EGFR Activating Mutation, Leptomeningeal Metastasis, NSCLC
Conditions
Keywords
Leptomeningeal Metastasis, Non-Small Cell Lung Cancer, EGFR Activating Mutation, Almonertinib, Bevacizumab
Brief summary
A prospective, open-label, multi-center, single-arm study of Almonertinib combined With Bevacizumab for EGFR-mutant NSCLC patients with leptomeningeal metastasis.
Detailed description
This is a prospective, open-label, multi-center, single-arm study to evaluate the efficacy and safety of Almonertinib combined with Bevacizumab for EGFR-mutant NSCLC patients with leptomeningeal metastasis. ALL patients were treated with Almonertinib 110mg oral daily and Bevacizumab 15mg/kg intravenous every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent.
Interventions
DRUGAlmonertinib
110 mg oral once daily
DRUGBevacizumab
15 mg/kg intravenous on Day 1 of 21 day cycles (every 3 weeks)
Sponsors
Jiangsu Hansoh Pharmaceutical Co., Ltd.
Second Affiliated Hospital of Nanchang University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, age in 18-75 years. 2. The Eastern Cooperative Oncology Group (ECOG) physical status score is 0-2 and has not deteriorated in the previous 2 weeks, with a minimum expected survival of 12 weeks. 3. Histologically confirmed patients with NSCLC leptomeningeal metastasis by positive cerebrospinal fluid cytological examination. 4. Tumor tissue samples or blood are confirmed to be EGFR sensitive mutations (including exon 19 deletion or L858R). 5. There must be at least one measurable extracranial lesion that has not been locally treated at the time of enrollment. 6. Females should be using adequate contraceptive measures throughout the study; should not be breastfeeding at the time of screening, during the study and until 3 months after completion of the study; and must have a negative pregnancy test prior to start of dosing if of childbearing potential or must have evidence of non-childbearing potential by fulfilling 1 of the following criteria at Screening: a) Postmenopausal defined as age more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments. b) Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more, following cessation of exogenous hormonal treatments, and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory. c) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not by tubal ligation. 7. Male patients should be willing to use barrier contraception (i.e., condoms). 8. For inclusion in study, patient must provide a written informed consent.
Exclusion criteria
1. Treatment with any of the following: a) Prior treatment with systemic anti-cancer therapy for locally advancer or metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug. b) Prior treatment with an EGFR TKI. c) Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug. d) Radiotherapy with a limited field of radiation for palliation within 4 week of the first dose of study drug, with the exception of patients receiving radiation to \> 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug. e) Medications that are predominantly CYP3A4 strong inhibitors or inducers or sensitive substrates of CYP3A4 with a narrow therapeutic range within 7 days of the first dose of study drug. 2. Patients with other malignancies, except basal cell carcinoma and carcinoma in situ. 3. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment, with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy. 4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension or active bleeding diatheses, which, in the Investigator's opinion, makes it undesirable for the patient to participate in the trial OR which would jeopardize compliance with the protocol such as active infection. Screening for chronic conditions is not required.. 5. Refractory nausea, vomiting, or chronic gastrointestinal diseases, inability to swallow the study drug, or previous significant bowel resection that would preclude adequate absorption of Almonertinib. 6. Any of the following cardiac criteria: a) Mean resting corrected QT interval (QTc) \> 470 ms obtained from 3 electrocardiograms (ECGs), using the screening clinic's ECG machine and Fridericia's formula for QT interval correction (QTcF). b) Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval \> 250 ms). c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, 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. d) Left ventricular ejection fraction (LVEF)\< 50%. 