Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian CancerPhase 1NCT02264678

Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents

A Phase 1 study testing Administration of ceralasertib, Administration of ceralasertib in combination with olaparib and Administation of ceralasertib in combination with durvalumab in people with Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer, run by AstraZeneca at 28 sites in 4 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial summary

Who is it for?: Ages 18 to 130 years
Conditions the study is for: Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer
What is being tested?: Administration of ceralasertib, Administration of ceralasertib in combination with olaparib and Administation of ceralasertib in combination with durvalumab
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 358 participants
Where: 28 sitesin 4 countries
Study dates: 31 Oct 2014to 30 Dec 2026
Phase: Phase 1
Are there results?: Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 130 years
All sexes
No healthy volunteers
Adult, Older adult

Principal Inclusion criteria:

Aged at least 18
The presence of a solid malignant tumour that is not considered appropriate for further standard treatment
Module 2 Part B study expansions, and Module 3: patients must have a tumour at least 1 cm in size that can be measured using a CT or MRI scan
Module 2 Part B All (except B5): No previous treatment with PARP inhibitor.
Module 2 Part B1 Study expansion: advanced gastric adenocarcinoma (including GEJ) patients with ATM deficient tumours
Module 2 Part B2 Study expansion: advanced gastric adenocarcinoma (including GEJ) patients with ATM proficient tumours
Module 2 Part B3 Study expansion: Second or thrid line HER2 negative breast cancer
Module 2 Part B4 Study expansion: Second or third line triple negative breast cancer (TNBC)
Module 2 Part B5 Study expansion: BRCAm or RAD51C/Dm or PALB2m or HRD positive status ovarian cancer patient who are Platinum Sensitive Relapsed and have previously progressed on a licensed PARPi
Module 3: advanced recurrent or metastatic non-small cell lung cancer, or head and neck squamous cell carcinoma
Module 4: any advanced solid tumours except gastric, gastro-oesophageal, oesophageal or colorectal cancer with a small bowel resection
Module 4: Ability to comply with an overnight fast of at least 10 hours prior to dosing and 4 hours after dosing as mandated, and ability to eat a high fat meal as mandated
Module 5 All: Ovarian fallopian tube or primary peritonial cancer, previous treatment with PARP inhibitor, platinum-sensitive relapsed ovarian cancer
Module 5 Part B: known or suspected BRCA mutation, PALB2 mutation, RAD51C/D mutation or HRD positive status

Principal exclusion criteria

A diagnosis of ataxia telangiectasia
Prior exposure to an ATR inhibitor
Bad reaction to ceralasertib
Module 2: Contra-indicated for treatment with olaparib
Module 3: Contra-indicated for treatment with durvalumab
Module 4: Mean resting corrected QT interval (QTc) >470 msec or history of familial long QT syndrome.
Module 4: Patients with type I or type II diabetes
Module 5: Known hypersensitivity to PARP including AZD5305

Trial locations and contacts

28 sites in 4 countries.

Country

City, postcode or hospital

28 sites in 4 countries

United Kingdom11 sites

Research Site
Bristol, BS2 8ED
Research Site
Cambridge, CB2 0QQ
Research Site
Coventry, CV2 2DX
Research Site
London, SW3 6JJ
Research Site
London, W12 0HS
Research Site
London, W1G 6AD
Research Site
London, W1T 7HA
Research Site
Manchester, M20 4GJ
Research Site
Oxford, OX3 7LE
Research Site
Sutton, SM2 5PT
Research Site
Withington, M20 4BX

Other trials in United Kingdom

United States8 sites

Research Site
Boston, Massachusetts, 02215
Research Site
Duarte, California, 91010
Research Site
Irvine, California, 92618
Research Site
Los Angeles, California, 90024
Research Site
Los Angeles, California, 90089
Research Site
New York, New York, 10065
Research Site
Newport Beach, California, 92663
Research Site
Philadelphia, Pennsylvania, 19104

Other trials in United States

South Korea5 sites

Research Site
Goyang-si, 10408
Research Site
Seongnam-si, 13620
Research Site
Seoul, 03080
Research Site
Seoul, 03722
Research Site
Seoul, 06351

Other trials in South Korea

France4 sites

Research Site
Bordeaux, 33076
Research Site
Lyon, 69373
Research Site
Saint-Herblain, 44805
Research Site
Villejuif, 94805

Other trials in France

About this study

Official title: A Modular Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Ceralasertib in Combination With Cytotoxic Chemotherapy and/or DNA Damage Repair/Novel Anti-cancer Agents in Patients With Advanced Solid Malignancies.

This is a modular, phase I/ phase 1 b, open-label, multicentre study of ceralasertib administered orally in combination with cytotoxic chemotherapy regimens and/or novel anti-cancer agents, to patients with advanced malignancies. The study design allows an investigation of optimal combination dose of ceralasertib with other anti-cancer treatments, with intensive safety monitoring to ensure the safety of the patients. The initial combination to be investigated is ceralasertib with carboplatin. The second combination to be investigated is ceralasertib with Olaparib. The third combination to be investigated is ceralasertib with durvalumab. The fourth module will investigate the effect of food on ceralasertib absorption and the effect of ceralasertib on ECG parameter. The fifth module to be investigated is ceralasertib with AZD5305.

Read the detailed description

This is a modular, phase I, two part, open-label, multicentre study of ceralasertib, administered orally, in combination with cytotoxic chemotherapy regimens and/or novel anti-cancer agents, to patients with advanced/metastatic solid malignancies. The study design allows an escalation of the dose of ceralasertib in combination with the standard dose and schedule of either cytotoxic chemotherapies and/or novel anti-cancer agents, with intensive safety monitoring to ensure the safety of the patients. There are two parts to each combination module of this study; part A, dose escalation and an optional part B, cohort expansions in particular patient groups. The initial combination module will be with Carboplatin (module 1). The second combination will be with Olaparib (module 2). The third combination will be with durvalumab (module 3), the fourth combination will be AZD5305 (Module 5). The option to start further combination modules will be the decision of the Safety Review Committee (SRC), based on emerging preclinical data and, safety and tolerability information from the initial combination. Combinations of ceralasertib with novel anti-cancer agents may also be explored. Once a minimally biologically active dose of ceralasertib, for that combination module, has been identified from part A of that module, the SRC may decide to commence part B if deemed to be necessary. This may include cohort expansions of specific patient groups to explore preliminary anti-tumour activity or the effect of food or particular drug combinations on drug pharmacokinetics. The fourth module will investigate the effect of food on ceralasertib absorption and whether ceralasertib has an effect on QT.

Conditions: Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer
Being tested: Administration of ceralasertib, Administration of ceralasertib in combination with olaparib, Administation of ceralasertib in combination with durvalumab, Administration of ceralasertib monotherapy, Administration of ceralasertib and olaparib
Keywords: ATM deficient, ATM proficient, HER2 negative, Breast, Gastric, Head & Neck, Lung, Ovarian
Medical subject headings: Ovarian Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Administration of ceralasertibDrug
An oral formulation of ceralasertib will be used. In Module 2 Part A1, patients will receive a single dose of ceralasertib on Day 1, followed by 4 to 6 days washout, before multiple dosing.
Administration of ceralasertib in combination with olaparibDrug
An oral formulations of ceralasertib and olaparib will be used. In Module 2 Part A2, patients will receive either a single or twice daily dose of ceralasertib followed by 4 to 6 days washout, before multiple dosing with ceralasertib and olaparib. In Module 2 Part B, patients will receive ceralasertib and olaparib at the dose, frequency and schedule recommended from Module 2 Part A2. Cycle 0 may be omitted at the discretion of the sponsor.
Administation of ceralasertib in combination with durvalumabDrug
An oral formulation of ceralasertib will be used. Durvalumab is given via IV infusion. In Module 3 Part A, patients will receive an initial single dose of ceralasertib on Day 1, followed by multiple dosing in combination with durvalumab. In Module 3 Serial Tumour Biopsy Extension and Part B expansion cohorts, patients will receive ceralasertib at the dose, frequency and schedule recommended from Module 3 Part A, in combination with durvalumab.
Administration of ceralasertib monotherapyDrug
Module 4 Part A and Module 4 Part B Cohort 3: During C0, patients will receive ceralasertib monotherapy orally once a day on 3 non-consecutive days and ceralasertib twice a day on 5 consecutive days. After the patients have completed C0 (Part A) they may transition to Module 4 Part B cohort 3 where they will continue to receive ceralasertib monotherapy
Administration of ceralasertib and olaparibDrug
Module 4 Part B Cohort 1:
After completion of Part A (C0), the patient may transition to Part B and be allocated to receive ceralasertib in combination with olaparib as decided by the investigator.
Administration of ceralasertib and durvalumabDrug
Module 4 Part B Cohort 2:
After completion of Part A (C0), the patient may transition to Part B and be allocated to receive ceralasertib in combination with durvalumab as decided by the investigator.
Administration of ceralasertib in combination with AZD5305Drug
An oral formulations of ceralasertib and AZD5305 will be used. In Module 5 Part A, patients will receive a single dose of ceralasertib on cycle 0 Day 1 as per dose level cohort. In Module 5 Part B, patients will receive ceralasertib and AZD5305: C1 onwards (as per dose level cohort allocated).
Administration of ceralasertib in combination with carboplatinDrug
An oral formulation of ceralasertib will be used. In Module 1 Part A, patients will receive a single dose of ceralasertib on Day 1, followed by multiple dosing in combination with carboplatin. A maximum of 6 cycles (21 days per cycle) of treatment will be given. In Module 1 Part B, patients will receive ceralasertib and carboplatin at the dose, frequency and schedule recommended from Module 1 Part A.

