A Randomised, Open-label Phase III Trial Evaluating the Addition of Denosumab to Standard First-line Anticancer Treatment in Advanced NSCLC
Phase: PHASE3
Conditions: Lung Cancer Non-small Cell Stage IV
Sponsor: ETOP IBCSG Partners Foundation

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SPLENDOUR
ETOP 5-12
EORTC 08111
A randomised, open-label phase III trial evaluating the addition of
denosumab to standard first-line anticancer treatment in advanced
NSCLC
Survival imProvement in Lung cancEr iNduced by DenOsUmab theRapy
Sponsor: European Thoracic Oncology Platform (ETOP)
Coordinated by European Organization for Research and Treatment of
Cancer (EORTC)
In collaboration with
EudraCT number: 2013-003156-21
Amgen number: 20080166
Version 1.1
ETOP c/o IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern
Phone: +41 31 389 93 91
Fax: +41 31 389 93 92
EORTC HQ, Avenue E. Mounier 83/11, 1200 Brussels, Belgium
Phone: +32 2 774 16 11
Fax: +32 2 772 35 45

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Contacts
Trial Chair
Solange Peters, MD
Address
Tel:
Fax:
Email:
Département d'Oncologie
Centre Hospitalier Universitaire Vaudois
1011 Lausanne – Switzerland
+41 79 556 01 92
+41 21 314 67 89 (assistant)
+41 21 314 01 67
solange.peters@etop-eu.org
EORTC Trial Co-Chair
and chair of EORTC
Lung Cancer Group
Mary O’Brien
Address
Tel:
Email:
Royal Marsden Hospital
Downs Rd, Sutton, UK
+44 208 661 3276
+44 208 643 0373
Mary.obrien@rmh.nhs.uk
EORTC Trial Co-Chair
Translational research
Sarah Danson, PhD
Address
Tel:
Fax:
Email:
Academic Unit of Clinical Oncology
CR-UK/YCR Sheffield Cancer Research
Centre
University of Sheffield
Weston Park Hospital
Whitham Road, Sheffield S10 2SJ, UK
+44 114 226 5235
+44 114 226 5364
S.Danson@sheffield.ac.uk
Trial Co-Chair and
Chairman ETOP
Rolf Stahel, MD
Address
Tel:
Fax:
Email:
Laboratory of Molecular Oncology
Clinic of Oncology
University Hospital Zuerich
Häldeliweg 4
CH-8044 Zürich, Switzerland
+41 44 634 28 71
+41 44 634 28 72
rolf.stahel@usz.ch
Pathology
Keith Kerr, MD
Address
Tel:
Fax:
Email:
Department of Pathology
Aberdeen Royal Infirmary
Foresterhill
AB25 2ZN Aberdeen
United Kingdom
+44 1224 550948
+44 1224 663002
k.kerr@abdn.ac.uk
Statistics
Baktiar Hasan, PhD
Urania Dafni, ScD
Address
Tel:
Email:
Address
Tel:
Fax:
Email:
EORTC
Avenue Emmanuel Mounier 83/11
1200 Brussels, Belgium
+32 2 774 1642
baktiar.hasan@eortc.be
Frontier Science Foundation - Hellas
118-120 Papadiamantopoulou Str.
15773, Zografou, Athens, Greece
+30 21 07 71 09 02
+30 21 07 71 09 03
udafni@frontier-science.gr

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Clinical Research
Physician
Project Manager
Data Manager
Sandrine Marreaud
Benedicte Marchal
Larissa Polders
Address
Tel:
Email:
Tel:
Email:
Tel:
Email:
EORTC
Avenue Emmanuel Mounier 83/11
1200 Brussels, Belgium
+32 2 774 1005
sandrine.marreaud@eortc.be
+32 2 774 1685
benedicte.marchal@eortc.be
+32 2 774 1056
larissa.polders@eortc.be
Drug supply
Address
Tel:
Fax:
Email:
ETOP Drug Supply Office
c/o IBCSG Coordinating Center
Effingerstrasse 40
3008 Bern, Switzerland
+41 31 389 93 91
+41 31 389 92 29
drugsupply@etop-eu.org
Regulatory Affairs
Barbara Ruepp, MD
Address
Tel:
Fax:
Email:
ETOP Safety and Regulatory Office
c/o IBCSG Coordinating Center
Effingerstrasse 40
3008 Bern, Switzerland
+41 31 389 93 91
+41 31 389 92 29
regulatoryoffice@etop-eu.org
ETOP Coordinating
Office
Anita Hiltbrunner
Rudolf Maibach
Viktor Zsuffa
Address
Tel:
Fax:
Email:
c/o IBCSG Coordinating Center
Effingerstrasse 40
3008 Bern, Switzerland
+41 31 389 93 91
+41 31 389 92 29
anita.hiltbrunner@etop-eu.org
rudolf.maibach@etop-eu.org
SPLENDOUR@etop-eu.org
EORTC
Pharmacovigilance
Unit
Tel:
Fax:
Email:
+32 2 774 16 76
+32 2 772 80 27
pharmacovigilance@eortc.be
Central Europe
Cooperative Oncology
Group CECOG
Coordinating Office
Christoph Zielinski,
MD,
CECOG President
Elisabeth Lindner,
Managing Director
Regina Knittelfelder,
Senior Project
Manager
Dagmar Just, Public
Affairs Officer
Address
Tel:
Fax:
Email:
Tel:
Email:
Tel:
Email:
Tel:
Email:
CECOG, Schlagergasse 6/6, A-1090 Vienna,
Austria
+43 1 409 77 25
+43 1 409 77 26
christoph.zielinski@meduniwien.ac.at
+43 1 409 77 25
elisabeth.lindner@cecog.at
+43 1 409 77 25
regina.knittelfelder@cecog.at
+43 1 409 77 25
dagmar.just@cecog.at
In collaboration with Amgen.

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Principal Investigator Protocol Signature Page
SPLENDOUR
I have read the protocol and agree that it contains all necessary details for conducting this
trial. I will conduct the trial as outlined in the following protocol and in compliance with
GCP, and will apply due diligence to avoid protocol deviations. I will provide copies of the
protocol and all drug information relating to pre-clinical and prior clinical experience
furnished to me by ETOP and EORTC, to all physicians responsible to me who participate
in this trial. I will discuss this material with them to assure that they are fully informed
regarding the drugs and the conduct of the trial. I agree to keep accurate records on all
patient information including patient's informed consent statement, drug shipment and
return forms, and all other information collected during the trial for a minimum period of 15
years.
Name of Principal Investigator:___________________________________________
Institution’s name and place:___________________________________________
_____________________________________________________ ______________
Signature
Date

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TABLE OF CONTENTS
Section
Page
1.
Protocol Summary............................................................................................................9
2.
List of abbreviations .......................................................................................................17
3.
Background and Rationale..............................................................................................18
3.1.
Bone metastasis in lung cancer ...............................................................................18
3.2.
Skeletal Related Events (SREs) in lung cancer.......................................................18
3.3.
Prevention of SREs .................................................................................................18
3.4.
Denosumab..............................................................................................................19
3.5.
Survival impact of denosumab treatment................................................................19
3.6.
Biological hypothesis for direct antitumor effect of denosumab ............................19
3.7.
Biomarkers in RANK pathway inhibitor trial.........................................................20
3.8.
Trial hypothesis.......................................................................................................20
3.9.
Trial treatment.........................................................................................................21
3.10.
Overall risk/benefit assessment ...........................................................................21
3.11.
Rationale for trial design .....................................................................................21
4.
Objectives and endpoints................................................................................................21
4.1.
General objectives...................................................................................................21
4.2.
Primary endpoint.....................................................................................................22
4.3.
Secondary endpoints ...............................................................................................22
5.
Trial design, duration and termination ...........................................................................22
6.
Patient selection..............................................................................................................24
6.1.
Inclusion criteria......................................................................................................24
6.2.
Exclusion criteria.....................................................................................................25
7.
Investigator authorisation procedure ..............................................................................26
8.
Patient screening and registration/randomisation...........................................................27
8.1.
Screening.................................................................................................................27
8.2.
Registration procedure for screening (step 1) .........................................................28
8.3.
Randomisation procedure (step 2)...........................................................................28
8.4.
Stratification............................................................................................................29
9.
Investigational drug........................................................................................................29
9.1.
Description of investigational drug.........................................................................29
9.2.
Packaging and labelling ..........................................................................................30
9.3.
Receipt of the drug..................................................................................................30
9.4.
Storage and handling...............................................................................................30
9.5.
Unused trial drugs supplies .....................................................................................30
10. Trial treatments...............................................................................................................30
10.1.
Drug combinations ..............................................................................................30
10.2.
Pemetrexed ..........................................................................................................32
10.3.
Cisplatin, Carboplatin and/or Gemcitabine .........................................................32
10.4.
Denosumab..........................................................................................................32
10.5.
Precautions...........................................................................................................32
10.6.
Concomitant treatment ........................................................................................32
10.7.
Treatment delay and dose modification for toxicity............................................33
10.8.
Treatment duration ..............................................................................................38
11. Safety of chemotherapy and investigational product .....................................................38
11.1.
Cisplatin...............................................................................................................38
11.2.
Carboplatin ..........................................................................................................38

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11.3.
Gemcitabine.........................................................................................................40
11.4.
Pemetrexed ..........................................................................................................40
11.5.
Denosumab ..........................................................................................................41
12. Serious adverse events reporting....................................................................................44
12.1.
Definitions ...........................................................................................................44
12.2.
Exceptions ...........................................................................................................45
12.3.
Severity assessment .............................................................................................46
12.4.
Causality assessment ...........................................................................................46
12.5.
Expectedness assessment.....................................................................................46
12.6.
Reporting procedure for investigators .................................................................46
12.7.
Reporting responsibilities for EORTC ................................................................47
12.8.
Pregnancy and lactation reporting.......................................................................47
13. Endpoints definition .......................................................................................................48
13.1.
Overall survival ...................................................................................................48
13.2.
Progression-free survival.....................................................................................48
13.3.
Response..............................................................................................................48
13.4.
Toxicity................................................................................................................48
14. Biological material and translational research................................................................49
14.1.
Serum...................................................................................................................49
14.2.
Tumour tissue ......................................................................................................49
14.3.
Banking of biological material ............................................................................50
15. Trial procedures..............................................................................................................50
15.2.
Baseline evaluations (within 28 days prior to registration).................................51
15.3.
Before start of treatment......................................................................................52
15.4.
Evaluations before and during per protocol first-line chemotherapy..................52
15.5.
End of first-line chemotherapy treatment visit....................................................52
15.6.
Evaluations after per protocol first-line chemotherapy and before first
progression.........................................................................................................................52
15.7.
Evaluations at first documented progression.......................................................53
15.8.
Evaluations after first progression.......................................................................53
15.9.
Arm B: End of denosumab treatment visit ..........................................................53
16. Case report forms and documentation............................................................................54
16.1.
Case report forms.................................................................................................54
16.2.
CRF submission schedule....................................................................................55
16.3.
Data flow .............................................................................................................56
17. Statistical considerations ................................................................................................56
17.1.
Primary Objective................................................................................................56
17.2.
Sample size..........................................................................................................56
17.3.
Statistical analysis plan........................................................................................56
17.4.
Interim analyses...................................................................................................59
17.5.
End of trial...........................................................................................................59
18. Criteria for termination of the trial .................................................................................59
18.1.
Discontinuation of protocol treatment for individual patients.............................59
18.2.
General criteria for termination of the trial .........................................................60
19. Ethics aspects, regulatory approval, and Patient Informed Consent ..............................60
19.1.
Ethics Review Board/Ethics Committee .............................................................61
19.2.
Regulatory approval procedures..........................................................................61
19.3.
Informed consent .................................................................................................61
19.4.
Premature withdrawal..........................................................................................62
20. Governance and administrative issues............................................................................62

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20.1.
Steering Committee.............................................................................................62
20.2.
Independent Data Monitoring Committee...........................................................62
20.3.
Publication...........................................................................................................62
20.4.
Clinical trial insurance.........................................................................................62
20.5.
Quality Assurance/Quality control ......................................................................63
20.6.
Protocol adherence ..............................................................................................63
20.7.
Data protection ....................................................................................................63
20.8.
Record Retention.................................................................................................63
21. References ......................................................................................................................64
Appendices
1. Template for patient information and informed consent form
2. RECIST criteria V1.1

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1.
Protocol Summary
SPLENDOUR
A randomised, open-label phase III trial evaluating the addition of denosumab
to standard first-line anticancer treatment in advanced NSCLC
Sponsor: European Thoracic Oncology Platform (ETOP)
Trial Coordinator: European Organization for Research and Treatment of Cancer
(EORTC)
Pharma Partner: AMGEN
Population: Patients with untreated advanced NSCLC, PS 0-2, with or without bone
metastasis at diagnosis
Design:
Sample size: 1000
Trial treatment:
ARM A:
4 – 6 cycles of doublet chemotherapy + best supportive care
ARM B:
4 – 6 cycles of doublet chemotherapy + denosumab 120 mg, s.c. every 3-4
weeks
until
unacceptable
toxicity,
patient
refusal
or
patient’s
death.
Denosumab will be continued upon tumour progression and concomitantly to
First-line
Stage IV
NSCLC
Stratify:
- Bone mets
- Region
- ECOG PS
- Histology
R
A
N
D
O
M
I
S
E
4-6 cycles chemotherapy
every 3 weeks + BSC
4-6 cycles chemotherapy
every 3 weeks
Denosumab every 3-4 weeks
A
B
Blood
Blood
Blood
Progression
Translational research:
Trial treatment
Screening, eligibility and enrolment
Follow
-up
FFPE
FFPE

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subsequent lines of systemic treatment, as long as tolerable for the patient. In
cycle 1, an additional dose will be given on day 8.
Doublet chemotherapy (3 week cycles):
CisGem:
cisplatin 75 mg/m2, i.v. day 1, plus gemcitabine 1250 mg/m2, i.v., days 1 and 8
CarboGem: carboplatin AUC 5 , i.v. day 1, plus gemcitabine 1250 mg/m2, i.v. days 1 and 8
In patients with non-squamous cell histology only, pemetrexed may be administered instead
of gemcitabine:
CisPem:
cisplatin 75 mg/m2, i.v. day 1, plus pemetrexed 500 mg/m2 i.v. day 1
CarboPem: carboplatin AUC 5 , i.v. day 1, plus pemetrexed 500 mg/m2 i.v. day 1
Daily supplementation with calcium (500 mg) and vitamin D (400U) will be administered
to all patients (mandatory for pts in arm B (denosumab) and recommended in arm A if they
receive zoledronic acid according to local guidelines). Patients treated with pemetrexed will
receive folic acid 0.4 – 1 mg/day and vit B12 1000 IU s.c. 1 week before first dose and then
every 3 cycles.
Rationale:
Denosumab is a fully human monoclonal IgG2 antibody binding with a high affinity to
RANKL. In a pivotal phase III trial in patients with solid tumors (other than breast or
prostate) or multiple myeloma and bone metastasis, denosumab was shown to be non
inferior – with a trend toward superiority – to zoledronic acid in delaying time to first SRE
(HR, 0.84; 95% CI, 0.71 to 0.98; non-inferiority P= .0007, representing 16% reduction in
hazard). Regarding non-small cell lung cancer (NSCLC), the effect of denosumab on time to
first on-study SRE relative to zoledronic acid by tumour stratification factors resulted in a
HR of 0.84 for NSCLC (n=702; 95% CI, 0.64 to 1.10; P=0.20). Overall survival was similar
between both treatment groups. Interestingly, an ad hoc analysis examining overall survival
was performed for distinct strata, demonstrating an OS HR of 2.26 for myeloma (n=180;
95% CI, 1.13 to 4.50), and 1.08 for other solid tumours (95% CI, 0.90 to 1.30).
In the 811 patients with lung cancer, including non-small cell lung cancer (NSCLC) and
small-cell lung cancer (SCLC), denosumab treatment was associated with significantly
improved overall survival versus zoledronic acid (8.9 vs 7.7 mos., HR=0.80 (95% CI, 0.67–
0.95), P = 0.01). Specifically, in NSCLC, a HR of 0.79 (9.5 vs. 8.1 mos., 95% CI, 0.65 to
0.95) was described. Further subgroup analysis could demonstrate this OS difference
through distinct NSCLC histologic subtypes, maybe to some higher extent in squamous
histology (adenocarcinoma 9.6 vs. 8.2 mos., HR=0.80 (95% CI, 0.62–1.02), P = 0.0751, and
squamous 8.6 vs. 6.4, HR=0.68 (95% CI, 0.47–0.97), P = 0.0350).
Cancer metastasis to the bone results from the active engagement and interaction with the
bone microenvironment. RANKL-mediated increased bone turnover and osteoclast activity
may mechanically enhance tumour growth. RANK and RANKL expressions have been
observed in some tumour types with early clinical data, suggesting a potential anti-tumour
effect of RANK pathway inhibitors.
This phase III prospective trial will evaluate the potential of denosumab - as an antitumour
agent - to increase survival of advanced NSCLC with or without bone metastasis.

