Narlumosbartmab Combined With Neoadjuvant Chemotherapy in Bone-derived Malignancies With Osteolytic Lesions and Multinucleated Giant Cells

Comparison of Narlumosbartmab Combined With Neoadjuvant Chemotherapy and Neoadjuvant Chemotherapy Alone in Bone-derived Malignancies With Osteolytic Lesions and Multinucleated Giant Cells in Local Recurrence Rates: a Prospective, Randomized, Controlled, Two-arm, Open, Single-center Clinical Trial

Malignant tumor of bone is rare with poor prognosis. Surgery is the main treatment for non- metastatic bone tumor. Although neoadjuvant chemotherapy for non-metastatic bone tumor cannot improve survival rate based on adjuvant chemotherapy, it can reduce and clarify tumor boundary. Control of local recurrence rate is the core objective of oncotherapy. Surgery way and boundary have a significant effect on prognosis of non- metastatic bone tumor. Narlumosbartmab, a RANKL inhibitor, can make tumor boundary clear and reduce surgical difficulty by inhibiting osteoclast. This is a prospective, randomized, controlled, two-arm, open, single-center clinical trial to compare the efficacy and safety of narlumosbartmab combined with neoadjuvant chemotherapy and neoadjuvant chemotherapy alone in bone-derived malignancies with bone lytic lesions and multinucleated giant cells. Investigators mainly observe the local recurrence rate to evaluate the survival benefit for patients with poor prognosis.

Study Overview

• Status: Recruiting
• Conditions: Malignant Bone Tumor
• Intervention / Treatment: Drug: doxorubicin、cisplatin、methotrexate、ifosfamide; Drug: narlumosbartmab plus doxorubicin、cisplatin、methotrexate、ifosfamide

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lu Xie, M.D.; Phone Number: 13401044719; Email: xielu@pkuph.edu.cn

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100044
      • Recruiting
      • Peking University People's Hospital
      • Contact: Lu Xie, M.D.; Phone Number: +8613401044719; Email: xie.lu@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age is more than 8 years old and no gender limitation.
2. Histopathologically confirmed high-grade bone-origin malignancies of the limb with the following subtypes: high-grade osteosarcoma, Ewing sarcoma or Ewing sarcoma, malignant giant cell tumor, and undifferentiated pleomorphic sarcoma of bone (the pathological descriptions of the above disease types must include multinuclear giant cell components). Local tumors and isolated lung lesions must be confirmed by pathological diagnosis and multiple lung metastases must be determined by an experienced thoracic surgeon to be resectable.
3. For newly treated tumors that have not been treated with standard therapy and surgery is performed at our center and the necrosis rate is measured.
4. The ECOG physical status score is 0-1, and the expected survival period is more than 6 months.
5. Hb≥ 120g/L，ANC≥1.5×109/L，PLT≥ 100×109/L Cr≤ 1.5×ULN，BUN≤ 2.5×ULN, TB≤ 1.5×ULN, AST and ALT≤ 2.5×ULN, ALB≥ 30 g/L INR）≤1.5，PT and APTT≤1.5×ULN
6. Pregnancy test (urine beta-HCG) negative (for sexually active women of childbearing age).
7. Sign an informed consent form (or legal representative sign) to demonstrate that patients understand the purpose of the study and the procedures required by the study and are willing to participate in the study.

Exclusion Criteria:

1. Past or current jaw osteomyelitis or jaw necrosis; Failure to recover from dental or oral surgery; Acute dental or jaw diseases requiring oral surgery; Those who planned to undergo invasive dental surgery during the study period.
2. Any planned intravenous or oral bisphosphonate therapy during the study period.
3. Past or current use of anti-nuclear factor κB activator ligand (RANKL) antibodies, such as disumab.
4. Metastatic lesions determined by doctors to be unresectable.
5. Have had other malignancies in the past 3 years, are currently being treated with other anti-tumor drugs, or are currently receiving other specific treatments for giant cell tumors of bone (such as radiation, chemotherapy, or embolization).
6. Central nervous system metastases with obvious symptoms, such as headache, brain edema, blurred vision, etc.
7. Uncontrolled hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, despite best medical treatment).
8. Patients with grade II or above myocardial ischemia or myocardial infarction, poorly controlled arrhythmias (including QTc interval ≥450 ms for men and ≥470 ms for women).
9. Patients with grade Ⅲ to Ⅳ cardiac insufficiency according to NYHA criteria, or with left ventricular ejection fraction (LVEF) < 50% indicated by heart color ultrasound, or had myocardial infarction within 6 months before enrollment, or with grade II or above heart failure according to NYHA criteria, uncontrolled angina, uncontrolled severe ventricular arrhythmia, and clinically significant pericardial disease, or electrocardiogram indicates acute ischemia or abnormal active conduction system.
10. Uncontrolled co-morbidities include, but are not limited to poorly controlled diabetes, persistent active infections, or mental illness or social conditions that may affect participants' compliance with the study.
11. Abnormal coagulation function (INR >1.5 or prothrombin time (PT) > ULN+4 seconds or APTT >1.5 ULN), have a tendency to bleed or are receiving thrombolytic or anticoagulant therapy.
12. Patients with a history of psychotropic drug abuse and are unable to quit or have mental disorders.
13. With significant factors affecting the absorption of oral drugs, such as inability to swallow, chronic diarrhea and intestinal obstruction.
14. Patients with active viral hepatitis B or hepatitis C, or those with active infections requiring antimicrobial treatment (e.g. antibiotics, antiviral drugs, antifungal drugs).
15. Have participated in clinical trials of other antitumor drugs within 4 weeks.
16. Known allergic reactions, hypersensitivities, or intolerances to chemotherapy agents or their excipients.
17. During lactation.
18. Patients received vaccination during the course of treatment, or within 4 weeks of vaccination.
19. Any condition which, in the opinion of the investigator, is likely to harm the subject or cause the subject to be unable to meet or perform the study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: neoadjuvant chemotherapy	Drug: doxorubicin、cisplatin、methotrexate、ifosfamide; doxorubicin(37.5mg/m^2/d)、cisplatin(120mg/m^2/d)、methotrexate(8-12g/m^2/d)、ifosfamide(2.4g/m^2/d)
Experimental: narlumosbartmab plus neoadjuvant chemotherapy	Drug: narlumosbartmab plus doxorubicin、cisplatin、methotrexate、ifosfamide; Narlumosbartmab is combined with neoadjuvant chemotherapy at 120mg i.h. in day 1, 8, 15, 28 and every 28 days after that.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
local recurrence rate	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		2 years
Event-free survival		2 years
tumor necrosis rate		12 weeks
R0 removal rate	R0 remove mains the pathological margin is negative.	12 weeks

Collaborators and Investigators

• Sponsor: Peking University People's Hospital
• Investigators: Principal Investigator: Lu Xie, M.D., Musculoskeletal Tumor Center of Peking University People's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: February 25, 2024
• First Submitted That Met QC Criteria: March 4, 2024
• First Posted (Actual): March 8, 2024

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Narlumosbartmab; Malignant bone tumor; Multinucleated giant cell; Osteoclast-like giant cell; Osteolytic; RANKL inhibitor
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Musculoskeletal Diseases; Bone Diseases; Bone Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cisplatin; Ifosfamide; Isophosphamide mustard; Doxorubicin; Liposomal doxorubicin; Methotrexate
• Other Study ID Numbers: PKUPH-sarcoma 18

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No