Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Durvalumab · 82 trials · 83 indications
* Incidence of grade ≥ 3 AEs * Incidence of imAE, defined as an AE that is associated with drug exposure and is consistent with an immune-mediated mechanism of action and there is no clear alternate etiology. * Incidence of AEs that lead to treatment delays/interruptions or permanent discontinuation.
Incidence of Grade 3 or 4 \[possibly treatment-related adverse events (PRAEs)\] as observed prior to RC.
Safety and tolerability will be evaluated by the proportion of treated patients with occurrence of AEs, SAEs and AESIs, as assessed by CTCAE v5.0.
Overall survival (OS) in FAS (HER2 IHC 3+) population OS is defined as time from randomization date until the date of death due to any cause. The comparison will include all randomized patients, regardless of whether the patient withdraws from therapy or receives another anticancer therapy. The measure of interest is the hazard ratio of OS.
PRAE is defined as an AE which has been assessed by the investigator to be possibly related to IMP.
A PRAE is defined as an AE that has been assessed by the Investigator to be possibly related to study treatment. A PRAE will be included if it has onset or worsens (by Investigator report of an increase in CTCAE (common terminology criteria for adverse events) grade relative to pre-treatment) within 6 months of initiation of study intervention and it has CTCAE Grade 3 or 4 recorded within this timeframe.
The primary endpoint of this study is the incidence of Grade 3/4 PRAEs (CTCAE v5.0) of durvalumab combined with gemcitabine-based chemotherapy within 6 months of starting study intervention regardless of length of infusion. PRAEs are where the investigator answered yes to the question "Do you consider that there is a reasonable possibility that the event may have been caused by the investigational product?".
PRAE is defined as an AE which has been assessed by the investigator to be possibly related to IMP.
ORR is defined as the number (%) of participants with a confirmed objective tumour response (complete response \[CR\] or partial response \[PR\]) as determined by the investigator per Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1).
Safety endpoint
To monitor safety and tolerability of continuous study treatment to patients who continue to benefit at the end of the clinical trial by measuring the primary outcome of Serious Adverse Events (SAEs).
Defined as time from randomisation until progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR), or death due to any cause in participants with PD-L1 TC ≥ 50%.
Progression Free Survival (PFS) as assessed by BICR, per RECIST 1.1.
Incidence of Grade 3 or higher adverse events to evaluate safety and tolerability profile of durvalumab + Platinum (cisplatin or carboplatin) plus etoposide (EP) treatment was assessed.
Immune mediated adverse events (imAEs) were assessed to evaluate safety and tolerability profile of durvalumab + EP treatment. An imAE is defined as an AESI that is associated with drug exposure and is consistent with an immune-mediated mechanism of action (MOA) and where there is no clear alternate etiology.
Participants in Cohort 1 MRD+ will be assessed for ctDNA levels at baseline and end of treatment, expected to be 4 cycles of 3 weeks per cycle (defined as ctDNA evaluable set or ctDES). The outcome will be assessed as the number of participants with a ≥ 3 fold decrease in ctDNA level, a number without dispersion.
Frequency of Adverse Events.
Clinical chemistry will be assessed by liver function assessment (ALT, AST, albumin, total bilirubin measured in units per dL)
Clinical chemistry will be assessed by kidney function assessment in mg/dL
Clinical chemistry will be assessed by thyroid function assessment in units per mL.
Hematology will be assessed by white cell count, platelet count, absolute neutrophil count and absolute lymphocyte count.
Eastern Cooperative Oncology Group (ECOG) performance status scale range 0 to 5, where 0 is fully active, able to carry on all pre disease performance without restriction - best outcome and 5 -death - worst outcome.
Event-free survival (EFS;) is defined as the time from randomization to the first occurrence of any of the following events: recurrence of disease post-radical cystectomy, the first documented progression in participants who did not receive radical cystectomy, failure to undergo radical cystectomy in participants with residual disease, or death due to any cause, up to 3 years.
Patients with AEs grade ≥ 3 acording to NCI CTCAE v5.0
Patients with immune-mediated adverse events (imAE) per patient
An immune-mediated adverse event (imAE) is defined as an AESI that is associated with drug exposure and is consistent with an immune-mediated mechanism of action and where there is no clear alternate aetiology.
DFS was defined as the time from the date of randomization until any one of the following events, whichever occurred first: Date of disease recurrence using Investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 OR Date of death from any cause.
EFS is the time from date of randomization until the date of disease progression or death.
To assess the efficacy in terms of PFS in PD-L1 High population
DFS was defined as the time from the date of randomization until either of the following events, whichever occurred first: disease recurrence using Investigator RECIST 1.1 assessments (i.e., local or regional recurrence, distant recurrence, second primary NSCLC) or death from any cause.
RFS (per RECIST 1.1 criteria as assessed by BICR) will be defined as the time from the date of randomization until the date of the first objective radiologic recurrence or death due to any cause, whichever occurs first.
Overall Survival (OS) was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The second interim analysis was pre-specified after approximately 397 OS events occurred in both arms (59% maturity).
Overall Survival (OS) was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The second interim analysis was pre-specified after approximately 397 OS events occurred in both arms (59% maturity).
Overall Survival (OS) was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The second interim analysis was pre-specified after approximately 397 OS events occurred in both arms (59% maturity).
Main Cohort
Osimertinib Cohort
PFS defined as time from date of randomisation until date of tumour progression or death by any cause, regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression
To determine the efficacy of durvalumab in combination with platinum based chemotherapy and bevacizumab and continued as maintenance in combination with bevacizumab and olaparib versus SoC platinum based chemotherapy in combination with bevacizumab by assessment of PFS (using investigator assessment according to Response Evaluation Criteria in Solid Tumours version 1.1 \[RECIST 1.1\]) in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Per MTP, the comparison of SoC+D+O v SoC in the Non-tbRCAm patients is a primary endpoint. SoC+D v SoC is reported separately as a secondary endpoint. Results for tBRCAm SoC+D+O are not presented as this was prespecified to be assessed only in the Non-tBRCAm patients.
To determine the efficacy of durvalumab and olaparib assessed by PFS in the first line treatment of patients with newly diagnosed advanced ovarian cancer. Per MTP, the comparison of SoC+D+O v SoC in the Non-tBRCAm HRD positve population is a primary endpoint. SoC+D v SoC is reported separately as a secondary endpoint. Results for tBRCAm SoC+D+O are not presented as as this was prespecified to be assessed only in the Non-tBRCAm patients.
Defined as the lack of any viable tumour cells after complete evaluation in the resected lung cancer specimen and all sampled regional lymph nodes.
An event is defined as documented RECIST 1.1 local or distant recurrence of lung cancer; death due to any cause; disease progression that precludes surgery or discovered upon attempting surgery that prevents completion of surgery.
PFS per Blinded Independent Central Review (BICR) assessment will be defined as the time from the date of randomization until the date of first objective disease progression or death
The PFS per Response Evaluation Criteria in Solid Tumors 1.1. (RECIST 1.1) using blinded independent central review (BICR) assessments was defined as the time from the date of randomization until the date of objective disease progression (PD) or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anti-cancer therapy prior to progression. The PD was defined as at least a 20% increase in the sum of diameters of target lesions (TLs) and an absolute increase of \>=5 millimeters (mm), taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. Median PFS was calculated using the Kaplan-Meier technique.
pCR rate is defined as the proportion of patients whose pathological staging was T0N0M0 as assessed per central pathology review using specimens obtained via radical cystectomy following the neoadjuvant treatment. The denominator for pCR will be the number of patients in the FAS.
EFS is defined as the time from randomization to the first recurrence of disease post radical cystectomy, time of first documented progression in patients who were medically precluded for radical cystectomy, or time of expected surgery in patients who refuse to undergo a radical cystectomy or failure to undergo a radical cystectomy in participants with residual disease, or the time of death due to any cause, whichever occurs first
PFS per RECIST 1.1 assessed by BICR was defined as the time from the date of randomization until the date of objective disease progression (PD) or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anticancer therapy prior to progression. PD was defined as at least a 20% increase in the sum of diameters of target lesions (TLs), taking as reference the smallest previous sum of diameters (nadir) - this included the baseline sum if that was the smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm) from nadir. Median PFS was calculated using Kaplan-Meier method and its confidence interval (CI) using Brookmeyer-Crowley method.
OS was defined as the time from the date of randomization until death due to any cause. Median OS was calculated using Kaplan-Meier method and its CI using Brookmeyer-Crowley method.
Disease-free survival using Investigator disease assessments.
The PFS per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) using blinded independent central review (BICR) assessments was defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdrew from therapy or received another anti-cancer therapy prior to progression. The PD was defined as at least a 20% increase in the sum of diameters of target lesions. Median PFS was calculated using the Kaplan-Meier technique.
OS was defined as the time from the date of randomization until death due to any cause, regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy. Any participant not known to have died at the DCO date was censored based on the last recorded date on which the participant was known to be alive. If the last known date alive or if the date of death was after the DCO date, participants were censored at the DCO date. This primary outcome measure presents OS analysis of Treme 300mg x1 dose + Durva 1500 mg vs Sora 400 mg at the time of the final analysis DCO (27Aug2021).
PFS (per RECIST version 1.1 \[RECIST 1.1\] using Blinded Independent Central Review \[BICR\] assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique. The final analysis of PFS in the global cohort was pre-specified after approximately 497 BICR PFS events occurred across the D + SoC and SoC alone treatment arms (75% maturity).
OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The final analysis of OS in the global cohort was pre-specified after approximately 532 OS events occurred across the D + SoC and SoC alone treatment arms (80% maturity).
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An interim analysis of OS in the global cohort was pre-specified after approximately 318 OS events occurred each between the D + EP and EP groups (60% maturity), and between the D + T + EP and EP groups (60% maturity). At the global cohort interim analysis DCO (11 March 2019), comparison of OS in the D + EP versus (vs) EP groups had crossed the pre-specified boundary. Since these results were considered final in terms of formal statistical testing, they are presented here as a primary outcome measure. Analysis of OS for D + EP vs EP and for D + T + EP vs EP at the time of the global cohort final analysis is presented separately in the subsequent primary outcome measure.
