E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Lung cancer called "non small cell lung cancer (NSCLC)” that has spread to other parts of your body (metastatic) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025055 |
E.1.2 | Term | Lung cancer non-small cell stage IV |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate whether the addition of denosumab to standard firstline platinum-based doublet chemotherapy in advanced NSCLC improves overall survival. |
|
E.2.2 | Secondary objectives of the trial |
- 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
- to assess the tolerability of the two regimens
- to evaluate potential predictive biomarkers for denosumab activity |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 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 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
a) Trial treatment
b) Submission of biomaterial for central testing |
|
E.4 | Principal 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.
Exception:
Neoadjuvant or adjuvant chemotherapy or radio-chemotherapyare 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 immue 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
- Previous bisphosphonate exposure which
- exceeds 2 prior doses of i.v. bisphosphonates
AND/OR
- exceeds a cumulative exposure of 1 year oral bisphosphonates |
|
E.5 End points |
E.5.1 | Primary end point(s) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from the date of randomisation until death from any cause. |
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E.5.2 | Secondary end point(s) |
- Progression-free survival (PFS) based on RECIST 1.1
- Response based on RECIST 1.1
- Toxicity profile of denosumab
- Evaluation of potential predictive biomarkers for denosumab activity |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PFS: time from date of randomisation until objective
disease progression or death, whichever occurs first
- Response of the tumour is defined according to RECIST 1.1 criteria
- Toxicity profile of denosumab: Adverse events classified according to NCI CTCAE V4
- 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Stratifications: Bone mets, Region, ECOG PS, Histology |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Bulgaria |
France |
Germany |
Ireland |
Israel |
Italy |
Poland |
Romania |
Slovenia |
Spain |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of trial occurs when all of the following criteria have been satisfied:
- All patients have been off protocol-specified treatment for at least thirty days, or a maximum of 2 years after the final analysis, estimated to be done at month 56 after inclusion of the first patient.
- Trial is mature for the analysis of the primary endpoint (observation of 847 deaths)
- Database has been fully cleaned and frozen for the final analysis
Note: follow-up will be life-long for all patients. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |