Trial registered on ANZCTR


Trial ID
ACTRN12616000352404
Ethics application status
Approved
Date submitted
29/02/2016
Date registered
18/03/2016
Date last updated
13/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
NIVORAD - A randomised phase 2 trial of nivolumab and stereotactic ablative body radiotherapy in advanced non-small cell lung cancer, progressing after first or second line chemotherapy.
Scientific title
NIVORAD - A randomised phase 2 trial of nivolumab and stereotactic ablative body radiotherapy in advanced non-small cell lung cancer, progressing after first or second line chemotherapy.
Secondary ID [1] 288518 0
Nil
Universal Trial Number (UTN)
Trial acronym
NIVORAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced non-small cell lung cancer, progressing after first of second line chemotherapy 297595 0
Condition category
Condition code
Cancer 297792 297792 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Nivolumab 240mg every 2 weeks plus Stereotactic Ablative Body Radiotherapy (SABR).
Nivolumab (240mg) will be administered as an intravenous infusion every 2 weeks until disease progression or prohibitive toxicity.
SABR (18-20 Gy) will be administered to a single lesion between days 8 - 14 of cycle 1 of Nivolumab. The specific day of SABR will be at clinical discretion of the treating radiation oncologist. Participants will receive 1 or 2 fractions of SABR, dependent on tumour location, determined by clinical discretion of the treating radiologist. Each SABR treatment will take approximately 1 hour.
Intervention code [1] 293882 0
Treatment: Drugs
Intervention code [2] 293883 0
Treatment: Devices
Comparator / control treatment
Nivolumab 240mg every 2 weeks alone (control). Nivolumab is continued until disease progression or prohibitive toxicity.
Control group
Active

Outcomes
Primary outcome [1] 297317 0
Progression free survival (PFS) at 6 months (RECIST 1.1)
Timepoint [1] 297317 0
6 months from randomisation
Secondary outcome [1] 320708 0
Objective tumour response rate (OTRR, RECIST 1.1)
Timepoint [1] 320708 0
1 year and 2 years after randomisation of all planned participants
Secondary outcome [2] 320709 0
Adverse events (CTCAE v4.03 and RTOG/EORTC RMSS)
Timepoint [2] 320709 0
1 year and 2 years after randomisation of all planned participants
Secondary outcome [3] 320710 0
Progression Free Survival (PFS) at 1 year and 2 years.
Progression Free Survival will be measured at the interval between the date of randomisation until the date that disease progression is first observed, or the date of death from any cause, whichever occurs first. Disease progression will be determined by a comparing imaging (scans) of documented disease prior to treatment to the first positive scan following study treatment.
Timepoint [3] 320710 0
1 year and 2 years after randomisation of all planned participants.
Secondary outcome [4] 320711 0
Overall survival (OS) at 1 year and 2 years
Overall Survival will be measured as the interval from the date of randomisation to the date of death from any cause.

Timepoint [4] 320711 0
1 year and 2 years after randomisation of all planned participants.
Secondary outcome [5] 321236 0
Tertiary studies aim to identify predictive biomarkers that will allow us to select patients most likely to respond to, and derive benefit from this treatment as well as the presence of other biomarkers whose presence may be indicative of better or worse longer term outcomes such as survival. These may include biomarkers which are often studied amongst patients with non-small cell lung cancer such as PD-L1 expression, EGFR and KRAS mutational status but also novel biomarkers relating to effects of radiation on the immune response.
Timepoint [5] 321236 0
Blood samples for translational research, including the identification of biomarkers will be collected on D1, D15 and D29 of study treatment with an additional blood taken within 72 hours of SABR (if D15 bloods do not fall within this 72 hour period). Predictive and prognostic biomarkers will be determined based on patient outcomes such as objective response to treatment based on PD-L1 expression and overall survival.

