Clinical trial NCT06734702: Neoadjuvant Immunotherapy Plus Chemotherapy Followed by Concurrent Chemoradiotherapy and Consolidative Immunotherapy for Locally Advanced Non-small Cell Lung Cancer
Official title: Neoadjuvant Immunotherapy Plus Chemotherapy Followed by Concurrent Chemoradiotherapy and Consolidative Immunotherapy Compared With Concurrent Chemoradiotherapy and Consolidative Immunotherapy in Locally Advanced Non-small Cell Lung Cancer: A Randomized, Phase III Controlled Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Neoadjuvant Therapy
Concurrent Chemoradiotherapy
Immunotherapy
Locally Advanced Non-Small Cell Lung Cancer
Keywords: Neoadjuvant therapy
Concurrent Chemoradiotherapy
Immunotherapy
Locally Advanced Non-Small Cell Lung Cancer
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2024-12-16
Enrollment: 300
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: Consolidative immunotherapy following concurrent chemoradiotherapy, based on the PACIFIC trial, has become the standard treatment for locally advanced non-small cell lung cancer (LANSCLC), leading to a 5-year survival rate of over 40%. The optimal timing of radiotherapy combined with immunotherapy still requires further exploration. This phase III, randomized controlled clinical trial is to investigate the efficacy and safety of neoadjuvant immuno-chemotherapy followed by concurrent chemoradiotherapy and consolidative immunotherapy, compared with concurrent chemoradiotherapy and consolidative immunotherapy in LANSCLC patients.

Detailed description: This phase III, randomized controlled trial aims to investigate the efficacy and safety of neoadjuvant immuno-chemotherapy followed by concurrent chemoradiotherapy and consolidative immunotherapy, compared with concurrent chemoradiotherapy and consolidative immunotherapy in LANSCLC patients. Patients will be randomized in a 2:1 ratio to the following two groups: (1) Study group: Patients in this group will receive two cycles of neoadjuvant therapy. After neoadjuvant therapy, they will undergo concurrent chemoradiotherapy, followed by consolidative immunotherapy for a maximum duration of 12 months. (2) Control group: Patients in this group will receive concurrent chemoradiotherapy, followed by consolidative immunotherapy for a maximum duration of 12 months. Patients will be stratified by the following factors: Age (\< 65 years vs. ≥ 65 years); Gender (Male vs. Female); Stage (IIIA vs. IIIB/C).

Eligibility criteria: Inclusion Criteria:

* Signed and Dated Informed Consent: Written informed consent must be provided prior to any study procedures, with the consent form signed and dated by the participant.
* Age Range: Male or female patients aged 18 to 75 years.
* Diagnosis: Patients must have locally advanced, unresectable (stage III) non-small cell lung cancer (NSCLC), with histological or cytological confirmation of the diagnosis.
* Previous Treatment: Patients must not have received prior chemotherapy, radiotherapy, surgery, targeted therapy, or immunotherapy.
* Tumor Sample Requirement: Tumor tissue samples must be provided, and they should be sufficient for analysis. The samples must be unstained and archived.
* Life Expectancy: Patients must have an expected survival of at least 12 weeks.
* Performance Status (PS): The patient's WHO Performance Status (PS) must be 0 or 1.
* Pregnancy Testing: Postmenopausal women, or women who have had a negative urine or serum pregnancy test within 14 days before the study medication (HCG sensitivity ≥ 25 IU/L or equivalent).
* Breastfeeding: Women must not be breastfeeding.
* Women of childbearing potential (WOCBP) must agree to use contraception during the study treatment period and for 5 months after the last dose of the investigational drug (i.e., 30 days \[ovulation cycle\] + approximately 5 half-lives of the study drug).
* Men who have sexual relations with WOCBP must agree to use contraception during the study treatment period and for 7 months after the last dose of the investigational drug (i.e., 90 days \[sperm renewal cycle\] + approximately 5 half-lives of the study drug).
* Males with no sperm production are exempt from contraception requirements. WOCBP who are not sexually active are exempt from contraception but must still undergo pregnancy testing as outlined above.
* Organ and Bone Marrow Function: The following laboratory parameters must be met:

Forced expiratory volume in 1 second (FEV1) ≥ 800 mL Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L Platelets ≥ 100 × 10⁹/L Hemoglobin ≥ 9.0 g/dL Calculated creatinine clearance using the Cockcroft-Gault formula ≥ 50 mL/min Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) AST and ALT ≤ 2.5 × ULN

Exclusion Criteria:

* Patients meeting any of the following criteria should not be enrolled in the study:
* Concurrent participation in another clinical trial, except for observational (non-interventional) studies.
* Histological subtype of mixed small-cell and non-small-cell lung cancer. Use of immunosuppressive drugs within 28 days before treatment, except for intranasal or inhaled corticosteroids at physiological doses or systemic corticosteroids ≤10 mg/day of prednisone or equivalent.
* Prior treatment with anti-PD-1 or anti-PD-L1 antibodies.
* Major surgery within 4 weeks prior to enrollment (excluding procedures for vascular access).
* History or active autoimmune diseases within the past two years.
* Active or a history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
* History of primary immunodeficiency.
* History of organ transplantation requiring immunosuppressive therapy.
* Average corrected QT interval (QTc) ≥470 ms calculated from three ECG cycles using the Bazett formula.
* Uncontrolled comorbidities, including but not limited to: Persistent or active infections. Symptomatic congestive heart failure. Poorly controlled hypertension. Unstable angina. Cardiac arrhythmias. Active peptic ulcer disease or gastritis. Active bleeding disorders. Hepatitis C or HIV infection. HBsAg-positive patients with HBV DNA \>500 IU/mL. Mental or social conditions that may limit adherence to study requirements or compromise the ability to provide informed consent.
* Known history of tuberculosis.
* Receipt of a live attenuated vaccine within 30 days before study initiation or planned during the study period.
* History of another primary malignancy within the past 5 years, except for adequately treated basal or squamous cell carcinoma of the skin or in situ cervical cancer.
* Pregnancy, breastfeeding, or not using effective contraception (for men and women of reproductive potential).

Patients in the experimental group should not proceed to concurrent chemoradiotherapy if any of the following criteria are met:

* Presence of distant metastases.
* Locoregional progression making definitive concurrent chemoradiotherapy unfeasible due to normal tissue dose constraints (assessed by the radiation oncologist).
* WHO performance status score of 2-4.
* Impaired organ or bone marrow function, including:

Forced expiratory volume in 1 second (FEV1) \<800 mL. Absolute neutrophil count (ANC) \<1.5 × 10⁹/L. Platelets \<100 × 10⁹/L. Hemoglobin \<9.0 g/dL. Creatinine clearance (Cockcroft-Gault formula) \<50 mL/min. Serum bilirubin \>1.5 × upper limit of normal (ULN). AST and ALT \>2.5 × ULN.

- Patient withdrawal from the study.

Patients should not proceed to consolidation immunotherapy if any of the following criteria are met:

* Disease progression during concurrent chemoradiotherapy.
* Use of immunosuppressive drugs within 28 days before the first dose of tislelizumab, except for physiological doses of intranasal or inhaled corticosteroids or systemic corticosteroids ≤10 mg/day of prednisone or equivalent. Use of corticosteroids to manage chemoradiotherapy-related toxicity is permitted.
* Persistent unresolved CTCAE grade \>2 toxicities from prior chemoradiotherapy.
* Grade ≥2 pneumonitis resulting from prior chemoradiotherapy.
* Any prior grade ≥3 immune-related adverse event (irAE) or unresolved irAE \> grade 1.

Primary outcomes:
measure: Median Progression-Free Survival
timeFrame: 2 years
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 1-2 months after treatment
measure: Overall survival (OS)
timeFrame: 2 years
measure: Failure patterns
timeFrame: 2 years
measure: Safety: Adverse Events of Grade 2 or Higher
timeFrame: 1 years after treatment
measure: Quality of life assessed by Quality of Life Core 30
timeFrame: 1 years after treatment
measure: Quality of life assessed by Quality of Life LC13
timeFrame: 1 years after treatment
measure: The percentage of patients who are eligible for consolidative immunotherapy following chemoradiotherapy
timeFrame: 1 year
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Sun yat-sen University Cancer Center
state: Guangdong
Study officials:
affiliation: Sun yat-sen universtiy cancer center
name: Hui Liu, Professor
role: PRINCIPAL_INVESTIGATOR
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