Patients With Advanced Non-small Cell Lung Cancer With Meningeal Progression After Osimertinib Treatment
Conditions
Keywords
NSCLC, Leptomeningeal Metastases, Leptomeningeal Carcinomatosis, Meningeal Metastases, EGFR, Osimertinib, Zorifertinib
Brief summary
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.
Interventions
DRUGZorifertinib and Osimertinib Combination Therapy
Zorifertinib 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.
Sponsors
Alpha Biopharma (Jiangsu) Co., Ltd.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For inclusion in the study, patients must meet all of the following criteria. 1. The patient or the guardian is required to understand and sign the informed consent form of this study. 2. 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). 3. 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. 4. 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. 5. Subjects with meningeal progression and brain parenchyma progression are allowed to be enrolled. 6. Subjects must have at least one repeatedly evaluable, measurable target lesion (intracranial and/or extracranial) according to mRECIST 1.1 criteria or a repeatedly evaluable lesion according to RANO-LM criteria. 7. Subjects must be ≥ 18 years old before signing the informed consent form (ICF). 8. If there are neurological symptoms, the following conditions must be met: Able to take and swallow oral medication; No need to increase the hormone dose to enhance control of central nervous system symptoms for at least 1 week before study treatment. If a patient is taking hormone for the purpose of treating endocrine dysfunction or tumor-related symptoms (not central nervous system-related), the dose must be stable or reduced within 5 days before the study medication. Note: The hormone dose should be stable 5 days before the baseline brain MRI. 9. All toxicities related to anti-tumor therapy (including radiotherapy) must have resolved to ≤ Grade 1 (CTCAE 5.0, it is sufficient for neurotoxicity related to platinum treatment to resolve to ≤ Grade 2 \[CTCAE\]) before starting the study treatment. Patients with alopecia of any grade are allowed to be enrolled. 10. The screening period examination of patients must meet the followings: * Neutrophil count ≥ 1.5 x 109/L * Platelet ≥ 100 x 109/L * Hemoglobin ≥ 9 g/dL * Blood creatinine ≤ 1.5 x ULN, or creatinine clearance (Cockcroft-Gault formula) ≥ 50 mL/min * Total bilirubin ≤ 1.5 x ULN (for patients with Gilbert's syndrome or metastases to liver, ≤3 x ULN is acceptable) * Glutamic-oxaloacetic transferase ≤ 2 x ULN (for patients with metastases to liver, ≤ 3 x ULN is acceptable) * Glutamic-pyruvic transaminase ≤ 2 x ULN (for patients with metastases to liver, ≤ 3 x ULN is acceptable) 11. The estimated survival time of subjects is ≥ 6 weeks. 12. Karnofsky Performance Status (KPS) scale score ≥ 60.
Exclusion criteria
Patients must not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determination of Recommended Dose Based on Incidence of Dose-Limiting Toxicities (DLTs) | During the first 21 days of continuous administration for each participant in the dose-escalation phase. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose until last dose (up to 12 months). | Frequency, severity, and relationship to study treatment of all AEs and SAEs. |
| Objective Response Rate (ORR) for Leptomeningeal Metastases (per RANO-LM) | From first dose until disease progression or death from any cause, assessed up to 12 months. | 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. |
| Leptomeningeal Progression-Free Survival (LM-PFS) (per RANO-LM) | From first dose until leptomeningeal progression or death from any cause, assessed up to 12 months. | 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 |
| Leptomeningeal Progression-Free Survival (LM-PFS) Rate at 3, 6, and 9 Months | Assessed at 3, 6, and 9 months from first dose. | Proportion of participants without leptomeningeal progression (as per RANO-LM criteria) at 3, 6, and 9 months after first dose. |
| Overall Survival (OS) Rate at 3, 6, and 9 Months | Assessed at 3, 6, and 9 months from first dose. | Proportion of participants alive at 3, 6, and 9 months after first dose. |
| Cerebrospinal Fluid (CSF) Cytological Response Rate | CSF samples are collected at screening, at Week 6 (Day 22, corresponding to Cycle 2 Day 1 of a 21-day cycle), and every 6 weeks thereafter until disease progression, assessed up to 12 months. | Proportion of participants achieving clearance of tumor cells (conversion from positive to negative cytology) in cerebrospinal fluid (CSF). |
| Complete Response (CR) Rate Based on Neurological Examination | Assessed at screening and at the end of every 21-day treatment cycle until disease progression, assessed up to 12 months. | Proportion of participants achieving a Complete Response (CR) based on protocol-specified neurological examination. |
| Objective Response Rate (ORR) for Overall Tumors (per mRECIST 1.1) | From first dose until disease progression or death from any cause, assessed up to 12 months. | Proportion of participants achieving Complete Response (CR) or Partial Response (PR) in overall systemic tumor burden, as assessed by the investigator using mRECIST 1.1 criteria. |
| Duration of Response (DoR) for Overall Tumors (per mRECIST 1.1) | From first documented response until progression or death, assessed up to 12 months. | Time from the first documented overall tumor response (CR or PR) to the first documented overall disease progression or death due to any cause, whichever occurs first, assessed using mRECIST 1.1 criteria. |
| Progression-Free Survival (PFS) for Overall Tumors (per mRECIST 1.1) | From first dose until overall progression or death, assessed up to 12 months. | Time from first dose to the first documented overall disease progression as per mRECIST 1.1 criteria, or death from any cause, whichever occurs first. |
| Objective Response Rate (ORR) for Intracranial Tumors (per mRECIST 1.1) | From first dose until intracranial disease progression or death from any cause, assessed up to 12 months. | Proportion of participants achieving Complete Response (CR) or Partial Response (PR) in intracranial tumor burden, as assessed by the investigator using mRECIST 1.1 criteria. |
| Duration of Response (DoR) for Intracranial Tumors (per mRECIST 1.1) | From first documented response until intracranial progression or death, assessed up to 12 months. | Time from the first documented intracranial tumor response (CR or PR) to the first documented intracranial disease progression or death due to any cause, whichever occurs first, assessed using mRECIST 1.1 criteria. |
| Change in Neurological Assessment in Neuro-Oncology (NANO) Score | Assessed at screening, on Days 1, 8, 15 (Cycle 1), and at the end of each subsequent 21-day treatment cycle until the End of Treatment visit, assessed up to 12 months. | Change from baseline in the Neurological Assessment in Neuro-Oncology (NANO) score, as specified for leptomeningeal metastasis (NANO-LM). The NANO scale evaluates 9 neurological domains, with an overall response score where higher scores indicate worsening neurological function. |
| Progression-Free Survival (PFS) for Intracranial Tumors (per mRECIST 1.1) | From first dose until intracranial progression or death, assessed up to 12 months. | Time from first dose to the first documented intracranial disease progression as per mRECIST 1.1 criteria, or death from any cause, whichever occurs first. |
Countries
China
Contacts
CONTACTJohn Ge, M.D
Outcome results
None listed