Clinical trial NCT02051218: Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks
Official title: Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks - A Non-Inferiority Phase III Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Metastatic Breast Cancer
Metastatic Prostate Cancer
Bone Metastases
Keywords: metastatic breast cancer
castration resistant metastatic prostate cancer
bone metastases
Denosumab
XGEVA
de-escalation
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2014-01-31
Enrollment: 1380
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

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.

Primary outcomes:
measure: Time to first on-trial symptomatic skeletal event (SSE; Clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression).
timeFrame: at the latest 5 years after randomization.
Secondary outcomes:
measure: Toxicity (focus on hypocalcaemia and osteonecrosis of the jaw)
timeFrame: at the latest 5 years after randomization.
measure: Time to first and subsequent on-trial SSE
timeFrame: at the latest 5 years after randomization.
measure: Quality of Life measured by FACT-G and FACT-BP
timeFrame: at the latest 5 years after randomization.
measure: Skeletal morbidity period rate (SMPR)
timeFrame: at the latest 5 years after randomization.
measure: Skeletal morbidity rate (SMR)
timeFrame: at the latest 5 years after randomization.
measure: Health economic analysis
timeFrame: at the latest 5 years after randomization.
measure: Bone turnover markers
timeFrame: at the latest 5 years after randomization.
measure: Overall Survival (OS)
timeFrame: at the latest 5 years after randomization.
Other outcomes:
Locations:
city: Feldkirch
country: Austria
facility: Landeskrankenhaus Feldkirch
city: Wels
country: Austria
facility: Klinikum Wels-Grieskrichen GmbH
city: Düsseldorf
country: Germany
facility: Uniklinik Düsseldorf, Urologische Klinik
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf, Frauenheilkunde/Geburtshilfe
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Ulm
country: Germany
facility: Universitäts-Frauenklinik Ulm
city: Aarau
country: Switzerland
facility: Hirslanden Klinik Aarau
city: Aarau
country: Switzerland
facility: Kantonspital Aarau
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Basel
country: Switzerland
facility: Universitaetsspital Basel
city: Basel
country: Switzerland
facility: Brustzentrum Basel - Praxis für ambulante Tumortherapie
city: Basel
country: Switzerland
facility: St. Claraspital AG
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
city: Bern
country: Switzerland
facility: Klinik Engeried / Praxis Oncocare
city: Bern
country: Switzerland
facility: Inselspital, Bern
city: Biel
country: Switzerland
facility: Spitalzentrum Biel
city: Brig
country: Switzerland
facility: Spitalzentrum Oberwallis
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
city: Chêne-Bougeries
country: Switzerland
facility: Centre du Sein de Genève, Clinique des Grangettes
city: Frauenfeld
country: Switzerland
facility: Kantonsspital Frauenfeld - Brustzentrum
city: Fribourg
country: Switzerland
facility: Hopital Fribourgeois
city: Genolier
country: Switzerland
facility: Clinique De Genolier
city: Genève 14
country: Switzerland
facility: Hopitaux Universitaires de Geneve
city: La Chaux-de-Fonds
country: Switzerland
facility: Hôpital neuchâtelois
city: Lausanne
country: Switzerland
facility: CCAC Lausanne
city: Lausanne
country: Switzerland
facility: CHUV
city: Liestal
country: Switzerland
facility: Kantonsspital Liestal
city: Locarno
country: Switzerland
facility: Fondazione Oncologia / Oncologia ematologia
city: Lugano
country: Switzerland
facility: Oncologia Varini & Calderoni & Christinat
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital
city: Luzern
country: Switzerland
facility: Hirslanden Klinik St. Anna Luzern
city: Männedorf
country: Switzerland
facility: Onkologie Zentrum Spital Männedorf
city: Münsterlingen
country: Switzerland
facility: Kantonsspital Muensterlingen
city: Olten
country: Switzerland
facility: Kantonsspital Olten
city: Sargans
country: Switzerland
facility: Rundum Onkologie am Bahnhofpark
city: Schlieren
country: Switzerland
facility: Spital Limmattal
city: Sion
country: Switzerland
facility: Hôpital du Valais Sion
city: Solothurn
country: Switzerland
facility: Bürgerspital Solothurn - Zentrum für Onkologie und Hämatologie
city: St. Gallen
country: Switzerland
facility: Tumor and Brustzentrum Ostschweiz TBZO
city: St. Gallen
country: Switzerland
facility: Tumor and Brustzentrum Ostschweiz TBZO
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Thun
country: Switzerland
facility: Spital STS AG
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: Onkologie Bellevue
city: Zurich
country: Switzerland
facility: Onkozentrum Klinik im Park
city: Zürich
country: Switzerland
facility: Brustzentrum-Zürich
city: Zürich
country: Switzerland
facility: Klinik für Hämatologie und Onkologie Hirslanden Zürich AG
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich
city: Zürich
country: Switzerland
facility: Stadtspital Zürich Triemli
Study officials:
affiliation: Kantonsspital Graubünden
name: Roger von Moos, PD MD
role: STUDY_CHAIR
affiliation: Cantonal Hospital of St. Gallen
name: Arnoud Templeton, MD
role: STUDY_CHAIR
affiliation: Cantonal Hospital of St. Gallen
name: Silke Gillessen, Prof
role: STUDY_CHAIR
affiliation: Kantonsspital Winterthur KSW
name: Andreas Müller, MD
role: STUDY_CHAIR
References: