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Trial registered on ANZCTR


Registration number
ACTRN12624001373561
Ethics application status
Approved
Date submitted
15/10/2024
Date registered
18/11/2024
Date last updated
18/11/2024
Date data sharing statement initially provided
18/11/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study to Evaluate the Benefit of Adding Durvalumab After Chemotherapy, Durvalumab and Surgery in Patients With Early-stage, Operable, Non-small Cell Lung Cancer.
Scientific title
An International, Multicentre, Open-label Randomised Phase III Trial to Evaluate the Benefit of Adding Adjuvant Durvalumab After Neoadjuvant Chemotherapy Plus Durvalumab in Patients With Stage IIB-IIIB (N2) Resectable NSCLC
Secondary ID [1] 312714 0
NCT06284317
Secondary ID [2] 312715 0
ETOP 25-23
Secondary ID [3] 312716 0
TOGA 23/010
Secondary ID [4] 312717 0
CTC 0401
Universal Trial Number (UTN)
Trial acronym
ADOPT-lung
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non Small Cell Lung Cancer 334739 0
Condition category
Condition code
Cancer 331300 331300 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Protocol treatment consists of 3-4 cycles of neoadjuvant (pre-surgical) durvalumab in combination with platinum-based doublet chemotherapy, followed by surgery. Following surgical resection patients that meet protocol eligibility criteria will be randomised to receive either adjuvant durvalumab for 12 cycles (experimental arm) or observation (control arm).

Neo-adjuvant treatment 3-4 cycles of neoadjuvant durvalumab infusion in combination with platinum-based doublet chemotherapy:

Neoadjuvant durvalumab: 3-4 cycles of durvalumab given via intravenous infusion at a fixed dose of 1500 mg i.v. every 3 weeks (±1 week).

Chemotherapy: 3-4 cycles of platinum-based doublet chemotherapy given
every 3 weeks (±1 week) at the investigator’s discretion

Neoadjuvant treatment is administered intravenously in the clinic/hospital. Adherence to the intervention will be monitored by site staff and recorded in the study database.

Adjuvant treatment (experimental)

Experimental: Durvalumab is given at a fixed dose of 1500 mg intravenous infusion every 4 weeks (±1 week) until relapse or unacceptable toxicity, for a maximum of 12 cycles after surgery.

Adjuvant treatment is administered intravenously in the clinic/hospital. Adherence to the intervention will be monitored by site staff and recorded in the study database.


Intervention code [1] 329239 0
Treatment: Drugs
Comparator / control treatment
No Intervention: Observation - Observation only
Control group
Active

Outcomes
Primary outcome [1] 339055 0
Disease free survival (DFS) in patients without complete pathological response (pCR).
Timepoint [1] 339055 0
DFS in patients who do not achieve complete pathological response (pCR) will be measured from randomisation. Participants will be assessed via CT-scans before randomisation (if pre-surgery CT-scan is older than 6 weeks), and thereafter every 12 weeks (±2 week) in year 1, every 6 months (±1 month) in year 2 and year 3, until relapse. Participants will be followed for up to 5 years from enrolment.
Secondary outcome [1] 438409 0
DFS in the ITT cohort (with and without pCR), measured from randomisation
Timepoint [1] 438409 0
DFS in the ITT cohort (with and without pCR) will be measured from randomisation. Participants will be assessed via CT-scans before randomisation (if pre-surgery CT-scan is older than 6 weeks), and thereafter every 12 weeks (±2 week) in year 1, every 6 months (±1 month) in year 2 and year 3, until relapse. Participants will be followed for up to 5 years from enrolment.
Secondary outcome [2] 438410 0
DFS in patients with pCR will be assessed as a secondary measure of clinical efficacy in the adjuvant treatment phase.
Timepoint [2] 438410 0
DFS in patients with pCR will be measured from randomisation. Participants will be assessed via CT-scans before randomisation (if pre-surgery CT-scan is older than 6 weeks), and thereafter every 12 weeks (±2 week) in year 1, every 6 months (±1 month) in year 2 and year 3, until relapse. Participants will be followed for up to 5 years from enrolment.
Secondary outcome [3] 438411 0
Overall survival (OS) in patients with/without pCR (ITT cohort) will be assessed as a secondary measure of clinical efficacy in the adjuvant treatment phase.
Timepoint [3] 438411 0
OS will be assessed in the adjuvant treatment phase (after randomisation). Participants will be followed for up to 5 years from enrolment.
Secondary outcome [4] 438412 0
DFS in patients with/without ctDNA clearance will be assessed as a secondary measure of clinical efficacy in the adjuvant treatment phase.
Timepoint [4] 438412 0
DFS in patients with/without ctDNA clearance will be assessed from randomisation. Participants will be assessed via CT-scans before randomisation (if pre-surgery CT-scan is older than 6 weeks), and thereafter every 12 weeks (±2 week) in year 1, every 6 months (±1 month) in year 2 and year 3, until relapse. Participants will be followed for up to 5 years from enrolment.
Secondary outcome [5] 438413 0
Time to recurrence (TTR) in patients with/without pCR (ITT cohort) will be assessed as a secondary measure of clinical efficacy in the adjuvant treatment phase.
Timepoint [5] 438413 0
Time to recurrence (TTR) in patients with/without pCR (ITT cohort) will be measured from randomisation. Participants will be assessed via CT-scans before randomisation (if pre-surgery CT-scan is older than 6 weeks), and thereafter every 12 weeks (±2 week) in year 1, every 6 months (±1 month) in year 2 and year 3, until relapse. Participants will be followed for up to 5 years from enrolment.
Secondary outcome [6] 438414 0
Time to treatment discontinuation (TTD) in patients with/without pCR (ITT cohort) will be assessed as a secondary measure of clinical efficacy in the adjuvant treatment phase.
Timepoint [6] 438414 0
TTD will be measured from randomisation. Participants will be followed for up to 5 years from enrolment. Relapse will be assessed via CT-scans before randomisation (if pre-surgery CT-scan is older than 6 weeks), and thereafter every 12 weeks (±2 week) in year 1, every 6 months (±1 month) in year 2 and year 3, Adverse events, laboratory parameters, and vital signs will be assessed at every clinical visit during adjuvant treatment phase after randomisation for toxicity.
Secondary outcome [7] 440712 0
Toxicity according to CTCAE v5.0 will be assessed as a secondary measure of clinical efficacy in the adjuvant treatment phase.
Timepoint [7] 440712 0
Toxicity will be measured from randomisation. Adverse events, laboratory parameters, and vital signs will be assessed at every clinical visit during adjuvant treatment phase after randomisation and at the end of treatment visit for toxicity. For participants who are randomised to the experimental arm, clinical visits and treatment with durvalumab will occur every 4 weeks (±1 week) until relapse or unacceptable toxicity, for a maximum of 12 cycles after surgery. Patients who are randomised to the observation arm will proceed to the end of treatment visit.
Participants will be followed for up to 5 years from enrolment.

