Trametinib Plus Anlotinib Combined With Tislelizumab in KRAS-mutant NSCLC

NCT06456138 | Not Yet Recruiting Phase 1

• 1 other identifier: ATT-RAS-001
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

KRAS Mutation-Related Tumors; Advanced Lung Cancer; Refractory Tumor

Keywords

KRAS-mutant NSCLC; Trametinib; Anlotinib; Tislelizumab

Outcome Measures

Primary Outcomes (2)

• RP2D

  recommended phase 2 dose

  up to 12 months

• PFS

  progression-free survival

  up to 18 months

Secondary Outcomes (4)

• ORR

  up to 12 months

• OS

  up to 24 months

• DOR

  up to 18 months

• AEs

  up to 24 months

Study Arms (1)

Trametinib + Anlotinib + Tislelizumab

EXPERIMENTAL

In Phase I, there are four treatment arms: anlotinib (6 mg) plus trametinib (1 mg) plus tislelizumab (200 mg, Q3W), anlotinib (6 mg) plus trametinib (2 mg) plus tislelizumab (200 mg, Q3W), anlotinib (8 mg) plus trametinib (1 mg) plus tislelizumab (200 mg, Q3W), and anlotinib (8 mg) plus trametinib (2 mg) plus tislelizumab (200 mg, Q3W). In Phase II, there is one treatment arm including trametinib (RP2D) plus anlotinib (RP2D) plus tislelizumab (200 mg, Q3W).

Drug: Trametinib; Drug: Anlotinib; Drug: Tislelizumab

Interventions

Trametinib DRUG

Trametinib will be administrated orally every day.

Trametinib + Anlotinib + Tislelizumab

Anlotinib DRUG

Anlotinib will be administrated orally from day 1 to day 14 per 21-day cycle.

Trametinib + Anlotinib + Tislelizumab

Tislelizumab DRUG

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.

Trametinib + Anlotinib + Tislelizumab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• KRAS mutation positive detected by ARMS or NGS;
• Have been treated with 1st line of standard therapy and experienced disease progression;
• Patients who were assessed as CR, PR, or SD (reduction) after being treated with 2 cycles of anlotinib and trametinib.
• No active brain metastases;
• Age ≥18 years and ≤75 years;
• ECOG PS score: 0 to 2;
• Palliative radiotherapy must be completed 7 days before the first dose of study drug is administered;
• The main organs function is normal, that is, the following criteria met:
• Good hematopoietic function, defined as absolute neutrophil count ≥1.5×10\^9 /L, platelet count≥100 ×10\^9 /L, hemoglobin ≥90g/L \[no blood transfusion or no erythropoietin (EPO) dependence within 7 days before enrollment\]
• 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;
• 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.
• Patients are voluntarily enrolled into the study, sign the informed consent form and have good compliance.

You may not qualify if:

• Small cell lung cancer (including mixed small cell and non-small cell lung cancer);
• Patients who have received previous treatment ≥ 4th lines of standard therapies.;
• There are obvious bleeding symptoms or active autoimmune disease;
• Patients with other driver mutation.
• Patients with many factors affecting oral medication, such as dysphagia, gastrointestinal resection, chronic diarrhea and intestinal obstruction;
• 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;
• Patients with severe and / or uncontrolled diseases, such as:
• 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);
• Active or uncontrolled serious infection;
• Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
• Not completely controlled eye inflammation or eye infection, or any condition that may lead to the above-mentioned ocular diseases
• Poorly controlled diabetes (fasting blood glucose (FBG) \> 10mmol/L);
• Routine urine test result indicates that urine protein ≥++, and 24-hour urine protein quantitation is confirmed to be \> 1.0 g;
• Active tuberculosis, etc.;
• 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;

Sponsors & Collaborators

• Shanghai Chest Hospital: lead
• BeiGene: collaborator
• Chia Tai Tianqing Pharmaceutical Group Co., Ltd.: collaborator
• Novartis: collaborator

Study Sites (1)

Shanghai Chest Hospital

Shanghai, China

Location

MeSH Terms

Conditions

Neoplasms

Interventions

trametinib; anlotinib; tislelizumab

Study Officials

• Baohui Han, MD, PhD

  Shanghai Chest Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tianqing Chu, MD, PhD

CONTACT

+86 13661775640; ctqxkyy@163.com

Jun Lu, MD, PhD

CONTACT

+86 2122200000; lujun512@yahoo.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 5, 2024
• First Posted: June 13, 2024
• Study Start: July 1, 2024
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2028
• Last Updated: June 13, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)