Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy

Study Overview
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Brief Summary
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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
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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

Official Title
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A Randomised, Open-label Phase III Trial Evaluating the Addition of Denosumab to Standard First-line Anticancer Treatment in Advanced NSCLC

Conditions
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Lung Cancer Non-small Cell Stage IV

Intervention / Treatment
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* Drug: Denosumab
* Other: None, standard chemotherapy only


Participation Criteria
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Eligibility Criteria
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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 Trial treatment 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: None, standard chemotherapy only<br>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<br>* 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<br>|
| Experimental: Standard chemotherapy + Denosumab<br>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<br>* 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).<br>* Other names: XGEVA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | 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. | Time from the date of randomisation until death from any cause, assessed up to 56 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) based on RECIST 1.1 | 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. 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. | Time from date of randomisation until objective disease progression or death, whichever occurs first, assessed up to 56 months | 
| Response based on RECIST 1.1 | For details to RECIST 1.1 criteria, see protocol appendix 2 | Response of the tumour is defined according to RECIST 1.1 criteria, assessed up to 56 months | 
| Toxicity profile of denosumab | Toxicity profile of denosumab: Adverse events classified according to NCI CTCAE V4 | Assessed up to 56 months | 
| Evaluation of potential predictive biomarkers for denosumab activity | Collection of tumor material at randomisation (and highly desirable at progression) and collection of serum samples at baseline, at day 1 of cycles 3 (week 7) and at first progression | Assessed at baseline, week 7 and at progression (maximum of 56 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, stage IV