Characteristics and Mechanism of Denosumab-treated Giant Cell Tumor of Bone

Giant Cell Tumor of Bone Clinical Trial

— D-Gct  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03259152
• Other study ID #: ZZ3592-2017
• Status: Recruiting
• Phase: Phase 3
• First received: August 17, 2017
• Last updated: August 23, 2017
• Start date: May 1, 2016
• Est. completion date: May 1, 2019

Study information

• Verified date: May 2017
• Source: Hebei Medical University Third Hospital
• Contact: Zhuang Zhou, Ph.D
• Phone: +86 18833130669
• Email: 39094572[@]qq.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: May 1, 2019
• Est. primary completion date: May 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Bone Neoplasms
• Giant Cell Tumor of Bone
• Giant Cell Tumors

Intervention

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.

Locations

Country	Name	City	State
China	Zhuang Zhou	Shijiazhuang	Hebei

Sponsors (1)

Lead Sponsor	Collaborator
Hebei Medical University Third Hospital

Country where clinical trial is conducted

China, 

References & Publications (3)

Deveci MA, Paydas S, Gönlüsen G, Özkan C, Biçer ÖS, 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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Primary	Molecular analysis (Immunohistochemistry for RANKL, RANK, OPG,Col-I, VEGF)	For collagen RANKL (Receptor Activator for Nuclear Factor-? B Ligand), RANK (Receptor Activator for Nuclear Factor-? 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
Primary	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 Col1a1, Col2a1, 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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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 = [(p/6) × height × width × depth]. If CT or MRI were not available, tumor volume was measured on two-plane radiograghs.	6 month

External Links

•   Description of Denosumab