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

Sponsor

Swiss Group for Clinical Cancer Research (Other)

Overall Status

Recruiting

CT.gov ID

NCT02051218

Collaborator

(none)

1,380

Enrollment

Locations

Arms

100.5

Anticipated Duration (Months)

27.6

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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 Design

Study Type:

Interventional

Anticipated 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 :

Jul 16, 2014

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

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

Arm

Intervention/Treatment

Active Comparator: Arm A (standard arm)

Denosumab 120mg (XGEVA®) sc. q4w

Drug: Denosumab (standard dosing)

Denosumab 120mg (XGEVA®) sc. q4w

Other Names:

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 Names:

XGEVA®

Outcome Measures

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). [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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Landeskrankenhaus Feldkirch	Feldkirch	Austria	6800
2	Klinikum Wels-Grieskrichen GmbH	Wels	Austria	4600
3	Uniklinik Düsseldorf, Urologische Klinik	Düsseldorf	Germany	40225
4	Universitätsklinikum Düsseldorf, Frauenheilkunde/Geburtshilfe	Düsseldorf	Germany	40225
5	Universitätsmedizin Göttingen	Göttingen	Germany	37075
6	Universitätsklinikum Schleswig-Holstein	Lübeck	Germany	23538
7	Universitäts-Frauenklinik Ulm	Ulm	Germany	89075
8	Hirslanden Klinik Aarau	Aarau	Switzerland	CH-5001
9	Kantonspital Aarau	Aarau	Switzerland	CH-5001
10	Kantonsspital Baden	Baden	Switzerland	CH-5404
11	Universitaetsspital Basel	Basel	Switzerland	4031
12	Brustzentrum Basel - Praxis für ambulante Tumortherapie	Basel	Switzerland	4052
13	St. Claraspital AG	Basel	Switzerland	CH-4016
14	Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli	Bellinzona	Switzerland	6500
15	Klinik Engeried / Praxis Oncocare	Bern	Switzerland	3012
16	Inselspital, Bern	Bern	Switzerland	CH-3010
17	Spitalzentrum Biel	Biel	Switzerland	CH-2501
18	Spitalzentrum Oberwallis	Brig	Switzerland	3900
19	Kantonsspital Graubünden	Chur	Switzerland	7000
20	Centre du Sein de Genève, Clinique des Grangettes	Chêne-Bougeries	Switzerland	1224
21	Kantonsspital Frauenfeld - Brustzentrum	Frauenfeld	Switzerland	8501
22	Hopital Fribourgeois	Fribourg	Switzerland	1708
23	Clinique De Genolier	Genolier	Switzerland	1272
24	Hopitaux Universitaires de Geneve	Genève 14	Switzerland	1211
25	Hôpital neuchâtelois	La Chaux-de-Fonds	Switzerland	2300
26	CCAC Lausanne	Lausanne	Switzerland	1004
27	CHUV	Lausanne	Switzerland	1011
28	Kantonsspital Liestal	Liestal	Switzerland	CH-4410
29	Fondazione Oncologia / Oncologia ematologia	Locarno	Switzerland	6600
30	Oncologia Varini & Calderoni & Christinat	Lugano	Switzerland	6900
31	Luzerner Kantonsspital	Luzern	Switzerland	6000
32	Hirslanden Klinik St. Anna Luzern	Luzern	Switzerland	6006
33	Onkologie Zentrum Spital Männedorf	Männedorf	Switzerland	8708
34	Kantonsspital Muensterlingen	Münsterlingen	Switzerland	8596
35	Kantonsspital Olten	Olten	Switzerland	4600
36	Rundum Onkologie am Bahnhofpark	Sargans	Switzerland	7320
37	Spital Limmattal	Schlieren	Switzerland	8952
38	Hôpital du Valais Sion	Sion	Switzerland	1951
39	Bürgerspital Solothurn - Onkologiezentrum	Solothurn	Switzerland	4600
40	Brustzentrum Ostschweiz	St. Gallen	Switzerland	9016
41	Zentrum fuer Tumordiagnostikund Praevention	St. Gallen	Switzerland	CH-9006
42	Kantonsspital St. Gallen	St. Gallen	Switzerland	CH-9007
43	Spital STS AG	Thun	Switzerland	3600
44	Kantonsspital Winterthur	Winterthur	Switzerland	8401
45	Onkologie Bellevue	Zurich	Switzerland	8001
46	Onkozentrum Klinik im Park	Zurich	Switzerland	8038
47	Brustzentrum-Zürich	Zürich	Switzerland	8005
48	Klinik für Hämatologie und Onkologie Hirslanden Zürich AG	Zürich	Switzerland	8032
49	Universitätsspital Zürich	Zürich	Switzerland	8091
50	Stadtspital Zürich Triemli	Zürich	Switzerland	CH-8063