Characteristics and Mechanism of Denosumab-treated Giant Cell Tumor of Bone (D-Gct)

Clinical, Pathologic Characteristics and Its Mechansim of Denosumab Treated Giant Cell Tumor of Bone

Giant cell tumor of bone (GCTb) is a primary, osteolytic, benign tumor of the bone. Surgery is the commonly used treatment. Discovery of RANKL and its human monoclonal antibody, denosumab, led to use of denosumab for treatment of GCT. The aim of this study was to evaluate clinical and pathological results of treatment of relapsed or refractoriness GCT with denosumab and to assess adverse effect profile and recurrence rate.

Study Overview

• Status: Unknown
• Conditions: Giant Cell Tumor of Bone
• Intervention / Treatment: Drug: Denosumab

Detailed Description

Giant cell tumor of bone (GCTb) is an aggressive, benign bone tumor. GCTb, which was first defined by Cooper and Travers, can produce pulmonary metastasis, albeit rarely (1-6%). GCTb constitutes 5% of primary bone tumors and 20% of benign bone tumors. Histologically, the tumour consists of a proliferation of mononuclear cells, accompanied by a population of non-neoplastic osteoclast-like giant cells and mononuclear osteoclast precursors. Currently, it is thought that proliferating neoplastic cells produce a number of cytokines and mediators, including the receptor activator of nuclear factor κ-B-ligand (RANK-RANKL) system, that recruit osteoclast precursors and induce their maturation into multinucleated osteoclast. The standard management of GCTb is based on surgery with several local adjuvant treatments like methacrylate cement, phenol or cryotherapy to reduce the risk of recurrence, while bisphosphonates are used in some cases to decrease bone resorption and for pain relief in inoperable tumours or metastatic disease. In the last 5 years the use of denosumab, a fully human monoclonal antibody already licensed for postmenopausal osteoporosis and prevention of skeletal related events in bone metastases from solid tumours, has been introduced in the treatment strategy of GCTb. In this study we examined the clinical, radiological, histological and underlying mechanism features of a series of GCTb, before and after denosumab administration, comparing baseline and resection specimens. Moreover, we examined the safety of the drug and on the angiogenesis through the determination of microvascular density (MVD).

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Zhuang Zhou, Ph.D; Phone Number: +86 18833130669; Email: 39094572@qq.com
• Study Contact Backup: Name: Guochuan Zhang, M.D.; Phone Number: +86 13932110889

Study Locations

• China
  • Hebei
    • Shijiazhuang, Hebei, China, 050000
      • Recruiting
      • Zhuang Zhou
      • Contact: Zhuang Zhou, Ph.D; Phone Number: +86 18833130669; Email: 39094572@qq.com
      • Contact: Guochuan Zhang, M.D.; Phone Number: +86 13932110889

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Giant cell tumor of bone patients confirmed by clinical, medical imaging and Pathology.

Exclusion Criteria:

