ANZCTR - Registration

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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]

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)

Condition category

Condition code

Cancer

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]

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]

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]

After surgery conducted on day 29

Secondary outcome [1]

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]

Day 29

Secondary outcome [2]

Frequency of CTCAE v.4.03 grade 3/4 toxicity in each arm

Timepoint [2]

3 months post surgery

Secondary outcome [3]

Rate of R0 resection rate in each arm (assessed pathologically)

Timepoint [3]

Day 29

Secondary outcome [4]

Radiological response (by CT scanning +/- FDG-PET) for each arm

Timepoint [4]

Within 1-2 weeks prior to surgery

Secondary outcome [5]

Proportion of participants in each arm who experience surgical delay due to treatment-related adverse events (TRAE)

Timepoint [5]

Day 29

Secondary outcome [6]

Progression free survival (measured from time of randomization to first relapse of NSCLC or death from any cause)

Timepoint [6]

3 years post surgery

Secondary outcome [7]

Overall survival (measured from time of randomization to death from any cause)

Timepoint [7]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [2]

The Prince Charles Hospital - Chermside

Recruitment hospital [3]

Princess Alexandra Hospital - Woolloongabba

Recruitment postcode(s) [1]

4029 - Herston

Recruitment postcode(s) [2]

4032 - Chermside

Recruitment postcode(s) [3]

4102 - Woolloongabba

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Amgen Australia Pty. Ltd.

Address [1]

Level 7, 123 Epping Road, North Ryde, NSW 2113

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Brisbane and Women's Hospital Human Research Ethics Committee

Ethics committee address [1]

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]

Australia

Date submitted for ethics approval [1]

30/07/2018

Approval date [1]

06/09/2018

Ethics approval number [1]

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

A/Prof Brett Hughes

Address

Cancer Care Services
Royal Brisbane and Women's Hospital, Cnr Butterfield St and Herston Rd, Herston, QLD 4029

Country

Australia

Phone

+61 7 3646 7983

Fax

brett.hughes@health.qld.gov.au

Contact person for public queries

Name

Annette Cubitt

Address

Medical Oncology Clinical Trials Unit
Cancer Care Services
Royal Brisbane and Women's Hospital, Cnr Butterfield St and Herston Rd, Herston, QLD 4029

Country

Australia

Phone

+61 7 3646 7712

Fax

annette.cubitt@health.qld.gov.au

Contact person for scientific queries

Name

Elizabeth Ahern

Address

Department of Medical Oncology, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, QLD 4029

Country

Australia

Phone

+61 7 3646 8111

Fax

elizabeth.ahern2@health.qld.gov.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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

Source	Title	Year of Publication	DOI
Embase	Pharmacodynamics 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).	2019	https://dx.doi.org/10.1186/s13063-019-3951-x
Embase	How 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?.	2020	https://dx.doi.org/10.1016/j.jtho.2020.07.011
Dimensions AI	Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells	2020	https://doi.org/10.1038/s41467-020-20138-8
Dimensions AI	Young Consultant Oral Session Abstracts	2020	https://doi.org/10.1111/ajco.13416
Embase	Role of RANKL in cancer development and metastasis.	2021	https://dx.doi.org/10.1007/s00774-020-01182-2
Dimensions AI	Immuno-PET Molecular Imaging of RANKL in Cancer	2021	https://doi.org/10.3390/cancers13092166
Dimensions AI	Improved Characteristics of RANKL Immuno-PET Imaging Using Radiolabeled Antibody Fab Fragments	2022	https://doi.org/10.3390/pharmaceutics14050939

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added manually

Documents added automatically