To determine the efficacy (as assessed by best response) of osimertinib in patients with locally advanced or metastatic NSCLC and only an EGFR exon 20 mutation, deletion and/or insertion, which are T790M-ve.
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Best response defined by RECIST 1.1
Secondary outcome
- Progression free survival (PFS) is defined by RECIST 1.1
- Duration of response
- Overall survival
- Treatment- related adverse events (CTC-AE, v4.0)
Background summary
Osimertinib is an oral, potent, irreversible EGFR-TKI selective for sensitizing
(EGFRm) and T790M resistance mutation with a significant selectivity margin
against wild-type EGFR. As a result, osimertinib can effectively block EGFR
signalling both in EGFR single mutant cells with activating EGFR mutations and
in double mutant cells bearing the resistance T790M mutation. Osimertinib is
registered in patients with advanced T790M positive NSCLC and is currently
under investigation as a treatment option in: 1) Patients with advanced EGFRm
NSCLC who are treatment naïve; 2) In combination with novel agents for patients
with EGFR TKI resistant NSCLC. Data from the ongoing phase I AURA study
(D5160C00001) in patients with T790M positive NSCLC who were previously treated
with EGFR TKI, have achieved promising efficacy with osimertinib; 54.2% 95% CI
(40.8%, 67.3%) of subjects achieved a response, 91.5% 95% CI (81.3%, 97.2%)
achieved disease control, medium duration of response of 12.4 months 95% CI
(8.3, NC) and median PFS based on 38% maturity of data was 13.5 months 95% CI
(8.3, NC), as assessed by blinded independent central review. Promising
evidence of efficacy was also observed in patients with EGFRm treatment naïve
NSCLC treated with osimertinib as first line EGFR TKI. Across the clinical
development programme, osimertinib has demonstrated a manageable safety
profile.
Study objective
To determine the efficacy (as assessed by best response) of osimertinib in
patients with locally advanced or metastatic NSCLC and only an EGFR exon 20
mutation, deletion and/or insertion, which are T790M-ve.
Study design
Based on the safety, pharmacokinetic and preliminary efficacy data, 160 mg once
daily is selected as the recommended phase II dose. No dosage adjustment is
required due to patient age, body weight, gender, ethnicity and smoking status.
Intervention
See study design
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits, where they will undergo physical examinations, vital sign measurements,
blood tests for safety assessment, pregnancy testing (for females of child
bearing potential), and monitoring for adverse events. In addition, every 6
weeks (until week 24) and then every 12 weeks, patients will undergo
radiographic assessment of their tumors (by CT) until disease progression.
Blood will also be collected at certain visits for research purposes. The
frequency of visits and number of procedures carried out during this trial
would be considered as standard of care. These procedures are conducted by
medically trained professionals and every effort will be made to minimise any
risks or discomfort to the patient.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
1. Provision of informed consent prior to any study specific procedures
2. Patients must be >= 18 years of age.
3. Locally advanced or metastatic non-small cell lung cancer, not amenable to
curative surgery or radiotherapy
4. Presence of an EGFR exon 20, non-T790M, mutation, deletions and/or insertion
only,
5. ECOG performance score of 0-2
6. Patients must have a life expectancy >= 12 weeks.
7. Females should be using adequate contraceptive measures, should not be
breast feeding and must have a negative pregnancy test prior to start of dosing
if of child-bearing potential or must have evidence of non-child-bearing
potential by fulfilling one of the following criteria two weeks before
screening. Male patients should be willing to use barrier contraception.
8. Patient is willing and able to comply with the protocol for the duration of
the study including undergoing treatment and scheduled visits and examinations
including follow up.
9. At least one lesion, not previously irradiated, 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 computed tomography (CT) or magnetic
resonance imaging (MRI) and which is suitable for accurate repeated
measurements.
10. Brain metastasis, if asymptomatic, are allowed. In case of symptomatic
brain metastasis, patient must have had radiotherapy and stable for at least 2
weeks.
Exclusion criteria
1. Presence of a T790M mutation or other tumour driven mutations,
translocations or amplifications (e.g. common EGFR mutations, KRAS, BRAF V600E,
ALK, ROS1)
2. Patient is unwilling and unable to comply with the protocol for the duration
of the study including undergoing treatment and scheduled visits and
examinations including follow up
3. Previous treatment with EGFR-TKI
4. Patients currently receiving (or unable to stop use prior to receiving the
first dose of study treatment) medications or herbal supplements known to be
potent inducers of CYP3A4 (at least 3 weeks prior).
5. Any unresolved toxicities from 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 or immune mediated pneumonitis or hepatitis
previously treated with IO therapy.
6. Any evidence of severe or uncontrolled systemic diseases, including
uncontrolled hypertension and active bleeding diatheses.
7. Patients with symptomatic central nervous system (CNS) metastases who are
neurologically unstable
8. Past medical history of interstitial lung disease (ILD), drug-induced ILD,
radiation pneumonitis requiring steroid treatment, or any evidence of
clinically active ILD
9. Inadequate bone marrow reserve or organ function.
10. Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) > 470 msec obtained from 1
electrocardiograms, using the screening clinic ECG machine derived QTc value
- Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG (e.g., complete left bundle branch block, third degree heart block,
second degree heart block)
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years of age
in first degree relatives or any concomitant medication known to prolong the QT
interval
11. Refractory nausea and vomiting, chronic gastrointestinal diseases,
inability to swallow the formulated product or previous significant bowel
resection that would preclude adequate absorption of osimertinib
12. Males and females of reproductive potential who are not using an effective
method of birth control and females who are pregnant or breastfeeding or have a
positive (urine or serum) pregnancy test prior to study entry
13. Judgment by the Investigator that the patient should not participate in
the study if the patient is unlikely to comply with study procedures,
restrictions and requirements
14. History of hypersensitivity active or inactive excipients of osimertinib or
drugs with a similar chemical structure or class to osimertinib
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-004734-28-NL |
| CCMO | NL64116.042.17 |
| Other | NTR, nummer volgt |