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. This primary outcome measure presents OS for the analysis of D + EP vs EP and D + T + EP vs EP at the time of the global cohort final analysis DCO (27 January 2020). Analysis of D + EP vs EP at the global cohort interim analysis DCO is presented in the previous primary outcome measure. Analysis of D + T + EP vs D + EP (global cohort final analysis) is presented as a secondary outcome measure.
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An analysis of OS for D + EP vs EP in the China cohort was pre-specified at approximately 60% maturity (to ensure a similar maturity to the interim analysis of the Global cohort). This primary outcome measure presents OS for analysis of D + EP vs EP at the China cohort first analysis DCO (06 January 2020), and is comparable in terms of maturity with the interim analysis of OS for D + EP vs EP in the Global cohort. Analysis of OS for D + EP vs EP and for D + T + EP vs EP at the time of the China cohort second analysis is presented separately in the subsequent primary outcome measure.
OS was defined as the time from date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. An analysis of OS for D + T + EP vs EP in the China cohort was pre-specified at approximately 80% maturity (to ensure a similar maturity to the final analysis of the Global cohort). This primary outcome measure presents OS for analysis of D + EP vs EP and D + T + EP vs EP at the time of the China cohort second analysis DCO (02 November 2020), and is comparable in terms of maturity with the final analysis of OS for D + EP vs EP and D + T + EP vs EP in the Global cohort. Analysis of D + EP vs EP at the China cohort first analysis DCO is presented in the previous primary outcome measure. Analysis of D + T + EP vs D + EP (China cohort second analysis) is presented as a secondary outcome measure.
OS is defined as the time from the date of randomization until death due to any cause (date of death or censoring-date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive.
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
defined as the interval in whole days between date of randomisation and date of death from any cause
defined as the interval in whole days between date of randomisation until date of progression/persistence/recurrence/death
pCR rate is the proportion of participants with absent invasive carcinoma in the breast and lymph nodes at time of surgery; in situ disease only is considered pCR; if off-treatment prior to surgery than considered not pCR.
The progression-free survival (PFS) is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse.
Objective response rate(ORR) by RECIST 1.1
defined as the time from the randomization to the time of the first event that is either recurrent (local or distant) bladder cancer, a new primary bladder cancer or death from any cause
pCRR will be analysed based on the percentage of patients who obtained a pathological complete response. Pathologic response will be evaluated on cystectomy tumor sample
Changes in ctDNA levels (from baseline to C1/C2) compared with objective RECIST radiological response at 26 weeks
1-year progression free survival (PFS) depicted as the 1-year in-field-progression-free survival and 1-year distant metastasis free survival
number of treatment discontinuations due to toxicity
Event-free survival (EFS), is defined as the time from randomization to the time when a failure event is observed. Failure is define by Local-regional progression or recurrence, Distant metastasis, Non-protocol RT, chemotherapy, Surgery or death.
Time to progression
Efficacy endpoint
PFS is defined as the time from randomization until the date of confirmed PD (per Response Evaluation Criteria in Solid Tumours, Version 1.1 \[RECIST 1.1\] as assessed by the Investigator) or death due to any cause. The measure of interest is the hazard ratio (HR) and the corresponding 95% confidence interval (CI).
PFS is defined as the time from randomization until the date of confirmed PD (per RECIST 1.1 as assessed by the Investigator) or death due to any cause. The measure of interest is the PFS rate and the corresponding 95% CI at 6 months.
PFS is defined as the time from randomization until the date of confirmed PD (per RECIST 1.1 as assessed by the Investigator) or death due to any cause. The measure of interest is the PFS rate and the corresponding 95% CI at 12 months.
Resection rate is defined as the proportion of all participants who underwent definitive surgery. Participants who undergo (ie, start) surgery with the goal of complete tumour resection will be counted as meeting this endpoint.
12 month landmark PFS, APF12, where PFS is defined as the time from the first dose of study intervention in the induction phase until objective disease progression (as assessed by the investigator per RECIST v1.1) or death from any cause, whichever comes first.
The safety and tolerability profile of durvalumab as defined by Grade 3 and Grade 4 PRAEs within 6 months from the initiation of durvalumab treatment. A PRAE was any TEAE with a possible relatedness to durvalumab, or where the relatedness was missing. If relatedness of a TEAE was missing at the primary DCO (30 March 2023) the TEAE was considered a PRAE.
Clinical Benefit is the count of participants who have achieved a CR (Complete Response), PR (Partial Response), or SD (Stable Disease), assessed by RECIST 1.1 response criteria Response Evaluation Criteria in Solid Tumors (RECIST) is a standard measure of how well cancer patients respond to treatment. Possible scores are CR (total disappearance of all target lesions), PR (at least a 30% decrease of the sum of the longest diameter of all target lesions), PD (Progressive Disease; at least a 20% increase of the sum of the longest diameter of all target lesions), and SD (neither a sufficient decrease for PR, or sufficient increase for PD). This outcome measure will report the count of subjects who achieved any Clinical Benefit, Clinical Benefit for 3 months, and Clinical Benefit for 6 months.
Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0
Occurrence of dose limiting toxicities
Changes in laboratory parameters (every in appropriate units) compared to baseline results.
Changes in vital signs results compared to baseline results.
Changes in ECG results compared to baseline results.
Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.
To determine the safety and toxicity profile of rechallenging with durvalumab in patients who previously discontinued immunotherapy due to irAE.
Immune related or radiation therapy related toxicity of special interest are identifitied as: * Any Grade 4 immune-related AE * Any ≥ Grade 3 colitis * Any ≥ Grade 3 renal failure/nephritis * Any ≥ Grade 3 non-infectious pneumonitis irrespective of duration * Any Grade 3 immune-related AE, excluding colitis, renal failure/nephritis and pneumonitis, that does not downgrade to ≤ Grade 2 within 3 days after onset of the event despite maximal medical supportive care including systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days * Liver transaminase elevation ≥ 5 ULN or total bilirubin \> 3 × ULN will be considered a DLT regardless of duration or reversibility * Any increase in AST or ALT \> 3 × ULN and concurrent increase in total bilirubin \> 2 × ULN
Feasibility of performing surgery within 6 weeks after the last neo-adjuvant treatment. This would indicate that there were no significant delays or toxicities that would results in surgery being delayed.
To demonstrate improved tumour response of the primary tumour and nodal metastases in arms 2 or 3 versus arm 1 using residual cancer burden (RCB 0-1 vs. RCB 2-3) at time of surgery.
Safety and tolerability of Durvalumab as defined by Grade 3 and Grade 4 TRAEs following IV infusion administration was assessed.
Major pathological response rate is defined as percentage of participants with \<=10% residual viable tumor cells in the resected specimen.
Pathological response is defined as the absence of muscle- invasive bladder cancer at post-treatment biopsy (≤cT1). Cystoscopy and bladder biopsy six weeks since the end of radiotherapy.
Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
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.
The maximum tolerated dose is defined as the highest dose studied, for which the observed incidence of DLT is less than 33%. Number of Participants with Dose-limiting Toxicities (DLTs) in Phase I and Phase II will be reported.
Progression free survival (PFS) rate will be assessed at 3 months in the platinum resistant group using Kaplan-Meier methods. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
6-month progression-free survival rate is the probability of patients remaining alive and progression-free at 6 months from study entry estimated using Kaplan-Meier methods. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesion
* Defined as Dose Level 2 if 0 or 1 dose limiting toxicities (DLTs) are seen in patients at that dose level, or Dose Level 1 if 2+ DLTs are seen in Dose Level 2 but only 0 or 1 DLTs are seen in patients at Dose Level 1. * A DLT is defined as the occurrence of an adverse event (AE) that is at least possibly related to the investigational product (IP) or investigational regimen (IR)
The Maximum Tolerated Dose (MTD) and Dose Limiting Toxicities (DLT) will be discovered by using the 3+3 study design.
A minimum of 3 patients will initially be enrolled in each cohort, if none of the first 3 patients experiences a dose limiting toxicity (DLT), the doses in that cohort will be deemed safe and tolerable and escalation may continue. DLTs will be grade 4 neutropenia or thrombocytopenia, grade 3 hemolysis, grade 4 immune related AEs. If 1 of the first 3 evaluable patients in a cohort experiences a DLT, the cohort will be expanded to at least 6 patients. If there are no further DLTs in the first 6 DLT-evaluable patients, the doses in that cohort will be deemed safe and tolerable and escalation may continue. If a DLT is observed in ≥ 33% of patients (e.g., 2 or more of up to 6 patients), the dose combination at which this occurs will be considered intolerable and the MTD will have been exceeded for radiotherapy If the MTD is exceeded in any cohort, the highest dose combination at which fewer than 33% experience a DLT will be declared the combination MTD.
Occurrence of AEs in Part 1 graded according to NCI CTCAE v5.0
Occurrence of SAEs in Part 1 graded according to NCI CTCAE v5.0
Occurrence of AEs in Part 2 graded according to NCI CTCAE v5.0
Occurrence of SAEs in Part 2 graded according to NCI CTCAE v5.0
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.
DLT: Any study drug related Grade (G)3 or higher toxicity including: any G3/G4 immune-mediated AE, any G3/4 noninfectious pneumonitis/colitis, transaminase elevation (TE) \>8x upper limit of normal (ULN) or total bilirubin (TBL) \>5xULN, increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>=3xULN along with TBL \>=2xULN, isolated liver TE \>5 but =\<8xULN or isolated TBL \>3 but =\<5xULN that does not downgrade to G1 or less within 14 days of onset, G3 nausea/vomiting/diarrhea that does not resolve to G2 or less within 3 days of maximal supportive care (MSC), G3/4 febrile neutropenia, G3/4 neutropenia not associated with fever/systemic infection, G4 anemia, G3 anemia with clinical sequelae/requires \>2 units of red blood cells transfusion, thrombocytopenia (G4 \>=7 days, G3 that did not improve by at least 1 grade within 7 days, G3/4 associated with G3/higher hemorrhage).
Number of participants with at least common terminology criteria for adverse events (CTCAE v5.0) 2-grade shift from baseline (last assessment prior to first dose) to worst toxicity grade in clinical laboratory parameters are reported. Clinical laboratory parameter analysis included hematology, clinical chemistry, coagulation, and urinalysis.
