Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy

Phase 2

Active, not recruiting

Conditions: Non-Small Cell Lung Cancer

Interventions: Drug: Durvalumab
Drug: Olaparib
Drug: Ceralasertib
Drug: Danvatirsen
Drug: Oleclumab
Drug: Vistusertib
Drug: Trastuzumab deruxtecan
Drug: Cediranib

Registration Number: NCT03334617

Lead Sponsor: AstraZeneca

Brief Summary: This is an open-label, multi-centre, umbrella Phase II study in participants with metastatic NSCLC who have progressed on an anti-PD-1/PD-L1 containing therapy. This study is modular in design, allowing initial assessment of the efficacy, safety, and tolerability of multiple treatment arms.

Detailed Description: This is an open-label, multi-centre, umbrella Phase II study in participants with metastatic non-small cell lung cancer (NSCLC) who have progressed on an anti-programmed cell death-1/anti-programmed cell death ligand 1 (anti-PD-1/PD-L1) containing therapy. This study is modular in design, consisting of a number of treatment cohorts, allowing evaluation of the efficacy, safety, and tolerability of multiple treatment arms. There is currently no established therapy for participants who have received immune checkpoint inhibitors and platinum-doublet therapies, and novel treatments are urgently needed.

This protocol has a modular design, with the potential for future treatment arms to be added via protocol amendment.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 528

Inclusion Criteria

Not provided

Exclusion Criteria

Participants whose tumour samples have targetable alterations in epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase (ALK) at initial diagnosis are excluded. In addition, participants whose tumour samples are known to have targetable alterations in ROS1, BRAF, MET or RET, are to be excluded.
Active or prior documented autoimmune or inflammatory disorders.
Active infection including tuberculosis, hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive human immunodeficiency virus [HIV] 1/2 antibodies).
Female participant who are pregnant or breastfeeding, or male or female participants of reproductive potential who are not willing to employ effective birth control.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients, or history of severe hypersensitivity reactions to other monoclonal antibodies.
Participant has spinal cord compression or symptomatic brain metastases.
Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Participants may receive treatment with bisphosphonates or receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitors for the treatment of bone metastases.
History of active primary immunodeficiency.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Module 1 Cohort A.1.HRR: Durvalumab 1500 mg + Olaparib 300 mg	Durvalumab	Participants with detectable aberrations, mutation detected in a homologous recombination repair gene (HRRm) will receive IV infusion of durvalumab 1500 mg every 4 weeks (Q4W) in combination with oral olaparib 300 mg (2 × 150 mg) tablets twice a day (BD) until disease progression is confirmed.
Module 3 Cohort A.3.ATM: Durvalumab 1500 mg + AZD6738 240 mg	Durvalumab	Participants who are ataxia telangiectasia mutated (ATM)-deficiecy will receive oral AZD6738 240 mg tablet BD for 7 days in Cycle 0 (Days 1 to 7). Thereafter, participants will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral AZD6738 240 mg tablet BD in each cycle between Days 22 and 28 in each 28-day cycle, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 3 Cohort B.3.PRI: Durvalumab 1500 mg + AZD6738 240 mg	Durvalumab	Participants who had anti-PD-1/PD-L1 containing therapy but had progression of disease within ≤ 24 weeks from the start of treatment (PRI) will receive oral AZD6738 240 mg tablet BD for 7 days in Cycle 0 (Days 1 to 7). Thereafter, participants will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral AZD6738 240 mg tablet BD between Days 22 and 28 in each 28-day cycle, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 1 Cohort A.1.HRR: Durvalumab 1500 mg + Olaparib 300 mg	Olaparib	Participants with detectable aberrations, mutation detected in a homologous recombination repair gene (HRRm) will receive IV infusion of durvalumab 1500 mg every 4 weeks (Q4W) in combination with oral olaparib 300 mg (2 × 150 mg) tablets twice a day (BD) until disease progression is confirmed.
Module 1 Cohort B.1.ACQ: Durvalumab 1500 mg + Olaparib 300 mg	Olaparib	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (acquired resistance; ACQ) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral olaparib 300 mg (2 × 150 mg) tablets BD until disease progression is confirmed.
Module 2 Cohort B.2.ACQ: Durvalumab 1500 mg + Danvatirsen 200 mg	Durvalumab	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (ACQ) will receive IV infusion of AZD9150 (danvatirsen) 200 mg as loading dose on Days 1, 3, 5 of Cycle 0 (7-day-lead-in period). Thereafter, participants will receive AZD9150 200 mg every week (QW) on Days 1, 8, 15, and 22 of each 28-day cycle in combination with IV infusion of durvalumab 1500 mg Q4W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 3 Cohort A.3.ATM: Durvalumab 1500 mg + AZD6738 240 mg	Ceralasertib	Participants who are ataxia telangiectasia mutated (ATM)-deficiecy will receive oral AZD6738 240 mg tablet BD for 7 days in Cycle 0 (Days 1 to 7). Thereafter, participants will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral AZD6738 240 mg tablet BD in each cycle between Days 22 and 28 in each 28-day cycle, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 1 Cohort A.1.LKB: Durvalumab 1500 mg + Olaparib 300 mg	Durvalumab	Participants with detectable aberrations in liver kinase B1 (LKB1) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral olaparib 300 mg (2 × 150 mg) tablets BD until disease progression is confirmed.
