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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02051218
Recruitment Status : Recruiting
First Posted : January 31, 2014
Last Update Posted : November 20, 2018
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research

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.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Metastatic Prostate Cancer Bone Metastases Drug: Denosumab (reduced dosing) Drug: Denosumab (standard dosing) Phase 3

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1380 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks - A Non-Inferiority Phase III Trial
Actual Study Start Date : July 16, 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Denosumab

Arm Intervention/treatment
Active Comparator: Arm A (standard arm)
Denosumab 120mg (XGEVA®) sc. q4w
Drug: Denosumab (standard dosing)
Denosumab 120mg (XGEVA®) sc. q4w
Other Name: XGEVA®

Experimental: Arm B (reduced arm)
Denosumab 120mg (XGEVA®) sc. q4w [weeks 1, 5, 9] followed by Denosumab 120mg (XGEVA®) sc. q12w [weeks 13, 25, …]
Drug: Denosumab (reduced dosing)
3x Denosumab 120mg (XGEVA®) sc. q4w followed by Denosumab 120mg (XGEVA®) sc. q12w
Other Name: XGEVA®

Primary Outcome Measures :
  1. Time to first on-trial symptomatic skeletal event (SSE; Clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression). [ Time Frame: at the latest 5 years after randomization. ]
    A SSE is defined as one of the following events: Clinically significant pathological fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.

Secondary Outcome Measures :
  1. Toxicity (focus on hypocalcaemia and osteonecrosis of the jaw) [ Time Frame: at the latest 5 years after randomization. ]
  2. Time to first and subsequent on-trial SSE [ Time Frame: at the latest 5 years after randomization. ]
  3. Quality of Life measured by FACT-G and FACT-BP [ Time Frame: at the latest 5 years after randomization. ]
  4. Skeletal morbidity period rate (SMPR) [ Time Frame: at the latest 5 years after randomization. ]
  5. Skeletal morbidity rate (SMR) [ Time Frame: at the latest 5 years after randomization. ]
  6. Health economic analysis [ Time Frame: at the latest 5 years after randomization. ]
  7. Bone turnover markers [ Time Frame: at the latest 5 years after randomization. ]
  8. Overall Survival (OS) [ Time Frame: at the latest 5 years after randomization. ]

