P01.035 Nivolumab and Temozolomide (TMZ) vs TMZ alone in newly diagnosed elderly patients (pts) with Glioblastoma (GBM) (NUTMEG): Trial in progress
Abstract Background TMZ with short course radiotherapy (RT) is an option for elderly GBM patients. Nivolumab is a PD-1 inhibitor with known safety profile in GBM. An increase of mutations as we age is well documented in GBM and in cancer in general. A higher mutational load is associated with increased response to nivolumab. NUTMEG examines activity of nivolumab added to TMZ in GBM patients 65 years or older. Methods NUTMEG patients will receive RT (40Gy/15 fractions) concurrently with TMZ 75mg/m2. Post-radiation, the experimental group will receive nivolumab (240 mg days 1 and 15 Q 28 days for cycles 1–4; then 480 mg day 1 Q 28 days for cycles 5–6) with adjuvant TMZ (150-200mg/m2 days 1–5 Q 28 days) for 6 cycles. The standard treatment group will receive same dose and schedule of TMZ. The primary endpoint is Overall Survival (OS). Secondary endpoints include: 6-month (mo) Progression Free Survival (PFS-6), adverse events using NCI CTCAE v4.03 incorporating immune related AEs, QoL (EORTC QLQ-30, BN-20, and EuroQol EQ-5D-5L), Neurologic Assessment in Neuro-Oncology (NANO) Scale and correlation between modified RANO and immune-related RANO in the experimental arm. Translational research (TR) endpoints include mutational burden deciphered by whole exome sequencing; immune-related markers PD-L1, CD3+, CD4+, CD8+ and FOXP3 tumour infiltrating lymphocytes (TILs) and correlation with clinical outcomes. Advanced MRI will assess distribution of perfusion and diffusion, 3D morphometric and texture features and pH-weighted imaging correlated with clinical and TR endpoints. Safety will be reviewed by an independent data safety monitoring committee. Assuming a median OS of 9 mo, and accrual of 18mo and ≥24 mo follow-up 102 patients will be randomized in a 2:1 allocation (68 in the experimental arm and 34 in the control arm). This randomized phase II design targets a hazard ratio (HR) TMZ + nivolumab: TMZ for survival between experimental and control arms with a 90% CI of HR/1.46 to HR*1.46. If the upper limit is less than 1, we would conclude TMZ + nivolumab to be superior to warrant further investigation. This phase II design may be converted to a larger phase III trial if, at the end of the study, the number of events is sufficiently large. Progress At 28 May 2018, 5/18 study sites are open in Australia with 5 patients randomized. ACTRN12617000267358. Supported by NHMRC Project grant APP1125204 and Bristol-Myers Squibb.
Khasraw, M; McDonald, K; Yip, S; Verhaak, RG; Heimberger, AB; Hall, M; Barnes, E; Hovey, E; Ellingson, BM; Lwin, Z
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