Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy

NCT02129699 | Terminated Phase 3 Results DMC

• 4 other identifiers: ETOP 5-12 / EORTC 081112013-003156-2120080166SNCTP000000954
• Study Type: interventional
• Target: 595
• Locations: 11 countries
• Sites: 66

Brief 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.

Conditions

Lung Cancer Non-small Cell Stage IV

Keywords

NSCLC; stage IV

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Progression-free Survival (PFS) Based on RECIST 1.1

  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

  Response of the tumour is defined according to RECIST 1.1 criteria, assessed up to 56 months

• Toxicity Profile of Denosumab

  Assessed up to 56 months

• Overall Survival by Membranous RANK Expression.

  Up to maximum of 56 months

• Overall Survival by Cytoplasmic RANK Expression.

  up to a maximum of 56 months

Study Arms (2)

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.

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.

Drug: Denosumab

Interventions

Denosumab DRUG

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).

Also known as: XGEVA

Standard chemotherapy + Denosumab

None, standard chemotherapy only OTHER

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

None, standard chemotherapy only

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• ETOP IBCSG Partners Foundation: lead
• European Organisation for Research and Treatment of Cancer - EORTC: collaborator
• Amgen: collaborator

Study Sites (66)

Univ. Klinik für Innere Medizin V

Innsbruck, Austria

Location

KH der Elisabethinen Linz

Linz, Austria

Location

AKH Wien

Vienna, Austria

Location

Otto-Wagner-Spital Department 1

Vienna, Austria

Location

Otto-Wagner-Spital Department 2

Vienna, Austria

Location

Onze Lieve Vrouw Ziekenhuis

Aalst, Belgium

Location

University Hosptial Ghent

Ghent, Belgium

Location

Centre Hospitalier Regional De La Citadelle

Liège, 14000, Belgium

Location

Clinique et Maternite Sainte Elisabeth

Namur, 5000, Belgium

Location

Centre hospitalier universitaire d'Angers

Angers, France

Location

Centre Hospitalier Annecy

Annecy, France

Location

Centre Hospitalier De Beauvais

Beauvais, 60021, France

Location

Hôpitale de la Cavale Blanche - CHRU de BREST

Brest, 29606, France

Location

GHPSO (Sie de Creil)

Creil, France

Location

Centre Hospitalier Intercommunal Creteil

Créteil, France

Location

Hospital Center Le Mans

Le Mans, France

Location

Hôpital du Cluzeau

Limoges, France

Location

CHBS Lorient

Lorient, France

Location

Hôpital Louis Pradel

Lyon, France

Location

Assistance Publique-Hôitaux de Marseille

Marseille, France

Location

Institut Paoli-Calmettes

Marseille, France

Location

Centre Hospitalier de Meaux

Meaux, France

Location

Centre Hospitalier Universitaire Rennes

Rennes, France

Location

Clinique Mutualiste de l'Estuaire

Saint-Nazaire, France

Location

CHICAS

Sisteron, France

Location

Hôpital de Villefranche-sur-Saône

Villefranche-sur-Saône, 69655, France

Location

ASKLEPIOS - Fachkliniken München - Gauting

München, Germany

Location

Pius Hospital

Oldenburg, Germany

Location

Cork University Hospital

Cork, Ireland

Location

Beaumont Hospital

Dublin, Ireland

Location

Mater Miscordia University Hospital

Dublin, Ireland

Location

Mater Private Hospital

Dublin, Ireland

Location

St James's Hospital

Dublin, Ireland

Location

The Adelaide and Meath Hospital

Dublin, Ireland

Location

University Hospital Galway

Galway, Ireland

Location

University Hospital Limerick

Limerick, Ireland

Location

Hospital Waterford

Waterford, Ireland

Location

S.G Moscati Hospital

Aversa, Italy

Location

IRCCS Azienda Ospedaliera Universitaria San Martino

Genova, Italy

Location

San Paolo Hospital

Milan, Italy

Location

Ospedale San Gerardo

Monza, 20900, Italy

Location

Maria Sklodowska-Curie Memorial Car

Gliwice, Poland

Location

University Clinic Golnik

Golnik, Slovenia

Location

Institute of Oncology Ljubljana

Ljubljana, Slovenia

Location

Hospital General de Alicante

Alicante, Spain

Location

Hospital De La Santa Creu I Sant Pau

Barcelona, 08025, Spain

Location

Institut Català d'Oncologia - L'Hospitalet

Barcelona, Spain

Location

Hospital General Castellón

Castelló, Spain

Location

Hospital Universitario Reina Sofia

Córdoba, Spain

Location

Complejo Hospitalario de Jaén

Jaén, Spain

Location

H. U. Insular Gran Canaria

Las Palmas, Spain

Location

Regional Universitario Carlos Haya

Málaga, Spain

Location

H Morales Meseguer

Murcia, Spain

Location

Hospital Son Espases

Palma de Mallorca, Spain

Location

Hospital Arnau Vilanova Valencia

Valencia, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, Spain

Location

Kantonsspital Graubünden

Chur, Switzerland

Location

HFR Fribourg

Fribourg, Switzerland

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, Switzerland

Location

Kantonsspital Luzern

Lucerne, 6016, Switzerland

Location

Onkologiezentrum Berner Oberland

Thun, 3600, Switzerland

Location

Kantonsspital Winterthur

Winterthur, 8401, Switzerland

Location

Universitätsspital Zürich

Zurich, Switzerland

Location

Aberdeen Royal Infirmary

Aberdeen, United Kingdom

Location

Oxford University Hospitals Trust

Oxford, United Kingdom

Location

Weston Park Hospital

Sheffield, United Kingdom

Location

Related Publications (5)

• 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.

  PMID: 15197804 BACKGROUND

• 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.

  PMID: 17451841 BACKGROUND

• 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.

  PMID: 21343556 BACKGROUND

• 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.

  PMID: 21326202 BACKGROUND

• 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.

  PMID: 23154554 BACKGROUND

Related Links

• Sponsor

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Denosumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The study steering committee decided to close the study prematurely due to poor accrual. The primary analysis is therefore underpowered.

Results Point of Contact

• Title: European Thoracic Oncology Platform
• Organization: European Thoracic Oncology Platform

SPLENDOUR@etop-eu.org

+41 31389 93 91

Study Officials

• 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

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2014
• First Posted: May 2, 2014
• Study Start: January 6, 2015
• Primary Completion: February 29, 2020
• Study Completion: February 29, 2020
• Last Updated: September 19, 2024
• Results First Posted: April 25, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (17); SL (2); BE (4); DE (2); IE (9); PL (1); IT (4); ES (12); CH (7); AU (5); GB (3)