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Objectives and endpoints:
The primary objective is to evaluate whether the addition of denosumab to standard first-
line chemotherapy in advanced NSCLC improves overall survival.
Secondary objectives are 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, and to assess the tolerability of the two regimens.
The translational research objective is to evaluate potential predictive biomarkers for
denosumab activity.
Primary endpoint: overall survival
Secondary endpoints:

Progression free survival (PFS) based on RECIST 1.1

Response based on RECIST 1.1

Toxicity profile of denosumab; toxicities will be assessed and graded according to
CTCAE v 4.

Evaluation of potential predictive biomarkers for denosumab activity
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).

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.

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
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
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 radio-
chemotherapy, 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

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
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.
Statistical considerations:
Phase III trial, with futility Interim Analysis (IA).
Primary endpoint: Overall Survival (OS)
Patient population: All randomised patients (ITT)
Power, sample size and trial duration:
Using 90% power and a one-sided type I error of 2.5%, demonstration of an increase in
overall survival to 11.25 months in the experimental arm relative to 9 months in the control
arm (equivalent to HR = 0.80) requires observation of 847 deaths. The total sample size is
1000 patients, which could increase in case the event rate is lower than expected.
Interim Futility Analysis (IA):
The trial is designed with a futility IA, based on a non-binding O’Brien-Fleming boundary,
at 30% of the overall trial information time. This will be an event driven IA, when 254
deaths have been observed overall, and is expected to occur by 22.5 months from the date
the first patient is randomised. At this time accrual is expected to have reached
approximately 58% of the total.
Duration: If the trial is completed with full accrual, the maximum overall duration is
expected to be approximately 51 months.
Translational research:
The collection of tumor and serum samples is required in this trial. This material will
constitute an invaluable and precious source for biological research in the context of this
trial.
Translational research looking at potential predictive biomarkers of denosumab activity will
be performed on serum and tumor tissue.
Analysis of serum samples by ELISA includes CTX, osteoprotegerin (OPG), propeptide of
type I procollagen (PINP), osteopontin (OPN), free RANKL and RANKL-OPG. These may

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be changed and the panel of serum biomarkers will include best candidates at the time of
analysis.
The following evaluations are proposed for translational research on FFPE tumor tissue:
IHC (and/or RT-PCR) for RANKL & RANK, and potentially NF-kappaB activation
evaluation (RT-PCR and/or IHC) and bone sialoprotein (BSP) which in tumour has been
correlated with bone metastasis progression and high levels are associated with poor
prognosis; and osteopontin (OPN) levels in primary tumour may correlate with tumour
aggressiveness. Again, these may be adapted in the future to include best candidates
available at the time of evaluation.

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Trial schedule
≤28
days
prior
rando
At
rando
Cyc
1
Cyc
2
Cyc
3
Cyc
4
Cyc
5*)
Cyc
6*)
30 (+/- 5) days
after stop of first
line
chemotherapy
After stop of
first line
chemotherapy,
before first
progression 17
At first
pro-
gression
After
first
progres-
sion
Arm B:
30 (+/- 5)
days after
stop of
denosumab
Follow-
up:
every 8
weeks18
Written informed
consent 1
X
Medical history
X
Tumour material 2
X
Blood sample 3
X
X
X
Physical exam, PS,
blood pressure, weight
X
X
X
X
X
X
X
X
X
X
X
Baseline symptoms
X
Haematology 4
X
X
X
X
X
X
X
X
X
X
Chemistry 5
X
X
X
X
X
X
X
X
X 16
X
X 16
X
Pregnancy test 6
X
PET-CT or CT 7
X
CT scan 8
X
X 11
X 11
X
Bone scan 9
X
√
√11
√11
√
Brain CT or MRI 10
√
√
√11
√11
√
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Cis or Carbo12
X
X
X
X
X
X
Gemcitabine13
X
X
X
X
X
X
Pemetrexed (non
squamous only) 14
X
X
X
X
X
X
Arm B: Denosumab 15
X 15
X
X
X
X
X
X
X
X
Survival status and
further lines of
treatment
X
X
X
X
X
X = mandatory; √= if clinically indicated
*) Administration of cycles 5 and 6 follows local investigator decision

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Legend for schedule:
1 –
before any trial-specific intervention; maximum two weeks before randomisation
2 –
submit tumour material from biopsy: FFPE block or cell block; or at least 10 unstained slides
3 –
A blood sample for translational research should be taken at baseline, on day 1 of cycle 3, and at the time of first progression (within 4 weeks of PD).
4 –
Haematology: haemoglobin, neutrophils, platelets
5 –
Blood chemistry: serum creatinine, ALT, bilirubin, total calcium, albumin
6 –
Pregnancy test for women of childbearing potential within 14 days before start of treatment
7 –
PET-CT or CT of thorax and abdomen at screening.
8 –
CT of thorax and abdomen on day 1 of cycle 4, then every 12 weeks until first progression has been fully documented (see also footnote 10); thereafter according to
local standard of care.
9 –
In the event of equivocal results, further confirmation using bone MRI, CT, X-Ray or biopsy is recommended. Bone scan at baseline not required for patients who have
undergone a PET-CT at baseline; Bone imaging (including bone scan) during treatment only in case of suspected bone metastases.
10 – Brain CT or MRI in case of clinically suspected brain metastasis.
11 – For patients who discontinued per-protocol first-line chemotherapy trial treatment due to toxicity rather than progressive disease, restaging (CT scan chest and abdomen,
brain scan if applicable) should be repeated if not already performed within 30 days prior to the last dose of trial treatment, and then every 12 weeks until progression.
12 – Choice of the investigator
13 – Gemcitabine (on days 1 and 8 of cycle) OR pemetrexed on day 1 of cycle will be delivered in addition to the platinum compound according to local investigator.
14 – Pemetrexed option is restricted to non-squamous histology.
15 – Denosumab is administered every 3-4 weeks until unacceptable toxicity or patient refusal. In cycle 1, an additional dose will be given on day 8. Denosumab will be
continued upon tumour progression and concomitantly to subsequent lines of systemic treatment.
16 – After first-line chemotherapy, while still on denosumab treatment: only total calcium, albumin
17 - After first line per protocol chemotherapy, clinical FU including physical exam should be according to local standard of care, according to denosumab schedule and
subsequent anticancer treatment schedules, every 6-8 weeks, until first progression. In the observation arm, adverse events have to be documented at the same schedule.
18 – After first progression has been fully documented, visits and imaging (CT) will be done according to local standard of care. Survival status and adverse events will be
captured every 8 weeks until death. In arm B denosumab treatment continues for an unlimited time.

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2.
List of abbreviations
ALT
Alanine transaminase
CRF
Case report form
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
EGFR
Epidermal growth factor receptor
FFPE
Formalin fixed, paraffin embedded
GCP
Good Clinical Practice
IB
Investigator brochure
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
INR
International Normalized Ratio
IP
Investigational Product
ITT
Intention to treat
HR
Hazard ratio
LLN
Lower limit of normal lab value
NSCLC
Non-small cell lung cancer
OPG
Osteoprotegerin
ORTA
Online Randomised Trials Access
OS
Overall survival
PFS
Progression free suvival
PINP
Propeptide of type 1 procollagen
RANK
Receptor activator of nuclear factor-KappaB
RANKL
Receptor activator of nuclear factor-KappaB ligand
RDC
Remote data capture
RECIST
Response Evaluation Criteria In Solid Tumours
SAE
Serious adverse event
SADR
Serious adverse drug reaction
SmPC
Summary of product characteristics
SRE
Skeletal related event
SUSAR
Suspected unexpected serious adverse reaction
ULN
Upper limit of normal lab value
VEGF
Vascular endothelial growth factor

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3.
Background and Rationale
3.1.
Bone metastasis in lung cancer
Lung cancer is the most common neoplasm worldwide, and overall survival rates are poor,
with a median and 5-year survival expectations in advanced disease of about one year and
less than 5% of patients, respectively. As the life expectancy of individuals with lung cancer
increases, symptom control measures are growing in importance. Bone metastases represent
a significant cause of morbidity in patients with advanced cancer and are common in lung
cancer. Notably, about 30-50% of patients suffering from lung cancer develop bone
metastases at some point, affecting 2/3 of them already at the time of diagnosis.
3.2.
Skeletal Related Events (SREs) in lung cancer
Patients with metastatic bone disease may suffer from skeletal-related events (SREs), such
as fractures, pain requiring radiation or bone surgery, spinal cord compression, – severely
affecting their quality of life as well as absorbing significant hospital and financial
resources. Owing to short survival times, data on the incidences of SREs are limited. Lung
cancer patients are known to present with a high frequency of SREs, comparable to other
solid tumours often metastasizing to bone, like breast and prostate cancers 1,2, while the
occurrence of NSCLC SRE was shown to predict an unexpectedly short life expectancy for
these patients 3.
3.3.
Prevention of SREs
3.3.1.
Zoledronic acid
Zoledronic acid acts on bone metabolism by disrupting the HMG-CoA reductase pathway
and
blocking
osteoclastogenesis,
as
well
as
osteoclast
cytoskeletal
arrangement.
Bisphosphonates
have
shown
efficacy in
randomised
placebo-controlled
trials
for
preventing and delaying SREs and improving QoL in patients with solid tumours, including
NSCLC, while concomitantly preventing the increase in pain that accompanies progression
of malignant bone disease 1,2,4. Clinical experience suggests that bisphosphonates are rarely
used in treatment regimens for NSCLC despite evidence that they are an effective treatment
of bone metastases and prevention of SREs in this population 1. One of the reasons for this
may be the potential adverse effects of these agents. Orally administered bisphosphonates
are associated with gastrointestinal intolerance, while nephrotoxicity and osteonecrosis of
the jaw are usually linked with i.v. agents 5-7.
3.3.2.
Targeting Receptor Activator of NF-KappaB (RANK) pathway
Recently, targeting the osteoprotegerin (OPG)/receptor activator of nuclear factor-KappaB
ligand (RANKL)/(RANK) pathway was demonstrated to be an interesting strategy in
patients suffering from virtually all bone-metastatic advanced solid tumours 8-10.
The RANK pathway plays a major role in osteoclasts function and therefore contributes to
the subtle regulation of bone turnover. RANK is a member of the tumour necrosis factor
receptor (TNFR) superfamily. RANK and OPG are both receptors for RANKL. However,
whereas RANK signaling is stimulated upon RANKL binding, OPG is a secreted decoy
receptor that acts as a natural inhibitor of the pathway 11. Biologically, RANKL is a potent
osteoclastogenic factor expressed on osteoblasts and osteocytes, promoting survival,
proliferation, differentiation, and activation of mature osteoclasts. While the RANK

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pathway is specifically involved in bone homeostasis, its deregulation was shown to be an
initiator of SREs in cancer.
3.4.
Denosumab
Denosumab is a fully human monoclonal IgG2 antibody binding with a high affinity to
RANKL. It is specific and does not demonstrate significant binding to other members of the
TNF ligand superfamily. As a result of its specific mechanism of action on the bone matrix,
denosumab has become a new option for the treatment of osteoporosis 12.
In breast cancer, denosumab was demonstrated superior to zoledronic acid in delaying time
to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority),
associated with a greater reduction in bone turnover markers. Overall survival, disease
progression, and rates of adverse events were similar between groups 10.
In a pivotal phase 3 trial in patients with solid tumours and multiple myeloma (other than
breast or prostate) and bone metastasis, denosumab was shown to be non-inferior – with a
trend toward superiority – to zoledronic acid in delaying time to first SRE (HR, 0.84; 95%
CI, 0.71 to 0.98; P= .0007, representing 16% reduction in hazard). Regarding NSCLC, the
effect of denosumab on time to first on-study SRE relative to zoledronic acid by tumour
stratification factors resulted in an HR of 0.84 for NSCLC (95% CI, 0.64 to 1.10; P=0.20) 9.
3.5.
Survival impact of denosumab treatment
Overall survival in solid tumours was similar between both treatment groups. Interestingly,
an ad hoc analysis examining overall survival was performed for three distinct strata,
demonstrating an OS HR of 2.26 for myeloma (95% CI, 1.13 to 4.50), and 1.08 for other
solid tumours (95% CI, 0.90 to 1.30). In the 811 patients with lung cancer, including non-
small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), denosumab treatment
was associated with significantly improved overall survival versus zoledronic acid (8.9 vs
7.7 mos., HR, 0.80 (95% CI, 0.67–0.95), P = 0.01). Specifically, in NSCLC, a HR of 0.78
(9.5 vs. 8.0 mos., 95% CI, 0.65 to 0.94) was described, while the same trend remained in a
statistically non-significant way in SCLC (7.6 vs. 5.1 mos., HR, 0.81 (95% CI, 0.52–1.26),
P = 0.3580). Further subgroup analysis could demonstrate this OS difference through
distinct NSCLC histological subtypes, maybe to some higher extent in squamous histology
(adenocarcinoma 9.6 vs. 8.2 mos., HR 0.80 (95% CI, 0.62–1.02, P = 0.0751 and squamous
8.6 vs. 6.4 mos., HR 0.68 (95% CI, 0.47–0.97) P = 0.0350) 9.
3.6.
Biological hypothesis for direct antitumor effect of denosumab
Apart from bone matrix cells, the transmembrane RANK protein is strongly expressed on
lymphocytes, dendritic cells, fibroblasts, and mammary gland and RANK mRNA is also
found in skeletal muscle, liver, small and large intestine and adrenal gland 13. Of therapeutic
interest, its presence was also demonstrated in some specific types of cancer cells, notably in
NSCLC, osteosarcoma as well as in breast and prostate cancer 14-16.
A direct impact of RANK and RANKL on tumour cell proliferation has been hypothesized,
with a potential similar stimulatory effect as observed on osteoclasts. RANK signalling
accelerated tumorigenesis in mouse mammary tumour virus (MMTV)-RANK transgenic
mice as well as in the MMTV-Neu transgenic mouse model 17,18. In animal models, RANKL
was shown to increase invasiveness of mammary and prostate cancer as measured by the
propensity of the tumours to generate metastatic spread, notably to the lung 19. Promotion of
cell migration was also consistently demonstrated in xenograft models using other breast,
prostate and melanoma cancer cell lines 20,21.