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02051218

Contact: Andrea Fuhrer, PhD +41 31 389 91 91

Uniklinik Düsseldorf, Urologische Klinik Recruiting
Düsseldorf, Germany, 40225
Contact: Anja Lorch, Prof    +49 211 81 08776   
Principal Investigator: Anja Lorch, Prof         
Universitätsklinikum Düsseldorf, Frauenheilkunde/Geburtshilfe Recruiting
Düsseldorf, Germany, 40225
Contact: Eugen Ruckhäberle, Prof    +49 311 81-08087   
Principal Investigator: Eugen Ruckhäberle, Prof         
Universitätsklinikum Schleswig-Holstein Recruiting
Lübeck, Germany, 23538
Contact: Achim Rody, Prof    +49 451 500 41700   
Principal Investigator: Achim Rody         
Universitäts-Frauenklinik Ulm Recruiting
Ulm, Germany, 89075
Contact: Jens Huober, Prof    +49 731 500 58511   
Principal Investigator: Jens Huober, Prof         
Hirslanden Klinik Aarau Recruiting
Aarau, Switzerland, CH-5001
Contact: Razvan Popescu, MD    +41 62 836 78 30   
Principal Investigator: Razvan Popescu, MD         
Kantonspital Aarau Recruiting
Aarau, Switzerland, CH-5001
Contact: Tobias Wehrhahn, MD    +41 62 838 59 27   
Principal Investigator: Tobias Wehrhahn, MD         
Kantonsspital Baden Recruiting
Baden, Switzerland, CH-5404
Contact: Priska Bützberger, MD    +41 56 486 27 62   
Principal Investigator: Priska Bützberger, MD         
Universitaetsspital Basel Recruiting
Basel, Switzerland, 4031
Contact: Sacha Rothschild, MD    +41 61 265 25 25   
Principal Investigator: Sacha Rothschild, MD         
Brustzentrum Basel - Praxis für ambulante Tumortherapie Recruiting
Basel, Switzerland, 4052
Contact: David Roger Thorn, MD    +41 61 279 98 22   
Principal Investigator: David Roger Thorn, MD         
St. Claraspital AG Recruiting
Basel, Switzerland, CH-4016
Contact: Arnoud Templeton, MD    +41 61 685 83 30   
Principal Investigator: Arnoud Templeton, MD         
Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli Recruiting
Bellinzona, Switzerland, 6500
Contact: Olivia Pagani, MD    +41 91 811 84 35   
Principal Investigator: Olivia Pagani, MD         
Klinik Engeried / Praxis Oncocare Recruiting
Bern, Switzerland, 3012
Contact: Katharina Buser, MD    +41 31 309 95 01   
Principal Investigator: Katharina Buser, MD         
Inselspital, Bern Recruiting
Bern, Switzerland, CH-3010
Contact: Julian Schardt, MD    +41 31 632 11 55   
Principal Investigator: Julian Schardt, MD         
Spitalzentrum Biel Recruiting
Biel, Switzerland, CH-2501
Contact: Martin Zweifel, MD    +41 32 324 36 62   
Principal Investigator: Martin Zweifel, MD         
Spitalzentrum Oberwallis Recruiting
Brig, Switzerland, 3900
Contact: Catherine Mengis Bay, MD    +41 27 604 36 60   
Principal Investigator: Catherine Mengis Bay, MD         
Kantonsspital Graubünden Recruiting
Chur, Switzerland, 7000
Contact: Roger von Moos, MD, PD    +41 81 256 66 47   
Principal Investigator: Roger von Moos, MD, PD         
Centre du Sein de Genève, Clinique des Grangettes Recruiting
Chêne-Bougeries, Switzerland, 1224
Contact: Mahbiz Nobahar Corke, MD    +41 22 545 80 06   
Principal Investigator: Mahbiz Nobahar Corke, MD         
Kantonsspital Frauenfeld - Brustzentrum Recruiting
Frauenfeld, Switzerland, 8501
Contact: Mathias Fehr, MD    +41 52 723 72 53   
Principal Investigator: Mathias Fehr, MD         
Hopital Fribourgeois Recruiting
Fribourg, Switzerland, 1708
Contact: Marc Küng, MD    +41 26 426 72 43   
Principal Investigator: Marc Küng, MD         
Clinique De Genolier Recruiting
Genolier, Switzerland, 1272
Contact: Volker Kirchner, MD    +41 22 366 94 42   
Principal Investigator: Volker Kirchner, MD         
Hopitaux Universitaires de Geneve Recruiting
Genève 14, Switzerland, 1211
Contact: Alexandre Bodmer, MD    +41 22 372 40 14   
Principal Investigator: Alexandre Bodmer, MD         
Hôpital neuchâtelois Recruiting
La Chaux-de-Fonds, Switzerland, 2300
Contact: Agnes Auteri, MD    +41 79 559 41 93   
Principal Investigator: Agnes Auteri, MD         
CCAC Lausanne Recruiting
Lausanne, Switzerland, 1004
Contact: Pierre Bohanes, MD    +41 (21) 646 79 94   
Principal Investigator: Pierre Bohanes, MD         
CHUV Recruiting
Lausanne, Switzerland, 1011
Contact: Khalil Zaman, MD    +41 79 556 78 01   
Principal Investigator: Khalil Zaman, MD         
Kantonsspital Liestal Recruiting
Liestal, Switzerland, CH-4410
Contact: Bettina Seifert, MD    +41 61 925 34 03   
Principal Investigator: Bettina Seifert, MD         
Fondazione Oncologia / Oncologia ematologia Recruiting
Locarno, Switzerland, 6600
Contact: Augusto Pedrazzini, MD    +41 91 752 3535   
