Trial Title:
Aumolertinib Combined Intrathecal Chemotherapy for Leptomeningeal Metastasis From EGFR-Mutated NSCLC and Prognostic Value of Dynamic Changes in cfDNA Profiles
NCT ID:
NCT05810350
Condition:
Non-small Cell Lung Cancer
Conditions: Official terms:
Neoplasm Metastasis
Pemetrexed
Conditions: Keywords:
EGFR
cfDNA
leptomeningeal metastasis
NSCLC
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Aumolertinib
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Aumonertinib 165mg orally once daily and intrathecal chemotherapy with pemetrexed
Description:
Patients receive Aumonertinib 165mg orally once daily and intrathecal chemotherapy with
pemetrexed (30 mg was administered on days 1 and 8) once every 3 weeks.
Arm group label:
aumolertinib combined Ommaya reservoir intrathecal chemotherapy
Summary:
This is a prospective, open-label, single-arm clinical trial. The aim of this study is to
evaluate the efficacy and safety of almonertinib and intrathecal chemotherapy in patients
with advanced EGFR mutation positive (EGFRm+) non-small cell lung cancer (NSCLC) and
leptomeningeal metastasis, and to explore the predictive value of dynamic changes of
cfDNA in cerebrospinal fluid for efficacy and prognosis. A total of 40 subjects who met
the inclusion criteria were enrolled in the study and received almonertinib (165mg, oral,
once a day) combined with intrathecal infusion. Before and after treatment, cerebrospinal
fluid was extracted for cfDNA detection by a 49 gene detection panel. Treatment continued
until disease progression or other discontinuation criteria were met. In addition, the
subjects received regular hematological and imaging examinations to evaluate the
condition. Finally, through data analysis, the progression-free survival (PFS), disease
control rate (DCR), objective response rate (ORR), duration of response (DoR), and
overall survival (OS) of patients with EGFR mutation-positive advanced NSCLC and
leptomeningeal metastasis who received almonertinib combined with intrathecal infusion
chemotherapy were evaluated. The dynamic changes of cfDNA in cerebrospinal fluid before
and after treatment were explored and the correlation between the dynamic changes of
cfDNA in cerebrospinal fluid and the therapeutic effect was explored.
Detailed description:
This study is a prospective, open-label, single-arm clinical trial to explore the
efficacy and safety of almonertinib and intrathecal chemotherapy in patients with
advanced NSCLC and leptomeningeal metastasis and the predictive value of cfDNA changes
for efficacy and prognosis. A total of 40 patients aged 18 years or older with confirmed
advanced NSCLC with leptomeningeal metastases and an EGFR sensitive mutation (exon 19
deletion or 21 L858R) are expected to be enrolled. The intervention was almonertinib
(165mg orally, once daily) combined with intrathecal infusion therapy (pemetrexed 30 mg
by injection on days 1 and 8 of each cycle). Treatment continued until disease
progression or other discontinuation criteria were met.
Relevant examinations and data collection during the study were as follows. CSF
collection: Approximately 15mL of CSF was collected from each sample, and sampling was
performed before C1D1 administration and within one week after PD (24 hours after the
previous day's administration). Venous blood sample collection: subjects who underwent
CSF sampling were performed before C1D1 and C2D1 administration (24 hours after the
previous day's dose) and within 1 week after PD. Before treatment, all enrolled patients
underwent neurological examination, complete blood count, serum biochemistry, coagulation
indexes, blood tumor markers, cytological and CSF tumor markers, electrocardiogram, brain
and spinal cord MRI, chest and abdominal CT, and bone scan. The blood and CSF tests
described above were performed for each treatment cycle. Imaging was performed every 2
months or if clinical progression was suspected until death. Before each intrathecal
infusion, LM-related neurological symptoms, PS score, Neuro-oncology Working Group (RANO)
score, and headache score were assessed and recorded in detail. Adverse events (AEs) were
graded and recorded according to the Common Terminology Criteria for Adverse Events
(CTCAE, version 5.0).
The primary objective was to evaluate the progression-free survival (PFS) of almonertinib
versus intrathecal chemotherapy in patients with advanced EGFR mutation-positive NSCLC
and leptomeningeal metastases. The secondary study objectives were: first, to evaluate
the efficacy of almonertinib and intrathecal chemotherapy in the treatment of advanced
NSCLC with leptomeningeal metastases: disease control rate (DCR), objective response rate
(ORR), duration of response (DoR), and overall survival (OS); Intracranial: intracranial
progression-free survival (iPFS), intracranial disease control rate (iDCR), intracranial
objective response rate (iORR), and intracranial duration of response (iDoR). Second,
evaluate the time to symptom improvement of almonertinib versus intrathecal chemotherapy
in patients with EGFR mutation-positive advanced NSCLC and leptomeningeal metastases.