Eligibility
Key inclusion criteria
1. Adult (18 years or over) with a histologically or cytologically confirmed diagnosis of NSCLC.
2. At least one site of metastasis which is suitable for stereotactic radiotherapy, but for which radiotherapy is not urgently required at the time of enrollment. This must be outside of BOTH the thorax, and the central nervous system, and must not have been previously irradiated. The lesion/s is not required to be measurable or evaluable and must be nominated before randomisation. This lesion will be irradiated in patients randomised to receive radiation.
3. At least one lesion (target or non-target according to RECIST 1.1) that is separate and in addition to the lesion nominated for irradiation. This lesion cannot have been irradiated previously.
4. Must have relapsed after receiving 1 or 2 lines of chemotherapy for advanced disease including a platinum-based doublet. Maintenance chemotherapy following first line chemotherapy is considered a second line of chemotherapy.
5. ECOG performance status of 0 or 1 at the time of randomisation.
6. Adequate bone marrow function (done within 14 days prior to randomisation and with values within the ranges specified below). Blood transfusions are permissible.
*White blood cell count greater than or equal to 2 x 10^9/L
* Absolute neutrophil count greater than or equal to 1.5 x 10^9/L
* Platelets greater than or equal to 100 x 10^9/L
* Haemoglobin greater than or equal to 90 g/L
7. Adequate liver function (done within 14 days prior to randomisation and with values within the ranges specified below):
* Alanine transaminase less than or equal to 3 x upper limit of normal (ULN)
* Aspartate aminotransferase less than or equal to 3 x ULN
* Total bilirubin less than or equal to 1.5 x ULN (except patients with Gilbert Syndrome, who can have total bilirubin less than or equal to x ULN)
8. Adequate renal function (done within 14 days prior to randomisation and with values within the ranges as follows:
* Serum creatinine less than or equal to 1.5 x ULN
or
* Creatinine clearance (CrCl) greater than or equal to 40 mL/min (use Cockroft-Gault formula)
9. Tumour tissue (formalin-fixed paraffin embedded) must be available for PD-L1 testing. Patients will not be selected by PD-L1 status.
10. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Active, known or suspected autoimmune disease. Patients are not excluded if they have vitiligo, type 1 diabetes mellitus, residual hypothyroidism due to an autoimmune condition requiring only hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
2. Any condition requiring systemic treatment with either corticosteroids (greater than 10mg daily prednisone or equivalent dose of an alternative corticosteroid) or other immunosuppressive medications within 14 days of study drug administration. Intranasal, inhaled or topical steroids are permitted in the absence of active autoimmune disease.
3. Patients with leptomeningeal or uncontrolled brain metastases are excluded. Controlled brain metastases are those which have been treated and are radiologically and/or clinically stable, and the patient is asymptomatic and does not require corticosteroids.
4. Actionable mutation for which an approved, targeted therapeutic is available, e.g. known mutation of epidermal growth factor receptor (EGFR) or translocation of anaplastic lymphoma kinase.
5. Chemotherapy in the last 4 weeks.
6. Radiotherapy in the last 6 weeks.
7. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways.
8. Current treatment with other investigational drugs or anti-cancer therapy.
9. Life expectancy of less than 3 months.
10. History of another malignancy within 3 years prior to randomisation. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 3 years after definitive primary treatment.
11. Positive test for hepatitis B virus surface antigen (HBVsAg) or antibodies to hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
12. History of other significant infection, including HIV. HIV testing not mandatory unless clinically indicated.
13. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.
14. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception to avoid pregnancy for 23 weeks after the last dose of nivolumab. Women of childbearing potential must have a negative pregnancy test done within 24 hours prior to randomisation. Men must have been surgically sterilised or use a (double if required) barrier method of contraception if they are sexually active with a woman of child bearing potential for a period of 31 weeks after the last dose of nivolumab.

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)
Patients must meet all eligibility criteria before being randomised.

Randomisation will be performed in an internet based central randomisation system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Minimisation with stratification for,
1. Age (18-70 years versus older than 70)
2. Lines of previous chemotherapy (one versus two)
3. Histology (squamous versus non-squamous)
4. Treating institution
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
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
Actual
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 5255 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 5256 0
Prince of Wales Hospital - Randwick
Recruitment hospital [3] 5257 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [4] 5258 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 5259 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [6] 5260 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [7] 7288 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [8] 7289 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [9] 7290 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [10] 7291 0
The Alfred - Prahran
Recruitment hospital [11] 7292 0
Peninsula Oncology Centre - Frankston
Recruitment hospital [12] 7293 0
The Townsville Hospital - Douglas
Recruitment hospital [13] 7294 0
Genesis Cancer Care - Wesley - Auchenflower
Recruitment hospital [14] 7295 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [15] 7296 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [16] 7297 0
Royal Hobart Hospital - Hobart
Recruitment hospital [17] 7298 0
Nambour General Hospital - Nambour
Recruitment hospital [18] 7299 0
Sunshine Hospital - St Albans
Recruitment hospital [19] 7300 0
Sydney Adventist Hospital - Wahroonga
Recruitment postcode(s) [1] 15060 0
2050 - Camperdown
Recruitment postcode(s) [2] 15061 0
2485 - Tweed Heads
Recruitment postcode(s) [3] 15062 0
3065 - Fitzroy
Recruitment postcode(s) [4] 15063 0
3004 - Prahran
Recruitment postcode(s) [5] 15064 0
3199 - Frankston
Recruitment postcode(s) [6] 15065 0
4814 - Douglas
Recruitment postcode(s) [7] 15066 0
4066 - Auchenflower
Recruitment postcode(s) [8] 15067 0
5042 - Bedford Park
Recruitment postcode(s) [9] 15068 0
6009 - Nedlands
Recruitment postcode(s) [10] 15069 0
7000 - Hobart
Recruitment postcode(s) [11] 15070 0
4560 - Nambour
Recruitment postcode(s) [12] 15071 0
3021 - St Albans
Recruitment postcode(s) [13] 15072 0
5022 - Henley Beach
Recruitment postcode(s) [14] 15073 0
2076 - Wahroonga
Recruitment outside Australia
Country [1] 8572 0
New Zealand
State/province [1] 8572 0
Auckland

Funding & Sponsors
Funding source category [1] 292865 0
Commercial sector/Industry
Name [1] 292865 0
Bristol-Myers Squibb Company
Address [1] 292865 0
345 Park Avenue, New York, New York 10154
Country [1] 292865 0
United States of America
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country
Australia
Secondary sponsor category [1] 291611 0
Other Collaborative groups
Name [1] 291611 0
Australian Lung Cancer Trials Group
Address [1] 291611 0
Level 2, 11 Finchley Street Milton QLD 4064
Country [1] 291611 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294366 0
Northern Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 294366 0
Research Office
Kolling Building, Level 13
Royal North Shore Hospital
St Leonards NSW 2065
Ethics committee country [1] 294366 0
Australia
Date submitted for ethics approval [1] 294366 0
23/10/2015
Approval date [1] 294366 0
07/12/2015
Ethics approval number [1] 294366 0
RESP/15/311 (HREC/15/HAWKE/430)

Summary
Brief summary
The aim of this study is to determine the activity and safety of treating an asymptomatic, extrathoracic metastasis with a single fraction of SABR, during immunotherapy with nivolumab in advanced NSCLC progressing after 1 or 2 lines of chemotherapy.

Who is it for?
Adults with advanced non-small-cell lung cancer (NSCLC) progressing after 1 or 2 lines of chemotherapy and with an asymptomatic, extrathoracic metastasis suitable for SABR. Tumour blocks must be available to test for PD-L1 expression.

Study details
Participants will be randomly allocated in a ratio of 2:1 to either nivolumab 240mg every 2 weeks plus SABR (experimental) or nivolumab 240mg every 2 weeks alone (control). Nivolumab is continued until disease progression or prohibitive toxicity.

Participants will be assessed regularly for treatment response and side effects during the treatment and follow up phase. Clinical assessments will be performed before each cycle of nivolumab (2 weekly) and CT scans at baseline, week 6, 12, 18, 24 then 12 weekly until progression. Anticancer treatments and survival will be reviewed every 12 weeks after progression. This will enable us to determine the activity and safety of each treatment option in patients with an asymptomatic, extrathoracic metastasis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63450 0
A/Prof Paul Mitchell
Address 63450 0
Austin Hospital
145 Studley Road
Heidelberg VIC 3084
Country 63450 0
Australia
Phone 63450 0
+61 3 9496 3546
Fax 63450 0
Email 63450 0
nivorad@ctc.usyd.edu.au
Contact person for public queries
Name 63451 0
Ms Nivorad Trial Coordinator
Address 63451 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 63451 0
Australia
Phone 63451 0
+61 2 9562 5000
Fax 63451 0
Email 63451 0
nivorad@ctc.usyd.edu.au
Contact person for scientific queries
Name 63452 0
A/Prof Paul Micthell
Address 63452 0
Austin Hospital
145 Studley Road
Heidelberg VIC 3084
Country 63452 0
Australia
Phone 63452 0
+61 3 9496 3546
Fax 63452 0
Email 63452 0
nivorad@ctc.usyd.edu.au