Outcome
| Type |
Measure |
Description |
Time frame |
Safety issue |
| Other |
HLA alleles associated with susceptibility to drug related AEs (such as but not limited to hypersensitivity). |
To collect and store germline DNA for exploration of the role of HLA alleles in developmental toxicity. |
On Cycle 1 Day 1 only (each cycle is 28 days) |
|
| Other |
Overall survival, in patients who cross over after progression on savolitinib plus placebo |
Defined as time from randomisation until the date of death due to any cause |
The primary analysis will occur 6 months after the last patient is randomised. The final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died. |
|
| Primary |
Objective Response Rate (ORR) |
ORR will be performed based on Investigator assessment of disease progression by RECIST 1.1. |
The primary analysis will occur 6 months after the last patient is randomised. |
|
| Secondary |
Progression-free Survival (PFS) |
PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by the investigator or death due to any cause. |
The primary analysis will occur 6 months after the last patient is randomised. |
|
| Secondary |
Duration of Response (DoR) |
DoR is defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 as assessed by the investigator or death in the absence of disease progression. |
The primary analysis will occur 6 months after the last patient is randomised. |
|
| Secondary |
Tumour Size Assessment (TSA) |
TSA is defined as the percentage change from baseline in TLs at 12 weeks per RECIST 1.1 as assessed by the investigator. |
The primary analysis will occur 6 months after the last patient is randomised. |
|
| Secondary |
Overall Survival (OS) |
OS is defined as time from randomisation until the date of death due to any cause. |
The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died. |
|
| Secondary |
Objective Response Rate (ORR) |
Objective response rate in patients who cross over after progression on savolitinib plus placebo, defined as the proportion of patients with measurable disease who have a CR or PR as determined by the investigator at the local site per RECIST 1.1. |
The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died. |
|
| Secondary |
Progression Free Survival |
Progression free survival in patients who cross over after progression on savolitinib plus placebo, defined as time from the first dose in the cross over period until progression per RECIST 1.1 as assessed by the investigator or death due to any cause. |
The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died. |
|
| Secondary |
Duration of Response |
Duration of response in patients who cross over after progression on savolitinib plus placebo, defined as the time from the date of first documented response during the cross-over period until date of documented progression per RECIST 1.1 as assessed by the investigator or death in the absence of disease progression. |
The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died. |
|
| Secondary |
Tumour Size Assessment |
Tumour size assessment in patients who cross over after progression on savolitinib plus placebo, defined as the percentage change from baseline in TLs at 12 weeks per RECIST 1.1 as assessed by the investigator. |
The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died. |
|
| Secondary |
Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies). |
To determine the prevalence of ctDNA clearance after savolitinib plus osimertinib or savolitinib plus placebo treatment in this patient population |
The primary analysis will occur 6 months after the last patient is randomised. |
|
| Secondary |
Plasma concentrations of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) |
To evaluate the PK of savolitinib and osimertinib. |
Cycle 1, Day 1: Pre-dose and 1 and 3 hours post-dose; Cycle 2, Day 1: Pre-dose and 1 and 3 hours post-dose; Cycle 3, Day 1: Pre dose and 1, 3, 4, and 6 hours post-dose; Cycles 6 and 11, Day 1: Pre-dose only. (Each Cycle is 28 days). |
|
| Secondary |
Time dependency of the PK of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) |
To evaluate the PK of savolitinib and osimertinib. |
C3h Cycle 2 Day 1/C3h Cycle 1 Day 1; Cpre-dose Cycle 3 Day 1/Cpre-dose Cycle 2 Day 1; Cpre-dose Cycle 6 Day 1/Cpre-dose Cycle 2 Day 1; Cpre-dose Cycle 11 Day 1/Cpre-dose Cycle 2 Day 1. (Each Cycle is 28 days) |
|
| Secondary |
AUCss of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) |
To evaluate the PK of savolitinib and osimertinib. |
Cycle 3, Day 1 (Each Cycle is 28 days) |
|
| Secondary |
Cssmax of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) |
To evaluate the PK of savolitinib and osimertinib. |
Cycle 3, Day 1 (Each Cycle is 28 days) |
|
| Secondary |
Tssmax of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) |
To evaluate the PK of savolitinib and osimertinib. |
Cycle 3, Day 1 (Each Cycle is 28 days) |
|
| Secondary |
CLss/F of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib) |
To evaluate the PK of savolitinib and osimertinib. |
Cycle 3, Day 1 (Each Cycle is 28 days) |
|
| Secondary |
Number and percentage of subjects with adverse events (AEs) in different categories: All AEs |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Continuous collection from First dose until study termination, on average 12 months |
|
| Secondary |
Number and percentage of subjects with adverse events (AEs) in different categories: Serious AEs |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Continuous collection from First dose until study termination, on average 12 months |
|
| Secondary |
Number and percentage of subjects with adverse events (AEs) in different categories: Causally related AEs |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Continuous collection from First dose until study termination, on average 12 months |
|
| Secondary |
Number and percentage of subjects with adverse events (AEs) in different categories: Discontinuations due to AEs |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Continuous collection from First dose until study termination, on average 12 months |
|
| Secondary |
Number and percentage of subjects with adverse events (AEs) in different categories: Deaths |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Continuous collection from First dose until study termination, on average 12 months |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Albumin |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Alkaline phosphatase |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in ALT |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 10, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Amylase |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in AST |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 10 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation(an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Total bilirubin |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Total Calcium |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Creatinine |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Glucose |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation(an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Magnesium |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Sodium |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Potassium |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Total Protein |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in BUN or urea |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Lactate dehydrogenase |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Haematocrit |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Haemoglobin |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Leucocyte cell count |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Platelet count |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Red blood cell count |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Reticulocytes |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Neutrophil count |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Lymphocyte count |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
|
| Secondary |
Number of subjects with at least one treatment emergent change in laboratory parameters in Eosinophil count |
To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo. |
Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year) |
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