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Trial registered on ANZCTR


Registration number
ACTRN12615000323527
Ethics application status
Approved
Date submitted
20/03/2015
Date registered
9/04/2015
Date last updated
5/10/2024
Date data sharing statement initially provided
20/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase III Prospective Double Blind Placebo Controlled Randomized Study of Adjuvant MEDI4736 In Completely Resected Non-Small Cell Lung Cancer
Scientific title
A Phase III Prospective Double Blind Placebo Controlled Randomized Study on the effect of Adjuvant MEDI4736 on Disease Free Survival In patients with Completely Resected Non-Small Cell Lung Cancer
Secondary ID [1] 286275 0
NCIC CTG Identifier: BR.31
Secondary ID [2] 286276 0
ClinicalTrials.gov Identifier: NCT02273375
Universal Trial Number (UTN)
Trial acronym
BR.31
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lung cancer 294341 0
Condition category
Condition code
Cancer 294658 294658 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
MEDI4736 by intravenous infusion. MEDI4736 is supplied as a vialed liquid solution containing 500mg (nominal) MEDI4736. The solution contains 50mg/mL MEDI4736, 26mM histidine/histidine-HCl, 275mM trehalose dehydrate, 0.02% (w/v) polysorbate 80, at pH 6.0.
Treatment from Day 1 for a maximum of 12 months or study drug withdrawal if this occurs earlier.
Dosages are as follows: 20mg/kg every 4 weeks for 12 months.
Intervention code [1] 291296 0
Treatment: Drugs
Comparator / control treatment
Matched Saline PLACEBO by intravenous infusion. Treatment from Day 1 for a maximum of 12 months or study drug withdrawal if this occurs earlier.
Infusions occur every 4 weeks for 12 months.
Control group
Placebo

Outcomes
Primary outcome [1] 294414 0
Compare Disease free survival (DFS) for patients with NSCLC that is PD-L1 positive using the RECIST criteria
Timepoint [1] 294414 0
Time Frame: 5.5 years
Secondary outcome [1] 313244 0
Compare Disease Free Survival in all randomized patients using the RECIST criteria
Timepoint [1] 313244 0
Time Frame: 7 years
Secondary outcome [2] 313245 0
Compare overall survival (OS) for patients with NSCLC that is PD-L1 positive using a p-value and a Lan-DeMets error spending function with O'Brian-Fleming type boundaries.
Timepoint [2] 313245 0
Time Frame: 5.5 years
Secondary outcome [3] 313246 0
Compare overall survival for all randomized patients using a p-value
Timepoint [3] 313246 0
Time Frame: 7 years
Secondary outcome [4] 313247 0
Compare Lung cancer specific survival for patients with NSCLC that is PD-L1 positive and all randomized patients using a p-value
Timepoint [4] 313247 0
Time Frame: 7 years
Secondary outcome [5] 313248 0
Evaluate the nature, severity and frequency of adverse effects and tolerability of MEDI4736 using NCI CTC AE Version 4.0
Timepoint [5] 313248 0
Time Frame: every 6 months
Secondary outcome [6] 313249 0
Evaluate the Quality of life between the two treatment arms
The quality of life (QoL) of patients will be assessed using EORTC QLQ-C30 and the lung cancer module (QLQ-LC13) questionnaires
Timepoint [6] 313249 0
Time Frame: 5.5 years
Secondary outcome [7] 313250 0
Determine survival benefits participants judge necessary to make adjuvant immunotherapy worthwhile using the Preferences for Adjuvant Immunotherapy Questionnaire
Timepoint [7] 313250 0
Time Frame: 5.5 years
Secondary outcome [8] 313251 0
Determine the incremental cost effectiveness and cost utility ratios for MEDI4736 by analysis of the EQ-5D questionnaire and determine through the US Valuation of the EuroQoL EQ-5D Health States.
Timepoint [8] 313251 0
Time Frame: 5.5 years
Secondary outcome [9] 313252 0
Evaluate the predictive/prognostic significance of PD-L1 expression by tissue sampling
Timepoint [9] 313252 0
Time Frame: 5.5 years
Secondary outcome [10] 313253 0
Evaluation of changes in plasma/serum cytokines and other blood and tissue based biomarkers after treatment with MEDI4736 and at disease event
Timepoint [10] 313253 0
Time Frame: 5.5 years
Secondary outcome [11] 313254 0
Explore polymorphisms that may be associated with outcomes by analysis of blood samples. Polymorphisms known or suspected to be associated with the outcomes of completely resected NSCLC, platinum based ACT as well as immune pathways and response to immunotherapies will be analysed in the lab using these blood samples.
Timepoint [11] 313254 0
Time Frame: Baseline only

