Low-dose Nivolumab and Lenalidomide in Relapsed/Refractory Hodgkin Lymphoma - A Single Arm Phase II Trial Open Access

1. Low dose nivolumab is adequate for complete PD1 receptor occupancy on T-cells, which and persists beyond recommended dosing time-points.

2. Low dose Nivolumab has clinical efficacy in Hodgkin lymphoma and is a cost-effective alternative to standard dosing.

Based on previous reports of the clinical efficacy of low-dose nivolumab, we hypothesized that a flat 40mg nivolumab would be adequate to saturate available PD-1 receptors on circulating T cells, and would show clinical efficacy in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL), and conducted this single arm trial in 20 patients with R/R cHL. Patients received nivolumab 40mg every 2 weeks (NIV40) with lenalidomide 10mg (21/28) (LEN10). PD-1 receptor occupancy (RO) was analyzed by flow cytometry at peak and trough. Plasma drug levels were measured at 4 time-points. Patients were assessed for response after 4 doses of nivolumab. Median dose of nivolumab was 0.7mg/kg (range 0.4-0.8). Twelve patients (60%) had a CR and six (30%) had a PR. In patients undergoing autologous stem cell transplant, a mean CD34 dose of 11.7x10ˆ6/kg (range 3.9-26.5) was achieved with G-CSF mobilization. At median follow-up of 15 months (range 10.5-22.4), PFS for the whole cohort was 83.5% (95% CI 56.8% to 94.4%), and RFS in transplanted patients was 92.9% (95% CI 56.6% to 98.9%). 1 hour after the first NIV40 infusion (peak), complete PD1 RO was noted and at 14 days post-infusion (trough), CD8+ T cells continued to show full RO (p=0.611). Pharmacokinetics: Simple linear regression did not identify sex, age, creatinine or body weight as significant factors influencing the AUC_tau. Immunomodulation with NIV40LEN10 is effective in R/R cHL Flow cytometry for PD-1 RO should be studied in clinical trials as a potential biomarker to guide dosing, leading to rationalized use of PD-1 inhibitors.