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

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.

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)

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.

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

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

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

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

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

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

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

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

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

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

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

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

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 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 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 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.

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 (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.

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

Safety measures: AEs assessments (CTCAE grading)

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)

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)

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)

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)

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)

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

Blood samples will be collected to assess plasma concentration of AZD5305 at a series of time points to derive Cmax.

Blood samples will be collected to assess plasma concentration of AZD5305 at a series of time points to derive Tmax.

Blood samples will be collected to assess plasma concentration of AZD5305 at a series of time points to derive AUC.