Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer

Muscle Invasive Bladder Cancer Clinical Trial

— BISCAY  

Official title:

An Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Multi-Centre, Multi-arm Phase 1b Study in Patients With Muscle Invasive Bladder Cancer (MIBC) Who Have Progressed on Prior Treatment (BISCAY).

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02546661
• Other study ID #: D2615C00001
• Secondary ID: GU 118BISCAY2015
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: October 3, 2016
• Est. completion date: June 28, 2024

Study information

• Verified date: March 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open label, multi-drug, biomarker-directed, multi-centre, multi-arm, Phase 1b study in patients with muscle invasive bladder cancer (MIBC) (urothelial) who have progressed on prior treatment. This study is modular in design, allowing evaluation of the safety, tolerability, pharmacokinetics and anti-tumour activity of multiple agents as monotherapy and as combinations of different novel anti-cancer agents. The study will consist of a number of study modules (sub-studies), each evaluating the safety and tolerability of a specific agent or combination.

Description:

This is an open label, multi-drug, biomarker-directed, multi-centre, multi-arm, Phase 1b study in patients with muscle invasive bladder cancer (MIBC) (urothelial) who have progressed on prior treatment. This study is modular in design, allowing evaluation of the safety, tolerability, pharmacokinetics and anti-tumour activity of multiple agents as monotherapy and as combinations of different novel anti-cancer agents. The study will consist of a number of study modules (sub-studies), each evaluating the safety and tolerability of a specific agent or combination in patients whose tumours express specific genomic alterations relevant to the molecules under investigation and whose disease has progressed following prior therapy. The allocation of patients to specific modules will depend on the specific eligible genomic alterations identified in their tumours. Each module will determine the appropriate combination dose for further clinical evaluation based on safety, tolerability and efficacy profile. A maximum tolerated dose will be defined and each arm expanded appropriately to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected combination doses. Module A includes an AZD4547 monotherapy arm and a MEDI4736 (durvalumab) + AZD4547 combination therapy arm and will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with AZD4547 given orally to selected patients with MIBC with tumours that have fibroblast growth factor receptor mutations or fibroblast growth factor receptor fusions. Module B will investigate the safety and tolerability of MEDI4736 given intravenously in combination with olaparib (AZD2281, Lynparza) given orally to selected patients with MIBC whose tumors have mutations in a homologous recombination repair gene panel and whose disease had progressed following prior therapy. Module C will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with AZD1775 given orally to selected patients with MIBC whose tumours have mutations in genes involved in cell cycle regulation (e.g., loss of either retinoblastoma 1 or cyclin-dependent kinase inhibitor 2A or amplification of cyclin E1 or MYC family genes). Module D will investigate the safety and tolerability of MEDI4736 given intravenously as monotherapy to patients with MIBC who do not qualify for Modules A, B or C. Module E will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with vistusertib (AZD2014) given orally to patients with MIBC whose tumours do not show genomic alterations that would be eligible for other study modules. Patients whose MIBC tumours harbour the following genomic alterations that have potential to respond to a mammalian target of rapamycin (mTOR) inhibitor will also be included in Module E: RICTOR amplification, or TSC1/1 mutations. Module F will investigate the safety and tolerability of MEDI4736 given intravenously in combination with AZD9150 given intravenously to patients with MIBC whose tumours do not show genomic alterations that would be eligible for other modules. Module G will investigate the safety and tolerability of MEDI4736 given intravenously in combination with selumetinib (AZD6244) given orally to patients with MIBC. Patients in this module will not be selected for any specific tumour genomic alteration.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 156
• Est. completion date: June 28, 2024
• Est. primary completion date: March 18, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

Inclusion Criteria for all Modules:

1. Metastatic MIBC

2. 2nd/3rd line

3. Failed adjuvant/neo-adjuvant chemotherapy <1 yr

4. 1 lesion =10 mm at baseline in the longest diameter suitable for accurate repeated measurement

5. WHO perf. status 0-1

For Module A:

1. M/F =25

2. Confirmation of FGFR3 mutation or FGFR fusion

For Module B:

1. Hgb =10 g/dL

2. Deleterious mutation, deletion or truncation in any HRR genes

For Module C:

1. Tumour harbours a deletion or inactivating mutation of the CDKN2A or RB1 genes and/or amplification of CCNE1, MYC, MYCL or MYCN genes

For Module E:

1. Contraception must be sustained throughout treatment with vistusertib and 16 wks after last dose

For Module F:

1. Adequate organ and marrow function, defined as Leukocytes =3.0x10(exp9)/L; ANC =1.5x10(exp9)/L; platelets =100x10(exp9)/L

2. Contraceptive measures must be sustained throughout treatment with AZD9150 and for 180 days after the last dose.

Exclusion Criteria for all Modules:

1. Immunotherapy, chemotherapy, anticancer agents, radiotherapy <4 weeks, or radiotherapy for palliation <2 weeks, any study drugs <30 days.

2. Major surgery <4 weeks

3. Unresolved toxicities from prior therapy

4. Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy

5. Immunosuppressive drugs <28 days

6. Any of the following: Autoimmune disease =2 yr; IBD; primary immunodeficiency; organ transplant requiring immunosuppressives

7. Spinal cord compression or brain metastases, treated and stable & not requiring steroids for at least 4 weeks

8. Severe or uncontrolled systemic disease

9. Any of the following: Mean QTc =470 ms; abnormalities in resting ECG; factors that increase the risk of QTc prolongation or arrhythmia; uncontrolled hyper/hypotension; LVEF <55%; atrial fibrillation; NYHA Grade II-IV; severe valvular disease; uncontrolled angina; stroke/TIA <6 months; acute coronary syndrome <6 months

10. Any of the following laboratory values: ANC <1.5x10(exp9)/L; Platelets <100x10(exp9)/L; Hgb <9.0 g/dL; ALT >2.5xULN or >5xULN with liver mets; Total bilirubin >1.5 times ULN or with Gilbert's disease =2×ULN; Creatinine >1.5xULN concurrent with creatinine clearance <50 mL/min; Corrected Ca >ULN, PO4 >ULN

11. Active infection including tuberculosis, hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus. Patients with a past or resolved HBV infection are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

12. Live attenuated vaccination <30 days

For Module A:

1. Prior exposure to: Nitrosourea or mitomycin C <6 weeks; any agent with FGFR inhibition as its primary pharmacology; AZD4547; potent inhibitors/inducers of CYP3A4, inhibitors of CYP2D6 or substrates of CYP3A4 <2 wks

2. Ophthalmological criteria: RPED; laser treatment or intraocular injection for macular degeneration; age-related macular degeneration; retinal vein occlusion; retinal degenerative disease; other clinically relevant chorioretinal defect

3. Refractory nausea/vomiting, chronic GI diseases, or previous bowel resection

For Module B:

1. Transfusion <120 days

2. Concurrent medications that are strong inhibitors of cytochrome P450 (CYP) 3A (CYP3A) or strong inducers of CYP3A4.

3. Previous treatment with PARP inhibitor, including olaparib

4. Patients with history of MDS or AML

For Module C:

1. Prior exposure to any of the following: Nitrosourea or mitomycin C <6 wks; any agent with Wee1 inhibition as its primary pharmacology; prior treatment with AZD1775

2. Any drugs or products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with narrow therapeutic index, or moderate to strong inhibitors/inducers of CYP3A4

3. Herbal preparations

4. Refractory nausea and vomiting or chronic GI diseases

5. Cardiac disease <6 months

For Module E:

1. Minor surgery <14 days of first dose

2. Exposure to specific substrates of OATP1B1, OATP1B3, MATE1 and MATE2K <5x half-life before treatment. Exposure to strong/moderate inhibitors/inducers of CYP3A4/5, Pgp (MDR1) and BRCP if taken within washout periods before the first dose

3. Haemopoietic growth factors (filgrastim, sargramostim, GM-CSF) <14 days prior to treatment

4. Other mTOR inhibitors

5. Renal disease or renal tubular acidosis

6. Uncontrolled Type 1 or 2 diabetes

For Module F:

1. AST = 2.5xULN or =5xULN with liver metastases

For Module G:

1. Have had prior treatment with a MEK, Ras or Raf inhibitor.

2. Any of the following ophthalmic criteria: Current or past history of central serous retinopathy, detachment of retinal pigmented epithelium, or retinal vein occlusion; intraocular pressure (IOP) >21 mmHg; uncontrolled glaucoma (irrespective of IOP)

3. Baseline left ventricular ejection fraction (LVEF) <55% measured by echocardiogram (ECHO) or, if allowed, a multigated acquisition (MUGA) scan. Appropriate correction to be used if a MUGA is performed.

