Background: Results of conventional induction chemotherapies in PCNSL need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results in the relapse setting, supporting to further assess their combination with standard high-dose methotrexate-based chemotherapy. Methods: Patients (pts) with newly diagnosed PCNSL, aged 18 to 60, were randomized to receive four 28-day cycles of either ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3+3 design for ibrutinib 420/560/280 mg (D3 to D14 and D17 to D28) and lenalidomide 20 mg D1 to 14/20 mg D1 to 21/15 mg D1 to 21. Responder pts then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle. We present the results of the phase IB, including the toxicities that occurred throughout induction therapy. Results: 26 pts (median age 52) were randomized, 13 in each treatment group. Four DLTs (/21 evaluable pts) have been observed: grade 5 aspergillosis and pneumocystosis (N=1, ibrutinib 560 mg and concurrent high-dose corticosteroids without prophylaxis), grade 4 catheter-related infection > 7 days (N=1, lenalidomide 20 mg D1-14) and grade 3 increased alanine aminotransferase > 7 days (N=1, lenalidomide 20 mg D1-14 and N=1, lenalidomide 15 mg D1-21). RP2D of ibrutinib and lenalidomide were 560 mg (D3-14 and D17-28) and 15 mg (D1-21) respectively, in combination with R-MPV. One Lyell’s syndrome was reported as a serious adverse event (AE) at cycle 2 in the lenalidomide arm. Grade ≥3 treatment-related AEs occurring in ≥2 pts at any time during induction treatment are detailed in the table. After 4 induction cycles, 3/11 evaluable pts had CR/CRu and 7/11 had partial response (PR) in the ibrutinib group. In the lenalidomide arm, 6/10 evaluable pts had CR/CRu and 4/10 had PR. Survivals will be presented. Conclusions: Targeted induction immunochemotherapy with ibrutinib or lenalidomide and R-MPV is feasible for newly diagnosed PCNSL and shows promising response rates. Adverse events should be monitored carefully. The phase II part of the study is ongoing and opened to patients up to 65 years old. Clinical trial information: NCT04446962.