Clinical trial NCT02129699: Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy
Official title: A Randomised, Open-label Phase III Trial Evaluating the Addition of Denosumab to Standard First-line Anticancer Treatment in Advanced NSCLC
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Lung Cancer Non-small Cell Stage IV
Keywords: NSCLC
stage IV
Lead sponsor: ETOP IBCSG Partners Foundation
Sponsor class: NETWORK
Collaborators: name: European Organisation for Research and Treatment of Cancer - EORTC
name: Amgen
First posted: 2014-05-02
Enrollment: 595
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Overall Survival
timeFrame: 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:
measure: Progression-free Survival (PFS) Based on RECIST 1.1
timeFrame: Time from date of randomisation until objective disease progression or death, whichever occurs first, assessed up to a maximum of 56 months
measure: Number of Participants With Response (CR+PR) Based on RECIST 1.1
timeFrame: Response of the tumour is defined according to RECIST 1.1 criteria, assessed up to 56 months
measure: Toxicity Profile of Denosumab
timeFrame: Assessed up to 56 months
measure: Overall Survival by Membranous RANK Expression.
timeFrame: Up to maximum of 56 months
measure: Overall Survival by Cytoplasmic RANK Expression.
timeFrame: up to a maximum of 56 months
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Univ. Klinik für Innere Medizin V
city: Linz
country: Austria
facility: KH der Elisabethinen Linz
city: Wien
country: Austria
facility: AKH Wien
city: Wien
country: Austria
facility: Otto-Wagner-Spital Department 1
city: Wien
country: Austria
facility: Otto-Wagner-Spital Department 2
city: Aalst
country: Belgium
facility: Onze Lieve Vrouw Ziekenhuis
city: Ghent
country: Belgium
facility: University Hosptial Ghent
city: Liege
country: Belgium
facility: Centre Hospitalier Regional De La Citadelle
city: Namur
country: Belgium
facility: Clinique et Maternite Sainte Elisabeth
city: Angers
country: France
facility: Centre hospitalier universitaire d'Angers
city: Annecy
country: France
facility: Centre Hospitalier Annecy
city: Beauvais Cedex
country: France
facility: Centre Hospitalier De Beauvais
city: Brest
country: France
facility: Hôpitale de la Cavale Blanche - CHRU de BREST
city: Creil
country: France
facility: GHPSO (Sie de Creil)
city: Creteil
country: France
facility: Centre Hospitalier Intercommunal Creteil
city: Le Mans
country: France
facility: Hospital Center Le Mans
city: Limoges
country: France
facility: Hôpital du Cluzeau
city: Lorient
country: France
facility: CHBS Lorient
city: Lyon
country: France
facility: Hôpital Louis Pradel
city: Marseille
country: France
facility: Assistance Publique-Hôitaux de Marseille
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Meaux
country: France
facility: Centre Hospitalier de Meaux
city: Rennes
country: France
facility: Centre Hospitalier Universitaire Rennes
city: Saint-Nazaire
country: France
facility: Clinique Mutualiste de l'Estuaire
city: Sisteron
country: France
facility: CHICAS
city: Villefranche-sur-saône
country: France
facility: Hôpital de Villefranche-sur-Saône
city: München
country: Germany
facility: ASKLEPIOS - Fachkliniken München - Gauting
city: Oldenburg
country: Germany
facility: Pius Hospital
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Dublin
country: Ireland
facility: Mater Miscordia University Hospital
city: Dublin
country: Ireland
facility: Mater Private Hospital
city: Dublin
country: Ireland
facility: St James's Hospital
city: Dublin
country: Ireland
facility: The Adelaide and Meath Hospital
city: Galway
country: Ireland
facility: University Hospital Galway
city: Limerick
country: Ireland
facility: University Hospital Limerick
city: Waterford
country: Ireland
facility: Hospital Waterford
city: Aversa
country: Italy
facility: S.G Moscati Hospital
city: Genova
country: Italy
facility: IRCCS Azienda Ospedaliera Universitaria San Martino
city: Milan
country: Italy
facility: San Paolo Hospital
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Gliwice
country: Poland
facility: Maria Sklodowska-Curie Memorial Car
city: Golnik
country: Slovenia
facility: University Clinic Golnik
city: Ljubljana
country: Slovenia
facility: Institute of Oncology Ljubljana
city: Alicante
country: Spain
facility: Hospital General de Alicante
city: Barcelona
country: Spain
facility: Hospital De La Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia - L'Hospitalet
city: Castelló
country: Spain
facility: Hospital General Castellón
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Jaén
country: Spain
facility: Complejo Hospitalario de Jaén
city: Las Palmas
country: Spain
facility: H. U. Insular Gran Canaria
city: Malaga
country: Spain
facility: Regional Universitario Carlos Haya
city: Murcia
country: Spain
facility: H Morales Meseguer
city: Palma de Mallorca
country: Spain
facility: Hospital Son Espases
city: Valencia
country: Spain
facility: Hospital Arnau Vilanova Valencia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
city: Fribourg
country: Switzerland
facility: HFR Fribourg
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Luzern
country: Switzerland
facility: Kantonsspital Luzern
city: Thun
country: Switzerland
facility: Onkologiezentrum Berner Oberland
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals Trust
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
Study officials:
affiliation: Trial Chair, CHUV Lausanne, Switzerland
name: Solange Peters, MD, PhD
role: STUDY_CHAIR
affiliation: EORTC Trial Co-Chair, Royal Marden Hospital, Sutton, UK
name: Mary O'Brien, MD
role: STUDY_CHAIR
affiliation: EORTC Trial Co-Chair, University of Sheffield, Sheffield, UK
name: Sarah Danson, PhD
role: STUDY_CHAIR
affiliation: Trial Co-Chair, University Hospital of Zuerich, Switzerland
name: Rolf Stahel, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.