Study groups in NCT02264678
Study group	Role	What they receive
Module 2 Part A1	Experimental	Module 2 Part A1: ascending doses of ceralasertib will be administered alone to define the maximum tolerated dose (MTD) and/or a continuous, tolerable Recommended Dose (RD) to take into Module 2 Part A2. Receives: Drug: Administration of ceralasertib
Module 2 Part A2	Experimental	Module 2 Part A2: ascending doses of ceralasertib will be administered in combination with olaparib to patients to define the dose, frequency and schedule of ceralasertib and olaparib to take into Module 2 Part B. Receives: Drug: Administration of ceralasertib in combination with olaparib
Module 2 Part B1	Experimental	Module 2 Part B1: Patients with second line 'ATM deficient' gastric adenocarcinoma including GEJ adenocarcinoma will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2. Receives: Drug: Administration of ceralasertib in combination with olaparib
Module 2 Part B2	Experimental	Module 2 part B2: Patients with second line 'ATM proficient' gastric adenocarcinoma including GEJ adenocarcinoma will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2. Receives: Drug: Administration of ceralasertib in combination with olaparib
Module 2 Part B3	Experimental	Module 2 Part B3: Patient with second or third line breast cancer with BRCA mutations (somatic or germline), excluding HER2 positive breast cancer will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2. Receives: Drug: Administration of ceralasertib in combination with olaparib
Module 2 Part B4	Experimental	Module Part B4: Patients with second or third line triple negative breast cancer with no known BRCA mutations. This expansion will be enriched for patients with disease harbouring a HRR-related gene mutation (HRRm) will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2. Receives: Drug: Administration of ceralasertib in combination with olaparib
Module 3 Part A	Experimental	Module 3 Part A: cohort escalation of ceralasertib in combination with durvalumab in HNSCC or NSCLC patients to define the dose, frequency and schedule of ceralasertib and durvalumab to take into Module 3 Part B. Additionally, Module 3 Part A will include a serial tumour biopsy cohort to evaluate the Proof of Mechanism of ceralasertib in HNSCC and NSCLC patients. Receives: Drug: Administation of ceralasertib in combination with durvalumab
Module 3 Part B	Experimental	Module 3 Part B: cohort expansions of ceralasertib in combination with durvalumab in HNSCC or NSCLC patients at dose, frequency and schedule from Module 3 Part A. Receives: Drug: Administation of ceralasertib in combination with durvalumab
Module 2 Part B5	Experimental	Patients with BRCA mutant or RAD51C/D mutant (either germline or somatic) or HRD-positive status epithelial ovarian, fallopian tube, or primary peritoneal cancer according to local testing. Patients must be platinum sensitive and previously progressed on a licensed PARPi. The cohort will be split into 2 groups: Cohort 1 - without intervening chemotherapy following progression on a PARPi, Cohort 2 - with intervening chemotherapy following progression on a PARPi. Patients will receive ceralasertib and olaparib, at the RP2D dose, frequency and schedule established from Module 2 Part A2. Receives: Drug: Administration of ceralasertib in combination with olaparib
Module 4 (FE/QT)	Experimental	Ceralasertib monotherapy will be administered on a number of days during Cycle 0 to assess the effect of food on ceralasertib absorption and effect of ceralasertib on ECG parameters under various conditions (fasted, fed, steady state). From C1 onwards, patients who participated in C0 will be allocated to either ceralasertib in combination with olaparib or durvalumab, or ceralasertib monotherapy and assessed for safety. Receives: Drug: Administration of ceralasertib monotherapy; Drug: Administration of ceralasertib and olaparib; Drug: Administration of ceralasertib and durvalumab
Module 5 Part A	Experimental	Module 5 Part A: ascending doses of ceralasertib will be administered in combination with AZD5305 to patients to define the MTD, RP2D. In case this first dose level is not tolerated, alternative schedules will be evaluated. Receives: Drug: Administration of ceralasertib in combination with AZD5305
Module 5 Part B	Experimental	Module 5 Part B: cohort expansions of ceralasertib in combination with AZD5305 in ovarian patients at dose, frequency and schedule from Module 5 Part A. Receives: Drug: Administration of ceralasertib in combination with AZD5305
Module 1 Part A	Experimental	Module 1 Part A: ascending doses of ceralasertib in combination with carboplatin AUC5 will be administered to patients to define the maximum tolerated dose (MTD) and/or a continuous, tolerable Recommended Dose (RD). Receives: Drug: Administration of ceralasertib in combination with carboplatin
Module 1 Part B	Experimental	Module 1 Part B: patients with advanced lung adenocarcinoma with low expression of ATM will receive ceralasertib and carboplatin, at the dose, frequency and schedule recommended from Module 1 Part A. Receives: Drug: Administration of ceralasertib in combination with carboplatin

What is being measured

The primary outcome is the main question the study is designed to answer.

