Clinical trial NCT03801200: Apatinib Combined With Radiotherapy in Patient With BM From Drive Gene Negative NSCLC
Official title: A Prospective, Multicenter, Randomized Controlled Trial of Apatinib Combined With Radiotherapy in Patient With Brain Metastases From Drive Gene Negative NSCLC
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: NSCLC
Keywords: Brain metastasis
Apatinib
Radiotherapy
NSCLC
Drive gene negative
Lead sponsor: Hubei Cancer Hospital
Sponsor class: OTHER
First posted: 2019-01-11
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of concurrent radiotherapy with Apatinib in patients with Brain Metastases from drive gene wide-type Non-small-cell Lung Cancer (NSCLC).

Detailed description: Brain metastases (BM) develop in 22-54% of NSCLC patients during the disease course. NSCLC patients with BM with a median overall survival (OS) of 2-3 months when treated with systemic corticosteroid alone, and a median OS of 3-6 months when treated with whole brain radiation therapy (WBRT). Recently, several studies have reported the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for EGFR mutation NSCLC patients with BM. The median OS of EGFR mutation patients with BM significantly improved with TKIs treatment, which ranged from 11.8 to 18.8 months. However, for the EGFR wide-type NSCLC patients with BM, the prognosis remains poor.

It was found that the combination of anti-VEGF drugs and brain radiotherapy can not only reduce the volume of peritumoral brain edema (PTBE), reduce the intracranial pressure, relieve the symptoms of nerve compression, reduce the risk of brain hernia during brain radiotherapy, and but also inhibit the hypoxia of tumor cells, increase the radiosensitivity of tumor cells, and ultimately improve the efficacy of radiotherapy.

Apatinib, a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor (VEGFR) and mildly inhibits c-Kit and c-SRC, has been reported to show efficacy among some patients with malignant supratentorial gliomas.

Therefore, the investigators initiated this study to evaluate the efficacy and safety of concurrent radiotherapy with Apatinib in patients with Brain Metastases from drive gene wide-type Non-small-cell Lung Cancer (NSCLC).

Eligibility criteria: Inclusion Criteria:

1. Age 18-75 years old, male or female, signed informed consent;
2. The primary lesion is confirmed by histopathology. The patient with brain metastases confirmed by histopathology or imaging confirmed the brain metastases. All patients with non-small cell lung cancer brain metastases should be recommended for EGFR mutation and ALK gene rearrangement assay，exclusion of patients with NSCLC brain metastases with positive EGFR-sensitive mutations and ALK gene rearrangement detection for TKI treatment; After multidisciplinary consultation and evaluation, patients with single or local multiple metastatic tumors with well-controlled primary lesions, who have the economic ability and are willing to undergo surgery for brain metastatic tumors were excluded.
3. Observable imaging data such as CT, MRI, etc., have measurable lesions as defined by RECIST 1.1 (R09-0262);
4. ECOG PS score: 0-2;
5. Hemogram index: RBC≥3.0×1012/L, WBC≥3.5×109/L, ANC≥1.5×109/L, PLT≥100×109/L, Hb≥90g/L
6. the expected survival time ≥ 3 months
7. Renal function: Cr≤1.2×UNL (upper limit of normal value);
8. Liver function: total bilirubin ≤ 1.5 × UNL; ALT, AST ≤ 1.5 × UNL

Exclusion Criteria:

1. . Allergies, known to be hypersensitive to any excipients in the study drug. ;
2. . Patients with recurrent brain metastases have previously received brain radiation therapy
3. . Patients with high fever and acute infection;
4. . Patients with active, progressive bleeding or a significant bleeding tendency in the primary lesion;
5. . Participated in any clinical trial of research drugs within 4 weeks prior to enrollment
6. . Diarrhea is the main symptom of the important or newly diagnosed acute gastrointestinal diseases, such as Crohn's disease, malabsorption or any cause of CTC ≥ 2 grade diarrhea.
7. . Current clinically relevant cardiovascular disease or medical history, such as refractory hypertension, NYHA grade 3 congestive heart failure, unstable angina or poorly controlled arrhythmias. Myocardial infarction occurred 6 months before randomization.
8. . Absolute neutrophil count \<1000/mm3;
9. . Platelet count \<50000/mm3;
10. . According to the investigator's point of view, any other serious disease or organ system dysfunction that may affect patient safety or interfere with the safety assessment of the test drug, such as proteinuria (CTCAE4.0-≥3), severe liver and kidney dysfunction (CTCAE4.0-≥3), hand-foot syndrome (CTCAE4.0-≥3) and so on.
11. . There are ulcers, intestinal perforations, and intestinal obstruction.
12. . Pregnant and lactating women
13. . Suspected or indeed have a history of alcohol and drug abuse

Primary outcomes:
measure: Intracranial progression-free survival (iPFS)
timeFrame: Evaluated in 24 months since the treatment began
Secondary outcomes:
measure: Disease control rate (DCR)
timeFrame: 4 weeks after Radiotherapy.
measure: Objective response rate (ORR)
timeFrame: 4 weeks after Radiotherapy.
measure: intracranial time to progress (ITTP)
timeFrame: Tumor assesment at 4 weeks and 12 weeks after radiotherapy, and then every 12 weeks, up to 24 months
measure: Overall survival (OS)
timeFrame: Tumor assesment at 4 weeks and 12 weeks after radiotherapy, and then every 12 weeks, up to 24 months
measure: Rate of Peritumoalbrainedema (PTBE)
timeFrame: 4 weeks after Radiotherapy.
Other outcomes:
Locations:
city: Wuhan
country: China
facility: Hubei Cancer hospital
state: Hubei
Study officials:
affiliation: Associate dean
name: Desheng Hu
role: STUDY_DIRECTOR
References:
citation: Ma J, Pi G, Bi J, Li Y, He H, Li Y, Hu D, Verma V, Han G. Concurrent Apatinib and Brain Radiotherapy in Patients With Brain Metastases From Driver Mutation-negative Non-small-cell Lung Cancer: Study Protocol for an Open-label Randomized Controlled Trial. Clin Lung Cancer. 2021 Mar;22(2):e211-e214. doi: 10.1016/j.cllc.2020.10.007. Epub 2020 Oct 21.