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Trial registered on ANZCTR


Registration number
ACTRN12618001121257
Ethics application status
Approved
Date submitted
27/06/2018
Date registered
6/07/2018
Date last updated
19/09/2019
Date data sharing statement initially provided
19/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Pre-Operative Programmed Death-1 (PD1) Checkpoint Blockade and Receptor Activator of NFkB Ligand (RANKL) Inhibition in Non-Small Cell Lung Cancer (NSCLC) (POPCORN) - a trial for patients with resectable NSCLC
Scientific title
Pharmacodynamics of Pre-Operative PD1 Checkpoint Blockade and Receptor Activator of NFkB Ligand (RANKL) Inhibition in Non-Small Cell Lung Cancer (NSCLC) - a phase 1B/2 trial
Secondary ID [1] 295332 0
20177440 Amgen ISS
Universal Trial Number (UTN)
U1111-1216-3415
Trial acronym
POPCORN
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Non-small cell lung cancer (NSCLC) 308536 0
Condition category
Condition code
Cancer 307504 307504 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A randomized, 2-arm trial of neoadjuvant (pre-operative) therapy in patients with resectable stage 1A (>2cm) - 3A non-small cell lung cancer (NSCLC). The two arms are as follows:
Arm 1: nivolumab 3 mg/kg intravenously days 1, 15 (followed by surgery on day 29)
Arm 2: nivolumab 3 mg/kg intravenously days 1, 15 PLUS denosumab 120 mg subcutaneously days 1, 15 (followed by surgery on day 29). Note: participants in Arm 2 will also receive daily oral vitamin D and calcium supplementation (doses at the discretion of the treating clinician) for the duration of denosumab therapy.
Intervention code [1] 301659 0
Treatment: Drugs
Comparator / control treatment
Arm 1 and Arm 2 will be run concurrently to determine the additional pharmacodynamic activity of denosumab with nivolumab compared with nivolumab alone. Arm 1 (nivolumab alone) is considered to be the control arm.
Control group
Active

Outcomes
Primary outcome [1] 306478 0
Pharmacodynamic correlates of neoadjuvant therapy for each arm (exploratory) including:
• T-cell receptor (TCR) clonality in the tumor and peripheral blood, comparing baseline and on-/post-treatment samples
• RNA/transcription profile and genomic changes in tumor and/or peripheral blood, and association with treatment response
• Expression of markers of interest via multiplex immunohistochemistry
Timepoint [1] 306478 0
After surgery conducted on day 29
Secondary outcome [1] 348639 0
Rates of major pathological response, MPR in each arm (assessed pathologically as 10% or less viable tumour cells remaining in surgically resected tumor specimen)
Timepoint [1] 348639 0
Day 29
Secondary outcome [2] 348640 0
Frequency of CTCAE v.4.03 grade 3/4 toxicity in each arm
Timepoint [2] 348640 0
3 months post surgery
Secondary outcome [3] 348641 0
Rate of R0 resection rate in each arm (assessed pathologically)
Timepoint [3] 348641 0
Day 29
Secondary outcome [4] 348642 0
Radiological response (by CT scanning +/- FDG-PET) for each arm
Timepoint [4] 348642 0
Within 1-2 weeks prior to surgery
Secondary outcome [5] 348643 0
Proportion of participants in each arm who experience surgical delay due to treatment-related adverse events (TRAE)
Timepoint [5] 348643 0
Day 29
Secondary outcome [6] 348762 0
Progression free survival (measured from time of randomization to first relapse of NSCLC or death from any cause)
Timepoint [6] 348762 0
3 years post surgery
Secondary outcome [7] 348763 0
Overall survival (measured from time of randomization to death from any cause)
Timepoint [7] 348763 0
3 years post surgery