Module 2 Cohort B.2.PRI: Durvalumab 1500 mg + Danvatirsen 200 mg	Durvalumab	Participants who had anti-PD-1/PD-L1 containing therapy but had progression of disease within ≤ 24 weeks from the start of treatment (PRI) will receive IV infusion of AZD9150 (danvatirsen) 200 mg as loading dose on Days 1, 3, 5 of Cycle 0 (7-day-lead-in period). Thereafter, participants will receive AZD9150 200 mg every week (QW) on Days 1, 8, 15, and 22 of each 28-day cycle in combination with IV infusion of durvalumab 1500 mg Q4W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 3 Cohort B.3.ACQ: Durvalumab 1500 mg + AZD6738 240 mg	Ceralasertib	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (ACQ) will receive oral AZD6738 240 mg tablet BD for 7 days in Cycle 0 (Days 1 to 7). Thereafter, participants will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral AZD6738 240 mg tablet BD between Days 22 and 28 in each 28-day cycle, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 1 Cohort A.1.LKB: Durvalumab 1500 mg + Olaparib 300 mg	Olaparib	Participants with detectable aberrations in liver kinase B1 (LKB1) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral olaparib 300 mg (2 × 150 mg) tablets BD until disease progression is confirmed.
Module 1 Cohort B.1.PRI: Durvalumab 1500 mg + Olaparib 300 mg	Durvalumab	Participants who had anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) containing therapy but had progression of disease within ≤ 24 weeks from the start of treatment (primary resistance; PRI) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral olaparib 300 mg (2 × 150 mg) tablets BD until disease progression is confirmed.
Module 1 Cohort B.1.PRI: Durvalumab 1500 mg + Olaparib 300 mg	Olaparib	Participants who had anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) containing therapy but had progression of disease within ≤ 24 weeks from the start of treatment (primary resistance; PRI) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral olaparib 300 mg (2 × 150 mg) tablets BD until disease progression is confirmed.
Module 1 Cohort B.1.ACQ: Durvalumab 1500 mg + Olaparib 300 mg	Durvalumab	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (acquired resistance; ACQ) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral olaparib 300 mg (2 × 150 mg) tablets BD until disease progression is confirmed.
Module 2 Cohort B.2.PRI: Durvalumab 1500 mg + Danvatirsen 200 mg	Danvatirsen	Participants who had anti-PD-1/PD-L1 containing therapy but had progression of disease within ≤ 24 weeks from the start of treatment (PRI) will receive IV infusion of AZD9150 (danvatirsen) 200 mg as loading dose on Days 1, 3, 5 of Cycle 0 (7-day-lead-in period). Thereafter, participants will receive AZD9150 200 mg every week (QW) on Days 1, 8, 15, and 22 of each 28-day cycle in combination with IV infusion of durvalumab 1500 mg Q4W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 2 Cohort B.2.ACQ: Durvalumab 1500 mg + Danvatirsen 200 mg	Danvatirsen	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (ACQ) will receive IV infusion of AZD9150 (danvatirsen) 200 mg as loading dose on Days 1, 3, 5 of Cycle 0 (7-day-lead-in period). Thereafter, participants will receive AZD9150 200 mg every week (QW) on Days 1, 8, 15, and 22 of each 28-day cycle in combination with IV infusion of durvalumab 1500 mg Q4W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 5 Cohort B.5.ACQ: Durvalumab 1500 mg + Oleclumab 3000 mg	Oleclumab	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (ACQ) will receive IV infusion of oleclumab 3000 mg Q2W for 2 cycles and then Q4W thereafter in combination with IV infusion of durvalumab 1500 mg Q4W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 6 Cohort A.6.HER2e: Durvalumab 1120 mg + Trastuzumab deruxtecan 5.4mg/kg	Durvalumab	Participants whose tumours express human epidermal growth factor receptor 2 (HER2) mutations will receive IV infusion of trastuzumab deruxtecan (T-DXd) 5.4 mg/kg every 3 weeks (Q3W) in combination with IV infusion of durvalumab 1120 mg Q3W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 3 Cohort B.3.PRI: Durvalumab 1500 mg + AZD6738 240 mg	Ceralasertib	Participants who had anti-PD-1/PD-L1 containing therapy but had progression of disease within ≤ 24 weeks from the start of treatment (PRI) will receive oral AZD6738 240 mg tablet BD for 7 days in Cycle 0 (Days 1 to 7). Thereafter, participants will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral AZD6738 240 mg tablet BD between Days 22 and 28 in each 28-day cycle, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 3 Cohort B.3.ACQ: Durvalumab 1500 mg + AZD6738 240 mg	Durvalumab	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (ACQ) will receive oral AZD6738 240 mg tablet BD for 7 days in Cycle 0 (Days 1 to 7). Thereafter, participants will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral AZD6738 240 mg tablet BD between Days 22 and 28 in each 28-day cycle, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 4 Cohort A.4.RIC: Durvalumab 1500 mg + Vistusertib 125 mg	Durvalumab	Participants with detectable genetic