Tislelizumab Combined With Pemetrexed/ Carboplatin in Patients With Brain Metastases of Non-squamous NSCLC

• ClinicalTrials.gov Identifier: NCT04507217
• Recruitment Status: Completed
• First Posted: August 11, 2020
• Last Update Posted: May 25, 2023
• Sponsor: Sun Yat-sen University
• Information provided by (Responsible Party): Li Zhang, MD, Sun Yat-sen University

Tracking Information

• First Submitted Date: August 6, 2020
• First Posted Date: August 11, 2020
• Last Update Posted Date: May 25, 2023
• Actual Study Start Date: September 15, 2020
• Actual Primary Completion Date: November 15, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 12, 2020)

Progression-Free Survival (PFS) rate at 12 months according to RECIST v1.1 [ Time Frame: 12months ]

Progression-free survival is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first

Original Primary Outcome Measures (submitted: August 6, 2020)

PFS rate at 12 months [ Time Frame: 12months ]

Progression-Free Survival (PFS) rate at 12 months according to RECIST v1.1 Progression-free survival is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first.

Current Secondary Outcome Measures (submitted: May 23, 2023)

• Objective Response Rate (ORR) according to RECIST v1.1 [ Time Frame: 36 months ]
  ORR is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR).
• Progression-free survival (PFS) according to RECIST v1.1 [ Time Frame: 12 months ]
  Progression-free survival is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first.
• Overall Survival (OS) [ Time Frame: 36 months ]
  OS is defined as the time from the starting date of study drug to the date of death due to any cause
• Progression-free survival (PFS) according to RANO-BM [ Time Frame: 36 months ]
  PFS2 is defined as the time from first intracranial disease progression to second/subsequent disease progression (intracranial or extracranial) after initiation of new anti-cancer therapy, or death from any cause, whichever occurs first
• Duration of Response (DoR) according to RECIST v1.1 [ Time Frame: 36 months ]
  DoR is defined as the time from the date for first documented response of complete response (CR) or partial response (PR) to the date of first documented of disease progression or death, whichever occurs first
• Incidence and severity of treatment-emergent AEs (TEAEs) [ Time Frame: 36 months ]
  TEAEs graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0
• Neurocognitive impairment [ Time Frame: 36 months ]
  Neurocognitive impairment according to Hopkins Verbal Learning Test-Revised（HVLT-R）

Original Secondary Outcome Measures (submitted: August 6, 2020)

• ORR [ Time Frame: 36 months ]
  Objective Response Rate (ORR) according to RECIST v1.1 ORR is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR).
• Progression-free survival (PFS) [ Time Frame: 36 months ]
  Progression-free survival is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death
• OS [ Time Frame: 36 months ]
  OS is defined as the time from the starting date of study drug to the date of death due to any cause.
• Progression-free survival 2 (PFS2) of patients who have only intracranial PD at first in Cohort1 according to RECIST v1.1 [ Time Frame: 36 months ]
  PFS2 is defined as the time from first intracranial disease progression to second/subsequent disease progression (intracranial or extracranial) after initiation of new anti-cancer therapy, or death from any cause, whichever occurs first.
• Duration of Response (DoR) according to RECIST v1.1 [ Time Frame: 36 months ]
  DoR is defined as the time from the date for first documented response of complete response (CR) or partial response (PR) to the date of first documented of disease progression or death, whichever occurs first.
• Incidence and severity of treatment-emergent AEs (TEAEs) graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 [ Time Frame: 36 months ]
  • Incidence and severity of treatment-emergent AEs (TEAEs) graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0
• Neurocognitive impairment according to Hopkins Verbal Learning Test-Revised（HVLT-R） [ Time Frame: 36 months ]
  • Neurocognitive impairment according to Hopkins Verbal Learning Test-Revised（HVLT-R）

• Current Other Pre-specified Outcome Measures (submitted: May 23, 2023): PD-L1 expression, TMB, and other potential predictive biomarkers, correlated with response to treatment [ Time Frame: 36 months ]

Original Other Pre-specified Outcome Measures (submitted: August 6, 2020)

• • PD-L1 expression, TMB, and other potential predictive biomarkers, correlated with response to treatment [ Time Frame: 36 months ]
  • PD-L1 expression, TMB, and other potential predictive biomarkers, correlated with response to treatment
• • Progression-free survival based on intracranial response (iPFS) according to RECIST 1.1 and RANO-BM [ Time Frame: 36 months ]
  • Progression-free survival based on intracranial response (iPFS) according to RECIST 1.1 and RANO-BM

Descriptive Information

• Brief Title: Tislelizumab Combined With Pemetrexed/ Carboplatin in Patients With Brain Metastases of Non-squamous NSCLC
• Official Title: A Phase II, Open-Label, Multicenter, Prospective Clinical Study to Investigate the Efficacy and Safety of Tislelizumab Combined With Pemetrexed/ Carboplatin in Patients With Brain Metastases of Non-squamous Non-small Cell Lung Cancer
• Brief Summary: This is a phase II, Open-Label, Multicenter, Prospective Clinical Study to Investigate the Efficacy and Safety of Tislelizumab Combined with Pemetrexed/ Carboplatin in Patients with Brain Metastases of Non-squamous Non-small Cell Lung Cancer. The primary end point is PFS, and secondary endpoint is ORR, OS, DoR and Neurocognitive impairment. during the study, the exploratory objectives including (1) PD-L1 expression, TMB, and other potential predictive biomarkers, correlated with response to treatment (2) Progression-free survival based on intracranial response (iPFS) according to RECIST 1.1 and RANO-BM
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Tislelizumab Combined with Pemetrexed/ Carboplatin