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Interestingly, the implication of NF-κB – a crucial component of RANK signalling – in lung
tumour development is progressively being recognized. Notably, using genetically-
engineered mouse models of lung adenocarcinoma, in which the tumours are initiated by
oncogenic KRAS activation in lung epithelial cells, the NF-κB pathway, both in tumour
epithelial cells and in myeloid cells, was recently shown to participate in tumour
development 22-27.
3.7.
Biomarkers in RANK pathway inhibitor trial
3.7.1.
RANK and RANKL tumour cell expression
Very few data are available about RANK and RANKL expression prevalence in NSCLC.
IHC methodological limitations make the testing process very delicate and hardly
reproducible to date. The available IHC data in 42 NSCLC demonstrate a positivity of
RANK and RANKL in respectively 56% and 75% among lung adenocarcinoma and 34%
and 19% among squamous cell carcinoma 28. In addition, RT-PCR data presented in a poster
by Tometsko in 2006 show that RANK mRNA expression was significantly higher in
primary human lung tumours than in normal lung tissue, and is detectable on human lung
cell lines isolated from various metastatic sites. By flow cytometry, high RANK surface
protein expression was detected on cell lines that were isolated from bone metastases while
it was low on cell lines isolated from metastases in the pleural cavity.
Serum measurement of RANKL can be done through a quantitative determination of total
(free RANKL and RANKL complexed to OPG) soluble RANKL in serum and
osteoprotegerin (OPG) levels to provide surrogate measurement of baseline status of the
RANKL-RANK-OPG pathway.
3.7.2.
Bone resorption markers
The osteoclasts cause breakdown of type I collagen transverse cross-links, the main
constituent of the bone’s organic matrix, resulting in the release of degradation molecules
such as pyridinoline, deoxypyridinoline, N-telopeptides (NTX) and C-telopeptides (CTX).
N-telopeptide is one of several unique breakdown products of type I collagen released into
circulation with degradation of bone. These products are released into the blood and
excreted in the urine, and constitute markers of bone resorption and formation. Urinary N-
telopeptide levels have been shown to be extremely sensitive measures of bone resorption
when corrected by urinary creatinine levels 29.
Zoledronic acid and denosumab treatments immediately and consistently reduced urinary N-
telopeptide/creatinine ratios. The detection of the recent CTX markers in blood is associated
with the presence and progression of bone metastases and is linked to the prognosis and the
response to pharmacological treatment 30. Normalisation of NTX levels with zoledronic acid
is associated with improved survival in NSCLC 31. Osteopontin (OPN) levels in advanced
NSCLC correlate with therapeutic response and survival
32. Propeptide of type 1
procollagen (PINP) is raised in the serum of lung cancer patients compared to normal sera
33.
3.8.
Trial hypothesis
Although both the HMG-CoA reductase and RANK pathways are physiologically involved
in bone turnover, the RANK pathway was specifically highlighted in preclinical and clinical
studies that reported an increased expression of the RANK/RANKL proteins and abnormal
OPG/RANKL ratios in patients having cancer with bone metastases. Cancer metastasis to

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the
bone
results
from
the
active
engagement
and
interaction
with
the
bone
microenvironment. RANKL-mediated increased bone turnover and osteoclast activity may
enhance tumour growth in bone by mechanically facilitating cancer cell establishment. In
addition, RANK/RANKL expression per se has been observed in some tumour types, and
RANK inhibitors might reduce tumour aggressiveness and metastatic capabilities via
distinct mechanisms.
The retrospective, unplanned nature of lung cancer survival data imposes some limitations
in interpreting these data and implies bias risks. However, based on previous data involving
the RANK pathway in tumour biology, it is obvious that this warrants further pre-clinical
and prospective clinical investigation. This trial aims at evaluating the potential of
denosumab – as an antitumor agent – to increase survival of advanced NSCLC with or
without bone metastasis, in the context of a strong and unique European collaboration.
3.9.
Trial treatment
All patients will receive standard, platinum-based chemotherapy combined with pemetrexed
or gemcitabine for first-line NSCLC. The number of cycles of doublet chemotherapy will be
between 4 and 6 cycles, according to the institution’s policy. Similarly, pemetrexed or
erlotinib maintenance treatment after doublet chemotherapy is allowed in both arms.
Patients will be randomised between Arm A, chemotherapy plus best supportive care (BSC),
and Arm B, chemotherapy plus denosumab. Denosumab will be administered every 3-4
weeks, and should be continued beyond chemotherapy lifelong or until unacceptable
toxicity or patient refusal.
3.10.
Overall risk/benefit assessment
All patients will receive standard first-line treatment for NSCLC. The addition of
denosumab to the standard treatment poses only a small risk for toxic effects, and the
protocol prescribes precautions to be taken to avoid these. Denosumab has potential to
prolong overall survival in these patients. Overall, the trial design offers a favourable benefit
to risk ratio.
3.11.
Rationale for trial design
The hypothesis underlying the trial is that the addition of denosumab will significantly
prolong overall survival. Both survival being primary endpoint and thus not subjected to
bias, as well as denosumab being continued over a long period of time justify an open-
labelled strategy. An open-label randomisation is justified since denosumab will be
administered at a 3- or 4-week schedule as opposed to the 3-week chemotherapy, and since
denosumab can be continued for an unlimited time after stop of chemotherapy.
4.
Objectives and endpoints
4.1.
General objectives
The primary objective is to evaluate whether the addition of denosumab to standard first-
line chemotherapy in advanced NSCLC improves overall survival.
Secondary objectives are 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, and to assess the tolerability of the two regimens.

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The translational research objective is to evaluate potential predictive biomarkers for
denosumab activity.
Translational research looking at potential predictive biomarkers of denosumab activity will
be performed in an exploratory manner on blood and tumor tissue.
4.2.
Primary endpoint
Overall Survival (OS). For definition, see section 13.1
4.3.
Secondary endpoints
4.3.1.
Progression free survival (PFS) based on RECIST 1.1
4.3.2.
Response based on RECIST 1.1
4.3.3.
Toxicity profile of denosumab; toxicities will be assessed and graded according to
CTCAE v 4.
4.3.4.
Evaluation of potential predictive biomarkers for denosumab activity (see section
14 on biomaterial and translational research).
5.
Trial design, duration and termination
This is a multinational, multi-center, randomised, open-label phase III trial evaluating the
addition of denosumab to standard first-line anticancer treatment in advanced NSCLC. The
primary endpoint is overall survival (OS) measured from the date of randomisation.
Trial design:
First-line
Stage IV
NSCLC
Stratify:
- Bone mets
- Region
- ECOG PS
- Histology
R
A
N
D
O
M
I
S
E
4-6 cycles chemotherapy
every 3 weeks + BSC
4-6 cycles chemotherapy
every 3 weeks
Denosumab every 3-4 weeks
A
B
Blood
Blood
Blood
Progression
Translational research:
Trial treatment
Screening, eligibility and enrolment
Follow
-up
FFPE
FFPE

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Doublet chemotherapy cycles last 3 weeks:
CisGem:
cisplatin 75 mg/m2, i.v. day 1, plus gemcitabine 1250 mg/m2, i.v., days 1 and
8
CarboGem:
carboplatin AUC 5 , i.v. day 1, plus gemcitabine 1250 mg/m2, i.v., days 1 and
8
In patients with non-squamous cell histology only, pemetrexed may be administered instead
of gemcitabine:
CisPem:
cisplatin 75 mg/m2, i.v. day 1, plus pemetrexed 500 mg/m2 i.v. day 1
CarboPem:
carboplatin AUC 5 , i.v. day 1, plus pemetrexed 500 mg/m2 i.v. day 1
Patients will be randomised to one of two treatment regimens as follows:
ARM A :
4 – 6 cycles of one of the above combinations + best supportive care
ARM B :
4 – 6 cycles of one of the above combinations + denosumab 120 mg, s.c.
every 3-4 weeks until unacceptable toxicity, patient refusal or patient’s
death. Denosumab will be continued every 3-4 weeks upon tumour
progression and concomitantly to subsequent lines of systemic treatment, as
long as tolerable for the patient. In cycle 1, an additional dose will be given
on day 8.
Frequency of administration is 3-4 weeks and is left to investigator's
preference. For practical reasons, it is encouraged to consider 3-weekly
administration during first-line chemotherapy and 4-weekly schedule after
first-line chemotherapy, in particular when no chemotherapy is delivered or
when chemotherapy is not cycled on a 3-weeks basis.
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 847 deaths for the
final analysis has been reached.
Daily supplementation with calcium (500 mg) and vitamin D (400U) will be administered
to all patients (mandatory for pts in arm B (denosumab) and recommended in arm A if they
receive zoledronic acid according to local guidelines). Patients treated with pemetrexed will
receive folic acid 0.4 – 1 mg/day and vit B12 1000 IU s.c. 1 week before first dose and then
every 3 cycles.
Patient accrual is expected to be completed within 37 months including a run-in-period of 6
months. Treatment and follow-up is expected to extend the trial duration to a total of 51
months. All patients will be followed until death – thus follow-up estimated up to 3 years
following the enrolment of the last patient.
The trial will end with the preparation of the final report, scheduled for month 56 after the
inclusion of the first patient.
Systemic therapy beyond first-line trial treatment will be delivered according to local
standards (including maintenance). Locoregional therapy is left to the investigator’s
discretion according to medical need.

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6.
Patient selection
Written informed consent needs to be obtained prior to any trial specific intervention.
Patients should only be selected and consented for screening if they fulfil the criteria in the
next section:
6.1.
Inclusion criteria
6.1.1.
Histologically or cytologically confirmed advanced stage IV non-small cell lung
carcinoma (NSCLC), according to 7th TNM classification
6.1.2.
Age ≥18 years
6.1.3.
ECOG performance status 0-2 (see below *)
6.1.4.
Measurable or evaluable disease (according to RECIST 1.1 criteria).
6.1.5.
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
6.1.6.
Adequate haematological function: neutrophils 1.5 ×109/L, platelets 100×109/L,
and hemoglobin 9 g/dL
6.1.7.
Adequate liver function:
-
ALT 3 × ULN (5 × ULN if liver metastasis are present)
-
Total bilirubin 2 x ULN
6.1.8.
Adequate renal function: calculated creatinine clearance 30 mL/min (according to
the formula of Cockroft-Gault)
6.1.9.
Life expectancy of at least 3 months.
6.1.10. 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.
6.1.11. 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.
6.1.12. 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

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* ECOG Performance Status:
PS 0
Fully active, able to carry on all pre-disease performance without restriction
PS 1
Restricted in physically strenuous activity but ambulatory and able to carry out work
of a light or sedentary nature, e.g., light housework, office work
PS 2
Ambulatory and capable of all self-care but unable to carry out any work activities.
Up and about more than 50% of waking hours
PS 3
Capable of only limited self care, confined to bed or chair more than 50% of waking
hours
PS 4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
6.2.
Exclusion criteria
6.2.1.
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)
6.2.2.
Patients with documented brain metastases (systematic screening of patients not
mandatory)
6.2.3.
Prior chemotherapy or molecular targeted therapy for metastatic disease, with the
exception
of
neoadjuvant
or
adjuvant
chemotherapy
or
definitive
radio-
chemotherapy, if terminated more than 6 months before registration.
6.2.4.
Any investigational agent(s) within 30 days prior to randomisation
6.2.5.
Concurrent bisphosphonate administration
6.2.6.
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
6.2.7.
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.)
6.2.8.
Documented active infection with Hepatitis B virus or Hepatitis C virus, known
infection with human immunodeficiency virus (HIV)
6.2.9.
Known hypersensitivity to any of the components of the treatment
6.2.10. Severe, uncorrected hypocalcaemia or hypercalcaemia

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-
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
6.2.11. Legal incapacity or limited legal capacity
6.2.12. 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
6.2.13. Women who are pregnant or breastfeeding
6.2.14. 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).
6.2.15. 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.
6.2.16. Previous bisphosphonate exposure which
-
exceeds 2 prior doses of i.v. bisphosphonates
AND/OR
-
exceeds a cumulative exposure of 1 year oral bisphosphonates.
7.
Investigator authorisation procedure
Investigators will be authorised to randomise patients in this trial only once they have
returned the following documents to the ETOP/EORTC Headquarters:
7.1.1.
The updated signed and dated curriculum vitae of the Principal Investigator in
English with proof of GCP training.
7.1.2.
The (updated) list of normal ranges for the investigator’s institution signed and
dated by the head of the laboratory. Please make sure normal ranges are provided
also for those tests required by the protocol but not routinely done at the
investigator’s institution.
7.1.3.
The signed Confirmation of Interest by the investigator form (EORTC sites) stating
that the investigator will fully comply with the protocol. This must include an
estimate of yearly accrual and a statement on any conflict of interest that may arise
due to trial participation.
NB: A signed conflict of interest disclosure form will be required only if a possible
conflict is declared on the Confirmation of Interest by the investigator form.
7.1.4.
A copy of the favourable opinion of the local or national (whichever is applicable)
ethics committee mentioning the documents that were reviewed (including the

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version numbers and version dates of all documents). A list of all members of the
ethics committee is also requested.
7.1.5.
A copy of the translated and adapted (according to all national requirements)
Patient Information / Informed Consent sheet. Version numbers and dates must be
clearly stated on each page.
7.1.6.
The signature log-list of the staff members with a sample of each authorized
signature and the indication of the level of delegations. In case patients receive
treatment at a satellite institution, i.e. outside the authorized institution, details on
the satellite institution, including the CV of the local investigator, normal lab
ranges and the approval of an ethics committee will have to be transmitted to the
ETOP/EORTC Headquarters. Please keep in mind that all communication is done
ONLY between the primary institution and the ETOP/EORTC Headquarters.
7.1.7.
The full name, address, phone numbers and e-mail address of the local pharmacist
who will be responsible for the trial medication.
7.1.8.
An accreditation, a certification, an established quality control / external quality
assessment or another validation should be provided for the own laboratory.
The center specific list of required documents will be included in the protocol activation
package, with proper instructions as required by this protocol, your group and / or the
applicable national law.
The new investigator will be added to the “authorisation list”, and will be allowed to
register/randomise patients in the trial as soon as
7.1.9.
All
the
above
mentioned
documents
are
available
at
the
ETOP/EORTC
Headquarters.
7.1.10. All applicable national legal and regulatory requirements are fulfilled.
Patient randomisation from centers not (yet) included on the authorisation list will not be
accepted.
8.
Patient screening and registration/randomisation
8.1.
Screening
Complete the following steps to screen and enroll a patient on this trial.
8.1.1.
Note that written informed consent has to be obtained from the patient prior to any
trial-specific intervention including submission of tissue for translational research.
8.1.2.
Screening: Verify eligibility (including absence of EGFR mutation if tested) and
register the patient in ORTA immediately after having signed informed consent.
The date the Informed Consent Form and the consent to biological material
submission section of the Informed Consent Form were signed by the patient and
the date signed by the investigator are both required to complete the eligibility
checklist.
8.1.3.
Patients have to be randomised maximum two weeks after informed consent.