The number of subjects with adverse events/serious adverse events
Number of patients with adverse events and with serious adverse events including abnormal clinical observations, DLT, abnormal Electrocardiogram (ECG) parameters, abnormal laboratory assessments and abnormal vital signs that changed from baseline.
Measured: From baseline until 28 days after discontinuation of study treatment for Module 1, 2 and 5 or until 90 days after discontinuation of study treatment for Module 3 and 4
Module 4 only: Effect of food on ceralasertib absorption by Intensive PK assessments after a single oral dose of ceralasertib (Part A)
Intensive PK sampling at defined timepoints to measure Geometric mean and 90% CI for the ratio of fed:
fasted in area under the plasma concentration time curve from zero to the last measurable time point (AUC0-t), area under the plasma concentration time curve from zero to infinity (AUC)
Measured: From 0h to 24h on Day 2 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days
Module 4 only: Effect of ceralasertib on ECG parameters (HR, PR, QRS and QTcF) by ECG recordings
Change from baseline HR, PR, QRS and QTcF (ΔHR, ΔPR, ΔQRS and ΔQTcF) Categorical outliers for QTcF, HR, PR, and QRS Frequency of treatment emergent T and U wave abnormalities If a substantial HR effect is observed (i.e., the absolute value of the largest least squares [LS] mean ΔHR is greater than 10bpm in the by-time point analysis), other correction methods such as individualised and optimised individualised HR corrected QT interval (QTcI) will be explored and compared.
The method that removes the HR dependence of the QT interval most efficiently will be chosen as the primary correction method.
Measured: From 0h to 24h on Day 2, Day 8 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days

Secondary outcomes (29)

Maximum Observed Plasma Concentration (Cmax) of ceralasertib
Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Cmax.
Measured: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
Time to observed Cmax (Tmax) for ceralasertib
Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Tmax.
Measured: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
Area under the plasma concentration-time curve (AUC) for ceralasertib
Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive AUC.
Measured: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
Maximum Observed Plasma Concentration (Cmax) of Carboplatin
Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Cmax.
Measured: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Time to observed Cmax (Tmax) for Carboplatin
Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Tmax.
Measured: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Area under the plasma concentration-time curve (AUC) for Carboplatin
Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive AUC.
Measured: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Maximum Observed Plasma Concentration (Cmax) of Olaparib
Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Cmax.
Measured: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Time to observed Cmax (Tmax) for Olaparib
Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Tmax.
Measured: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Area under the plasma concentration-time curve (AUC) for Olaparib
Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive AUC.
Measured: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Maximum Observed Plasma Concentration (Cmax) of durvalumab
Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Cmax.
Measured: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Time to observed Cmax (Tmax) for durvalumab
Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Tmax.
Measured: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Area under the plasma concentration-time curve (AUC) for durvalumab
Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive AUC.
Measured: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Assessment of pharmacodynamic biomarker changes
Evaluation of ceralasertib activity in the tumour by assessment of pharmacodynamic biomarker changes which may include, but are not limited to functional ATR inhibition, ctDNA and CTCs.
Measured: Biopsies of tumour at baseline and last day of dosing
Best objective response
Best objective response will be determined for each patient based on the best response recorded from start of study treatment to end of treatment, including any assessments for confirmation after the end of treatment using RECIST 1.1.
Measured: From first dose to confirmed progressive disease (approximately 1 year)
Objective response rate
Objective response rate is defined as the percentage of patients who have at least one response of CR or PR prior to any evidence of progression (as defined by RECIST 1.1) that is confirmed at least 4 weeks later.
Measured: From first dose to confirmed progressive disease (approximately 1 year)
Percentage change in tumour size
Percentage change in tumour size will be determined for patients with measurable disease at baseline and is derived at each visit by the percentage change from baseline in the sum of the diameters of TLs. The best percentage change in tumour size will be the patient's value representing the largest decrease (or smallest increase) from baseline in tumour size using RECIST 1.1.
Measured: From first dose to confirmed progressive disease (approximately 1 year)
Durable response rate
Duration of response will be defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint using RECIST 1.1.
Measured: From first documented response to confirmed progressive disease (approximately 1 year)
Progression free survival
Progression free survival (PFS) is defined as the time from start of treatment (first dose of ceralasertib) until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the subject withdraws from therapy or receives another anti-cancer therapy prior to progression using RECIST 1.1.
Measured: From first dose to confirmed progressive disease (approximately 1 year)
Survival assessment /status
Module 2 only. To be obtained for all patients who received ceralasertib and olaparib in part A2, B1, B2, B3, B4 and B5.
Measured: From first dose to confirmed progressive disease (approximately 1 year)
Module 4: Safety and tolerability in terms of AE and SAE as recorded in safety measures
Safety measures: AEs assessments (CTCAE grading)
Measured: From baseline until 28 days after discontinuation of study treatment for Module 4 Part B cohort 1 and cohort 3, or until 90 days after discontinuation of study treatment for Module 4 Part B cohort 2
Module 4 only: Effect of food on ceralasertib absorption by Cmax in a fasted and fed state (Part A)
Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in Cmax - Maximum plasma concentration (Cmax)
Measured: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Module 4 only: Effect of food on ceralasertib absorption by Tmax in a fasted and fed state (Part A)
Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in Tmax - time to reach maximum plasma concentration (Tmax)
Measured: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Module 4 only: Effect of food on ceralasertib absorption by clearance in a fasted and fed state (Part A)
Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in apparent clearance following oral administration (CL/F)
Measured: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Module 4 only: Effect of food on ceralasertib absorption by apparent volume of distribution in a fasted and fed state (Part A)
Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in apparent volume of distribution (Vz/F)
Measured: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Module 4 only: Effect of food on ceralasertib absorption by terminal half-life and terminal rate constant in a fasted and fed state (Part A)
Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in terminal rate constant (λz), and terminal half-life (t1/2)
Measured: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Module 4: The number of subjects with adverse events/serious adverse events
Number of patients with adverse events and with serious adverse events including abnormal clinical observations, abnormal vital signs, and abnormal laboratory assessments that changed from baseline
Measured: From baseline until 28 days after discontinuation of study treatment for Module 4 Part B cohort 1 and cohort 3, or until 90 days after discontinuation of study treatment for Module 4 Part B cohort 2
Module 5 only: Maximum Observed Plasma Concentration (Cmax) of AZD5305
Blood samples will be collected to assess plasma concentration of AZD5305 at a series of time points to derive Cmax.
Measured: At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)
Module 5 only: Time to observed Cmax (Tmax) for AZD5305
Blood samples will be collected to assess plasma concentration of AZD5305 at a series of time points to derive Tmax.
Measured: At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)
Module 5 only: Area under the plasma concentration-time curve (AUC) for AZD5305
Blood samples will be collected to assess plasma concentration of AZD5305 at a series of time points to derive AUC.
Measured: At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

31 Oct 201430 Dec 2026

First posted15 Oct 2014 (estimated)
Study start31 Oct 2014
Primary completion4 Mar 2025
Study completion30 Dec 2026 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (3)Papers the sponsor has linked to this study.
Other trials for Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian CancerStudies of the same condition, open and under way.
More trials run by AstraZenecaThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 358 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02264678
Sponsor's protocol ID: D5330C00004
Other IDs: 2023-505006-41-00, 2014-002233-66, 2014, 2023
Status last verified: Jul 2026
First submitted: 30 Jul 2014
Last updated: 24 Jul 2026
Results posted: No
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Expanded access: Available

Publications

Lopez JS, Im SA, Postel-Vinay S, Campone M, El-Khoueiry AB, Abida W, Arkenau T, Lee KW, Rha SY, Jodrell DI, Roylance R, Irurzun-Arana I, Jones GN, Lukashchuk N, Stephens C, Norris C, Loembe AB, Dean E, Krebs MG. Safety and efficacy of ceralasertib, an ATR kinase inhibitor, combined with olaparib: dose escalation in advanced solid tumours and dose expansion in advanced breast cancer. Br J Cancer. 2026 Sep 30. doi: 10.1038/s41416-026-03601-z. Online ahead of print.
PubMed 42816529
Lopez JS, Harrington KJ, Im SA, Lee KW, Postel-Vinay S, Thomas JS, Lukashchuk N, Willis SE, Irurzun-Arana I, Webb B, Nehra J, Lau A, Loembe AB, Dean E, Krebs MG. Phase 1 study of ceralasertib, an ATR kinase inhibitor, in combination with durvalumab in patients with recurrent or metastatic NSCLC or HNSCC. Br J Cancer. 2026 Jun;134(11):1568-1579. doi: 10.1038/s41416-026-03408-y. Epub 2026 Mar 31.
PubMed 41917211
Smith G, Alholm Z, Coleman RL, Monk BJ. DNA Damage Repair Inhibitors-Combination Therapies. Cancer J. 2021 Nov-Dec 01;27(6):501-505. doi: 10.1097/PPO.0000000000000561.
PubMed 34904813

Study at a glance

From the registry record, last updated by the sponsor on 24 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Modular Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Ceralasertib in Combination With Cytotoxic Chemotherapy and/or DNA Damage Repair/Novel Anti-cancer Agents in Patients With Advanced Solid Malignancies.
ClinicalTrials.gov ID: NCT02264678
Acronym / sponsor ID: D5330C00004
Conditions: Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer
Keywords: ATM deficient, ATM proficient, HER2 negative, Breast, Gastric, Head & Neck, Lung, Ovarian
Phase: Phase 1
Study type: Interventional
Recruitment status: Active, not recruiting
Enrolment: 358 participants (actual)
Lead sponsor: AstraZenecaIndustry (pharma, biotech, devices)
Study start: 31 Oct 2014 (actual)
Primary completion: 4 Mar 2025 (actual)
Study completion: 30 Dec 2026 (estimated)
First posted: 15 Oct 2014 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 14

