Clinical Trials /

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

NCT03778229

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib
  • Official Title: A Phase II, Single Arm Study Assessing Efficacy of Osimertinib With Savolitinib in Patients With EGFRm+ MET+, Locally Advanced or Metastatic Non Small Cell Lung Cancer Who Have Progressed Following Osimertinib Treatment (SAVANNAH Study)

Clinical Trial IDs

  • ORG STUDY ID: D5084C00007
  • SECONDARY ID: 2018-003012-51
  • NCT ID: NCT03778229

Conditions

  • Carcinoma

Interventions

DrugSynonymsArms
osimertinibosimertinib + savolitinib
savolitinibosimertinib + savolitinib

Purpose

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+, 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+ tumour by central FISH, central IHC or
      certain local NGS testing (requirements summarised in the main body of the protocol and fully
      explained in the Central Laboratory Manual). In patients centrally confirmed as MET+, MET+ is
      defined as a) high expression of MET (by IHC) and/or b) 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.
    

Trial Arms

NameTypeDescriptionInterventions
osimertinib + savolitinibExperimentalosimertinib + savolitinib
  • osimertinib
  • savolitinib

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
             (including either exon 19 deletion and/or L858R) which is not amenable to curative
             therapy.

          -  Documented radiologic disease progression following treatment with osimertinib
             (osimertinib does not need to be the most recent therapy).

          -  MET amplification/high expression as determined by FISH (central), IHC (central) or
             NGS (local) testing on tumour tissue collected following progression on prior
             osimertinib treatment.

          -  Available tissue from a recent biopsy for MET analysis or willingness to collect
             additional tissue for central testing.

          -  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.

          -  Received at least 1 but no more than 3 prior lines of therapy (may include
             investigational therapy) in the locally advanced/metastatic setting.

          -  No more than one prior line of chemotherapy regimen

          -  A chemotherapy regimen including a programmed cell death-1 (PD1) or a PD1 ligand 1 (PD
             L1) agent is acceptable, provided it was not the most recent line of therapy.

          -  No more than 2 prior lines of therapy containing EGFR TKI are acceptable

          -  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 total bilirubin ≤ ULN OR

          -  Total bilirubin >ULN to ≤1.5x ULN with ALT and AST ≤ ULN

          -  Adequate renal function - 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 >1.5 times ULN.

          -  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.

          -  Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically
             stable on low molecular weight heparin for ≥2 weeks.

          -  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 of childbearing potential must be using highly effective contraceptive
             measures and have a negative pregnancy test.

          -  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 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) Acute myocardial infarction Stroke or transient ischemic attack Uncontrolled
        hypertension (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

          -  Known serious active infection e.g. tuberculosis or human immunodeficiency virus

          -  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.

          -  Inadequate bone marrow reserve or organ function as demonstrated by any of the
             following laboratory values Absolute neutrophil count <1.5 x 109/L Platelet count <100
             x 109/L Haemoglobin <90 g/L

          -  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).

          -  Patients who have received ≥4 lines of systemic therapy for NSCLC.

          -  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 or
             strong inhibitors of CYP3A4, strong inhibitors of CYP1A2, or CYP3A4 substrates which
             have a narrow therapeutic range within 2 weeks of the first dose of study treatment (3
             weeks for St John's Wort).

          -  Warfarin is not permitted (low molecular weight heparin is allowed).

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1
Time Frame:Up to approximately 36 months after 1st patient dosed (117 centrally confirmed MET+ FISH patients).
Safety Issue:
Description:To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+ (determined centrally by FISH), locally advanced or metastatic NSCLC who have progressed on osimertinib. The primary analysis of ORR will occur when all patients have had the opportunity to be treated for 6 months.

Secondary Outcome Measures

Measure:Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.
Time Frame:Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).
Safety Issue:
Description:To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+ (centrally confirmed by IHC and in all patients) locally advanced or metastatic NSCLC who have progressed on osimertinib.
Measure:PFS by investigator assessment in accordance with RECIST 1.1.
Time Frame:Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).
Safety Issue:
Description:To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+, locally advanced or metastatic NSCLC who have progressed on osimertinib. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.
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), version 3 (QLQ-C30 v3).
Time Frame:Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).
Safety Issue:
Description:To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in patients centrally confirmed as MET positive by FISH, by IHC and in all patients.
Measure:Plasma concentrations of osimertinib, savolitinib and their metabolites.
Time Frame: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)
Safety Issue:
Description:To evaluate the pharmacokinetics of osimertinib and savolitinib in this patient population.
Measure:Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies).
Time Frame:From date of first dose until the date of first documented progression, up to approximately 36 months.
Safety Issue:
Description:To determine the rate of ctDNA clearance after osimertinib and savolitinib treatment in patients centrally confirmed as MET positive by FISH, by IHC and in all patients.
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.
Time Frame:Continuously from first dose to 28 (+/-7) days after discontinuation of study drug, or up to approximately 36 months.
Safety Issue:
Description:To evaluate the safety and tolerability of savolitinib in combination with osimertinib.
Measure:Overall Survival by investigator assessment in accordance with RECIST 1.1.
Time Frame:Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).
Safety Issue:
Description:To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+, locally advanced or metastatic NSCLC who have progressed on osimertinib. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.
Measure:Duration of Response by investigator assessment in accordance with RECIST 1.1.
Time Frame:Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).
Safety Issue:
Description:To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+, locally advanced or metastatic NSCLC who have progressed on osimertinib. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.
Measure:Percentage change in tumour size by investigator assessment in accordance with RECIST 1.1.
Time Frame:Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).
Safety Issue:
Description:To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+, locally advanced or metastatic NSCLC who have progressed on osimertinib. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.
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).
Time Frame:Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).
Safety Issue:
Description:To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Non Small Cell Lung Cancer
  • epidermal growth factor receptor mutation positive
  • hepatocyte growth factor receptor
  • savolitinib
  • Osimertinib
  • AZD9291
  • AZD6094
  • volitinib

Last Updated