• (1) less than 14 patients; 2) pregnant patients; 3) A patient who receives other medications during treatment.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pre-Denosumab GctB; Specimens obtained during biopsy	Drug: Denosumab; Denosumab (trade names Prolia and Xgeva) is a human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.Denosumab is a RANKL inhibitor, which works by preventing the development of osteoclasts which are cells that break down bone.; Other Names: Xgeva or Prolia
Experimental: Post-Denosumab GctB; Specimen after administration of Denosumab	Drug: Denosumab; Denosumab (trade names Prolia and Xgeva) is a human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.Denosumab is a RANKL inhibitor, which works by preventing the development of osteoclasts which are cells that break down bone.; Other Names: Xgeva or Prolia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular analysis (Immunohistochemistry for RANKL, RANK, OPG,Col-I, VEGF)	For collagen RANKL (Receptor Activator for Nuclear Factor-κ B Ligand), RANK (Receptor Activator for Nuclear Factor-κ B), OPG (Osteoprotegerin), Col-I (type I Collagen), VEGF (Vascular Endothelial Growth Factor) immunohistochemistry, sections were deparaffinized, rehydrated, and immunostained with a SA1024 SABC-POD kit and Kit-0017 DAB detection kit. Briefly, antigen retrieval was performed, and endogenous peroxidases were then inactivated prior to incubation with primary antibodies overnight at 4°C. This was followed by incubation with a biotinylated secondary antibody and a streptavidin-biotin complex peroxidase solution. Diaminobenzidine (DAB) chromogen was applied and counterstained with hematoxylin for antibody detection. Images were captured by a microscope system at 400-magnification. The integrated optical density values of each factor were semiquantitatively analyzed using Imaging Pro Plus 6.0 software.	6 month
Molecular analysis (RT-PCR for RANKL, RANK, OPG,Col-I, VEGF)	Tissures mRNA was extracted using TRIzol reagent (Invitrogen, Carlsbad, CA). The RNA concentration and quality were assessed using a Quawell Q5000 spectrophotometer (Quawell, San Jose, CA). Reverse transcription PCR was performed using a Gene Amp 7700 Sequence Detection System (Applied Biosystems, Foster City, CA) and custom-designed, validated primers for Col1α1, Col2α1, Aggrecan, MMP-13, and ADAMTS-4. GAPDH was used as the housekeeping gene. Relative gene expression changes were reported using the 2(-Delta Delta C(T)) method as previously described. The experiment was repeated in triplicate to ensure accuracy.	6 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analog Score - Pain evaluation	Visual analog scale [VAS] is a measure of pain intensity. It is a continuous scale comprised of a horizontal (called horizontal visual analogue scale) or,vertical called vertical visual analog scale usually 10 cm or 100 mm length [both the gradations are used]. It is anchored by two verbal descriptors, one for each symptom extreme. For pain intensity, the scale is most commonly anchored by "no pain" (score of 0) and "pain as bad as it could be" or "worst imaginable pain" (score of 100 [on 100-mm scale]	6 months
Hematology test - Tartrate Resistant Acid Phosphatase	Tartrate-resistant acid phosphatase, a bone resorption marker, is secreted from osteoclasts and this marker is reported to be high in patients with giant cell tumor of bone. We investigated the effects of denosumab and the usefulness of a tartrate-resistant acid phosphatase as a monitoring marker in the management of a refractory giant cell tumor of bone. Tartrate-resistant acid phosphatase secretion was measured in the patient's serum to monitor the response to denosumab, and a rapid normalization of the marker was observed after the first denosumab administration.	6 months
Follow-up for recrudescence	Patients were followed up regularly for local or systemic tumor recurrence by X-ray, CT, MRI, ECT. The follow-up period was 3 months.	6 month to 1 year
Morphological change - HE (Hematoxylin-Eosin) staining	For histological analysis of the adjacent intervertebral disc and fusion mass, the tissures of the Giant cell tumor of bone were fixed in 10% neutral buffered formalin, decalcified in 10% EDTA-2Na for 3 months, and then embedded in paraffin. They were subsequently cut into 5-mm sections with cationic slides. Slides of the tissures of the Giant cell tumor of bone were stained with H&E and captured by a microscope system (BX53; Olympus, Tokyo, Japan).	6 month
Micro-vessel density or area by IHC - stained slides	IHC - stained for VEGF images were used for microvessel density (MVD) and vascular bud relative area analysis. MVD was measured by counting the number of cartilage endplate vascular buds (an average of cephalic and caudal vascular buds). The ratio of vascular bud area to the total endplate area was measured for vascular bud relative area analysis using the grid method. MVD and vascular bud relative area analyses were repeated at least three times for enhanced accuracy	6 month
Imaging changes by X-ray, CT, MRI, ECT.	The patients' clinical information, images from radiographs, CT and MRI before and after Denosumab-treatment were recorded and analyzed. Tumor volume was measured on coronal, transverse, and sagital MRI or CT scansof the lesion; and maximum height, width, and depth were recorded; and the volume was calculated using the formula of an ellopsoid mass volume = [(π/6) × height × width × depth]. If CT or MRI were not available, tumor volume was measured on two-plane radiograghs.	6 month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	The CTCAE v.4 criteria was used to evaluate late toxicity for all patients. Toxicity scores were recalculated for patients treated before publication of CTCAE v4.0 scale.	3 year

Collaborators and Investigators

• Sponsor: Hebei Medical University Third Hospital
• Investigators: Principal Investigator: Zhuang Zhou, Ph.D, Hebei Medical University Third Hospital

Publications and helpful links

General Publications

• Girolami I, Mancini I, Simoni A, Baldi GG, Simi L, Campanacci D, Beltrami G, Scoccianti G, D'Arienzo A, Capanna R, Franchi A. Denosumab treated giant cell tumour of bone: a morphological, immunohistochemical and molecular analysis of a series. J Clin Pathol. 2016 Mar;69(3):240-7. doi: 10.1136/jclinpath-2015-203248. Epub 2015 Sep 3.
• Deveci MA, Paydas S, Gonlusen G, Ozkan C, Bicer OS, Tekin M. Clinical and pathological results of denosumab treatment for giant cell tumors of bone: Prospective study of 14 cases. Acta Orthop Traumatol Turc. 2017 Jan;51(1):1-6. doi: 10.1016/j.aott.2016.03.004. Epub 2016 Oct 24.
• Rutkowski P, Ferrari S, Grimer RJ, Stalley PD, Dijkstra SP, Pienkowski A, Vaz G, Wunder JS, Seeger LL, Feng A, Roberts ZJ, Bach BA. Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone. Ann Surg Oncol. 2015 Sep;22(9):2860-8. doi: 10.1245/s10434-015-4634-9. Epub 2015 Jun 2.

Helpful Links

• Description of Denosumab

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Anticipated): May 1, 2019
• Study Completion (Anticipated): May 1, 2019

Study Registration Dates

• First Submitted: August 17, 2017
• First Submitted That Met QC Criteria: August 19, 2017
• First Posted (Actual): August 23, 2017

Study Record Updates

• Last Update Posted (Actual): August 24, 2017
• Last Update Submitted That Met QC Criteria: August 23, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Clinical; Giant cell tumor of bone; Denousmab; Pathologic; Mechansim
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Musculoskeletal Diseases; Bone Diseases; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Bone Neoplasms; Giant Cell Tumors; Giant Cell Tumor of Bone; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: ZZ3592-2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: We have not yet planned to to make individual participant data (IPD) available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No