Description:
A multicentre, open-label, single-arm, molecular profiling study of patients with EGFR
mutation-positive locally advanced or metastatic NSCLC treated with osimertinib.
Title
- Brief Title: A Molecular Profiling Study of Patients With EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated With Osimertinib
- Official Title: A Multicentre, Open-label, Single-arm, Molecular Profiling Study of Patients With EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated With Osimertinib
Clinical Trial IDs
- ORG STUDY ID:
D5161C00003
- NCT ID:
NCT03239340
Conditions
- EGFR Mutation Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Interventions
| Drug | Synonyms | Arms |
|---|
| Osimertinib | TAGRISSO, AZD9291 | Osimertinib |
Purpose
A multicentre, open-label, single-arm, molecular profiling study of patients with EGFR
mutation-positive locally advanced or metastatic NSCLC treated with osimertinib.
Detailed Description
Study design This is a phase II, open-label, single-arm tissue and plasma acquisition study
assessing the efficacy, safety and underlying resistance mechanisms of osimertinib (80 mg
orally, once daily) as first-line treatment in patients with locally advanced or metastatic
EGFR mutation positive non-small cell lung cancer who are EGFR tyrosine kinase inhibitor
treatment-naïve and eligible for first-line treatment. Participants with EGFR
mutation-positive non-small cell lung cancer will be required to consent to 2 mandatory
tumour biopsies to be considered for enrolment in this study. The first biopsy will be done
prior to initiating treatment with osimertinib and the second biopsy will be obtained any
time between Investigator assessed, Response Evaluation Criteria in Solid Tumours version 1.1
(RECIST 1.1)-defined progression and up to 7 days after the discontinuation of osimertinib. A
third optional biopsy may be taken during the course of treatment at the Investigator's
discretion if the patient consents and if clinically feasible. Tumour tissue and plasma
samples will be collected and examined for genetic and non genetic aberrations that may be
important in determining response and resistance to the treatment that participants will
receive as a part of their cancer care. Patients should continue on osimertinib until
progression or until other treatment discontinuation criteria are met. However, if patients
continue to show clinical benefit to treatment as judged by the Investigator, patients may
continue to receive osimertinib beyond RECIST 1.1-defined progression. Therefore, there is no
maximum duration of treatment. Tumour assessments are to be performed at baseline and then
every 8 weeks until progression. Patients will be followed up for a period of 28 days
following discontinuation of osimertinib. Target patient population Male and female patients
aged 18 years and over with locally advanced or metastatic pathologically confirmed
adenocarcinoma of the lung, not amenable to curative surgery or radiotherapy. Patients will
have a tumour that harbours one of the EGFR mutations known to be associated with EGFR
tyrosine kinase inhibitor sensitivity, either alone or in combination with other EGFR
mutations (EGFR mutation status determined by a local laboratory). Patients must be EGFR
tyrosine kinase inhibitor treatment-naïve and eligible to receive first line treatment with
osimertinib. Osimertinib is an oral, potent, selective, irreversible inhibitor of both EGFR
tyrosine kinase inhibitor sensitizing and resistance mutations in non-small cell lung cancer
with a significant selectivity margin over wild type EGFR. Osimertinib (80 mg orally, once
daily) will be administered. Doses may be reduced to 40 mg if needed.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Osimertinib | Experimental | An oral, potent, selective, irreversible inhibitor of both EGFR tyrosine kinase inhibitor sensitizing and resistance mutations in non-small cell lung cancer | |
Eligibility Criteria
Inclusion Criteria:
1. Provision of informed consent prior
2. Patients aged 18 years or older
3. Patients with histological confirmation of locally advanced or metastatic NSCLC
4. Patients with M1 stage according to the Tumor, Node and Metastasis Classification of
Malignant Tumours (TNM)
