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

  • STATUS
    Recruiting
  • End date
    Feb 15, 2023
  • participants needed
    259
  • sponsor
    AstraZeneca
Updated on 3 June 2021
renal function
cancer
measurable disease
neutrophil count
EGFR
chemotherapy regimen
line of therapy
metastatic non-small cell lung cancer

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

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 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 osimertinib. Patients must have confirmation of MET-amplified/overexpressed tumour by central FISH testing (requirements summarised in the main body of the protocol and fully explained in the Central Laboratory Manual). In patients centrally confirmed as MET-amplified/overexpressed, MET-amplification/overexpression is defined as increased MET gene copy number (by FISH). 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. Treatment will continue od in 28 day cycles until either objective disease progression, unacceptable toxicity occurs, consent is withdrawn or another discontinuation criterion is met.

Details
Condition Carcinoma, Vulvar Dysplasia and Carcinoma, Advanced Malignancies, carcinomas
Treatment Osimertinib, Savolitinib
Clinical Study IdentifierNCT03778229
SponsorAstraZeneca
Last Modified on3 June 2021

Eligibility

Yes No Not Sure

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 first line osimertinib
MET-amplification as determined by FISH (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
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
obtained within 2 years of submission for MET analysis
sufficient tissue to meet the minimum tissue requirement defined in the
current Laboratory Manual
Adequate haematological function defined as
Absolute neutrophil count 1500/L
Prior lines of therapy in locally advanced/metastatic setting: Only prior 1L osimertinib treatment in metastatic setting is permitted
Haemoglobin 9 g/dL (no transfusion in the past 2 weeks)
Platelets 100,000/L (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
Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for 2 weeks
Adequate coagulation parameters: INR <1.5 x ULN and activated partial thromboplastin time <1.5 x ULN unless patients are receiving therapeutic anti coagulation which affects these parameters
ECOG/WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks
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
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

Exclusion Criteria

Unresolved toxicities from any prior therapy greater than Common Terminology Criteria for Adverse Events (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)
Mean resting correct QT interval (QTcF) >470 msec for women and >450 msec for
Acute myocardial infarction
men at Screening, obtained from 3 ECGs using the screening clinic ECG machine
Stroke or transient ischemic attack
derived QTcF value
Uncontrolled hypertension (BP 150/95 mmHg despite medical therapy)
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
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
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)
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
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
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
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 2 weeks of the first dose of study treatment (3 weeks for St John's Wort)
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