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A patient can only be randomized after verification of eligibility. Both the eligibility
check and randomisation must be done before the start of the protocol treatment.
Patients should be registered immediately after signing informed consent directly on the
EORTC online randomization system (ORTA = online randomized trials access),
accessible 24 hours a day, 7 days a week, through the internet. To access the interactive
registration program, the investigator needs a username and a password (which can be
requested at www.eortc.be/random).
In case of problems investigators can phone the EORTC Headquarters from 9.00 am to 5.00
pm (Belgian local time) from Monday through Friday in order to register patients via the
EORTC call center. Registration via the phone is not available on Belgian holidays. A list of
these holidays is available on the EORTC web site (www.eortc.be/random) and it is updated
annually.
Through Internet: www.eortc.be/random
If no connection available by phone: +32 2 774 16 00
8.2.
Registration procedure for screening (step 1)
Standard information requested:

EORTC institution number

EORTC protocol number

step number: 1

name of the responsible investigator

patient's code (maximum 4 alphanumerics)

patient's birth date (day/month/year)
Protocol specific questions:

date of written informed consent (day/month/year) signed by the patient and the
date signed by the investigator are both required
At the end of the procedure, a patient sequential identification (SeqID) number will be
assigned. This number will allow the identification of the patients in the VISTA/Remote
Data Capture system (VISTA/RDC) that will be used to complete the Case Report Forms.
8.3.
Randomisation procedure (step 2)
Patients have to be randomised as soon as possible, but not later than 2 weeks after having
obtained written informed consent.
A patient can only be randomised after verification of eligibility. Both the eligibility
check and randomisation must be done before the start of the protocol treatment
Standard information requested:

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
institution number

protocol number

name of the responsible investigator

step number: 2

choose the seqID of the patient from drop-down list

patient's birth date (day/month/year)

for EORTC sites: group affiliation
-
primary group affiliation
-
secondary group affiliation
Protocol specific questions:

all eligibility criteria will be checked one by one

actual values for the eligibility parameters will be requested when applicable

stratification factors

date foreseen for protocol treatment start
Once eligibility has been verified, the treatment will be randomly allocated to the patient.
8.4.
Stratification
Patients will be centrally randomised. A block design technique will be used for random
treatment allocation stratifying by:
-
Presence vs absence of bone metastases as assessed by bone scan or
alternatively by PET-scan
-
Geographical region according to pemetrexed availability, maintenance
strategy, and standard of care
-
ECOG performance status 0 or 1 vs 2
-
Squamous vs other histology
Treatment allocation is not blinded (open label).
9.
Investigational drug
Denosumab is the investigational drug used in this trial. Denosumab will be supplied.
Please consult the Drug Supply Manual for a description of drug supply logistics as well as
labelling, packaging, handling, drug accountability and destruction of unused drugs.
9.1.
Description of investigational drug
Denosumab (XGEVA®) is a human monoclonal IgG2 antibody produced in a mammalian
cell line (CHO) by recombinant DNA technology. It is indicated for the prevention of
skeletal related events (pathological fracture, radiation to bone, spinal cord compression or
surgery to bone) in adults with bone metastases from solid tumours.

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9.2.
Packaging and labelling
Each vial contains 120 mg of denosumab in 1.7 ml of solution (70 mg/ml). Each 1.7 ml of
solution contains 78 mg sorbitol (E420).
Pharmaceutical form: Solution for injection (injection). Clear, colourless to slightly yellow
solution; may contain trace amounts of translucent to white proteinaceous particles.
9.3.
Receipt of the drug
Denosumab will be supplied by Amgen directly to the sites. The investigational site will
check the condition of denosumab upon arrival and sign a proof of delivery form.
Any
damaged shipments will be replaced. See the Drug Supply Manual for details.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by
the study site should be recorded on the Drug Accountability Log. In the event that
denosumab is destroyed at site a certification of destruction form should be generated and
retained in the Trial Master File
9.4.
Storage and handling
Store denosumab in a refrigerator between 2°C and 8°C. See the Drug Supply Manual for
details.
9.5.
Unused trial drugs supplies
At the close of the trial, any quantities of the IP which remain unused will either be disposed
of at the study site or returned to Amgen with the appropriate documentation. See the Drug
Supply Manual for details.
10.
Trial treatments
Drug therapy is to begin within 10 days of randomisation.
10.1.
Drug combinations
The following chemotherapy combinations may be used in cycles lasting 3 weeks each:
In patients with all histologies:
CisGem:
Cisplatin 75 mg/m2, i.v. day 1, plus Gemcitabine 1250 mg/m2, i.v., days 1
and 8
CarboGem:
Carboplatin AUC 5 , i.v. day 1, plus Gemcitabine 1250 mg/m2, i.v., days 1
and 8
In patients with non-squamous cell histology only, pemetrexed may be administered instead
of gemcitabine:
CisPem:
Cisplatin 75 mg/m2, i.v. day 1, plus Pemetrexed 500 mg/m2 i.v. day 1
CarboPem:
Carboplatin AUC 5 , i.v. day 1, plus Pemetrexed 500 mg/m2 i.v. day 1

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Patients will be randomised to one of two treatment regimens as follows:
ARM A :
4 – 6 cycles of one of the above combinations + best supportive care
ARM B :
4 – 6 cycles of one of the above combinations + denosumab 120 mg, s.c.
every 3-4 weeks until unacceptable toxicity, patient refusal, or patient’s
death.
Denosumab
will
be
continued
upon
tumour
progression
and
concomitantly to subsequent lines of systemic treatment, as long as tolerable
for the patient. In cycle 1, an additional dose will be given on day 8.
Frequency of administration is 3-4 weeks and is left to investigator's
preference. For practical reasons, it is encouraged to consider 3-weekly
administration during first-line chemotherapy and 4-weekly schedule after
first-line chemotherapy, in particular when no chemotherapy is delivered or
when chemotherapy is not cycled on a 3-weeks basis.
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 847 deaths for the
final analysis has been reached.
Cisplatin, carboplatin, gemcitabine and pemetrexed are standard treatment for NSCLC and
have to be sourced locally and will not be reimbursed.
Daily supplementation with calcium (500 mg) and vitamin D (400U) will be administered
to all patients (mandatory for pts in arm B (denosumab) and recommended in arm A if they
receive zoledronic acid according to local guidelines). Patients treated with pemetrexed will
receive folic acid 0.4 – 1 mg/day and vit B12 1000 IU s.c. 1 week before first dose and then
every 3 cycles. These supplements will have to be sourced locally and will not be
reimbursed.
Notes:

In arm A, in patients with bone metastasis, zoledronic acid is recommended to be
administered concomitantly to first line platinum doublet and thereafter continued
as a bone protective drug after progression even if chemotherapy has to be changed
to second-line, until unacceptable toxicity, patient refusal or patient’s death.
Administration schedule and duration is left to investigator’s discretion.

The addition of bevacizumab to platinum-based chemotherapy is not allowed

Maintenance chemotherapy with pemetrexed (non squamous histology only) or
erlotinib is allowed

Pemetrexed should only be administered if calculated creatinine clearance ≥45
mL/min

After disease progression to first-line chemotherapy, further treatment is up to
investigator’s choice in both arms

Denosumab will be continued upon tumour progression and concomitantly to
subsequent lines of systemic treatment, as long as tolerable for the patient.

Maintenance is allowed (pemetrexed or erlotinib, according to local standard of
care).

Crossover of treatment arms is not allowed in this trial.

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10.2.
Pemetrexed
10.2.1. Premedication and dosing of pemetrexed
To reduce the incidence and severity of skin reactions, a corticosteroid should be given the
day prior to, on the day of, and the day after each pemetrexed administration. The
corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a
day. To reduce toxicity, patients treated with pemetrexed must also receive vitamin
supplementation. Patients must take oral folic acid or a multivitamin containing folic acid
(400 to 1000 μg) on a daily basis. At least five doses of folic acid must be taken during the
seven days preceding the first dose of pemetrexed, and dosing must continue during the full
course of therapy and for 21 days after the last dose of pemetrexed. Patients must also
receive an intramuscular injection of vitamin B12 (1000 μg) in the week preceding the first
dose of pemetrexed and once every three cycles thereafter. Subsequent vitamin B12
injections may be given on the same day as pemetrexed. The dosing of pemetrexed is based
on the patient’s total body surface area (m2).
10.3.
Cisplatin, Carboplatin and/or Gemcitabine
The combinations should be administered according to local guidelines including
premedication.
Antiemetic prophylaxis and therapy is recommended to be administered according to local
rules.
Hydration is left open as some centers are performing cisplatin therapy in an ambulatory
setting. Standard i.v. hydration is however recommended before and after cisplatin
treatment, e.g. 1000 ml NaCl 0.9% i.v. over 2 hours before and 2000 ml NaCl 0.9% i.v. after
cisplatin.
10.4.
Denosumab
Administration by subcutaneous injection should be performed by an individual who has
been adequately trained in injection techniques.
10.5.
Precautions
Women of childbearing potential and sexually active men must use effective contraception
during the trial and 5 months thereafter.
10.6.
Concomitant treatment
The following treatments are allowed during the treatment phase of the trial:

Approved drugs for other medical indications than cancer

Palliative and supportive care, including analgesic radiotherapy, antiemetics as well
as G-CSF according to standard guidelines

Safe alternative medicine if potential interactions with trial drugs can be excluded
The following treatments are NOT allowed:

For first-line chemotherapy treatment: Investigational drugs

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
Denosumab is not allowed in Arm A

Bisphosphonates are not allowed in Arm B

Non-IP denosumab
10.7.
Treatment delay and dose modification for toxicity
10.7.1. General remarks on dose modifications
In general:

In cases of conflicting recommendations, use the most restrictive treatment
adjustment

In case of missing recommendations, adaptations must be made according to local
standards of care

No dose re-escalation is allowed after reduction

After a dose/drug modification has been done, it should be maintained for the
subsequent cycles (e.g. switch from cisplatin to carboplatin or from pemetrexed to
gemcitabine).
The trial chair should be contacted in case the investigator has any doubts about treatment
delays and/or dose reductions.

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10.7.2. CisGem dose reductions and delays
Grade/count
Cisplatin
Gemcitabine
Platelet count decreased
At day 1 of cycle
<100×109/L
Delay* cycle start until recovery to
>100×109/L
If <50×109/L at any time
during cycle
No change at start
of next cycle
Start next cycle at
75% of dose
Second occurrence
<50×109/L
No change at start
of next cycle
Start next cycle at
50% of dose
Third occurrence
<50×109/L
Next cycle with
75% dose
Omit day 8
Neutrophil count
decreased
<1.0 ×109/L at day 1 of
cycle
Delay* until
recovery to >1.0
×109/L
And no change at
start of next cycle
Delay* until
recovery to >1.0
×109/L
<0 .5 ×109/L at any time
during cycle
No change at start
of next cycle
Start next cycle at
75% of dose
Second occurrence <0.5
×109/L at any time during
cycle
Reduce to 75% of
dose
Reduce to 50% of
dose
Third occurrence <0.5
×109/L at any time during
cycle
Reduce to 50% of
dose
Reduce to 50% of
dose
Febrile neutropenia
3, 4
Add G-CSF at day 3-4 for a minimum of 3
days in all subsequent cycles
Renal impairment
Creatinine clearance
<60ml/min at day 1 of
cycle
Replace by
carboplatin AUC 5
No change
Creatinine clearance
<30ml/min at day 1 of
cycle
Discontinue
No change
Ototoxicity
Grade 3 or 4 on day 1 of
cycle
Replace by
carboplatin AUC 5
No change
Other toxicities
(except specific AEs
above, nausea, alopecia
and fatigue) *
First occurrence of grade
3 or 4
Reduce to 75% of
dose
Reduce to 75% of
dose
second occurrence of
grade 3 or 4
Replace by
carboplatin AUC 5
Reduce to 50% of
dose
* Delay for a maximum of 4 weeks until recovery to ≤grade 2. If no recovery within 4
weeks, the patient stops chemotherapy and is treated according to local recommendations.
Denosumab should be continued in arm B.

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10.7.3. CisPem dose reductions and delays
Grade/count
Cisplatin
Pemetrexed
Platelet count
decreased
At day 1 of cycle
<100×109/L
Delay* cycle start until recovery to >100×109/L
If <50×109/L at any
time during cycle
No change at start of
next cycle
Start next cycle at 75%
of dose
Second occurrence
<50×109/L
No change at start of
next cycle
Start next cycle at 50%
of dose
Third occurrence
<50×109/L
Next cycle with 75%
dose
No change
neutrophil count
decreased
<1.0 ×109/L at day 1
of cycle
Delay* until recovery
to >1.0 ×109/L
Delay* until recovery to
>1.0 ×109/L
< 0.5 ×109/L at any
time during cycle
No change at start of
next cycle
Start next cycle at 75%
of dose
Second occurrence
<0.5 ×109/L at any
time during cycle
Reduce to 75% of dose
Reduce to 50% of dose
Third occurrence <0.5
×109/L at any time
during cycle
Reduce to 50% of dose
Reduce to 50% of dose
Febrile neutropenia
3, 4
Add G-CSF at day 3-4
for a minimum of 3
days in all subsequent
cycles
Add G-CSF at day 3-4
for a minimum of 3
days in all subsequent
cycles
Renal impairment
Creatinine clearance
<60 and >45ml/min at
day 1 of cycle
Replace by carboplatin
AUC 5
No change
Creatinine clearance
<45ml/min at day 1
of cycle
Replace by carboplatin
AUC 5
Replace by gemcitabine
Creatinine clearance
<30ml/min at day 1
of cycle
Discontinue
Replace by gemcitabine
Ototoxicity
3,4 on day 1 of cycle
Replace by carboplatin
AUC 5
No change
Neurotoxicity
Grade 2
Replace by carboplatin
AUC 5
No change
Grade 3, 4
Replace by carboplatin
AUC 5
Replace by gemcitabine
Other toxicities
(except specific AEs
above, nausea,
alopecia and fatigue) *
First occurrence of
grade 3 or 4
Reduce to 75% of dose
Reduce to 75% of dose
Reduce to 50% of dose
in case of grade 3/4
mucositis
second occurrence of
grade 3 or 4
Replace by carboplatin
AUC 5
Reduce to 50% of dose
* Delay for a maximum of 4 weeks until recovery to ≤grade 2. If no recovery within 4
weeks, the patient stops chemotherapy and is treated according to local recommendations.
Denosumab should be continued in arm B.

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10.7.4. CarboGem dose reductions and delays
Grade/count
Carboplatin
Gemcitabine
Platelet count decreased
At day 1 of cycle
<100×109/L
Delay* cycle start until recovery to
>100×109/L
If <50×109/L at any time
during cycle
Start next cycle at
75% of dose
Start next cycle at
75% of dose
Second occurrence
<50×109/L
No change at start
of next cycle
Start next cycle at
50% of dose
Third occurrence
<50×109/L
Next cycle with
50% dose
No change
Neutrophil count
decreased
<1.0 ×109/L at day 1 of
cycle
Delay* until
recovery to >1.0
×109/L
Delay* until
recovery to >1.0
×109/L
<0.5 ×109/L at any time
during cycle
No change at start
of next cycle
Start next cycle at
75% of dose
Second occurrence < .5
×109/L at any time during
cycle
Start next cycle at
75% of dose
No change
Third occurrence < .5
×109/L at any time during
cycle
Start next cycle at
75% of dose
Reduce to 50% of
dose
Fourth occurrence < .5
×109/L at any time during
cycle
Reduce to 50% of
dose
Reduce to 50% of
dose
Febrile neutropenia
3, 4
Add G-CSF at day 3-4 for a minimum of 3
days in all subsequent cycles
Renal impairment
Creatinine clearance
<30ml/min at day 1 of
cycle
no change
no change
Other toxicities
(except specific AEs
above, nausea, alopecia
and fatigue) *
First occurrence of grade
3 or 4
Reduce to 75% of
dose
Reduce to 75% of
dose
second occurrence of
grade 3 or 4
No change
Reduce to 50% of
dose
Third occurrence of grade
3 or 4
Reduce to 50% of
dose
No change
* Delay for a maximum of 4 weeks until recovery to ≤grade 2. If no recovery within 4
weeks, the patient stops chemotherapy and is treated according to local recommendations.
Denosumab should be continued in arm B.

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10.7.5. CarboPem dose reductions and delays
Grade/count
Carboplatin
Pemetrexed
Platelet count decreased
At day 1 of cycle
<100×109/L
Delay* cycle start until recovery to
>100×109/L
If <50×109/L at any time
during cycle
Start next cycle at
75% of dose
Start next cycle at 75%
of dose
Second occurrence
<50×109/L
No change at start
of next cycle
Start next cycle at 50%
of dose
Third occurrence
<50×109/L
Next cycle with
50% dose
No change
neutrophil count
decreased
<1.0 ×109/L at day 1 of
cycle
Delay* cycle start until recovery to >1.0
×109/L
<0 .5 ×109/L at any time
during cycle
No change at start
of next cycle
Start next cycle at 75%
of dose
Second occurrence <0.5
×109/L at any time
during cycle
Start next cycle at
75% of dose
No change
Third occurrence <0.5
×109/L at any time
during cycle
Start next cycle at
75% of dose
Start next cycle at 50%
of dose
Fourth occurrence <0.5
×109/L at any time
during cycle
Start next cycle at
50% of dose
Start next cycle at 50%
of dose
Febrile neutropenia
3, 4
Add G-CSF at day 3-4 for a minimum of 3
days in all subsequent cycles
Renal impairment
Creatinine clearance
<45ml/min at day 1 of
cycle
No change
Replace by
gemcitabine
Creatinine clearance
<30ml/min at day 1 of
cycle
Discontinue
Replace by
gemcitabine
Neurotoxicity
Grade 2
No change
No change
Grade 3, 4
No change
Replace by
gemcitabine
Other toxicities
(except specific AEs
above, nausea, alopecia
and fatigue) *
First occurrence of
Grade 3, 4
Reduce to 75% of
dose
Reduce to 75% of dose
Reduce to 50% of dose
in case of grade 3/4
mucositis
Second occurrence of
grade 3 or 4
No change
Reduce to 50% of dose
Third occurrence of
grade 3 or 4
Reduce to 50% of
dose
no change
* Delay for a maximum of 4 weeks until recovery to ≤grade 2. If no recovery within 4
weeks, the patient stops chemotherapy and is treated according to local recommendations.
Denosumab should be continued in arm B.

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10.8.
Treatment duration
Patients remain on trial-specified chemotherapy until one of the following events:

Chemotherapy: Maximum of 6 cycles

Documented progression according to RECIST v1.1

Unacceptable toxicity

Medical condition that prevents further treatment

Patient refuses further treatment

Patient withdraws consent

Patient becomes pregnant
Patients in Arm B remain on denosumab treatment through trial-specified chemotherapy and
further lines of treatment until one of the following events:

Unacceptable toxicity attributed to denosumab

Medical condition that prevents further treatment

Patient refuses further treatment

Patient withdraws consent

Patient becomes pregnant

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 847 deaths for the final analysis has been
reached.
11.
Safety of chemotherapy and investigational product
11.1.
Cisplatin
11.1.1. Known adverse reactions
Please refer to the latest version of the SmPC.
The most frequently reported adverse events (>10%) of cisplatin were haematological
(leukopenia, thrombocytopenia and anaemia), gastrointestinal (anorexia, nausea, vomiting
and diarrhoea), ear disorders (hearing impairment), renal disorders (renal failure,
nephrotoxicity, hyperuricaemia) and fever.
Serious toxic effects on the kidneys, bone marrow and ears have been reported in up to
about one third of patients given a single dose of cisplatin; the effects are generally dose-
related and cumulative.
11.2.
Carboplatin
11.2.1. Known adverse reactions

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The following adverse events have been reported; please refer to the latest version of the
SmPC for details.
Cardiac disorders
Cardiovascular events (cardiac failure, embolism), cerebrovascular events (apoplexy),
hypertension.
Blood and lymphatic system disorders
Myelosuppression, leukopenia, haemorrhagic complications, infectious complications,
febrile neutropenia.
Single cases of life-threatening infections and bleeding have occurred.
Myelosuppression is the dose-limiting toxicity of carboplatin.
Respiratory, thoracic and mediastinal disorders
Pulmonary fibrosis manifested by tightness of the chest and dyspnoea.
Nervous system disorders
Peripheral neuropathies, central nervous symptoms
Eye disorders
Transient visual disturbances, sometimes including transient sight loss, optic neuritis
Ear and labyrinth disorders
Subclinical decrease in hearing acuity, consisting of high-frequency (4000-8000 Hz) hearing
loss determined by audiogram, clinical ototoxicity.
Gastrointestinal disorders
Nausea, vomiting, painful gastro-intestinal disorders, diarrhoea, constipation, mucositis,
taste alteration, anorexia.
Renal and urinary disorders
Renal toxicity, renal function impairment, as defined by a decrease in the creatinine
clearance below 60 ml/min, may also be observed.
Skin and subcutaneous tissue disorders
Alopecia.
Metabolism and nutrition disorders
Decreases
in
serum
electrolytes
(sodium,
magnesium,
potassium
and
calcium),
hyponatraemia.
Neoplasms benign, malignant and unspecified (including cysts and polyps)

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Secondary malignancies (including promyelocytic leukaemia which occurred 6 years after
monotherapy with carboplatin and preceding irradiation) have been reported following
administration of carboplatin as a single agent or in combination therapy (causal relationship
not established).
General disorders and administration site conditions
Hyperuricaemia, asthenia, malaise, urticaria. flu-like syndrome, erythematous rash, pruritis,
fever and chills without evidence of infection; injection site reactions such as pain,
erythema, swelling, urticaria and necrosis; haemolytic uraemic syndrome.
Immune system disorders
Allergic reactions (e.g. skin rash, urticaria, erythematous rash, and fever with no apparent
cause or pruritus), anaphylaxis, anaphylactic shock, angio-oedema and anaphylactoid
reactions, including bronchospasm, urticaria, facial oedema and facial flushing, dyspnoea,
hypotension, dizziness, wheezing, and tachycardia.
Hepatobiliary disorders
Abnormalities of liver function tests, severe hepatic dysfunction (including acute liver
necrosis).
11.3.
Gemcitabine
11.3.1. Known adverse reactions
Please refer to the latest version of the SmPC.
Prolongation of the infusion time and increased dosing frequency have been shown to
increase toxicity.
The most commonly reported adverse drug reactions associated with Gemcitabine treatment
include: nausea with or without vomiting, raised liver transaminases (AST/ALT) and
alkaline phosphatase, reported in approximately 60% of patients; proteinuria and haematuria
reported in approximately 50% of patients; dyspnoea reported in 10-40% of patients
(highest incidence in lung cancer patients); allergic skin rashes occur in approximately 25%
of patients and are associated with itching in 10% of patients.
11.4.
Pemetrexed
11.4.1. Known adverse reactions
Please refer to the latest version of the SmPC.
The most commonly reported undesirable effects related to pemetrexed, whether used as
monotherapy or in combination, are bone marrow suppression manifested as anaemia,
neutropenia, leucopenia, thrombocytopenia; and gastrointestinal toxicities, manifested as
anorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, and stomatitis.
Other undesirable effects include renal toxicities, increased aminotransferases, alopecia,
fatigue, dehydration, rash, infection/sepsis and neuropathy. Rarely seen events include
Stevens-Johnson syndrome and Toxic epidermal necrolysis.

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11.5.
Denosumab
11.5.1. Known adverse reactions
Infections and infestations: uncommon: cellulitis (see below)
Immune system disorder: uncommon: drug hypersensitivity
Metabolism and nutrition disorders: common: hypocalcaemia, hypophosphataemia.
Respiratory, thoracic and mediastinal disorders: very common: dyspnoea
Gastrointestinal disorders: very common: diarrhea; common: tooth extraction
Skin and subcutaneous tissues: common: hyperhidrosis
Musculoskeletal and connective tissue disorders: common: osteonecrosis of the jaw (see
below); musculoskeletal pain.
Please also refer to the latest version of the IB.
Description of selected adverse reactions:
Hypersensitivity Reactions
All monoclonal antibodies have the potential to be associated with hypersensitivity
reactions, including anaphylactic reactions. In pivotal clinical studies evaluating prevention
of skeletal-related events (SREs) in subjects with advanced malignancies involving bone,
drug hypersensitivity events (preferred term) were reported in 0.9% of subjects in the
denosumab group and 0.4% of subjects in the zoledronic acid group.
An imbalance for
events potentially associated with hypersensitivity disfavoring denosumab compared with
zoledronic acid was observed in these clinical studies (5.4% denosumab, 3.8% zoledronic
acid).
A comprehensive safety assessment of anaphylactic reactions with denosumab treatment
was performed. The assessment included a medical review of clinical trial adverse events
and postmarketing cases. Two nonstudy cases of anaphylactic reaction in the postmarketing
setting were assessed as causally related to denosumab ; both had a positive rechallenge.
Time to onset for each case was consistent with anaphylactic reaction events subsequent to
denosumab 120 mg q4w administration. None of these cases was fatal. As a result
hypersensitivity, including anaphylactic reactions, has been added as an identified risk for
denosumab .
Atypical Femoral Fracture
Atypical femoral fractures are defined as fractures occurring with no trauma or minimal
trauma, such as a fall from a standing height or less, that result in subtrochanteric or
proximal diaphyseal fractures anywhere along the femur from just distal to the lesser
trochanter to just proximal to the supracondylar flare.
These fractures usually have a
characteristic appearance on imaging studies of a simple transverse or oblique fracture,
often with beaking of the cortex and diffuse cortical thickening of the proximal femoral
shaft. Subtrochanteric and diaphyseal fractures together account for about 5% to 10% of all
hip/femoral fractures; of these, a subset of approximately 17% to 29% is atypical.
The
causes of atypical femoral fracture are likely multi-factorial. Atypical femoral fractures have
been reported in patients with certain co-morbid conditions (eg, vitamin D deficiency,
rheumatoid arthritis, hypophosphatasia) and in patients receiving certain pharmaceutical
agents (eg, bisphosphonates, glucocorticoids, proton pump inhibitors).
Events also have

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occurred in patients not receiving any antiresorptive therapy.
Epidemiologic evidence
suggests an association of atypical femoral fracture with long-term bisphosphonate
(antiresorptive) therapy.
An assessment of events of atypical femoral fracture in cancer patients administered
denosumab was performed. One case from clinical trials with denosumab 120 mg q4w was
positively adjudicated as atypical femoral fracture. As a result atypical femoral fracture has
been added as an identified risk for denosumab.
Hypocalcaemia:
In three phase III active-controlled clinical trials in patients with advanced malignancies
involving bone, hypocalcaemia was reported in 9.6% of patients treated with denosumab
and 5.0% of patients treated with zoledronic acid.
A grade 3 decrease in serum calcium levels was experienced in 2.5% of patients treated with
denosumab and 1.2% of patients treated with zoledronic acid. A grade 4 decrease in serum
calcium levels was experienced in 0.6% of patients treated with denosumab and 0.2% of
patients treated with zoledronic acid
In the postmarketing setting, severe symptomatic hypocalcaemia (including fatal cases) has
been reported.
Osteonecrosis of the jaw (ONJ):
In three phase III active-controlled clinical trials in patients with advanced malignancies
involving bone, ONJ was confirmed in 1.8% of patients treated with denosumab and 1.3%
of patients treated with zoledronic acid. Clinical characteristics of these cases were similar
between treatment groups. Among subjects with confirmed ONJ, most (81% in both
treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental
appliance. In addition most subjects were receiving or had received chemotherapy . Patients
with certain identified risk factors for ONJ were excluded from participation in the pivotal
studies.
ONJ is an identified risk for denosumab and is addressed in several sections of the XGEVA
(denosumab 120 mg Q4W) core safety information, including the warnings and adverse
reactions sections. The current risk minimization language in the denosumab core safety
information includes the following instructions:

A dental examination with appropriate preventive dentistry should be considered
prior to treatment with denosumab in patients with risk factors for ONJ.

