CompletedPhase 2ACTRN12617000267358

A Randomised Phase II Study of NivolUmab and TeMozolomide vs Temozolomide alone in newly diagnosed Elderly patients with Glioblastoma (NUTMEG)

A Randomised Phase II Study of NivolUmab and TeMozolomide vs Temozolomide alone in newly diagnosed Elderly patients with Glioblastoma (NUTMEG) to analyse overall survival.

Sponsor

The University of Sydney

Enrollment

102 participants

Start Date

Mar 2, 2018

Study Type

Interventional

Conditions

Glioblastoma (GBM, astrocytoma WHO grade IV)

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.

Eligibility

Sex: Both males and femalesMin Age: 65 Yearss

Inclusion Criteria9

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 Criteria8

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 > 4mg/day of dexamethasone or >20 mg/day prednisone (or equivalent) at the time of screening.
For a condition other than GBM, the need for > 2mg/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 steroids, and adrenal replacement steroid doses > 10 mg/day prednisone (or equivalent), which are permitted in the absence of active autoimmune disease.

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Interventions

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

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.