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Trial registered on ANZCTR


Trial ID
ACTRN12617001468314
Ethics application status
Approved
Date submitted
5/10/2017
Date registered
17/10/2017
Date last updated
17/10/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Durvalumab and Tremelimumab +/- Platinum-Based Chemotherapy in Patients With Metastatic Squamous or Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Scientific title
A Randomized Trial of Durvalumab and Tremelimumab +/- Platinum-Based Chemotherapy in Patients With High-Risk, Metastatic (Stage IV) Squamous or Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Secondary ID [1] 292723 0
NCT03057106
Universal Trial Number (UTN)
Trial acronym
BR.34
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lung Cancer Metastatic 304489 0
Condition category
Condition code
Cancer 303825 303825 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each patient will receive 1500 mg of durvalumab and 75 mg of tremelimumab given intravenously every 28 days for 4 cycles. This will be immediately followed by maintenance which includes 1500 mg durvalumab given intravenously every 28 days until progressive disease (PD).

Intervention code [1] 298968 0
Treatment: Drugs
Comparator / control treatment
Each patient will receive 1500 mg of durvalumab and 75 mg of tremelimumab given intravenously every 21 days for 4 cycles. This will be given with chemotherapy as below.

- Non-Squamous Cell: Chemotherapy includes pemetrexed, (500 mg/m2) and cisplatin (75 mg/m2) or carboplatin (carboplatin AUC 5) given intravenously on day 1 for 4 cycles (each cycle is 21 days). This will be immediately followed by maintenance which includes 1500 mg of durvalumab and 500 mg/m2 pemetrexed given intravenously on day 1 every 28 days until PD.
- Squamous Cell: Chemotherapy includes gemcitabine (1250 mg/m2 (if with cisplatin) or 1000 mg/m2 (if with carboplatin) on D1 and D8) and cisplatin (75 mg/m2) or carboplatin (AUC 5) given on day 1 for 4 cycles (each cycle is 21 days). This will be immediately followed by maintenance which includes 1500 mg of durvalumab given intravenously on day 1 every 28 days until PD.
Clinical discretion of the treating physician to give cisplatin or carboplatin.
(Neither of the two study arms are considered to be a control)
Control group
Active

Outcomes
Primary outcome [1] 303185 0
Overall Survival - time from randomization to the date of death
Timepoint [1] 303185 0
33 months post enrolment of first participant
Secondary outcome [1] 338170 0
Progression-free Survival using RECIST 1.1 - time from randomization to the date of the first documented disease progression
Timepoint [1] 338170 0
1 year
Secondary outcome [2] 338171 0
Objective Response Rate using RECIST 1.1 and iRECIST - proportion of patients with a documented complete response, partial response (CR + PR) based on iRECIST criteria. The primary estimate of ORR will be based on all patients randomized, and compared using Cochran- Mantel-Haeszel test stratified by stratification factors at randomization between the study new treatment and the standard control arms.
Timepoint [2] 338171 0
33 months post enrolment of first participant
Secondary outcome [3] 338172 0
Number and Severity (assessed as a composite) of Adverse Events - using the NCI Common Terminology Criteria for Adverse Events Version 4.0. A Fisher's exact test will be used to compare adverse events between the study new treatment and the standard control arms if required.
Timepoint [3] 338172 0
33 months post enrolment of first participant
Secondary outcome [4] 338173 0
Cost Effectiveness of Durvalumab and Tremelimumab concurrently with combination chemotherapy - The mean overall cost per patient for each of the two study treatment arms will be calculated to determine the addition cost per life-year gained. This will be assessed using EQ-5D.
Timepoint [4] 338173 0
Prior to randomization, Day 1 of each cycle whilst on treatment, 4 weeks after completion of protocol therapy and every 12 weeks until disease progression.
Secondary outcome [5] 338174 0
To correlate the expression of tissue (including PD-L1) and blood markers (exploratory) with outcomes and response.
Timepoint [5] 338174 0
Baseline (blood and tissue), cycle 4 (blood only) and at disease progression (blood only)
Secondary outcome [6] 338620 0
Quality of life will be assessed using EORTC QLQ-C30 and the lung cancer module (QLQ-LC13) questionnaires plus additional study specific questions (assessed as a composite).
Timepoint [6] 338620 0
Baseline, Day 1 of each cycle, 4 weeks after completion of protocol therapy. every 12 weeks until disease progression,

