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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Swiss Group for Clinical Cancer Research
Sponsor:
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier:
NCT02051218
First received: January 29, 2014
Last updated: September 9, 2014
Last verified: September 2014
  Purpose

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 Intervention Phase
Metastatic Breast Cancer
Metastatic Prostate Cancer
Bone Metastases
Drug: Denosumab (reduced dosing)
Drug: Denosumab (standard dosing)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Swiss Group for Clinical Cancer Research:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
    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:
  • Toxicity (focus on hypocalcaemia and osteonecrosis of the jaw) [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: Yes ]
  • Time to first and subsequent on-trial SSE [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Quality of Life [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Skeletal morbidity period rate (SMPR) [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Skeletal morbidity rate (SMR) [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Health economic analysis [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Bone turnover marker change [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]
  • Overall Survival (OS) [ Time Frame: at the latest 5 years after randomization. ] [ Designated as safety issue: No ]

Estimated Enrollment: 1380
Study Start Date: July 2014
Estimated Study Completion Date: December 2022
Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)
3x Denosumab 120mg (XGEVA®) sc. q4w followed by Denosumab 120mg (XGEVA®) sc. q12w
Drug: Denosumab (reduced dosing)
3x Denosumab 120mg (XGEVA®) sc. q4w followed by Denosumab 120mg (XGEVA®) sc. q12w
Other Name: XGEVA®

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 bisphosphonates or denosumab are used).
  • Liver transaminases within normal range 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02051218

