Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib

Study Overview
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Brief Summary
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This study (the SAVANNAH study) will investigate the efficacy of osimertinib in combination with savolitinib in patients with EGFRm+ and MET+, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib

Detailed Description
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The combination of osimertinib with savolitinib in this study (the SAVANNAH study) will explore if the combination will overcome MET-amplification as a mechanism of resistance. The SAVANNAH study will investigate the efficacy of osimertinib in combination with savolitinib in patients with EGFRm+ and MET-amplified/overexpressed, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib. Eligible patients will be those with histologically or cytologically confirmed diagnosis of EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+) NSCLC that is locally advanced or metastatic and is not amenable to further surgery or radiotherapy with curative intent. The disease must have progressed following treatment with first line osimertinib. Patients must have confirmation of MET-amplified/overexpressed tumour by central FISH and IHC testing (requirements summarised in the main body of the protocol and fully explained in the Central Laboratory Manual). Patients must not have received prior or current treatment with savolitinib or another MET inhibitor. All patients confirmed as eligible will begin treatment on Day 1 with osimertinib + savolitinib combination therapy or placebo to osimertinib + savolitinib. Treatment will continue in 28 day cycles until either objective disease progression by investigator per RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn or another discontinuation criterion is met.

Official Title
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A Phase II Study Assessing the Efficacy of Osimertinib in Combination With Savolitinib in Patients With EGFRm+ and MET+, Locally Advanced or Metastatic Non Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib.