Third, we evaluated the safety of almonertinib and intrathecal infusion chemotherapy in
patients with EGFR mutation-positive advanced NSCLC and leptomeningeal metastases. The
objectives of this pilot study were as follows: 1) To evaluate the correlation between
baseline and post-treatment cfDNA changes in CSF and treatment response; Second, the
correlation between baseline CSF cfDNA status and patient prognosis; Third, sensitivity
analysis based on baseline CSF cfDNA mutations and leptomeningeal metastases after
targeted therapy.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age at least 18 years old.
- The Eastern Cancer Organization Collaboration Group (ECOG) had a physical fitness
score of 0 to 3, and had not worsened in the previous 2 weeks, with a minimum
expected survival of 12 weeks.
- NSCLC confirmed by histology or cytology, positive cerebrospinal fluid cytology, and
combined with central nervous system function and brain imaging findings, diagnosed
as NSCLC with meningeal metastasis (including advanced patients who had relapsed or
were initially diagnosed after previous surgical treatment; GPA is recommended for
grading and typing in the diagnosis of meningeal metastasis from lung cancer).
- Tumor tissue samples or blood samples were tested and confirmed as EGFR sensitive
mutations (including exon 19 deletion or L858R, both alone or coexisting with other
EGFR site mutations). The first choice is to submit tumor tissue for examination; If
the tumor tissue is inaccessible or the subject is not eligible for tissue biopsy, a
blood sample may be sent for examination.
- The patient has implanted an Ommaya capsule;
- CT examination of clinical symptom areas (spine and/or brain) and/or head within the
past 3 months to rule out contraindications to cerebrospinal fluid examination;
- The subjects agreed to provide two cerebrospinal fluid samples (before treatment and
within one week after disease progression) for genetic testing;
- Women of childbearing age need to take appropriate contraceptive measures and should
not breastfeed three months after screening and discontinuing study treatment.
"Before starting administration, the pregnancy test was negative, or one of the
following criteria was met to demonstrate that there was no risk of pregnancy:
1. Postmenopause is defined as amenorrhea at least 12 months after age greater
than 50 years and cessation of all exogenous hormone replacement therapy.
2. Women younger than 50 years of age may also be considered postmenopausal if
they have amenorrhea for 12 months or more after stopping all exogenous hormone
therapy, and their luteinizing hormone (LH) and follicle stimulating hormone
(FSH) levels are within the laboratory postmenopausal reference values.
3. Have undergone irreversible sterilization surgery, including hysterectomy,
bilateral ovariectomy, or bilateral salpingectomy, except for bilateral tubal
ligation.
- Male subjects should use barrier contraception (i.e., condoms) three months after
screening and discontinuation of study treatment.
- The subject voluntarily participated and signed an informed consent form in writing.
Exclusion Criteria:
- Have received any of the following treatments:
1. Within 4 weeks before the first administration of the investigational drug, the
subject had undergone major surgery (such as craniotomy, thoracotomy, or
laparotomy). The definition of major surgical surgery refers to Level 3 and
Level 4 surgery specified in the "Management Measures for Clinical Application
of Medical Technology" implemented on November 1, 2018;
2. Within 7 days before the first administration of the study drug, a strong
CYP3A4 inhibitor, inducer, or CYP substrate (CYP2C8, CYP2D6, etc.) was used.
3. Subjects with other malignant tumors, excluding basal cell carcinoma of the
skin and carcinoma in situ.
- At the beginning of the study treatment, there was a residual toxicity greater than
CTCAE level 3 that could not be alleviated from previous treatment.
- There are pleural effusion/peritoneal effusion requiring clinical intervention
(patients who do not require drainage of the effusion or who have been stable for 2
weeks or more after drainage can be enrolled); Presence of pericardial effusion
(small amounts of pericardial effusion that are stable for 2 weeks or more are
allowed to be included in the group). If local use (such as thoracic perfusion) of
anti-tumor drugs is used during drainage, and at least 5 drug half-lives or 21 days
(whichever is shorter) must be eluted before the first administration of the study
treatment before enrollment;
- Subjects are unwilling to provide cerebrospinal fluid samples or clinical
information;
- Subjects have contraindications for cerebrospinal fluid examination;
- Previously or currently suffering from primary malignant tumors of the central
nervous system;
- Suffering from autoimmune or inflammatory diseases of the central nervous system
(not limited to multiple sclerosis, neurosarcoidosis, chronic fungal, rickettsial,
or bacterial meningitis);
- Subjects who are allergic to the MRI contrast agent gadolinium or who cannot
tolerate MRI examination (such as having a cardiac pacemaker, having metal in their
body, etc.).