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 (body temperature, blood pressure, and pulse rate).
The OR is defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 criteria. The CR is defined as disappearance of all target lesions (TLs) and non-target lesions (NTLs), normalization of tumor marker level, any pathological lymph nodes (target and non-target) must have reduction in short axis \< 10 mm, and no new lesion. The PR is defined as at least a 30% decrease in the sum of the diameters (SoD) of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. In Part 2, randomization occurred between Day -8 and the same date as dosing.
Assessment of safety and tolerability of each treatment arm
The occurrence of a severe adverse event (meeting pre-specified criteria) that is at least possibly related to durvalumab and/or the novel oncology therapy in 6 DLT-evaluable patients
Only for phase 1 portion of the study
Only for phase 1 portion of the study
Only for phase 1 portion of the study
Dose limiting toxicities are defined as any Grade 3 or higher treatment-related (related to any study drug) toxicity that occurs during the DLT evaluation period. Number of participants with DLTs are reported.
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event is any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, is a congenital anomaly/birth defect in offspring of a study participant, is an important medical event that may jeopardize the participant or may require medical intervention. 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 vital signs and physical examinations reported as TEAEs are reported.
Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.
Number of participants with abnormal electrocardiograms (ECGs) and echocardiograms (ECHOs) reported as TEAEs are reported.
| Arm | Type | Description |
|---|---|---|
| Durvalumab | EXPERIMENTAL | Durvalumab after completion of CRT |
| ddMVAC cohort | EXPERIMENTAL | Durvalumab + chemotherapy |
| gem/cis cohort | EXPERIMENTAL | Durvalumab + chemotherapy |
| Trastuzumab deruxtecan + rilvegostomig | EXPERIMENTAL | Trastuzumab deruxtecan (T-DXd; DS-8201a) in combination with rilvegostomig arm |
| Trastuzumab deruxtecan | EXPERIMENTAL | Trastuzumab deruxtecan (T-DXd; DS-8201a) arm |
| Standard of Care | ACTIVE_COMPARATOR | Gemcitabine and cisplatin in combination with durvalumab arm |
| Durvalumab + Gemcitabine based chemotherapy | EXPERIMENTAL | Participants will receive durvalumab 1500mg every 3 or 4 weeks, in combination with continuation of all or some of the original background gemcitabine based chemotherapy every 3 or 2 weeks for up to a maximum of 8 cycles of chemotherapy. Durvalumab 1500mg is given as a 60-minute IV infusion in the first cycle (Day 1) and as a 30-minute IV infusion in following cycles. Upon completing 8 cycles of background gemcitabine-chemotherapy, or after discontinuing any of the combination chemotherapies due to toxicity before completing 8 cycles, participants are eligible to continue receiving durvalumab 1500 mg IV every 4 weeks either alone or in combination with gemcitabine-based chemotherapy (with the exception of paclitaxel), as per investigator's discretion. |
| Durvalumab + BCG | EXPERIMENTAL | Participants will receive Durvalumab for 13 cycles every 4 weeks (q4w) for a maximum 12 months. All participants will receive BCG (supplied by the site) intravesically, as induction weekly for 6 weeks. Patients will subsequently receive BCG for maintenance for 3 weekly doses at 3,6,12,18, and up to 24 months, at the physician's discretion. |
| durvalumab in combination with gemcitabine-based chemotherapy | EXPERIMENTAL | single-arm |
| Durvalumab plus Tremelimumab | EXPERIMENTAL | Participants will receive a single priming dose of Tremelimumab plus Durvalumab at Day 1 (Week 0), followed by Durvalumab monotherapy starting at Week 4 and continuing until clinical progression, confirmed RECIST 1.1-defined radiological progression, unacceptable toxicity, withdrawal of consent, or any intervention discontinuation criteria. |
| cohort 1 | EXPERIMENTAL | durvalumab in combination with tremelimumab |
| cohort 2 | EXPERIMENTAL | durvalumab in combination with tremelimumab |
| Arm A: Durvalumab + Domvanalimab | EXPERIMENTAL | Durvalumab and domvanalimab as an IV infusion q4w, starting on Day 1 for up to a maximum of 12 months |
| Arm B: Durvalumab + Placebo | ACTIVE_COMPARATOR | Durvalumab + placebo as an IV infusion q4w starting on Day 1 for up to a maximum of 12 months |
| Arm A: Durvalumab and Oleclumab | EXPERIMENTAL | Durvalumab on Day 1 of each 28-day cycle + Oleclumab on Days 1 and 15 of cycles 1 and 2, then on Day 1 of each subsequent 28-day cycle for up to 12 months |
| Arm B: Durvalumab and Monalizumab | EXPERIMENTAL | Durvalumab + Monalizumab on Day 1 of each 28-day cycle for up to 12 months. Placebo infusion will be administered on Day 15 of cycles 1 and 2 only |
| Arm C: Durvalumab and Placebo | ACTIVE_COMPARATOR | Durvalumab on Day 1 of each 28-day cycle + Placebo on Days 1 and 15 of cycles 1 and 2, then on Day 1 of each subsequent 28-day cycle for up to 12 months |
| Durvalumab - (cisplatin or carboplatin) - Etoposide | EXPERIMENTAL | Participants will receive durvalumab dose A administered via intravenous (IV) infusion concurrently with platinum-based chemotherapy and etoposide every 3 weeks (q3w). Thereafter, durvalumab monotherapy will be continued every 4 weeks post-chemotherapy unless specific treatment discontinuation criteria are met. |
| Cohort 1 minimal residual disease positive (MRD+) | EXPERIMENTAL | Subjects with detectable ctDNA will receive 4 cycles of platinum doublet chemotherapy \[carboplatin/pemetrexed\], tremelimumab (75 mg IV every 21 days) and durvalumab (1500 mg IV every 21 days), except subjects with squamous cell carcinoma histology will receive carboplatin/paclitaxel. Subjects will be evaluated with PET/CT and/or computed tomography (CT) thorax every 12 weeks. Following ctDNA evaluation, in the absence of progression or toxicity, subject will continue with durvalumab to complete 1 year of treatment as standard of care. |
| Cohort 2 minimal residual disease negative (MRD ) | EXPERIMENTAL | Subjects with undetectable ctDNA at study enrollment will receive standard of care durvalumab (10 mg/kg every 2 weeks, or equivalent, for 1 year). If subjects in Cohort 2 MRD progress prior to close of study, blood will be drawn for ctDNA testing. |
| Durvalumab + Tremelimumab + Enfortumab Vedotin | EXPERIMENTAL | Participants will receive 3 preoperative 21-day cycles of Durvalumab + Enfortumab Vedotin and 2 cycles of Tremelimumab, followed by radical cystectomy, followed by 1 cycle of postoperative Tremelimumab and 9 cycles of Durvalumab. Each postoperative cycle is 28 days. |
| Durvalumab + Enfortumab vedotin | EXPERIMENTAL | Participants will receive 3 preoperative 21-day cycles of Durvalumab + Enfortumab Vedotin, followed by radical cystectomy, followed by 9 cycles of Durvalumab. Each postoperative cycle is 28 days. |
| Cystectomy with or without approved Adjuvant Therapy. | ACTIVE_COMPARATOR | Participants may receive SoC (nivolumab approved as adjuvant treatment for MIBC based on high risk criteria) per approved label in the country OR Participants receive standard of care surgery (radical cystectomy) alone. |
| Durvalumab in Combination with Platinum-Etoposide | EXPERIMENTAL | Durvalumab 1500 mg via IV infusion will be concurrently administered with first-line chemotherapy (EP) on an every 3 week (q3w) schedule for 4 to 6 cycles, and will continue to be administered post-chemotherapy on an every 4 week (q4w) schedule until confirmed progressive disease (PD) or unacceptable toxicity. |
| Durvalumab plus 4-6 cycles chemotherapy | EXPERIMENTAL | Participants will receive treatment with durvalumab + etoposide and either cisplatin or carboplatin (EP) for 4 to 6 cycles. Durvalumab will be administered at a dose of 1500 mg every 3 weeks (Q3W) with first-line chemotherapy (EP) and will continue to be administered as monotherapy every 4 weeks (Q4W) post-chemotherapy until progressive disease (PD). Prophylactic cranial irradiation (PCI) is allowed at the investigators' discretion as per SoC guidance for ES-SCLC. Patients will attend a safety follow up visit 90 days after last dose of durvalumab. |
| Placebo | PLACEBO_COMPARATOR | Intravenous administration of placebo |
| Arm B | PLACEBO_COMPARATOR | placebo product and FLOT chemotherapy |
| Arm A | EXPERIMENTAL | Durvalumab and FLOT chemotherapy |
| Arm 1: Durvalumab + definitive CRT | EXPERIMENTAL | Durvalumab + concurrent chemoradiation |
| Arm 2: Placebo + definitive CRT | PLACEBO_COMPARATOR | Placebo + concurrent chemoradiation |
| Durvalumab + SoC chemotherapy | EXPERIMENTAL | Intravenous administration of Experimental and Standard of Care Therapy |
| Placebo + SoC chemotherapy | PLACEBO_COMPARATOR | Intravenous administration of Placebo and Standard of Care Therapy |
| Arm C | PLACEBO_COMPARATOR | Durvalumab placebo (Q3W) + bevacizumab placebo (Q3W) |
| Treatment Arm | EXPERIMENTAL | Durvalumab + Gemcitabine + Cisplatin |
| Placebo Arm | PLACEBO_COMPARATOR | Placebo + Gemcitabine + Cisplatin |
| SoC SBRT + Durvalumab Therapy (Main Cohort) | EXPERIMENTAL | SBRT Durvalumab (PD-L1 monoclonal antibody) 1500 mg every 4 weeks \[q4w\] intravenously \[iv\] for up to 26 cycles or until progression or other discontinuation criteria are met. |
