Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy (SPLENDOUR)

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.

Study Overview

• Status: Terminated
• Conditions: Lung Cancer Non-small Cell Stage IV
• Intervention / Treatment: Other: None, standard chemotherapy only; Drug: Denosumab

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.

• Study Type: Interventional
• Enrollment (Actual): 595
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria
    • Univ. Klinik für Innere Medizin V
  • Linz, Austria
    • KH der Elisabethinen Linz
  • Wien, Austria
    • AKH Wien
  • Wien, Austria
    • Otto-Wagner-Spital Department 1
  • Wien, Austria
    • Otto-Wagner-Spital Department 2
• Belgium
  • Aalst, Belgium
    • Onze Lieve Vrouw Ziekenhuis
  • Ghent, Belgium
    • University Hosptial Ghent
  • Liege, Belgium, 14000
    • Centre Hospitalier Regional De La Citadelle
  • Namur, Belgium, 5000
    • Clinique et Maternite Sainte Elisabeth
• France
  • Angers, France
    • Centre hospitalier universitaire d'Angers
  • Annecy, France
    • Centre Hospitalier Annecy
  • Beauvais Cedex, France, 60021
    • Centre Hospitalier De Beauvais
  • Brest, France, 29606
    • Hôpitale de la Cavale Blanche - CHRU de BREST
  • Creil, France
    • GHPSO (Sie de Creil)
  • Creteil, France
    • Centre Hospitalier Intercommunal Creteil
  • Le Mans, France
    • Hospital Center Le Mans
  • Limoges, France
    • Hôpital du Cluzeau
  • Lorient, France
    • CHBS Lorient
  • Lyon, France
    • Hôpital Louis Pradel
  • Marseille, France
    • Institut Paoli-Calmettes
  • Marseille, France
    • Assistance Publique-Hôitaux de Marseille
  • Meaux, France
    • Centre Hospitalier de Meaux
  • Rennes, France
    • Centre Hospitalier Universitaire Rennes
  • Saint-Nazaire, France
    • Clinique Mutualiste de l'Estuaire
  • Sisteron, France
    • CHICAS
  • Villefranche-sur-saône, France, 69655
    • Hôpital de Villefranche-sur-Saône
• Germany
  • München, Germany
    • ASKLEPIOS - Fachkliniken München - Gauting
  • Oldenburg, Germany
    • Pius Hospital
• Ireland
  • Cork, Ireland
    • Cork University Hospital
  • Dublin, Ireland
    • Beaumont Hospital
  • Dublin, Ireland
    • St James's Hospital
  • Dublin, Ireland
    • Mater Private Hospital
  • Dublin, Ireland
    • Mater Miscordia University Hospital
  • Dublin, Ireland
    • The Adelaide and Meath Hospital
  • Galway, Ireland
    • University Hospital Galway
  • Limerick, Ireland
    • University Hospital Limerick
  • Waterford, Ireland
    • Hospital Waterford
• Italy
  • Aversa, Italy
    • S.G Moscati Hospital
  • Genova, Italy
    • IRCCS Azienda Ospedaliera Universitaria San Martino
  • Milan, Italy
    • San Paolo Hospital
  • Monza, Italy, 20900
    • Ospedale San Gerardo
• Poland
  • Gliwice, Poland
    • Maria Sklodowska-Curie Memorial Car
• Slovenia
  • Golnik, Slovenia
    • University Clinic Golnik
  • Ljubljana, Slovenia
    • Institute of Oncology Ljubljana
• Spain
  • Alicante, Spain
    • Hospital General de Alicante
  • Barcelona, Spain, 08025
    • Hospital de La Santa Creu I Sant Pau
  • Barcelona, Spain
    • Institut Català d'Oncologia - L'Hospitalet
  • Castelló, Spain
    • Hospital General Castellón
  • Córdoba, Spain
    • Hospital Universitario Reina Sofia
  • Jaén, Spain
    • Complejo Hospitalario de Jaén
  • Las Palmas, Spain
    • H. U. Insular Gran Canaria
  • Malaga, Spain
    • Regional Universitario Carlos Haya
  • Murcia, Spain
    • H Morales Meseguer
  • Palma de Mallorca, Spain
    • Hospital Son Espases
  • Valencia, Spain
    • Hospital Arnau Vilanova Valencia
  • Zaragoza, Spain
    • Hospital Universitario Miguel Servet
• Switzerland
  • Chur, Switzerland
    • Kantonsspital Graubünden
  • Fribourg, Switzerland
    • HFR Fribourg
  • Lausanne, Switzerland
    • Centre Hospitalier Universitaire Vaudois
  • Luzern, Switzerland, 6016
    • Kantonsspital Luzern
  • Thun, Switzerland, 3600
    • Onkologiezentrum Berner Oberland
  • Winterthur, Switzerland, 8401
    • Kantonsspital Winterthur
  • Zürich, Switzerland
    • Universitätsspital Zürich
• United Kingdom
  • Aberdeen, United Kingdom
    • Aberdeen Royal Infirmary
  • Oxford, United Kingdom
    • Oxford University Hospitals Trust
  • Sheffield, United Kingdom
    • Weston Park Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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,
• 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

  1. Trial treatment
  2. Submission of biomaterial for central testing

Exclusion Criteria:

• 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.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: None, standard chemotherapy only; 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.	Other: None, standard chemotherapy only; 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
Experimental: Standard chemotherapy + Denosumab; 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.	Drug: Denosumab; 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).; Other Names: XGEVA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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/	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.	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.	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.	up to a maximum of 56 months

Collaborators and Investigators

• Sponsor: ETOP IBCSG Partners Foundation
• Collaborators: European Organisation for Research and Treatment of Cancer - EORTC; Amgen
• Investigators: Study Chair: Solange Peters, MD, PhD, Trial Chair, CHUV Lausanne, Switzerland; Study Chair: Mary O'Brien, MD, EORTC Trial Co-Chair, Royal Marden Hospital, Sutton, UK; Study Chair: Sarah Danson, PhD, EORTC Trial Co-Chair, University of Sheffield, Sheffield, UK; Study Chair: Rolf Stahel, MD, Trial Co-Chair, University Hospital of Zuerich, Switzerland

Publications and helpful links

General 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.
• Henry 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.
• Scagliotti 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.
• Tsuya 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.
• Tan 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.

Helpful Links

• Sponsor

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2015
• Primary Completion (Actual): February 29, 2020
• Study Completion (Actual): February 29, 2020

Study Registration Dates

• First Submitted: April 30, 2014
• First Submitted That Met QC Criteria: April 30, 2014
• First Posted (Estimated): May 2, 2014

Study Record Updates

• Last Update Posted (Estimated): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 24, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: NSCLC; stage IV
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: ETOP 5-12 / EORTC 08111; 2013-003156-21 (EudraCT Number); 20080166 (Other Grant/Funding Number: AMGEN); SNCTP000000954 (Registry Identifier: Swiss National Clinical Trials Portal (SNCTP))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No