PCNSL is an aggressive primary brain tumor. Outcome and treatment options are poor for patients with recurrent/refractory disease. Response rates range between 30-60% with a progression free survival (PFS) of 2-6 months. PI3K inhibition, particular of the delta isoform, has shown promising clinical response in some B-cell malignancies. This phase II trial investigates the pan-PI3K inhibitor Buparlisib in patients with recurrent/refractory (r/r) PCNSL and SCNSL.
Eligible patients had r/r PCNSL/SCNSL, age ≥ 18, KPS ≥ 50, normal end-organ function, and unrestricted number of prior therapies. In patients with SCNSL, systemic disease needed to be absent. Enrolled patients received Buparlisib 100 mg daily. The trial was closed prematurely due to limited clinical response.
Four patients were enrolled at age 55, 60, 68, and 79 with a KPS of 90, 100, 90 and 60, respectively. Three were men; 50% had PCNSL. All had parenchymal disease. Median prior CNS directed treatment was 2 (range 1-3); all methotrexate regimens. Two grade 4 toxicities (lymphopenia and neutropenia) were observed that resolved after drug was held. The most common toxicities observed were hyperglycemia, thrombocytopenia, and lymphopenia. The overall response rate was 25% with one partial response. This patient developed psychiatric symptoms within 8 weeks of treatment and drug was discontinued. Three patients developed neurologic symptoms at a median of 37 days after trial drug initiation. All were found to have disease progression. The median progression free survival was 39 days with a median overall survival of 196 days. Buparlisib concentrations were assessed on day 15 of drug treatment in plasma and CSF 2h after drug dosing. Mean plasma concentration was 1104ng/ml (range: 844-1610); mean CSF concentration 139.5ng/ml (82.9-205). CSF concentration in the trial population (340nM; range 202-499) was below the IC50 observed to induce cell death in lymphoma cells in vitro (>500nM).
Patients with CNS lymphoma tolerate drug with acceptable toxicities. Treatment did not result in clinical response possibly due to CNS concentrations below a meaningful IC50. Buparlisib might also not have single agent activity in this disease.
Clinical trial identification
Legal entity responsible for the study
Memorial Sloan Kettering Cancer Center
All authors have declared no conflicts of interest.