Health Condition 1: C349- Malignant neoplasm of unspecifiedpart of bronchus or lung
Conditions
Interventions
Intervention1: Savolitinib once daily plus osimertinib once daily: 1:1 Assignment
Oral and once daily until disease progression or toxicity.
Control Intervention1: savolitinib once daily plus placebo
Sponsors
AstraZeneca AB
AstraZeneca Pharma India Ltd
Eligibility
Inclusion criteria
Inclusion criteria: Informed Consent 1 Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP. 2 Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling and analyses. Age 3. Patients must be = 18 years of age at the time of signing the informed consent All genders are permitted. Type of Patient and Disease Characteristics 4. 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. 5 Documented radiologic PD following treatment with osimertinib (osimertinib does not need to be the most recent therapy). 6 Have MET amplification as determined by central MET FISH testing on tumour specimen collected following progression on prior osimertinib treatment. 7 Available FFPE tumour specimen for central MET FISH analysis or willingness to collect an additional specimen for central testing, which fulfils the following requirements: i) Obtained following progression on previous osimertinib therapy. ii) Obtained within 2 years of submission for MET analysis. iii) Sufficient specimen to meet the minimum specimen requirement defined in the current Central Laboratory Manual. 8 At least one lesion, not previously irradiated, not biopsied during the screening period, that can be accurately measured at baseline as = 10 mm in the longest diameter (except lymph nodes which must have short axis = 15 mm) with CT or MRI, which is suitable for accurate repeated measurements. If only one measurable lesion exists, it is acceptable to be used as long as baseline tumour assessment scans are done at least 14 days after the screening tumour specimen collection is performed. 9. 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. i) No more than one prior line of chemotherapy regimen is acceptable. ii) A chemotherapy regimen including a programmed cell death-1 or a programmed cell death ligand-1 agent is acceptable, provided it was not the most recent line of therapy. i) No more than 2 prior lines of therapy containing EGFR-TKI are acceptable. 10 Adequate haematological function defined as: i) Absolute neutrophil count = 1500/µL ii) Haemoglobin = 9 g/dL (no transfusion in the past 2 weeks) iii) Platelets = 100000/µL (no transfusion in the past 10 days) 11 Adequate liver function defined as: ALT and AST = 2.5 × the ULN with TBL = ULN OR TBL > ULN to = 1.5 × ULN with ALT and AST = ULN 12 Adequate renal function defined as a creatinine 1.5 times ULN. 1
Exclusion criteria
Exclusion criteria: 1.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. 2 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 (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade = 2, malabsorption syndrome or previous significant bowel resection). 3 Any of the following cardiac diseases currently or within the last 6 months: i) Unstable angina pectoris ii) Congestive heart failure (NYHA Grade = 2) iii) Acute myocardial infarction iv) Stroke or transient ischemic attack v) Uncontrolled hypertension (BP = 150/95 mmHg despite medical therapy). vi) 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. vii) Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic events such as heart failure, congenital or familial long QT syndrome, family history of unexplained sudden death under 40 years of age in first-degree relatives, any concomitant medication known to prolong the QT interval and cause Torsade de Pointes, chronic hypokalaemia not correctable with supplements, or electrolyte abnormalities including: a) Serum/plasma potassium b) Serum/plasma magnesium c) Serum/plasma calcium viii) Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs, eg, complete left bundle branch block, third degree heart block, second degree heart block, P-R interval > 250 msec. Acute coronary syndrome 4. 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. 5 Major surgical procedures = 28 days of beginning study intervention or minor surgical procedures = 7 days. No waiting is required following port-a-cath placement 6 As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including renal transplant or active bleeding diatheses, which in the investigators opinion makes it undesirable for the patient to enter the study or which would jeopardise compliance with the CSP 7 Active HBV (positive HBsAg result) or HCV. Viral testing is not required for assessment of eligibility for the study. Patients with a past or resolved HBV or HCV infection are eligible if: i) Negative for HBsAg and positive for hepatitis B core antibody or ii) Positive for HBsAg, but for > 6 months have had normal transaminases and HBV DNA levels between 0 and 2000 IU/mL (inactive carrier state) and willing to start and maintain antiviral treatment for at least the duration of the study. iii) HBV DNA levels > 2000 IU/mL but on prophylactic antiviral treatment for the past 3 months and will maintain the antiviral treatment during the study iv) Patients with positive HCV antibody are eligible only if the polymerase chain reaction is negative for HCV ribonucleic acid. Known serious active infe
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To assess the ORR of savolitinib in combination with osimertinib versus savolitinib in combination with placebo in patients with EGFRmPLUS, MET amplified locally advanced or metastatic NSCLC who have progressed on previous osimertinib therapyTimepoint: Objective response rate is 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. Every 6 Weeks (± 7 days) up to 24 weeks relative to randomization, then Every 8 Weeks (± 7 days) until objective disease progression | — |
Secondary
| Measure | Time frame |
|---|---|
| To determine the efficacy of savolitinib in combination with osimertinib versus savolitinib in combination with placebo in patients with EGFRmPLUS, MET amplified locally advanced or metastatic NSCLC who have progressed on previous osimertinib therapyTimepoint: PFS until progression per RECIST 1.1 or death due to any cause. i) DOR is until date of progression per RECIST 1.1 or death in the absence of disease progression. ii) Tumour size assessment is defined as the percentage change from baseline in TLs at 12 weeks per RECIST 1.1 as assessed by the investigator. iii) OS is defined as time from randomisation until the date of death due to any cause ;To determine the prevalence of ctDNA clearance after savolitinib plus osimertinib or savolitinib plus placebo treatment in this patient populationTimepoint: Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies).;To evaluate the efficacy of savolitinib plus osimertinib in patients who cross-over after progression on savolitinib plus placeboTimepoint: Objective response rate- proportion of patients with CR or PR per RECIST 1.1. • PFS- time from the first dose in the cross-over period until progression per RECIST 1.1 or death. • DOR - time from the cross-over period until progression or death • Tumour size assessment is defined as the percentage change from baseline in TLs at 12 weeks per RECIST 1.1 as assessed by the investigator. ;To evaluate the PK of savolitinib and osimertinib. Timepoint: Plasma concentrations of savolitinib, osimertinib, and their metabolites. | — |
Countries
Argentina, Brazil, Chile, India, Taiwan, Thailand, United States of America, Viet Nam
Contacts
Public ContactMr Sandeep AV
AstraZeneca Pharma India Ltd
Outcome results
None listed