Patients who are suspected of having or who develop ONJ while on denosumab
should receive care by a dentist or an oral surgeon.
Incidence of ONJ was higher with longer duration of exposure. In Henry trial 9, positively
adjudicated ONJ occurred with cumulative incidence rates in the zoledronic acid and
denosumab groups of, respectively, 0.6% and 0.5% at 1 year, 0.9% and 1.1% at 2 years, and
1.3% and 1.1% at 3 years.
Skin infections (predominantly cellulitis) leading to hospitalization:
In three phase III active-controlled clinical trials in patients with advanced malignancies
involving bone, skin infections leading to hospitalisation (predominantly cellulitis) were
reported more frequently in patients receiving denosumab (0.9%) compared with zoledronic
acid (0.7%).

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In postmenopausal women with osteoporosis, skin infections leading to hospitalisation were
reported for 0.4% women receiving Prolia (denosumab 60 mg every 6 months) and for 0.1%
women receiving placebo.
Other special populations:
In a clinical study of patients without advanced cancer with severe renal impairment
(creatinine clearance < 30 ml/min) or receiving dialysis, there was a greater risk of
developing hypocalcaemia in the absence of calcium supplementation.
11.5.2. Contraindications and special warnings
Contraindications

Hypersensitivity to the active substance or to any of the excipients

Severe, untreated hypocalcaemia.
Special warnings and precautions for use
Calcium and Vitamin D supplementation:
Supplementation
with calcium
and
vitamin
D is
required
in
all
patients
unless
hypercalcaemia is present.
Hypocalcaemia:
Pre-existing hypocalcaemia must be corrected prior to initiating therapy with denosumab.
Hypocalcaemia can occur at any time during therapy with denosumab and most commonly
occurs within the first 6 months of dosing. Patients with severe renal impairment (creatinine
clearance < 30 ml/min) or receiving dialysis are at greater risk
of developing
hypocalcaemia. Monitoring of calcium levels in these patients is recommended. If
hypocalcaemia occurs while receiving denosumab, additional calcium supplementation may
be necessary. In the post marketing setting, severe symptomatic hypocalcaemia (including
fatal cases) has been reported.
Osteonecrosis of the jaw:
Osteonecrosis of the jaw (ONJ) was reported in patients treated with denosumab,
predominantly in patients with advanced malignancies involving bone. Patients who
developed ONJ in clinical studies generally had known risk factors for ONJ, including
invasive dental procedures (e.g., tooth extraction, dental implants, oral surgery), poor oral
hygiene or other pre-existing dental disease, advanced malignancies, infections, or
concomitant
therapies
(e.g.,
chemotherapy,
corticosteroids,
angiogenesis
inhibitors,
radiotherapy to the head and neck). A dental examination with appropriate preventive
dentistry should be considered prior to treatment with denosumab in patients with active
dental and jaw conditions (as listed above). While on treatment, patients should avoid
invasive dental procedures if possible. Good oral hygiene practices should be maintained
during treatment with denosumab. Patients who are suspected of having or who develop
ONJ while on denosumab therapy should receive care by a dentist or oral surgeon. In these
patients, extensive dental surgery to treat ONJ may exacerbate the condition.
Administration of investigational product will also be withheld 30 days prior to any elective
invasive oral/ dental procedure. Investigational product administration will be withheld until
documented evidence of complete mucosal healing following any invasive oral/ dental
procedure.

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12.
Serious adverse events reporting
ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors
follow specific procedures when notifying and reporting adverse events/reactions in clinical
trials. These procedures are described in this section of the protocol.
12.1.
Definitions
These definitions reflect the minimal regulatory obligations; specific protocol requirements
might apply in addition.
AE: An Adverse Event is defined as “any untoward medical occurrence in a patient or
clinical investigation subject administered a pharmaceutical product and which does not
necessarily have to have a causal relationship with this treatment”. An adverse event can
therefore be any unfavorable and unintended signs (such as rash or enlarged liver),
symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results
of blood tests, x-rays or scans) or a disease temporarily associated with the use of the
protocol treatment, whether or not considered related to the investigational medicinal
product.
AR: An Adverse reaction of an investigational medicinal product is defined as “any
noxious and unintended response to a medicinal product related to any dose administered”.
All adverse events judged by either the reporting investigator or the sponsor as having a
reasonable causal relationship to a medicinal product qualify as adverse reactions. The
expression reasonable causal relationship means to convey in general that there is evidence
or argument to suggest a causal relationship.
UAR: An Unexpected Adverse Reaction is “any adverse reaction, the nature, or severity of
which is not consistent with the applicable product information" (e.g. investigator's brochure
for an unapproved investigational product or summary of product characteristics (SmPC) for
a marketed product).
When the outcome of the adverse reaction is not consistent with the applicable product
information this adverse reaction should be considered as unexpected.
Severity: The term “severe” is often used to describe the intensity (severity) of a specific
event (as in mild, moderate or severe, or as described in CTC grades); the event itself,
however, may be of relative minor medical significance (such as severe headache). This is
not the same as “serious,” which is based on patient/event outcome or action criteria usually
associated with events that pose a threat to patient’s life or functioning. Seriousness (not
severity) serves as a guide for defining regulatory reporting obligations.
SAE: A Serious Adverse Event is defined as any untoward medical occurrence or effect in
a patient, whether or not considered related to the protocol treatment, that at any dose:

results in death

is life-threatening (i.e. an event in which the subject was at risk of death at the time
of event; it does not refer to an event which hypothetically might have caused death
if it was more severe)

requires inpatient hospitalization or prolongation of existing patient hospitalization

results in persistent or significant disability or incapacity

is a congenital anomaly or birth defect

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
is a medically important event or reaction.
Medical and scientific judgment should be exercised in deciding whether other situations
should be considered serious such as important medical events that might not be
immediately life-threatening or result in death or hospitalization but might jeopardize the
patient or might require intervention to prevent one of the other outcomes listed in the
definition above. Examples of such events are intensive treatment in an emergency room or
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in
hospitalization, or development of drug dependency or drug abuse.
SAR: A Serious Adverse Reaction is defined as any SAE which is considered related to
the protocol treatment.
SUSAR: Suspected Unexpected Serious Adverse Reaction.
SUSARs occurring in clinical investigations qualify for expedited reporting to the
appropriate Regulatory Authorities within the following timeframes:

Fatal or life-threatening SUSARs within 7 calendar days

Non-fatal or non-life-threatening SUSARs within 15 calendar days
Inpatient hospitalization: a hospital stay equal to, or greater than, 24 hours.
Second primary malignancy is one unrelated to the treatment of a previous malignancy
(and is NOT a metastasis from the previous malignancy).
Secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g.,
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary
malignancy is not considered a metastasis of the previous malignancy.
12.2.
Exceptions
The following situations do not need to be reported as SAEs:

Elective hospitalization for pre-existing conditions that have not been exacerbated
by trial treatment.

A hospitalization which was planned before the patient consented for trial
participation and where admission did not take longer than anticipated.

A hospitalization planned for protocol related treatment or protocol related
procedure as per institutional standard timelines.

Social and/or convenience admission to a hospital.

Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that
leads to the procedure is an (S)AE.

Situations where an untoward medical occurrence did not occur (palliative care,
rehabilitation, overdose without occurrence of an adverse event).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s)
present or detected at the start of the trial that do not worsen.
By convention, clinical events related to the primary cancer being studied or to the primary
cancer progression are not to be reported as SAEs, even if they meet any of the seriousness
criteria from the standard SAE definition, unless the event is more severe than expected and
therefore the investigator considers that their clinical significance deserves reporting.

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12.3.
Severity assessment
The severity of all AEs (serious and non-serious) in this trial should be graded using
CTCAE v4.0 www.eortc.org\investigators-area\ctc or
http://evs.nci.nih.gov/ftp1/CTCAE/About.html
12.4.
Causality assessment
The investigator is obligated to assess the relationship between protocol treatment and the
occurrence of each SAE following the definitions in this table:
Relationship to the
protocol treatment
Description
Reasonable possibility
There is a reasonable possibility that the protocol treatment
caused the event
No reasonable
possibility
There is no reasonable possibility that the protocol treatment
caused the event
The investigator will use clinical judgment to determine the relationship. Alternative causes,
such as natural history of the underlying diseases, medical history, concurrent conditions,
concomitant therapy, other risk factors, and the temporal relationship of the event to the
protocol treatment will be considered and investigated.
The decision will be recorded on the SAE form and if necessary the reason for the decision
will also be recorded.
12.5.
Expectedness assessment
The expectedness assessment is the responsibility of the sponsor of the trial. The
expectedness assessment will be performed against the following reference documents:

For cisplatin: Summary of Product Characteristics (SmPC)

For carboplatin: Summary of Product Characteristics (SmPC)

For gemcitabine: Summary of Product Characteristics (SmPC)

For pemetrexed: Summary of Product Characteristics (SmPC)

For denosumab: Investigator's Brochure.
12.6.
Reporting procedure for investigators
This procedure applies to all Serious Adverse Events (SAEs) occurring from the time a
subject has signed informed consent until 30 days after last protocol treatment
administration and to any SAE that occurs outside of the SAE detection period (after the 30-
days period), if it is considered to have a reasonable possibility to be related to the protocol
treatment or trial participation.
From date of informed consent till 30 days after last
dose of first-line chemotherapy or IP, whichever
occurs later :
All SAEs
From day 31 after last dose of first-line
chemotherapy or dose of IP, whichever occurs later:
Only related SAEs and second
primary cancer

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Any secondary malignancy should also be reported in expedited way on a SAE form
with the appropriate seriousness criteria!

All reporting must be done by the principal investigator or authorised staff member
(i.e. on the signature list) to confirm the accuracy of the report.

All SAE data must be collected on the trial-specific SAE form.

All SAEs must be reported immediately and no later than 24 hours from the time
the investigator or staff became aware of the event.

All SAE-related information needs to be provided in English.

All additional documents in local language must be accompanied by a translation in
English, or the relevant information must be summarized in a follow-up SAE report
form.

All SAE-related information has to be faxed to EORTC Pharmacovigilance Unit:
Fax No. +32 2 772 8027
To enable the Sponsor to comply with regulatory reporting requirements, all initial SAE
reports should always include the following minimal information: an identifiable patient
(SeqID), a suspect medicinal product if applicable, an identifiable reporting source, the
description of the medical event and seriousness criteria, as well as the causality assessment
by the investigator. Complete information requested on the SAE form of any reported
serious adverse event must be returned within 7 calendar days of the initial report. If the
completed form is not received within this deadline, the Pharmacovigilance Unit will make
a written request to the investigator.
Queries sent out by the EORTC Pharmacovigilance Unit need to be answered within 7
calendar days.
All forms need to be dated and signed by the principal investigator or any authorised staff
member (i.e. on the signature list).
12.7.
Reporting responsibilities for EORTC
The EORTC Pharmacovigilance Unit will forward all SAE reports to the appropriate
persons within the EORTC Headquarters, ETOP and to Amgen
The EORTC Pharmacovigilance Unit will provide a six-monthly summary which will be
added in the Trial Status Report and which will be accessible to all participating
investigators.
The EORTC Pharmacovigilance Unit will take in charge the reporting of SUSARs to the
Competent
Authorities,
Ethics
committees,
EudraVigilance
Clinical
Trial
Module
(EVCTM) and all participating investigators.
12.8.
Pregnancy and lactation reporting
Pregnancy occurring during a patient’s participation in this trial, although not considered an
SAE, must be notified to the EORTC Pharmacovigilance Unit within the same timelines as
an SAE (within 24 hours) on a Pregnancy Notification Form. The outcome of a pregnancy
should be followed up carefully and any adverse outcome to the mother or the child should

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be reported. This also applies to pregnancies in female partners of a male patient
participating in this trial.
If a lactation case occurs while the female subject is taking protocol-required therapies
report the lactation case as specified below. In addition to reporting a lactation case during
the trial treatment, Investigators should monitor for lactation cases that occur after the last
dose of protocol-required therapies through 7 months.

Any pregnancy in a female subject or in a female partner of a male subject
diagnosed during the treatment period or within 7 months after trial treatment
discontinuation must be reported to the EORTC Pharmacovigilance Unit

This must be reported within 24 hours of first becoming aware of the event by fax,
to the Pharmacovigilance Unit on a Pregnancy Notification Form

If an SAE occurs in conjunction with the pregnancy, please also complete an SAE
form as explained in the SAE reporting chapter
13.
Endpoints definition
13.1.
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.
13.2.
Progression-free survival
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 (see Appendix 2). 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 (see section
10.8), including those who initiate non-protocol therapy prior to progression, will be
followed for disease progression and death.
13.3.
Response
The response of the tumour is defined according to RECIST 1.1 criteria, see appendix 2.
13.4.
Toxicity
Adverse events classified according to NCI CTCAE version 4. Electronic versions are
available on www.eortc.org\investigators-area\ctc or
http://evs.nci.nih.gov/ftp1/CTCAE/About.html

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14.
Biological material and translational research
The collection of tumour and serum samples is required in this trial. This material will
constitute an invaluable and precious source for biological research in the context of this
trial.
14.1.
Serum
14.1.1. Serum samples
Mandatory serial serum samples will be collected at baseline (prior to the start of
chemotherapy), on day 1 of cycle 3 and at progression.
Analysis of serum samples by ELISA includes CTX, osteoprotegerin (OPG), propeptide of
type I procollagen (PINP), osteopontin (OPN), free RANKL and RANKL-OPG. These may
be changed and the panel of serum biomarkers will include best candidates at the time of
analysis.
14.1.2. Collection, storage and submission of serum samples
Serum samples must be collected at baseline (prior to the start of chemotherapy), on day 1
of cycle 3 and at progression. Blood collection and serum preparation: see SPLENDOUR
biological samples manual. Serum will be aliquoted into cryovials and must be
immediately frozen at -80ºC and kept at the participating site until shipment. Shipments will
be organized centrally.
Serum samples will be sent to Sheffield biorepository, UK;
Kevin Corke, Room EU17
Sheffield Medical School
Beech Hill Road, Sheffield
S10 2RX, United Kingdom
and analysed at Northern General Hospital, Sheffield.
14.2.
Tumour tissue
Availability of a sample of tumour tissue is an eligibility criterium. The samples will be
collected after the patient has been randomised:
-
The preferred option is an FFPE block from a recent biopsy of the primary
tumour or metastasis; archival tissue from tumour resection is also an option;
-
If a tissue block is not available, a paraffin-embedded cell block (cytoblock) is
a valuable alternative to an FFPE tumour block. Cytology smears alone are not
accepted in this trial;
-
If neither a tumour block nor a cell block is available: 10 unstained slides with
wax protection.
There is no limitation regarding the age of the tumour sample in this trial. However, recent
samples are preferred and investigators should consider a new biopsy in patients relapsing
after surgery.
Please consult the SPLENDOUR biological samples manual for instructions on how to
prepare and ship block or slides.

