Clinical trial NCT04606771: A Study Comparing Savolitinib Plus Osimertinib vs Savolitinib Plus Placebo in Patients With EGFRm+ and MET Amplified Advanced NSCLC
Official title: A Multi-centre Phase II, Double-Blind, Randomised Study of Savolitinib in Combination With Osimertinib vs Savolitinib in Combination With Placebo in Patients With EGFRm+ and MET Amplified Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Keywords: Locally
Advanced
Metastatic
Carcinoma
Non-Small Cell Lung Cancer
Osimertinib
Tagrisso
Savolitinib
MET
EGFR
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-10-28
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1. Patients will take savolitinib 300mg tablets QD within 15 minutes after the start of a meal except for the day on which PK samples are taken. Patients will take osimertinib 80mg tablet once daily with/without food except for the day on which PK samples are taken. On the day when PK samples are taken both savolitinib \& osimertinib will be administered after a meal prepared by the clinic
2. Patients will take savolitinib 300mg tablets QD within 15 minutes after the start of a meal except for the day on which PK samples are taken. Patients will take placebo to osimertinib 80mg tablet once daily with/without food except for the day on which PK samples are taken. On the day when PK samples are taken both savolitinib \& placebo to osimertinib will be administered within 15 minutes after a meal prepared by the clinic

In addition to comparing the ORR between groups, this study will also assess safety and tolerability, DoR, DCR, OS, PFS and other measures of antitumor activity
Primary purpose: TREATMENT

Brief summary: This study will compare the activity of the combination of savolitinib and osimertinib against the combination of savolitinib with placebo to osimertinib in patients with Epidermal Growth Factor Receptor Mutation Positive and MET amplified, locally advanced or metastatic non-small cell lung cancer who have progressed following treatment with osimertinib.

Detailed description: Resistance to EGFR-TKIs is a clinical problem. One of the mechanisms for resistance to osimertinib is amplification of the MET receptor tyrosine kinase, which activates downstream intracellular signalling independent of EGFR. This study will explore the individual contribution of savolitinib to MET mediated osimertinib resistance, by assessing the response to dual pathway blockade of EGFRm and MET to overcome MET mediated resistance to osimertinib versus inhibition of the MET pathway alone by investigating the efficacy of savolitinib plus osimertinib versus savolitinib plus placebo to osimertinib (hereafter referred to as placebo) in patients with EGFRm+ and MET amplified, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib. This is a multi centre, Phase II, double blind, randomised study.

Patients will be randomised in a ratio of 1:1 to receive treatment with savolitinib once daily plus osimertinib once daily or savolitinib once daily plus placebo. Randomisation will be stratified according to the number ofprior lines of therapy (ie, osimertinib monotherapy as first line or ≥ second line \[which includes patients who received osimertinib monotherapy before or after chemotherapy\]). All patients confirmed as eligible will begin treatment on Day 1 with savolitinib plus osimertinib or savolitinib plus placebo. Treatment will continue once daily in 28 day cycles until either objective PD by RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn, or another discontinuation criterion is met.

After progression, patients can be unblinded, and patients initially randomised to the savolitinib plus placebo arm may cross-over to open-label savolitinib plus osimertinib following investigator assessed objective PD to ensure that all patients enrolled may have the opportunity to receive the combination of savolitinib plus osimertinib.

Eligibility criteria: Inclusion Criteria:

* Patients must be ≥ 18 years of age at the time of signing the informed consent (≥ 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 that is permitted in the osimertinib national label (such as exon 19 deletion and/or L858R), which is not amenable to curative therapy.
* Documented radiologic PD following treatment with osimertinib (osimertinib does not need to be the most recent therapy).
* Have MET amplification as determined by central MET FISH testing on tumour specimen collected following progression on prior osimertinib treatment.
* At least measurable target lesion
* Patients must have received at least one but no more than 3 prior lines of therapy (including investigational therapy) in the locally advanced/metastatic setting.
* Adequate haematological, liver and renal function
* Eastern Cooperative Oncology Group/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 breastfeeding, and must have a negative pregnancy test.
* Male patients 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 intervention. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing study intervention.