Arm	Type	Receives
Module 2 Part A1	Experimental	Drug: Administration of ceralasertibModule 2 Part A1: ascending doses of ceralasertib will be administered alone to define the maximum tolerated dose (MTD) and/or a continuous, tolerable Recommended Dose (RD) to take into Module 2 Part A2.
Module 2 Part A2	Experimental	Drug: Administration of ceralasertib in combination with olaparibModule 2 Part A2: ascending doses of ceralasertib will be administered in combination with olaparib to patients to define the dose, frequency and schedule of ceralasertib and olaparib to take into Module 2 Part B.
Module 2 Part B1	Experimental	Drug: Administration of ceralasertib in combination with olaparibModule 2 Part B1: Patients with second line 'ATM deficient' gastric adenocarcinoma including GEJ adenocarcinoma will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.
Module 2 Part B2	Experimental	Drug: Administration of ceralasertib in combination with olaparibModule 2 part B2: Patients with second line 'ATM proficient' gastric adenocarcinoma including GEJ adenocarcinoma will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.
Module 2 Part B3	Experimental	Drug: Administration of ceralasertib in combination with olaparibModule 2 Part B3: Patient with second or third line breast cancer with BRCA mutations (somatic or germline), excluding HER2 positive breast cancer will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.
Module 2 Part B4	Experimental	Drug: Administration of ceralasertib in combination with olaparibModule Part B4: Patients with second or third line triple negative breast cancer with no known BRCA mutations. This expansion will be enriched for patients with disease harbouring a HRR-related gene mutation (HRRm) will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.
Module 3 Part A	Experimental	Drug: Administation of ceralasertib in combination with durvalumabModule 3 Part A: cohort escalation of ceralasertib in combination with durvalumab in HNSCC or NSCLC patients to define the dose, frequency and schedule of ceralasertib and durvalumab to take into Module 3 Part B. Additionally, Module 3 Part A will include a serial tumour biopsy cohort to evaluate the Proof of Mechanism of ceralasertib in HNSCC and NSCLC patients.
Module 3 Part B	Experimental	Drug: Administation of ceralasertib in combination with durvalumabModule 3 Part B: cohort expansions of ceralasertib in combination with durvalumab in HNSCC or NSCLC patients at dose, frequency and schedule from Module 3 Part A.
Module 2 Part B5	Experimental	Drug: Administration of ceralasertib in combination with olaparibPatients with BRCA mutant or RAD51C/D mutant (either germline or somatic) or HRD-positive status epithelial ovarian, fallopian tube, or primary peritoneal cancer according to local testing. Patients must be platinum sensitive and previously progressed on a licensed PARPi. The cohort will be split into 2 groups: Cohort 1 - without intervening chemotherapy following progression on a PARPi, Cohort 2 - with intervening chemotherapy following progression on a PARPi. Patients will receive ceralasertib and olaparib, at the RP2D dose, frequency and schedule established from Module 2 Part A2.
Module 4 (FE/QT)	Experimental	Drug: Administration of ceralasertib monotherapy, Drug: Administration of ceralasertib and olaparib, Drug: Administration of ceralasertib and durvalumabCeralasertib monotherapy will be administered on a number of days during Cycle 0 to assess the effect of food on ceralasertib absorption and effect of ceralasertib on ECG parameters under various conditions (fasted, fed, steady state). From C1 onwards, patients who participated in C0 will be allocated to either ceralasertib in combination with olaparib or durvalumab, or ceralasertib monotherapy and assessed for safety.
Module 5 Part A	Experimental	Drug: Administration of ceralasertib in combination with AZD5305Module 5 Part A: ascending doses of ceralasertib will be administered in combination with AZD5305 to patients to define the MTD, RP2D. In case this first dose level is not tolerated, alternative schedules will be evaluated.
Module 5 Part B	Experimental	Drug: Administration of ceralasertib in combination with AZD5305Module 5 Part B: cohort expansions of ceralasertib in combination with AZD5305 in ovarian patients at dose, frequency and schedule from Module 5 Part A.
Module 1 Part A	Experimental	Drug: Administration of ceralasertib in combination with carboplatinModule 1 Part A: ascending doses of ceralasertib in combination with carboplatin AUC5 will be administered to patients to define the maximum tolerated dose (MTD) and/or a continuous, tolerable Recommended Dose (RD).
Module 1 Part B	Experimental	Drug: Administration of ceralasertib in combination with carboplatinModule 1 Part B: patients with advanced lung adenocarcinoma with low expression of ATM will receive ceralasertib and carboplatin, at the dose, frequency and schedule recommended from Module 1 Part A.