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The following evaluations are proposed for translational research: IHC (and/or RT-PCR) for
RANKL & RANK, and potentially NF-kappaB activation evaluation (RT-PCR and/or IHC)
and bone sialoprotein (BSP) which in tumour has been correlated with bone metastasis
progression and high levels are associated with poor prognosis 34; and osteopontin (OPN)
levels in primary tumour may correlate with tumour aggressiveness 35. These may be
adapted in the future to include best candidates available at the time of evaluation.
14.2.1. Submission of FFPE material
The following items must be submitted for all patients:
1. FFPE material as described above
2. Pertinent pathology report (please black out name and any other identifier, and add
the seqID issued by the ORTA system, see section 8.2)
Highly desirable:
3. Tumour or cell block and pathology report from re-biopsy at progression
The FFPE tissue blocks may be returned to the site upon request after samples have been
removed for analysis.
Slides should be covered with wax immediately after cutting. They will be stored at 4°C in
the dark to avoid any degrading.
Samples have to be sent to the ISREC lab
Swiss Institute for Experimental Cancer Research (ISREC)
EPFL-SV-ISREC
Dr. Etienne Meylan
EPFL SV ISREC UPMEYLAN
Station 19
CH-1015 Lausanne, Switzerland
according to specific instructions in the SPLENDOUR procedures manual.
14.3.
Banking of biological material
The ETOP and EORTC have established a central repository for tissue blocks/slides and
serum samples from every patient enrolled in this trial.
The required tissue material
(described in the previous sections) is submitted to, catalogued, and maintained in the
ISREC lab. Serum samples are submitted to the Sheffield biorepository.
15.
Trial procedures
This section gives an overview of procedures, clinical and laboratory evaluations and
follow-up investigations.
The trial consists of the following stages:
15.1.1. Screening: the screening period must occur within 28 days before randomisation in
ORTA.
Baseline
evaluations
must
be
done
within
28
days
prior
to
randomisation.Trial specific examinations may only be done after informed consent
has been signed by the patient, and within 14 days before randomisation.

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15.1.2. Treatment phase:
Drug therapy is to begin within 10 days after randomisation.
Upon
first
disease
progression
or
completion
of
first-line
per
protocol
chemotherapy treatment, further therapy will be at the discretion of the treating
physician.
In arm B, Denosumab will be continued upon tumour progression and
concomitantly to subsequent lines of systemic treatment, as long as tolerable for
the patient.
15.1.3. End of per protocol first-line chemotherapy: an end of treatment visit will occur 30
+/-5 days following the last dose of first-line chemotherapy.
15.1.4. Arm B: End of denosumab treatment: an end of treatment visit will occur 30 +/-5
days following the last dose of denosumab.
15.1.5. Follow-up period: every 6-8 weeks following end of treatment visit until death,
patients will be followed up to document outcome and further lines of treatment.
Between end of treatment and progression, the visit schedule needs to follow the
one corresponding to the treatment phase, see section 15.6.
15.2.
Baseline evaluations (within 28 days prior to registration)
15.2.1. Medical history including symptoms, smoking history, medications, comorbidities
and allergies
15.2.2. Physical examination including blood pressure [mmHg], ECOG performance status
(see text box in section 6.1), and body weight [kg]
15.2.3. Haematology: haemoglobin, neutrophils, platelets
15.2.4. Blood chemistry: serum creatinine, ALT, bilirubin, total calcium, albumin
15.2.5. Renal function: serum creatinine and creatinine clearance calculated according to
Cockroft-Gault.
15.2.6. Hepatic function: ALT, bilirubin
15.2.7. Pregnancy test for women of childbearing potential within 14 days before start of
treatment
15.2.8. Bone scan: Bone scan at baseline not requested for patients who have undergone a
PET-CT at baseline; In the event of equivocal results of the bone scan, further
confirmation using bone MRI, CT, X-Ray or biopsy is recommended.
15.2.9. CT scan of thorax and upper abdomen with i.v. contrast (alone or in combination
with PET). In the presence of clinically suspected metastases outside the thorax
(e.g. brain, bone or lower abdomen), additional CT of the affected body part is
recommended.
15.2.10. CT scan or MRI of brain is not mandatory and only recommended in case of
clinically suspected brain metastasis

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15.3.
Before start of treatment
15.3.1. Take baseline samples for translational research
-
1 block of FFPE tissue from biopsy, surgery or cytology
-
Pathology report
-
Blood sample
send the FFPE samples to the central lab within 12 weeks after randomisation.
15.4.
Evaluations before and during per protocol first-line chemotherapy
On day 1 of every 3-week treatment cycle:
15.4.1. Recording of adverse events
15.4.2. Physical examination including blood pressure, performance status, and body
weight
15.4.3. Haematology: haemoglobin, neutrophils, platelets
15.4.4. Blood chemistry: serum creatinine, ALT, bilirubin, total calcium, albumin
15.4.5. CT thorax and upper abdomen on day 1 of cycle 4, then every 12 weeks until first
progression has been fully documented. Additional exams (MRI, PET-CT, etc,)
might be performed upon symptoms or suspicion of progression, according to local
standards and can serve as documentation of progression according to RECIST.
15.4.6. On day 1 of cycle 3: Blood sample for translational research
15.5.
End of first-line chemotherapy treatment visit
At the end of first-line chemotherapy and irrespective of the reason for stopping, an end-
of-treatment visit at the center is to be scheduled after 30 (+/- 5) days following last
chemotherapy treatment day. The following procedures should be performed:
15.5.1. Recording adverse events
15.5.2. Physical examination including blood pressure, performance status, and body
weight
15.5.3. Haematology: haemoglobin, neutrophils, platelets
15.5.4. Blood chemistry: serum creatinine, ALT, bilirubin, total calcium, albumin
15.6.
Evaluations after per protocol first-line chemotherapy and before first
progression
For patients who discontinue chemotherapy without documented progression, clinical
follow-up should be done every 6-8 weeks according to local standard of care and
subsequent anticancer treatment schedules, and in Arm B according to denosumab
treatment:
15.6.1. Documentation of further treatments

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15.6.2. Adverse events every 6-8 weeks
15.6.3. Arm B: Total calcium, albumin at every denosumab administration (q3 or 4 weeks)
15.6.4. Every 12 weeks: CT thorax and upper abdomen (Additional exams (MRI, PET-
CT, etc) might be performed upon symptoms or suspicion of progression,
according to standard of care and can serve as documentation of progression
according to RECIST.).
15.7.
Evaluations at first documented progression
15.7.1. CT thorax and upper abdomen, document progression on the respective CRF
15.7.2. Physical examination including blood pressure and performance status
15.7.3. Haematology: haemoglobin, neutrophils, platelets
15.7.4. Blood chemistry: serum creatinine, ALT, bilirubin, total calcium, albumin
15.7.5. Documentation of further treatments
15.7.6. Blood sample for translational research
15.7.7. Tumour re-biopsy is encouraged for testing of further predictive markers and
translational research at the central reference laboratory
15.8.
Evaluations after first progression
After documented first progression, patients should be documented every 8 weeks for
15.8.1. Survival information until death
15.8.2. Further lines of treatment every 6-8 weeks until death
15.8.3. Adverse events every 6-8 weeks
15.9.
Arm B: End of denosumab treatment visit
At the end of denosumab treatment and irrespective of the reason for stopping, an end-of-
treatment visit at the center is to be scheduled after 30 (+/- 5) days following last denosumab
treatment day. In the unlikely case that denosumab treatment is stopped before first-line
chemotherapy, this visit should take place after stop of first-line chemotherapy. The
following procedures should be performed:
15.9.1. Recording adverse events
15.9.2. Physical examination including blood pressure and performance status
15.9.3. Haematology: haemoglobin, neutrophils, platelets
15.9.4. Blood chemistry: serum creatinine, ALT, bilirubin, total calcium, albumin

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16.
Case report forms and documentation
16.1.
Case report forms
Data will be reported on the forms specifically designed by the ETOP/EORTC Headquarters
for this trial. Forms should be electronically sent to the EORTC Headquarters through the
VISTA/RDC (Remote Data Capture) system, with the exception of the SAE form, paper
lactation form and paper pregnancy notification form which are a paper CRF.
Serious adverse events and pregnancies should be reported immediately according to
the procedures detailed in this protocol (see section 12.6).
A. Before the treatment starts:
The patient must be registered and randomised in the trial by INTERNET or in case of
problems by phone.
The electronic CRFs to be completed for a patient are available on the VISTA/RDC website
one
day
after
the
registration/randomisation
on
http://rdc.eortc.be/
or
on
http://www.eortc.be/ in the section for investigators.
The paper CRF (only SAE form, lactation form and pregnancy notification form) will be
made available to the institution at the time the institution is authorised.
B. During/after treatment
The list of forms to be completed for this trial and their submission schedule are available
on the VISTA/RDC website and are also described in the "Guidelines for completion of
case report forms" that are provided to each participating investigator.
ALL Forms must be electronically approved and sent by the responsible investigator
or one of his/her authorised staff members.

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16.2.
CRF submission schedule
CRFs will only be available on-line on the VISTA/RDC website. No paper forms will be
used, with the exception of a paper SAE form and of a paper lactation and a paper
pregnancy notification form.
CRF forms
To be completed
Eligibility checklist
At randomisation of the patient.
On-study form
At baseline, within 1 week after randomisation of the patient.
Assessment form
At baseline;
At D1 of each cycle;
At end of treatment visit.
Initial measurements form
At baseline, within 1 week after randomisation of the patient.
Biochemistry form
At D1 of each cycle;
At end of treatment visit.
Hematology form
At D1 of each cycle;
At end of treatment visit.
Treatment form
At the end of each cycle.
Adverse events form
At baseline;
At the end of each cycle;
At end of treatment visit
Follow-up measurements
form
Every 12 weeks until progression;
Patients who discontinue treatment before progression: every
12 weeks until progression
Pregnancy form
Paper form; by Fax, within 24 hours of first becoming aware of
the pregnancy to EORTC Pharmacovigilance Unit
Lactation form
Paper form; by Fax, within 24 hours of first becoming aware of
the lactation to EORTC Pharmacovigilance Unit
Serious adverse event
form
Paper form; by Fax, within 24h of first becoming aware of
SAE to EORTC Pharmacovigilance Unit
Follow-up form
Every 8 weeks after treatment discontinuation until death.
Consult the “Guidelines for completion of case report forms" for detailed instructions on
how to complete, save and submit the electronic and paper CRFs.

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16.3.
Data flow
The forms must be completed electronically, with the exception of the paper SAE forms,
according to the schedule defined in the guidelines for completion of Case Report Forms.
The list of staff members authorised to enter data (with a sample of their signature) must be
identified on the signature log and sent to the EORTC Headquarters by the responsible
investigator before the start of the trial. To enter the RDC system, the investigator or
authorised staff member needs to use the same username and password that are used to
access the interactive randomisation program (ORTA).
In all cases, it remains the responsibility of the principal investigator to check that data are
entered in the database as soon as possible and that the electronic forms are filled out
completely and correctly.
The EORTC Headquarters will perform extensive consistency checks on the received data
and will issue queries in case of inconsistent data. The queries for the electronic forms will
appear in the VISTA/RDC system and must be answered there directly.
The EORTC data manager will subsequently apply the corrections into the database.
When satellite institutions are involved, all contact is made exclusively with the primary
institution, for purposes of data collection and all other trial related issues.
If an investigator (or an authorised staff member) needs to modify a CRF after the form has
been electronically sent to the EORTC Headquarters, he/she should create a request for data
correction in the VISTA/RDC system.
17.
Statistical considerations
17.1.
Primary Objective
This randomised phase III trial will evaluate the potential of denosumab – as an antitumour
agent – to increase survival in patients with stage IV NSCLC with or without bone
metastasis.
17.2.
Sample size
Using 90% power and a one-sided type I error of 2.5%, demonstration of an increase in
median overall survival to 11.25 months in the experimental arm relative to 9 months in the
control arm (equivalent to HR = 0.80) requires observation of 847 deaths. Assuming an
accrual rate of 15 patients/month for the first 6 months and 30 patients/month thereafter, an
accrual of 1000 patients would be required with corresponding accrual period of 37 months
and an extra 14 months follow up time after the last patient entry to reach the above required
number of events. The accrual in the bone mets stratum is expected to be 300 patients (30%
of the total), with 700 for the non-bone mets stratum. The same median OS and
improvement in the experimental arm is assumed for both strata.
The trial is designed with a futility interim analysis (IA), to be performed at 30% of the
information time. If the trial is completed with full accrual, the maximum overall duration is
expected to be 51 months.
17.3.
Statistical analysis plan
17.3.1. Analysis populations

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
Intention-to-treat population (ITT): All randomized patients will be analyzed in
the arm they were allocated by randomisation.

Per protocol population: All patients who do not have any major deviation from
eligibility criteria and have started their allocated treatment (at least one dose of the
study drug(s))

Safety population: All patients who have started their allocated treatment (at least
one dose of the study drug(s))
A patient will be considered to be eligible if he/she did not have any major deviation from
the patient entry criteria listed in section 6 of the protocol. Potential eligibility problems will
be assessed by the Clinical Research Physician at time of medical review.
17.3.2. Statistical methods
Time to event endpoints
The analyses of the primary and secondary endpoints (OS, PFS) will be performed on all
randomised patients according to the intention to treat principle.
The null hypothesis for the primary endpoint will be tested at a significance level of 0.05 (or
0.025 if based on one-sided test). If the primary hypothesis is rejected, the null hypothesis
for the secondary endpoint of progression free survival will be tested at a significance level
of 0.05 (or 0.025 if based on one-sided test).
To preserve the Type I error for other
secondary analyses, the Hommel procedure will be used to account for multiple testing.
Estimates and confidence intervals
Estimates of the median PFS and OS are obtained by the Kaplan Meier technique. The (1-α)
confidence interval (CI) for the median will be calculated using the reflected CI method.
Follow-up time will be estimated based on the reverse Kaplan Meier method.
Estimates of the event-free rate at a fixed time point will be obtained using the Kaplan
Meier technique and (1-α) CI will be calculated by Greenwood’s estimation of the standard
deviation. Estimates of hazard ratios and their (1-α) CI will be obtained by Cox regression.
Kaplan Meier Curves will be drawn for both the experimental and control arms on the same
plot.
Response rate (objective; complete and partial response) will be analyzed for all eligible
patients according to the treatment assigned at randomization (intention-to-treat analysis
population).
Inference: Test statistics for comparisons
A log-rank test stratified by the randomisation stratification factors will be used to compare
the experimental versus the control arms for the time to event endpoints.
Fisher’s exact test will be used to compare the differences in overall response rate between
the two groups.
Toxicity
Analysis for toxicity is based on the safety population. The worst grade of toxicity/adverse
events observed over the whole treatment period according to CTCAE version 4 will be
displayed. In the primary analysis, no formal statistical analysis will be performed to
compare toxicity in both arms.