amplifications in rapamycin-insensitive companion of mechanistic target of rapamycin complex-2 (RICTOR) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral vistusertib 125 mg tablets BD on an intermittent dosing schedule of 2 days on, 5 days off, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 5 Cohort A.5.73H: Durvalumab 1500 mg + Oleclumab 3000 mg	Durvalumab	Participants with high expression of cluster of differentiation 73 (CD73) will receive IV infusion of oleclumab 3000 mg every 2 weeks (Q2W) for 2 cycles and then Q4W thereafter in combination with IV infusion of durvalumab 1500 mg Q4W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 10 Cohort C.10.160: Durvalumab 1500 mg + Ceralasertib 160 mg	Durvalumab	Participants, independent of their molecular aberration status, will receive oral ceralasertib (AZD6738) 160 mg tablet BD for 7 days in Cycle 0 (Days 1 to 7). Thereafter, participants will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral ceralasertib 160 mg tablet BD between Days 22 and 28 in each 28-day cycle, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 4 Cohort A.4.RIC: Durvalumab 1500 mg + Vistusertib 125 mg	Vistusertib	Participants with detectable genetic amplifications in rapamycin-insensitive companion of mechanistic target of rapamycin complex-2 (RICTOR) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral vistusertib 125 mg tablets BD on an intermittent dosing schedule of 2 days on, 5 days off, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 9 Cohort B.9.ACQ: Durvalumab 1500 mg + Ceralasertib 240 mg	Durvalumab	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (ACQ) will receive IV infusion of durvalumab 1500 mg Q4W plus oral ceralasertib (AZD6738) 240 mg tablets BD for 14 days from Day 15 to Day 28 of each 28-day cycle, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 10 Cohort C.10.240: Durvalumab 1500 mg + Ceralasertib 240 mg	Durvalumab	Participants, independent of their molecular aberration status, will receive oral ceralasertib (AZD6738) 240 mg tablet BD for 7 days in Cycle 0 (Days 1 to 7). Thereafter, participants will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral ceralasertib 240 mg tablet BD between Days 22 and 28 in each 28-day cycle, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 5 Cohort A.5.73H: Durvalumab 1500 mg + Oleclumab 3000 mg	Oleclumab	Participants with high expression of cluster of differentiation 73 (CD73) will receive IV infusion of oleclumab 3000 mg every 2 weeks (Q2W) for 2 cycles and then Q4W thereafter in combination with IV infusion of durvalumab 1500 mg Q4W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 5 Cohort B.5.PRI: Durvalumab 1500 mg + Oleclumab 3000 mg	Durvalumab	Participants who had anti-PD-1/PD-L1 containing therapy but had progression of disease within ≤ 24 weeks from the start of treatment (PRI) will receive IV infusion of oleclumab 3000 mg Q2W for 2 cycles and then Q4W thereafter in combination with IV infusion of durvalumab 1500 mg Q4W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 5 Cohort B.5.PRI: Durvalumab 1500 mg + Oleclumab 3000 mg	Oleclumab	Participants who had anti-PD-1/PD-L1 containing therapy but had progression of disease within ≤ 24 weeks from the start of treatment (PRI) will receive IV infusion of oleclumab 3000 mg Q2W for 2 cycles and then Q4W thereafter in combination with IV infusion of durvalumab 1500 mg Q4W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 5 Cohort B.5.ACQ: Durvalumab 1500 mg + Oleclumab 3000 mg	Durvalumab	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (ACQ) will receive IV infusion of oleclumab 3000 mg Q2W for 2 cycles and then Q4W thereafter in combination with IV infusion of durvalumab 1500 mg Q4W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 6 Cohort A.6.HER2e: Durvalumab 1120 mg + Trastuzumab deruxtecan 5.4mg/kg	Trastuzumab deruxtecan	Participants whose tumours express human epidermal growth factor receptor 2 (HER2) mutations will receive IV infusion of trastuzumab deruxtecan (T-DXd) 5.4 mg/kg every 3 weeks (Q3W) in combination with IV infusion of durvalumab 1120 mg Q3W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 7 Cohort B.7.ACQ: Durvalumab 1500 mg + Cediranib 20 mg	Durvalumab	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (ACQ) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral cediranib (AZD2171) 20 mg tablets daily for 5 days on, 2 days off (starting on Cycle 1 Day 1 of durvalumab), until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 7 Cohort B.7.ACQ: Durvalumab 1500 mg + Cediranib 20 mg	Cediranib	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (ACQ) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral cediranib (AZD2171) 20 mg tablets daily for 5 days on, 