Savolitinib combine with Durvalumab in EGFR wild-type locally advanced or metastatic NSCLC - SOUND

Exclusion Criteria

• Participants are excluded from the study if any of the following criteria apply:
• 1.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). therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade
• ≥2, malabsorption syndrome or previous significant bowel resection).
• 2.Any of the following cardiac diseases diagnosed currently or within the last 6 months:
• (a)Unstable angina pectoris
• (b)Congestive heart failure (New York Heart Association [NYHA] ≥Grade 2)
• (c)Acute myocardial infarction
• (d)Stroke or transient ischemic attack
• (e)Ventricular arrhythmias
• 3.Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy) ≤28 days of beginning study drug.
• 4.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.
• (a)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.
• 5.Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs ≤28 days of beginning study drug, eg, complete left bundle branch block, third degree heart block, second degree heart block, P-R interval >250 msec.
• 6.Acute coronary syndrome diagnosed currently or within the last 6 months.
• 7.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.
• 8.Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days.
• 9.Active hepatitis B (HBV) (positive HBV surface antigen [HBsAg] result) or hepatitis C (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:
• (a)Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc] or
• (b)Positive for HBsAg, but for >6 months have had normal transaminases and HBV DNA levels between 0 to 2000 IU/mL (inactive carrier state) and willing to start and maintain antiviral treatment for at least the duration of the study.
• (c)Patients with a past or resolved HBV infection must have monthly monitoring of ALT and HBV DNA
• (d)HBV DNA levels >2000 IU/mL but on prophylactic antiviral treatment for the past 3 months and must maintain the antiviral treatment during the study.
• Patients with positive HCV antibody are eligible only if the polymerase chain reaction is negative for HCV ribonucleic acid.
• 10.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*, such as
• - Hemochromatosis
• - Alpha-1 Antitrypsin deficiency
• - Autoimmune hepatitis (AIH)
• - Primary sclerosing cholangitis (PSC)
• - Primary biliary cirrhosis (PBC)
• - Biopsy-confirmed Non-Alcoholic Steatohepatitis (NASH) with advanced fibrosis
• - Biopsy- confirmed Alcoholic Steatohepatitis with advanced fibrosis
• - Wilson's disease.
• - Hepatocellular carcinoma* Patients with liver metastases are eligible, provided they meet other eligibility criteria, including liver biochemistry criteria.
• 11.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.
• 12.Having gene mutations sensitive to targeted drugs for EGFR, ALK and ROS-1.
• 13.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
• 14.Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 2 weeks prior to start of study intervention. Subjects with leptomeningeal metastases are ineligible.
• 15.Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
• 16.Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc].
• The following are exceptions to this criterion:
• (a)Patients with vitiligo or alopecia
• (b)Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
• (c)Any chronic skin condition that does not require systemic therapy
• (d)Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician
• (e)Patients with celiac disease controlled by diet alone
• 17.Known serious active infection including, but not limited to, tuberculosis, or human immunodeficiency virus (positive human immunodeficiency virus 1/2 antibodies). Testing is not required for assessment of eligibility for the study.
• 18.Known contraindications to durvalumab administration.
• 19.Known hypersensitivity to the active or inactive excipients of durvalumab or savolitinib or drugs with a similar chemical structure or class.
• 20.Prior exposure to immune-mediated therapy including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines.
• 21.Prior exposure to any HGF/MET inhibitor, e.g., foretinib, crizotinib, cabozantinib, merestinib, onartuzumab, capmatinib, tepotinib, etc.
• 22.As judged by the investigator, any 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 in the trial or which would jeopardise compliance with the protocol.
• 23.Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumor embolisation, or monoclonal antibodies) of early stage NSCLC within 14 days prior to the first dose of study intervention.
• 24.Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 30 days prior to the first dose of study intervention or concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the off-treatment follow-up period of an interventional study.
• 25.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• 26.Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.
• 27.Previous enrolment in the present study.
• 28.Without civil capacity or with restricted civil capacity.
• 29.Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
• (a)Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• (b)Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
• (c)Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• 30.Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and up to 30 days after the last dose of durvalumab
• 31.Any other reasons judged by the leading investigator to prevent the subject from participating in this study
• 32.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) will be excluded.