4. Previous moderate or severe impairment of LVEF (<45% on echocardiography or equivalent on MUGA) even if full recovery has occurred.

5. Male or female patients with reproductive potential and, as judged by the investigator, are not employing an effective method of birth control and female patients who are breastfeeding.

6. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.

7. Receiving or have received systemic therapy with nitrosoureas, mitomycin or suramin within 6 weeks prior to starting study treatment.

Related Conditions & MeSH terms

• Muscle Invasive Bladder Cancer
• Urinary Bladder Neoplasms

Intervention

Drug:
• AZD4547
AZD4547 Monotherapy vs. MEDI4736 (durvalumab) + AZD4547 1:1 Randomization.
• MEDI4736
MEDI4736
• Olaparib
MEDI4736 (durvalumab) + Olaparib
• AZD1775
MEDI4736 (durvalumab) + AZD1775
• Vistusertib
MEDI4736 (durvalumab) + Vistusertib
• AZD9150
MEDI4736 (durvalumab) + AZD9150
• Selumetinib
MEDI4736 (durvalumab) + Selumetinib

Locations

Country	Name	City	State
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Vancouver	British Columbia
France	Research Site	Bordeaux
France	Research Site	Caen
France	Research Site	LYON cedex 08
France	Research Site	Marseille Cedex 9
France	Research Site	Saint Herblain Cedex
France	Research Site	Toulouse Cedex
Spain	Research Site	Badalona
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Madrid
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Southampton
United States	Research Site	Cleveland	Ohio
United States	Research Site	Fort Myers	Florida
United States	Research Site	Los Angeles	California
United States	Research Site	Nashville	Tennessee
United States	Research Site	New Haven	Connecticut
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Canada,  France,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Mutation status of cancer associated genes in circulating tumour DNA (ctDNA).	Plasma and serum samples will be collected and assessed for circulating tumour DNA to explore the mutation status of cancer associated genes.	Blood samples for assessment of ctDNA will be collected at screening, on Day 1 of Cycles 1, 2, 3, and 4 (up to 91 days) and at disease progression.
Other	Biomarker Analysis of Blood and Tissue	Biomarker analysis of blood and tissue to assess exploratory markers, which may include but is not limited to: immune cell gene expression profiles and cytokine profiles within the peripheral and tumoural compartments,; the presence of IFN-?, tumour necrosis factor-a, IL-2, IL-6, IL-10, IL-8, and IL-12 as well as antibodies against tumour, self, or viral antigens,; expression of PD-L1,; CD8 and the number and phenotype of immune cells such as T-cells.; Markers relevant to the targeted therapy, for example FGFR and ligand expression and PD markers, for example pErk, pS6 and ?H2AX will also be measured in tumour paired biopsy samples.; Biomarker assessments that may have the potential to identify patients likely to respond to treatment with the agents studied in this modular protocol will be investigated to determine a patient's biomarker status and for possible correlation with efficacy endpoints.	Up to 12 months
Other	Correlation of biomarkers to response and/or development of cancer	To explore potential biomarkers in residual biological samples (e.g., tumour, plasma and/or serum) which may influence development of cancer (and associated clinical characteristics) and/or response.	Throught out study (up to 18 months)
Other	Estimate overall survival (OS)	To estimate the overall survival for patients have been pre-screened but do not enter the main part of the study.	Up to 18 months
Other	Objective Response Rate (ORR) (by modified RECIST 1.1)	The percentage of patients who have a confirmed response of CR or PR as assessed by the investigator using a modified RECIST 1.1. Modified RECIST 1.1 will be used for patients receiving MEDI4736 because of response may occur after progression has been initially determined. Patients receiving MEDI4736 may continue to receive treatment and be followed after an initial assessment of progression until subsequent confirmation. Confirmed progression is defined as =20% increase in sum of diameters of target lesions compared to the nadir at 2 consecutive visits; and/or significant progression (worsening) of non-target lesions (NTLs) or new lesions (NLs) at the confirmatory scan; and/or new unequivocal lesions at the confirmatory scan. If progression is not confirmed then the visit response is assessed as SD/PR or CR and the patient should continue scheduled scans. If progression is confirmed the visit response should be assessed as progressive disease.	16 weeks and 52 weeks
Primary	Module A: The frequency and nature of adverse events related to AZD4547 monotherapy.	The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of AZD4547 monotherapy given orally to selected patients with MIBC who have progressed following prior therapy.	Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
Primary	Module A: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and oral AZD4547.	The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with AZD4547 given orally to selected patients with MIBC who have progressed following prior therapy.	Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
Primary	Module B: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and oral olaparib.	The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with olaparib given orally to selected patients with MIBC who have progressed following prior therapy.	Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
Primary	Module C: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral AZD1775.	The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with AZD1775 given orally to selected patients with MIBC who have progressed following prior therapy.	Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
Primary	Module D: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) monotherapy.	The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) monotherapy given intravenously to selected patients with MIBC who have progressed following prior therapy.	Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
Primary	Module E: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral vistusertib.	The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI 4736 (durvalumab) given intravenously in combination with vistusertib given orally to selected patients with MIBC who have progressed following prior therapy.	Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
Primary	Module F: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and intravenous AZD9150.	The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of intravenous MEDI4736 (durvalumab) in combination with intravenous AZD9150 in selected patients with MIBC who have progressed following prior therapy.	Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
Primary	Module G: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral selumetinib.	The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI 4736 (durvalumab) given intravenously in combination with selumetinib given orally to selected patients with MIBC who have progressed following prior therapy.	Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
Primary	All Modules: Change from baseline in clinical chemistry parameters.	Changes from baseline in clinical chemistry parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.	Days 1, 8, 15, and 22 of Cycle 1, Days 1, 15, and 22 of Cycles 2 and 3 and every 4 weeks thereafter, and at discontinuation.
Primary	All Modules: Change from baseline in haematology parameters.	Changes from baseline in haemotology parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.	Days 1, 8, 15, and 22 of Cycle 1, Days 1, 15, and 22 of Cycles 2 and 3 and every 4 weeks thereafter, and at discontinuation.
Primary	All Modules: Change from baseline in urinalysis results.	Changes from baseline in urinalysis findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.	Days 1, 8, 15, and 22 of Cycle 1, Days 1, 15, and 22 of Cycles 2 and 3 and every 4 weeks thereafter, and at discontinuation.
Primary	All Modules: Change from baseline in vital signs.	Changes from baseline in vital signs will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.	Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation.
Primary	All Modules: Change from baseline in physical examination findings.	Changes from baseline in physical examination findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.	Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation.
Primary	All Modules: Change from baseline in ECG findings.	Changes from baseline in ECG findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.	ECGs will be collected at screening, Day 1, Cycle 1and then Day 1 of each cycle from Cycle 2 onwards.
Primary	All Modules: Change from baseline in ejection fraction determined by assessing ECHO/MUGA scans.	Changes from baseline in ejection fraction determined by assessing ECHO/MUGA scans will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.	Ejection fraction will be measured at screening, on Day 1, Cycle 1, and every 12 weeks thereafter (relative to the first dose of study drug) up to Cycle 7, and then every 16 weeks thereafter.
Primary	All Modules: Change from baseline in coagulation parameters	Changes from baseline in coagulation parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.	Coagulation parameters will be measured at screening, on Day 1, Cycle 1, and every 12 weeks thereafter (relative to the first dose of study drug) up to Cycle 7, and then every 16 weeks thereafter.