Who may qualify

Ages: 18 to 130 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Administration of ceralasertibAn oral formulation of ceralasertib will be used. In Module 2 Part A1, patients will receive a single dose of ceralasertib on Day 1, followed by 4 to 6 days washout, before multiple dosing.	Drug	Module 2 Part A1
Administration of ceralasertib in combination with olaparibAn oral formulations of ceralasertib and olaparib will be used. In Module 2 Part A2, patients will receive either a single or twice daily dose of ceralasertib followed by 4 to 6 days washout, before multiple dosing with ceralasertib and olaparib. In Module 2 Part B, patients will receive ceralasertib and olaparib at the dose, frequency and schedule recommended from Module 2 Part A2. Cycle 0 may be omitted at the discretion of the sponsor.	Drug	Module 2 Part A2, Module 2 Part B1, Module 2 Part B2, Module 2 Part B3, Module 2 Part B4, Module 2 Part B5
Administation of ceralasertib in combination with durvalumabAn oral formulation of ceralasertib will be used. Durvalumab is given via IV infusion. In Module 3 Part A, patients will receive an initial single dose of ceralasertib on Day 1, followed by multiple dosing in combination with durvalumab. In Module 3 Serial Tumour Biopsy Extension and Part B expansion cohorts, patients will receive ceralasertib at the dose, frequency and schedule recommended from Module 3 Part A, in combination with durvalumab.	Drug	Module 3 Part A, Module 3 Part B
Administration of ceralasertib monotherapyModule 4 Part A and Module 4 Part B Cohort 3: During C0, patients will receive ceralasertib monotherapy orally once a day on 3 non-consecutive days and ceralasertib twice a day on 5 consecutive days. After the patients have completed C0 (Part A) they may transition to Module 4 Part B cohort 3 where they will continue to receive ceralasertib monotherapy	Drug	Module 4 (FE/QT)
Administration of ceralasertib and olaparibModule 4 Part B Cohort 1: After completion of Part A (C0), the patient may transition to Part B and be allocated to receive ceralasertib in combination with olaparib as decided by the investigator.	Drug	Module 4 (FE/QT)
Administration of ceralasertib and durvalumabModule 4 Part B Cohort 2: After completion of Part A (C0), the patient may transition to Part B and be allocated to receive ceralasertib in combination with durvalumab as decided by the investigator.	Drug	Module 4 (FE/QT)
Administration of ceralasertib in combination with AZD5305An oral formulations of ceralasertib and AZD5305 will be used. In Module 5 Part A, patients will receive a single dose of ceralasertib on cycle 0 Day 1 as per dose level cohort. In Module 5 Part B, patients will receive ceralasertib and AZD5305: C1 onwards (as per dose level cohort allocated).	Drug	Module 5 Part A, Module 5 Part B
Administration of ceralasertib in combination with carboplatinAn oral formulation of ceralasertib will be used. In Module 1 Part A, patients will receive a single dose of ceralasertib on Day 1, followed by multiple dosing in combination with carboplatin. A maximum of 6 cycles (21 days per cycle) of treatment will be given. In Module 1 Part B, patients will receive ceralasertib and carboplatin at the dose, frequency and schedule recommended from Module 1 Part A.	Drug	Module 1 Part A, Module 1 Part B

Primary outcome

The number of subjects with adverse events/serious adverse events
Time frame: From baseline until 28 days after discontinuation of study treatment for Module 1, 2 and 5 or until 90 days after discontinuation of study treatment for Module 3 and 4
Number of patients with adverse events and with serious adverse events including abnormal clinical observations, DLT, abnormal Electrocardiogram (ECG) parameters, abnormal laboratory assessments and abnormal vital signs that changed from baseline.
Module 4 only: Effect of food on ceralasertib absorption by Intensive PK assessments after a single oral dose of ceralasertib (Part A)
Time frame: From 0h to 24h on Day 2 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days
Intensive PK sampling at defined timepoints to measure Geometric mean and 90% CI for the ratio of fed: fasted in area under the plasma concentration time curve from zero to the last measurable time point (AUC0-t), area under the plasma concentration time curve from zero to infinity (AUC)
Module 4 only: Effect of ceralasertib on ECG parameters (HR, PR, QRS and QTcF) by ECG recordings
Time frame: From 0h to 24h on Day 2, Day 8 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days
Change from baseline HR, PR, QRS and QTcF (ΔHR, ΔPR, ΔQRS and ΔQTcF) Categorical outliers for QTcF, HR, PR, and QRS Frequency of treatment emergent T and U wave abnormalities If a substantial HR effect is observed (i.e., the absolute value of the largest least squares [LS] mean ΔHR is greater than 10bpm in the by-time point analysis), other correction methods such as individualised and optimised individualised HR corrected QT interval (QTcI) will be explored and compared. The method that removes the HR dependence of the QT interval most efficiently will be chosen as the primary correction method.