Contacts
Contact: Lukas Stalder, PhD +41 31 389 91 99 lukas.stalder@sakk.ch

Locations
Switzerland
Kantonspital Aarau Recruiting
Aarau, Switzerland, CH-5001
Contact: Philippe von Burg, MD    +41 62 838 59 94    philippe.vonburg@ksa.ch   
Principal Investigator: Philippe von Burg, MD         
Hirslanden Klinik Aarau Recruiting
Aarau, Switzerland, CH-5001
Contact: Razvan Popescu, MD    +41 62 836 78 30    Razvan.Popescu@hirslanden.ch   
Principal Investigator: Razvan Popescu, MD         
Kantonsspital Baden Recruiting
Baden, Switzerland, CH-5404
Contact: Priska Bützberger, MD    +41 56 486 27 62    priska.buetzberger@ksb.ch   
Principal Investigator: Priska Bützberger, MD         
Universitaetsspital Basel Recruiting
Basel, Switzerland, 4031
Contact: Sacha Rothschild, MD    +41 61 265 25 25    sacha.rothschild@usb.ch   
Principal Investigator: Sacha Rothschild, MD         
St. Claraspital AG Recruiting
Basel, Switzerland, CH-4016
Contact: Dieter Köberle, MD    +41 61 685 85 85    dieter.koeberle@claraspital.ch   
Principal Investigator: Dieter Köberle, MD         
Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli Recruiting
Bellinzona, Switzerland, 6500
Contact: Olivia Pagani, MD    +41 91 811 84 35    olivia.pagani@ibcsg.org   
Principal Investigator: Olivia Pagani, MD         
Inselspital, Bern Recruiting
Bern, Switzerland, CH-3010
Contact: Julian Schardt, MD    +41 31 632 11 55    julian.schardt@insel.ch   
Principal Investigator: Julian Schardt, MD         
Klinik Engeried / Praxis Oncocare Recruiting
Bern, Switzerland, 3012
Contact: Katharina Buser, MD    +41 31 309 95 01    kbuser@oncocare.ch   
Principal Investigator: Katharina Buser, MD         
Spitalzentrum Biel Recruiting
Biel, Switzerland, CH-2501
Contact: Markus Borner, Prof    41-32-324-3714    markus.borner@szb-chb.ch   
Principal Investigator: Markus Borner, Prof         
Kantonsspital Graubünden Recruiting
Chur, Switzerland, 7000
Contact: Roger von Moos, MD, PD    +41 81 256 66 47    roger.vonmoos@ksgr.ch   
Principal Investigator: Roger von Moos, MD, PD         
Hopital Fribourgeois Recruiting
Fribourg, Switzerland, 1708
Contact: Marc Küng, MD    +41 26 426 72 43    marc.kueng@h-fr.ch   
Principal Investigator: Marc Küng, MD         
Hopitaux Universitaires de Geneve Recruiting
Genève 14, Switzerland, 1211
Contact: Alexandre Bodmer, MD    +41 22 372 40 14    alexandre.bodmer@hcuge.ch   
Principal Investigator: Alexandre Bodmer, MD         
Kantonsspital Liestal Recruiting
Liestal, Switzerland, CH-4410
Contact: Bettina Seifert, MD    +41 61 925 34 03    bettina.seifert@ksli.ch   
Principal Investigator: Bettina Seifert, MD         
Fondazione Oncologia / Oncologia ematologia Recruiting
Locarno, Switzerland, 6600
Contact: Augusto Pedrazzini, MD    +41 91 752 3535    a.pedrazzini@oncologia-pedrazzini.ch   
Principal Investigator: Augusto Pedrazzini, MD         
Oncologia Varini & Calderoni & Christinat Recruiting
Lugano, Switzerland, 6900
Contact: Antonello Calderoni, MD    +41 91 922 69 88    antonello@calderoni.ch   
Principal Investigator: Antonello Calderoni, MD         
Kantonsspital Muensterlingen Recruiting
Muensterlingen, Switzerland, 8596
Contact: Roman Inauen, MD    +41 71 686 11 11    roman.inauen@stgag.ch   
Principal Investigator: Roman Inauen, MD         
Kantonsspital Olten Recruiting
Olten, Switzerland, 4600
Contact: Catrina Uhlmann Nussbaum, MD    +41 62 311 42 41    cuhlmann_ol@spital.ktso.ch   
Principal Investigator: Catrina Uhlmann Nussbaum, MD         
Hôpital du Valais Sion Recruiting
Sion, Switzerland, 1951
Contact: Sandro Anchisi, Dr. med.    +41 (27) 603 45 00    sandro.anchisi@hopitalvs.ch   
Principal Investigator: Sandro Anchisi, Dr. med.         
Kantonsspital St. Gallen Recruiting
St. Gallen, Switzerland, 9007
Contact: Arnoud Templeton, MD    +41 71 494 11 11    arnoud.templeton@kssg.ch   
Principal Investigator: Arnoud Templeton, MD         
Zentrum fuer Tumordiagnostikund Praevention Recruiting
St. Gallen, Switzerland, CH-9006
Contact: Friedemann Honecker, MD    +41 71 243 00 43    friedemann.honecker@zetup.ch   
Principal Investigator: Friedemann Honecker, MD         
SpitalSTS AG Simmental-Thun-Saanenland Recruiting
Thun, Switzerland, 3600
Contact: Daniel Rauch    +41 33 226 26 45    daniel.rauch@spitalstsag.ch   
Principal Investigator: Daniel Rauch, MD         
Kantonsspital Winterthur Recruiting
Winterthur, Switzerland, 8401
Contact: Andreas Müller, MD    41-052-266-2552    Andreas.mueller@ksw.ch   
Principal Investigator: Andreas Müller, MD         
Onkozentrum Klinik im Park Recruiting
Zurich, Switzerland, 8038
Contact: Urs Huber, MD    41-43-344-3333    huber@1st.ch   
Principal Investigator: Urs Huber, MD         
Hirslanden Onkozentrum Zürich Recruiting
Zürich, Switzerland, 8032
Contact: Thomas von Briel, Dr. med.    +41 (44) 387 35 35    vonbriel@onkozentrum.ch   
Principal Investigator: Thomas von Briel, Dr. med.         
Stadtspital Triemli Recruiting
Zürich, Switzerland, 8063
Contact: Dirk Kienle, Dr. med.    +41 (44) 466 11 11    dirk.kienle@triemli.zuerich.ch   
Principal Investigator: Dirk Kienle, Dr. med.         
Universitätsspital Zürich Recruiting
Zürich, Switzerland, 8091
Contact: Cédric Poyet, Dr. med.    +41 (44) 255 11 11    cedric.poyet@usz.ch   
Principal Investigator: Cédric Poyet, Dr. med.         
Sponsors and Collaborators
Swiss Group for Clinical Cancer Research
Investigators
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
  More Information

No publications provided

Responsible Party: Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier: NCT02051218     History of Changes
Other Study ID Numbers: SAKK 96/12
Study First Received: January 29, 2014
Last Updated: September 9, 2014
Health Authority: Switzerland: Ethikkommission
Switzerland: Swissmedic

Keywords provided by Swiss Group for Clinical Cancer Research:
metastatic breast cancer
castration resistant metastatic prostate cancer
bone metastases
Denosumab
XGEVA
de-escalation

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasm Metastasis
Prostatic Neoplasms
Breast Diseases
Genital Diseases, Male
Genital Neoplasms, Male
Neoplasms
Neoplasms by Site
Neoplastic Processes
Pathologic Processes
Prostatic Diseases
Skin Diseases
Urogenital Neoplasms

ClinicalTrials.gov processed this record on November 25, 2014