Eligibility
Key inclusion criteria
- Patients must have histologically and/or cytologically confirmed diagnosis of squamous or non-squamous, non-small cell carcinoma of the lung. Patients with poorly differentiated tumours will only be eligible if NSCLC is confirmed by immunohistochemistry markers (TTF1/P63 or P40/CK5). Patients with known sensitizing EGFR mutations or known ALK-fusion are not eligible.
- Patients must be high risk, defined as the presence of one or more of the following unfavourable prognostic factors:
- Stage IVB disease
- Stage IVA disease with at least one of the following: (Elevated LDH, weight loss greater than or equal to 5% over 3 months before randomization, poorly differentiated histology.)
- Patients must have an adequate histopathology specimen and must consent to release this specimen for protocol required testing. This is a mandatory component of the study.
- Patient must consent to provision of samples of blood in order that the specific correlative marker assays proscribed may be conducted.
- All patients must have measurable disease as defined by RECIST 1.1 All radiology
studies must be performed within 28 days prior to randomization (within 35 days if
negative).
The criteria for defining measurable disease are as follows:
- CT scan (with slice thickness of 5 mm) greater than or equal to 10 mm (longest diameter)
- Physical exam (using calipers) greater than or equal to 10 mm
- Lymph nodes by CT scan greater than or equal to 15 mm (measured in short axis)
Measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease, unless disease progression has been documented.
- Patients must be 18 years of age or older.
- ECOG performance status of 0 or 1.
- Absolute neutrophils greater than or equal to 1.5 x 10^9/L
- Platelets greater than or equal to 100 x 10^9/L
- Hemoglobin greater than or equal to 90 g/L
- Bilirubin greater than or equal to 1.5 x UNL (upper limit of normal)
- AST and ALT greater than or equal to 2.5 x UNL (if liver metastases are present, less than or equal to 5 x UNL) Creatinine less than 1.25 UNL or Creatinine clearance greater than or equal to 45 mL/min
- Cytotoxic Chemotherapy: Patients may not have received prior cytotoxic chemotherapy for advanced/metastatic disease.
- Adjuvant Chemotherapy: Patients may have had prior adjuvant therapy for completely
resected disease, providing it has been completed at least 12 months prior to randomization.
- Patients treated with concurrent chemotherapy/radiation regimens for unresectable locally advanced Stage III disease will be eligible providing it has been completed at least 12 months prior to randomization.
- Other Systemic Therapy: Patients may not have received prior EGFR or alk inhibitors.
- Patients may not have received prior treatment with immune-based therapy, including durvalumab and tremelimumab vaccines or oncolytic viral therapy. Patients must have recovered from any reversible treatment related toxicities prior to randomization.
- Prior external beam radiation is permitted provided a minimum of 14 days (2 weeks) have elapsed between the last dose of radiation and date of randomization.
- Concurrent radiotherapy is not permitted.
- Patients must have recovered from any acute toxic effects from radiation prior to randomization.
- Surgery: Previous surgery is permitted provided that wound healing has occurred and at least 14 days have elapsed (major surgery) prior to randomization.
- Patient must be able (i.e. sufficiently fluent) and willing to complete the quality of life and health economics questionnaires.
- Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements.
- Patients must be accessible for treatment and follow-up. All randomized patients must be followed and treated at participating centres.
- In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient randomization.
- Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception while on study and for 6 months after the last dose of durvalumab and tremelimumab or for 3 months after the last dose of durvalumab alone.
Minimum age
18 Years
Maximum age
No limit
Gender
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 of the cervix, or other solid tumours curatively treated with no evidence of disease for greater than or equal to 3 years.
- 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, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
- Patients with alopecia.
- Patients with Grave's disease, vitiligo or psoriasis not requiring systemic
treatment (within the last 2 years).
- Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on
hormone replacement.
- History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the 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 or grade greater than or equal to 3 infusion reaction.
- Live attenuated vaccination administered within 30 days prior to randomization
- History of hypersensitivity to durvalumab or tremelimumab or any excipient. Patients who have received other treatment or other antibodies must not have had intolerabletoxicity or required steroids to manage toxicity.
- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) greater than or equal to 470 msec in screening ECG measured using standard institutional method or history of familial long QT syndrome.
- Patients who have 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 now controlled, should have a LVEF greater than or equal to 45%. (Note: patients with uncomplicated controlled hypertension do not require LVEF measurement in the absence of other significant cardiac history)
- Concurrent treatment with other investigational drugs or anti-cancer therapy
- Patients with untreated brain or meningeal metastases are not eligible. Patients with treated CNS disease who have radiologic AND clinical evidence of stable brain metastases, with no evidence of cavitation or hemorrhage in the brain lesion, are eligible providing that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least 1 week prior to randomization).
- Pregnant or Lactating Women: Women of childbearing potential must have a pregnancy test (urine or serum) proven negative within 14 days prior to randomization. If urine test is positive, pregnancy testing may then include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of hCG, as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. Men and women of child-bearing potential must agree to use adequate contraception.
- Patients with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol (including corticosteroid administration), or would put the patient at risk. This includes but is not limited to:
- Contraindications to the use of pemetrexed, gemcitabine, cisplatin and/or
carboplatin (consult product monograph);
- History of significant neurologic or psychiatric disorder which would impair the
ability to obtain consent or limit compliance with study requirements;
- Active infection requiring systemic therapy; (including any patient known to have
active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) or
tuberculosis);
- Active peptic ulcer disease or gastritis;
- Known pneumonitis or pulmonary fibrosis with clinically significant impairment of
pulmonary function.

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)
Randomisation will be conducted using a central computer based system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be done through a web-based, password operated electronic data capture system.

Subjects will be stratified by:
• Squamous vs. non-squamous NSCLC
• IVA vs. IVB (disease stage)
• smoking status (< 100 cigarettes vs previous vs current)

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

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,TAS,WA,VIC
Recruitment hospital [1] 8972 0
Gosford Hospital - Gosford
Recruitment hospital [2] 8973 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [3] 8974 0
Campbelltown Hospital - Campbelltown
Recruitment hospital [4] 8975 0
Liverpool Hospital - Liverpool
Recruitment hospital [5] 8976 0
Epworth Richmond - Richmond
Recruitment hospital [6] 8977 0
Concord Repatriation Hospital - Concord
Recruitment hospital [7] 8979 0
Prince of Wales Hospital - Randwick
Recruitment hospital [8] 8980 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [9] 8981 0
The Canberra Hospital - Garran
Recruitment hospital [10] 8982 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [11] 8983 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [12] 8984 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [13] 8985 0
St George Hospital - Kogarah
Recruitment hospital [14] 8986 0
The Prince Charles Hospital - Chermside
Recruitment hospital [15] 8987 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [16] 8988 0
Border Medical Oncology - Albury
Recruitment postcode(s) [1] 17469 0
2250 - Gosford
Recruitment postcode(s) [2] 17470 0
3220 - Geelong
Recruitment postcode(s) [3] 17471 0
2560 - Campbelltown
Recruitment postcode(s) [4] 17472 0
2170 - Liverpool
Recruitment postcode(s) [5] 17473 0
3121 - Richmond
Recruitment postcode(s) [6] 17474 0
2139 - Concord
Recruitment postcode(s) [7] 17476 0
2031 - Randwick
Recruitment postcode(s) [8] 17477 0
3084 - Heidelberg
Recruitment postcode(s) [9] 17478 0
2605 - Garran
Recruitment postcode(s) [10] 17479 0
6009 - Nedlands
Recruitment postcode(s) [11] 17480 0
4102 - Woolloongabba
Recruitment postcode(s) [12] 17481 0
3144 - Malvern
Recruitment postcode(s) [13] 17482 0
2217 - Kogarah
Recruitment postcode(s) [14] 17483 0
4032 - Chermside
Recruitment postcode(s) [15] 17484 0
3065 - Fitzroy
Recruitment postcode(s) [16] 17485 0
3690 - Wodonga