5. Patients with an EGFR deletion or mutation known (from tumour biopsy or plasma) to be
associated with EGFR TKI sensitivity
6. Existence of measurable or evaluable disease (as per RECIST 1.1 criteria).
7. Possibility of obtaining sufficient tissue sample, via a biopsy or surgical resection
of the primary tumour or metastatic tumour tissue
8. WHO performance status 0-1
9. Life expectancy ≥12 weeks
10. Capacity to swallow
11. Patients able to complete study and within geographical proximity allowing for
adequate follow up
12. Resolution of all acute toxic effects of previous anticancer therapy
13. Female patients should be using highly effective contraceptive measures, and must have
a negative pregnancy test prior to start of dosing if of childbearing potential
14. Male patients should be willing to use barrier contraception
Exclusion Criteria:
1. Locally advanced lung cancer candidate for curative treatment through radical surgery
and/or radio(chemo)therapy
2. Patients diagnosed with another lung cancer subtype
3. Patients with an EGFR exon 20 insertion
4. Patients with just one measurable or evaluable tumour lesion that has been resected or
irradiated prior to their enrolment in the study
5. Second active neoplasia
6. Treatment with an investigational drug within five half-lives of the compound
7. Participation in another clinical study with an investigational product (IP) during
the last 3 weeks before the first day of study treatment
8. Patients who have received prior immunotherapies
9. Patients who have received prior EGFR treatments for lung cancer
10. Patients who have received prior treatment with an EGFR TKI including in the adjuvant
setting
11. Patients who have received previous treatment for metastatic or stage IV disease
12. Prior treatment with cytotoxic chemotherapy for advanced NSCLC
13. Patients with a history of cancer that has been completely treated, with no evidence
of malignant disease currently cannot be enrolled in the study if their chemotherapy
was completed less than 6 months prior and/or have received a bone marrow transplant
less than 2 years before the first day of study treatment
14. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of
starting study treatment with the exception of alopecia and grade 2, prior
platinum-therapy related neuropathy
15. Any evidence of severe or uncontrolled systemic diseases
16. Patients who have had a surgical procedure unrelated to the study within 14 days or
major surgery within 1 month prior to the administration of the study drug
17. Past medical history of interstitial lung disease, drug-induced interstitial lung
disease, radiation pneumonitis
18. Any of the following cardiac criteria: Mean resting QT interval corrected for heart
rate (QTc) more than 470 msec, obtained from 3 ECGs, 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 and second degree heart block. Any factors that increase the risk
of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia,
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
19. Spinal cord compression, symptomatic and unstable brain metastases except for those
patients who have completed definitive therapy, and have had a stable neurological
status for at least 2 weeks after completion of definitive therapy. 20.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
21.Inadequate bone marrow reserve or organ function 22.Female patients who are
breastfeeding 23.Patients currently receiving medications or herbal supplements known to be
potent inducers of cytochrome P450 24.Patient unwilling to undergo a biopsy at the time of
disease progression 25.History of hypersensitivity to active or inactive excipients of
osimertinib or drugs with a similar chemical structure or class to osimertinib 26.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 27.Involvement in
the planning and/or conduct of the study 28.Previous enrolment in the present study
| Maximum Eligible Age: | 130 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Proportion of patients with a given tumour genetic and proteomic marker at the point of disease progression as defined by the Investigator |
| Time Frame: | Tumour Genetic and Proteomic markers will be assessed from tissue samples collected prior to initiation of treatment and at the time of disease progression for max 4.2 years |
| Safety Issue: | |
| Description: | To characterize the frequency of genetic and proteomic markers at disease progression regardless of their prevalence. |
Secondary Outcome Measures
| Measure: | Progression-free survival (PFS) |
| Time Frame: | At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years |
| Safety Issue: | |
| Description: | PFS is defined as the time from first dose of osimertinib until the date of Investigator assessed RECIST 1.1-defined progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to progression. |
| Measure: | Objective Response Rate (ORR) |
| Time Frame: | At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years |
| Safety Issue: | |
| Description: | ORR is defined as the number (%) of patients with at least one visit response of complete response or partial response that is confirmed at least 4 weeks later. |
| Measure: | Duration of Response (DoR) |
| Time Frame: | From time of first documented response until date of documented progression or death in the absence of disease progression or end of study up to max 4.2 years |
| Safety Issue: | |
| Description: | DoR is defined as the time from the date of first documented response, (that is subsequently confirmed) until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint. |
| Measure: | Time toTreatment Discontinuation or Death (TTD) |
| Time Frame: | At every visit from enrolment to end of treatment or death or end of study for max 4.2 years |
| Safety Issue: | |
| Description: | TTD is defined as the time from the date of first dose of osimertinib to the earliest of treatment discontinuation or death. |
| Measure: | Time to first subsequent therapy or Death (TFST) |
| Time Frame: | At every visit from enrolment to start of first subsequent therapy or death or end of study for max 4.2 years |
| Safety Issue: | |
| Description: | TFST is defined as the time from the date of first dose of osimertinib to the earlier of the date of anticancer therapy start date following study treatment discontinuation, or death. |
| Measure: | Disease Control Rate |
| Time Frame: | At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years |
| Safety Issue: | |
| Description: | Percentage of patients who have a best overall response, complete response, partial response or stable disease. |
| Measure: | PFS in patient subgroups defined by molecular profile |
| Time Frame: | At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years |
| Safety Issue: | |
| Description: | PFS will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, epidermal growth factor receptor (EGFR) Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived circulating tumour deoxyribonucleic acid (ctDNA). |
| Measure: | ORR in patient subgroups defined by molecular profile |
| Time Frame: | At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years |
| Safety Issue: | |
| Description: | ORR will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA. |
| Measure: | TTD in patient subgroups defined by molecular profile |
| Time Frame: | At every visit from enrolment to start of first subsequent therapy or death or end of study for max 4.2 years |
| Safety Issue: | |
| Description: | TTD will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA. |
| Measure: | Tumour shrinkage/depth of response in patient subgroups defined by molecular profile |
| Time Frame: | At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years |
| Safety Issue: | |
| Description: | Tumour shrinkage is defined as the best change from baseline in the sum of diameters of target lesions. Tumour shrinkage/depth of response will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA. |
| Measure: | Proportion of patients with pre-specified characteristics will be summarised by molecular profile |
| Time Frame: | At baseline |
| Safety Issue: | |
| Description: | The patient characteristics will include: gender (male/female), age (<65yrs/>65yrs), race (Asian/non Asian), and WHO Performance Status (0/1). These will be summarized by subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | AstraZeneca |
Trial Keywords
- EGFR, NSCLC, Lung Cancer, Biopsy, Molecular Profiling
Last Updated
July 26, 2021
