Reduced Dose-density of Denosumab for Unresectable GCTB (REDUCE)

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

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.

Study Overview

• Status: Terminated
• Conditions: Bone Giant Cell Tumor
• Intervention / Treatment: Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Bologna, Italy
    • IRCCS Istituto Ortopedico Rizzoli
• Netherlands
  • Leiden, Netherlands, 2300
    • Leiden University Medical Centre
• Spain
  • Barcelona, Spain, 08041
    • Hospital De La Santa Creu I Sant Pau
  • Barcelona, Spain
    • Vall d'Hebron Institut d'Oncologia
  • Barcelona, Spain, 08908
    • Institut Catala d'Oncologia - ICO L'Hospitalet - Hospital Duran i Reynals (Institut Catala D'Oncologia)
  • Madrid, Spain, 28040
    • Hospital Universitario San Carlos
• United Kingdom
  • London, United Kingdom
    • University College London Hospitals NHS Foundation Trust - University College Hospital
  • Oxford, United Kingdom, OX3 7LE
    • Oxford University Hospitals NHS Trust - Churchill Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: Amgen
• Investigators: Study Chair: Emanuela Palmerini, IRCCS Instituto Ortopedico Rizzoli; Study Chair: Hans Gelderblom, Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2019
• Primary Completion (Actual): July 30, 2020
• Study Completion (Actual): July 30, 2020

Study Registration Dates

• First Submitted: August 3, 2018
• First Submitted That Met QC Criteria: August 3, 2018
• First Posted (Actual): August 8, 2018

Study Record Updates

• Last Update Posted (Actual): January 6, 2021
• Last Update Submitted That Met QC Criteria: January 4, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Giant cell tumor of bone; denosumab
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Giant Cell Tumors; Giant Cell Tumor of Bone; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: EORTC 1762-STBSG; 2018-002096-17 (EudraCT Number); 20177203 (Other Identifier: Amgen)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All publications must comply with the terms specified in the EORTC Policy 009 "Release of Results and Publication Policy".

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No