Neoplasms

Musculoskeletal Diseases

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Bone Neoplasms

Giant Cell Tumors

Giant Cell Tumor of Bone

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Bone Diseases

Neoplasms, Bone Tissue

All Drugs and Chemicals

Bone Density Conservation Agents

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immunoglobulin G

Denosumab

Immunoglobulins, Intravenous

Immunologic Factors

120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15.

To determine how safe denosumab is in treating subjects with giant cell tumor of bone (GCTB)

To determine how safe denosumab is in treating subjects with GCTB

Study of Denosumab in Subjects With Giant Cell Tumor of Bone

An Open-label, Multi-center, Phase 2 Study of Denosumab in Subjects With Giant Cell Tumor of Bone

AE defined as any untoward medical occurrence in a clinical trial participant. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v3.0) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. Investigator assessed AEs for relatedness to study drug. Results are presented for treatment-emergent events (TEAEs) and included all AEs occurring from first dose in initial treatment phase to end of initial treatment phase (or for participants entering retreatment, from first dose in initial treatment phase until end of retreatment phase).

Serum samples for clinical chemistry were collected on study day 1 (baseline), day 15, week 5 and each study visit Q4W thereafter until last study visit for the on-study period (ie, until end of initial treatment phase). The parameters included albumin, calcium (albumin-adjusted), creatinine, magnesium and phosphate. Results are presented for number of participants who experienced the maximum toxicity grade for each of these clinical parameters. The maximum toxicity grade experienced by each participant was based on CTCAE, v3.0, and are summarized for Grade 3 and 4. Increases and decreases in relationship to the normal parameter ranges are indicated as 'Above' and 'Below' respectively.

Time to disease progression or recurrence during the on-study period was defined as the time interval (in days) from the date of first dose of study drug to the date of earliest Progressive Disease (PD) during the initial treatment phase. PD was defined as the response of progressive disease, locally recurrent disease or relapse as captured in the Disease Status page of the Case Report Form. If a participant had not had PD by the end of the initial treatment phase date, time to disease progression or recurrence were censored at her/his end of initial treatment phase date. Since median time to disease progression or recurrence for participants in cohort 1 was not reached, Kaplan-Meier estimates for the probability (expressed as a percentage) of participants in cohort 1 to have disease progression or recurrence at months 6, 12, 24, 36 and 60 are presented.

The percentage of participants without any surgery at month 6 was equivalent to the number of participants without any surgery by month 6 divided by the number of cohort 2 participants who had an opportunity to complete 6 months of treatment, expressed as a percentage.

Blood samples for determination of serum denosumab concentration levels were obtained from participants included in the pharmacokinetic (PK) substudy at baseline (prior to administration of study drug on day 1) and at scheduled time points during the study up to week 25.

Amgen

Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).

All participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.

Denosumab 120 mg Q4W (All Cohorts)

Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.

Cohort 1 (Denosumab 120 mg Q4W)

Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.

Cohort 2 (Denosumab 120 mg Q4W)

Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.

Cohort 3 (Denosumab 120 mg Q4W)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

White or Caucasian

Black or African American

Hispanic or Latino

Asian

Native Hawaiian or Other Pacific Islander

Other

Race/Ethnicity, Customized

Primary resectable

Primary unresectable

Recurrent resectable

Recurrent unresectable

GCTB Disease Type

The overall baseline population consisted of the 532 participants enrolled into the treatment phase of the study.

Study Director

Any TEAE

Serious TEAE

Fatal TEAE

TEAE leading to treatment phase discontinuation

TEAE leading to study drug discontinuation

CTCAE Grade 3, 4, or 5

Any TEAE related to study drug

The safety analysis set included all enrolled participants who received at least one dose of denosumab on the study.

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

Calcium corrected Grade 3 (Above)

Calcium corrected Grade 4 (Above)

Calcium corrected Grade 3 (Below)

Calcium corrected Grade 4 (Below)

Phosphate Grade 3 (Below)

Magnesium Grade 3 (Above)

Magnesium Grade 3 (Below)

Creatinine Grade 3 (Above)

Albumin Grade 3 (Below)

Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters

Month 6

Month 12

Month 24

Month 36

Month 60

The efficacy analysis set included all enrolled participants who were eligible for the study, and who received at least one dose of denosumab on the study. Analysis was performed on cohort 1 only.

Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability

The efficacy analysis set included all enrolled participants who were eligible for the study, and who received at least one dose of denosumab on the study. Analysis was performed on cohort 2 only for those who had the opportunity to be on-study for at least 6 months.

Percentage of Participants Without Any On-Study Surgery at Month 6 for Cohort 2

Day 1

Day 8

Day 15

Week 5

Week 9

Week 13

Week 17

Week 25

Adolescent participants enrolled in the PK substudy who received at least 1 dose of denosumab with baseline PK measurement and at least 1 post-baseline PK measurement were included in the adolescent PK analysis set. Participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.

Adolescent PK Subset (Denosumab 120 mg Q4W)

Adult participants enrolled in the PK substudy who received at least 1 dose of denosumab with baseline PK measurement and at least 1 post-baseline PK measurement were included in the adult PK analysis set. Participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.

Adult PK Subset (Denosumab 120 mg Q4W)

The PK analysis set included all participants who received at least 1 dose of denosumab with baseline PK measurement and at least 1 post-baseline PK measurement. Only participants with available data at each time point were included in the analysis.

Mean Serum Denosumab Trough Concentrations

Participants with surgically unsalvageable disease (eg, sacral, spinal giant cell tumor of bone (GCTB), or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 milligrams (mg) subcutaneously (SC) once every 4 weeks (Q4W), starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.

Overall Study

Vasodilator Agents

Puerarin

12 immunohistochemical sections were scored under the microscope (staining intensity scores: negative 0 points, weak 1 point, medium 2 points, strong 3 points; positive cell frequency scores: less than 5% 0 points, 2-25% 1 point, 26-50% 2 points, 51-75% 3 points, greater than 75% 4 points).

gene expression levels

Changye Zou, MD

Based on network pharmacology analysis, this study aims to explore the potential therapeutic targets and molecular mechanisms of puerarin on giant cell tumor of bone (GCTB) genes.

The giant cell tumor of bone's pathological genes were discovered from DisGeNET and GeneCards databases. The therapeutic genes of puerarin were gathered from Swiss Target Prediction, CTD(Comparative Toxicogenomics Database), PharmMapper, and TCMSP databases (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform). Cytoscape software was used with the MCODE algorithm to calculate key potential therapeutic targets of puerarin against GCTB. The bulk RNA-seq datasets (GSE102193) were used to identify differential expression of potential therapeutic genes. The sc RNA-seq (GSE168664) was utilized to determine the expression distribution of different cell clusters. Essential targets of puerarin against GCTB underwent function and pathway enrichment assays to elucidate biological processes and signaling pathways. Furthermore, the investigators conducted a comparison to determine if the primary biological processes and pathways following denosumab treatment exhibit resemblances to the potential mechanisms of puerarin action. Molecular docking and dynamics simulation were conducted to evaluate interactions between selected potential therapeutic targets and puerarin. Immunohistochemical (IHC) and immunofluorescence (IF) staining were performed to identify the expression of crucial markers in human GCTB tissue. Expression levels of pivotal genes in primary BMSC cells and primary GCTB cells and their alteration following puerarin treatment in primary GCTB cells were evaluated.The significance of differences between groups was estimated by the Student t-test or Wilcoxon test. In all the statistical analyses, data with two-tailed p \< 0.05 were considered statistically significant.

Immunohistochemistry (IHC) and immunofluorescence staining were performed on the GCTB tissues of 145 patients (2 normal tissues, 51 recurrent, and 92 primary) from the First Affiliated Hospital of Sun Yat sen University to verify the differential expression and distribution of P27 and ESR1 in recurrent and primary lesions of giant cell tumor of bone patients. One patient's tissue was used for transcriptome sequencing to analyze changes in gene expression levels before and after routine treatment.

Network Pharmacology Prediction: Mechanism Study of Puerarin in the Treatment of Giant Cell Tumors of Bone

Treatment of Giant Cell Bone Tumor With Purerin: New Insights From Network Pharmacology, Bioinformatics Analysis, and Experimental Verification

The datasets are available from the corresponding author (zouchy@mail.sysu.edu.cn) on reasonable request after SCI online.