Eligibility
Key inclusion criteria
Histologically confirmed diagnosis of primary non-small cell carcinoma of the lung

*Patients must be classified post-operatively as Stage IB (greater than or equal to 4cm in the longest diameter), II or IIIA on the basis of pathologic criteria
-Complete surgical resection of the primary NSCLC is also mandatory. All gross disease must have been removed at the end of surgery. All surgical margins of resection must be negative for tumour. Resection may be accomplished by open or VATS techniques


Prior Systemic Therapy:
*Pre-operative (neo-adjuvant) platinum based or other chemotherapy is not permissible.

*Patients may have received prior post-operative platinum based chemotherapy as per standard of care.

*No prior anticancer therapy for treatment of NSCLC other than standard post-operative adjuvant chemotherapy is permissible.

Radiation:

*Pre-operative radiation therapy is not permissible.
*Patients with N2 disease only who receive adjuvant post-operative radiation therapy are eligible provided they meet the protocol specified timing criteria for surgery, adjuvant chemotherapy and randomization.

*The patient must have an ECOG performance status of 0, 1.

*Hematology: . Absolute neutrophil count greater than or equal to 1.5 x 109/L or greater than or equal to 1,500/microlitres Platelets greater than or equal to 100 x 109/L or greater than or equal to 100,000/microlitres

*Biochemistry:

Total bilirubin* within normal institutional limits
Alkaline phosphatase less than or equal to 2.5 x institutional upper limit of normal
AST(SGOT) and ALT(SGPT) less than or equal to 2.5 x institutional upper limit of normal
Creatinine Clearance greater than or equal to 50 ml/min

* excluding Gilbert's syndrome

Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by Cockcroft Formula:

For females, GFR is equivalent to
[1.04 x (140-age) x weight in kg] / serum creatinine in micromol/L

For males, GFR is equivalent to
[1.23 x (140-age) x weight in kg] / serum creatinine in micromol/L

*Patient able and willing to complete the QoL, economics and other questionnaires. The baseline assessment must already have been completed within required timelines prior to randomization. Inability (illiteracy, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible

*Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate

*Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up

*Protocol treatment is to begin within 2 working days of patient randomization
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
*Patients with a history of other malignancies, except:
• adequately treated non-melanoma skin cancer,
• curatively treated in-situ cancer, or
• other malignancies curatively treated with no evidence of disease for > 5 years following the end of treatment and which, in the opinion of the treating physician, do not have a substantial risk of recurrence of the prior malignancy.

*A combination of small cell and non-small cell lung cancer, pulmonary carcinoid tumour or large cell neuroendocrine carcinoma (LCNEC).

*History of autoimmune disease, including but not limited to myasthenia gravis, myositis,
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. NOTE: patients with Grave’s disease and/or psoriasis not requiring systemic therapy within the last two years from randomization and patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement are not excluded.

* History of primary immunodeficiency, history of allogenic organ transplant, use of
immunosuppressive agents within 28 days of randomization* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy. * NOTE: Intranasal/inhaled corticosteroids or systemic steroids that do not to exceed 10 mg/day
of prednisone or equivalent dose of an alternative corticosteroid are permissible.

*Live attenuated vaccination administered within 30 days prior to randomization.

*History of hypersensitivity to MEDI4736 or any excipient.

*Patients who experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if controlled, must have a LVEF > 50% within 12 weeks prior to randomization

*Concurrent treatment with other investigational drugs or anti-cancer therapy

*Patients with active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol. This includes but is not limited to:
• known clinical diagnosis of tuberculosis;
• known active hepatitis B infection (positive HBV surface antigen (HBsAg)). Patients with a
past or resolved hepatitis B infection (defined as presence of hepatitis B core antibody (anti-HBc) and absence of HBSAg) are eligible;
• known active hepatitis C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RA;
• known human immunodeficiency virus infection (positive HIV antibodies);
• known pneumonitis or pulmonary fibrosis with clinically significant impairment of pulmonary function.

