Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks

NCT ID: NCT02051218

Last Updated: 2025-12-30

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 1380 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-16
• Study Completion Date: 2028-12-31

Brief Summary

The aim of the trial is to test the hypothesis that the benefit of denosumab is maintained if administered only every 12 weeks as compared to every 4 weeks.

Detailed Description

Denosumab, a monoclonal antibody against RANK-Ligand has been shown superior to zoledronic acid in delaying time to a first on-study skeletal related event (SRE) in patients with solid tumors, with no effects on disease progression or survival. Many SREs were silent compression fractures found only because of scheduled imaging. The approved dose of denosumab is 120 mg s.c. every 4 weeks (q4w). Although generally well tolerated, there is a time-dependent increase in osteonecrosis of the jaw in up to 8% of patients. Cases of fatal hypocalcaemia were observed during post marketing surveillance.

The optimal dose and schedule for denosumab is unknown. Denosumab is associated with considerable costs and may add toxicity; thus a study of de-escalation is warranted.

The aim of the trial is to test the hypothesis that the benefit of Denosumab is maintained if administered 120 mg q12w as compared to 120 mg q4w. The primary endpoint of this open-label randomized phase III non-inferiority trial is time to first on-trial symptomatic skeletal event (SSE: i.e. clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression). With a non-inferiority margin of 1.2 for the hazard ratio, a power 80% and a type I error 5%, the total sample size is 1380. Secondary endpoints are safety, time to subsequent on-trial SSE, quality of life, health economic outcomes, and change in bone turnover markers. This study is open for international collaboration.

Conditions

Metastatic Breast Cancer; Metastatic Prostate Cancer; Bone Metastases

Keywords

metastatic breast cancer; castration resistant metastatic prostate cancer; bone metastases; Denosumab; XGEVA; de-escalation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: NONE

Study Groups

Arm B (reduced arm)

Denosumab 120mg (XGEVA®) sc. q4w \[weeks 1, 5, 9\] followed by Denosumab 120mg (XGEVA®) sc. q12w \[weeks 13, 25, …\]

Group Type: EXPERIMENTAL

Denosumab (reduced dosing)

Intervention Type: DRUG

3x Denosumab 120mg (XGEVA®) sc. q4w followed by Denosumab 120mg (XGEVA®) sc. q12w

Arm A (standard arm)

Denosumab 120mg (XGEVA®) sc. q4w

Group Type: ACTIVE_COMPARATOR

Denosumab (standard dosing)

Intervention Type: DRUG

Denosumab 120mg (XGEVA®) sc. q4w

Interventions

Denosumab (reduced dosing)

3x Denosumab 120mg (XGEVA®) sc. q4w followed by Denosumab 120mg (XGEVA®) sc. q12w

Intervention Type: DRUG

Denosumab (standard dosing)

Denosumab 120mg (XGEVA®) sc. q4w

Intervention Type: DRUG

Other Intervention Names

XGEVA®; XGEVA®

Eligibility Criteria

Inclusion Criteria

• Patient has given written informed consent.
• Histologically confirmed diagnosis of breast or prostate cancer before randomization.
• Patient has metastatic breast cancer (stage IV, all subtypes allowed) or prostate cancer (stage IV) and bone metastases and is planned to receive or is receiving antineoplastic treatment.
• Patients with prostate cancer must have evidence of disease progression on continuous androgen deprivation therapy (CRPC).
• Patients must have ≥ 3 bone metastases (lytic or blastic or mixed). The lesions must be documented by radiological evaluation within 12 weeks before randomization (by X-Ray, CT scan, PET-CT, MRI scan or bone scintigraphy).
• WHO performance status 0-2
• Age ≥ 18 years.
• Corrected serum calcium ≥ 2 mmol/l and ≤ 3 mmol/l (medical treatments to obtain serum calcium levels in the normal range are allowed, as far as no denosumab is used. Maximally 1 dose of bisphosphonates in the case of hypercalcemia is allowed, if the bisphosphonate was applied at least 3 weeks before the first dose of denosumab).
• Liver transaminases not more than 1.5 x ULN or not more than 3 x ULN with liver metastases. Serum total bilirubin ≤ 1.5 x ULN (≤ 2.0 x ULN in case of known Gilbert's disease)
• Women are not breastfeeding. Women with child-bearing potential are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. A negative pregnancy test before inclusion (within 7 days) into the trial is required for all women with child-bearing potential.
• Men agree not to father a child during participation in the trial and during 12 months thereafter.

Exclusion Criteria

• Definite contraindication for denosumab (e.g. hypocalcaemia [Albumin-corrected serum calcium < 2.0 mmol/l]).
• History or current evidence of osteonecrosis of the jaw.
• Non-healed mucosa in oral cavity (by surgery or as a side effect of any other treatment).
• Jaw or dental conditions that require oral surgery or if surgery or invasive dental procedures are planned.
• Prior use of denosumab for bone metastases (dose 120 mg every 4 weeks) or bisphosphonates to treat bone metastases. Patients treated with denosumab or bisphosphonates against osteopenia or osteoporosis are allowed to enter the trial if the last dose was more than 28 days before randomization.
• Patients with known osteoporosis (T-score ≤ -2.5) at study entry (since fractures from osteoporosis are difficult to be discriminated from fractures through bone metastases).
• Radiotherapy or surgery to the bone within the last two weeks before randomization or planned within 6 weeks after randomization.
• Presence or history of CNS metastases or leptomeningeal disease. A MRI evaluation within 12 weeks before randomization must be performed in case of suspicious symptoms.
• Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, filling out QoL forms.
• Concurrent treatment in a clinical trial with SSE or SRE as primary endpoint.
• Known hypersensitivity to trial drug or hypersensitivity to any other component of the trial drug (e.g. fructose).
• Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information.
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Swiss Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Roger von Moos, PD MD

Role: STUDY_CHAIR

Kantonsspital Graubünden

Arnoud Templeton, MD

Role: STUDY_CHAIR

Cantonal Hospital of St. Gallen

Silke Gillessen, Prof

Role: STUDY_CHAIR

Cantonal Hospital of St. Gallen

Andreas Müller, MD

Role: STUDY_CHAIR

Kantonsspital Winterthur KSW

Locations

Landeskrankenhaus Feldkirch

Feldkirch, , Austria

Klinikum Wels-Grieskrichen GmbH

Wels, , Austria

Uniklinik Düsseldorf, Urologische Klinik

Düsseldorf, , Germany

Universitätsklinikum Düsseldorf, Frauenheilkunde/Geburtshilfe

Düsseldorf, , Germany

Universitätsmedizin Göttingen

Göttingen, , Germany

Universitätsklinikum Schleswig-Holstein

Lübeck, , Germany

Universitäts-Frauenklinik Ulm

Ulm, , Germany

Hirslanden Klinik Aarau

Aarau, , Switzerland

Kantonspital Aarau

Aarau, , Switzerland

Kantonsspital Baden

Baden, , Switzerland

Universitaetsspital Basel

Basel, , Switzerland

Brustzentrum Basel - Praxis für ambulante Tumortherapie

Basel, , Switzerland

St. Claraspital AG

Basel, , Switzerland

Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli

Bellinzona, , Switzerland

Klinik Engeried / Praxis Oncocare

Bern, , Switzerland

Inselspital, Bern

Bern, , Switzerland

Spitalzentrum Biel

Biel, , Switzerland

Spitalzentrum Oberwallis

Brig, , Switzerland

Centre du Sein de Genève, Clinique des Grangettes

Chêne-Bougeries, , Switzerland

Kantonsspital Graubünden

Chur, , Switzerland

Kantonsspital Frauenfeld - Brustzentrum

Frauenfeld, , Switzerland

Hopital Fribourgeois

Fribourg, , Switzerland

Hopitaux Universitaires de Geneve

Geneva, , Switzerland

Clinique De Genolier

Genolier, , Switzerland

Hôpital neuchâtelois

La Chaux-de-Fonds, , Switzerland

CCAC Lausanne

Lausanne, , Switzerland

CHUV

Lausanne, , Switzerland

Kantonsspital Liestal

Liestal, , Switzerland

Fondazione Oncologia / Oncologia ematologia

Locarno, , Switzerland

Luzerner Kantonsspital

Lucerne, , Switzerland

Hirslanden Klinik St. Anna Luzern

Lucerne, , Switzerland

Oncologia Varini & Calderoni & Christinat

Lugano, , Switzerland

Onkologie Zentrum Spital Männedorf

Männedorf, , Switzerland

Kantonsspital Muensterlingen

Münsterlingen, , Switzerland

Kantonsspital Olten

Olten, , Switzerland

Tumor and Brustzentrum Ostschweiz TBZO

Sankt Gallen, , Switzerland

Tumor and Brustzentrum Ostschweiz TBZO

Sankt Gallen, , Switzerland

Kantonsspital St. Gallen

Sankt Gallen, , Switzerland

Rundum Onkologie am Bahnhofpark

Sargans, , Switzerland

Spital Limmattal

Schlieren, , Switzerland

Hôpital du Valais Sion

Sion, , Switzerland

Bürgerspital Solothurn - Zentrum für Onkologie und Hämatologie

Solothurn, , Switzerland

Spital STS AG

Thun, , Switzerland

Kantonsspital Winterthur

Winterthur, , Switzerland

Onkologie Bellevue

Zurich, , Switzerland

Brustzentrum-Zürich

Zurich, , Switzerland

Klinik für Hämatologie und Onkologie Hirslanden Zürich AG

Zurich, , Switzerland

Onkozentrum Klinik im Park

Zurich, , Switzerland

Universitätsspital Zürich

Zurich, , Switzerland

Stadtspital Zürich Triemli

Zurich, , Switzerland

Countries

Austria; Germany; Switzerland

References

Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.

Reference Type: DERIVED

PMID: 38979716 (View on PubMed)

Other Identifiers

000000685

Identifier Type: OTHER

Identifier Source: secondary_id

2014-001189-87

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SAKK 96/12

Identifier Type: -

Identifier Source: org_study_id