Trial Title:
Trametinib Plus Anlotinib Combined With Tislelizumab in KRAS-mutant NSCLC
NCT ID:
NCT06456138
Condition:
KRAS Mutation-Related Tumors
Advanced Lung Cancer
Refractory Tumor
Conditions: Official terms:
Lung Neoplasms
Tislelizumab
Trametinib
Conditions: Keywords:
KRAS-mutant NSCLC
Trametinib
Anlotinib
Tislelizumab
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Trametinib
Description:
Trametinib will be administrated orally every day.
Arm group label:
Trametinib + Anlotinib + Tislelizumab
Intervention type:
Drug
Intervention name:
Anlotinib
Description:
Anlotinib will be administrated orally from day 1 to day 14 per 21-day cycle.
Arm group label:
Trametinib + Anlotinib + Tislelizumab
Intervention type:
Drug
Intervention name:
Tislelizumab
Description:
Tislelizumab will be administered at full dose (200mg, Q3W) on the patient who received
the efficacy evaluation of stable disease (SD) or partial response (PR) or complete
response (CR) after 2 cycles' treatment of trametinib plus anlotinib.
Arm group label:
Trametinib + Anlotinib + Tislelizumab
Summary:
Lung cancer is the most common cause of cancer-related death worldwide. Approximately 85%
to 90% of lung cancer cases are non-small cell lung cancer (NSCLC), of which KRAS is one
of the most common driver genes, occurring in 25-30% of lung adenocarcinomas and 3-5% of
squamous cell carcinomas. KRAS-mutant NSCLC had been considered undruggable in past
decades. This research sought to address a significant challenge in treating NSCLC with
KRAS mutations, which are notoriously difficult to target effectively. Here, we proposal
that the combined use of anlotinib and trametinib combined with tislelizumab may form an
effective strategy for the treatment of KRAS-mutant NSCLC patients.
Detailed description:
This is a phase 1/2, open-label, multi-center study aimed at exploring the potential
therapeutic efficacy of tislelizumab (intravenous), trametinib (oral) and anlotinib
(oral) in KRAS-mutant advanced non-small cell lung cancer patients. The primary
objectives were safety, recommended phase 2 dose (RP2D) in Phase I and PFS in Phase II.
The secondary aim of the study is to evaluate the progression-free survival (PFS),
overall survival (OS), adverse events (AEs), and duration of response (DOR) of the
combined strategy in these patients. If the RP2D is reached in Phase I, Phase II will be
started; if RP2D is not reached in Phase I, Phase II will not be started. The number of
subjects is determined according to the actual situation of dose climbing. All patients
will be of histo- and/or cytopathology confirmed. Determination of the KRAS mutation type
will be performed in the pathological department of Shanghai Chest Hospital, Shanghai
Jiao Tong University School of Medicine. Both ARMS method or targeted sequencing are
acceptable. It is not acceptable for subjects with the presence of other driver gene
mutation. All eligible subjects must have adequate renal, hepatic, and hematologic
function, as defined in "inclusion criteria".
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. According to the 8th edition of the AJCC/UICC TNM staging system for NSCLC, patients
with locally advanced (stage III B/III C), metastatic or recurrent (stage IV) NSCLC
confirmed by histology or cytology who are unable to undergo surgery and radical
concomitant radiochemotherapy and are confirmed to have at least one measurable
lesion according to RECIST 1.1.
2. KRAS mutation positive detected by ARMS or NGS;
3. Have been treated with 1st line of standard therapy and experienced disease
progression;
4. Patients who were assessed as CR, PR, or SD (reduction) after being treated with 2
cycles of anlotinib and trametinib.