*Pregnant or lactating women. Women of childbearing potential must have a urine pregnancy test proven negative within 14 days prior to randomization. Men and women of child-bearing potential must agree to use adequate contraception

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/06/2015
Actual
4/12/2015
Date of last participant enrolment
Anticipated
15/10/2019
Actual
21/02/2020
Date of last data collection
Anticipated
28/03/2025
Actual
Sample size
Target
110
Accrual to date
Final
114
Recruitment outside Australia
Country [1] 6693 0
New Zealand
State/province [1] 6693 0
Country [2] 6694 0
Canada
State/province [2] 6694 0
Country [3] 6695 0
United States of America
State/province [3] 6695 0
Country [4] 6696 0
Italy
State/province [4] 6696 0
Country [5] 6697 0
Spain
State/province [5] 6697 0
Country [6] 6698 0
Hungary
State/province [6] 6698 0
Country [7] 6699 0
Taiwan, Province Of China
State/province [7] 6699 0
Country [8] 6700 0
Korea, Republic Of
State/province [8] 6700 0
Country [9] 6701 0
France
State/province [9] 6701 0
Country [10] 6702 0
Netherlands
State/province [10] 6702 0
Country [11] 21791 0
Taiwan, Province Of China
State/province [11] 21791 0
Country [12] 21792 0
China
State/province [12] 21792 0
Country [13] 21793 0
Singapore
State/province [13] 21793 0
Country [14] 21794 0
Poland
State/province [14] 21794 0
Country [15] 21795 0
Ukraine
State/province [15] 21795 0
Country [16] 21796 0
Brazil
State/province [16] 21796 0
Country [17] 21797 0
Bulgaria
State/province [17] 21797 0
Country [18] 21798 0
Romania
State/province [18] 21798 0
Country [19] 21799 0
Hungary
State/province [19] 21799 0
Country [20] 21800 0
Japan
State/province [20] 21800 0

Funding & Sponsors
Funding source category [1] 290830 0
Other Collaborative groups
Name [1] 290830 0
Canadian Cancer Trials Group
Country [1] 290830 0
Canada
Primary sponsor type
University
Name
NHMRC Clinical Trials Centre
Address
The University of Sydney
119-143 Missenden Road, Camperdown, NSW 2050
Country
Australia
Secondary sponsor category [1] 289522 0
Other Collaborative groups
Name [1] 289522 0
Canadian Cancer Trials Group
Address [1] 289522 0
Cancer Clinical Trials Division
Cancer Research Institute
Queen's University
10 Stuart St
Kingston ON Canada K7L 3N6
Country [1] 289522 0
Canada
Other collaborator category [1] 278406 0
Other Collaborative groups
Name [1] 278406 0
Thoracic Oncology Group Association
Address [1] 278406 0
PO Box 1103 Thornbury VIC 3071
Country [1] 278406 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292453 0
Royal Prince Alfred Human Research Ethics Committee
Ethics committee address [1] 292453 0
Ethics committee country [1] 292453 0
Australia
Date submitted for ethics approval [1] 292453 0
13/10/2014
Approval date [1] 292453 0
16/12/2014
Ethics approval number [1] 292453 0
HREC/14/RPAH/442

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 55362 0
A/Prof Sue-Anne McLachlan
Address 55362 0
St Vincent's Hospital, Melbourne
41 Victoria Parade, Fitzroy VIC 3065
Country 55362 0
Australia
Phone 55362 0
+61 2 9562 5000
Fax 55362 0
Email 55362 0
br.31.study@sydney.edu.au
Contact person for public queries
Name 55363 0
BR.31 Trial Coordinator
Address 55363 0
NHMRC Clinical Trials Centre, University of Sydney
119-143 Missenden Road, Camperdown NSW 2050
Country 55363 0
Australia
Phone 55363 0
+61 2 9562 5000
Fax 55363 0
Email 55363 0
br.31.study@sydney.edu.au
Contact person for scientific queries
Name 55364 0
BR.31 Clinical Lead
Address 55364 0
NHMRC Clinical Trials Centre, University of Sydney
119-143 Missenden Road, Camperdown NSW 2050
Country 55364 0
Australia
Phone 55364 0
+61 2 9562 5000
Fax 55364 0
Email 55364 0
br.31.study@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Only grouped data which does not identify individual participants will be published


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
No additional documents have been identified.