Principal Investigator: Augusto Pedrazzini, MD         
Oncologia Varini & Calderoni & Christinat Recruiting
Lugano, Switzerland, 6900
Contact: Antonello Calderoni, MD    +41 91 922 69 88   
Principal Investigator: Antonello Calderoni, MD         
Luzerner Kantonsspital Recruiting
Luzern, Switzerland, 6000
Contact: Ralph Winterhalder, MD    +41 41 205 58 75   
Principal Investigator: Ralph Winterhalder, MD         
Hirslanden Klinik St. Anna Luzern Recruiting
Luzern, Switzerland, 6006
Contact: Christian Spirig, MD    +41 41 208 32 10   
Principal Investigator: Christian Spirig, MD         
Onkologie Zentrum Spital Männedorf Recruiting
Männedorf, Switzerland, 8708
Contact: Andreas Hochstrasser, MD    +41 44 922 30 00   
Principal Investigator: Andreas Hochstrasser, MD         
Kantonsspital Muensterlingen Recruiting
Münsterlingen, Switzerland, 8596
Contact: Roman Inauen, MD    +41 71 686 11 11   
Principal Investigator: Roman Inauen, MD         
Kantonsspital Olten Recruiting
Olten, Switzerland, 4600
Contact: Catrina Uhlmann Nussbaum, MD    +41 62 311 42 41   
Principal Investigator: Catrina Uhlmann Nussbaum, MD         
Rundum Onkologie am Bahnhofpark Recruiting
Sargans, Switzerland, 7320
Contact: Stefan Greuter, MD    +41 81 720 06 20   
Principal Investigator: Stefan Greuter, MD         
Spital Limmattal Recruiting
Schlieren, Switzerland, 8952
Contact: Alix Stern, MD    +41 44 733 22 48   
Principal Investigator: Alix Stern, MD         
Hôpital du Valais Sion Recruiting
Sion, Switzerland, 1951
Contact: Sandro Anchisi, Dr. med.    +41 (27) 603 45 00   
Principal Investigator: Sandro Anchisi, Dr. med.         
Bürgerspital Solothurn - Onkologiezentrum Recruiting
Solothurn, Switzerland, 4600
Contact: Philippe von Burg, MD    +41 32 627 47 00   
Principal Investigator: Philippe von Burg, MD         
Zentrum fuer Tumordiagnostikund Praevention Recruiting
St. Gallen, Switzerland, CH-9006
Contact: Friedemann Honecker, MD    +41 71 243 00 43   
Principal Investigator: Friedemann Honecker, MD         
Kantonsspital St. Gallen Recruiting
St. Gallen, Switzerland, CH-9007
Contact: Sabine Schmid, MD    +41 71 494 11 11   
Principal Investigator: Sabine Schmid, MD         
Spital STS AG Recruiting
Thun, Switzerland, 3600
Contact: Daniel Rauch, MD    +41 58 636 26 45   
Principal Investigator: Daniel Rauch, MD         
Kantonsspital Winterthur Recruiting
Winterthur, Switzerland, 8401
Contact: Andreas Müller, MD    41-052-266-2552   
Principal Investigator: Andreas Müller, MD         
Onkologie Bellevue Recruiting
Zurich, Switzerland, 8001
Contact: Basil A. Bättig, MD    +41 44 261 61 11   
Principal Investigator: Basil A. Bättig, MD         
Onkozentrum Klinik im Park Recruiting
Zurich, Switzerland, 8038
Contact: Urs Huber, MD    41-43-344-3333   
Principal Investigator: Urs Huber, MD         
Brustzentrum-Zürich Recruiting
Zürich, Switzerland, 8005
Contact: Andreas Trojan, Prof    +41 (43) 344 33 33   
Principal Investigator: Andreas Trojan, Prof         
Hirslanden Onkozentrum Zürich Recruiting
Zürich, Switzerland, 8032
Contact: Thomas von Briel, Dr. med.    +41 (44) 387 35 35   
Principal Investigator: Thomas von Briel, Dr. med.         
Universitätsspital Zürich Recruiting
Zürich, Switzerland, 8091
Contact: Thomas Hermanns, MD    +41 44 255 51 67   
Principal Investigator: Thomas Hermanns, MD         
Stadtspital Triemli Recruiting
Zürich, Switzerland, CH-8063
Contact: Susanna Stoll, MD    +41 44 416 34 75   
Principal Investigator: Susanna Stoll, MD         
Sponsors and Collaborators
Swiss Group for Clinical Cancer Research
Study Chair: Roger von Moos, PD MD Kantonsspital Graubünden
Study Chair: Arnoud Templeton, MD Cantonal Hospital of St. Gallen
Study Chair: Silke Gillessen, Prof Cantonal Hospital of St. Gallen
Study Chair: Andreas Müller, MD Kantonsspital Winterthur KSW

Responsible Party: Swiss Group for Clinical Cancer Research Identifier: NCT02051218     History of Changes
Other Study ID Numbers: SAKK 96/12
000000685 ( Other Identifier: SNCTP )
2014-001189-87 ( EudraCT Number )
First Posted: January 31, 2014    Key Record Dates
Last Update Posted: November 20, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Swiss Group for Clinical Cancer Research:
metastatic breast cancer
castration resistant metastatic prostate cancer
bone metastases

Additional relevant MeSH terms:
Prostatic Neoplasms
Neoplasm Metastasis
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Prostatic Diseases
Genital Diseases, Male
Neoplastic Processes
Pathologic Processes
Bone Density Conservation Agents
Physiological Effects of Drugs