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Trial registered on ANZCTR


Registration number
ACTRN12617000267358
Ethics application status
Approved
Date submitted
6/02/2017
Date registered
22/02/2017
Date last updated
31/07/2019
Date data sharing statement initially provided
31/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised Phase II Study of NivolUmab and TeMozolomide vs Temozolomide alone in newly diagnosed Elderly patients with Glioblastoma (NUTMEG)
Scientific title
A Randomised Phase II Study of NivolUmab and TeMozolomide vs Temozolomide alone in newly diagnosed Elderly patients with Glioblastoma (NUTMEG) to analyse overall survival.
Secondary ID [1] 291088 0
COGNO 16/01, CTC 0156, BMS protocol number: BMS CA209-823
Universal Trial Number (UTN)
Trial acronym
NUTMEG
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma (GBM, astrocytoma WHO grade IV) 301893 0
Condition category
Condition code
Cancer 301561 301561 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All patients will receive radiotherapy (40Gy/ 15 fractions, weekdays over 21 days) concurrently with temozolomide (TMZ) tablets 75mg/m2 daily for 21 days.
After a 4 week break the experimental group will receive nivolumab intravenous infusions (240 mg days 1 and 15 every 28 days for cycles 1-4; then 480 mg day 1 every 28 days for cycles 5-6) with concurrent adjuvant temozolomide tablets days 1-5, every 28 days) for 6 cycles. TMZ will be dosed at 150mg/m2 for the first cycle. If well tolerated TMZ is then given at 200mg/m2 for cycles 2 - 6.

The intervention will not be personalised.

The elderly population involved in this trial may be vulnerable to increased toxicity. Therefore the study will have a lead in phase wherein safety data of the first 10 evaluable patients on the experimental arm will be reviewed by an independent data safety monitoring committee (IDSMC) and thereafter as required by the IDSMC. The IDSMC will also examine recruitment and treatment adherence.
Intervention code [1] 297073 0
Treatment: Drugs
Comparator / control treatment
All patients will receive RT (40Gy/ 15 fractions) concurrently with temozolomide (TMZ) 75mg/m2.
Patients assigned to the control group will receive the standard treatment of adjuvant temozolomide (150-200mg/m2 days 1-5 every 28 days) for 6 cycles.
Control group
Active

Outcomes
Primary outcome [1] 300973 0
Overall Survival (OS) - to see if the combination of adjuvant nivolumab with temozolomide improves the overall survival outcomes of GBM patients.
Timepoint [1] 300973 0
Until patient death
Secondary outcome [1] 331301 0
6 months Progression Free Survival (PFS-6) using RANO criteria
Timepoint [1] 331301 0
6 months after randomisation
Secondary outcome [2] 331302 0
Adverse events using NCI CTCAE v4.03 incorporating immune related AEs
Timepoint [2] 331302 0
Until study treatment finishes/disease progression. Patients are assessed after each cycle (28 days) of treatment for adverse events.
Secondary outcome [3] 331303 0
QoL outcomes as assessed by EORTC QLQ-30, BN-20, and EuroQol EQ-5D-5L
Timepoint [3] 331303 0
Until study treatment finishes/disease progression. Patients complete QOL forms prior to starting treatment, after radiotherapy, prior to every treatment cycle (28 days), at the end of treatment and every 2 months throughout the follow-up period. The follow up period continues until death, loss to follow up or withdrawal of consent.
Secondary outcome [4] 331304 0
Neurologic functioning using the Neurologic Assessment in Neuro-Oncology (NANO) Scale
Timepoint [4] 331304 0
Patients are assessed at baseline then every 8 weeks until study treatment finishes/disease progression.
Secondary outcome [5] 331305 0
The correlation between RANO and immune related RANO in the experimental arm only
Timepoint [5] 331305 0
Patients are assessed at screening then every 8 weeks until study treatment finishes/disease progression.

Eligibility
Key inclusion criteria
1. Adults, aged greater than or equal to 70 years, or aged 65-69 years if long course RT is inappropriate, with newly diagnosed histologically confirmed GBM (WHO grade IV glioma including gliosarcoma) following surgery
2. Tissue available for MGMT testing
3. ECOG 0-2
4. Life expectancy of >12 weeks
5. Adequate bone marrow function (platelets > 100 x 10^9/L, ANC > 1.5 x 10^9/L)
6. Adequate liver function (ALT/AST < 1.5 x ULN)
7. Adequate renal function (creatinine clearance > 30 ml/min measured using Cockroft-Gault
8. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments including MRI
9. Signed, written informed consent
Minimum age
65 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may impact with the administration of study related treatments or procedures
2. Other co-morbidities or conditions that may compromise assessment of key outcomes
3. Prior chemotherapy or cranial radiation within the last 5 years. Prior or concomitant therapies for GBM (except surgery).
4. History of another malignancy within 2 years prior to registration. 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 2 years after definitive primary treatment.
5. Significant infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated
6. Active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
7. A condition other than GBM, requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days prior to randomisation. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone or equivalent, are permitted in the absence of active autoimmune disease.

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Prior to randomisation patients will be stratified according to the following factors -
* ECOG (0 vs 1/2)
* Age (less than or equal to 70 vs greater than 70)
* MGMT status (methylated vs unmethylated)
* Surgery (gross macroscopic resection vs biopsy or debulking)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
This trial is a phase II randomised (2:1) multi-centre open label design
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
This is a randomised phase II design to estimate the hazard ratio (HR) TMZ + nivolumab: TMZ for survival between experimental and control arms with a 90% confidence interval of [HR/1.462 to HR*1.462]. If the upper limit is less than 1, then we would conclude TMZ + nivolumab to be superior to TMZ and worthy of further investigation.

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
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 10706 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 10707 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 10708 0
Gosford Hospital - Gosford
Recruitment hospital [4] 10709 0
Epworth Richmond - Richmond
Recruitment hospital [5] 10710 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 10711 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [7] 10712 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [8] 10713 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [9] 10714 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [10] 10715 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [11] 10716 0
Campbelltown Hospital - Campbelltown
Recruitment hospital [12] 10717 0
Prince of Wales Hospital - Randwick
Recruitment hospital [13] 10718 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [14] 10719 0
Icon Cancer Care Wesley - Auchenflower
Recruitment hospital [15] 10720 0
Newcastle Private Hospital - New Lambton Heights
Recruitment hospital [16] 14358 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [17] 14359 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [18] 14360 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [19] 14361 0
Wollongong Hospital - Wollongong
Recruitment postcode(s) [1] 22427 0
2065 - St Leonards
Recruitment postcode(s) [2] 22428 0
4029 - Herston
Recruitment postcode(s) [3] 22429 0
2250 - Gosford
Recruitment postcode(s) [4] 22430 0
3121 - Richmond
Recruitment postcode(s) [5] 22431 0
7000 - Hobart
Recruitment postcode(s) [6] 22432 0
2050 - Camperdown
Recruitment postcode(s) [7] 22433 0
5042 - Bedford Park
Recruitment postcode(s) [8] 22434 0
4102 - Woolloongabba
Recruitment postcode(s) [9] 22435 0
3000 - Melbourne
Recruitment postcode(s) [10] 22436 0
3084 - Heidelberg
Recruitment postcode(s) [11] 22437 0
2560 - Campbelltown
Recruitment postcode(s) [12] 22438 0
2031 - Randwick
Recruitment postcode(s) [13] 22439 0
6009 - Nedlands
Recruitment postcode(s) [14] 22440 0
4066 - Auchenflower
Recruitment postcode(s) [15] 22441 0
2305 - New Lambton Heights
Recruitment postcode(s) [16] 27361 0
2444 - Port Macquarie
Recruitment postcode(s) [17] 27362 0
3168 - Clayton
Recruitment postcode(s) [18] 27363 0
5000 - Adelaide
Recruitment postcode(s) [19] 27364 0
2500 - Wollongong

Funding & Sponsors
Funding source category [1] 295524 0
Government body
Name [1] 295524 0
NHMRC Project Funding
Address [1] 295524 0
16 Marcus Clarke Street, Canberra City ACT 2600
Country [1] 295524 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NSW 2006
Australia
Country
Australia
Secondary sponsor category [1] 294347 0
None
Name [1] 294347 0
Address [1] 294347 0
Country [1] 294347 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296849 0
Northern Sydney Local Health District HREC
Ethics committee address [1] 296849 0
Research Office
Kolling Building, Level 13
Royal North Shore Hospital
St Leonards NSW 2065
Tel (02) 9926 4590 Fax (02) 9926 6179
Ethics committee country [1] 296849 0
Australia
Date submitted for ethics approval [1] 296849 0
12/04/2017
Approval date [1] 296849 0
29/06/2017
Ethics approval number [1] 296849 0

Summary
Brief summary
This study aims to investigate effect of Nivolumab and Temozolomide vs Temozolomide alone on overall survival in newly diagnosed elderly patients with glioblastoma.

Who is it for?
You may be eligible to join this study if you are aged 65 years or above, with newly diagnosed histologically confirmed GBM (WHO grade IV glioma including gliosarcoma) following surgery.

Study details
Participants will be allocated to either experimental or control group in a 2:1 ratio by chance (randomly). Patients assigned to the experimental group will receive a course of nivolumab via intravenous infusion (240 mg on days 1 and 15 every 28 days for cycles 1-4; then 480 mg day 1 every 28 days for cycles 5-6) in addition to the standard regimen of Temozolomide (TMZ) tablets and radiotherapy. Patients assigned to the control group will receive the standard treatment of adjuvant temozolomide (150-200mg/m2 days 1-5 every 28 days) for 6 cycles and standard radiotherapy treatment (40 Gy administered in 15 fractions).

The study aims to evaluate whether the combination of adjuvant nivolumab with temozolomide improves overall survival outcomes for this patient population. The outcome of the study will help determine the most effective treatment for patients with glioblastoma in the future.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72218 0
Dr Mustafa Khasraw
Address 72218 0
NHMRC Clinical Trials Centre,
University of Sydney
Lifehouse Level 6
119–143 Missenden Road,
Camperdown NSW 2050
Country 72218 0
Australia
Phone 72218 0
+61 2 95625000
Fax 72218 0
+61 2 95625094
Email 72218 0
nutmeg@ctc.usyd.edu.au
Contact person for public queries
Name 72219 0
Mrs NUTMEG Trial Coordinator
Address 72219 0
NHMRC Clinical Trials Centre,
University of Sydney
Lifehouse Level 6
119–143 Missenden Road,
Camperdown NSW 2050
Country 72219 0
Australia
Phone 72219 0
+61 2 95625000
Fax 72219 0
+61 2 95625094
Email 72219 0
nutmeg@ctc.usyd.edu.au
Contact person for scientific queries
Name 72220 0
Mrs NUTMEG Trial Coordinator
Address 72220 0
NHMRC Clinical Trials Centre,
University of Sydney
Lifehouse Level 6
119–143 Missenden Road,
Camperdown NSW 2050
Country 72220 0
Australia
Phone 72220 0
+61 2 95625000
Fax 72220 0
+61 2 95625094
Email 72220 0
nutmeg@ctc.usyd.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
What supporting documents are/will be available?
No other documents available
Summary results
No Results