Eligibility
Key inclusion criteria
Inclusion Criteria for enrolment:

1. Histologically confirmed NSCLC.

2. Stage IIB-IIIB (T1-4 N0-2) according to 8th edition of the TNM staging system of lung cancer.
Stage III assessment should include samples of lymph nodes at levels 4, bilaterally, and level 7 to rule out stage IIIB N3 disease.
T4 tumours will only be eligible if they are defined as T4 based only on their size (>7cm); any other reason will be considered ineligible.

3. Known PD-L1 status, as tested locally using a validated assay. To ensure comparability of results, it is strongly encouraged that PD-L1 testing is done with the Ventana PD-L1 (SP263) assay.

4. Absence of EGFR mutation or ALK translocation, as tested locally.

5. Primary tumour resectable and functionally operable as assessed per local multidisciplinary tumour board (cardiac evaluation, pulmonary function and diffusion capacity, comorbidity).

6. Adequate haematological function:

Haemoglobin greater than/equal to 90 g/L
Absolute neutrophil count (ANC) greater than/equal to 1.5 x10^9/L
Platelet count greater than/equal to 100 x10^9/L.

7. Adequate renal function: Measured creatinine clearance (CL) >40 mL/min or calculated
CL >40 mL/min calculated by the Cockcroft-Gault formula (greater than/equal to 45mL/min for pemetrexed-based chemotherapy, greater than/equal to 60mL/min for cis-platinum-based chemotherapy)

8. Adequate liver function:

ALT and AST less than/equal to 2.5x institutional ULN
Total serum bilirubin less than/equal to 1.5x institutional ULN (patients with Gilbert's syndrome may be allowed to be enrolled after consultation with the study team.

9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

10. Patient has to be fit to receive at least one of the platinum-based chemotherapy regimens as indicated in the protocol, according to local standards.

11. Age greater than/equal to 18 at the time of enrolment.

12. Body weight >30 kg.

13. Life expectancy of at least 12 weeks.

14. Women of childbearing potential, including women who had their last menstruation in the last 2 years, must have a negative urinary or serum pregnancy test at screening before enrolment. Pregnancy test must be repeated within 3 days before the first dose of protocol treatment.

15. Written IC for study participation must be signed and dated by the patient and the investigator prior to any study-related intervention.

Eligibility Criteria for randomisation:

1. Surgical resection must have been completed. Note: Participants who have had only had segmentectomy or wedge resections are not eligible for randomisation.

2. Patients must have complete resection: R0 or R1 resection.

3. Patients must be fit to receive adjuvant treatment with durvalumab.

4. Patients must have no evidence of metastatic disease as assessed by CT scan.

5. Documentation of pathological response as per local review must be available.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria for enrolment:

1. T4 with invasion of heart, great vessels, carina, trachea, oesophagus, or spine.

2. Any previous or concurrent treatments for NSCLC.

3. Any previous immunotherapy.

4. Major surgical procedure (as per investigators assessment) within 28 days before enrolment.

5. History of allogenic organ transplantation.

6. Active or prior documented autoimmune disease or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

a) Patients with vitiligo or alopecia.
b) Patients with type I diabetes.
c) Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement.
d) Any chronic skin condition that does not require systemic therapy. Patients without active disease in the last 5 years may be included but only after consultation with the study team.
e) Patients with celiac disease controlled by diet alone.

7. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease (ILD), or serious chronic gastrointestinal conditions associated with diarrhoea.

8. Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.

9. History of another primary malignancy except for:

a) Malignancy treated with curative-intent and with no known active disease 5 years before the first dose of durvalumab and of low potential risk for recurrence.
b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
c) Adequately treated carcinoma in situ without evidence of disease.

10. History of leptomeningeal carcinomatosis.

11. History of active primary immunodeficiency.

12. Active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HbsAg) or HBV core antibody (anti-HBc).

Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HbsAg) are eligible.

Participants positive for HCV antibody are only eligible if polymerase chain reaction is negative for HCV RNA.

13. Known HIV infection that is not well-controlled (as per local assessment).

All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load for 3 months, CD4+ count of 500 cell per mm3, no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 3 months on the same anti-HIV medication.

14. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

a) Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
b) Systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or its equivalent.
c) Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).

15. Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab.

Note: Patients in the ADOPT-lung trial, should not receive live vaccine whilst receiving durvalumab and for up to 30 days after the last dose.

16. Concurrent enrolment in another interventional clinical trial.

17. Known allergy or suspected hypersensitivity to durvalumab or its excipients.

18. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.

19. Female patients who are pregnant or in the period of lactation.

20. Female patients of childbearing potential and sexually active men who are not willing to use a highly effective contraceptive method during the trial until at least 90 days after the last dose of protocol treatment.

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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/03/2030
Actual
Sample size
Target
290
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 27232 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 27233 0
Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [3] 27234 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 27235 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [5] 27236 0
The Alfred - Melbourne
Recruitment hospital [6] 27237 0
Eastern Health - Box Hill
Recruitment hospital [7] 27238 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [8] 27239 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [9] 27240 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [10] 27241 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 43314 0
2065 - St Leonards
Recruitment postcode(s) [2] 43315 0
2050 - Camperdown
Recruitment postcode(s) [3] 43316 0
2747 - Kingswood
Recruitment postcode(s) [4] 43317 0
3000 - Melbourne
Recruitment postcode(s) [5] 43318 0
3128 - Box Hill
Recruitment postcode(s) [6] 43319 0
4102 - Woolloongabba
Recruitment postcode(s) [7] 43320 0
5042 - Bedford Park
Recruitment postcode(s) [8] 43321 0
6009 - Nedlands
Recruitment postcode(s) [9] 43322 0
7000 - Hobart
Recruitment outside Australia
Country [1] 26497 0
Switzerland
State/province [1] 26497 0

Funding & Sponsors
Funding source category [1] 317146 0
Commercial sector/Industry
Name [1] 317146 0
AstraZeneca
Country [1] 317146 0
Switzerland
Primary sponsor type
Other
Name
ETOP IBCSG Partners Foundation
Address
Country
Switzerland
Secondary sponsor category [1] 319413 0
University
Name [1] 319413 0
The University of Sydney
Address [1] 319413 0
Country [1] 319413 0
Australia
Other collaborator category [1] 283134 0
Other Collaborative groups
Name [1] 283134 0
Thoracic Oncology Group Australia (TOGA)
Address [1] 283134 0
Country [1] 283134 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315897 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 315897 0
Ethics committee country [1] 315897 0
Australia
Date submitted for ethics approval [1] 315897 0
27/05/2024
Approval date [1] 315897 0
30/08/2024
Ethics approval number [1] 315897 0
X24-0161 & 2024/ETH00951

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

Contacts
Principal investigator
Name 136138 0
Prof Ben Solomon
Address 136138 0
Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne VIC 3052
Country 136138 0
Australia
Phone 136138 0
+61 3 8559 5000
Fax 136138 0
Email 136138 0
ben.solomon@petermac.org
Contact person for public queries
Name 136139 0
Trial Coordinator
Address 136139 0
NHMRC Clinical Trials Centre Locked Bag 77 Camperdown NSW 1450
Country 136139 0
Australia
Phone 136139 0
+61 2 9562 5000
Fax 136139 0
Email 136139 0
adopt.study@sydney.edu.au
Contact person for scientific queries
Name 136140 0
Trial Coordinator
Address 136140 0
NHMRC Clinical Trials Centre Locked Bag 77 Camperdown NSW 1450
Country 136140 0
Australia
Phone 136140 0
+61 2 9562 5000
Fax 136140 0
Email 136140 0
adopt.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
Individual participant data will not be made publicly available. 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.