| SoC SBRT + Placebo Therapy (Main Cohort) | PLACEBO_COMPARATOR | SBRT Placebo (matching placebo for infusion) every 4 weeks iv for up to 26 cycles or until progression or other discontinuation criteria are met. |
| SoC SBRT + Osimertinib Therapy (Osimertinib cohort, single-arm, open-label separate cohort) | EXPERIMENTAL | SBRT Osimertinib 80mg every day \[qd\] for oral administration up to 36 months or until progression. Osimertinib treatment should start within 7 to 14 days after completion of SBRT |
| Durvalumab (intravenous infusion) | EXPERIMENTAL | durvalumab + standard of care concurrent chemoradiation therapy(SoC CCRT) followed by durvalumab monotherapy up to 24 months or until PD from the date of randomization |
| Placebo (matching placebo for intravenous infusion) | PLACEBO_COMPARATOR | placebo + standard of care concurrent chemoradiation therapy(SoC CCRT) |
| Arm 1 | ACTIVE_COMPARATOR | Platinum-based chemotherapy in combination with bevacizumab and durvalumab placebo (saline IV infusion) followed by maintenance bevacizumab, durvalumab placebo (saline IV infusion) and olaparib placebo (tablets). |
| Arm 2 | EXPERIMENTAL | Platinum-based chemotherapy in combination with bevacizumab and durvalumab followed by maintenance bevacizumab, durvalumab and olaparib placebo. |
| Arm 3 | EXPERIMENTAL | Platinum-based chemotherapy in combination with bevacizumab and durvalumab followed by maintenance bevacizumab, durvalumab and olaparib. |
| tBRCAm cohort | EXPERIMENTAL | Platinum-based chemotherapy in combination with bevacizumab and durvalumab followed by maintenance bevacizumab, durvalumab and olaparib. Bevacizumab is optional according to local practice. |
| Arm 1: Durvalumab with platinum-based chemotherapy | EXPERIMENTAL | Patients will receive durvalumab 1500 mg in combination with platinum-based chemotherapy every 3 weeks for up to 4 cycles prior to surgery, followed by durvalumab 1500 mg monotherapy every 4 weeks for up to 12 cycles after surgery unless disease is deemed unresectable, disease recurrence, or unacceptable toxicity The platinum-based chemotherapy will be based on tumour histology and Investigator discretion: * cisplatin with pemetrexed * carboplatin with pemetrexed * carboplatin with paclitaxel * cisplatin with gemcitabine (or carboplatin with gemcitabine for patients who have comorbidities or who are unable to tolerate cisplatin per the investigator's judgment) |
| Arm 2: Placebo with platinum-based chemotherapy | PLACEBO_COMPARATOR | Patients will receive placebo in combination with platinum-based chemotherapy every 3 weeks for up to 4 cycles prior to surgery, followed by placebo monotherapy every 4 weeks for up to 12 cycles after surgery unless disease is deemed unresectable, disease recurrence, or unacceptable toxicity The platinum-based chemotherapy will be based on tumour histology and Investigator discretion: * cisplatin with pemetrexed * carboplatin with pemetrexed * carboplatin with paclitaxel * cisplatin with gemcitabine (or carboplatin with gemcitabine for patients who have comorbidities or who are unable to tolerate cisplatin per the investigator's judgment) |
| Durvalumab Therapy | EXPERIMENTAL | Durvalumab (PD-L1 monoclonal antibody)1500 mg every 4 weeks \[q4w\] intravenously \[iv\] until clinical progression/deterioration or confirmed radiological progression) |
| Placebo Therapy | PLACEBO_COMPARATOR | Placebo (matching placebo for infusion every 4 weeks iv until clinical progression/deterioration or confirmed radiological progression) |
| Durvalumab + Placebo | EXPERIMENTAL | Durvalumab monotherapy: Durvalumab (1500 mg intravenous \[IV\]) q4w in combination with placebo saline solution (IV) q4w for up to 4 doses/cycles each, followed by durvalumab 1500 mg q4w. The first durvalumab monotherapy 1500 mg dose q4w will be 4 weeks after the final dose of durvalumab in combination with placebo saline solution. |
| Durvalumab + Tremelimumab | EXPERIMENTAL | Durvalumab in combination with tremelimumab: Durvalumab (1500 mg IV) q4w in combination with tremelimumab (75 mg IV) q4w for up to 4 doses/cycles each, followed by durvalumab 1500 mg q4w. The first durvalumab monotherapy 1500 mg dose q4w will be 4 weeks after the final dose of durvalumab in combination with tremelimumab. |
| Placebo + Placebo | PLACEBO_COMPARATOR | Placebo: Placebo saline solution (IV) q4w in combination with a second placebo saline solution (IV) q4w for up to 4 doses/cycles each, followed by a single placebo saline solution q4w. The first placebo saline solution monotherapy dose q4w will be 4 weeks after the final dose of the 2 placebo saline solutions in combination. |
| Durvalumab in Combination with SoC Chemotherapy | EXPERIMENTAL | Durvalumab every 3 weeks in concurrence with chemotherapy, followed by durvalumab monotherapy every 4 weeks. All patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles: * cisplatin+ gemcitabine * If the patient is cisplatin-ineligible, carboplatin + gemcitabine |
| Durvalumab in Combination with Tremelimumab+SoC Chemotherapy | EXPERIMENTAL | Durvalumab and Tremelimumab every 3 weeks in concurrence with chemotherapy, followed by durvalumab monotherapy every 4 weeks Tremelimumab will be provided for 4 cycles. All patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles: * cisplatin+ gemcitabine * If the patient is cisplatin-ineligible, carboplatin + gemcitabine |
| SoC Chemotherapy | ACTIVE_COMPARATOR | Patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles: * cisplatin+ gemcitabine * If the patient is cisplatin-ineligible, carboplatin + gemcitabine |
| Durvalumab plus BCG (induction + maintenance) | EXPERIMENTAL | Durvalumab (MEDI4736) plus Bacillus Calmette-Guerrin (BCG) combination therapy |
| Durvalumab plus BCG (induction only) | EXPERIMENTAL | Durvalumab (MEDI4736) plus Bacillus Calmette-Guerrin (BCG) combination therapy |
| BCG treatment (Standard of care therapy) | ACTIVE_COMPARATOR | Bacillus Calmette-Guerrin (BCG) standard of care treatment |
| Arm 1: Durvalumab + platinum-based chemotherapy and radiation | EXPERIMENTAL | Durvalumab ((MEDI4736) in concurrence with platinum-based chemo-radiation therapy. All patients will receive 1 of the following platinum-based standard of care chemotherapy options, based on Investigator discretion, in addition to radiation therapy: * cisplatin/etoposide * carboplatin/paclitaxel * pemetrexed/cisplatin * pemetrexed/carboplatin At the completion of standard of care chemoradiation therapy (SoC CRT), patients with complete response, partial response or stable disease will continue to receive durvalumab as consolidation treatment. |
| Arm 2: Placebo + platinum-based chemotherapy and radiation | PLACEBO_COMPARATOR | Placebo in concurrence with platinum-based chemo-radiation therapy. All patients will receive 1 of the following platinum-based standard of care chemotherapy options, based on Investigator discretion, in addition to radiation therapy: * cisplatin/etoposide * carboplatin/paclitaxel * pemetrexed/cisplatin * pemetrexed/carboplatin At the completion of standard of care chemoradiation therapy (SoC CRT), patients with complete response, partial response or stable disease will continue to receive placebo as consolidation treatment. |
| Arm 4 | ACTIVE_COMPARATOR | Sorafenib |
| Treatment Arm 1 | EXPERIMENTAL | durvalumab + tremelimumab combination therapy + SoC chemotherapy |
| Treatment Arm 2 | EXPERIMENTAL | durvalumab monotherapy + SoC chemotherapy |
| Treatment Arm 3 | ACTIVE_COMPARATOR | SoC chemotherapy alone |
| Arm 1: Durvalumab | EXPERIMENTAL | Anti-PD-L1 monoclonal Antibody monotherapy |
| Arm 2: Standard of Care | ACTIVE_COMPARATOR | Standard of Care Platinum-Based chemotherapy |
| Combination Therapy | EXPERIMENTAL | Durvalumab (PD-L1 monoclonal antibody) + Tremelimumab (monoclonal antibody directed against CTLA-4) |
| Arm 1 (control): chemoradiotherapy | ACTIVE_COMPARATOR | Concomitant chemoradiotherapy, 3-weekly cisplatin 100mg/m2 or weekly 40mg/m2 with Intensity Modulated Radiotherapy (IMRT) using 70 gray (Gy) in 35F(fractions) +/- neck dissection as indicated by clinical and radiological assessment 3-months post treatment. This is the international gold standard. |
| Arm 5: Durvalumab + Arm 1 | EXPERIMENTAL | One dose of induction durvalumab 1500mg by intravenous (IV) infusion followed by arm 1 within four weeks. Within one-two weeks after the completion of arm 1, durvalumab 1500mg every four weeks will be initiated for a total of 6 months |
| HER2 Positive | EXPERIMENTAL | Participants will be enrolled into one of two cohorts: HER2 positive IBC (cohort 1) and HER2 low IBC (cohort 2). * HER2-positive determined locally by the current ASCO/CAP guidelines * Participants will receive trastuzumab deruxtecan plus durvalumab for eight cycles prior to surgery. (Cycle Length is 21 days) * After surgery, Participants will receive therapy per physician's choice and to reflect current standard of care. |
| HER2-Low | EXPERIMENTAL | Participants will be enrolled into one of two cohorts: HER2 positive IBC (cohort 1) and HER2 low IBC (cohort 2) * HER2-low tumor expression (IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested) * Participants will receive trastuzumab deruxtecan plus durvalumab for eight cycles prior to surgery (Cycle Length is 21 days) * After surgery, Participants will receive therapy per physician's choice and to reflect current standard of care. |
