosis protein (cIAP) 1 and X-linked inhibitor of apoptosis protein (XIAP) that has been shown to have potent proapoptotic and tumor growth inhibitory activity in nonclinical models. The Phase 1 portion of the study (completed) will determine the MTD, RP2D, and recommended dosing regimen. The Phase 2 portion will evaluate activity in selected tumor types. Subjects will continue to receive their assigned treatment throughout the study until the occurrence of disease progression, death, or unacceptable treatment-related toxicity, or until the study is closed by the sponsor.

Phase 1-2 Study of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas

Phase 1-2 Study of the Safety, Pharmacokinetics, and Preliminary Activity of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas

Incidence of dose-limiting toxicities (DLTs) and other adverse events (AEs)

Antitumor activity by objective response rate

Antitumor activity by disease control rate

Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC).

Assessment of pharmacokinetic parameter maximum concentration (Cmax).

Assessment of pharmacokinetic parameter minimum concentration (Cmin).

Assessment of pharmacokinetic parameter time to maximum concentration (Tmax)

Assessment of pharmacokinetic parameter elimination half life (t½).

Assessment of pharmacokinetic parameter of other secondary PK parameters of ASTX660 if data permit.

Assessment of pharmacokinetic parameter analysis of ASTX660 metabolites if applicable.

Time from the date of the earliest assessment of complete response or partial response to the date of relapse or death, whichever occurs earlier, or the last efficacy assessment date for subjects without a relapse or death.

Number of days from the start of the study treatment to disease progression or death, whichever occurs first.

Number of days from the day the subject received the first study treatment to the date of death, regardless of cause.

Percentage degradation of cIAP1 protein in PBMCs from baseline, in response to ASTX660 treatment.

Skin and Connective Tissue Diseases

Breast Neoplasms

Triple Negative Breast Neoplasms

Death

Breast Diseases

Skin Diseases

Pharmaceutical Solutions

Respiratory System Agents

Amino Acids

Immune Checkpoint Inhibitors

Pembrolizumab

Pulmonary Surfactants

Antineoplastic Agents, Immunological

Histidine

Increasing doses of ASTX660 in combination with a fixed dose of pembrolizumab to establish the maximum tolerated dose (MTD) of ASTX660 and Pembrolizumab when given in combination in patients with advanced solid tumours.

escalating doses of ASTX660 will be investigated in combination with a fixed dose of Pembrolizumab (200mg). ASTX660 administration will follow a 7 day on / 14 day off pattern (ie dosing for 7 consecutive days leading up to administration of the immune check-point inhibitors). Therefore in Cycle 1, ASTX660 will be given alone from Day 1 to Day 7, followed by a 14 day break, then taken again in Cycle 2 . Each cycle will run for a period of 21 days, with ASTX660 taken always on Days 1 to 7 and Pembrolizumab given always on Day 8.

Up to 4 dose levels of ASTX660 will be explored.

Patients in Part B will be treated at the RP2D as determined by the SRC after the initial dose escalation (Part A) has been completed. The treatment schedule will be the same as that for Part A, i.e. each cycle will be 21 days-long. Pembrolizumab will always be administered on D8 of every cycle. ASTX660 will be taken daily on Days 1-7.

Part B will be split into 3 cohorts; Cohort B1, Cohort B2 and Cohort B3.

Cohort B1: Patients with Immune-checkpoint refractory tumours Cohort B2: Patients with PD-L1 positive Cervical Cancer Cohort B3: Patients with Triple Negative Breast Cancer

ASTX660 will be supplied as capsules. Each hydroxylpropyl methylcellulose (HPMC) capsule contains either 30 mg or 90 mg of ASTX600 free-base equivalents, suitable for oral administration. Bottles are labelled with the capsule strength (ie, 30 mg or 90 mg) and are further distinguished by different-colored labels. Each bottle contains 14 capsules and an oxygen-absorber (not to be consumed).

Pembrolizumab Solution for Infusion 100 mg/vial is a liquid drug product supplied as a clear to opalescent solution, essentially free of visible particles, in Type I glass vials and manufactured using the fully formulated drug substance with L-histidine as buffering agent, polysorbate 80 as surfactant, and sucrose as stabilizer/tonicity modifier.

