The Efficacy and Safety of Narlumosbart in Combination With Stereotactic Body Radiation Therapy to Improve the Efficacy of First-line Chemotherapy Combined With Immunotherapy in Patients With Bone Metastases From Advanced Non-small Cell Lung Cancer

NCT06738160 | Recruiting Phase 2

• 2 other identifiers: 2024-NSCLC-SBRTSACA-AX202407
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

Introduction: Immunotherapy in combination with chemotherapy have been recommended as the first-line treatment of driver-negative advanced non-small cell lung cancer (NSCLC), but the efficacy is worse in NSCLC patients with bone metastases due to the immunosuppressive microenvironment. Studies have shown that not only the nuclear factor kappa-B ligand (RANKL) inhibitors but also Stereotactic Body Radiation Therapy (SBRT) play a significant role in improving the tumor immune microenvironment. Therefore, narlumosbart，a monoclonal antibody (mAb) targeting RANKL，in combination with SBRT may have synergistic effects and improve efficacy of immunotherapy and chemotherapy in driver-negative advanced NSCLC patients with bone metastases. Methods: This single-arm, single-center phase II clinical trial will enroll NSCLC patients with bone metastases who have not received any systemic therapy. Patients will receive narlumosbart and bone target lesion SBRT in combination with first-line treatment immunotherapy and chemotherapy after screening eligible subjects. Narlumosbart, 120mg/time, subcutaneous injection, will be administered every 4 weeks. For the treatment of SBRT for bone metastases, the dose of 24Gy/3F is used for spinal metastases, and 30Gy/5F or 35Gy/5F is used for non-spinal lesions. Chemotherapy combined with immune checkpoint inhibitor therapy will be used in accordance with the guidelines. The primary endpoint is to assess the objective response rate of NSCLC patients with bone metastases from narlumosbart combined with SBRT and first-line chemotherapy and immunotherapy. The secondary endpoints include safety and tolerability, progression-free survival, overall survival, bone-related events, pain score, and quality of life. Sample size was calculated using the Simon's Two-Stage method. 9 patients will be enrolled in the first stage. If ≥ 2 patients achieve CR/PR, the second stage of enrollment will be performed. If fewer than 2 patients achieve CR/PR, the trial will be terminated. In the second phase, 15 patients will be enrolled. 27 subjects will be enrolled in this project, considering the dropout rate of 10%. Wangjun Yan AND Zhengfei Zhu are the Co-Principal Investigators of this study.

Conditions

Immunotherapy; NSCLC; Stereotactic Body Radiation Therapy (SBRT)

Outcome Measures

Primary Outcomes (1)

• Objective response rate, ORR

  2 years

Secondary Outcomes (4)

• Incidence of AEs, SAEs, and AE-Related Treatment Discontinuation

  2 years

• Progression free survival, PFS

  2 years

• Overall survival (OS)

  2 years

• Incidence of bone-related events (SREs)

  2 years

Study Arms (1)

Narlumosbart + SBRT

EXPERIMENTAL

This is a single-arm, phase II trial evaluating the efficacy and safety of narlumosbart (120 mg SC Q4W) combined with stereotactic body radiation therapy (SBRT) and standard first-line chemo-immunotherapy in driver gene-negative advanced NSCLC patients with bone metastases. Narlumosbart is an anti-RANKL mAb. SBRT dose: 24 Gy/3F for spinal lesions; 30-35 Gy/5F for non-spinal lesions, delivered 3 days prior to chemo-immunotherapy. Chemo-immunotherapy follows standard guidelines. Treatment continues until progression, toxicity, or withdrawal.The trial uses Simon two-stage design with H₀=25%, H₁=50%, α=0.05, power=0.8; 9 patients in stage 1, with ≥2 responses triggering stage 2 (+15 patients), and \<2 responses stopping the trial. Total sample size is 27 including 10% dropout. A sensitivity analysis is pre-specified: if stage-1 ORR falls between 25% and 40%, protocol revision to H₁=40% with sample size adjustment will be considered, pending ethics approval.

Drug: Narlumosbart; Radiation: Stereotactic Body Radiation Therapy

Interventions

Stereotactic Body Radiation Therapy RADIATION

SBRT will be delivered within one week before the first chemo-immunotherapy cycle. All patients undergo contrast-enhanced CT simulation (1-1.5 mm slice thickness); MRI fusion (T1/T2/STIR) is mandatory for spinal metastases. Target delineation: GTV = visible tumor on CT/MRI; CTV = involved vertebral body sector(s) per ISRC guidelines for spinal lesions, or GTV + 3-5 mm margin for non-spinal lesions; PTV = CTV + 1-2 mm margin. Dose prescription: 24 Gy in 3 fractions for spinal metastases; 30-35 Gy in 5 fractions for non-spinal lesions. Treatment plans use VMAT or IMRT. Daily cone-beam CT (CBCT) is performed before each fraction for image guidance; 6-degree-of-freedom couch corrections are used for spinal lesions. Respiratory motion management (e.g., 4D-CT, gating) is applied for mobile lesions if motion exceeds 5 mm. Patient-specific quality assurance (PSQA) is performed before the first fraction, with gamma analysis (3%/2 mm criteria and ≥95% passing rate) required.

