A trial to learn how well osimertinib with savolitinib works in people with non-small cell lung cancer (NSCLC) that has gotten worse after initial treatment with osimertinib.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Oct 2019 → ongoing

Decision date (initial)

2024-07-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2024-512581-34-00

EudraCT number

2018-003012-51

ClinicalTrials.gov

NCT03778229

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To determine the efficacy of savolitinib (300mg OD) in combination with osimertinib in patients with EGFRm+, MET-amplified/overexpressed, locally advanced or metastatic NSCLC who have progressed on osimertinib.

Secondary objectives 6

1. To determine/evaluate the following: - efficacy of savolitinib (300mg OD) in combination with osimertinib in patients with EGFRm+, MET-amplified/overexpressed (centrally by FISH and centrally by IHC) locally advanced or metastatic NSCLC having progressed on osimertinib.
2. Efficacy of savolitinib (300 mg BiD and 600 mg OD) in combination with osimertinib in patients with EGFRm+, MET-amplified/overexpressed locally advanced or metastatic NSCLC having progressed on osimertinib.
3. Efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed, locally advanced or metastatic NSCLC who have progressed on osimertinib - impact of savolitinib and osimertinib on disease related symptoms and HRQoL in all patients.
4. Pharmacokinetics of osimertinib and savolitinib in all patients.
5. Prevalence of ctDNA clearance after osimertinib and savolitinib treatment in all patients.
6. Safety and tolerability of savolitinib in combination with osimertinib.

Conditions and MedDRA coding

EGFRm+ and MET+, Locally Advanced or Metastatic Non Small Cell Lung Cancer.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Patients must be ≥18 years of age (≥20 years of age in Japan). All genders are permitted.
2. 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.
3. Documented radiologic disease progression on first line osimertinib.
4. MET-amplification as determined by FISH (central) testing on tumour sample collected following progression on 1L osimertinib treatment.
5. Available tumour sample for central MET FISH and IHC analysis or willingness to collect additional sample 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
6. 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.
7. Prior lines of therapy in locally advanced/metastatic setting: Only prior 1L osimertinib treatment in metastatic setting is permitted.
8. 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)
9. Adequate liver function - ALT, AST ≤2.5 x ULN with TBL ≤ ULN OR - TBL >ULN to ≤1.5x ULN with ALT and AST ≤ ULN.
10. Adequate renal function - defined as a serum 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 only required when creatinine is >1.5 times ULN.
11. 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.
12. 12- Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for ≥2 weeks.
13. ECOG/WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
14. Females must be using highly effective 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.
15. Males with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following

Exclusion criteria 16

1. 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.
2. 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).
3. 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.
4. 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.
5. Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days.
6. 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.
7. 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.
8. 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.
9. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks prior to start of study treatment.
10. Past medical history of interstitial lung disease(ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
11. Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib.
12. Prior or current treatment with savolitinib or another MET inhibitor (eg, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib).
13. 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.
14. 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).
15. 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.
16. Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall Response Rate (ORR) by investigator assessment in accordance with RECIST 1.1.

Secondary endpoints 6

1. ORR by investigator assessment in accordance with RECIST 1.1.
2. 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.
3. Mean change from baseline in EORTC QLQ-C30 and QLQ-LC13.
4. Plasma concentrations of osimertinib, savolitinib and their metabolites.
5. Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies).
6. AEs, SAEs and discontinuation rate due to AEs. Clinical chemistry/haematology including LFTs. ECHOs, ECGs and vital signs including blood pressure and heart rate.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications