2. BR.31
A Phase III Prospective Double Blind Placebo Controlled Randomized Study of MEDI4736 in Completely Resected Non-Small Cell Lung Cancer

3. Planned sample size: 1100 patients
Current schema
Completely resected Stage IB ≥4 cm, II, IIIA NSCLC 
REGISTER
Central lab determination of PD-L1 status
(PD-L1 ≥25% tumours only after 600 patients enrolled)
RANDOMIZE*
ARM A
MEDI mg/kg
IV Day 1 every cycle
q4 weekly
Until 1 year from date of first treatment or earlier if disease relapse/new primary malignancy or unmanageable toxicity
End of treatment assessments
(4 and 12 weeks from date of last infusion)
Follow up for disease event and survival**
ARM B
Placebo *
Randomization will be 2:1 to the active treatment arm **
q12 weekly until 2 years from randomization, then q6 months in year 3, then annually until disease event.
After disease event follow for survival q6 monthly until 3 years from randomization, then annually.
Planned sample size: 1100 patients
Stratification:
Stage [IB (≥4 cm) vs. II vs. IIIA]
Pre-treatment PD-L1 expression [A (≥50%) vs. B (25-49%) vs. C (1-24%) vs. D (<1%)]
Adjuvant platinum-based chemotherapy [≥300 mg/m2 cisplatin or equivalent vs. <300 mg/m2 vs. no chemotherapy]
Accruing centre
Nodal sampling/dissection conducted in accordance with European Society of Thoracic Surgeons (ESTS) guidelines [yes vs. no]
Endpoints:
Primary endpoint: Disease free survival (DFS) for patients with NSCLC that is PD-L1 positive
Secondary endpoints: DFS in all randomized patients, Overall survival (OS) for patients with NSCLC that is PD-L1 positive, OS for all randomized patients, Lung cancer specific survival for patients with NSCLC that is PD-L1 positive and all randomized patients, Adverse effects and tolerability of MEDI4736, Quality of life, Survival benefits participants judge necessary to make adjuvant immunotherapy worthwhile, Economic evaluation (cost effectiveness and cost utility), Evaluation of predictive/prognostic significance of PD-L1 expression, Evaluation of changes in plasma/serum cytokines and other blood and tissue based biomarkers after treatment with MEDI4736 and at disease event, Exploratory pharmacogenomic assays (baseline only)

4. Significant changes implemented with Amendment #3
Item
Prior to Amendment #3 implementation
With Amendment #3 implementation
Mediastinal nodal sampling according to ESTS guidelines
Required
Strongly recommended
Added as a stratification factor
MEDI4736/placebo administration
10 mg/kg q2 weekly for 6 months (13 infusions), then:
20 mg/kg q4 weekly for 6 months (7 infusions)
20 mg/kg q4 weekly for 12 months (13 infusions)
Unblinding requests
Patients will not be unblinded for information only or to permit participation in another clinical trial
On a case-by-case basis and at the request of the treating physician, patients may be unblinded post-progression to determine whether a patient is an appropriate candidate for a standard of care therapy

5. Active sites – Clinipace
Country
(Cooperative Group)
Number of sites activated
Number of sites pending activation
China (CTONG) NA
25 (Start April 2017)
Hungary (CEEOG) 1
Italy (NCI Naples) 24
Japan (WJOG) 17 3
Poland (CEEOG) 9
Singapore
South Korea (KCSG) 10
Taiwan
USA
Current as of 30 May 2016

6. Active sites – Cooperative groups
Country
(Cooperative Group )
Number of sites activated
Number of sites pending activation
Australia + New Zealand
(ALTG) 23 4
Canada (CCTG ) 29
France (IFCT) 48 12
The Netherlands
(NVALT) 9
Spain (GECP) 17
OVERALL TOTAL
189 (81%) 44
Current as of 30 May 2016

7. BR.31 worldwide accrual to 2016May31
Per
Registratie: 417
Randomisatie: 279
Total registrations = 191 Total randomizations = 117

8. Registrations and Randomizations by Month
Current as of 31 May 2016

9. Site Activity (1)
A screen failure log has been implemented to capture data on all patients screened or approached for consent to participate on the BR.31 trial, but who were either found to be ineligible or were unwilling to participate
Accrual and screening activity (a registration, randomization or screen failure log entry) was examined for all sites on 02May2016
Sites were divided into 3 categories:
Site with activity
Sites that have been open for 3-6 months with no activity
Sites that have been open for more than 6 months with no activity

10. Site Activity (3)
Country
Total Number of Active Sites in Country
Number of Sites With No Activity for 3-6 Months
Number of Sites With No Activity for >6 Months
Australia 21 3
Canada 30 1
France * 46 12 9
Hungary *
Italy 25 2
Japan * 17 4
New Zealand
Republic of Korea 10
Singapore *
Spain * 7
Taiwan
United States
Total
188 29
* No screen failure survey entries for this country
Responses received indicate continued interest in study

11. Review of Patients

12. Reported reasons patients have not been registered
513 entries in web-based screen failure log to 31 May 2016

13. Changes in submitted screen failure reasons over time

14. Improvements in screening success
Screening success = # registered patients x 100%
# registered patients + # reported screen failures
Attrition = # reported as never going to be randomized x 100%
# registered patients

15. Reasons registered patients were not randomized
Number of patients
Patient choice 10
Did not meet eligibility criteria or complete pre-randomization tests 8
Creatinine clearance <50mL/min 2
LVEF <50%
QTc >470 msec 1
No clean head CT/MRI within protocol timelines
ECOG >1
Relapse 5
Intercurrent illness
Death 3
Total 28
Current as of 31 May 2016

16. Trial Management Updates

17. Patient reimbursement (1)
Data from the screen failure log indicated 15% of patients were declining to participate due to expenses associated with travel to the treating site
The Canadian investigator community voiced strong support for patient reimbursement and indicated that it could have a positive impact on accrual
AstraZeneca provided C$1.1M (C$1000 per randomized patient) for patient reimbursement program
Implemented in March 2016

18. Significant changes planned for Amendment #4
Item
Prior to Amendment #4 implementation
With
Amendment #4 implementation
Reason for change
Dose modifications and consent risks
Various
Update
To reflect latest AstraZeneca durvalumab protocols
Sub-study for pharmacokinetic sampling and immunogenicity testing
Add
Response to FDA Letter of Advice
Address issues related to type I error rates
Assessment of amylase and lipase
Not required
Required
Inclusion of CTONG (China) as collaborative group
Accrual expansion
Lung function tests
Arterial blood gas required
Accept pulse oximetry
Acceptability of results from less invasive test
Patients with history of chronic TB
Ineligible
Only active TB excluded

19. Status NVALT

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