Description:
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.
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
ETOP 5-12 / EORTC 08111
- SECONDARY ID:
2013-003156-21
- SECONDARY ID:
20080166
- SECONDARY ID:
SNCTP000000954
- NCT ID:
NCT02129699
Conditions
- Lung Cancer Non-small Cell Stage IV
Interventions
| Drug | Synonyms | Arms |
|---|
| Denosumab | XGEVA | Standard chemotherapy + Denosumab |
Purpose
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
Trial Arms
| Name | Type | Description | Interventions |
|---|
| None, standard chemotherapy only | Other | 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 | Experimental | 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. | |
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Overall survival |
| Time Frame: | Time from the date of randomisation until death from any cause, assessed up to 56 months |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Progression-free survival (PFS) based on RECIST 1.1 |
| Time Frame: | Time from date of randomisation until objective disease progression or death, whichever occurs first, assessed up to 56 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Response based on RECIST 1.1 |
| Time Frame: | Response of the tumour is defined according to RECIST 1.1 criteria, assessed up to 56 months |
| Safety Issue: | |
| Description: | For details to RECIST 1.1 criteria, see protocol appendix 2 |
| Measure: | Toxicity profile of denosumab |
| Time Frame: | Assessed up to 56 months |
| Safety Issue: | |
| Description: | Toxicity profile of denosumab: Adverse events classified according to NCI CTCAE V4 |
| Measure: | Evaluation of potential predictive biomarkers for denosumab activity |
| Time Frame: | Assessed at baseline, week 7 and at progression (maximum of 56 months) |
| Safety Issue: | |
| Description: | 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 |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | European Thoracic Oncology Platform |
Trial Keywords
Last Updated
August 11, 2020
