Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy

Phase 3

Terminated

Conditions: Lung Cancer Non-small Cell Stage IV

Interventions: Other: None, standard chemotherapy only
Drug: Denosumab

Registration Number: NCT02129699

Lead Sponsor: ETOP IBCSG Partners Foundation

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 595

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
None, standard chemotherapy only	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.
Standard chemotherapy + Denosumab	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.

Primary Outcome Measures

Name	Time	Method
Overall Survival	Overall survival was measured from the date of randomization to the date of death, whatever the cause, up to a maximum of 56 months	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.

Secondary Outcome Measures

Name	Time	Method
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	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.
Overall Survival by Cytoplasmic RANK Expression.	up to a maximum of 56 months	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.
Overall Survival by Membranous RANK Expression.	Up to maximum of 56 months	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.
Toxicity Profile of Denosumab	Assessed up to 56 months	Number of patients with serious adverse events classified according to NCI CTCAE V4.
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	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/

Trial Locations

Locations (66): Univ. Klinik für Innere Medizin V
🇦🇹
Innsbruck, Austria
KH der Elisabethinen Linz
🇦🇹
Linz, Austria
AKH Wien
🇦🇹
Wien, Austria
Otto-Wagner-Spital Department 1
🇦🇹
Wien, Austria
Otto-Wagner-Spital Department 2
🇦🇹
Wien, Austria
Onze Lieve Vrouw Ziekenhuis
🇧🇪
Aalst, Belgium
University Hosptial Ghent
🇧🇪
Ghent, Belgium
Centre Hospitalier Regional De La Citadelle
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Liege, Belgium
Clinique et Maternite Sainte Elisabeth
🇧🇪
Namur, Belgium
Centre hospitalier universitaire d'Angers
🇫🇷
Angers, France
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Univ. Klinik für Innere Medizin V
🇦🇹Innsbruck, Austria