CTNI-51. PHASE IB STUDY OF COPANLISIB, A PAN PI3K INHIBITOR, IN COMBINATION WITH IBRUTINIB, A BTK INHIBITOR, IN RELAPSED OR REFRACTORY PRIMARY CNS LYMPHOMA

Abstract INTRODUCTION Primary central nervous system lymphoma (PCNSL) is an aggressive malignancy with poor prognosis for relapsed/refractory (r/r) disease. Inhibitors of the Bruton’s tyrosine kinase (BTK) signaling node yield radiographic response but early resistance is common. Here, we combine the BTK inhibitor ibrutinib with pan PI3K inhibitor, copanlisib. METHODS Eligible patients had r/r PCNSL, age≥18, ECOG≤2. Patients were dosed with concurrent daily ibrutinib and weekly intravenous copanlisib (days 1, 8, 15 of 28-day cycle) or sequentially treated with 1 cycle daily ibrutinib then 2 cycles copanlisib days 1, 8, 15. Strong CYP3A4/5 inducers/inhibitors were prohibited. RESULTS Eighteen patients were enrolled; 14 to concurrent therapy, 4 sequential. Median age was 63 (range, 40-80), ECOG 1 (0-2), 10 women, 4 men. Patients had a median of 2 prior treatments (range, 1-10) and 11 (61%) were chemo-refractory. Prior treatments included methotrexate (MTX) (n=18), ibrutinib (n=6), radiation (n=2), and transplant (n=5). Partial or complete response was observed in patients treated concurrently (n=8, 57%) and sequentially (n=2, 50%). Median progression-free survival was 3 months. Pharmacokinetic data demonstrated low plasma (Cmax: 17.9 ng/mL) and nearly undetectable CSF (Cmax: 0.01 ng/mL) levels of ibrutinib during concurrent treatment suggesting direct drug-drug interaction. During sequential therapy, plasma levels of ibrutinib were in the expected range (serum Cmax: 212 ng/mL). There was 1 grade 5 lung infection (PJP pneumonia). Grade 3 and 4 events included rash (n=6), lymphocyte count decrease (n=4), 2 instances each of hypertension and elevation of aspartate and alanine aminotransferase, 1 instance of neutropenia, thrombocytopenia, hyperglycemia, and aspergillosis. The most common grade 1/2 events were hyperglycemia (n=11) and nausea (n=6). DISCUSSION Combination copanlisib and ibrutinib yielded radiographic responses though this likely reflected effects of copanlisib rather than combination therapy. Sequential dosing is required for copanlisib and ibrutinib to reach cytotoxic levels. This study reiterates the importance of real-time pharmacokinetic monitoring.