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Trial registered on ANZCTR


Registration number
ACTRN12618001742268
Ethics application status
Approved
Date submitted
11/10/2018
Date registered
23/10/2018
Date last updated
19/09/2023
Date data sharing statement initially provided
19/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Non small cell lung cancer trial of durvalumab and tremelimumab in advanced epidermal growth factor receptor (EGFR) mutant disease.
Scientific title
A Phase 2 trial of durvalumab (MEDI4736) and tremelimumab with chemotherapy in metastatic EGFR mutant non-squamous non-small cell lung cancer (NSCLC) following progression on EGFR Tyrosine Kinase Inhibitors (TKIs) (ILLUMINATE).
Secondary ID [1] 296092 0
CTC 0209
Secondary ID [2] 296369 0
ALTG 16/009
Universal Trial Number (UTN)
Trial acronym
ILLUMINATE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
EGFR mutant advanced non small cell lung cancer. 309728 0
Condition category
Condition code
Cancer 308537 308537 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
During induction, patients will receive 4 cycles of durvalumab 1500mg and tremelimumab 75mg with cisplatin 75mg/m2 (or carboplatin AUC 5 if cisplatin is contra-indicated), and pemetrexed 500mg/m2 via intravenous infusion every 3 weeks.

Followed immediately by a maintenance phase of durvalumab 1500mg and pemetrexed 500mg/m2 once every 4 weeks via intravenous infusion until disease progression or intolerance.
Intervention code [1] 312470 0
Treatment: Drugs
Comparator / control treatment
The 2 cohorts, cohort 1 participants with no evidence of T790M and cohort 2 participants with evidence of T790M will be compared.
Control group
Active

Outcomes
Primary outcome [1] 307514 0
Objective tumour response rate (OTRR) as defined by RECIST 1.1. Objective tumour response (OTR) is defined as a partial response or compete response by RECIST 1.1. OTRR is defined as the proportion (percentage) of participants with a confirmed CR or PR according to RECIST 1.1.
Timepoint [1] 307514 0
36 months post enrolment of first participant.
Secondary outcome [1] 352121 0
Disease control (Disease Control Rate (DCR) = Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) as defined by RECIST 1.1.
Timepoint [1] 352121 0
36 months post enrolment of first participant.
Secondary outcome [2] 352122 0
Objective tumour response rate (OTRR) as defined by iRECIST. Objective tumour response (OTR) is defined as a partial response or compete response by iRECIST. OTRR is defined as the proportion (percentage) of participants with a confirmed CR or PR according to iRECIST.
Timepoint [2] 352122 0
33 months post enrolment of first participant.
Secondary outcome [3] 352123 0
Progression-free survival (PFS) as defined by RECIST 1.1 and iRECIST. PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death, whichever occurs first. Disease progression is defined according to RECIST 1.1 and iRECIST.
Timepoint [3] 352123 0
36 months post enrolment of first participant.
Secondary outcome [4] 352130 0
Progression-free survival at 12 months (PFS12) as defined by RECIST 1.1 and iRECIST. PFS at 12 months taken to mean 1 calendar year, i.e. 365 days. Study participants who have stable disease, partial response or complete response confirmed at the first scheduled assessment after 12 months according to RECIST v1.1 will be considered to have attained PFS at 12 months.
Timepoint [4] 352130 0
12 months post enrolment of last participant.
Secondary outcome [5] 352131 0
Overall survival (OS) is defined as the interval from the date of registration to date of death from any cause, or the date of last known follow-up alive.
Timepoint [5] 352131 0
36 months from enrolment of first participant.
Secondary outcome [6] 352132 0
Number and Severity (assessed as a composite) of Adverse Events - using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
Timepoint [6] 352132 0
36 months post enrolment of first participant.

Eligibility
Key inclusion criteria
1. Adults, aged 18 years and older (subjects from Taiwan must be 20 years or older) with histologically and/or cytologically confirmed non-squamous non-small cell lung cancer with EGFR mutation of Exon 19 deletion or Exon 21 L858R point mutation.
• Patients with co-mutations are allowed as long as one of the mutation is either Exon 19 deletion or Exon 21 L858R point mutation
2. Disease that has progressed and either:
(i) No evidence of EGFR T790M resistance mutation in both tissue re-biopsy and plasma after EGFR tyrosine kinase inhibitor therapy (TKI)*
OR
(ii) T790M mutation (detected in tissue re-biopsy, plasma or both) and progression on 3rd generation EGFR TKI; patients are allowed to have one prior line of TKI therapy before 3rd generation TKI
*Patients who have progressed after first-line or second-line osimertinib where previous testing has not detected a denovo (first-line) or acquired (second-line) T790M resistance mutation are classified as T790M mutation negative.
3. Measurable disease according to RECIST 1.1.
4. ECOG performance status of 0 or 1.
5. Adequate bone marrow function as defined below (within 14 days prior to registration and with values within the ranges specified below):
• Platelets greater or equal to 100 x 109/L
• Absolute neutrophil count (ANC) greater or equal to 1.0 x 109/L (greater or equal to 1000 per mm3)
• Haemoglobin greater or equal to 90 x g/L
6. Adequate liver function (within 14 days prior to registration and with values within the ranges specified below):
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x institutional upper limit of normal (ULN). (or less than or equal to 5 x ULN if liver metastases are present)
• Bilirubin less than or equal to 1.5 x ULN
7. Adequate renal function (within 14 days prior to registration): Measured creatinine clearance greater than 40 mL/min or Calculated creatinine clearance greater than 40 mL/min by the Cockcroft-Gault formula92 or by 24-hour urine collection for determination of creatinine clearance
8. Provision of a pre-treatment tumour tissue sample from a biopsy taken within 42 days prior to enrolment (core biopsy preferred) to determine NSCLC histology and for translational research.
9. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients.
10. Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
11. Signed written informed consent (main study and optional biobanking).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior immunotherapy with checkpoint inhibitors, including prior anti-PD-1/anti-PD-L1 or anti-CTLA-4 antibodies.
2. Prior chemotherapy for advanced NSCLC.
• For recurrent, incurable disease, prior adjuvant chemotherapy or concurrent chemotherapy and radiotherapy with curative intent is allowed, but must have been completed more than 6 months ago.
3. Prior EGFR TKI therapy
• Prior EGFR TKI (e.g., erlotinib, gefitinib, afatinib or osimertinib), including experimental TKI agents are allowed, but must be stopped 7 days prior to the first dose of study treatment. (If sufficient washout time has not occurred due to schedule or PK properties, an alternative appropriate washout time based on known duration and time to reversibility of drug related adverse events could be agreed upon by emailing the ILLUMINATE Study Team (illuminate@ctc.usyd.edu.au)).
• Patients treated with more than 2 lines of prior EGFR TKI are not permitted on the study.
4. Mixed histology with any small cell or squamous component.
5. Life expectancy of less than 3 months.
6. Current enrolment or participation in another clinical study with an unregistered investigational product during the last 12 months, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study must first be discussed with ILLUMINATE Study Team (illuminate@ctc.usyd.edu.au)) before study enrolment.
7. Any unresolved toxicity NCI CTCAE Grade greater or equal to 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Patients with Grade greater or equal to 2 neuropathy will be evaluated on a case-by-case basis after consultation with the ILLUMINATE Study Team (illuminate@ctc.usyd.edu.au)
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the ILLUMINATE Study Team (illuminate@ctc.usyd.edu.au)
8. Radiotherapy or major surgery (as defined by the local investigator) within 4 weeks of the first dose of study drug. Note the following exceptions, which have a 2-week washout:
• Local surgery on isolated lesions for palliative intent
• Radiotherapy to control CNS disease identified during screening
9. History of pneumonitis or pulmonary fibrosis with clinically significant impairment of pulmonary function.
10. History of active primary immunodeficiency or allogeneic transplant.
11. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis (with the exception of diverticulosis), 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:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• 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 physician
• Patients with celiac disease controlled by diet alone
12. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.
13. History of another primary malignancy except for
14. Spinal cord compression, symptomatic and unstable brain metastases, except for those patients who have completed definitive therapy, are not on steroids equivalent to oral prednisone of 10mg/day or greater, and have a stable neurological status for at least 2 weeks after commencement of the definitive therapy. Patients with asymptomatic brain metastases can be eligible for inclusion if in the opinion of the Investigator immediate definitive treatment is not indicated.
15. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
16. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
17. Live attenuated vaccine within 30 days prior to the first dose of study drug, whilst receiving study drug and up to 30 days after the last dose of study drug.
18. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.
19. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab plus tremelimumab combination therapy.
20. Known allergy or hypersensitivity to any of the study drugs or excipients.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The study consists of two cohorts. For each cohort, 48 evaluable patients per cohort provides 80% power to distinguish an OTRR of 30% or more versus historical OTRR of 15% or less with a one-sided type 1 error of 5%, using Simon's minimax design. A futility analysis (stopping rule) is based on first 23 patients where we need to see 4 or more patients respond before further recruitment to the full sample size.