29 secondary outcomes

Maximum Observed Plasma Concentration (Cmax) of ceralasertib
Time frame: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
Time to observed Cmax (Tmax) for ceralasertib
Time frame: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
Area under the plasma concentration-time curve (AUC) for ceralasertib
Time frame: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
Maximum Observed Plasma Concentration (Cmax) of Carboplatin
Time frame: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Time to observed Cmax (Tmax) for Carboplatin
Time frame: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Area under the plasma concentration-time curve (AUC) for Carboplatin
Time frame: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Maximum Observed Plasma Concentration (Cmax) of Olaparib
Time frame: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Time to observed Cmax (Tmax) for Olaparib
Time frame: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Area under the plasma concentration-time curve (AUC) for Olaparib
Time frame: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Maximum Observed Plasma Concentration (Cmax) of durvalumab
Time frame: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Time to observed Cmax (Tmax) for durvalumab
Time frame: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Area under the plasma concentration-time curve (AUC) for durvalumab
Time frame: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Assessment of pharmacodynamic biomarker changes
Time frame: Biopsies of tumour at baseline and last day of dosing
Best objective response
Time frame: From first dose to confirmed progressive disease (approximately 1 year)
Objective response rate
Time frame: From first dose to confirmed progressive disease (approximately 1 year)
Percentage change in tumour size
Time frame: From first dose to confirmed progressive disease (approximately 1 year)
Durable response rate
Time frame: From first documented response to confirmed progressive disease (approximately 1 year)
Progression free survival
Time frame: From first dose to confirmed progressive disease (approximately 1 year)
Survival assessment /status
Time frame: From first dose to confirmed progressive disease (approximately 1 year)
Module 4: Safety and tolerability in terms of AE and SAE as recorded in safety measures
Time frame: From baseline until 28 days after discontinuation of study treatment for Module 4 Part B cohort 1 and cohort 3, or until 90 days after discontinuation of study treatment for Module 4 Part B cohort 2
Module 4 only: Effect of food on ceralasertib absorption by Cmax in a fasted and fed state (Part A)
Time frame: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Module 4 only: Effect of food on ceralasertib absorption by Tmax in a fasted and fed state (Part A)
Time frame: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Module 4 only: Effect of food on ceralasertib absorption by clearance in a fasted and fed state (Part A)
Time frame: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Module 4 only: Effect of food on ceralasertib absorption by apparent volume of distribution in a fasted and fed state (Part A)
Time frame: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Module 4 only: Effect of food on ceralasertib absorption by terminal half-life and terminal rate constant in a fasted and fed state (Part A)
Time frame: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
Module 4: The number of subjects with adverse events/serious adverse events
Time frame: From baseline until 28 days after discontinuation of study treatment for Module 4 Part B cohort 1 and cohort 3, or until 90 days after discontinuation of study treatment for Module 4 Part B cohort 2
Module 5 only: Maximum Observed Plasma Concentration (Cmax) of AZD5305
Time frame: At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)
Module 5 only: Time to observed Cmax (Tmax) for AZD5305
Time frame: At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)
Module 5 only: Area under the plasma concentration-time curve (AUC) for AZD5305
Time frame: At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)

Results and safety

This study is still under way. Results are not available in the source record yet.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 24 Jul 2026.
Derived from this study: PubMed 42816529Lopez JS, Im SA, Postel-Vinay S, Campone M, El-Khoueiry AB, Abida W, Arkenau T, Lee KW, Rha SY, Jodrell DI, Roylance R, Irurzun-Arana I, Jones GN, Lukashchuk N, Stephens C, Norris C, Loembe AB, Dean E, Krebs MG. Safety and efficacy of ceralasertib, an ATR kinase inhibitor, combined with olaparib: dose escalation in advanced solid tumours and dose expansion in advanced breast cancer. Br J Cancer. 2026 Sep 30. doi: 10.1038/s41416-026-03601-z. Online ahead of print.
Derived from this study: PubMed 41917211Lopez JS, Harrington KJ, Im SA, Lee KW, Postel-Vinay S, Thomas JS, Lukashchuk N, Willis SE, Irurzun-Arana I, Webb B, Nehra J, Lau A, Loembe AB, Dean E, Krebs MG. Phase 1 study of ceralasertib, an ATR kinase inhibitor, in combination with durvalumab in patients with recurrent or metastatic NSCLC or HNSCC. Br J Cancer. 2026 Jun;134(11):1568-1579. doi: 10.1038/s41416-026-03408-y. Epub 2026 Mar 31.
Derived from this study: PubMed 34904813Smith G, Alholm Z, Coleman RL, Monk BJ. DNA Damage Repair Inhibitors-Combination Therapies. Cancer J. 2021 Nov-Dec 01;27(6):501-505. doi: 10.1097/PPO.0000000000000561.
Individual participant dataSharing planned: Yes. Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

28 sites in 4 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 24 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 28 sites in United Kingdom, United States, South Korea, France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The number of subjects with adverse events/serious adverse events (time frame: From baseline until 28 days after discontinuation of study treatment for Module 1, 2 and 5 or until 90 days after discontinuation of study treatment for Module 3 and 4). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02264678, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jul 2026.