7. Inadequate bone marrow reserve or organ function, as demonstrated by any of the following laboratory values: a) Absolute neutrophil count (ANC) \<1.5×10\^9 / L. b) Platelet count \<100×10\^9 / L. c) Hemoglobin \<90 g/L (\<9 g/dL). d) Alanine aminotransferase \> 2.5 × upper limit of normal (ULN) if no demonstrable liver metastases or \> 5 × ULN in the presence of liver metastases. e) Aspartate aminotransferase (AST) \> 2.5 × ULN if no demonstrable liver metastases or \> 5 × ULN in the presence of liver metastases. f) Total bilirubin (TBL) \> 1.5 × ULN if no liver metastases or \> 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases. g) Creatinine \> 1.5 × ULN concurrent with creatinine clearance \< 50 mL/min (measured or calculated by the Cockcroft-Gault equation); confirmation of creatinine clearance is only required when creatinine is \> 1.5 × ULN. h) ALB \<28 g/L. 8. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis that required steroid treatment, or any evidence of clinically active interstitial lung disease. 9. Women who are breastfeeding or have a positive urine or serum pregnancy test at the Screening Visit. 10. History of hypersensitivity to any active or inactive ingredient of Almonertinib, or to drugs with a similar chemical structure or class to Almonertinib. 11. 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. 12. Any severe and uncontrolled ocular disease that may, in the ophthalmologist's opinion, present a specific risk to the patient's safety. 13. Any disease or condition that, in the opinion of the Investigator, would compromise the safety of the patient or interfere with study assessments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From date of enrollment until the date of death, up to 2 years | OS is the time from the date of enrollment until death due to any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Symptom Resolution | From baseline, then every 3 weeks, up to 2 years | Time to symptom resolution is the time from first drug dosage date (C1D1) until the date of symptom resolution |
| Progression Free Survival (PFS) | From baseline, then every 6 weeks, up to 2 years | PFS is the time from date of enrollment until the date of PD (by investigator assessment) or death |
| Objective Response Rate (ORR) | From baseline, then every 6 weeks, up to 2 years | ORR is the proportion of patients with a best overall response of complete response or partial response (CR+PR) |
| Disease Control Rate (DCR) | From baseline, then every 6 weeks, up to 2 years | DCR is the proportion of patients with a best overall response of complete response, partial response or stable disease(CR+PR+SD) |
| Duration of Response (DoR) | From baseline, then every 6 weeks, up to 2 years | DoR is the time from date of first documented response until the date of PD (by investigator assessment) or death |
| Intracranial Progression Free Survival (iPFS) | From baseline, then every 6 weeks, up to 2 years | Intracranial progression-free survival |
| Intracranial Objective Response Rate (iORR) | From baseline, then every 6 weeks, up to 2 years | Intracranial objective response rate |
| Intracranial Duration of Response (iDoR) | From baseline, then every 6 weeks, up to 2 years | Intracranial duration of response |
| Extracranial Progression Free Survival (ePFS) | From baseline, then every 6 weeks, up to 2 years | Extracranial progression-free survival |
| Extracranial Objective Response Rate (eORR) | From baseline, then every 6 weeks, up to 2 years | Extracranial objective response rate |
| Extracranial Disease Control Rate (eDCR) | From baseline, then every 6 weeks, up to 2 years | Extracranial disease control rate |
| Extracranial Duration of Response (eDoR) | From baseline, then every 6 weeks, up to 2 years | Extracranial duration of response |
| Assess the safety of Almonertinib Combined With Bevacizumab | From baseline, then every 3 weeks, up to 2 years | Number of adverse events (AEs)/serious adverse events (SAEs) |
| Intracranial Disease Control Rate (iDCR) | From baseline, then every 6 weeks, up to 2 years | Intracranial disease control rate |
Other
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the correlation between the results of CSF genetic testing and drug resistance mechanisms | CSF samples will be collected on Cycle 1 Day 1, Cycle 2 Day 1 and within one week after disease progression (each cycle is 21 days) | Evaluate the correlation between the results of CSF genetic testing and drug resistance mechanisms |
Countries
China
Contacts
Primary ContactLiu Anwen, PhD
Backup ContactHuang Long, PhD
Outcome results
None listed