5. No active brain metastases;
6. Age ≥18 years and ≤75 years;
7. ECOG PS score: 0 to 2;
8. Palliative radiotherapy must be completed 7 days before the first dose of study drug
is administered;
9. The main organs function is normal, that is, the following criteria met:
10. Good hematopoietic function, defined as absolute neutrophil count ≥1.5×10^9 /L,
platelet count≥100 ×10^9 /L, hemoglobin ≥90g/L [no blood transfusion or no
erythropoietin (EPO) dependence within 7 days before enrollment]
11. Biochemical test results should meet the following criteria: BIL < 1.25 times the
upper limit of normal value (ULN); ALT and AST < 2.5 × ULN; in case of liver
metastases, ALT and AST < 5 × ULN; Cr ≤1.5×ULN or creatinine clearance (CCr)
≥60ml/min; Coagulation function is good, INR and PT ≤1.5 times ULN; if the subject
is receiving anticoagulant treatment, PT should be within the prescribed range of
use of anticoagulant drugs;
12. Women of child-bearing age should agree to take contraceptive measures (such as
intrauterine devices, contraceptives or condoms) during the study and within 6
months after the study; non-breast-feeding patients whose serum or urinary pregnancy
test should be negative; male patients should agree to take contraceptive measures
during the study and within 6 months after the study.
13. Patients are voluntarily enrolled into the study, sign the informed consent form and
have good compliance.
Exclusion Criteria:
1. Small cell lung cancer (including mixed small cell and non-small cell lung cancer);
2. Patients who have received previous treatment ≥ 4th lines of standard therapies.;
3. There are obvious bleeding symptoms or active autoimmune disease;
4. Patients with other driver mutation.
5. Patients with many factors affecting oral medication, such as dysphagia,
gastrointestinal resection, chronic diarrhea and intestinal obstruction;
6. Patients who are known to have active brain metastases, spinal cord compression,
carcinomatous meningitis, or brain or leptomeningeal disease diagnosed by CT or MRI
at the time of screening;
7. Patients with severe and / or uncontrolled diseases, such as:
8. Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 6 months before randomization, severe uncontrolled arrhythmias;
uncontrolled blood pressure (systolic blood pressure > 140 mmHg, diastolic blood
pressure > 90 mmHg);
9. Active or uncontrolled serious infection;
10. Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic
active hepatitis;
11. Not completely controlled eye inflammation or eye infection, or any condition that
may lead to the above-mentioned ocular diseases
12. Poorly controlled diabetes (fasting blood glucose (FBG) > 10mmol/L);
13. Routine urine test result indicates that urine protein ≥++, and 24-hour urine
protein quantitation is confirmed to be > 1.0 g;
14. Active tuberculosis, etc.;
15. Uncontrolled hypercalcemia (> 1.5 mmol/L calcium ion or calcium > 12 mg/dL or
corrected serum calcium > ULN), or symptomatic hypercalcemia requiring continued
diphosphate therapy;
16. Long-term unhealed wounds or fractures;
17. Patients who have a history of psychotropic drug abuse and cannot abstain from it or
have mental disorders;
18. Patients who are known to have severe allergies (≥ grade 3) to active ingredients
and any excipients of study drugs;
19. Patients who have other malignant tumors (except radical cervical carcinoma in situ,
non-melanoma skin cancer, etc.) at the same time; patients who are evaluated by the
investigator to have concomitant diseases that seriously endanger the safety of the
patients or affect the patients completing the study.
20. The subjects or their sexual partners cannot or refuse to take effective
contraceptive measures during the clinical trial.
21. Pregnant or breast-feeding women.
22. Patients who are allergic to any medicine or any ingredient; the patients with a
history of treatments involving MEK inhibitors (trametinib, selumetinib, etc.) and
RTKs inhibitors (anlotinib, sorafenib, apatinib, cabozantinib, etc.) were considered
ineligible.
23. Patients in other situations who are evaluated by the investigator to be ineligible
to be enrolled.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Shanghai Chest Hospital
Address:
City:
Shanghai
Country:
China
Contact:
Last name:
Baohui Han, MD, PhD
Phone:
+86 18930858216
Email:
18930858216@163.com
Contact backup:
Last name:
Jun Lu, MD, PhD
Phone:
+86 13601887656
Email:
lujun512@yahoo.com
Start date:
July 1, 2024
Completion date:
December 31, 2028
Lead sponsor:
Agency:
Shanghai Chest Hospital
Agency class:
Other
Collaborator:
Agency:
BeiGene
Agency class:
Industry
Collaborator:
Agency:
Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
Agency class:
Industry
Collaborator:
Agency:
Novartis
Agency class:
Industry
Source:
Shanghai Chest Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06456138