Eligibility
Key inclusion criteria
- Histological or cytological diagnosis of NSCLC.
- Baseline histological specimen from primary tumor (and locoregional lymph node metastasis if clinically suspected) must be available for all patients.
- Primary tumor must be measurable on CT scan (RECIST v.1.1 criteria).
- Stage IA (>2cm) - IIIA confirmed by FDG-PET scan (it is strongly recommended that mediastinal nodal status in patients with N2 nodes is pathologically confirmed). Staging is according to 8th edition UICC/AJCC 2017.
- Considered to be surgically resectable by thoracic surgeon.
- No prior therapy for NSCLC.
- Age greater than or equal to 18 years.
- ECOG Performance Status 0-1.
- Peripheral neuropathy no worse than grade I.
- Patients on study with reproductive potential, or female partners with reproductive potential, must use an effective contraceptive method during the trial and for 3 months after the completion of chemotherapy.
- Adequate organ function including the following:
­ expected FEV1 following surgery greater than or equal to 1.0 L/sec
­ adequate bone marrow reserve: ANC at least 1.5 x 109/L, platelets at least 100 x 109/L, haemoglobin at least 100 g/L
­ hepatic: bilirubin at least 1.5 times ULN; ALP, AST and/or ALT at least 3 times ULN
­ renal: creatinine clearance at least 60 mL/min (calculated). If the creatinine clearance is between 50 and 60 mL/min, then determination of glomerular filtration rate by nuclear medicine scan may be carried out and this result used for eligibility.
- Ability to give written informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Small cell or mixed small cell histology subtypes.
- Known active neoplastic disease present for 5 years before enrolment, other than non-melanoma skin cancer or adequately treated stage I in situ cervical cancer.
- Patients receiving another investigational drug or anti-cancer treatment within 4 weeks prior to 1st infusion of study medication.
- Previous treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways.
- Previous treatment with denosumab.
- Active infection, which in the opinion of the Investigator would compromise the patient’s ability to tolerate therapy.
- Currently pregnant or breast feeding.
- Serious concomitant medical or psychiatric disorders which would compromise the safety of the patient or their ability to receive study therapy or complete the study.
- Significant cardiovascular disease.
- Patient in whom corticosteroid premedication is contraindicated.
- Active, known or suspected autoimmune disease.
- Any condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone or equivalent dose of an alternative corticosteroid) or other immunosuppressive medications within 14 days of study drug administration.
- History of severe hypersensitivity reactions to any of the study medications.
- Have received a recent (within 30 days) or are receiving concurrent yellow fever vaccination or other live attenuated vaccination.
- Unhealed or planned dental/oral surgery, current or previous osteonecrosis or osteomyelitis of the jaw.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed and randomisation conducted via a secure web-based interactive randomisation system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation to either Arm 1 or 2 will be performed by random computerised allocation and stratified by participating site, maximum tumor diameter, histology (squamous vs. non-squamous) and clinical stage by minimisation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Pharmacodynamics
Statistical methods / analysis
Pathological, genomic and immunologic analyses on biospecimens analyzed and compared between groups using two-sided P-values with significance level set at 0.05.
Kaplan-Meier method used to calculate progression-free survival (time between randomization and first evidence of disease progression or death from any cause) and overall survival (time between randomization and death from any cause)

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
26/11/2018
Actual
22/05/2019
Date of last participant enrolment
Anticipated
25/05/2020
Actual
Date of last data collection
Anticipated
24/05/2023
Actual
Sample size
Target
30
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 11246 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 11247 0
The Prince Charles Hospital - Chermside
Recruitment hospital [3] 14831 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 23122 0
4029 - Herston
Recruitment postcode(s) [2] 23123 0
4032 - Chermside
Recruitment postcode(s) [3] 28083 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 299921 0
Commercial sector/Industry
Name [1] 299921 0
Amgen Australia Pty. Ltd.
Country [1] 299921 0
Australia
Primary sponsor type
Hospital
Name
Royal Brisbane and Women's Hospital
Address
Royal Brisbane and Women's Hospital, Cnr Butterfield St and Herston Rd, Herston, QLD 4029
Country
Australia
Secondary sponsor category [1] 299289 0
None
Name [1] 299289 0
Address [1] 299289 0
Country [1] 299289 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300790 0
Royal Brisbane and Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 300790 0
HREC Office, Executive Suites, Lower Ground Floor, Dr James Mayne Building, RBWH, Cnr Butterfield St and Herston Rd, Herston, QLD 4029
Ethics committee country [1] 300790 0
Australia
Date submitted for ethics approval [1] 300790 0
30/07/2018
Approval date [1] 300790 0
06/09/2018
Ethics approval number [1] 300790 0
HREC/18/QRBW/43659

Summary
Brief summary
This study is designed to test the potential activity/benefit, safety and feasibility of adding a drug commonly used for bone protection (denosumab) to an immunotherapy drug (nivolumab) before surgery in patients with non-small cell lung cancer (NSCLC) for whom surgery has been recommended.