Changye Zou

Department of Orthopedic Oncology, The First Affiliated Hospital of Sun Yat-sen University

Wounds and Injuries

Nervous System Diseases

Synovitis

Giant Cell Tumor of Tendon Sheath

Synovitis, Pigmented Villonodular

Joint Diseases

Tendinopathy

Muscular Diseases

Pigmented Villonodular Synovitis

Global Clinical Leader

TGCT is a rare disease that is difficult to manage, surgical resection is the primary treatment currently available. To date no disease registry exists and there is little data available detailing the management of patients with diffuse TGCT (d-TGCT), the burden of d-TGCT for patients (including pain, joint stiffness, swelling, reduced mobility and quality of life) or the economic impact of d-TGCT.

This study aims to collect data by an observational disease registry involving no intervention to the patient or changes to investigators treatment decisions.

GCT is a rare, benign, but potentially locally aggressive and recurrent disease. Treatment pattern and treatment initiation, continuation or changes are solely at the discretion of the physician and the patient.

There will be no attempt to influence the prescribing patterns of any individual treating physician. All medication will be prescribed in the usual standard of care and will not be provided by the study sponsor.

Participation in the study will in no way influence payment or reimbursement for any treatment received by patients during the study.

It is the responsibility of the investigator and his study staff to enter all relevant patient data required for this registry in the electronic Case Report Form (eCRF) and in the patients' medical records.

Approximately 15 sites from up to 6 European Countries (France, Germany, Italy, The Netherlands, Spain and United Kingdom) and 4 sites from the US are planned to participate. The sites will be specialized sites that treat d-TGCT regularly.

Tenosynovial Giant Cell Tumors (TGCT) Observational Platform Project

A Disease Registry for Patients With Tenosynovial Giant Cell Tumors (TGCT), Also Known as Pigmented Villonodular Synovitis (PVNS) and Giant Cell Tumor of the Tendon Sheath (GCT-TS)

The management plan received among the patients was collected from information routinely recorded in the patient files / medical records.

The current TGCT treatment plan among the patients was collected from information routinely recorded in the patient files / medical records.

Type of treatment plan received among the patients was collected from information routinely recorded in the patient files / medical records.

The status of treatment plan among the patients was collected from information routinely recorded in the patient files / medical records.

Type of current TGCT treatment among the patients was collected from information routinely recorded in the patient files / medical records.

Tumor severity classification was collected from information routinely recorded in the patient files / medical records. ). Tumor severity classification was based on MRI. In this classification scheme, moderate diffuse TGCT is characterized by intra- and/or extra-articular disease, without or with involvement of muscle/tendinous tissue/ligaments. Severe diffuse TGCT is characterized by intra- and extra-articular involvement and involvement of at least one of the 3 structures (muscle/tendinous tissue/ligaments).

Complications due to surgery were collected from information routinely recorded in the patient files / medical records.

Tumor recurrence was collected from information routinely recorded in the patient files / medical records.

Time since most recent tumor recurrence was collected from information routinely recorded in the patient files / medical records.

Time from baseline to first tumor recurrence was collected from information routinely recorded in the patient files / medical records.

The BPI short form is a self administered questionnaire that assesses severity of pain, impact of pain on daily function, location of pain, pain medications and amount of pain relief in the past 24 hours or the past week. The BPI pain severity and interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes), where lower scores indicate better clinical outcome.

The Worst Stiffness numerical rating scale (NRS) is a one-item self-administered, patient-reported outcome questionnaire assessing the "worst" stiffness in the last 24 hours. The NRS for this item ranges from 0 ("no stiffness") to 10 ("stiffness as bad as you can imagine"), where lower scores indicate better clinical outcome.

PROMIS® (Patient-Reported Outcomes Measurement Information System) is a set of person-centered measures that evaluates and monitors physical, mental, and social health. Physical function scores range from 0 (worst physical function) to 100 (best physical function, where higher scores indicate better clinical outcome.

