A research study to investigate how well the standard treatment (chemotherapy) in combination with denosumab works compared with the standard treatment alone in patients with advanced NSCLC.

Phase 1

Conditions: advanced NSCLC
MedDRA version: 19.0Level: LLTClassification code 10025055Term: Lung cancer non-small cell stage IVSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2013-003156-21-PL

Lead Sponsor: ETOP (European Thoracic Oncology Platform) c/o IBCSG Coordinating Center

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 1000

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)
- Availability of tumour tissue for translational research:
- preferred: FFPE block from primary tumour or metastasis,
- alternatively: cell block
- if no block available: 10 unstained slides with wax protection
- 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 creatinine clearance = 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 14 days before beginning treatment
- 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 5 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
a) Trial treatment
b) Submission of biomaterial for central testing
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 550
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 450

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)
- Prior chemotherapy or molecular targeted therapy for metastatic disease, with the exception of neoadjuvant or adjuvant chemotherapy or definitive radiochemotherapy, if terminated more than 6 months before registration.
- 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 = 150/100 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, corrected calcium (with albumin level) >3 mmol/l
- hypocalcaemia: total calcium <2 mmol/l, corrected calcium (with albumin level) < 1.9 mmol/l
- Legal incapacity or limited legal capacity
- Medical or psychological condition 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. (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
- Previous bisphosphonate exposure which
- exceeds 2 prior doses of i.v. bisphosphonates
AND/OR
- exceeds a cumulative exposure of 1 year oral bisphosphonates

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Secondary Objective: - to compare progression free survival (PFS) and response rate (RR, based on RECIST 1.1) in patients treated with standard first-line chemotherapy with or without denosumab<br>- to assess the tolerability of the two regimens<br>- to evaluate potential predictive biomarkers for denosumab activity;Main Objective: To evaluate whether the addition of denosumab to standard firstline chemotherapy in advanced NSCLC improves overall survival.;Primary end point(s): Overall survival ;Timepoint(s) of evaluation of this end point: Time from the date of randomisation until death from any cause.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Progression-free survival (PFS) based on RECIST 1.1<br>- Response based on RECIST 1.1<br>- Toxicity profile of denosumab<br>- Evaluation of potential predictive biomarkers for denosumab activity;Timepoint(s) of evaluation of this end point: - PFS: time from date of randomisation until objective<br>disease progression or death, whichever occurs first<br><br>- Response of the tumour is defined according to RECIST 1.1 criteria<br><br>- Toxicity profile of denosumab: Adverse events classified according to NCI CTCAE V4<br><br>- Evaluation of potential predictive biomarkers for denosumab activity: collection of tumor at randomisation and collection of serum samples at baseline, at dady 1 of cycles 3 and at first progression