Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy

NCT ID: NCT02129699

Last Updated: 2024-09-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 595 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-06
• Study Completion Date: 2020-02-29

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: OTHER

None, standard chemotherapy only

Intervention Type: 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

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.

Group Type: EXPERIMENTAL

Denosumab

Intervention Type: 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).

Interventions

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).

Intervention Type: DRUG

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

Intervention Type: OTHER

Other Intervention Names

XGEVA

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: collaborator

Amgen

INDUSTRY

Sponsor Role: collaborator

ETOP IBCSG Partners Foundation

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Solange Peters, MD, PhD

Role: STUDY_CHAIR

Trial Chair, CHUV Lausanne, Switzerland

Mary O'Brien, MD

Role: STUDY_CHAIR

EORTC Trial Co-Chair, Royal Marden Hospital, Sutton, UK

Sarah Danson, PhD

Role: STUDY_CHAIR

EORTC Trial Co-Chair, University of Sheffield, Sheffield, UK

Rolf Stahel, MD

Role: STUDY_CHAIR

Trial Co-Chair, University Hospital of Zuerich, Switzerland

Locations

Univ. Klinik für Innere Medizin V

Innsbruck, , Austria

KH der Elisabethinen Linz

Linz, , Austria

AKH Wien

Vienna, , Austria

Otto-Wagner-Spital Department 1

Vienna, , Austria

Otto-Wagner-Spital Department 2

Vienna, , Austria

Onze Lieve Vrouw Ziekenhuis

Aalst, , Belgium

University Hosptial Ghent

Ghent, , Belgium

Centre Hospitalier Regional De La Citadelle

Liège, , Belgium

Clinique et Maternite Sainte Elisabeth

Namur, , Belgium

Centre hospitalier universitaire d'Angers

Angers, , France

Centre Hospitalier Annecy

Annecy, , France

Centre Hospitalier De Beauvais

Beauvais, , France

Hôpitale de la Cavale Blanche - CHRU de BREST

Brest, , France

GHPSO (Sie de Creil)

Creil, , France

Centre Hospitalier Intercommunal Creteil

Créteil, , France

Hospital Center Le Mans

Le Mans, , France

Hôpital du Cluzeau

Limoges, , France

CHBS Lorient

Lorient, , France

Hôpital Louis Pradel

Lyon, , France

Assistance Publique-Hôitaux de Marseille

Marseille, , France

Institut Paoli-Calmettes

Marseille, , France

Centre Hospitalier de Meaux

Meaux, , France

Centre Hospitalier Universitaire Rennes

Rennes, , France

Clinique Mutualiste de l'Estuaire

Saint-Nazaire, , France

CHICAS

Sisteron, , France

Hôpital de Villefranche-sur-Saône

Villefranche-sur-Saône, , France

ASKLEPIOS - Fachkliniken München - Gauting

München, , Germany

Pius Hospital

Oldenburg, , Germany

Cork University Hospital

Cork, , Ireland

Beaumont Hospital

Dublin, , Ireland

Mater Miscordia University Hospital

Dublin, , Ireland

Mater Private Hospital

Dublin, , Ireland

St James's Hospital

Dublin, , Ireland

The Adelaide and Meath Hospital

Dublin, , Ireland

University Hospital Galway

Galway, , Ireland

University Hospital Limerick

Limerick, , Ireland

Hospital Waterford

Waterford, , Ireland

S.G Moscati Hospital

Aversa, , Italy

IRCCS Azienda Ospedaliera Universitaria San Martino

Genova, , Italy

San Paolo Hospital

Milan, , Italy

Ospedale San Gerardo

Monza, , Italy

Maria Sklodowska-Curie Memorial Car

Gliwice, , Poland

University Clinic Golnik

Golnik, , Slovenia

Institute of Oncology Ljubljana

Ljubljana, , Slovenia

Hospital General de Alicante

Alicante, , Spain

Hospital De La Santa Creu I Sant Pau

Barcelona, , Spain

Institut Català d'Oncologia - L'Hospitalet

Barcelona, , Spain

Hospital General Castellón

Castelló, , Spain

Hospital Universitario Reina Sofia

Córdoba, , Spain

Complejo Hospitalario de Jaén

Jaén, , Spain

H. U. Insular Gran Canaria

Las Palmas, , Spain

Regional Universitario Carlos Haya

Málaga, , Spain

H Morales Meseguer

Murcia, , Spain

Hospital Son Espases

Palma de Mallorca, , Spain

Hospital Arnau Vilanova Valencia

Valencia, , Spain

Hospital Universitario Miguel Servet

Zaragoza, , Spain

Kantonsspital Graubünden

Chur, , Switzerland

HFR Fribourg

Fribourg, , Switzerland

Centre Hospitalier Universitaire Vaudois

Lausanne, , Switzerland

Kantonsspital Luzern

Lucerne, , Switzerland

Onkologiezentrum Berner Oberland

Thun, , Switzerland

Kantonsspital Winterthur

Winterthur, , Switzerland

Universitätsspital Zürich

Zurich, , Switzerland

Aberdeen Royal Infirmary

Aberdeen, , United Kingdom

Oxford University Hospitals Trust

Oxford, , United Kingdom

Weston Park Hospital

Sheffield, , United Kingdom

Countries

Austria; Belgium; France; Germany; Ireland; Italy; Poland; Slovenia; Spain; Switzerland; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 15197804 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17451841 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21343556 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21326202 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23154554 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.etop-eu.org

Sponsor

Other Identifiers

2013-003156-21

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

20080166

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

SNCTP000000954

Identifier Type: REGISTRY

Identifier Source: secondary_id

ETOP 5-12 / EORTC 08111

Identifier Type: -

Identifier Source: org_study_id