Narlumosbart + SBRT

Narlumosbart DRUG

Narlumosbart is a fully humanized anti-RANKL monoclonal antibody (IgG4) with Fab arms identical to denosumab, demonstrating rapid and sustained suppression of bone resorption biomarkers in patients with bone metastases. It will be administered subcutaneously at 120 mg every 4 weeks. Calcium and vitamin D supplementation will be given concurrently to prevent hypocalcemia. Adverse events will be recorded and graded according to CTCAE v5.0. For jaw osteonecrosis, all patients will undergo a mandatory dental examination within 14 days before the first dose, with 3-monthly dental checks during treatment; suspected cases will be managed with oral surgeon consultation. Serum calcium will be monitored at baseline and prior to each dose (every 4 weeks). Corrected calcium \<2.0 mmol/L will be managed with oral calcium (500-1000 mg/day) and vitamin D (400-800 IU/day). Severe hypocalcaemia (\<1.8 mmol/L or symptomatic) will be treated with intravenous calcium gluconate.

Also known as: chemotherapy, Stereotactic Body Radiation Therapy

Narlumosbart + SBRT

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent prior to the implementation of any trial-related procedures;
• Age 18-80 years old;
• Histologically or cytologically confirmed stage IV NSCLC according to the TNM Classification of Malignant Tumours, 9th edition；
• Histologically confirmed bone metastases requiring local radiotherapy；
• Patients who have not undergone systemic drug therapy for lung cancer (including chemotherapy, targeting, immunotherapy, etc.);
• Driver genes (EGFR, ALK, ROS-1) negative in adenocarcinoma patients (genetic testing not required for squamous cell carcinoma) ;
• At least one evaluable non-bone lesion (refer to RECIST1.1);
• Bone metastases other than the lesions to be radiotherapy do not require local treatment (surgery or radiotherapy) intervention after evaluation;
• ECOG score 0-1 points;
• Expected survival time \> 3 months;
• Adequate organ function, defined as meeting all of the following laboratory criteria within 14 days prior to enrollment: 1) ANC ≥1.5×10⁹/L (no G-CSF); 2) Platelets ≥100×10⁹/L (no transfusion); 3) Haemoglobin ≥9 g/dL (no transfusion/EPO); 4) Bilirubin ≤1.5×ULN; 5) AST/ALT ≤2.5×ULN (≤5×ULN if liver metastases); 6) Creatinine ≤1.5×ULN or CrCl ≥60 mL/min; 7) INR/PT ≤1.5×ULN; 8) TSH within normal limits (or FT3/FT4 normal if TSH abnormal); 9) Cardiac enzymes (troponin I, CK-MB) ≤ ULN (isolated abnormalities not clinically significant are permitted).

You may not qualify if:

• The pathology is small cell lung cancer (SCLC), including lung cancer mixed with SCLC and NSCLC;
• The lesion is an isolated lesion and can be treated radically;
• Patients who need surgical treatment after the evaluation of the study are not allowed to enroll;
• The radiotherapy lesion to be treated has been treated with radiotherapy or the lesion to be treated cannot be treated with radiotherapy after evaluation;
• Presence of active brain metastases;
• Other malignancies within 5 years (except cured non-melanoma skin cancer or carcinoma in situ);
• Prior treatment with anti-PD-1, anti-PD-L1, or RANKL-targeting agents;or used investigational device treatment within 4 weeks prior to the first dose;
• Active autoimmune disease requiring systemic therapy;
• Presence of clinically uncontrollable pleural effusion/ascites effusion (subjects who do not need to drain the effusion or stop draining for 3 days without significant increase in effusion can be enrolled);
• Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
• Presence of active bone metabolism disease (Paget bone disease, Cushing's syndrome, and hyperprolactinemia), rheumatoid arthritis, uncontrolled hyper/hypothyroidism, hyperparathyroidism/hypoparathyroidism;
• Those who are known to be allergic to the active ingredients or excipients such as sintilimab, pemetrexed, nalusopaimab, carboplatin, cisplatin, paclitaxel, etc., of the drug in this study;
• Have not recovered adequately from toxicity and/or complications induced by any of the interventions (i.e., ≤ grade 1 or to baseline, excluding fatigue or alopecia, prior to initiation of treatment);
• Known history of human immunodeficiency virus (HIV) infection (i.e., HIV 1/2 antibody positive);
• Untreated active hepatitis B (defined as HBsAg positive and HBV-DNA copy number detected at the same time greater than the upper limit of normal in the laboratory department of the research center);

Sponsors & Collaborators

• Fudan University: lead

Study Sites (1)

Fudan University Shanghai Cancer Center

Shanghai, Shanghai Municipality, China

RECRUITING

MeSH Terms

Interventions

Drug Therapy; Radiosurgery

Intervention Hierarchy (Ancestors)

Therapeutics; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Central Study Contacts

Zhengfei Zhu

CONTACT

+86-18017312901; fuscczzf@163.com

Wangjun Yan

CONTACT

13917966770; yanwj@fudan.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Masking Details: Masking Description
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Model Description

Study Record Dates

• First Submitted: December 13, 2024
• First Posted: December 17, 2024
• Study Start: February 15, 2025
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2028
• Last Updated: July 23, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: After publication of the main results, for a period of 5 years.
• Access Criteria: Qualified researchers with a methodologically sound proposal and a signed data access agreement. Requests should be directed to the corresponding author.

Locations

CN (1)