- According to the judgment of the researcher, there are any serious or poorly
controlled systemic diseases, such as poorly controlled hypertension, active
hemorrhagic constitution, or active infection. There is no need to screen for
chronic diseases.
- Clinically severe gastrointestinal dysfunction may affect the intake,
transportation, or absorption of drugs, such as inability to take orally,
uncontrollable nausea or vomiting, a history of extensive gastrointestinal
resection, untreated recurrent diarrhea, atrophic gastritis, untreated stomach
diseases requiring long-term administration of mass pump inhibitors, Crohn's
disease, ulcerative colitis, and so on.
- Hepatic encephalopathy, hepatorenal syndrome, or cirrhosis.
- Meet any of the following cardiac examination results:
1. The mean value of the QT interval (QTcF) corrected by Fridericia's formula from
three electrocardiogram (ECG) examinations at rest is>470 msec;
2. resting ECG indicates conduction or ECG morphological abnormalities (such as
complete left bundle branch block, 3rd degree atrioventricular block, 2nd
degree atrioventricular block, and PR interval>250 msec);
3. The presence of any factors that increase the risk of QTc prolongation or
arrhythmia events, such as heart failure, hypokalemia, congenital long QT
syndrome, a family history of long QT syndrome, or any concomitant medication
that causes unexplained sudden death or prolongs the QT interval in immediate
family members under the age of 40;
4. Left ventricular ejection fraction (LVEF)<50%.
- Insufficient bone marrow reserve or organ function, reaching any of the following
laboratory limits (no corrective treatment within 1 week before laboratory
examination and blood sampling):
1. Absolute neutrophil count<1.5 × 109 / L；
2. Platelet count<100 × 109 / L；
3. Hemoglobin<90 g/L (<9 g/dL);
4. If there is no clear liver metastasis, alanine aminotransferase is>3 times the
upper normal limit (ULN); If there is liver metastasis, alanine
aminotransferase>5 × ULN；
5. If there is no clear liver metastasis, aspartate aminotransferase>3 × ULN； If
there is liver metastasis, aspartate aminotransferase>5 × ULN；
6. If there is no clear liver metastasis, total bilirubin>1.5 × ULN； Or presence
of Gilbert syndrome (unconjugated hyperbilirubinemia) or liver metastasis with
total bilirubin>3 × ULN；
7. Creatinine>1.5 × ULN and creatinine clearance<50 mL/min (calculated using the
Cockcroft Gault formula); Only when creatinine>1.5 × It is only necessary to
confirm the creatinine clearance rate at ULN;
8. Serum albumin (ALB)<28 g/L.
- Active fungal, bacterial, and/or viral infections that require systemic treatment.
- Female subjects who are pregnant, nursing, or planning to become pregnant during the
study period.
- Have a history of interstitial lung disease, a history of drug-induced interstitial
lung disease, a history of radiation pneumonia requiring steroid treatment, or any
evidence of clinically active interstitial lung disease.
- A history of hypersensitivity to any active or inactive component of aumolertinib,
or to drugs with a chemical structure similar to or in the same category as
aumolertinib.
- Patients who are allergic to or contraindicated to pemetrexed.
- Any serious or uncontrolled ocular lesions (especially severe dry eye syndrome, dry
corneal conjunctivitis, severe exposure keratitis, or other diseases that may
increase epithelial damage) that, in the judgment of a doctor, may increase the
safety risk of the subject; Or eye abnormalities that require surgery or are
expected to require surgical treatment during the study period.
- Subjects who, according to the judgment of the investigator, may have poor
compliance with the research procedures and requirements, such as having a clear
history of neurological or mental disorders (including epilepsy or dementia), or
currently suffering from mental disorders.
- The investigator determines that there are any conditions that endanger the safety
of the subject or interfere with the evaluation of the study, or other conditions
that the researcher believes are not suitable for enrollment.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
chongqing University Three Gorges Hospital
Address:
City:
Chongqing
Country:
China
Status:
Recruiting
Contact:
Last name:
Wei Wang
Start date:
January 1, 2023
Completion date:
December 31, 2024
Lead sponsor:
Agency:
Three Gorges Hospital of Chongqing University
Agency class:
Other
Source:
Three Gorges Hospital of Chongqing University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05810350
