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

Primary Purpose

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

Status

Recruiting

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

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

Administration of ceralasertib and durvalumab

Administration of ceralasertib in combination with AZD5305

Administration of ceralasertib in combination with carboplatin

About this trial

This is an interventional treatment trial for Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer focused on measuring ATM deficient, ATM proficient, HER2 negative, Breast, Gastric, Head & Neck, Lung, Ovarian

Eligibility Criteria

18 Years - 130 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Principal Inclusion criteria:

Aged at least 18
The presence of a solid malignant tumour that is not considered appropriate for further standard treatment
Module 1 and 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 1 Part B Study expansion: second line lung adenocarcinoma with ATM deficient tumours.
Module 2 Part B All - 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
Module2 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: BRCA mutant or RAD51C/D mutant or HRD positive status ovarian cancer patient who are Platinum sensitive 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

Principal exclusion criteria

A diagnosis of ataxia telangiectasia
Prior exposure to an ATR inhibitor
Bad reaction to ceralasertib
Module 1: Contra-indicated for treatment with carboplatin
Module 2: Contra-indicated for treatment with olaparib
Module 3: Contra-indicated for treatment with durvalumab

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm 13

Arm 14

Arm Type

Experimental

Arm Label

Module 2 Part A1

Module 2 Part A2

Module 2 Part B1

Module 2 Part B2

Module 2 Part B3

Module 2 Part B4

Module 3 Part A

Module 3 Part B

Module 2 Part B5

Module 4 (FE/QT)

Module 5 Part A

Module 5 Part B

Module 1 Part A

Module 1 Part B

Arm Description

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Module 5 Part A: ascending doses of ceralasertib will be administered in combination with AZD5305 to patients to define the MTD, RP2D.

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.

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).

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.

Outcomes

Primary Outcome Measures

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.

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)

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Module 4: Safety and tolerability in terms of AE and SAE as recorded in safety measures

Safety measures: AEs assessments (CTCAE grading)

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)

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)

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)

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)

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)

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

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.

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.

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.

Full Information

NCT ID

NCT02264678

First Posted

July 30, 2014

Last Updated

October 24, 2023

Sponsor

AstraZeneca

1. Study Identification

Unique Protocol Identification Number

NCT02264678

Brief Title

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

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.

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

October 31, 2014 (Actual)

Primary Completion Date

June 18, 2026 (Anticipated)

Study Completion Date

June 18, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

466 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Module 2 Part A1

Arm Type

Experimental

Arm Description

Arm Title

Module 2 Part A2

Arm Type

Experimental

Arm Description

Arm Title

Module 2 Part B1

Arm Type

Experimental

Arm Description

Arm Title

Module 2 Part B2

Arm Type

Experimental

Arm Description

Arm Title

Module 2 Part B3

Arm Type

Experimental

Arm Description

Arm Title

Module 2 Part B4

Arm Type

Experimental

Arm Description

Arm Title

Module 3 Part A

Arm Type

Experimental

Arm Description

Arm Title

Module 3 Part B

Arm Type

Experimental

Arm Description

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.

Arm Title

Module 2 Part B5

Arm Type

Experimental

Arm Description

Arm Title

Module 4 (FE/QT)

Arm Type

Experimental

Arm Description

Arm Title

Module 5 Part A

Arm Type

Experimental

Arm Description

Module 5 Part A: ascending doses of ceralasertib will be administered in combination with AZD5305 to patients to define the MTD, RP2D.

Arm Title

Module 5 Part B

Arm Type

Experimental

Arm Description

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.

Arm Title

Module 1 Part A

Arm Type

Experimental

Arm Description

Arm Title

Module 1 Part B

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Administration of ceralasertib

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Administration of ceralasertib in combination with olaparib

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Administation of ceralasertib in combination with durvalumab

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Administration of ceralasertib monotherapy

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Administration of ceralasertib and olaparib

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Administration of ceralasertib and durvalumab

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Administration of ceralasertib in combination with AZD5305

Intervention Description

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 Day1 followed by 6 days washout, before multiple dosing with ceralasertib and AZD5305. In Module 5 Part B, patients will receive ceralasertib and AZD5305 at the dose, frequency and schedule recommended from Module 5 Part A.

Intervention Type

Drug

Intervention Name(s)

Administration of ceralasertib in combination with carboplatin

Intervention Description

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.

Primary Outcome Measure Information:

Title

The number of subjects with adverse events/serious adverse events

Description

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

Title

Module 4 only: Effect of food on ceralasertib absorption by Intensive PK assessments after a single oral dose of ceralasertib (Part A)

Description

Time Frame

From 0h to 24h on Day 2 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days

Title

Module 4 only: Effect of ceralasertib on ECG parameters (HR, PR, QRS and QTcF) by ECG recordings

Description

Time Frame

From 0h to 24h on Day 2, Day 8 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days

Secondary Outcome Measure Information:

Title

Maximum Observed Plasma Concentration (Cmax) of ceralasertib

Description

Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Cmax.

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)

Title

Time to observed Cmax (Tmax) for ceralasertib

Description

Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Tmax.

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)

Title

Area under the plasma concentration-time curve (AUC) for ceralasertib

Description

Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive AUC.

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)

Title

Maximum Observed Plasma Concentration (Cmax) of Carboplatin

Description

Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Cmax.

Time Frame

At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)

Title

Time to observed Cmax (Tmax) for Carboplatin

Description

Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Tmax.

Time Frame

At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)

Title

Area under the plasma concentration-time curve (AUC) for Carboplatin

Description

Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive AUC.

Time Frame

At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)

Title

Maximum Observed Plasma Concentration (Cmax) of Olaparib

Description

Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Cmax.

Time Frame

At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)

Title

Time to observed Cmax (Tmax) for Olaparib

Description

Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Tmax.

Time Frame

At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)

Title

Area under the plasma concentration-time curve (AUC) for Olaparib

Description

Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive AUC.

Time Frame

At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)

Title

Maximum Observed Plasma Concentration (Cmax) of durvalumab

Description

Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Cmax.

Time Frame

At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)

Title

Time to observed Cmax (Tmax) for durvalumab

Description

Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Tmax.

Time Frame

At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)

Title

Area under the plasma concentration-time curve (AUC) for durvalumab

Description

Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive AUC.

Time Frame

At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)

Title

Assessment of pharmacodynamic biomarker changes

Description

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.

Time Frame

Biopsies of tumour at baseline and last day of dosing

Title

Best objective response

Description

Time Frame

From first dose to confirmed progressive disease (approximately 1 year)

Title

Objective response rate

Description

Time Frame

From first dose to confirmed progressive disease (approximately 1 year)

Title

Percentage change in tumour size

Description

Time Frame

From first dose to confirmed progressive disease (approximately 1 year)

Title

Durable response rate

Description

Time Frame

From first documented response to confirmed progressive disease (approximately 1 year)

Title

Progression free survival

Description

Time Frame

From first dose to confirmed progressive disease (approximately 1 year)

Title

Survival assessment /status

Description

Module 2 only. To be obtained for all patients who received ceralasertib and olaparib in part A2, B1, B2, B3, B4 and B5.

Time Frame

From first dose to confirmed progressive disease (approximately 1 year)

Title

Module 4: Safety and tolerability in terms of AE and SAE as recorded in safety measures

Description

Safety measures: AEs assessments (CTCAE grading)

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

Title

Module 4 only: Effect of food on ceralasertib absorption by Cmax in a fasted and fed state (Part A)

Description

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)

Time Frame