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17.3.3. Pre-planned sensitivity or exploratory analyses
As a sensitivity analysis, other baseline disease factors namely gender, smoking status, age,
carboplatin versus cisplatin will be used as adjustment factors in Cox regression analysis, in
addition to the stratification factors used for randomisation. A log rank test with no
adjustment factors to compare the two arms will also be performed as a sensitivity analysis.
For the secondary endpoint PFS, due to possible variation in time window used by centre for
disease assessment, a method based on interval censoring will be used in the sensitivity
analysis 36. Proportional hazards assumption will be checked using the method described by
Grambsch and Therneau 37. If the data clearly do not follow proportional hazards, medical
explanations should be identified and alternative statistical methods will be explored.
Subgroup-analysis by stratification factors used in randomisation will be conducted.
17.3.4. Prognostic factor analyses
Except for the analyses described in the previous sub-section, there are no other prognostic
factor analyses foreseen in the current protocol.
17.3.5. Data recoding and display
Frequency tables will be tabulated (by treatment group or otherwise) for all categorical
variables by the levels of the variables as they appear on the CRF (with %). Categories with
a text field specification will be tabulated as categories and then supplemented by a listing
with the following information for the patients fulfilling the condition for the specification
(patient id, institution, treatment group, value of the item and text field contents).
Dates relating to events prior to entry will be presented as the delay in days (or weeks,
months, or years) between the past event and the date of entry (date of randomisation – date
of past event + 1) and presented using the median and range. For example, on the
randomisation checklist, the date of last administration of prior treatment (or the date of first
diagnosis of the cancer) will be presented as the time elapsed (in days, weeks, months or
years, as appropriate) since the day of the last administration and the date of entry on trial
(date of randomisation – last administration/diagnosis +1).
Other delays (eg. re-treatment delays) are presented as continuous variables using the
median and range.
Continuous variables for which a coding system exists (such as for laboratory data) will be
recoded into categories (for adverse events, the CTCAE v.4 grading scale will be used).
Whenever no specific scale exists, lab data will be categorized based on the normal range:
for example, below the lower normal limit (when appropriate), within the normal range,
above the upper normal limit (ULN) and the degree to which it is above the ULN (for
example > 2.5 x ULN, > 5 x ULN, > 10 x ULN). For laboratory data, the nadir is generally
displayed. The nadir in a given cycle is the lowest laboratory value in that cycle; the overall
nadir for a patient is the lowest laboratory value across all cycles.
Other continuous variables (for example age, dose) are presented using the median and
range (minimum, maximum).
DI observed




weeks
m
mg
2
=



weeks
duration
total
dose
total
m
mg
2

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The relative dose intensity is calculated as the ratio of the dose intensity as calculated above
to the dose intensity indicated in the protocol. The dose intensity indicated in the protocol is
obtained as the dose specified per cycle (in mg/m²).
The dose intensity and the relative dose intensity are presented using median and ranges.
The relative dose intensity can also be presented in categories (≤70%, >70-90%, >90-110%,
>110-120%, >120%.
If appropriate, continuous data may also be presented in categories (for example, age may
also be grouped in decades).
17.4.
Interim analyses
The trial is designed with a futility IA, at 30% of the overall trial information time. This will
be an event driven IA, when 254 deaths have been observed overall, expected to occur by
22.5 months from the date the first patient is randomised. At this time accrual is expected to
have reached 58% of the total.
The Lan-Demets spending function with O’Brien-Fleming-type stopping boundary is used
to determine the futility boundary at IA.
If the futility boundary is crossed, i.e. p>0.8423, the trial may be closed
based on the
recommendation of the Independent Data Monitoring Committee (IDMC).
If the futility
boundary is not crossed, the trial will continue to completion. The final analysis will be
performed in the overall trial population at one-sided alpha of 0.025, when the required
number of 847 events is observed at the estimated maximum trial duration of 51 months.
The Interim Analysis Report is confidential and will be reviewed by the IDMC which will
make a recommendation to continue or stop the trial based on the interim analysis results.
17.5.
End of trial
End of trial occurs when all of the following criteria have been satisfied:

All patients have been off protocol-specified treatment (first-line chemotherapy or
denosumab, whichever occurs later) 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.

The trial is mature for the analysis of the primary endpoint as defined above.

The database has been fully cleaned and frozen for the final analysis
Note: follow-up will be life-long for all patients.
18.
Criteria for termination of the trial
18.1.
Discontinuation of protocol treatment for individual patients
First-line chemotherapy should be stopped in the following situations:

Disease progression

Occurrence of unacceptable toxicities. Stopping protocol treatment is determined
by medical judgment of the treating physician.

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
Inter-current severe illnesses which would in the judgment of the investigator affect
assessments of the clinical status to a significant degree and require discontinuation
of protocol therapy. Note: Diagnosis of another neoplastic disease (second
malignant tumour) does not mandate a stop of trial therapy, patients may continue
to receive protocol treatment after appearance of a second primary tumour,
stopping protocol treatment is determined by the medical judgment of the treating
physician

Request by the patient (see also section 19.4)

If a patient refuses to have the treatments or follow-up examinations and tests
needed to determine whether the treatment is safe and effective

Patient becomes pregnant
Denosumab (arm B) should be continued upon tumour progression and concomitantly to
subsequent lines of systemic treatment. Denosumab should be stopped in the following
situations:

Occurrence of unacceptable toxicities attributed to denosumab. Stopping protocol
treatment is determined by medical judgment of the treating physician.

Request by the patient

If a patient refuses to have the treatments or follow-up examinations and tests
needed to determine whether the treatment is safe and effective

Patient becomes pregnant
The decision for discontinuation of protocol treatment of individual patients is taken by the
treating physician based on his medical evaluation and taking into account the patient’s
individual situation.
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 847 deaths for the final analysis has been reached.
18.2.
General criteria for termination of the trial
The trial may be discontinued early in parts or completely if the information on the product
leads to doubt as to the benefit/risk ratio, by decision of ETOP or Trial Steering Committee.
19.
Ethics aspects, regulatory approval, and Patient Informed Consent
The Investigator will ensure that this trial is conducted in full conformance with the
principles of the “Declaration of Helsinki” or with the laws and regulations of the country in
which the research is conducted, whichever affords the greater protection to the individual.
The trial must fully adhere to the principles outlined in “Guideline for Good Clinical
Practice” ICH Tripartite Guideline (January 1997) or with local law if it affords greater
protection to the patient. For studies conducted in the EU/EEA countries, the Investigator
will ensure compliance with the EU Clinical Trial Directive (2001/20/EC).

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19.1.
Ethics Review Board/Ethics Committee
All protocols and the patient informed consent forms must have the approval of a properly
constituted committee or committees responsible for approving clinical trials.
The ERB/IRB written, signed approval letter/form must contain approval of the designated
investigator, the protocol (identifying protocol title and version number), and of the patient
informed consent. Documentation of Ethics Committee approval must be sent to the ETOP
Coordinating Office/EORTC HQ prior to participating center activation .
Any modifications made to the protocol must be submitted to the appropriate ERB/IRB for
information or approval in accordance with local procedures and regulatory requirements
and to Health Authorities if required.
Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities
(if required), the investigator shall implement the protocol modifications. Protocol
modifications for urgent safety matters may be directly implemented following the
instructions of ETOP/EORTC.
19.2.
Regulatory approval procedures
There will be local, regional and country specific differences in the regulations concerning
the use of biological samples for research.
If applicable, in addition to the approval of the Ethics Committee according to national
legislation, the protocol, other protocol related documents including patient information and
informed consent and other documents as required locally must be submitted to and be
approved by the health authority. Documentation of health authority approval must be sent
to the ETOP Coordinating Office/EORTC HQ prior to Participating Center activation.
19.3.
Informed consent
Informed consent for each patient will be obtained prior to initiating any trial procedures in
accordance with the “Patient Information and Informed Consent" (see Appendix 1). One
signed and dated copy of the informed consent must be given to each patient and the
original copy must be retained in the investigator's trial records. The informed consent form
must be available in the case of data audits. Verification of signed informed consent and the
date signed are required for randomisation to this trial.
The "Declaration of Helsinki" recommends that consent be obtained from each potential
patient in biomedical research trials after the aims, methods, anticipated benefits, and
potential hazards of the trial, and discomfort it may entail, are explained to the individual by
the
physician
(http://www.wma.net/en/30publications/10policies/b3/index.html).
The
potential patient should also be informed of her right to not participate or to withdraw from
the trial at any time. The patient should be told that material from her tumour will be stored
and potentially used for additional studies not described in this protocol.
If the patient is in a dependent relationship to the physician or gives consent under duress,
the informed consent should be obtained by an independent physician.
By signing this
protocol, the investigator agrees to conduct the trial in accordance with Good Clinical
Practice and the "Declaration of Helsinki."
ETOP recognizes that each institution has its own local, national, and international
guidelines to follow with regard to informed consent.
Therefore, we provide a template
information sheet and informed consent form (Appendix 1), which can be edited to
incorporate information specific to your institution. The template Patient Information Sheet

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and Informed Consent has been written according to ICH guidelines which state the
Informed Consent should adhere to GCP and to the ethical principles that have origin in the
“Declaration of Helsinki”. The final version should receive the Institutional Review Board/
Local Ethics Committee approval in advance of its use. Centers should send their locally
modified patient information sheet and informed consent form to ETOP/EORTC HQ for
review and approval before submitting to their Ethics Committee.
19.4.
Premature withdrawal
Patients have the right to refuse further treatment for any reason and at any time. Patients
who decide to withdraw from the trial should be asked whether they also want to withdraw
their consent for their data to be used for the follow-up assessments, and whether they want
to withdraw consent for the use of biological samples. For the patient’s safety, a last
examination should be performed.
Patients may be withdrawn at any time from trial treatment at the discretion of the
investigator due to a serious adverse event, or based on any other relevant medical
condition. The patient will then be transferred to the follow-up phase and will be
documented as planned.
For criteria on early stop of trial treatment see section 18.1.
20.
Governance and administrative issues
20.1.
Steering Committee
A Steering Committee will be constituted for this trial. The Steering Committee is
responsible for maintaining the scientific integrity of the trial, for example, by
recommending changes to the protocol in light of emerging clinical or scientific data from
other trials. Membership will include the trial chair and co-chair, trial coordinators, trial
statisticians, EORTC and ETOP officials, representatives
from some participating
institutions and groups, and maybe a representative from Amgen. Steering Committee
guidelines are available.
20.2.
Independent Data Monitoring Committee
The trial will be presented for review to the ETOP IDMC at each of their semi-annual
meetings. Accrual and safety will be monitored. The Interim Analysis Report will be
reviewed by the IDMC which will make a recommendation to continue or stop the trial
based on the interim analysis results.
20.3.
Publication
The results of the trial will be published according to the ETOP/EORTC publication
guidelines.
20.4.
Clinical trial insurance
ETOP will contract the appropriate liability insurance for this trial. Patients who suffer
injuries due to the trial should report them immediately to their physician. The local
group/institution should report all alleged claims immediately to the ETOP Coordinating
Office.

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20.5.
Quality Assurance/Quality control
ETOP and EORTC conduct trials according to the ICH Good Clinical Practice (GCP)
guidelines. The Trial Data Manager reviews each CRF as it is received. In addition, the
ETOP/EORTC Medical Reviewer reviews each case at specific timepoints. ETOP/EORTC
conduct periodic audit visits to ensure proper trial conduct, verify compliance with GCP,
and perform source data verification.
The Investigator should ensure that source documents are made available to appropriately
qualified personnel from EORTC, ETOP, Amgen or its designees, or to health authority
inspectors after appropriate notification.
At regular intervals during the clinical trial, the Centre will be contacted, through
monitoring visits, letters or telephone calls, by a representative of the Monitoring Team to
review study progress, investigator and patient compliance with clinical trial protocol
requirements and any emergent problems. These monitoring visits will include but not be
limited to review of the following aspects: patient informed consent, patient recruitment and
follow-up,
SAE
documentation
and
reporting,
AEs
with
pre-specified
monitoring
documentation and reporting, AE documentation, dispensing IP, compliance with protocol,
drug accountability, concomitant therapy use, quality of data and storage of serum samples.
20.6.
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no
circumstances should the investigator contact ETOP or EORTC or personnel monitoring the
trial to request approval of a protocol deviation, as no deviations are permitted. The
investigator should document and explain any deviations from the approved protocol. The
investigator should promptly report any deviations to the Sponsor and to the EC concerned
in accordance with the applicable EC policies and procedures. If the investigator feels a
protocol deviation would improve the conduct of the trial this must be considered a protocol
amendment, and unless such an amendment is developed and activated by the sponsor and
approved by the IRB/IEC/REB it cannot be implemented. All protocol deviations will be
recorded.
20.7.
Data protection
The samples and data collected will be coded to protect patient confidentiality. Each patient
will have a unique identifier assigned by ORTA. Sites are responsible to keep a patient log
locally in order to be able to link the unique identifier to the record of the patient.
Biological material will be assigned the same unique identifier. No identifiable / personal
data will be stored in the trial database or the tissue repositories in the central labs.
Biological material will be transferred outside the treating institution for central screening
and review. Results of the assays will be coded only by the patient identifier.
20.8.
Record Retention
The center must retain all essential documents according to ICH GCP. This includes copies
of the patient trial records, which are considered as source data, patient informed consent
statement, laboratory printouts, drug inventory and destruction logs, and all other
information collected during the trial. These documents are to be stored until at least 15
years after the termination of the trial. EORTC guarantees access and availability of the data
entered into the clinical trial database for at least 15 years after the termination of the trial.

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Longer retention may be required for participating centers according to national regulations.
In the event that the Principal Investigator retires or changes employment, custody of the
records may be transferred to another competent person who will accept responsibility for
those records. Written notice of such transfer has to be given to ETOP/EORTC and the local
Ethics Committee at least one month in advance.
21.
References
1.
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zoledronic acid in the treatment of skeletal metastases in patients with nonsmall
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2.
Rosen LS, Gordon D, Tchekmedyian S, et al: Zoledronic acid versus placebo in the
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Other Solid Tumors Study Group. J Clin Oncol 21:3150-7, 2003
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Tsuya A, Kurata T, Tamura K, et al: Skeletal metastases in non-small cell lung
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Rosen LS, Gordon D, Kaminski M, et al: Long-term efficacy and safety of
zoledronic acid compared with pamidronate disodium in the treatment of skeletal
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Abrahamsen B: Adverse effects of bisphosphonates. Calcif Tissue Int 86:421-35,
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Gebara SN, Moubayed H: Risk of osteonecrosis of the jaw in cancer patients taking
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Kim NS, Kim HJ, Koo BK, et al: Receptor activator of NF-kappaB ligand regulates
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Mori K, Ando K, Heymann D, et al: Receptor activator of nuclear factor-kappa B
ligand (RANKL) stimulates bone-associated tumors through functional RANK
expressed on bone-associated cancer cells? Histol Histopathol 24:235-42, 2009
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Gonzalez-Suarez E, Branstetter D, Armstrong A, et al: RANK overexpression in
transgenic mice with mouse mammary tumor virus promoter-controlled RANK
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