Funding & Sponsors
Funding source category [1] 297364 0
Other Collaborative groups
Name [1] 297364 0
Canadian Cancer Trials Group
Address [1] 297364 0
Cancer Clinical Trials Division
Cancer Research Institute
Queen's University
10 Stuart St
Kingston ON Canada K7L 3N6
Country [1] 297364 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] 296341 0
Other Collaborative groups
Name [1] 296341 0
Canadian Cancer Trials Group
Address [1] 296341 0
Cancer Clinical Trials Division
Cancer Research Institute
Queen's University
10 Stuart St
Kingston ON Canada K7L 3N6
Country [1] 296341 0
Canada
Other collaborator category [1] 279682 0
Other Collaborative groups
Name [1] 279682 0
Australasian Lung Cancer Trials Group
Address [1] 279682 0
Australasian Lung Cancer Trials Group
Lung Foundation Australia
Level 2, 11 Finchley Street
Milton, QLD 4064
Country [1] 279682 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298466 0
Royal Prince Alfred Human Research Ethics Committee
Ethics committee address [1] 298466 0
Research Development Office
Royal Prince Alfred Hospital
Camperdown NSW 2050
Ethics committee country [1] 298466 0
Australia
Date submitted for ethics approval [1] 298466 0
13/06/2017
Approval date [1] 298466 0
20/09/2017
Ethics approval number [1] 298466 0
HREC/17/RPAH/309

Summary
Brief summary
The purpose of this study is to compare the effects of an immunotherapy combination of both durvalumab plus tremelimumab with or without chemotherapy on you and your lung cancer.

Who is it for?
You may be eligible to join this study if you are aged 18 years or over and have histologically and/or cytologically confirmed diagnosis of metastatic squamous or non-squamous, non-small cell carcinoma of the lung.

Study details
Participants will be allocated by chance to one of two treatment groups. Participant in both groups will receive durvalumab and tremelimumab every 28 days for 4 cycles followed by durvalumab every 28 days until disease progression. Participants in one group only will also receive additional chemotherapy during the first stage which will be dependent on Squamous or Non-Squamous Non-Small Cell Lung Cancer (NSCLC). Squamous Cell treatment will include gemcitabine and cisplatin or carboplatin while Non-Squamous Cell treatment will include pemetrexed and cisplatin or carboplatin.

Immunotherapy with immune checkpoint inhibitors has demonstrated superior efficacy compared to chemotherapy and has a favourable side effect profile in the treatment of a subset of patients with NSCLC. Combining immunotherapies in the second-line setting has resulted in higher anti-cancer activity, but increases risk of immune-related side effects. Combining immunotherapy with chemotherapy is a promising new approach, with early results indicating much higher anti-cancer activity then would be expected with either treatment alone with no additional toxicity. The combination of two immunotherapy agents, with or without chemotherapy may be the best way to balance the chances of prolonged anticancer responses seen with immunotherapy against the risk of side-effects associated with treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77170 0
A/Prof Brett Hughes
Address 77170 0
The Prince Charles Hospital
Rode Rd
Chermside, QLD, 4032
Country 77170 0
Australia
Phone 77170 0
+61 2 9562 5000
Fax 77170 0
Email 77170 0
BR.34@ctc.usyd.edu.au
Contact person for public queries
Name 77171 0
Ms Hannora Jurkovic
Address 77171 0
NHMRC Clinical Trials Centre, University of Sydney
119-143 Missenden Road, Camperdown NSW 2050
Country 77171 0
Australia
Phone 77171 0
+61 2 9562 5000
Fax 77171 0
Email 77171 0
BR.34@ctc.usyd.edu.au
Contact person for scientific queries
Name 77172 0
Ms Hannora Jurkovic
Address 77172 0
NHMRC Clinical Trials Centre, University of Sydney
119-143 Missenden Road, Camperdown NSW 2050
Country 77172 0
Australia
Phone 77172 0
+61 2 9562 5000
Fax 77172 0
Email 77172 0
BR.34@ctc.usyd.edu.au