Conditions
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Carcinoma

Intervention / Treatment
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* Drug: osimertinib
* Drug: savolitinib
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients must be ≥18 years of age (≥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 permitted in the osimertinib national label (such as either exon 19 deletion and/or L858R) which is not amenable to curative therapy. Documented radiologic disease progression on 1L osimertinib. MET amplification and/or overexpression (FISH10+ and/or IHC90+) as determined by FISH (central) and IHC (central) testing on tumour sample collected following progression on 1L osimertinib treatment. Available tumour sample for central MET FISH and IHC analysis or willingness to collect additional sample for central testing which fulfils the following requirements: Obtained following progression on previous osimertinib therapy; obtained within 2 years of submission for MET analysis; sufficient tissue to meet the minimum tissue requirement defined in the current Laboratory Manual. At least 1 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 1 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 sample collection is performed. Prior lines of therapy in locally advanced/metastatic setting: Only prior 1L osimertinib treatment in metastatic setting is permitted. Adequate haematological function defined as: Absolute neutrophil count ≥1500/μL Haemoglobin ≥9 g/dL (no transfusion in the past 2 weeks) Platelets ≥100,000/μL (no transfusion in the past 10 days) Adequate liver function ALT, AST ≤2.5 x ULN with TBL ≤ ULN OR TBL >ULN to ≤1.5x ULN with ALT and AST ≤ ULN Adequate renal function - defined as a serum creatinine <1.5 times the institutional ULN OR a glomerular filtration rate ≥50 mL/min. Confirmation of creatinine clearance is only required when creatinine is only required when creatinine is >1.5 times ULN. Adequate coagulation parameters: INR <1.5 and activated partial thromboplastin time <1.5 x ULN unless patients are receiving therapeutic anti coagulation which affects these parameters. Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for ≥2 weeks. The use of direct oral anticoagulants such as apixaban/rivaroxaban will be accepted as treatment for cancer related thromboembolism treatment. The use of warfarin for oral anticoagulation is not recommended. ECOG/WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks. Females must be using highly effective contraceptive measures, should not be breast feeding and must have a negative pregnancy test if of childbearing potential, or must have evidence of non-childbearing potential. Males 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 drug. Exclusion Criteria: Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia 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 (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥2, malabsorption syndrome or previous significant bowel resection). Any of the following cardiac diseases currently or within the last 6 months: Unstable angina pectoris Congestive heart failure (New York Heart Association [NYHA] ≥Grade 2) Acute myocardial infarction Stroke or transient ischemic attack Uncontrolled hypertension (blood pressure [BP] ≥150/95 mmHg despite medical therapy). Mean resting correct 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 such as heart failure, chronic hypokalaemia not correctable with supplements, congenital or familial long QT syndrome, family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes. 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 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 drug or has not recovered from side effects of such therapy. Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days Evidence of severe or uncontrolled systemic diseases, including renal transplant, active bleeding diatheses or uncontrolled hypertension, which in the investigator's opinion makes it undesirable for the patient to participate Active hepatitis B or C or known serious active infection e.g. tuberculosis or human immunodeficiency virus. Viral testing is not required for assessment of eligibility for the study. Known serious active infection including, but not limited to, tuberculosis, or human immunodeficiency virus (positive human immunodeficiency virus 1/2 antibodies). 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 treatment. Past medical history of interstitial lung disease(ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. History of liver cirrhosis of any origin and clinical stage; or history of other serious liver disease or chronic disease with relevant liver involvement, with or without normal LFTs, Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib Prior or current treatment with savolitinib or another MET inhibitor (eg, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib). Any cytotoxic chemotherapy, investigational agents or other anticancer 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 treatment 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 treatment) medications or herbal supplements known to be strong inducers of CYP3A4, strong inhibitors of CYP1A2 within 3 weeks of the first dose of study treatment (including St John's Wort). Participation in another clinical study with a cytotoxic, investigational product (IP), or other anticancer drug for the treatment of advanced NSCLC if received IP from that study within 14 days of the first dose of study treatment. 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: Under Protocol versions 1-6 the study model was single arm (open-label). Starting protocol version 7 patients will be randomised in a double blinded manner to receive savolitinib in combination with osimertinib or savolitinib with placebo to osimertinib with crossover option upon disease progression assessed by Investigator.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: osimertinib + savolitinib<br>osimertinib + savolitinib | Drug: osimertinib<br>* osimertinib (80 mg oral OD).<br>Drug: savolitinib<br>* savolitinib (300 mg oral OD or 300 mg oral BID or 600 mg oral OD)<br>|
| Placebo Comparator: placebo + savolitinib<br>placebo + savolitinib | Drug: savolitinib<br>* savolitinib (300 mg oral OD or 300 mg oral BID or 600 mg oral OD)<br>Drug: placebo<br>* placebo to osimertinib (oral OD)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1 | To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib | The primary (ORR) analysis for the study will be performed at 6 months after the last patient under CSP version 7.0 has been randomised to treatment. | 
| Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1 | To determine the efficacy of savolitinib (300 mg od) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib. | The primary (ORR) analysis for the study will be performed at 6 months after the last patient under CSP version 7.0 has been randomised to treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Overall Survival (OS) by all cause mortality. | To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1. | To describe the difference in the efficacy of savolitinib (300 mg bid) in combination with osimertinib and savolitinib (300 mg bid) in combination with placebo in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib therapy under CSP version 7.0. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Overall Survival (OS) by all cause mortality. | To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Overall Survival (OS) by all cause mortality. | To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1. | To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Overall Survival (OS) by all cause mortality. | To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Objective response rate (ORR) assessed by BICR in accordance with RECIST 1.1 | To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Duration of Response (DoR) assessed by BICR in accordance with RECIST 1.1 | To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Progression-free survival (PFS) assessed by BICR in accordance with RECIST 1.1 | To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality-of-life questionnaire (QLQ-C30). | To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in this patient population. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) complementary 13-item quality-of-life questionnaire - lung cancer symptoms questionnaire (QLQ-LC13). | To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in this patient population. | Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment | 
| Plasma concentrations of osimertinib, savolitinib and their metabolites. | To evaluate the pharmacokinetics of osimertinib and savolitinib in this patient population. | Blood sampling on Cycles 1 and 2 on Day 1 pre-dose, 1 hour and 3 hours post-dose; Day 1 of Cycles 3, 6, and 11; discontinuation visit (if discontinued due to liver toxicity) (One cycle = 28 days) | 
| 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 osimertinib and savolitinib treatment in this patient population. | From date of first dose until the date of first documented progression, up to approximately 36 months. | 
| AEs, SAEs and discontinuation rate due to AEs, as characterized and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event [CTCAE] v5. | To evaluate the safety and tolerability of savolitinib in combination with osimertinib and savolitinib in combination with placebo. | Continuously from first dose to 28 (+/-7) days after discontinuation of study drug, or up to approximately 36 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Small Cell Lung Cancer, epidermal growth factor receptor mutation positive, hepatocyte growth factor receptor, savolitinib, Osimertinib, AZD9291, AZD6094, volitinib