Who is it for?
You may be eligible for this study if you are aged 18 years or above and have a confirmed non-small cell lung cancer (NSCLC) for which surgery has been recommended to remove the cancer.

Study details
Participants will be randomly allocated (by chance) into one of two groups: in group 1, participants will receive two doses of nivolumab in the month prior to surgery, and in group 2, participants will receive two doses of denosumab in addition to the two doses of nivolumab in the month prior to surgery. Nivolumab is administered intravenously (i.e. directly into the vein) and denosumab is administered subcutaneously (i.e. as in injection under the skin). All participants will then proceed to surgery as planned. After surgery, no further trial medications are offered, but participants may be offered standard therapies according to the opinion of their treating clinicians. Those patients who receive denosumab will also be asked to take vitamin D and calcium supplementation during the course of their denosumab treatment.

It is hoped this study will confirm that two doses of nivolumab prior to lung cancer surgery results in significant rates of tumour shrinkage similar to a previous USA study, and that denosumab added to nivolumab may show evidence of better effectiveness.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84826 0
A/Prof Brett Hughes
Address 84826 0
Cancer Care Services
Royal Brisbane and Women's Hospital, Cnr Butterfield St and Herston Rd, Herston, QLD 4029
Country 84826 0
Australia
Phone 84826 0
+61 7 3646 7983
Fax 84826 0
Email 84826 0
brett.hughes@health.qld.gov.au
Contact person for public queries
Name 84827 0
Ms Annette Cubitt
Address 84827 0
Medical Oncology Clinical Trials Unit
Cancer Care Services
Royal Brisbane and Women's Hospital, Cnr Butterfield St and Herston Rd, Herston, QLD 4029
Country 84827 0
Australia
Phone 84827 0
+61 7 3646 7712
Fax 84827 0
Email 84827 0
annette.cubitt@health.qld.gov.au
Contact person for scientific queries
Name 84828 0
Dr Elizabeth Ahern
Address 84828 0
Department of Medical Oncology, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, QLD 4029
Country 84828 0
Australia
Phone 84828 0
+61 7 3646 8111
Fax 84828 0
Email 84828 0
elizabeth.ahern2@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Undecided


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbasePharmacodynamics of Pre-Operative PD1 checkpoint blockade and receptor activator of NFkB ligand (RANKL) inhibition in non-small cell lung cancer (NSCLC): Study protocol for a multicentre, open-label, phase 1B/2, translational trial (POPCORN).2019https://dx.doi.org/10.1186/s13063-019-3951-x
EmbaseRole of RANKL in cancer development and metastasis.2021https://dx.doi.org/10.1007/s00774-020-01182-2
EmbaseHow Is Receptor Activator of Nuclear Factor-kappabeta/Receptor Activator of Nuclear Factor-kappabeta Ligand Targeting Ranked as an Immuno-Oncology Target for NSCLC: a Pathway Unclear as yet?.2020https://dx.doi.org/10.1016/j.jtho.2020.07.011
Dimensions AIImproved Characteristics of RANKL Immuno-PET Imaging Using Radiolabeled Antibody Fab Fragments2022https://doi.org/10.3390/pharmaceutics14050939
Dimensions AIImmuno-PET Molecular Imaging of RANKL in Cancer2021https://doi.org/10.3390/cancers13092166
Dimensions AIInhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells2020https://doi.org/10.1038/s41467-020-20138-8
Dimensions AIYoung Consultant Oral Session Abstracts2020https://doi.org/10.1111/ajco.13416
N.B. These documents automatically identified may not have been verified by the study sponsor.