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Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib (SAVANNAH)

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ClinicalTrials.gov Identifier: NCT03778229
Recruitment Status : Recruiting
First Posted : December 18, 2018
Last Update Posted : May 31, 2019
Sponsor:
Collaborator:
Hutchison MediPharma
Information provided by (Responsible Party):
AstraZeneca

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.

Condition or disease Intervention/treatment Phase
Carcinoma Drug: osimertinib Drug: savolitinib Phase 2

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will continue od in 28 day cycles until either objective disease progression, unacceptable toxicity occurs, consent is withdrawn or another discontinuation criterion is met.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 172 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : January 9, 2019
Estimated Primary Completion Date : February 12, 2021
Estimated Study Completion Date : January 5, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: osimertinib + savolitinib
osimertinib + savolitinib
Drug: osimertinib
osimertinib (80 mg oral od).

Drug: savolitinib
savolitinib (300 mg oral OD or 600 mg oral OD)




Primary Outcome Measures :
  1. 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). ]
    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 :
  1. 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). ]
    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.

  2. 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). ]
    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.

  3. 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). ]
    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.

  4. 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) ]
    To evaluate the pharmacokinetics of osimertinib and savolitinib in this patient population.

  5. 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. ]
    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.

  6. 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. ]
    To evaluate the safety and tolerability of savolitinib in combination with osimertinib.

  7. 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). ]
    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.

  8. 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). ]
    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.

  9. 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). ]
    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.

  10. 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). ]
    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.


Other Outcome Measures:
  1. PRO CTCAE symptoms [ Time Frame: From date of consent until the date of first documented progression, up to approximately 36 months. ]
    To assess the impact of savolitinib in combination with osimertinib on patient reported treatment-related symptoms.

  2. Patient's Global Impression of Severity (PGIS) [ Time Frame: From date of consent until the date of first documented progression, up to approximately 36 months. ]
    To assess patients' overall impression of severity of cancer symptoms. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

  3. EQ-5D-5L [ Time Frame: From date of consent until the date of first documented progression, up to approximately 36 months. ]
    To explore the impact of treatment and disease on health state utility. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

  4. Longitudinal changes in circulating DNA and/or RNA compared with PFS, OS and ORR. [ Time Frame: 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) ]
    To assess the predictive value of changes in circulating biomarkers on clinical efficacy endpoints.

  5. Pharmacogenetic analyses on blood samples. [ Time Frame: Screening within 28 days before first dose; at first dose; 7 days after last dose. (One cycle = 28 days) ]
    To collect and store DNA (according to each country's local and ethical procedures) for future exploratory research into genes/genetic variation that may influence response (ie, distribution, safety, tolerability and efficacy) to study treatments and or susceptibility to disease (optional).

  6. Disease relevant or response markers in tumour tissue and circulating tumour DNA/RNA including but not limited to EGFR mutations and MET amplifications. [ Time Frame: 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) ]
    To collect and store tissue and plasma samples for companion diagnostic development and exploratory analyses.

  7. HLA alleles associated with susceptibility to drug related AEs (such as but not limited to hypersensitivity). [ Time Frame: On first day of study treatment at Cycle 1 Day 1. (One cycle = 28 days) ]
    To collect and store germline DNA for exploration of the role of HLA alleles in developmental toxicity.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03778229


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

  Show 55 Study Locations
Sponsors and Collaborators
AstraZeneca
Hutchison MediPharma
Investigators
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Principal Investigator: Geoffrey R Oxnard, MD Dana-Faber Cancer Institute
Principal Investigator: Myung-Ju Ahn, MD Samsung Medical Centre Sungkyunkwan University School of Medicine

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03778229     History of Changes
Other Study ID Numbers: D5084C00007
2018-003012-51 ( EudraCT Number )
First Posted: December 18, 2018    Key Record Dates
Last Update Posted: May 31, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by AstraZeneca:
Non Small Cell Lung Cancer
epidermal growth factor receptor mutation positive
hepatocyte growth factor receptor
savolitinib
Osimertinib
AZD9291
AZD6094
volitinib

Additional relevant MeSH terms:
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Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action