Reduced Dose-density of Denosumab for Unresectable GCTB

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.


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.