Pembrolizumab Solution for Infusion can be further diluted with normal saline or 5% dextrose in the concentration range of 1 to 10 mg/mL in IV containers made of polyvinyl chloride (PVC) or non-PVC material.

Anna Zachariou, PhD

Angela Little, RN

Juanita Lopez, MRCP

This is a multi-centre Phase I dose finding and proof-of-concept study of the combination of ASTX660 together with Pembrolizumab with expansion cohorts testing preliminary efficacy in immune-refractory cancers, triple negative breast cancer (TNBC), cervical cancer, and glioblastoma.

In contrast to the existing studies combining first-generation cIAP1/2 selective Smac mimetics with immune check point inhibitors, the ASTEROID Phase I clinical trial will be the first trial utilising triple cIAP1/2 and XIAP blockade by ASTX660 as a strategy to maximise immunogenic cell death and the generation of an efficient adaptive immune response. ASTX660 is not simply being used to repeat the data already being acquired with other first generation Smac mimetics. In contrast, we will investigate more in depth the mechanisms by which ASTX660 elicits its therapeutic effects both on tumour and on the host immune system. This will be critical to determine the best strategy to pursue in future later stage tumour specific trials of IAP antagonists in combination with immunotherapy, and to ensure appropriate molecular stratification biomarkers for the greatest benefit to patients.

ASTEROID: A Trial of ASTX660 in Combination With Pembrolizumab

ASTEROID:A Phase I Trial of ASTX660 in Combination With Pembrolizumab in Patients With Solid Tumours: Utilizing Triple IAP Blockade as a Strategy to Maximize Immunogenic Cell Death and the Generation of an Efficient Adaptive Immune Response

Determination of changes in immune cell population (using FACS) and host immune cell cytokine profile with single agent ASTX660 and the combination of ASTX660 and Pembrolizumab

Determination of changes in the tumour microenvironment including changes in tumour infiltrating lymphocytes (TILs), myeloid derived suppressor cells (MDSCs) and other immune cells.

Determination of changes in exploratory biomarkers including but not limited to immune transcriptome profile changes, PD-L1 expression and tumour lysate cytokine profiling in pre- and post-treatment tumour biopsies.

To evaluate the effect of ASTX660 on the tumour microenvironment including the evaluation of inflammatory cytokines downstream of NF-kB in paired tumour biopsies.

To evaluate changes in patient reported outcomes from baseline using the EORTCQLQ-C30

To estimate the overall survival (OS) in patients receiving the combination of pembrolizumab and ASTX660.

To determine the Maximum Tolerated Dose (MTD) of ASTX660 in combination with Pembrolizumab based on dose-limiting toxicities (DLTs) up to 6 weeks from start of treatment and the RP2D.

To determine the frequency, severity and causality of each adverse event to the combination of ASTX660 and Pembrolizumab according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

Assessment of disease response by imRECIST criteria, clinical benefit rate, best changes in tumour size, progression-free survival and duration of response.

Determination of the plasma levels of ASTX660 in Part A of the study, using validated assays

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)	NCT04155580	Acute Myeloid L...	ASTX660 ASTX727	18 Years -	Astex Pharmaceuticals, Inc.
Phase 1-2 Study of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas	NCT02503423	Solid Tumors Lymphoma	ASTX660	18 Years -	Astex Pharmaceuticals, Inc.
A Study of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)	NCT04155580	Acute Myeloid L...	ASTX660 ASTX727	18 Years -	Astex Pharmaceuticals, Inc.
ASTEROID: A Trial of ASTX660 in Combination With Pembrolizumab	NCT05082259	Advanced Cancer Cervical Cancer Triple Negative...	ASTX660 Pembrolizumab	18 Years -	Institute of Cancer Research, United Kingdom
A Study of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)	NCT04155580	Acute Myeloid L...	ASTX660 ASTX727	18 Years -	Astex Pharmaceuticals, Inc.
ASTEROID: A Trial of ASTX660 in Combination With Pembrolizumab	NCT05082259	Advanced Cancer Cervical Cancer Triple Negative...	ASTX660 Pembrolizumab	18 Years -	Institute of Cancer Research, United Kingdom

Spots Global Cancer Trial Database for astx660

Every month we try and update this database with for astx660 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for astx660

Every month we try and update this database with for astx660 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for astx660 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.