2 days off (starting on Cycle 1 Day 1 of durvalumab), until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 6 Cohort A.6.HER2m: Durvalumab 1120 mg + Trastuzumab deruxtecan 5.4mg/kg	Durvalumab	Participants whose tumours harbour selected HER2 mutations will receive IV infusion of T-DXd 5.4 mg/kg Q3W in combination with IV infusion of durvalumab 1120 mg Q3W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 6 Cohort A.6.HER2m: Durvalumab 1120 mg + Trastuzumab deruxtecan 5.4mg/kg	Trastuzumab deruxtecan	Participants whose tumours harbour selected HER2 mutations will receive IV infusion of T-DXd 5.4 mg/kg Q3W in combination with IV infusion of durvalumab 1120 mg Q3W, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 8 Cohort A.8.ATM: Ceralasertib 240 mg	Ceralasertib	Participants who are ATM-deficient or with detectable aberrations in the ATM gene will receive oral ceralasertib (AZD6738) 240 mg tablets BD from Day 1 to Day 14 of each 28-day cycle, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 9 Cohort B.9.PRI: Durvalumab 1500 mg + Ceralasertib 240 mg	Durvalumab	Participants who had anti-PD-1/PD-L1 containing therapy but had progression of disease within ≤ 24 weeks from the start of treatment (PRI) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral ceralasertib (AZD6738) 240 mg tablets BD for 14 days from Day 15 to Day 28 of each 28-day cycle, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 9 Cohort B.9.PRI: Durvalumab 1500 mg + Ceralasertib 240 mg	Ceralasertib	Participants who had anti-PD-1/PD-L1 containing therapy but had progression of disease within ≤ 24 weeks from the start of treatment (PRI) will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral ceralasertib (AZD6738) 240 mg tablets BD for 14 days from Day 15 to Day 28 of each 28-day cycle, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 9 Cohort B.9.ACQ: Durvalumab 1500 mg + Ceralasertib 240 mg	Ceralasertib	Participants who had progressive disease \> 24 weeks from the start of anti PD-1/PD-L1 containing therapy while still on that treatment (ACQ) will receive IV infusion of durvalumab 1500 mg Q4W plus oral ceralasertib (AZD6738) 240 mg tablets BD for 14 days from Day 15 to Day 28 of each 28-day cycle, until objective radiological disease progression, as long as, in the investigator's opinion, they were benefiting from treatment and did not meet any other discontinuation criteria.
Module 10 Cohort C.10.160: Durvalumab 1500 mg + Ceralasertib 160 mg	Ceralasertib	Participants, independent of their molecular aberration status, will receive oral ceralasertib (AZD6738) 160 mg tablet BD for 7 days in Cycle 0 (Days 1 to 7). Thereafter, participants will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral ceralasertib 160 mg tablet BD between Days 22 and 28 in each 28-day cycle, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 10 Cohort C.10.240: Durvalumab 1500 mg + Ceralasertib 240 mg	Ceralasertib	Participants, independent of their molecular aberration status, will receive oral ceralasertib (AZD6738) 240 mg tablet BD for 7 days in Cycle 0 (Days 1 to 7). Thereafter, participants will receive IV infusion of durvalumab 1500 mg Q4W in combination with oral ceralasertib 240 mg tablet BD between Days 22 and 28 in each 28-day cycle, until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.
Module 11 Cohort C.11.240: AZD6738 240 mg	Ceralasertib	Participants, independent of their molecular aberration status, will receive oral AZD6738 tablet 240 mg for 7 days (Days 1 to 7) in each 28-day cycle until objective radiological disease progression, however, participants may continue treatment if benefiting from treatment in the investigator opinion or did not meet any other discontinuation criteria.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Objective Response Per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1)	Baseline (<=28 days before treatment), then every 6 weeks for 24 weeks from Cycle 1 Day 1, then every 8 weeks (every 9 weeks in Module 6) until disease progression or 90 days after study drug discontinuation (approximately 2 years)	Objective response was defined as participants with a confirmed investigator-assessed response complete response (CR) or partial response (PR) based on RECIST v 1.1. The CR is defined as disappearance of all target (TL) and non-target lesions (NTL), and any pathological lymph node (whether target or nontarget) must have reduction in short axis to \<10 mm. The PR is defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum diameters, as long as criteria for progressive disease (PD) are not met. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from date of first documentation. Percentage of participants with objective response was reported.

