Clinical trial NCT03778229: Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib
Official title: 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.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Carcinoma
Keywords: Non Small Cell Lung Cancer
epidermal growth factor receptor mutation positive
hepatocyte growth factor receptor
savolitinib
Osimertinib
AZD9291
AZD6094
volitinib
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Hutchison Medipharma Limited
First posted: 2018-12-19
Enrollment: 367
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1
timeFrame: 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.
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1
timeFrame: 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 outcomes:
measure: Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Overall Survival (OS) by all cause mortality.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Overall Survival (OS) by all cause mortality.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Overall Survival (OS) by all cause mortality.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Overall Survival (OS) by all cause mortality.
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Objective response rate (ORR) assessed by BICR in accordance with RECIST 1.1
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Duration of Response (DoR) assessed by BICR in accordance with RECIST 1.1
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Progression-free survival (PFS) assessed by BICR in accordance with RECIST 1.1
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality-of-life questionnaire (QLQ-C30).
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: 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).
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: Plasma concentrations of osimertinib, savolitinib and their metabolites.
timeFrame: 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)
measure: Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies).
timeFrame: From date of first dose until the date of first documented progression, up to approximately 36 months.
measure: 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.
timeFrame: Continuously from first dose to 28 (+/-7) days after discontinuation of study drug, or up to approximately 36 months.
Other outcomes:
measure: CNS PFS by BICR assessments in accordance with RECIST 1.1
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: The presence/absence of CNS lesions at progression by BICR assessments in accordance with RECIST 1.1
timeFrame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
measure: PRO CTCAE symptoms
timeFrame: From date of consent until the date of first documented progression, up to approximately 36 months.
measure: Patient's Global Impression of Severity (PGIS)
timeFrame: From date of consent until the date of first documented progression, up to approximately 36 months.
measure: EQ-5D-5L
timeFrame: From date of consent until the date of first documented progression, up to approximately 36 months.
measure: Longitudinal changes in circulating DNA and/or RNA compared with PFS, OS and ORR.
timeFrame: Blood samples collected at Screening within 28 days before the first dose of study treatment; on day of first dose of study treatment; at discontinuation 7 days after last dose of study treatment. (One cycle = 28 days)
measure: Pharmacogenetic analyses on blood samples.
timeFrame: Screening within 28 days before first dose; at first dose; 7 days after last dose. (One cycle = 28 days)
measure: Disease relevant or response markers in tumour tissue and circulating tumour DNA/RNA including but not limited to EGFR mutations and MET amplifications.
timeFrame: Screening within 28 days before first dose; at first dose; 7 days after last dose. Tumour tissue collected during Pre-screening and at treatment discontinuation 7 days after last dose. (One cycle = 28 days)
measure: HLA alleles associated with susceptibility to drug related AEs (such as but not limited to hypersensitivity).
timeFrame: On first day of study treatment at Cycle 1 Day 1. (One cycle = 28 days)
Locations:
city: La Jolla
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Sacramento
country: United States
facility: Research Site
state: California
city: Washington
country: United States
facility: Research Site
state: District of Columbia
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Rochester
country: United States
facility: Research Site
state: Minnesota
city: Brooklyn
country: United States
facility: Research Site
state: New York
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Barretos
country: Brazil
facility: Research Site
city: Curitiba
country: Brazil
facility: Research Site
city: Goiania
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Rio de Janeiro
country: Brazil
facility: Research Site
city: Salvador
country: Brazil
facility: Research Site
city: Sao Paulo
country: Brazil
facility: Research Site
city: São José do Rio Preto
country: Brazil
facility: Research Site
city: São Paulo
country: Brazil
facility: Research Site
city: Calgary
country: Canada
facility: Research Site
state: Alberta
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Newmarket
country: Canada
facility: Research Site
state: Ontario
city: North York
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Santiago
country: Chile
facility: Research Site
city: Santiago
country: Chile
facility: Research Site
city: Santiago
country: Chile
facility: Research Site
city: Herlev
country: Denmark
facility: Research Site
city: København Ø
country: Denmark
facility: Research Site
city: Næstved
country: Denmark
facility: Research Site
city: Odense
country: Denmark
facility: Research Site
city: Vejle
country: Denmark
facility: Research Site
city: Ålborg
country: Denmark
facility: Research Site
city: Dijon
country: France
facility: Research Site
city: Marseille Cedex 20
country: France
facility: Research Site
city: Nantes
country: France
facility: Research Site
city: Paris Cedex 5
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Rennes
country: France
facility: Research Site
city: Bangalore
country: India
facility: Research Site
city: Chennai
country: India
facility: Research Site
city: Kolkata
country: India
facility: Research Site
city: New Delhi
country: India
facility: Research Site
city: Avellino
country: Italy
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Orbassano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Parma
country: Italy
facility: Research Site
city: Perugia
country: Italy
facility: Research Site
city: Peschiera Del Garda
country: Italy
facility: Research Site
city: Fukuoka
country: Japan
facility: Research Site
city: Hiroshima-shi
country: Japan
facility: Research Site
city: Kanazawa-shi
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Niigata-shi
country: Japan
facility: Research Site
city: Osakasayama
country: Japan
facility: Research Site
city: Sapporo-shi
country: Japan
facility: Research Site
city: Sunto-gun
country: Japan
facility: Research Site
city: Wakayama-shi
country: Japan
facility: Research Site
city: Yokohama-shi
country: Japan
facility: Research Site
city: Goyang-si
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Suwon
country: Korea, Republic of
facility: Research Site
city: Cordoba
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: San Sebastian
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Zaragoza
country: Spain
facility: Research Site
city: Hsinchu
country: Taiwan
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: New Taipei
country: Taiwan
facility: Research Site
city: Taichung City
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taoyuan
country: Taiwan
facility: Research Site
city: Ha Noi
country: Vietnam
facility: Research Site
city: Ho Chi Minh City
country: Vietnam
facility: Research Site
city: Ho Chi Minh
country: Vietnam
facility: Research Site
Study officials:
affiliation: Massachusetts General Hospital
name: Lecia V Sequist, MD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Samsung Medical Centre Sungkyunkwan University School of Medicine
name: Myung-Ju Ahn, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schmid S, Fruh M, Peters S. Targeting MET in EGFR resistance in non-small-cell lung cancer-ready for daily practice? Lancet Oncol. 2020 Mar;21(3):320-322. doi: 10.1016/S1470-2045(19)30859-9. Epub 2020 Feb 3. No abstract available.