A Randomised Controlled Trial to Investigate the Neurocognition in EGFR-mutant Advanced Non-small Cell Lung Cancer Patients With Symptomatic Brain Metastases Treated With Osimertinib or Osimertinib Plus Whole-brain Irradiation (WBI)
Overview
- Phase
- Phase 2
- Intervention
- Osimertinib and whole-brain irradiation
- Conditions
- Neurocognitive
- Sponsor
- Sun Yat-sen University
- Enrollment
- 88
- Locations
- 1
- Primary Endpoint
- neurocognitive function (HVLT-R)
- Status
- Recruiting
- Last Updated
- 5 years ago
Overview
Brief Summary
This is a prospective, randomised, positive-controlled, study to assess the neurocognitive function of upfront Osimertinib compared to whole-brain irradiation (WBI) plus Osimertinib in EGFR-mutant (Ex 19Del and L858R) NSCLC patients with symptomatic brain metastases, as well as the efficacy and safety.
Detailed Description
Account for patients with wild type EGFR, sample attrition , incidence rate of symptomatic brain metastasis(10%) and any other reasons for screen failure rate(50%), it is esimated that 88 patients will be randomized from 5 sites. Patients will be randomized 1:1, the experimental arm is upfront Osimertinib with WBI sequential therapy, while the control arm is Osimertinib plus WBI. Osimertinib at a dose of 80 mg once per day, until unacceptable adverse events or disease progression occurred. WBI could be given to patients in experimental arm at any time base on investigator's decision after treatment initiated. Patients will be stratifed at randomization by GPA score (3.5-4 vs \<3.5) and the mutation type (Ex19Del / L858R). Patients will undergo the neurocognition, efficacy and safety assessments at baseline, and every 8 weeks until treatment is completed or discontinued. About time to brain metastases symptoms deterioration, the assessment was repeated in the first week (on site), second week (through telephone) and fourth week (on site). The rest assessment will be as well as other evaluations repeated every 8 weeks. To evaluate the correlation and predictive or prognostic value between gene dynamic changes and clinical efficacy, the tissue, plasma and cerebrospinal fluid (CSF) samples will be collected at baseline. CSF will be collected in patients with intracranial progression. Plasma will be collected in all the patients at disease progression, while tissue is optional. Also, plasma will be collected at week 8(first evaluation of efficacy).
Investigators
Li Zhang, MD
Professor
Sun Yat-sen University
Eligibility Criteria
Inclusion Criteria
- •Provision of informed consent prior to any study specific procedures
- •Male or female, aged at least 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1
- •Life expectancy of at least 3 months
- •Histologically or cytologically documented metastatic NSCLC, which are not amenable to curative surgery or radiotherapy, patients must be classified as stage IIIB-IV. Staging will be according to the TNM staging system for lung cancer (8th edition)
- •Histologically documented that with sensitizing EGFR mutations(either L858R or Exon19del)
- •symptomatic brain metastasis, with at least three metastatic lesions in the brain which need WBI based on investigator's decision. Symptom score 1-6 point.(notes: Symptomatic definition: Symptoms without acute intervention or hospitalization, symptoms including but not limited in headache, nausea, dizziness, and sensory disturbance, but without hospitalization or medical emergency.)
- •HVLT-R score 15 point (Notes: this number is based on the data in a study in Chinese population)
- •At least 1 measurable lesion in the brain according to RECIST 1.1; At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter with computed tomography (CT) or magnetic resonance imaging (MRI).
- •No previous treatment with EGFR-TKI or other systemic treatment, as well as radiotherapy for brain metastases.
Exclusion Criteria
- •Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
- •Previous randomisation in the present study or previous treatment with osimertinib
- •Leptomeningeal met alone or synchronously is not allowed
- •History of hypersensitivity to active or inactive excipients of Osimertinib or drugs with similar chemical structure or class to Osimertinib
- •For patients, inability to collect plasma, CSF and tissue at baseline
- •Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
- •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 (at least 3 week prior) (Appendix D). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A
- •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.
- •Any of the following cardiac criteria:
- •Mean resting corrected QT interval (QTc) \> 470 msec obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value (Note: patients with congenital long QT syndrome (CLQTS) are excluded from this study.)
Arms & Interventions
whole-brain irradiation (WBI) plus Osimertinib
Osimertinib plus WBI, with Osimertinib at a dose of 80 mg once per day.
Intervention: Osimertinib and whole-brain irradiation
Osimertinib
Osimertinib with WBI sequential therapy, with Osimertinib at a dose of 80 mg once per day.
Intervention: Osimertinib
Outcomes
Primary Outcomes
neurocognitive function (HVLT-R)
Time Frame: at 4 months
measured as a significant deterioration (5-point drop compared with baseline) in Hopkins Verbal Learning Test-Revised (HVLT-R) total recall at 4 months
Secondary Outcomes
- intracranial overall response rate(assessed up to 60 months)
- intracranial disease control rate(assessed up to 60 months)
- Time to initiate WBI(assessed up to 36 months)
- intracranial progression-free survival(assessed up to 36 months)
- disease control rate(assessed up to 60 months)
- intracranial Duration of Response(assessed up to 60 months)
- Duration of Response(assessed up to 60 months)
- progression-free survival(assessed up to 36 months)
- overall response rate(assessed up to 60 months)