Exclusion Criteria:

* Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 at the time of starting study intervention with the exception of alopecia, haemoglobin ≥ 9 g/dL 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.
* Any of the following cardiac diseases currently or within the last 6 months:

  * Unstable angina pectoris
  * Congestive heart failure (NYHA Grade ≥ 2)
  * Acute myocardial infarction
  * Stroke or transient ischemic attack
  * Uncontrolled hypertension (BP ≥ 150/95 mmHg despite medical therapy).
  * Mean resting corrected 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
  * Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs.
  * 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 intervention or has not recovered from side effects of such therapy.
* Major surgical procedures ≤ 28 days of beginning study intervention or minor surgical procedures ≤ 7 days. No waiting is required following port-a-cath placement.
* As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including renal transplant or active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to enter the study or which would jeopardise compliance with the CSP.
* Active HBV (positive HBsAg result) or HCV. Viral testing is not required for assessment of eligibility for the study.
* Known serious active infection including, but not limited to, tuberculosis, or HIV (positive HIV 1/2 antibodies). 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 intervention.
* Past medical history of ILD, drug-induced ILD, radiation pneumonitis, which required steroid treatment, or any evidence of clinically active ILD.
* Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib.
* Prior or current treatment with savolitinib or another MET inhibitor (for example, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib).
* Patients who have received ≥ 4 lines of systemic therapy for NSCLC
* Any cytotoxic chemotherapy, investigational agents or other anti cancer 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 intervention 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 intervention) medications or herbal supplements known to be strong inducers of CYP3A4 or strong inhibitors of CYP1A2, or CYP3A4 substrates which have a narrow therapeutic range within 2 weeks of the first dose of study intervention (3 weeks for St John's Wort) will be excluded. All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4 during the study and for 3 months later the last dose intake.
* Participation in another clinical study with a cytotoxic, investigational product, or other anti cancer drug for the treatment of advanced NSCLC if received study intervention from that study within 14 days of the first dose of study intervention.
* Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Tumour assessments every 6 weeks from randomisation up to 24 weeks, then every 8 weeks until objective disease progression (maximum of approximately 25 months)
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Tumour assessments every 6 weeks from randomisation up to 24 weeks, then every 8 weeks until objective disease progression (maximum of approximately 25 months)
measure: Duration of Response (DoR)
timeFrame: Tumour assessments every 6 weeks from randomisation up to 24 weeks, then every 8 weeks until objective disease progression (maximum of approximately 25 months)
measure: Tumour Size Assessment (TSA)
timeFrame: Baseline and 12 weeks.
measure: Overall Survival (OS)
timeFrame: From the date of randomisation until death due to any cause, assessed up to the data cut-off date (21 December 2022) (maximum of approximately 25 months)
measure: Total Clearance in EGFR Mutations at 6-weeks After Therapy Initiation (Percentage Change From Baseline in EGFR Mutation Allele Frequencies).
timeFrame: 6-weeks after therapy initiation.
measure: Total Clearance in EGFR Mutations at 6-weeks After Therapy Initiation (Absolute Change From Baseline in EGFR Mutation Allele Frequencies).
timeFrame: 6-weeks after therapy initiation.
measure: PK Concentration Ratios on Multiple Dosing
timeFrame: C3h Cycle 2 Day 1/C3h Cycle 1 Day 1; Cpre-dose Cycle 3 Day 1/Cpre-dose Cycle 2 Day 1; Cpre-dose Cycle 6 Day 1/Cpre-dose Cycle 2 Day 1; Cpre-dose Cycle 11 Day 1/Cpre-dose Cycle 2 Day 1. (Each Cycle is 28 days)
measure: AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib)
timeFrame: Cycle 3, Day 1: Pre-dose and 1, 3, 4, and 6 hours post-dose
measure: Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib)
timeFrame: Cycle 3, Day 1: Pre-dose and 1, 3, 4, and 6 hours post-dose
measure: Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib)
timeFrame: Cycle 3, Day 1: Pre-dose and 1, 3, 4, and 6 hours post-dose
measure: CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib)
timeFrame: Cycle 3, Day 1 (Each Cycle is 28 days)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Sacramento
country: United States
facility: Research Site
state: California
city: Buenos Aires
country: Argentina
facility: Research Site
city: Delhi
country: India
facility: Research Site
city: Mumbai
country: India
facility: Research Site
city: Taichung City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taoyuan City
country: Taiwan
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Hat Yai
country: Thailand
facility: Research Site
city: Khon Kaen
country: Thailand
facility: Research Site
city: Muang
country: Thailand
facility: Research Site
city: Ha Noi
country: Vietnam
facility: Research Site
city: Hanoi
country: Vietnam
facility: Research Site
city: Ho Chi Minh city
country: Vietnam
facility: Research Site
Study officials:
References: