Lung Cancer Non-small Cell Stage IVPhase 3SPLENDOURNCT02129699
Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy
A Phase 3 study testing Denosumab and None, standard chemotherapy only in people with Lung Cancer Non-small Cell Stage IV, run by ETOP IBCSG Partners Foundation at 66 sites in 11 countries.
Trial summary
The purpose of this study is to investigate how well the standard treatment (platinum-based doublet chemotherapy) in combination with denosumab works compared with the standard treatment alone in patients with a type of lung cancer called "non small cell lung cancer" (NSCLC) that has spread to other parts of the body. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Lung Cancer Non-small Cell Stage IV
- What is being tested?
- Denosumab and None, standard chemotherapy only
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 595 participants
- Where
- 66 sitesin 11 countries
- Study dates
- 6 Jan 2015to 29 Feb 2020
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically or cytologically confirmed advanced stage IV non-small cell lung carcinoma (NSCLC), according to 7th TNM classification
- Age ≥ 18 years
- ECOG performance status 0-2
- Measurable or evaluable disease (according to RECIST 1.1 criteria) assessed within 28 days from randomization.
- Availability of tumour tissue (as assessed by the local pathologist) for translational research:
- preferred: FFPE block from primary tumour or metastasis,
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- alternatively: cell block
- if no block available: 10 freshly cut unstained slides.
- Adequate haematological function: neutrophils ≥ 1.5 ×109/L, platelets
- ≥ 100×109/L, and hemoglobin ≥ 9 g/dL
- Adequate liver function:
- ALT ≤ 3 × ULN ( ≤ 5 × ULN if liver metastasis are present)
- Total bilirubin < 2 x ULN
- Adequate renal function: calculated renal creatinine clearance (CrCl) ≥ 30 mL/min (according to the formula of Cockroft-Gault)
- Life expectancy of at least 3 months
- Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before enrollment. Pregnancy test has to be repeated within 14 days before treatment start.
- All sexually active men and women of childbearing potential must use an effective contraceptive method during the study treatment and for a period of at least 6 months following the last administration of trial treatment
- Written Informed Consent must be signed and dated by the patient and the investigator prior to any trial-related intervention for
- Trial treatment
- Submission of biomaterial for central testing
Who cannot join
- Patients with presence of documented sensitizing EGFR activating mutation or ALK rearrangements (screening following local standards is optional, but strongly encouraged in non-squamous histology)
- Patients with documented brain metastases (systematic screening of patients not mandatory; however, if the patient is symptomatic, brain metastases screening is recommended).
- Prior chemotherapy or molecular targeted therapy for metastatic disease.
- Exceptions:
- Neoadjuvant or adjuvant chemotherapy or radio-chemotherapy are allowed if terminated more than 6 months before registration.
- Previous radical radiotherapy without systemic treatment is allowed.
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- One previous line of systemic immunotherapy by checkpoint inhibitors is allowed and needs to be documented
- Concomitant treatment with immune checkpoint inhibitors
- Any investigational agent(s) within 30 days prior to randomisation
- Concurrent bisphosphonate administration
- Oral/ dental conditions (by visual inspection):
- Prior history or current evidence of osteomyelitis / osteonecrosis of the jaw
- Active dental or jaw condition which requires oral surgery
- Planned invasive dental procedure for the course of the trial
- Non-healed dental or oral surgery
- Evidence of any medical condition which would impair the ability of the patient to participate in the trial or might preclude therapy with trial drugs (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease, active infection, uncontrolled diabetes mellitus; uncontrolled arterial hypertension ≥ 160/100 mmHg, history of myocardial infarction in the last 3 months)
- Documented active infection with Hepatitis B virus or Hepatitis C virus, known infection with human immunodeficiency virus (HIV)
- Known hypersensitivity to any of the components of the treatment
- Severe, uncorrected hypocalcaemia or hypercalcaemia:
- hypercalcaemia: total calcium >3.1 mmol/l or corrected calcium (with albumin level) >3 mmol/l
- hypocalcaemia: total calcium <2 mmol/l or corrected calcium (with albumin level) < 1.9 mmol/l
- Legal incapacity or limited legal capacity
- Medical or psychological condition, including uncontrolled arterial hypertension (>160/110) despite adequate medication which in the opinion of the investigator would not permit the patient to complete the trial or sign meaningful informed consent
- Women who are pregnant or breastfeeding
- Any concurrent malignancy other than adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma, or prostate cancer Gleason score < 6. (Patients with a previous malignancy but without evidence of disease for ≥ 2 years will be allowed to enter the trial)
- Any previous exposure to denosumab, with the exception of a maximum of 2 previous doses of denosumab (Prolia®) more than 6 month before enrolment for osteoporosis treatment/prevention.
Trial locations and contacts
66 sites in 11 countries.
66 sites in 11 countries
France17 sites
Centre hospitalier universitaire d'Angers
Angers
Centre Hospitalier Annecy
Annecy
Centre Hospitalier De Beauvais
Beauvais, 60021
Hôpitale de la Cavale Blanche - CHRU de BREST
Brest, 29606
GHPSO (Sie de Creil)
Creil
Centre Hospitalier Intercommunal Creteil
Créteil
Hospital Center Le Mans
Le Mans
Hôpital du Cluzeau
Limoges
CHBS Lorient
Lorient
Hôpital Louis Pradel
Lyon
Assistance Publique-Hôitaux de Marseille
Marseille
Institut Paoli-Calmettes
Marseille
Centre Hospitalier de Meaux
Meaux
Centre Hospitalier Universitaire Rennes
Rennes
Clinique Mutualiste de l'Estuaire
Saint-Nazaire
CHICAS
Sisteron
Hôpital de Villefranche-sur-Saône
Villefranche-sur-Saône, 69655
Spain12 sites
Hospital General de Alicante
Alicante
Hospital De La Santa Creu I Sant Pau
Barcelona, 08025
Institut Català d'Oncologia - L'Hospitalet
Barcelona
Hospital General Castellón
Castelló
Hospital Universitario Reina Sofia
Córdoba
Complejo Hospitalario de Jaén
Jaén
H. U. Insular Gran Canaria
Las Palmas
Regional Universitario Carlos Haya
Málaga
H Morales Meseguer
Murcia
Hospital Son Espases
Palma de Mallorca
Hospital Arnau Vilanova Valencia
Valencia
Hospital Universitario Miguel Servet
Zaragoza
Ireland9 sites
Cork University Hospital
Cork
Beaumont Hospital
Dublin
Mater Miscordia University Hospital
Dublin
Mater Private Hospital
Dublin
St James's Hospital
Dublin
The Adelaide and Meath Hospital
Dublin
University Hospital Galway
Galway
University Hospital Limerick
Limerick
Hospital Waterford
Waterford
Switzerland7 sites
Kantonsspital Graubünden
Chur
HFR Fribourg
Fribourg
Centre Hospitalier Universitaire Vaudois
Lausanne
Kantonsspital Luzern
Lucerne, 6016
Onkologiezentrum Berner Oberland
Thun, 3600
Kantonsspital Winterthur
Winterthur, 8401
Universitätsspital Zürich
Zurich
Austria5 sites
Univ. Klinik für Innere Medizin V
Innsbruck
KH der Elisabethinen Linz
Linz
AKH Wien
Vienna
Otto-Wagner-Spital Department 1
Vienna
Otto-Wagner-Spital Department 2
Vienna
Belgium4 sites
Onze Lieve Vrouw Ziekenhuis
Aalst
University Hosptial Ghent
Ghent
Centre Hospitalier Regional De La Citadelle
Liège, 14000
Clinique et Maternite Sainte Elisabeth
Namur, 5000
Italy4 sites
S.G Moscati Hospital
Aversa
IRCCS Azienda Ospedaliera Universitaria San Martino
Genova
San Paolo Hospital
Milan
Ospedale San Gerardo
Monza, 20900
United Kingdom3 sites
Aberdeen Royal Infirmary
Aberdeen
Oxford University Hospitals Trust
Oxford
Weston Park Hospital
Sheffield
Germany2 sites
ASKLEPIOS - Fachkliniken München - Gauting
München
Pius Hospital
Oldenburg
Slovenia2 sites
University Clinic Golnik
Golnik
Institute of Oncology Ljubljana
Ljubljana
About this study
Official title: A Randomised, Open-label Phase III Trial Evaluating the Addition of Denosumab to Standard First-line Anticancer Treatment in Advanced NSCLC
The purpose of this study is to investigate how well the standard treatment (platinum-based doublet chemotherapy) in combination with denosumab works compared with the standard treatment alone in patients with a type of lung cancer called "non small cell lung cancer" (NSCLC) that has spread to other parts of the body.
Read the detailed description
The investigational medicinal product denosumab is a protein (monoclonal antibody) that works to slow down bone destruction caused by cancer spreading to the bone (bone metastasis). Denosumab is used in adults with cancer to prevent serious complications caused by bone metastasis (e.g., fracture, pressure on the spinal cord or the need to receive radiation therapy or surgery). Results from one study in lung cancer patients with bone metastasis suggested that adding denosumab to the standard chemotherapy may lead to a possible survival benefit.
All patients will receive standard chemotherapy consisting of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed, depending on the nature of the lung cancer, every 3 weeks for about 3-4 months:
Patients will be assigned to one of two groups, known as 'arms'.
The treatment for each arm will be as follows:
Arm A: 4 - 6 cycles of chemotherapy and best supportive care (including any bone protective agent except denosumab)
Arm B: 4 - 6 cycles of chemotherapy + denosumab 120 mg, administered subcutaneously every 3-4 weeks until unacceptable toxicity, patient refusal or patient's death. After stop of first-line chemotherapy, denosumab must be continued every 3-4 weeks lifelong, regardless of tumour progression and concomitantly with subsequent lines of systemic treatment, as long as tolerable for the patient.
Beyond primary analysis, all subjects randomised to ARM B and still benefitting from the drug will be offered denosumab at a dose of 120 mg s.c. until patient or physician elect to discontinue denosumab for any reason, and for a maximum of 2 years after the required number of events for the final analysis has been reached.
A total of 1000 patients from centers in Europe, Switzerland and Israel are expected to be enrolled in this study over a period of 37 months. The study will take approximately 56 months to be completed.
- Conditions
- Lung Cancer Non-small Cell Stage IV
- Being tested
- Denosumab, None, standard chemotherapy only
- Keywords
- NSCLC, stage IV
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DenosumabDrug
Also called XGEVA
Denosumab: 120 mg, s.c. every 3-4 weeks (in cycle 1 additional dose on day 8) until unacceptable toxicity, patient refusal or patient's death (max. 4 years 3 months).
None, standard chemotherapy onlyOther
Possible standard chemotherapies (3 weeks cycles, duration: 4 - 6 cycles):
Cisplatin 75 mg/m2 as an infusion on day 1 Gemcitabine 1250 mg/m2 as an infusion days 1 and 8 or Carboplatin AUC 5 as an infusion on day 1 Gemcitabine 1000 mg/m2 as an infusion days 1 and 8 or Cisplatin 75 mg/m2 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1 or Carboplatin AUC 5 as an infusion on day 1 Pemetrexed 500 mg/m2 as an infusion on day 1
| Study group | Role | What they receive |
|---|---|---|
| None, standard chemotherapy only | Other | 4 - 6 cycles of standard chemotherapy + best supportive care including any bone protective agent except denosumab.
Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed. Receives: Other: None, standard chemotherapy only |
| Standard chemotherapy + Denosumab | Experimental | 4 - 6 cycles of standard chemotherapy + denosumab 120 mg, administered subcutaneously every 3-4 weeks until unacceptable toxicity, patient refusal, or patient's death. Denosumab should be administered on day 1 of each cycle, before or after the administration of chemotherapy. After stop of first-line chemotherapy, denosumab must be continued life-long, regardless of tumour progression and concomitantly with subsequent lines of systemic treatment, as long as tolerable for the patient.
Standard chemotherapy consis of a combination of platinum-based doublet agents plus gemcitabine or pemetrexed. Receives: Drug: Denosumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival
OS will be defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of participants still alive will be censored at the moment of last follow-up. OS will be reported for all participants in both treatment arms.
Measured: Overall survival was measured from the date of randomization to the date of death, whatever the cause, up to a maximum of 56 months
Secondary outcomes (5)
Progression-free Survival (PFS) Based on RECIST 1.1
Progression-free survival (PFS) is defined as time from date of randomisation until objective disease progression or death, whichever occurs first. Disease progression and its evaluation are defined based on RECIST 1.1: Progressive disease (PD); > 20% increase in the sum of the longest diameter of target lesions, new lesions or non-equivocal progression in non-target disease.