| Durvalumab maintenance | OTHER | Patients will receive durvalumab intravenously 1500 mg every 4 weeks until disease progression, unacceptable toxicity, death or patient's decision for a maximum of 24 months. For patients receiving prophylactic cranial irradiation as per standard of care, the first dose of durvalumab may be delayed by up to 42 days from the end of the CRT. Radiological assessments will be planned every 12 weeks (± 7 days) of maintenance treatment. The first dose of durvalumab should be administered within 3 days of inclusion. |
| Cisplatin or Carboplatin + Etoposide + Durvalumab + Ceralasertib | EXPERIMENTAL | Initial Phase: Cycles 1-4 Cisplatin or Carboplatin: Day 1 Etoposide: Days 1-3 Durvalumab, 1500 mg: Day 1 q 3 weeks Maintenance Phase, Cycles 5+ Durvalumab, 1500 mg: Day 8 q 4 wks. Ceralasertib at 240mg po BID twice a day: Days 1-7 |
| Durvalumab(MEDI4736) and AZD6738 combination | EXPERIMENTAL | - |
| Surveillance | NO_INTERVENTION | - |
| Durvalumab plus Olaparib | EXPERIMENTAL | Durvalumab 1500 mg every 4 weeks for up to a maximum of 2 months (up to 2 doses/cycles) plus Olaparib 300 mg b.i.d. up to 56 days (2 cycles of 28 days each cycle). |
| Arm 1 - stopped after interims analyses | EXPERIMENTAL | Patients in arm 1 will receive a single dose of durvalumab of 1500 mg administered on day 1, 14 days prior to initiation of the radiotherapy. Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14. On week 5, 9, 13 and 17 patients will receive durvalumab (1500 mg) and tremelimumab (75 mg) for up to 4 doses/cycles and then continue 1500 mg durvalumab q4w starting on week 21 to complete a total of 12 months of therapy (overall 9 single doses durvalumab including the initial dose on day 1). |
| Radiation/Cisplatin | ACTIVE_COMPARATOR | All patients will receive standard fractionation radiation therapy (RT) scheme: 70 Gy in 35 fractions over 7 weeks (i.e. 2 Gy per fraction) Cisplatin IV 100 mg/m2 days 1, 22, 43 concurrently with RT |
| Radiation/Durvalumab + Adjuvant Durvalumab | EXPERIMENTAL | All patients will receive standard fractionation radiation therapy (RT) scheme: 70 Gy in 35 fractions over 7 weeks (i.e. 2 Gy per fraction) Concurrent Phase: Durvalumab IV 1500 mg, days -7 and 22 (the second dose is given concurrently with RT). Adjuvant Phase (to start 4 weeks after completion of concurrent phase): Durvalumab IV 1500 mg q4 weekly for 6 doses. |
| Radiation/Durvalumab + Adjuvant Durvalumab/Tremelimumab | EXPERIMENTAL | ARM CLOSED TO ACCRUAL WITH AMENDMENT #1 |
| Single Arm | EXPERIMENTAL | Durvalumab and Tremelimumab with Lenvatinib |
| Combination of olaparib and durvalumab after four cycles of standard 1st line treatment | EXPERIMENTAL | Study treatment (olaparib and durvalumab) starts with the initiation of maintenance therapy and is administered at a 28-day cycle until progression, unacceptable toxicity, or discontinuation for other reasons. Induction therapy (four cycles of carboplatin/cisplatin, etoposide, durvalumab (the administration of one induction cycle without durvalumab is permitted)) is administered as part of standard of care. |
| Arm A: Durvalumab + Tremelimumab + Platinum-based Chemotherapy | EXPERIMENTAL | Participants will receive durvalumab plus tremelimumab every 3 weeks (q3w) for four 21-day cycles in combination with chemotherapy followed by maintenance treatment period (durvalumab plus pemetrexed maintenance) every 4 weeks (q4w) until clinical progression or confirmed RECIST 1.1- defined radiological progression as assessed by the investigator, unacceptable toxicity, withdrawal of participant consent, or EOS, whichever comes first. During the maintenance treatment period, participants will receive additional doses of tremelimumab at Cycle 6 (Week 16) and Cycle 28 (Week 104 - at Investigator's discretion) along with durvalumab and pemetrexed. |
| Arm B: Pembrolizumab + Platinum-based Chemotherapy | EXPERIMENTAL | Participants will receive pembrolizumab regimen q3w for four 21-day cycles in combination with chemotherapy as induction treatment followed by maintenance treatment (pembrolizumab plus pemetrexed maintenance) q3w for up to 24 months, until clinical progression or confirmed RECIST 1.1- defined radiological progression as assessed by the investigator, unacceptable toxicity, withdrawal of participant consent, or EOS, whichever comes first. |
| Yttrium 90 glass microspheres TARE in combination with Durvalumab and Bevacizumab | EXPERIMENTAL | Participants will undergo Yttrium 90 glass microspheres TARE according to the dosimetry recommendation. |
| Arm 1: Oleclumab + Durvalumab + Platinum doublet chemotherapy (CTX) | EXPERIMENTAL | Participants will receive Durvalumab + Oleclumab + CTX as neoadjuvant treatment and Durvalumab + Oleclumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin |
| Arm 2: Monalizumab + Durvalumab + CTX | EXPERIMENTAL | Participants will receive Durvalumab + Monalizumab + CTX as neoadjuvant treatment and Durvalumab + Monalizumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin |
| Arm 3: Volrustomig (Dose Exploration) + CTX | EXPERIMENTAL | Participants will receive Volrustomig + CTX as neoadjuvant treatment and Volrustomig as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin |
| Arm 4: Dato-DXd + durvalumab + single agent platinum | EXPERIMENTAL | Participants will receive Dato-DXd + durvalumab + single agent platinum as neoadjuvant treatment and durvalumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on physician choice of as part of their treatment regimen prior to surgery: Carboplatin or Cisplatin |
| Arm 5: AZD0171 + durvalumab + CTX | EXPERIMENTAL | Participants will receive AZD0171 + durvalumab + CTX as neoadjuvant treatment and AZD0171 + durvalumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin |
| Arm 6: Rilvegostomig + CTX | EXPERIMENTAL | Participants will receive Rilvegostomig + CTX as neoadjuvant treatment and Rilvegostomig as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin |
| Arm 7: Dato-DXd + Rilvegostomig + single agent platinum | EXPERIMENTAL | Participants will receive Dato-DXd + Rilvegostomig + single agent platinum as neoadjuvant treatment and Rilvegostomig as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on physician choice of as part of their treatment regimen prior to surgery: Carboplatin or Cisplatin |
| Arm I: Durvalumab monotherapy + hypofractionated radiotherapy (RT) | EXPERIMENTAL | Participants undergo standard of care RT over 5 fractions once a day (QD) for 5 days. Within 3-10 days after completion of RT, participants receive durvalumab IV over 1 hour on day 1. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. |
| Arm II: Progression on prior programmed death-ligand 1 (PD-L1) checkpoint inhibitors | EXPERIMENTAL | Participants with progression on prior PD-L1 immune checkpoint inhibitor undergo standard of care hypofractionated radiotherapy (RT) over 5 fractions QD for 5 days and then receive a single, fixed dose of tremelimumab (300 mg IV) administered on Day 1, in combination with a fixed dose of durvalumab (1500 mg IV) every 28 days (+/-4 days for Cycles 2+), initiated within 3-10 days of completing RT, until confirmed radiographic progression or other criteria for discontinuation. |
| Arm III: No previous PD-L1 checkpoint inhibitor therapy | EXPERIMENTAL | Participants without prior PD-L1 immune checkpoint inhibitor therapy undergo standard of care hypofractionated radiotherapy (RT) over 5 fractions QD for 5 days and then receive a single fixed dose of tremelimumab (300 mg IV) administered on Day 1, in combination with durvalumab at fixed dose of 1500 mg IV every 28 days (+/-4 days for Cycles 2+), initiated within 3-10 days of completing RT, until confirmed radiographic progression or other criteria for discontinuation. |
| AZD2811 + Durvalumab | EXPERIMENTAL | Induction: Durvalumab + Platinum Chemotherapy (Carboplatin or cisplatin \& Etoposide) Maintenance: AZD2811 + Durvalumab |
| Cohort A | EXPERIMENTAL | Patients received standard radiotherapy \[60 gray (Gy) ± 10% or hypofractionated BED\] prior to study entry. |
| Cohort B | EXPERIMENTAL | Patients received palliative radiotherapy \[40 to \< 54 Gy or hypofractionated BED\] prior to study entry. |
| Arm A: Chemo-Immuno | EXPERIMENTAL | ArmA receives chemotherapy on D1 and immunotherapy on D8 of a 28-day cycle for the first 2cycles. After the first 2cycles, patients on Arm A and Arm B will be administered chemotherapy and immunotherapy on D1 of a 21day cycle for cycles 3 and 4. After 4cycles of chemo-immunotherapy, patients receive maintenance therapy with durvalumab and pemetrexed until treatment discontinuation. Maintenance therapy is administered on D1 of a 21day cycle. |
| Arm B: Immuno-Chemo | EXPERIMENTAL | ArmB receives immunotherapy on D1 and chemotherapy on D8 of a 28-day cycle for the first 2cycles. After the first 2cycles, patients on Arm A and Arm B will be administered chemotherapy and immunotherapy on D1 of a 21day cycle for cycles 3 and 4. After 4cycles of chemo-immunotherapy, patients receive maintenance therapy with durvalumab and pemetrexed until treatment discontinuation. Maintenance therapy is administered on D1 of a 21day cycle. |
| Arm 1A | EXPERIMENTAL | T-DXd and 5-fluorouracil (5-FU) |
| Arm 1B | EXPERIMENTAL | T-DXd and capecitabine |
| Arm 1C | EXPERIMENTAL | T-DXd and durvalumab |
| Arm 1D(b) | EXPERIMENTAL | T-DXd, capecitabine, and oxaliplatin |
| Arm 1E(a) | EXPERIMENTAL | T-DXd, 5-FU, and durvalumab |
| Arm 1E(b) | EXPERIMENTAL | T-DXd, capecitabine, and durvalumab |
| Arm 2A | ACTIVE_COMPARATOR | Trastuzumab, 5-FU or capecitabine, and cisplatin or oxaliplatin |
| Arm 2B | EXPERIMENTAL | T-DXd monotherapy |
| Arm 2C | EXPERIMENTAL | T-DXd, 5-FU or capecitabine |
| Arm 2D | EXPERIMENTAL | T-DXd, pembrolizumab and 5-FU or capecitabine |
| Arm 2E | EXPERIMENTAL | T-DXd and pembrolizumab |
| Arm 2F | EXPERIMENTAL | T-DXd, pembrolizumab and 5-FU or capecitabine |
| Arm 3A | EXPERIMENTAL | T-DXd, Volrustomig and 5-FU or capecitabine |
| Arm 3B | EXPERIMENTAL | T-DXd, Volrustomig and 5-FU or capecitabine |
| Arm 4A | EXPERIMENTAL | T-DXd, Rilvegostomig and 5-FU or capecitabine |
| Arm 4B | EXPERIMENTAL | T-DXd, Rilvegostomig and 5-FU or capecitabine |
| Part 5 Main Cohort | EXPERIMENTAL | T-DXd, Volrustomig and 5-FU or capecitabine |
| Part 5 Cohort 2 | EXPERIMENTAL | T-DXd, Volrustomig and 5-FU or capecitabine |
| Cohort 1: High Risk | ACTIVE_COMPARATOR | - |
| Cohort 2: Standard Risk - Arm A | ACTIVE_COMPARATOR | - |
| Cohort 2: Standard Risk - Arm B | ACTIVE_COMPARATOR | - |
| Chemotherapy and radiotherapy | EXPERIMENTAL | The combination of weekly paclitaxel 80 mg/m² IV followed by q2w dose-dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative radiation therapy on the primary tumour (3x8 Gy). |
| Chemotherapy and pre-operative radiotherapy plus durvalumab | EXPERIMENTAL | The combination of weekly paclitaxel 80 mg/m² IV followed by q2w dose-dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative radiation therapy on the primary tumour (3x8 Gy) with the addition of the anti-PD-L1 antibody durvalumab IV 1500 mg q4w. |
| Chemotherapy & pre-op radiotherapy + durvalumab + oleclumab | EXPERIMENTAL | The combination of weekly paclitaxel 80 mg/m² IV followed by q2w dose-dense doxorubicin-cyclophosphamide (ddAC) (60 mg/m² doxorubicin IV and 600 mg/m² cyclophosphamide IV) and pre-operative radiation therapy on the primary tumour (3x8 Gy) with the addition of the anti-PD-L1 antibody durvalumab IV 1500 mg q4w and the addition of the anti-CD73 antibody oleclumab IV 3000 mg q2w for 4 administrations, followed by q4w for 3 administrations. |
| WHO/ECOG PS 0 to 1 Cohort | EXPERIMENTAL | 100-120 participants will receive 1500 mg Durvalumab (MEDI4736) monotherapy via IV infusion q4w for up to a maximum of 24 months (up to 26 doses/cycles) with the last administration at Week 104. The study drug should be discontinued prior to 24 months if there is clinical progression or confirmed radiological progression or if there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. |
| WHO/ECOG PS 2 Cohort | EXPERIMENTAL | up to 30 participants will receive 1500 mg Durvalumab (MEDI4736) monotherapy via IV infusion q4w for up to a maximum of 24 months (up to 26 doses/cycles) with the last administration at Week 104. The study drug should be discontinued prior to 24 months if there is clinical progression or confirmed radiological progression or if there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. |
| Durvalumab 1500 mg | EXPERIMENTAL | Participants will receive durvalumab 1500 mg intravenously (IV) every 4 weeks (Q4W; on Week 1 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection will be planned between Day 29 and Day 42. After surgical resection, participants will be followed up to Day 105 (starting from Week 1 Day 1). |
| Durvalumab 1500 mg + Oleclumab 3000 mg | EXPERIMENTAL | Participants will receive durvalumab 1500 mg IV Q4W (on Week 1 Day 1) and oleclumab 3000 mg IV every 2 weeks (Q2W; on Week 1 Day 1 and Week 3 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection will be planned between Day 29 and Day 42. After surgical resection, participants will be followed up to Day 105 (starting from Week 1 Day 1). |
| Durvalumab 1500 mg + Monalizumab 750 mg | EXPERIMENTAL | Participants will receive durvalumab 1500 mg IV Q4W (on Week 1 Day 1) and monalizumab 750 mg IV Q2W (on Week 1 Day 1 and Week 3 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection will be planned between Day 29 and Day 42. After surgical resection, participants will be followed up to Day 105 (starting from Week 1 Day 1). |
| Durvalumab 1500 mg + Danvatirsen 200 mg | EXPERIMENTAL | Participants will receive danvatirsen 200 mg IV on Days 1, 3, and 5 of Week 0 (7-day danvatirsen lead-in period), followed by durvalumab 1500 mg IV Q4W (on Week 1 Day 1) and danvatirsen 200 mg IV every week (on Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, and Week 4 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection will be planned between Day 29 and Day 42. After surgical resection, participants will be followed up to Day 105 (starting from Week 1 Day 1). |
| Durvalumab/Olaparib Combination Therapy | EXPERIMENTAL | Durvalumab/Olaparib Combination Therapy: Durvalumab/SoC chemotherapy (initial therapy phase) followed by Durvalumab/Olaparib (maintenance phase) |
| Durvalumab Monotherapy | EXPERIMENTAL | Durvalumab Monotherapy: Durvalumab/SoC chemotherapy (initial therapy phase) followed by Durvalumab/placebo (maintenance phase) |
| Durvalumab and Cetuximab | EXPERIMENTAL | Durvalumab 500mg as a 120-minute intravenous infusion every two weeks. Cetuximab 400mg/m2 IV loading dose followed by weekly Cetuximab 250mg/m2 IV Treatment with Durvalumab continues until progression and Cetuximab may continue as maintenance |
| Arm 1: Durvalumab/Placebo | EXPERIMENTAL | Durvalumab 1500 mg intravenous (IV) every 4 weeks (q4w) starting on week 1 day 1/Placebo orally (PO) twice a day (BID) starting on week 1 day 1. |
| Arm 2: Durvalumab/Olaparib | EXPERIMENTAL | Durvalumab 1500 mg IV q4w starting on week 1 day 1/Olaparib PO 300 mg BID adjusted based on patient's creatinine clearance. |
| Module 1 Cohort A.1.HRR: Durvalumab 1500 mg + Olaparib 300 mg | EXPERIMENTAL | 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 A.1.LKB: Durvalumab 1500 mg + Olaparib 300 mg | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 6 Cohort A.6.HER2m: Durvalumab 1120 mg + Trastuzumab deruxtecan 5.4mg/kg | EXPERIMENTAL | 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 7 Cohort B.7.ACQ: Durvalumab 1500 mg + Cediranib 20 mg | EXPERIMENTAL | 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 8 Cohort A.8.ATM: Ceralasertib 240 mg | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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 | EXPERIMENTAL | 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. |
| Treatment (olaparib, tremelimumab, durvalumab) | EXPERIMENTAL | Patients receive olaparib PO BID, and tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with olaparib continues for up to 12 months in the absence of disease progression or unacceptable toxicity. Treatment with tremelimumab repeats every 4 weeks for up to 4 courses and treatment with durvalumab repeats every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity. |
| Phase I Dose Level 1: Durvalumab + Acalabruitinib | EXPERIMENTAL | * Acalabrutinib 100 mg twice per day by mouth on days 1-28 * Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle |
| Phase I Dose Level 2: Durvalumab + Acalabruitinib | EXPERIMENTAL | * Acalabrutinib 200 mg twice per day by mouth on days 1-28 * Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle |
| Expansion Cohort: Durvalumab + Acalabrutinib | EXPERIMENTAL | * Acalabrutinib 100 mg or 200 mg (depends on tolerable dose found in Phase I portion of study) twice per day by mouth on days 1-28 * Durvalumab 1500 mg intravenous on day 1 of a 28 day cycle |
| Dose Escalation and Expansion | EXPERIMENTAL | Part 1 of this trial will use a traditional 3+3 design will be used for this trial (i.e. cohort sizes of 3 patients for the first and second cohort at each dose level). Dose escalation will occur as long as there are minimal dose limiting toxicities.The expectation is that 9 patients will be enrolled to the trial during part 1.This is based on the expectation that all dose levels are safe (i.e. patients will not experience DLTs at all dose levels). The range of patients needed will be 6-12 patients. Part 2 of this trial will be an expansion cohort. A total of 8 additional patients will be enrolled at the dose level determined to be the MTD in part 1 of the study. These 8 patients will be used to confirm that the MTD is a safe combination, as well as provide additional patients to investigate the efficacy for the treatment combination. Note: Standard of care surgery will follow 3-6 weeks after medication and radiation treatment. |
| Radiotherapy plus Durvalumab | EXPERIMENTAL | A minimum of 3 patients will initially be enrolled in each cohort of this arm. Patients will be allocated to a radiotherapy dose and site cohort from the schedule at registration. There will be no intra-patient dose or site escalations. Cohorts will escalate in number of anatomical sites of radiotherapy and dose of radiotherapy given subject to safety. Durvalumab will be administered at a fixed dose every 4 weeks IV. |
| Module 1- T-DXd and Durvalumab | EXPERIMENTAL | T-DXd and Durvalumab |
| Module 2- T-DXd and Pertuzumab | EXPERIMENTAL | T-DXd and Pertuzumab |
| Module 3- T-DXd and Paclitaxel | EXPERIMENTAL | T-DXd and Paclitaxel (Arm not initiated in Part 2) |
| Module 4- T-DXd and Durvalumab and Paclitaxel | EXPERIMENTAL | T-DXd and Durvalumab and Paclitaxel (Arm not initiated in Part 1 and Part 2) |
