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Nivolumab and Temozolomide Versus Temozolomide Alone in Newly Diagnosed Elderly Patients With GBM (NUTMEG)

Primary Purpose

Glioblastoma Multiforme

Status

Active

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Nivolumab

Temozolomide

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme focused on measuring GBM, Astrocytoma WHO grade IV, Elderly, Nivolumab, Temozolomide

Eligibility Criteria

65 Years - undefined (Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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
Tissue available for MGMT testing
ECOG 0-2
Life expectancy of >12 weeks
Adequate bone marrow function (platelets > 100 x 10^9/L, ANC > 1.5 x 10^9/L)
Adequate liver function (ALT/AST < 1.5 x ULN)
Adequate renal function (creatinine clearance > 30 ml/min measured using Cockroft-Gault
Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments including MRI
Signed, written informed consent

Exclusion Criteria:

Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may impact with the administration of study related treatments or procedures
Other co-morbidities or conditions that may compromise assessment of key outcomes
Prior chemotherapy or cranial radiation within the last 5 years. Prior or concomitant therapies for GBM (except surgery).
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.
Significant infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated
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.
For symptoms related to GBM, the need for >4 mg/day of dexamethasone or >20 mg/day prednisone (or equivalent) at the time of screening.
For a condition other than GBM, the need for >2 mg/day of dexamethasone or >10 mg/day prednisone (or equivalent) or other immunosuppressive medications within 14 days prior to randomisation. Exceptions to this include the use of inhaled or topical steriods >10 mg/day prednisone (or equivalent), which are permitted in the absence of active autoimmune disease.

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Nivolumab and Temozolomide

Temozolomide

Arm Description

After radiotherapy and 4 week break, participants who are assigned to this arm will receive Nivolumab with concurrent adjuvant temozolomide treatment

After radiotherapy and 4 week break, participants who are assigned to this arm will receive the standard treatment of adjuvant temozolomide treatment

Outcomes

Primary Outcome Measures

Overall survival outcomes

Overall survival is defined as the interval from the date of randomisation to date of death from any cause, or date of last known follow-up alive. This will be calculated using the Kaplan-Meier method.

Secondary Outcome Measures

Progression Free Survival

Progression free survival (PFS) is defined as the interval from date of randomisation to the date of first evidence of disease progression or death from any cause, whichever occurs first. The PFS will be calculated using the Kaplan-Meier method and disease progression is defined according to modified Response Assessment in Neuro-Oncology (RANO) criteria.

Number and severity of adverse events

The NCI Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) will be used to classify and grade the intensity of adverse events.

Health related quality of life of participants (QLQ C-30)

Health related quality of life will be reported directly by the participants using the EORTC core quality of life questionnaire QLQ C-30. The QLQ-C30 is a 30-item questionnaire with 5 functional scales (physical, role, cognitive, emotional, and social), global health status, 3 symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged and transformed to 0-100 scale; higher score=better level of physical functioning.

Health related quality of life of participants (QLQ-BN20)

Health related quality of life will be reported directly by the participants using the EORTC core quality of life questionnaire brain cancer specific module (QLQ-BN20). The QLQ-BN20 consisted of 20 items assessing visual disorders, motor dysfunction, communication deficit, various disease symptoms (e.g. headaches and seizures), treatment toxicities (e.g. hair loss) and future uncertainty. All of the 20 items are rated on a 4 point scale (1=not at all, 4=very much), and were linearly transformed to a 0-100 scale, with higher scores indicating more severe symptoms.

Health related quality of life of participants (EuroQoL EQ-5D-5L)

Health related quality of life will be reported directly by the participants using the EORTC core quality of life questionnaire EuroQol EQ-5D-5L. The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and as overall health using a "thermometer" visual analog scale with response options ranging from 0 (worst imaginable health) to 100 (best imaginable health).

Neurologic function of participants

Cognitive function will be assessed by the Neurologic Assessment in Neuro-Oncology (NANO) scales. The NANO is a quantifiable evaluation of nine major domains for subjects with brain tumours. The domains include: gait, strength, ataxia, sensation, visual field, facial strength, language, level of consciousness, behaviour and overall. Each domain is rated on a scale of 0 to 3 where 0 represents normal and 3 represents the worst severity. The evaluation is based on direct observation/testing performed during routine office visits.

Correlating modified RANO and immune related RANO in the experimental arm

Site investigators will assess disease progression using modified RANO criteria for clinical decision making. The study team will coordinate image analysis and central review of MRI including modified RANO (both experimental and comparator arms) and iRANO (in the experimental arm).

Full Information

NCT ID

NCT04195139

First Posted

November 18, 2019

Last Updated

June 13, 2023

Sponsor

University of Sydney

Collaborators

Cooperative Trials Group for Neuro-Oncology

1. Study Identification

Unique Protocol Identification Number

NCT04195139

Brief Title

Nivolumab and Temozolomide Versus Temozolomide Alone in Newly Diagnosed Elderly Patients With GBM

Acronym

NUTMEG

Official Title

A Randomised Phase II Study of NivolUmab and TeMozolomide vs Temozolomide Alone in Newly Diagnosed Elderly Patients With Glioblastoma (NUTMEG)

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

February 22, 2018 (Actual)

Primary Completion Date

December 31, 2024 (Anticipated)

Study Completion Date

December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Sydney

Collaborators

Cooperative Trials Group for Neuro-Oncology

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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. 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.

Detailed Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glioblastoma Multiforme

Keywords

GBM, Astrocytoma WHO grade IV, Elderly, Nivolumab, Temozolomide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

All participants will receive radiotherapy (weekdays over 21 days) concurrently with temozolomide (TMZ) tablets 75mg/m2 daily for 21 days. After a 4 week break, participants will receive either experimental or standard treatment. Experimental treatment: Participants assigned to this group will receive nivolumab intravenous infusions (days 1 and 15 every 28 days with concurrent adjuvant temozolomide tablets days 1-5, every 28 days) for 6 cycles. Standard treatment: Participants assigned to this group will receive the standard treatment of adjuvant temozolomide (days 1-5 every 28 days) for 6 cycles.

Masking

None (Open Label)

Allocation

Randomized

Enrollment

103 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Nivolumab and Temozolomide

Arm Type

Experimental

Arm Description

After radiotherapy and 4 week break, participants who are assigned to this arm will receive Nivolumab with concurrent adjuvant temozolomide treatment

Arm Title

Temozolomide

Arm Type

Active Comparator

Arm Description

After radiotherapy and 4 week break, participants who are assigned to this arm will receive the standard treatment of adjuvant temozolomide treatment

Intervention Type

Drug

Intervention Name(s)

Nivolumab

Other Intervention Name(s)

Opdivo

Intervention Description

Participants 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).

Intervention Type

Drug

Intervention Name(s)

Temozolomide

Other Intervention Name(s)

Temodar, Temodal, Temcad

Intervention Description

Participants will receive temozolomide (TMZ) 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.

Primary Outcome Measure Information:

Title

Overall survival outcomes

Description

Time Frame

24 months post randomisation of first participant

Secondary Outcome Measure Information:

Title

Progression Free Survival

Description

Time Frame

6 months post randomisation

Title

Number and severity of adverse events

Description

The NCI Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) will be used to classify and grade the intensity of adverse events.

Time Frame