If neither event has been observed, then the patient is censored at the date of the last follow up examination.
Patients with new non-lung cancer malignancy must continue to be followed for progression of the original lung cancer.
Patients who discontinue treatment prior to documented disease progression, including those who initiate non-protocol therapy prior to progression, will be followed for disease progression and death.
Measured: Time from date of randomisation until objective disease progression or death, whichever occurs first, assessed up to a maximum of 56 months
Number of Participants With Response (CR+PR) Based on RECIST 1.1
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
For more details to RECIST 1.1 criteria, see https://recist.eortc.org/
Measured: Response of the tumour is defined according to RECIST 1.1 criteria, assessed up to 56 months
Toxicity Profile of Denosumab
Number of patients with serious adverse events classified according to NCI CTCAE V4.
Measured: Assessed up to 56 months
Overall Survival by Membranous RANK Expression.
Overall survival is defined as time from the date of randomisation until death from any cause. Patients who are still alive at last contact are censored at the date of last follow up.
Measured: Up to maximum of 56 months
Overall Survival by Cytoplasmic RANK Expression.
Overall survival is defined as time from the date of randomisation until death from any cause. Patients who are still alive at last contact are censored at the date of last follow up.
Measured: up to a maximum of 56 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2014 (estimated)
- Study start6 Jan 2015
- Primary completion29 Feb 2020
- Study completion29 Feb 2020
Why it stopped: Completion of recruitment was not feasible as accrual was slower than anticipated. Even if a benefit for denosumab could be shown, these results would be of very limited clinical impact by the time they would be available
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Lung Cancer Non-small Cell Stage IVStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 595 participants (actual)
Sponsor and investigators
- Lead sponsor
- ETOP IBCSG Partners Foundation
- Sponsor type
- Research network
- Responsible party
- Sponsor
- Investigators
- Solange Peters, MD, PhD, Study chair, Trial Chair, CHUV Lausanne, SwitzerlandMary O'Brien, MD, Study chair, EORTC Trial Co-Chair, Royal Marden Hospital, Sutton, UKSarah Danson, PhD, Study chair, EORTC Trial Co-Chair, University of Sheffield, Sheffield, UKRolf Stahel, MD, Study chair, Trial Co-Chair, University Hospital of Zuerich, Switzerland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02129699
- Sponsor's protocol ID
- ETOP 5-12 / EORTC 08111
- Other IDs
- 2013-003156-21, 20080166, SNCTP000000954
- Acronym
- SPLENDOUR
- Status last verified
- Sep 2026
- First submitted
- 30 Apr 2014
- Last updated
- 8 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Rosen LS, Gordon D, Tchekmedyian NS, Yanagihara R, Hirsh V, Krzakowski M, Pawlicki M, De Souza P, Zheng M, Urbanowitz G, Reitsma D, Seaman J. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer. 2004 Jun 15;100(12):2613-21. doi: 10.1002/cncr.20308.
PubMed 15197804Tsuya A, Kurata T, Tamura K, Fukuoka M. Skeletal metastases in non-small cell lung cancer: a retrospective study. Lung Cancer. 2007 Aug;57(2):229-32. doi: 10.1016/j.lungcan.2007.03.013. Epub 2007 Apr 23.
PubMed 17451841Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011 Mar 20;29(9):1125-32. doi: 10.1200/JCO.2010.31.3304. Epub 2011 Feb 22.
PubMed 21343556Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature. 2011 Feb 24;470(7335):548-53. doi: 10.1038/nature09707. Epub 2011 Feb 16.
PubMed 21326202Scagliotti GV, Hirsh V, Siena S, Henry DH, Woll PJ, Manegold C, Solal-Celigny P, Rodriguez G, Krzakowski M, Mehta ND, Lipton L, Garcia-Saenz JA, Pereira JR, Prabhash K, Ciuleanu TE, Kanarev V, Wang H, Balakumaran A, Jacobs I. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol. 2012 Dec;7(12):1823-1829. doi: 10.1097/JTO.0b013e31826aec2b.
PubMed 23154554