Primary	All Modules: Change from baseline in lipid profile	Changes from baseline in lipid profile will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.	Lipid profile will be measured at screening, on Day 1, Cycle 1, and every 12 weeks thereafter (relative to the first dose of study drug) up to Cycle 7, and then every 16 weeks thereafter.
Secondary	Objective response rate (ORR)	The percentage of patients who have a confirmed visit response of Complete Response (CR) or Partial Response (PR) as assessed by the investigator per RECIST 1.1.; Data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR.	16 weeks and 52 weeks
Secondary	Disease control rate (DCR)	Percentage of patients who have a confirmed visit response of CR or PR or stable disease (SD) =16 weeks as assessed by the investigator as per RECIST 1.1	16 weeks and 52 weeks
Secondary	Progression free survival (PFS)	The time from randomization until the date of objective disease progression or death (from any cause in the absence of progression) regardless of whether the patient withdraws from assigned therapy or receives another anticancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.	up to 12 months
Secondary	Duration of response (DoR)	Duration of response is defined as the elapsed time from the date of first documented response (CR/PR) as per RECIST Version 1.1 as assessed by the investigator until the date of documented progression or death in the absence of disease progression. The time of the initial response is defined as the latest of the dates contributing towards the first visit response of PR or CR.	up to 12 months
Secondary	Overall survival (OS) rate at 1 year	Defined as the proportion of patients surviving after 1 year from the start of treatment.	1 year
Secondary	Plasma concentration of AZD4547 (Module A)	The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.	Blood samples will be taken pre-dose on Days 1 and 8 of Cycle 1; pre-dose and 2, 3, 4 and 6 hours post-dose on Day 1 of Cycle 2; and pre-dose and 2 to 4 hours post-dose on Day 1 of Cycle 3.
Secondary	Plasma concentration of MEDI4736 (durvalumab) (Module A)	The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.	Blood samples will be taken pre-dose and end of infusion for Day 1 of Cycles 1 to 7 and for the post-Cycle 7 8-weekly assessments, and pre-dose for Day 8 of Cycle 1.
Secondary	Plasma concentration of olaparib (Module B)	The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.	Blood samples will be taken on Day 3 of Cycles 1 and pre-dose and 4 hr post-dose. Serial samples on Day 3 of Cycle 3, pre-dose, 1, 2, 4, 6, 8, and 10 hr post-dose.
Secondary	Plasma concentration of AZD1775 (Module C)	The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.	Blood samples will be taken on Day 8 at steady state at the following time points: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hr post-dose.
Secondary	Plasma concentration of MEDI4736 (durvalumab) (Module C)	The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.	Blood samples will be taken on Days 1 and 8 of Cycle 1 pre-dose and at the end of infusion (1 hour). Samples will also be collected on Day 1 of Cycles 2 to 7 pre-dose and at the end of infusion.
Secondary	Plasma concentration of MEDI4736 (durvalumab) (Module D)	The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.	Blood samples will be taken on Days 1 and 8 of Cycle 1
Secondary	Plasma concentration of vistusertib (Module E)	The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.	Blood samples will be collected pre-dose, and 2 and 4 hr post-dose on Day 1 of Cycle 1; and pre-dose and 2 to 6 hr post-dose (matched to biopsy) on Day 2 of Cycle 2.
Secondary	Plasma concentration of Medi4736 (durvalumab) (Module E).	The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.	Blood samples will be taken pre-dose and end of infusion for Day 1 of Cycles 1 to 7 and every 8 weeks thereafter and pre-dose for Day 8 of Cycle 1.
Secondary	Plasma concentration of AZD9150 (Module F)	The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.	Blood samples will be taken pre-dose of Days -7, -5, and -3 of the lead-in portion and thereafter prior to dosing and at the ned of infusion on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 (approximately 8 months).
Secondary	Plasma concentration of MEDI4736 (durvalumab) (Module F).	The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.	Blood samples will be taken pre-dose and end of infusion for Day 1 of Cycles 1 to 7 and every 8 weeks thereafter and pre-dose for Day 8 of Cycle 1.
Secondary	The presence of Anti-Drug Antibodies (ADA) and ADA neutralising antibodies to MEDI4736 will be assessed in patients receiving MEDI4736 in any sub-study module.	The formation of anti-drug antibodies and neutralizing antibodies will be assessed by validated methods.	Blood samples will be collected prior to MEDI4736 dosing on Day 1 of Cycles 1, 2 and 4 and every 12 weeks thereafter (up to 12 months).