ASTEROID: A Trial of ASTX660 in Combination With Pembrolizumab

NCT05082259 | Recruiting Phase 1

• 1 other identifier: CCR5199
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Advanced Cancer; Cervical Cancer; Triple Negative Breast Cancer

Outcome Measures

Primary Outcomes (3)

• Determination of MTD and RP2D

  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.

  12 months

• Safety and tolerability

  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.

  12 months

• Preliminary anti-tumour activity evaluation (in Part B)

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

  24 months

Secondary Outcomes (2)

• Preliminary anti-tumour activity evaluation (in Part A)

  12 months

• Pharmacokinetics of ASTX660

  12 months

Other Outcomes (6)

• Pharmacodynamics-1

  18 months

• Pharmacodynamics-2

  36 months

• Pharmacodynamics-3

  36 months

Study Arms (2)

Part A-Escalation

EXPERIMENTAL

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.

Drug: ASTX660; Drug: Pembrolizumab

Part B-Expansion

EXPERIMENTAL

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

Drug: ASTX660; Drug: Pembrolizumab

Interventions

ASTX660 DRUG

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).

Also known as: Tolinapant

Part A-Escalation; Part B-Expansion

Pembrolizumab DRUG

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.

Also known as: MK-3475

Part A-Escalation; Part B-Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• PART A: Patients with histologically or cytologically confirmed malignant advanced solid tumours, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient.
• PART B1: Patients with histologically or cytologically confirmed malignant advanced solid tumours (including melanoma, renal cell cancer, non-small cell lung cancer and head and neck squamous cell cancer), refractory to immune checkpoint inhibitors and for which no conventional therapy exists or is declined by the patient. Patients with other tumour types where immune checkpoint inhibitors are licensed can be considered upon discussion with the Chief Investigator.
• PART B2: Patients with histologically or cytologically confirmed cervical cancer, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient.
• PART B3: Patients with histologically or cytologically confirmed triple negative breast cancer, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient.
• PART B4 (no longer recruiting): Patients with histologically confirmed relapsed glioblastoma (GBM). Diagnosis of GBM will be based on WHO classification of CNS tumours, 5th edition (2021):
• IDH wild type diffuse astrocytic glioma with microvascular proliferation, OR necrosis, OR one or more of the following molecular features of GBM:
• TERT promoter mutation,
• EGFR gene amplification,
• gain/10 loss chromosome copy number changes.
• PART B5: Patients with histologically or cytologically confirmed ER positive HER2 negative breast cancer who have progressed on CDK4/6 inhibitor therapy.
• For Immune Checkpoint inhibitor refractory tumours, participants must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
• Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb.
• Has demonstrated disease progression after anti-PD-1/PD-L1 as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented disease progression, in the absence of rapid clinical progression (as defined in c below).
• Progressive disease has been documented within 24 weeks from commencing anti-PD-1/PD-L1 and no later than 12 weeks from the last dose of anti-PD-1/PD-L1 mAb.
• i) Progressive disease is determined according to iRECIST. ii) This determination is made by the investigator. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression.

You may not qualify if:

• Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy including Pembrolizumab or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and four weeks for investigational medicinal products, except for hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with castrate resistant prostate cancer or ovarian suppression in pre- or peri-menopausal women with endocrine-driven breast cancer, which are permitted, and bisphosphonates or RANK ligand antagonists that are permitted for the management of bone metastases.
• Current malignancies of other types, with the exception of adequately treated cone biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years or more and are deemed at negligible risk for recurrence, are eligible for the trial.
• Ongoing Grade 2 or greater toxicities from pre-existing conditions or previous treatments. Exceptions to this are alopecia and ongoing anticoagulation therapy due to prior thromboembolic episodes.
• Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible. NB. Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception \[condom plus spermicide\] and not to donate sperm during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
• For cohorts A, B1, B2, B3 and B5 only - Known untreated or active central nervous system (CNS) metastases (progressing or requiring corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:
• Evaluable or measurable disease outside the CNS is present.
• Radiographic demonstration of improvement or stability upon the completion of CNS-directed therapy at least 4 weeks after completion of CNS directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the baseline disease assessment.
• Not requiring corticosteroids.
• For Cohort B4 only (no longer recruiting):
• Participants with infratentorial tumors and tumors primarily located in or close to critical structures (e.g., brain stem). Patients with leptomeningeal disease.
• Patients with evidence of raised intracranial pressure or mass effect on imaging
• Patients unable to tolerate contrast enhanced MRI.
• Major surgery within four weeks of the first dose of study treatment.
• History of malabsorption syndrome or other condition that would interfere with enteral absorption.

Sponsors & Collaborators

• Institute of Cancer Research, United Kingdom: lead
• Astex Pharmaceuticals, Inc.: collaborator
• Merck Sharp & Dohme LLC: collaborator
• Cancer Research UK: collaborator

Study Sites (3)

Cambridge University Hospitals NHS Trust

Cambridge, CB2 0QQ, United Kingdom

RECRUITING

The Royal Marden NHS Foundation Trust - Drug Development Unit

Sutton, SM2 5PT, United Kingdom

RECRUITING

The Royal Marsden NHS Foundation Trust - Breast Unit

Sutton, SM2 5PT, United Kingdom

RECRUITING

MeSH Terms

Conditions

Uterine Cervical Neoplasms; Triple Negative Breast Neoplasms

Interventions

ASTX-660; pembrolizumab

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Breast Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Juanita Lopez, MRCP

  Royal Marsden Hospital NHS Foundation Trust

  STUDY DIRECTOR

Central Study Contacts

Anna Zachariou, PhD

CONTACT

02087224605; asteroid@icr.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 6, 2021
• First Posted: October 18, 2021
• Study Start: March 2, 2022
• Primary Completion: March 16, 2026
• Study Completion: March 16, 2026
• Last Updated: February 10, 2026

Record last verified: 2026-02

Locations

GB (3)