CTRI Number	CTRI/2020/12/029451 [Registered on: 01/12/2020] Trial Registered Prospectively
Last Modified On:	11/11/2023
Post Graduate Thesis	No
Type of Trial	Interventional
Type of Study	Drug
Study Design	Randomized, Parallel Group, Placebo Controlled Trial
Public Title of Study Modification(s)	Study in patients with EGFRm PLUS and MET Amplified Locally Advanced or Metastatic Non-Small Cell Lung Cancer who have progressed following treatment with Osimertinib with Savolitinib in Combination with Osimertinib vs Savolitinib in Combination with Placebo
Scientific Title of Study	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 PLUS and MET Amplified Locally Advanced or Metastatic Non-Small Cell Lung Cancer who have Progressed Following Treatment with Osimertinib
Secondary IDs if Any	Secondary ID  Registry  D5084C00009 Version 1.0 dated 09 JUN 2020  Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)	Name    Address    Phone     Fax     Email
Details Contact Person Scientific Query Modification(s)	Name  Mr Sandeep AV  Address  Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road Bangalore KARNATAKA 560045 India  Phone  91-9845079472   Fax  91-8067748857   Email  Sandeep.AV@astrazeneca.com
Details Contact Person Public Query Modification(s)	Name  Mr Sandeep AV  Address  Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road Bangalore KARNATAKA 560045 India  Phone  91-9845079472   Fax  91-8067748857   Email  Sandeep.AV@astrazeneca.com
Source of Monetary or Material Support	AstraZeneca AB (Study Sponsor company) 151 85 Sodertalje, Sweden
Primary Sponsor	Name  AstraZeneca AB  Address  151 85 Sodertalje, Sweden  Type of Sponsor  Pharmaceutical industry-Global
Details of Secondary Sponsor	Name  Address  AstraZeneca Pharma India Ltd  Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road, Bangalore – 560045, India
Countries of Recruitment	Argentina Brazil Chile India Taiwan Thailand United States of America Viet Nam
Sites of Study Modification(s)	No of Sites = 2   Contact Person  Name of Site  Site Address  Phone/Fax/Email  Dr Imran Shaikh  Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute  Dept. of Medical Oncology Consultant Medical Oncologist Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Rao Saheb, Achutrao Patwardhan Marg, Four Bungalows, Andheri West, Mumbai, PIN 400053 Mumbai   919699947210 imran.shaikh@kokilabenhospitals.com  Dr Ullas Batra  Rajiv Gandhi Cancer Institute and Research Centre  Senior Consultant and Unit Head, Chief of Thoracic Medical Oncologist Room no. 2251, Department of Medical Oncology, Sector 5 Rohini, PIN 110085 New Delhi   911147022222 ullasbatra@gmail.com
Details of Ethics Committee Modification(s)	No of Ethics Committees= 2   Name of Committee  Approval Status  Institutional Review Board Rajiv Gandhi Cancer Institute and Research Centre  Approved  Kokilaben Dhirubhai Ambani Hospital and Medical Research Institutional Ethics Committee,   Approved
Regulatory Clearance Status from DCGI Modification(s)	Status  Approved/Obtained
Health Condition / Problems Studied	Health Type  Condition  Patients  Malignant neoplasm of unspecifiedpart of bronchus or lung
Intervention / Comparator Agent Modification(s)	Type  Name  Details  Intervention  Savolitinib once daily plus osimertinib once daily  1:1 Assignment Oral and once daily until disease progression or toxicity.  Comparator Agent  savolitinib once daily plus placebo  1:1 Assignment Oral and once daily until disease progression or toxicity
Inclusion Criteria	Age From  18.00 Year(s) Age To  99.00 Year(s) Gender  Both  Details  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 the institutional ULN OR a glomerular filtration rate ≥ 50 mL/min, as assessed using the standard methodology at the investigating centre (eg, Cockcroft-Gault, Modification of Diet in Renal Disease or Chronic Kidney Disease Epidemiology Collaboration formulae, ethylenediaminetetraacetic acid clearance or 24-hour urine collection). Confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN. 13 Adequate coagulation parameters, defined as INR < 1.5 × ULN and activated partial thromboplastin time < 1.5 × ULN unless patients are receiving therapeutic anti-coagulation which affects these parameters. Use of warfarin is not permitted in this study, but LMWH is allowed (Appendix J). 14 Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on LMWH for ≥ 2 weeks. 15 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. 16 Ability to swallow and retain oral medications. 17 Willingness and ability to comply with study and follow-up procedures. Reproduction 18 Females of childbearing potential should be willing to use adequate contraceptive measures, should not be breastfeeding, and must have a negative pregnancy test if of childbearing potential, or must have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i) Post-menopausal is defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments. ii) Women under the age of 50 years would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous iii) hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution. iv) Women with documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. Further information is available in Appendix G (Definition of WOCBP and Acceptable Contraceptive Methods). 19 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.
ExclusionCriteria	Details  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 < LLN b) Serum/plasma magnesium < LLN c) Serum/plasma calcium < LLN 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 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. 9 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. 10 Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks prior to start of study intervention. 11 Past medical history of ILD, drug-induced ILD, radiation pneumonitis, which required steroid treatment, or any evidence of clinically active ILD. Prior/Concomitant Therapy 12 Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib. 13 Prior or current treatment with savolitinib or another MET inhibitor (for example, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib). 14 Patients who have received ≥ 4 lines of systemic therapy for NSCLC are not eligible. 15 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. 16 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 Johns 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 Prior/Concurrent Clinical Study Experience 17 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. 18 Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class. Other Exclusions 19 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 20 Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. 21 Previous enrolment in the present study. 22 For women only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding. 23 Patients unable to provide the required number of samples for MET analysis Exclusions from exploratory genetic research 24 Previous allogeneic bone marrow transplants. 25 Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection
Method of Generating Random Sequence	Stratified block randomization
Method of Concealment	Centralized
Blinding/Masking	Participant and Investigator Blinded
Primary Outcome Modification(s)	Outcome  TimePoints  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 therapy  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 Outcome	Outcome  TimePoints  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 therapy  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 population  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 placebo  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.   Plasma concentrations of savolitinib, osimertinib, and their metabolites.
Target Sample Size Modification(s)	Total Sample Size="56" Sample Size from India="6"
Phase of Trial	Phase 2
Date of First Enrollment (India) Modification(s)	08/12/2020
Date of First Enrollment (Global)	28/09/2020
Estimated Duration of Trial	Years="3" Months="0" Days="0"
Recruitment Status of Trial (Global) Modification(s)	Closed to Recruitment of Participants
Recruitment Status of Trial (India)	Completed
Publication Details	Not yet
Brief Summary	his is Multicenter 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   Approximately 56 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. At least half of the patients randomised into the study will be second-line patients who were treated with osimertinib as first-line therapy.   Patients will be stratified according to the number of prior 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. Patients 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.