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

Metastatic Breast Cancer Clinical Trial

Official title:

Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks - A Non-Inferiority Phase III Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02051218
• Other study ID #: SAKK 96/12
• Secondary ID: 0000006852014-00
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 16, 2014
• Est. completion date: December 31, 2028

Study information

• Verified date: March 2024
• Source: Swiss Group for Clinical Cancer Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1380
• Est. completion date: December 31, 2028
• Est. primary completion date: June 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bone Metastases
• Metastatic Breast Cancer
• Metastatic Prostate Cancer
• Neoplasm Metastasis
• Prostatic Neoplasms

Intervention

Drug:
• Denosumab (reduced dosing)
3x Denosumab 120mg (XGEVA®) sc. q4w followed by Denosumab 120mg (XGEVA®) sc. q12w
• Denosumab (standard dosing)
Denosumab 120mg (XGEVA®) sc. q4w

Locations

Country	Name	City	State
Austria	Landeskrankenhaus Feldkirch	Feldkirch
Austria	Klinikum Wels-Grieskrichen GmbH	Wels
Germany	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
Switzerland	Hirslanden Klinik Aarau	Aarau
Switzerland	Kantonspital Aarau	Aarau
Switzerland	Kantonsspital Baden	Baden
Switzerland	Brustzentrum Basel - Praxis für ambulante Tumortherapie	Basel
Switzerland	St. Claraspital AG	Basel
Switzerland	Universitaetsspital Basel	Basel
Switzerland	Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli	Bellinzona
Switzerland	Inselspital, Bern	Bern
Switzerland	Klinik Engeried / Praxis Oncocare	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	Genève 14
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	Oncologia Varini & Calderoni & Christinat	Lugano
Switzerland	Hirslanden Klinik St. Anna Luzern	Luzern
Switzerland	Luzerner Kantonsspital	Luzern
Switzerland	Onkologie Zentrum Spital Männedorf	Männedorf
Switzerland	Kantonsspital Muensterlingen	Münsterlingen
Switzerland	Kantonsspital Olten	Olten
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	Kantonsspital St. Gallen	St. Gallen
Switzerland	Tumor and Brustzentrum Ostschweiz TBZO	St. Gallen
Switzerland	Tumor and Brustzentrum Ostschweiz TBZO	St. Gallen
Switzerland	Spital STS AG	Thun
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	Onkologie Bellevue	Zurich
Switzerland	Onkozentrum Klinik im Park	Zurich
Switzerland	Brustzentrum-Zürich	Zürich
Switzerland	Klinik für Hämatologie und Onkologie Hirslanden Zürich AG	Zürich
Switzerland	Stadtspital Zürich Triemli	Zürich
Switzerland	Universitätsspital Zürich	Zürich

Sponsors (1)

Lead Sponsor	Collaborator
Swiss Group for Clinical Cancer Research

Countries where clinical trial is conducted

Austria,  Germany,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to first on-trial symptomatic skeletal event (SSE; Clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression).	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.	at the latest 5 years after randomization.
Secondary	Toxicity (focus on hypocalcaemia and osteonecrosis of the jaw)		at the latest 5 years after randomization.
Secondary	Time to first and subsequent on-trial SSE		at the latest 5 years after randomization.
Secondary	Quality of Life measured by FACT-G and FACT-BP		at the latest 5 years after randomization.
Secondary	Skeletal morbidity period rate (SMPR)		at the latest 5 years after randomization.
Secondary	Skeletal morbidity rate (SMR)		at the latest 5 years after randomization.
Secondary	Health economic analysis		at the latest 5 years after randomization.
Secondary	Bone turnover markers		at the latest 5 years after randomization.
Secondary	Overall Survival (OS)		at the latest 5 years after randomization.