A phase I/II study to evaluate the safety and efficacy of a novel long-acting interleukin-7, NT-I7, for patients with newly diagnosed high-grade gliomas after chemoradiotherapy: The interim result of the phase I data.
Authors: Campian Jian Li , Luo Jingqin , Avvaru Chai , Katumba Ruth , Kim Albert H , Dunn Gavin P. , Abraham Christopher , Bhatta Puspanjali , Yang Se Hwan , Fan Jean , Lee Byung Ha , Ranjitka Sunita , Le Ngocdiep T. , Ansstas George , Johanns Tanner Michael , Chheda Milan G , Huang Jiayi 
Published: June 2021

2040 Background: High-grade gliomas (HGG) patients can develop prolonged lymphopenia after standard radiation therapy (RT) and temozolomide (TMZ), which has been shown to correlate with worse survival. Interleukin-7 (IL-7) level, a cytokine that stimulates T-cell homeostasis and proliferation, is disproportionally low in HGG patients with lymphopenia. NT-I7 (efineptakin alfa) is the first-in-class long-acting recombinant human IL-7 that supports proliferation and survival of CD4+ and CD8+ T-cells in humans and mice. Our previous study demonstrated that NT-I7 could correct lymphopenia and improve the survival of orthotopic murine glioma models. The current study aims to examine the safety of administering NT-17 after chemoradiotherapy to HGG patients and its effect on systemic absolute lymphocyte count (ALC). Methods: All patients with newly diagnosed HGG who have completed concurrent RT/TMZ were considered eligible, regardless of ALC. NT-I7 was initially administered intramuscularly within 1 week after completion of RT/TMZ and then every 12 weeks for up to 4 doses. Patients also received adjuvant TMZ 4 weeks after RT/TMZ. The phase I study tested 6 dose levels of NT-I7, including 60, 120, 240, 540, 720, and 960 mcg/kg, adopting an accelerated phase for the first two doses followed by the standard 3+3 design. The primary endpoint was the safety of NT-I7 in HGG. The Phase II study is a double-blinded randomized study with 10 patients per arm to evaluate the effect of NT-I7 on ALC compared to placebo controls. Blood samples at baseline and during the NT-I7 administrations will be collected for immune profiling by CyTOF, single-cell RNA-sequencing, and cytokine analysis. Results: Phase I was completed with 19 patients (2 anaplastic oligodendrogliomas and 17 glioblastomas), with a median age of 58 years (range: 25-78). Median baseline ALC was 1000 cells/mm3 before NT-I7 administration, and the median baseline dexamethasone use was 0 mg/day (range 0-12). The median number of NT-I7 doses given was 2 (range: 2-4). Treatment-related adverse events (TRAEs) were dose-dependent. The most common TRAEs were grade 1/2 injection site reactions (50%), flu-like symptoms (26%), rash (21%), and fatigue (21%). Two patients had dose-limiting toxicities at 960 mcg/kg (a grade 3 elevated alanine aminotransferase and a grade 3 muscle pain). ALC was increased in a dose-dependent manner with a range of 1.3 – 4.1 fold at week 4 after NT-I7 injection and lasted up to 12 weeks. Thus, 720 mcg/kg was identified as the recommended phase II dose (RP2D). Conclusions: NT-I7 is well tolerated for HGG patients after chemoradiotherapy and has a RP2D of 720 mcg/kg. Immune profiling and cytokine analysis are ongoing and will be updated. The Phase II randomized study to evaluate the effect of NT-I7 vs placebo on ALC and survival is ongoing. Clinical trial information: NCT03687957.