| 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.1.3 | 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 in combination with osimertinib in patients with EGFRm+, MET+ (determined centrally by FISH), locally advanced or metastatic NSCLC who have progressed on osimertinib. |
|
| E.2.2 | Secondary objectives of the trial |
- To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+ (determined centrally by FISH and centrally confirmed by IHC and in all patients) locally advanced or metastatic NSCLC who have progressed on osimertinib.
- To assess the impact of savolitinib and osimertinib on disease related symptoms and HRQoL in this patient population (in patients MET+ by FISH, MET+ by IHC and in all patients).
- To evaluate the pharmacokinetics of osimertinib and savolitinib in this patient population (all patients).
- To determine the rate of ctDNA clearance after osimertinib and savolitinib treatment in this patient population (in patients MET+ by FISH, MET+ by IHC and in all patients).
- To evaluate the safety and tolerability of savolitinib in combination with osimertinib. |
|
| 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 (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 biopsy for MET analysis or willingness to collect additional tissue for central testing which fulfils the following requirements: 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.
- 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. |
|
| 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
- 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. |
|
| 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 |
| The primary analysis of ORR will occur when all patients have had the opportunity to be treated for 6 months. The final analysis of ORR will occur when 70% of patients have progressive disease or have died or 18 months after the last patient in (which ever occurs first). |
|
| E.5.2 | Secondary end point(s) |
- ORR by investigator assessment in accordance with RECIST 1.1.
- PFS by investigator assessment in accordance with RECIST 1.1.
OS
DoR
Percentage change in tumour size by investigator assessment 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 |
ORR & PFS: baseline; every 6 weeks after treatment start until Cycle 7 (C7), then every 8 weeks until disease progression. Survival follow-up every 12 weeks.
EORTC QLQ-C30 and QLQ-LC13: baseline; QLQ-C30 every 4 weeks after treatment start, QLQ-LC13 weekly after treatment start in C1 and C2, then every 4 weeks from C3 onwards; 7 days after treatment discontinuation.
Plasma concentrations: C1 and C2 on Day 1 pre-dose, 1 hour and 3 hours post-dose; Day 1 of C3, 6, and 11; discontinuation visit.
EGFR: Pre-dose on C1 Day 1; C1 Days 8, 15, 22; C2 Day 1; then at the time of every RECIST 1.1 scan
AEs, vital signs, ECGs, safety labs at every clinic visit (every 7 during C1, every 28 during treatment (MUGA/ECHO every 12 weeks), 7 days after final dose, 28 day follow-up). |
|
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| 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 | 25 |
| 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 |
| Denmark |
| France |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Taiwan |
| United States |
| Vietnam |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 24 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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