Clinical trial NCT04944069: Almonertinib With Bevacizumab for EGFR-Mutant NSCLC Patients With Leptomeningeal Metastasis
Official title: Almonertinib Combined With Bevacizumab for EGFR-Mutant NSCLC Patients With Leptomeningeal Metastasis: A Prospective, Open-label, Multi-center, Single-arm Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: NSCLC
Leptomeningeal Metastasis
EGFR Activating Mutation
Keywords: Leptomeningeal Metastasis
Non-Small Cell Lung Cancer
EGFR Activating Mutation
Almonertinib
Bevacizumab
Lead sponsor: Second Affiliated Hospital of Nanchang University
Sponsor class: OTHER
Collaborators: name: Jiangsu Hansoh Pharmaceutical Co., Ltd.
First posted: 2021-06-29
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From date of enrollment until the date of death, up to 2 years
Secondary outcomes:
measure: Time to Symptom Resolution
timeFrame: From baseline, then every 3 weeks, up to 2 years
measure: Progression Free Survival (PFS)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Objective Response Rate (ORR)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Disease Control Rate (DCR)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Duration of Response (DoR)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Intracranial Progression Free Survival (iPFS)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Intracranial Objective Response Rate (iORR)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Intracranial Disease Control Rate (iDCR)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Intracranial Duration of Response (iDoR)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Extracranial Progression Free Survival (ePFS)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Extracranial Objective Response Rate (eORR)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Extracranial Disease Control Rate (eDCR)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Extracranial Duration of Response (eDoR)
timeFrame: From baseline, then every 6 weeks, up to 2 years
measure: Assess the safety of Almonertinib Combined With Bevacizumab
timeFrame: From baseline, then every 3 weeks, up to 2 years
Other outcomes:
measure: Evaluate the correlation between the results of CSF genetic testing and drug resistance mechanisms
timeFrame: 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)
Locations:
city: Nanchang
country: China
facility: The Second Afiliated Hospital of Nanchang University
state: Jiangxi
Study officials:
affiliation: Second Affiliated Hospital of Nanchang University
name: Liu Anwen, PhD
role: STUDY_DIRECTOR
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