Phase 1b/2a study evaluating the combination of MN-166 (ibudilast) and temozolomide in patients with newly diagnosed and recurrent glioblastoma (GBM).

2016 Background: Ibudilast is a selective inhibitor of macrophage inhibitory factor (MIF) activity, which is upregulated in GBM and promotes stem cell growth. It also disrupts the interaction between MIF and CD74. When combined with temozolomide (TMZ) in preclinical studies, it attenuates the immunosuppressive properties of myeloid-derived suppressor cells and enhances tumor regression. This is a phase 1b/2a single-center, open-label, dose escalation study evaluating the safety, tolerability, and efficacy of the combination of Ibudilast and TMZ in newly diagnosed (nGBM) and recurrent (rGBM) GBM was initiated (NCT03782415). Methods: We included patients with nGBM who had completed concurrent chemoradiation, and patients with first GBM relapse who had a measurable enhancing disease. Patients were treated with monthly cycles of temozolomide (5 days of a 28-day cycle) and daily ibudilast, with a starting dose of 30 mg twice daily (BID), and escalated to a maximal dose of 50 mg BID. The primary objectives were to evaluate the safety and tolerability of the combination and determine the phase 2 recommended dose (R2PD) for phase 1b, and to evaluate the efficacy of the combination, determined by the 6-month progression-free survival rate (PFS-6) for phase 2a. A standard 3+3 design was used for phase 1b. For the rGBM cohort, a sample size of 30 provided 80% power to discriminate between historical 15% and 35% PFS-6 rates for rGBM patients. The trial would be considered successful if at least 8 patients were progression free at 6 months. Secondary objectives included overall survival (OS). Immunohistochemistry (IHC) studies were performed on archival tumor samples to evaluate factors of the tumor immune microenvironment. Results: 36 patients with nGBM and 26 patients with rGBM were included; 61% were males, with median age of 59 years. Ibudilast 50 mg BID was deemed to be the R2PD. PFS-6 was 44% (16 patients) in nGBM, and 31% (8 patients) in rGBM. The median OS was 21.0 months (17.7, 23.1) for nGBM and 8.6 months (7.8, 10.5) for rGBM. IHC evaluation on the original tumor tissue for patients with rGBM revealed a significantly higher CD3 positive cells infiltration, and elevated CD74 expression in tumors of patients who progressed at 5 months compared to those who did not. Conclusions: This study met its primary endpoint for rGBM, as the combination of ibudilast and TMZ was associated with a higher PFS-6 rate than historical controls. CD3 expression was a good predictor for tumor progression at 5 months in patients with rGBM. Encouraging preclinical studies suggest enhanced efficacy of ibudilast in GBM when combined to immune checkpoint blockade agents. Clinical trial information: NCT03782415 .