Reduced Dose-density of Denosumab for Unresectable GCTB

Study Overview
=================
Brief Summary
-----------------
This study is a multi-center, multi-national, open label, single arm phase 2 study of single-agent denosumab. The objective of the trial is to evaluate the risk versus benefit of denosumab in maintenance setting in patients requiring long-term use (> 1 year) of denosumab. For that purpose, the treatment schedule with reduced dose density (120mg SC 12-weekly instead of 4-weekly) will be investigated, starting after 1-year (12-15 months) of denosumab full dose, as per current label. The impact on OsteoNecrosis of the Jaw (ONJ) without compromising disease control will be assessed.

Official Title
-----------------
Reduced Dose-density of Denosumab for Maintenance Therapy of Unresectable Giant Cell Tumor of Bone: a Multicenter Phase II Study REDUCE

Conditions
-----------------
Bone Giant Cell Tumor

Intervention / Treatment
-----------------
* Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven primary or metastatic unresectable GCTB or resectable GCTB but not a candidate for surgery, excluding primary or metastatic GCTB in the jaw. Evidence of active disease at time of registration based on local investigator's assessment (according to RECIST v1.1) Age ≥ 18 years old and skeletally mature (ie, radiographic evidence of at least 1 mature long bone (e.g. humerus with closed growth epiphyseal plate) Patient must have received denosumab before entering this trial: The duration of treatment with full dose denosumab (120 mg SC ) as per current label must be at least 12 months and patient may have received up to 15 months of denosumab. And patient must have received at least 12 doses of denosumab 120 mg before entering into this trial. ECOG/WHO PS 0-2 Albumin-adjusted serum calcium level ≥ 2.0 mmol/L (8.0 mg/dL) Representative formalin fixed, paraffin embedded tumor blocks or unstained tissue slides, either from the primary tumor or a metastatic lesion, must be available for histological central review. Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 7 days prior to the first reduced dose of study treatment. WOCBP should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 5 months after the last treatment cycle. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include: Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) Intrauterine device (IUD) Intrauterine hormone-releasing system (IUS) Bilateral tubal occlusion Vasectomized partner Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient) Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 5 months after the last study treatment. Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations. Exclusion Criteria: Currently receiving other GCTB specific treatment (eg, radiation, chemotherapy, or embolization) Concurrent bisphosphonate treatment and calcitonin Known or suspected current diagnosis of underlying malignancy including high-grade sarcoma, osteosarcoma, fibrosarcoma, malignant giant cell sarcoma Known diagnosis of second malignancy within the past 5 years (subjects with definitively treated basal cell carcinoma and cervical carcinoma in situ are permitted) Creatinine clearance < 30 mL/min Hemoglobin < 10.0 g/dL or 6.2 mmol/L Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw Active dental or jaw condition which requires oral surgery, including tooth extraction Non-healed dental/oral surgery Planned invasive dental procedure for the course of the study Known hypersensitivity to the active substance or to any of the excipients (glacial acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 20) Treatment with other investigational device or drug 30 days prior to registration Known hypersensitivity to products to be administered during the study (calcium and/or vitamin D) Unstable systemic disease including active and uncontrolled infection, uncontrolled hypertension, unstable angina, congestive heart failure, or myocardial infarction within 6 months before registration Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denosumab<br>denosumab at reduced dose | Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]<br>* Denosumab 120 mg, SC, on day 1 of every 12-week cycle<br>* Other names: Xgeva;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | according to RECIST 1.1 | 5.8 years after first patient in | 
| Osteonecrosis of the jaw (ONJ) incidence |  | 5.8 years after first patient in | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | 5.8 years after first patient in | 
| Denosumab treatment duration |  | 5.8 years after first patient in | 
| Occurrence of Adverse Events | according to CTCAE v5.0 | 5.8 years after first patient in | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
denosumab, Giant cell tumor of bone