A Phase 1 Open Label, Dose Escalation Study of Nilotinib in Steroid Dependent/Refractory Chronic Graft-Versus-Host Disease

All subjects had extensive steroid dependent/refractory cGVHD treated previously with ≥ 2 agents. Previous treatment with imatinib was allowed. Steroid refractory was defined as progressive cGVHD despite prednisone ≥ 0.5 mg/kg/d for ≥ 1 month; steroid dependence was cGVHD requiring prednisone ≥0.25 mg/kg/d for ≥ 3 months. This was a dose escalation trial with 4 sequential dose levels: 200 mg daily, 200 mg twice daily, 400 mg daily, and 400 mg twice daily followed by a dose extension phase at the maximum tolerated dose (MTD). Enrollment followed a standard 3+3 design. Steroids and two other immunosuppressants were allowed. Steroids were tapered as tolerated and other immunosuppressant dosing remained constant. Safety was determined by the observation of adverse events graded according to CTCAE v. 4.0 criteria. Trough plasma nilotinib concentrations were determined by HPLC before the daytime day 8 dose.

Median age was 49 years (range 23–75). Mean time to study enrollment from transplant was 3.3 years (range 1.7–7.8) and from cGVHD diagnosis 2.9 years (range 0.4–6.6). Sixteen subjects have been enrolled and 14 are evaluable. The median follow-up is 4.5 months (range 0.1–8.0). The MTD was reached at 200 mg daily. The maximum administered dose (MAD) was 200 mg twice daily. The dose limiting toxicities (DLTs) were grade 3 Pneumocystis pneumonia and grade 3 asymptomatic lipase elevation. Grade 2–3 adverse events possibly/probably attributed to nilotinib are shown below; no grade 4–5 adverse events attributed to nilotinib have occurred to date. Median trough plasma concentration of nilotinib 1 week after drug initiation at the MTD was 997 nM (range 661–1380, n=3) and at the MAD was 3110 nM (range 1210–4200, n=3). Trough nilotinib concentrations were higher at the MAD and were associated with DLT occurrence.

200 mg daily is the MTD in the cGvHD population. Safety and clinical effect at the MTD is being evaluated in an ongoing 35 subject extension study. The MTD results in a trough plasma concentration that may be adequate to inhibit the nilotinib receptor targets except for NQO2. Confirmatory pharmacodynamic studies are planned.

Off Label Use: Nilotinib for treatment of chronic graft versus host disease.