The EQ-5D-5L questionnaire measures the patient's quality of life (QoL) based on the 5 dimensions mobility, self care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D index score ranges from 0 (worst QoL) to 1 (best QoL), where lower scores indicate worse clinical outcome. The EQ-5D VAS reports patient's self rated health ranging from 0 (worst health) to 100 (best health you can imagine), where lower scores indicate worse clinical outcome.

Health resource utilization was assessed by mean number of general practitioner visits, specialist visits, and physical therapy sessions. In addition, the mean number of days in rehabilitation and the number of work days missed were also reported.

The median number of days in rehabilitation and the number of work days missed were also reported.

TGCT outcome status was collected from information routinely recorded in the patient files / medical records.

Optimapharm

Daiichi Sankyo

Treatment-emergent adverse events and serious adverse events were not assessed in this non-interventional study. Adverse drug reactions suspected to be related to pexidartinib were only collated for patients from the United States.

All participants with diffuse tenosynovial giant cell tumors (d-TGCT) who were enrolled in the study.

Overall

Tenosynovial Giant Cell Tumors

<40 years

≥40 and <60 years

≥60 years

Age, Customized

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

Austria

Netherlands

United States

Italy

United Kingdom

France

Germany

Spain

Region of Enrollment

Knee joint

Ankle joint

Shoulder joint

Foot

Elbow joint

Wrist joint

Hand

Temporomandibular

Tumor location/affected joint

Pain

Limited range of movement

Swelling

Stiffness

Patient unable to judge

Current symptoms

Not applicable

Missing

Most disturbing symptom

4 current symptoms

3 current symptoms

2 current symptoms

Unknown/missing

Number of participants with current symptoms

Demographic and baseline characteristics were assessed in the Full Analysis Set.

This was an observational study and the quality of data has not been verified 100%. Baseline data were checked during on-site visits for all patients enrolled in Europe. Due to the COVID-19 pandemic, the planned on-site monitoring visits in the US could not be performed. Instead, more frequent and detailed remote visits were performed for these sites. Follow-up data for all patients were regularly monitored remotely. A certain amount of incorrect/incomplete data has to be assumed for all sites.

Contact for Clinical Trial Information

Any prior or concomitant therapies for managing TGCT-related symptoms

Any changes to concomitant therapies for managing TGCT-related symptoms since the last visit

Any changes to TGCT treatment (including also planned treatments) since the last visit

All participants with diffuse tenosynovial giant cell tumors (d-TGCT) who were enrolled at baseline in the study.

Baseline

Participants with diffuse tenosynovial giant cell tumors (d-TGCT) who were assessed within 1st year of the study.

Within 1st Year

Management plans were assessed in participants with available data in the Full Analysis Set. Participants may have be included in more than one category.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Denosumab in Subjects With Giant Cell Tumor of Bone	NCT00680992	Cancer Giant Cell Tumo... Giant Cell Tumo... Benign Giant Ce...	Denosumab	12 Years -	Amgen
Network Pharmacology Prediction: Mechanism Study of Puerarin in the Treatment of Giant Cell Tumors of Bone	NCT06331104	Giant Cell Tumo...	gene expression...	-	First Affiliated Hospital, Sun Yat-Sen University
Network Pharmacology Prediction: Mechanism Study of Puerarin in the Treatment of Giant Cell Tumors of Bone	NCT06331104	Giant Cell Tumo...	gene expression...	-	First Affiliated Hospital, Sun Yat-Sen University
Tenosynovial Giant Cell Tumors (TGCT) Observational Platform Project	NCT02948088	Giant Cell Tumo...		18 Years -	Daiichi Sankyo
Study of Denosumab in Subjects With Giant Cell Tumor of Bone	NCT00680992	Cancer Giant Cell Tumo... Giant Cell Tumo... Benign Giant Ce...	Denosumab	12 Years -	Amgen
Network Pharmacology Prediction: Mechanism Study of Puerarin in the Treatment of Giant Cell Tumors of Bone	NCT06331104	Giant Cell Tumo...	gene expression...	-	First Affiliated Hospital, Sun Yat-Sen University
Network Pharmacology Prediction: Mechanism Study of Puerarin in the Treatment of Giant Cell Tumors of Bone	NCT06331104	Giant Cell Tumo...	gene expression...	-	First Affiliated Hospital, Sun Yat-Sen University

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