Secondary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS) Per RECIST v1.1	Every 3 months after safety follow-up visit (90 days after study drug discontinuation) until planned database lock for a module (either 12 months after last participant has started treatment or when 75% of participants died) (approximately up to 2 years)	The PFS is defined as time from first dose of any study drug until date of objective disease progression (PD) per RECIST v1.1 or death by any cause, regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy prior to progression. The PD is defined as a \>= 20% increase in the sum of diameters of TLs and an absolute increase of \>= 5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters, or unequivocal progression of existing NTL. The PFS was analyzed using the Kaplan-Meier method
Overall Survival (OS)	Every 3 months after safety follow-up visit (90 days after study drug discontinuation) until planned database lock for a module (either 12 months after last participant has started treatment or when 75% of participants died) (approximately up to 2 years)	The OS is defined as the time from the first dose of any study drug until death due to any cause regardless of whether the participant withdraws from study treatment or receives subsequent cancer therapy. The overall survival was analyzed using the Kaplan-Meier method.
Best Percentage Change From Baseline in Tumour Size	Baseline (<=28 days prior to starting treatment) then every 6 weeks for first 24 weeks relative to the date of first dose/combination therapy (Cycle 1 Day 1), then every 8 weeks (except Module 6)/9 weeks (Module 6) thereafter (approximately up to 2 years)	The best percentage change in tumour size from baseline i.e. the maximum reduction from baseline or the minimum increase from baseline in absence of a reduction from baseline based on all post baseline assessments is reported. Tumour size is sum of the longest diameters (or short axis measurements for lymph nodes) of the target lesions. Baseline was defined as last evaluable assessment prior to starting treatment. The percentage change in target lesion tumour size at each week X for which data are available was obtained for each participant taking the difference between the sum of the target lesions at each week X and the sum of the target lesions at baseline divided by the sum of the target lesions at baseline multiplied by 100 (i.e. \[week X - baseline\]/baseline \* 100).
Percentage of Participants With Disease Control (DC) Per RECIST v1.1	At 12 and 24 weeks after the start of study drug	Module (M) 1, 4, 5, 6, 7, 8, 9, 11: DCR at 12 and 24 weeks is defined as percentage of participants who have best overall response (BoR) of CR or PR in first 13/25 weeks, respectively, post start of any study drug or with duration of SD for at least 11/23 weeks, respectively, after start of any study drug. M2, M3, M10: DCR at 12 and 24 weeks is defined as percentage of participants who have BoR of CR or PR within first 100 days (M2, M3, M10) or 184 days (M2, M3, M10) after start of any study drug, or have SD lasting at least 86 days (M2)/82 days (M3, M10), respectively, or 170 days (M2)/166 days (M3, M10), respectively, post start of any study drug. CR is defined as disappearance of all TL and NTLs, and any pathological lymph node (whether target or nontarget) must have reduction in short axis to \<10 mm. PR is defined as at least 30% decrease in sum of diameters of TLs, taking as reference baseline sum diameters, as long as criteria for PD are not met.
Duration of Response (DoR) Per RECIST v1.1	Baseline (<=28 days before treatment), then every 6 weeks for 24 weeks from Cycle 1 Day 1, then every 8 weeks (every 9 weeks in Module 6) until disease progression or 90 days after study drug discontinuation (approximately 2 years)	The DoR is defined as the time from the first documented confirmed response (CR or PR) until the first documented PD or death in the absence of disease progression. The CR is defined as disappearance of all TLs and NTLs, and any pathological lymph node (whether target or nontarget) must have reduction in short axis to \<10 mm. The PR is defined as at least a 30 decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters, as long as criteria for PD are not met. The PD is defined as a \>=20% increase in the sum of diameters of TLs and an absolute increase of \>=5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters, or unequivocal progression of existing NTL. The DoR was analyzed using the Kaplan-Meier method.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	Day 1 thorugh 58.6 months (maximum observed duration)	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs	Day 1 thorugh 58.6 months (maximum observed duration)	Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of hematology, clinical chemistry, and urinalysis.
Number of Participants With Abnormal Vital Signs Reported as TEAEs	Day 1 thorugh 58.6 months (maximum observed duration)	Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (blood pressure, pulse rate, temperature, and respiration rate).
Number of Participants With Abnormal Electrocardiogram (ECG) Parameters Reported as TEAEs	Day 1 thorugh 58.6 months (maximum observed duration)	Number of participants with abnormal ECGs reported as TEAEs are reported.
Number of Participants With Abnormal Physical Examination Findings Reported as TEAEs	Day 1 thorugh 58.6 months (maximum observed duration)	Number of participants with abnormal physical examination findings reported as TEAEs are reported. Any new or aggravated clinically relevant abnormal medical finding at a physical examination as compared with the pre-dose assessment was reported as an AE.