50 patients per cohort will be recruited, allowing for up to 4% for dropout prior to the first cycle (if rate is higher additional patients will be recruited to provide 48 evaluable patients in that cohort).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/12/2018
Actual
4/04/2019
Date of last participant enrolment
Anticipated
16/05/2022
Actual
29/11/2022
Date of last data collection
Anticipated
28/07/2023
Actual
30/06/2023
Sample size
Target
100
Accrual to date
Final
100
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 11959 0
St George Hospital - Kogarah
Recruitment hospital [2] 11961 0
Liverpool Hospital - Liverpool
Recruitment hospital [3] 11962 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [4] 11963 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [5] 11965 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [6] 11966 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [7] 11967 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [8] 11968 0
The Prince Charles Hospital - Chermside
Recruitment hospital [9] 11969 0
Royal Hobart Hospital - Hobart
Recruitment hospital [10] 12206 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [11] 18698 0
Gosford Hospital - Gosford
Recruitment hospital [12] 18699 0
Bankstown-Lidcombe Hospital - Bankstown
Recruitment postcode(s) [1] 24106 0
2217 - Kogarah
Recruitment postcode(s) [2] 24108 0
2170 - Liverpool
Recruitment postcode(s) [3] 24109 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 24110 0
3168 - Clayton
Recruitment postcode(s) [5] 24112 0
3000 - Melbourne
Recruitment postcode(s) [6] 24113 0
6009 - Nedlands
Recruitment postcode(s) [7] 24114 0
5042 - Bedford Park
Recruitment postcode(s) [8] 24115 0
4032 - Chermside
Recruitment postcode(s) [9] 24116 0
7000 - Hobart
Recruitment postcode(s) [10] 24384 0
3065 - Fitzroy
Recruitment postcode(s) [11] 33136 0
2250 - Gosford
Recruitment postcode(s) [12] 33137 0
2200 - Bankstown
Recruitment outside Australia
Country [1] 20858 0
Taiwan, Province Of China
State/province [1] 20858 0

Funding & Sponsors
Funding source category [1] 300680 0
Commercial sector/Industry
Name [1] 300680 0
Astra Zeneca
Country [1] 300680 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Lifehouse Level 6
119–143 Missenden Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 300208 0
None
Name [1] 300208 0
Address [1] 300208 0
Country [1] 300208 0
Other collaborator category [1] 280360 0
Other Collaborative groups
Name [1] 280360 0
Australasian Lung Cancer Trials Group
Address [1] 280360 0
Level 2, 11 Finchley Street Milton QLD 4064
Country [1] 280360 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301462 0
Sydney Local Health District - Royal Prince Alfred Hospital Zone
Ethics committee address [1] 301462 0
Ethics committee country [1] 301462 0
Australia
Date submitted for ethics approval [1] 301462 0
17/07/2018
Approval date [1] 301462 0
04/09/2018
Ethics approval number [1] 301462 0
X18-0284 & HREC/18/RPAH/402

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

Contacts
Principal investigator
Name 87090 0
Dr Chee Khoon Lee
Address 87090 0
St George Hospital
Gray St Kogarah NSW 2217
Country 87090 0
Australia
Phone 87090 0
+61 2 9562 5000
Fax 87090 0
Email 87090 0
chee.lee@sydney.edu.au
Contact person for public queries
Name 87091 0
Kate Ford
Address 87091 0
NHMRC Clinical Trials Centre
Lifehouse Level 6
119–143 Missenden Road
Camperdown NSW 2050
Country 87091 0
Australia
Phone 87091 0
+61 2 9562 5000
Fax 87091 0
Email 87091 0
illuminate.study@sydney.edu.au
Contact person for scientific queries
Name 87092 0
Kate Ford
Address 87092 0
NHMRC Clinical Trials Centre
Lifehouse Level 6
119–143 Missenden Road
Camperdown NSW 2050
Country 87092 0
Australia
Phone 87092 0
+61 2 9562 5000
Fax 87092 0
Email 87092 0
illuminate.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
SourceTitleYear of PublicationDOI
EmbaseEGFR mutations in lung cancer: Not all equal in the eyes of the immune system?.2019https://dx.doi.org/10.21037/atm.2019.09.132
N.B. These documents automatically identified may not have been verified by the study sponsor.