Zorifertinib With Osimertinib for NSCLC With Meningeal Progression
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorAlpha Biopharma (Jiangsu) Co., Ltd.
About this trial
This is a clinical trial that aims to test Zorifertinib when used together with a known drug, Osimertinib. The goal is to learn if this combination is safe and works for people with advanced Non-Small Cell Lung Cancer (NSCLC) whose cancer has spread to the membranes surrounding the brain and spinal cord (a condition called leptomeningeal metastases) after being treated with Osimertinib.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
The patient or the guardian is required to understand and sign the informed consent form of this study.
During the screening period, subjects must have a previous histological or cytological diagnosis of NSCLC with a sensitising EGFR mutation (including L858R and/or Exon19Del).
Only patients who have developed meningeal progression after osimertinib treatment (at a standard dose of 80 mg QD; if the dose is 160 mg QD, it must be reduced to 80 mg QD for at least 1 week before receiving study treatment) (new-onset meningeal progression, or patients with existing meningeal progression that is poorly controlled using osimertinib combined with available conventional treatment [CNS symptoms not relieved or CSF cytology not turning negative], but the available conventional treatment must be washed out for at least 4 weeks) and have no extracranial progression are allowed to be enrolled.
Subjects with leptomeningeal metastases should have the positive results of cerebrospinal fluid (CSF) cytology. Subjects with negative CSF cytology but highly suspected of leptomeningeal metastases in combination with CSF biochemical test and brain or spinal cord MRI imaging examination are allowed to be enrolled into the study.
Disqualifiers
Subjects who plan to receive brain radiotherapy or intrathecal injection during the period from signing ICF to study medication.
Radiotherapy history within 28 days before study drug administration is not allowed for enrollment, and palliative radiation to the skeleton occurring within 14 days before study drug administration is also not allowed for enrollment.
Subjects who have undergone major surgery (e.g. intrathoracic, intraperitoneal or pelvic surgery) within 4 weeks prior to the first dose of study treatment or who have not yet recovered from the side effects associated with such surgery are not allowed to be enrolled.
In addition to NSCLC, there are other malignant tumors, or a history of other malignant tumors within 5 years, except for the following cases: Complete resection of skin basal cell and squamous cell carcinoma and radical resection of any type of carcinoma in situ.
Trial design
Design model
Sequential
Treatments tested in this trial
Zorifertinib and Osimertinib Combination Therapy
DrugZorifertinib is an oral tablet (50 mg or 100 mg). Osimertinib is an oral tablet (80 mg). In this Phase 1 study, all participants will receive the combination. Osimertinib is given at a fixed dose of 80 mg once daily. Zorifertinib is given twice daily, with dose levels under evaluation (starting at 100 mg BID, potentially escalating to 150 mg BID, 200 mg BID, or higher). Dose escalation follows a "3+3" design based on dose-limiting toxicity (DLT) assessment in the first 21-day cycle. Treatment continues until disease progression, unacceptable toxicity, or meeting other discontinuation criteria.
Treatment groups
42 Participants
are divided into 1 treatment groupGroup A: Zorifertinib + Osimertinib (Dose Escalation)Experimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Determination of Recommended Dose Based on Incidence of Dose-Limiting Toxicities (DLTs)
A composite endpoint to determine the recommended dose of Zorifertinib in combination with Osimertinib. This is based on the occurrence of protocol-defined Dose-Limiting Toxicities (DLTs) within treatment. The Recommended Dose (RD) is the highest dose level at which the DLT rate is deemed acceptable by the Safety Review Committee (SRC) for further evaluation in the expansion cohort.
Time frame
During the first 21 days of continuous administration for each participant in the dose-escalation phase.Secondary outcomes
1
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Frequency, severity, and relationship to study treatment of all AEs and SAEs.
Time frame
From first dose until last dose (up to 12 months).2
Objective Response Rate (ORR) for Leptomeningeal Metastases (per RANO-LM)
Proportion of participants with leptomeningeal disease achieving a Complete Response (CR) or Partial Response (PR) as assessed by the investigator according to RANO-LM neuroimaging criteria.
Time frame
From first dose until disease progression or death from any cause, assessed up to 12 months.3
Leptomeningeal Progression-Free Survival (LM-PFS) (per RANO-LM)
Time from first dose to the first documented progression in the leptomeninges according to RANO-LM criteria, or death from any cause, whichever occurs first
Time frame
From first dose until leptomeningeal progression or death from any cause, assessed up to 12 months.4
Leptomeningeal Progression-Free Survival (LM-PFS) Rate at 3, 6, and 9 Months
Proportion of participants without leptomeningeal progression (as per RANO-LM criteria) at 3, 6, and 9 months after first dose.
Time frame
Assessed at 3, 6, and 9 months from first dose.Other outcomes
1
Correlation of Biomarker Status in Cerebrospinal Fluid (CSF) with Clinical Efficacy
The correlation between the presence/level of specific biomarkers (e.g., genetic alterations) in cerebrospinal fluid (CSF) and clinical efficacy outcomes (e.g., objective response rate, progression-free survival).
Time frame
CSF samples for analysis are collected at Screening, at Week 6 (Cycle 2 Day 1 of a 21-day cycle), and at the time of suspected disease progression; efficacy outcomes are assessed throughout the study, up to 12 months.Sponsors and contacts
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Source ClinicalTrials.gov