| Module 0- T-DXd | EXPERIMENTAL | T-DXd |
| Module 5 - T-DXd and Tucatanib | EXPERIMENTAL | T-DXd and tucatinib (Arm not initiated in Part 2) |
| Module 6 - T-DXd and Tucatinib | EXPERIMENTAL | T-DXd and tucatinib in patients with active brain metastases (Part 2 Only) (Arm not initiated) |
| Module 7 - T-DXd | EXPERIMENTAL | T-DXd monotherapy in patients with active brain metastases (Part 2 Only) |
| Module 1: T-DXd + capecitabine | EXPERIMENTAL | T-DXd: 5.4 mg/kg Q3W, intravenous use Capecitabine: 1000mg/m2 BID, days 1-14 Q3W, oral use |
| Module 2: T-DXd + durvalumab + paclitaxel | EXPERIMENTAL | T-DXd: 5.4 mg/kg Q3W, intravenous use Durvalumab: 1120 mg Q3W, intravenous use Paclitaxel: 80 mg/m2 QW in 3-week cycles, intravenous use |
| Module 3: T-DXd + capivasertib | EXPERIMENTAL | T-DXd: 5.4 mg/kg Q3W, intravenous use Capivasertib: 400 mg BID, oral use |
| Module 4: T-DXd + anastrozole | EXPERIMENTAL | T-DXd: 5.4 mg/kg Q3W, intravenous use Anastrozole: 1 mg daily, oral |
| Module 5: T-DXd + fulvestrant | EXPERIMENTAL | T-DXd: 5.4 mg/kg Q3W, intravenous use Fulvestrant: 500 mg Q4W, intramuscular use |
| Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | EXPERIMENTAL | Participants in Part 1 safety run-in arm (S1) will receive intravenous (IV) infusions of FOLFOX (5-fluorouracil \[5-FU\]: 2400 mg/m\^2 over 46-48 hours \[Day 1 and 2 of every 14-day Cycle\], oxaliplatin: 85 mg/m\^2, folinic acid: 400 mg/m\^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg every 4 weeks (Q4W) and IV oleclumab 3000 mg every 2 weeks (Q2W) till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met. |
| Part 2 (C1): FOLFOX + Bevacizumab | EXPERIMENTAL | Participants in Part 2 control 1 arm (C1) will receive IV infusions of FOLFOX (5-FU: 2400 mg/m\^2 over 46-48 hours \[Day 1 and 2 of every 14-day Cycle\], oxaliplatin: 85 mg/m\^2, folinic acid: 400 mg/m\^2) in combination with IV bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met. |
| Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab | EXPERIMENTAL | Participants in Part 2 experimental 1 arm (E1) will receive IV infusions of FOLFOX (5-FU: 2400 mg/m\^2 over 46-48 hours \[Day 1 and 2 of every 14-day Cycle\], oxaliplatin: 85 mg/m\^2, folinic acid: 400 mg/m\^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg Q4W and IV oleclumab 3000 mg Q2W till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion will be met. |
| A1 | EXPERIMENTAL | Durvalumab |
| A2 | EXPERIMENTAL | Durvalumab + danvatirsen |
| A3 | EXPERIMENTAL | Durvalumab + oleclumab |
| A4 | EXPERIMENTAL | MEDI5752 |
| B1 | EXPERIMENTAL | Durvalumab + Investigator's choice of chemotherapy |
| B2 | EXPERIMENTAL | Durvalumab + Investigator's choice of chemotherapy + danvatirsen |
| B3 | EXPERIMENTAL | Durvalumab + investigator's choice of chemotherapy + oleclumab |
| B4 | EXPERIMENTAL | MEDI5752 |
| A5 | EXPERIMENTAL | AZD2936 |
| B5 | EXPERIMENTAL | AZD2936 + chemotherapy |
| Arm 5 | EXPERIMENTAL | durvalumab + paclitaxel + oleclumab |
| Arm 6 | EXPERIMENTAL | durvalumab + trastuzumab deruxtecan |
| Arm 7 | EXPERIMENTAL | durvalumab + datopotamab deruxtecan |
| Arm 8 | EXPERIMENTAL | durvalumab + datopotomab deruxtecan (patients with PD-L1 positive status) |
| HNSCC Arm 1 | EXPERIMENTAL | Durvalumab + cisplatin with radiation in patients with locally advanced squamous cell carcinoma of the head and neck (HNSCC) |
| NSCLC Arm 1 | EXPERIMENTAL | Durvalumab + cisplatin and etoposide with radiation in patients with locally advanced, unresectable (Stage III) non-small-cell lung cancer (NSCLC) |
| NSCLC Arm 2 | EXPERIMENTAL | Durvalumab + carboplatin and paclitaxel with radiation in patients with locally advanced, unresectable (Stage III) non-small-cell lung cancer (NSCLC) |
| NSCLC Arm 3 | EXPERIMENTAL | Investigator's choice of carboplatin and pemetrexed OR cisplatin and pemetrexed |
| SCLC Arm 1 | EXPERIMENTAL | Patients should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin |
| SCLC Arm 2 | EXPERIMENTAL | Patients with limited-stage small-cell lung cancer (SCLC) should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin |
| SCLC Arm 3 | EXPERIMENTAL | Patients should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin. Note: Arm 3 will only be opened if the regimen in SCLC Arm 1 is safe and tolerable. |
| SCLC Arm 4 | EXPERIMENTAL | Patients should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin Note: Arm 4 will only be opened if the regimen in SCLC Arm 2 is safe and tolerable. |
| durvalumab+tremelimumab | EXPERIMENTAL | durvalumab plus tremelimumab |
| Durvalumab plus Trastuzumab | EXPERIMENTAL | Durvalumab q3w until PD Trastuzumab q3w x 6 |
| Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib | EXPERIMENTAL | Participants will receive intravenous (IV) dose of 3 milligrams per kilogram (mg/kg) durvalumab every 2 weeks (Q2W) from Day 1 up to 12 months along with oral 150 mg dabrafenib capsule twice daily (BID) and oral 2 mg trametinib tablet once daily (QD) until confirmed disease progression (PD), initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 3 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib. |
| Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib | EXPERIMENTAL | Participants will receive IV dose of 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral doses of dabrafenib 150 mg capsule BID and trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib. |
| Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent) | EXPERIMENTAL | Participants will receive concurrent doses of IV 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral dose of trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of trametinib. |
| Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential) | EXPERIMENTAL | Participants will receive sequential doses of oral trametinib tablet 2 mg QD from Day 1 to Day 42 and IV durvalumab 10 mg/kg Q2W starting from Day 29 (Week 5) up to 12 months. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months. |
| Name | Type | Description |
|---|---|---|
| Durvalumab | DRUG | Durvalumab (IV) every 4 weeks until a maximum of 24 months. |
| Methotrexate | DRUG | Chemotherapy agent. |
| Vinblastine | DRUG | Chemotherapy agent |
| Doxorubicin | DRUG | Chemotherapy agent |
| Cisplatin | DRUG | Chemotherapy agent |
| Gemcitabine | DRUG | Chemotherapy agent |
| Trastuzumab deruxtecan | DRUG | Experimental therapy by intravenous infusion |
| Rilvegostomig | DRUG | Experimental therapy by intravenous infusion |
| Gemcitabine monotherapy | DRUG | Gemcitabine monotherapy as background gemcitabine-based chemotherapy every 3 weeks (i.e., 8 cycles of durvalumab) |
| Gemcitabine + cisplatin | DRUG | Gemcitabine plus cisplatin as background gemcitabine-based chemotherapy every 3 weeks (i.e., 8 cycles of durvalumab) for WHO/ECOG PS 2 participants only |
| Gemcitabine + oxaliplatin | DRUG | Gemcitabine + oxaliplatin as background gemcitabine-based chemotherapy every 3 weeks (i.e., 8 cycles of durvalumab) |
| Gemcitabine + carboplatin | DRUG | Gemcitabine + carboplatin as background gemcitabine-based chemotherapy every 3 weeks (i.e., 8 cycles of durvalumab) |
| Gemcitabine + cisplatin + S-1 | DRUG | Gemcitabine + cisplatin + S-1 as background gemcitabine-based chemotherapy every 2 weeks (i.e, 4 cycles of durvalumab) |
| Gemcitabine + S-1 | DRUG | Gemcitabine + S-1 as background gemcitabine-based chemotherapy every 3 weeks (i.e., 8 cycles of durvalumab) |
| Gemcitabine + cisplatin + albumin-bound paclitaxel | DRUG | Gemcitabine + cisplatin + albumin-bound paclitaxel as background gemcitabine-based chemotherapy every 3 weeks (i.e., 8 cycles of durvalumab) |
| BCG | BIOLOGICAL | Participants will receive BCG via intravesical as induction weekly for 6 weeks starting at Week 1, Day 1 and subsequently for maintenance for 3 weekly doses up to 3, 6, 12, 18, and 24 months, at the physician's discretion as Standard of care. |
| Tremelimumab | DRUG | Participants will receive single dose of 300 mg through IV infusion at Day 1 |
| Domvanalimab | DRUG | Domvanalimab IV (Intravenous infusion) |
| Placebo | OTHER | Placebo IV (Intravenous infusion) |
| Oleclumab | DRUG | Oleclumab IV (intravenous infusion) |
| Monalizumab | DRUG | Monalizumab IV (intravenous infusion) |
| Carboplatin | DRUG | Participants will receive carboplatin via IV administration Day 1 of each cycle. |
| Etoposide | DRUG | Participants will receive etoposide via IV administration on days 1 to 3 of each cycle. |
| Pemetrexed | DRUG | 500mg/m2 on Day 1 of every 21-day cycle |
| Paclitaxel | DRUG | 175mg/m2 on Day 1 of every 21-day cycle |
| AVENIO ctDNA Surveillance Kit | DEVICE | Roche Sequencing and Life Science kit to detect minimal residue disease (MRD) |
| Enfortumab Vedotin | DRUG | Nectin-4-directed antibody and microtubule inhibitor conjugate |
| Radical Cystectomy | PROCEDURE | For cisplatin-ineligible or cisplatin-refusal patients |
| Durvalumab plus chemotherapy | DRUG | Drug: Durvalumab IV infusions every 3 weeks for 4-6 cycles and every 4 weeks thereafter until PD or other discontinuation criteria. Drug: Carboplatin 4-6 cycles every 3 weeks Drug: Cisplatin 4-6 cycles every 3 weeks Drug: Etoposide 4-6 cycles every 3 weeks |
| FLOT chemotherapy | DRUG | A combination treatment made up of flurouroacil + leucovorin + oxaliplatin + docetaxel |
| cisplatin + fluorouracil | DRUG | cisplatin + fluorouracil, as per Standard of Care |
