AZD9291, Brain Metastases, EGFR-TKI Resistant Mutation, Nonsmall Cell Lung Cancer
Conditions
Brief summary
The study aims to investigate the efficacy and safety of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.
Detailed description
Patients with confirmed EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI and concurrent with brain metastasis will be enrolled into the study. All eligible patients will have access to AZD9291 regimen through the ASTRIS study as long as they continue to show clinical benefit.
Interventions
DRUGAZD9291 80mg oral each day
All eligible patients will have access to AZD9291 regimen through the ASTRIS study as long as they continue to show clinical benefit.
RADIATIONRadiation therapy
Radiation therapy will be implemented according to investigator's clinical practice.Based on the guidelines provided for the interruption of ADZ9291 with brain radiation therapy, a 7-10 days washout period before radiotherapy and 1 week period after completion of brain radiothearpy before re-starting AZD9291.
Sponsors
AstraZeneca
Shandong Cancer Hospital and Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated written informed consent by the patient or legally acceptable representative prior to any study-specific procedures 2. Metastatic (stage IV) EGFRm NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation. 3. For patients with LM: Confirmed diagnosis of LM by positive CSF cytology. Diagnosis by MRI only is not eligible for study entry. At least one site of CNS leptomeningeal disease that can be assessed by magnetic resonance imaging (MRI) and which is suitable for repeat assessments. Measurable CNS or extracranial disease is not required. 4. For patients with measurable BM but without LM: At least one measurable intracranial lesion that, if previously irradiated, has progressed or not responded to radiation therapy, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter by magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements. Measurable extracranial disease is not required. 5. Prior therapy with an EGFR-TKI. Patients may have also received additional lines of treatment. 6. World Health Organization (WHO) performance status 0-2 with no deterioration over the previous 2 weeks and a minimum life expectancy of 3 months. 7. Adequate bone marrow reserve and organ function as demonstrated by complete blood count, biochemistry in blood and urine at baseline. 8. ECG recording at baseline showing absence of any cardiac abnormality as per exclusion criterion #10. 9. Female patients of childbearing potential must be using adequate contraceptive measures (see Restrictions, Section 3.5), must not be breast feeding, and must have a negative pregnancy test prior to start of dosing. Otherwise, they must have evidence of nonchild bearing potential as defined below: 1. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments 2. Women less than 50 years would be consider post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution 3. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 10. Male patients must be willing to use barrier contraception, i.e., condoms.
Exclusion criteria
Subjects should not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFSo (overall progression free survival) | 2 years | To assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI by PFSo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORRo (overall objective response rate) | 2 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| DCRe (extracranial disease control rate) | 2 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| DCRi (intracranial disease control rate) | 2 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| DoRo (overall duration of response) | 3 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| OS(overall survival) | 3 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| Adverse events/Serious adverse events | 2 years | To evaluate the safety and tolerability profile of AZD9291 and subgroups such as AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy and etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI. |
| QoL | 2 years | To assess disease-related symptoms and QoL in overall population as well as in pre-specified subgroups, e.g. AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI. |
| Cognitive function | 2 years | To assess disease-related symptoms and cognitive function in overall population as well as in pre-specified subgroups, e.g. AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI. |
| DoRe (extracranial duration of response) | 2 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| DoRi (intracranial duration of response) | 2 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| PFSe (extracranial progression-free survival) | 2 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| PFSi (intracranial progression-free survival) | 2 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| ORRe (extracranial objective response rate) | 2 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| ORRi (intracranial objective response rate) | 2 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
| DCRo (overall disease control rate) | 2 years | To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change of imputed ctDNA concentration before and after treatment | 2 years | To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples. |
| Proportion of each genetic mutation | 2 years | To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples. |
| Change from baseline in glucose and protein levels | 2 years | To evaluate the changes from baseline in CSF biochemistry to support the demonstration of the anti-tumour effect of AZD9291 in addition to CSF cytology. |
| Change from baseline in tumor cell count | 2 years | To evaluate the changes from baseline in CSF biochemistry to support the demonstration of the anti-tumour effect of AZD9291 in addition to CSF cytology. |
| AZD9291 concentration level in CSF/plasma | 2 years | To explore potential relation between relevant efficacy measures, biomarkers or safety variables and plasma or CSF concentration of AZD9291 (or metabolites). |
| T790M mutation positive rate | 2 years | To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples. |
| Concordance of T790M status between CSF and plasma | 2 years | To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples. |
Contacts
Primary ContactJinming Yu, MD.PhD.
Backup ContactLigang Xing, MD.PhD.
Outcome results
None listed