A Study Comparing Savolitinib Plus Osimertinib vs Savolitinib Plus Placebo in Patients With EGFRm+ and MET Amplified Advanced NSCLC

Study Overview
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Brief Summary
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This study will compare the activity of the combination of savolitinib and osimertinib against the combination of savolitinib with placebo to osimertinib in patients with Epidermal Growth Factor Receptor Mutation Positive and MET amplified, locally advanced or metastatic non-small cell lung cancer who have progressed following treatment with osimertinib.

Detailed Description
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Resistance to EGFR-TKIs is a clinical problem. One of the mechanisms for resistance to osimertinib is amplification of the MET receptor tyrosine kinase, which activates downstream intracellular signalling independent of EGFR. This study will explore the individual contribution of savolitinib to MET mediated osimertinib resistance, by assessing the response to dual pathway blockade of EGFRm and MET to overcome MET mediated resistance to osimertinib versus inhibition of the MET pathway alone by investigating the efficacy of savolitinib plus osimertinib versus savolitinib plus placebo to osimertinib (hereafter referred to as placebo) in patients with EGFRm+ and MET amplified, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib. This is a multi centre, Phase II, double blind, randomised study. Patients will be randomised in a ratio of 1:1 to receive treatment with savolitinib once daily plus osimertinib once daily or savolitinib once daily plus placebo. Randomisation will be stratified according to the number ofprior lines of therapy (ie, osimertinib monotherapy as first line or ≥ second line [which includes patients who received osimertinib monotherapy before or after chemotherapy]). All patients confirmed as eligible will begin treatment on Day 1 with savolitinib plus osimertinib or savolitinib plus placebo. Treatment will continue once daily in 28 day cycles until either objective PD by RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn, or another discontinuation criterion is met. After progression, patients can be unblinded, and patients initially randomised to the savolitinib plus placebo arm may cross-over to open-label savolitinib plus osimertinib following investigator assessed objective PD to ensure that all patients enrolled may have the opportunity to receive the combination of savolitinib plus osimertinib.

Official Title
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A Multi-centre Phase II, Double-Blind, Randomised Study of Savolitinib in Combination With Osimertinib vs Savolitinib in Combination With Placebo in Patients With EGFRm+ and MET Amplified Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Osimertinib + Savolitinib
* Drug: Savolitinib + Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be ≥ 18 years of age at the time of signing the informed consent (≥ 20 years of age in Japan). All genders are permitted Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity and that is permitted in the osimertinib national label (such as exon 19 deletion and/or L858R), which is not amenable to curative therapy. Documented radiologic PD following treatment with osimertinib (osimertinib does not need to be the most recent therapy). Have MET amplification as determined by central MET FISH testing on tumour specimen collected following progression on prior osimertinib treatment. At least measurable target lesion Patients must have received at least one but no more than 3 prior lines of therapy (including investigational therapy) in the locally advanced/metastatic setting. Adequate haematological, liver and renal function Eastern Cooperative Oncology Group/WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks. Females of childbearing potential should be willing to use adequate contraceptive measures, should not be breastfeeding, and must have a negative pregnancy test. Male patients with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following discontinuation of study intervention. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing study intervention. Exclusion Criteria: Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 at the time of starting study intervention with the exception of alopecia, haemoglobin ≥ 9 g/dL and Grade 2, prior platinum therapy related neuropathy. As judged by the investigator, active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy. Any of the following cardiac diseases currently or within the last 6 months: Unstable angina pectoris Congestive heart failure (NYHA Grade ≥ 2) Acute myocardial infarction Stroke or transient ischemic attack Uncontrolled hypertension (BP ≥ 150/95 mmHg despite medical therapy). Mean resting corrected QT interval (QTcF) > 470 msec for women and > 450 msec for men at Screening, obtained from 3 ECGs using the screening clinic ECG machine derived QTcF value. Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic events Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs. Acute coronary syndrome Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤ 28 days or limited field radiation for palliation ≤ 7 days prior to starting study intervention or has not recovered from side effects of such therapy. Major surgical procedures ≤ 28 days of beginning study intervention or minor surgical procedures ≤ 7 days. No waiting is required following port-a-cath placement. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including renal transplant or active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to enter the study or which would jeopardise compliance with the CSP. Active HBV (positive HBsAg result) or HCV. Viral testing is not required for assessment of eligibility for the study. Known serious active infection including, but not limited to, tuberculosis, or HIV (positive HIV 1/2 antibodies). Testing is not required for assessment of eligibility for the study. Presence of other active cancers, or history of treatment for invasive cancer, within the last 5 years. Patients with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (ie, non-invasive) are eligible, as are patients with history of non-melanoma skin cancer. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks prior to start of study intervention. Past medical history of ILD, drug-induced ILD, radiation pneumonitis, which required steroid treatment, or any evidence of clinically active ILD. Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib. Prior or current treatment with savolitinib or another MET inhibitor (for example, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib). Patients who have received ≥ 4 lines of systemic therapy for NSCLC Any cytotoxic chemotherapy, investigational agents or other anti cancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days prior to the first dose of study intervention with the exception of monotherapy osimertinib which may continue uninterrupted during screening. Patients currently receiving (or unable to stop use prior to receiving the first dose of study intervention) medications or herbal supplements known to be strong inducers of CYP3A4 or strong inhibitors of CYP1A2, or CYP3A4 substrates which have a narrow therapeutic range within 2 weeks of the first dose of study intervention (3 weeks for St John's Wort) will be excluded. All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4 during the study and for 3 months later the last dose intake. Participation in another clinical study with a cytotoxic, investigational product, or other anti cancer drug for the treatment of advanced NSCLC if received study intervention from that study within 14 days of the first dose of study intervention. Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will take savolitinib 300mg tablets QD within 15 minutes after the start of a meal except for the day on which PK samples are taken. Patients will take osimertinib 80mg tablet once daily with/without food except for the day on which PK samples are taken. On the day when PK samples are taken both savolitinib & osimertinib will be administered after a meal prepared by the clinic Patients will take savolitinib 300mg tablets QD within 15 minutes after the start of a meal except for the day on which PK samples are taken. Patients will take placebo to osimertinib 80mg tablet once daily with/without food except for the day on which PK samples are taken. On the day when PK samples are taken both savolitinib & placebo to osimertinib will be administered within 15 minutes after a meal prepared by the clinic In addition to comparing the ORR between groups, this study will also assess safety and tolerability, DoR, DCR, OS, PFS and other measures of antitumor activity
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Savolitinib 300 mg oral QD Osimertinib 80 mg oral QD | Drug: Osimertinib + Savolitinib<br>* Osimertinib 80 mg oral QD Savolitinib 300mg oral QD<br>|
| Experimental: Arm B<br>Savolitinib 300 mg oral QD Placebo to Osimertinib 80mg oral QD | Drug: Savolitinib + Placebo<br>* Savolitinib 300mg Oral QD Placebo to Osimertinib 80mg oral QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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). | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MET, Locally, Advanced, Metastatic, Carcinoma, Non-Small Cell Lung Cancer, Osimertinib, Tagrisso, Savolitinib, EGFR