| cisplatin + capecitabine | DRUG | cisplatin + capecitabine, as per Standard of Care |
| Radiation | RADIATION | 50-64Gy in total |
| Durvalumab + SoC chemotherapy | DRUG | Experimental Treatment |
| Placebo + SoC chemotherapy | OTHER | Placebo Comparator |
| Bevacizumab | DRUG | Bevacizumab IV (intravenous) |
| (Osimertinib cohort, single-arm, open-label separate cohort) | DRUG | Osimertinib 80 mg every day \[qd\] orally for up to 36 months or until progression or other discontinuation criteria are met. Osimertinib treatment should start from 7 to 14 days after completion of SBRT |
| external beam radiation therapy (EBRT) + brachytherapy | RADIATION | Radiation therapy per standard of care |
| Olaparib | DRUG | Olaparib tablets |
| Placebo olaparib | DRUG | Placebo tablets to match olaparib |
| Durvalumab placebo | DRUG | Matching placebo for intravenous infusion |
| Carboplatin+Paclitaxel | DRUG | Standard of care chemotherapy |
| Surgery | PROCEDURE | Expected within 40 days from the last dose of Investigational Product following the completion of neoadjuvant treatment. |
| Transarterial Chemoembolization (TACE) | PROCEDURE | TACE (chemo and embolic agent injection into the hepatic artery) |
| Cisplatin + Gemcitabine | DRUG | Cisplatin IV (intravenous)+ Gemcitabine IV(intravenous), as standard of care. |
| Carboplatin + Gemcitabine | DRUG | Carboplatin IV (intravenous)+ Gemcitabine IV(intravenous), as standard of care. |
| Durvalumab (MEDI4736) | BIOLOGICAL | Investigational product |
| Bacillus Calmette-Guerin (BCG) | BIOLOGICAL | Standard of care |
| Cisplatin/ Etoposide | DRUG | Cisplatin/ Etoposide, as per standard of care |
| Carboplatin/ Paclitaxel | DRUG | Carboplatin /Paclitaxel, as per standard of care |
| Pemetrexed/ Cisplatin | DRUG | Pemetrexed / Cisplatin, as per standard of care |
| Pemetrexed/ Carboplatin | DRUG | Pemetrexed / Carboplatin , as per standard of care |
| Tremelimumab (Regimen 1) | DRUG | Tremelimumab IV (intravenous infusion). |
| Tremelimumab (Regimen 2) | DRUG | Tremelimumab IV (intravenous infusion). |
| Sorafenib | DRUG | Sorafenib, as per standard of care |
| Durvalumab (Regimen 1) | DRUG | Durvalumab IV (intravenous infusion). |
| Durvalumab (Regimen 2) | DRUG | Durvalumab IV (intravenous infusion). |
| Abraxane + carboplatin | DRUG | Standard of care chemotherapy (squamous and non-squamous patients): Abraxane 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Carboplatin Area under the plasma drug concentration-time curve (AUC) 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3). |
| Pemetrexed + carboplatin | DRUG | Standard of care chemotherapy (non-squamous patients only): Pemetrexed 500 mg/m2 and carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3); then continue pemetrexed 500 mg/m2 maintenance \[i.e., q4w for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w (dependent on Investigator decision and local standards)\] until objective disease progression. |
| Pemetrexed + cisplatin | DRUG | Standard of care chemotherapy (non-squamous patients only): Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3); then continue pemetrexed 500 mg/m2 maintenance \[i.e., q4w for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w (dependent on Investigator decision and local standards)\] until objective disease progression. |
| Paclitaxel + carboplatin | DRUG | Chemotherapy Agents |
| Durvalumab +Tremelimumab | BIOLOGICAL | - |
| Radiotherapy | PROCEDURE | - |
| Ceralasertib | DRUG | Ceralasertib |
| Lenvatinib | COMBINATION_PRODUCT | Lenvatinib Oral |
| Pembrolizumab | DRUG | Participants will receive IV pembrolizumab q3w for four 21-days cycles as induction treatment. Pembrolizumab will also be given in the maintenance treatment phase q3w until clinical progression or confirmed RECIST 1.1- defined radiological progression as assessed by the investigator, unacceptable toxicity, withdrawal of participant consent, or EOS, whichever comes first. |
| Transarterial Radioembolization (TARE) | PROCEDURE | Yttrium 90 glass microspheres will be administered |
| Dato-DXd | DRUG | Participants will receive datopotamab deruxtecan (Dato-DXd) via intravenous route. |
| AZD0171 | DRUG | Participants will receive AZD0171 via intravenous route. |
| Pemetrexed/Cisplatin | DRUG | Pemetrexed/Cisplatin as chemotherapy |
| Pemetrexed/Carboplatin | DRUG | Pemetrexed/Carboplatin as chemotherapy |
| Carboplatin/Paclitaxel | DRUG | Carboplatin/Paclitaxel, as chemotherapy |
| Volrustomig | DRUG | Participants will receive Volrustomig via intravenous route. |
| Hypofractionated Radiation Therapy | RADIATION | Undergo hypofractionated RT |
| AZD2811 | DRUG | IV infusions through maintenance phase until PD or other discontinuation criteria. |
| Fluorouracil (5-FU) | DRUG | 5-FU: administered as an IV infusion |
| Capecitabine | DRUG | Capecitabine: administered orally |
| Oxaliplatin | DRUG | Oxaliplatin: administered as an IV infusion |
| Trastuzumab | BIOLOGICAL | Trastuzumab: administered as an IV infusion |
| Prednisone | DRUG | 0.5mg/kg; PO, Daily cycles 1 \& 2 |
| Stereotactic Body Radiotherapy | RADIATION | Pre-operative radiation therapy (boost dose) 3x8 Gy on the primary tumour at week 5 given in 3 fractions. The 3 fractions will be spread at the minimum over 3 days and at the maximum over 6 days. |
| Danvatirsen | COMBINATION_PRODUCT | Danvatirsen 200 mg IV will be administered on Days 1, 3, and 5 of Week 0 (7-day danvatirsen lead-in period) and later every week (on Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, and Week 4 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. |
| Placebo for Olaparib | DRUG | Matching tablet |
| Nab-paclitaxel+carboplatin | DRUG | Standard of Care chemotherapy (squamous and non-squamous patients) |
| Gemcitabine+carboplatin | DRUG | Standard of Care chemotherapy (squamous patients only) |
| Pemetrexed+carboplatin | DRUG | Standard of Care chemotherapy (non-squamous patients only) |
| Gemcitabine+cisplatin | DRUG | Standard of Care chemotherapy (squamous patients only) |
| Pemetrexed+cisplatin | DRUG | Standard of Care chemotherapy (non-squamous patients only) |
| Cetuximab | DRUG | Two hour infusion for loading dose followed by weekly one hour infusion |
| Vistusertib | DRUG | Participants will receive oral tablets of vistusertib as stated in arm description. |
| Cediranib | DRUG | Participants will receive oral tablets of cediranib as stated in arm description. |
| Laboratory Biomarker Analysis | OTHER | Correlative studies |
| Acalabrutinib | DRUG | Patients will take acalabrutinib orally every 12 hours (+/- 3 hours) daily. |
| Stereotactic Body Radiation Therapy (SBRT) | RADIATION | The starting RT dose level will be given as 6 Gy for 2 fractions (12 Gy total) every other day over approximately one week to sites of gross disease only to minimize exposure to normal tissue. If toxicity develops and surgery is delayed by more than 8 weeks (qualifying as a DLT), the radiation dose will be dropped per protocol for the next set of patients. If this dose is tolerated, the dose will be increased to 6 Gy for 3 fractions (18 Gy total) for the next 3 patients. |
| Standard of Care Therapy | PROCEDURE | Patients will proceed to surgical resection 3-6 weeks after radiation as recommended by the ENT surgeon. |
| Radiotherapy (cohort 6 only) | RADIATION | Cohort 6 patients (only) will receive: Day 8-Day 10: External Beam Radiotherapy to target site(s)- daily (ie. 5 further fractions to a total of 10 fractions) |
| Pertuzumab | DRUG | Pertuzumab: administered as an IV infusion |
| Tucatinib | DRUG | Tucatinib administered orally (tablet) twice daily |
| Capivasertib | DRUG | Capivasertib: administered orally |
| Anastrozole | DRUG | Anastrozole: administered orally |
| Fulvestrant | DRUG | Fulvestrant: administered as an IM injection |
| FOLFOX | DRUG | Participants will receive IV infusion of FOLFOX (5-FU, oxaliplatin, and folinic acid) as stated in arm description. |
| MEDI5752 | DRUG | MEDI5752 IV Every 3 weeks (q3w) |
| Nab-paclitaxel | DRUG | Nab-paclitaxel IV Days 1, 8, and 15 of each 21-day cycle |
| AZD2936 | DRUG | AZD2936 IV |
| Datopotamab deruxtecan | DRUG | Datopotamab deruxtecan iv 3-week cycles (once weekly) q3w |
| Cisplatin (dose level 4) | DRUG | IV |
| Cisplatin (dose level 3) | DRUG | IV |
| Carboplatin (dose level 1) | DRUG | IV |
| Carboplatin (dose level 2) | DRUG | IV |
| Etoposide (dose level 1) | DRUG | IV |
| Etoposide (dose level 2) | DRUG | IV |
| External beam radiation (dose level 1) | RADIATION | radiation therapy |
| External beam radiation (dose level 2) | RADIATION | radiation therapy |
| External beam radiation (hyperfractionated) | RADIATION | radiation therapy |
| Cisplatin (dose level 1) | DRUG | IV |
| Cisplatin (dose level 2) | DRUG | IV |
| External beam radiation (standard) | RADIATION | radiation therapy |
| tremelimumab + durvalumab | DRUG | 20 mg/kg durvalumab (MEDI4736) via IV infusion q4w and 1 mg/kg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 20 mg/kg durvalumab (MEDI4736) q4w starting on Week 16 for up to confirmed disease progression |
| Dabrafenib | DRUG | Oral dose of 150 mg dabrafenib capsule. |
| Trametinib | DRUG | Oral dose of 2 mg trametinib tablet. |
Inclusion Criteria: * Female or male patients aged ≥18 years at the time of signing the Informed Consent Form (ICF). * Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures. Additionally, signed and dated written genetic and/or b...