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• NSCLC Stage IV
• Brain Metastases
• PD-1 Antibody

Intervention

Drug: Tislelizumab, Carboplatin, Pemetrexed

Tislelizumab: 200mg administered intravenously (IV) on Day 1 of each 21-day cycle

Carboplatin: AUC 5 administered intravenously (IV) on Day 1 of each 21-day cycle, 4 cycles

Pemetrexed: 500mg/m2 administered intravenously (IV) on Day 1 of each 21-day cycle

Study Arms

Experimental: Eligible patients

tislelizumab (200mg) in combination with pemetrexed (500mg/m2) and carboplatin (AUC=5) intravenously on day 1 of a 3-week cycle for 4 cycles. Afterwards, patients without disease progression were treated with maintenance treatment with tislelizumab (200mg) plus pemetrexed (500mg/m2) every 3 weeks up to 24 months or until disease progression, unacceptable toxicity, or death.

Intervention: Drug: Tislelizumab, Carboplatin, Pemetrexed

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 23, 2023): 36
• Original Estimated Enrollment (submitted: August 6, 2020): 78
• Actual Study Completion Date: January 30, 2023
• Actual Primary Completion Date: November 15, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Disease-related inclusion criteria:

1. Histologically confirmed metastatic (Stage IV) not amenable to curative surgery or radiotherapy, non-squamous NSCLC according to American Joint Committee on Cancer (AJCC), 8th Edition.
2. Radiographically confirmed brain metastases;
3. No prior systemic treatment for stage IV NSCLC. (Bevacizumab administered for improving radiation-induced encephaledema during irradiating intracranial lesions is not considered as systemic therapy for stage IV NSCLC)
4. Patients with asymptomatic BM or symptoms can be controlled by low dose corticosteroids (≤ 10 mg/day of prednisone or equivalent) or antiepileptics drugs;
5. Patients with previous local treatment to BMs should be stable and suitable to receive the systemic treatment;
6. ECOG PS: 0 ~ 1
7. Extracranial measurable target lesions (per RECIST v1.1)

8. Life expectancy ≥ 3 months

   Have adequate hematology, clinical chemistry, and organ function as indicated by the following laboratory values (confirmed within 7 days prior to the first dose):

9. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin ≥ 90 g/L.
10. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × upper limit of normal [ULN].
11. Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.
12. Serum total bilirubin ≤ 1.5 × ULN (total bilirubin must be < 3 × ULN for patients with Gilbert's syndrome).

13. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN or AST and ALT ≤ 5 × ULN for patients with liver metastases.

    General inclusion criteria:

14. Able to provide written ICF signed by patient or by his/her legally authorized representative or guardian and can understand and agree to comply with the study protocol and follow-up procedures.
15. Male or female, aged 18 ~ 75 years on the day of signing ICF. Female patients of childbearing potential and non-sterile male patients must be willing to use a highly effective method of birth control for the duration of the study and for at least 120 days after the last dose of tislelizumab.

Exclusion Criteria:

Disease-related exclusion criteria:

1. Received prior therapies targeting PD-1, PD-L1, CTLA-4 or other immune checkpoints inhibitors.
2. Received prior systemic chemotherapy for advanced disease.
3. Have EGFR mutation or ALK gene translocation.
4. Patients iwith BMs that have received systemic treatment with corticosteroids (>10 mg/day of prednisone or equivalent) or other drugs to relieve or prevent symptoms of BMs.
5. Patients with intracranial metastases that are locally amenable.
6. Have received any approved systemic anticancer therapy or systemic immunomodulators (including but not limited to interferon, interleukin-2, and tumor necrosis factor) within 4 weeks prior to the first dose of study drug.
7. Have clinically uncontrolled pleural effusion or ascites that requires pleurocentesis or abdominal tapping for drainage within 2 weeks prior to the first dose of study drugs.

8. Active leptomeningeal metastasis.

   Exclusion criteria related to study drugs:

9. History of allergic reactions to any study drugs and their excipients.
10. Creatinine clearance (Ccr) < 45 mL/min.
11. Patients with active viral hepatitis that requires treatment as judged by the investigator: a. chronic hepatitis B virus carriers with HBV DNA ≥ 500 IU/mL (2500 copies/mL) (The HBV DNA test will be performed only for patients who have a positive antibody to hepatitis B core antigen (anti-HBc antibody) test); b. patients who have positive hepatitis C virus (HCV) RNA results (The HCV RNA test will be performed only for patients testing positive for HCV antibody).
12. Active autoimmune diseases that requires systemic treatment and may impact study treatment as assessed by investigator.

13. Any condition that required extensive chronic treatment with either corticosteroids or any other immunosuppressive medications that may impact study treatment as assessed by investigator.

    General exclusion criteria:

14. Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis infection, etc.; 1) Serious infections within 4 weeks before first dose, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia; 2) Receive therapeutic oral or intravenous antibiotics within 2 weeks before first dose. With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled systemic diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung diseases, etc.
15. Major surgery requiring general anesthesia within 4 weeks before first dose.
16. Underlying medical conditions or alcohol or drug abuse or dependence that are to be unfavorable for the administration of study drugs or may have affected the interpretation of the results or rendered the patient at high risk from treatment complications.
17. Concurrent participation in another therapeutic clinical study. Female patients who are pregnant, breastfeeding, or males and females patients planning to have child during the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04507217
• Other Study ID Numbers: BGB-A317-2003-IIT
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Li Zhang, MD, Sun Yat-sen University
• Original Responsible Party: Same as current
• Current Study Sponsor: Sun Yat-sen University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Sun Yat-sen University
• Verification Date: May 2023