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Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy (SPLENDOUR)

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ClinicalTrials.gov Identifier: NCT02129699
Recruitment Status : Active, not recruiting
First Posted : May 2, 2014
Last Update Posted : February 20, 2018
Sponsor:
Collaborators:
European Organisation for Research and Treatment of Cancer - EORTC
Amgen
Information provided by (Responsible Party):
European Thoracic Oncology Platform

April 30, 2014
May 2, 2014
February 20, 2018
January 6, 2015
September 2019   (Final data collection date for primary outcome measure)
Overall survival [ Time Frame: Time from the date of randomisation until death from any cause, assessed up to 56 months ]
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 [ Time Frame: Time from the date of randomisation until death from any cause, assessed up to 51 months ]
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.
Complete list of historical versions of study NCT02129699 on ClinicalTrials.gov Archive Site
  • 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 ]

    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.

  • 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 ]
    For details to RECIST 1.1 criteria, see protocol appendix 2
  • Toxicity profile of denosumab [ Time Frame: Assessed up to 56 months ]
    Toxicity profile of denosumab: Adverse events classified according to NCI CTCAE V4
  • Evaluation of potential predictive biomarkers for denosumab activity [ Time Frame: Assessed at baseline, week 7 and at progression (maximum of 56 months) ]
    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
  • 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 51 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. 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.

  • Response based on RECIST 1.1 [ Time Frame: Response of the tumour is defined according to RECIST 1.1 criteria, assessed up to 51 months ]
    For details to RECIST 1.1 criteria, see protocol appendix 2
  • Toxicity profile of denosumab [ Time Frame: Assessed up to 51 weeks ]
    Toxicity profile of denosumab: Adverse events classified according to NCI CTCAE V4
  • Evaluation of potential predictive biomarkers for denosumab activity [ Time Frame: Assessed at baseline, week 7 and at progression (maximum of 51 weeks) ]
    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
Not Provided
Not Provided
 
Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy
A Randomised, Open-label Phase III Trial Evaluating the Addition of Denosumab to Standard First-line Anticancer Treatment in Advanced NSCLC
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.

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

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Lung Cancer Non-small Cell Stage IV
  • Drug: Denosumab
    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).
    Other Name: XGEVA
  • Other: None, standard chemotherapy only

    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

  • 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.

    Intervention: Other: None, standard chemotherapy only
  • Experimental: Standard chemotherapy + 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.

    Intervention: Drug: Denosumab

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
514
1000
September 2020
September 2019   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Austria,   Belgium,   France,   Germany,   Ireland,   Italy,   Poland,   Slovenia,   Spain,   Switzerland,   United Kingdom
Bulgaria,   Israel,   Romania
 
NCT02129699
ETOP 5-12 / EORTC 08111
2013-003156-21 ( EudraCT Number )
20080166 ( Other Grant/Funding Number: AMGEN )
SNCTP000000954 ( Registry Identifier: Swiss National Clinical Trials Portal (SNCTP) )
Yes
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
European Thoracic Oncology Platform
European Thoracic Oncology Platform
  • European Organisation for Research and Treatment of Cancer - EORTC
  • Amgen
Study Chair: Solange Peters, MD, PhD Trial Chair, CHUV Lausanne, Switzerland
Study Chair: Mary O'Brien, MD EORTC Trial Co-Chair, Royal Marden Hospital, Sutton, UK
Study Chair: Sarah Danson, PhD EORTC Trial Co-Chair, University of Sheffield, Sheffield, UK
Study Chair: Rolf Stahel, MD Trial Co-Chair, University Hospital of Zuerich, Switzerland
European Thoracic Oncology Platform
February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP