| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| EGFRm+ and MET+, Locally Advanced or Metastatic Non Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029515 |
| E.1.2 | Term | Non-small cell lung cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the efficacy of savolitinib (300 mg bid) in combination with
osimertinib in patients with EGFRm+ and MET amplified/overexpressed
(FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who
have progressed following treatment with 1L osimertinib
To determine the efficacy of savolitinib (300 mg od) in combination with
osimertinib in patients with EGFRm+, MET amplified/overexpressed
(FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who
have progressed following osimertinib. |
|
| E.2.2 | Secondary objectives of the trial |
To determine/evaluate the following:
-efficacy of savolitinib (300 mg bid) in combination with osimertinib in
patients with EGFRm+ and MET amplified/overexpressed (FISH10+
and/or IHC90+) locally advanced or metastatic NSCLC who have
progressed following treatment with 1L osimertinib
-efficacy of savolitinib (300 mg od and 600 mg od, respectively) in
combination with osimertinib in patients with EGFRm+, MET
amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or
metastatic NSCLC who have progressed following treatment with 1L
osimertinib
-efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od,
respectively) in combination with osimertinib in patients with EGFRm+,
MET amplified/overexpressed (FISH10+ and/or IHC90+), locally
advanced or metastatic NSCLC who have progressed following treatment
of = 2L osimertinib
Due to the limited number of characters, not all secondary objectives are
listed in the form. All objectives are included in the study protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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 tissue 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 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. 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 of childbearing potential should be willing to use adequate 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. |
|
| E.4 | Principal 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 or known serious active infection e.g. tuberculosis or human immunodeficiency virus. Viral testing is not required for assessment of eligibility for the study.
- 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Response Rate (ORR) by investigator assessment in accordance with RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| ORR will be analyzed up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment |
|
| E.5.2 | Secondary end point(s) |
- ORR, DoR and PFS by investigator assessment in accordance with
RECIST 1.1.
- OS
- ORR, DoR, and PFS assessed by BICR in accordance with RECIST 1.1.
- Mean change from baseline in EORTC QLQ-C30 and QLQ-LC13.
- Plasma concentrations of osimertinib, savolitinib and their metabolites.
- Total clearance in EGFR mutations at 6-weeks after therapy initiation
(percentage and absolute change from baseline in EGFR mutation allele
frequencies).
- AEs, SAEs and discontinuation rate due to AEs.
Clinical chemistry/haematology including LFTs.
ECHOs, ECGs and vital signs including blood pressure and heart rate. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
secondary endpoints will be analyzed up to 15 months after the last
patient under CSP version 7.0 has been randomised to treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Health-related quality of life (HRQoL) |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| prior to CSP v7 the study is open-label, from CSP v7 it becomes double blind with crossover option |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| Canada |
| Chile |
| India |
| Japan |
| Korea, Republic of |
| Taiwan |
| United States |
| Viet Nam |
| France |
| Spain |
| Italy |
| Denmark |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of study is defined as the last expected visit/contact of the last patient undergoing the
study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 19 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 19 |
Print
