Phase IB part of LOC-R01, a LOC network non-comparative randomized phase IB/II study testing R-MPV in combination with escalating doses of lenalidomide or ibrutinib for newly diagnosed primary central nervous system lymphoma (PCNSL) patients

Abstract

Background: Results of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy.

Methods: Patients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders 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.

Results: Twenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell's syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively.

Conclusion: Targeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing.

Trial registration: NCT04446962.

Keywords: Ibrutinib; Lenalidomide; Phase IB trial; Primary central nervous system lymphoma.

Fig. 1

Schematic representation of the study treatment. R-MPV: rituximab 375 mg/m² D1, methotrexate 3.5 g/m² D1 and 15, procarbazine 100 mg/m² D1 to 7, vincristine 1.4 mg/m² D1 and D15 and prednisone 60 mg/day D1 to 5; R-Cytarabine: rituximab 375 mg/m², cytarabine 3 g/m²/D D1 and D2; ASCT: autologous stem cell transplantation; CR: complete response; uCR: unconfirmed complete response; PR: partial response; SD: stable disease; PD: progressive disease; w: weeks

Fig. 2

LOC-R01 phase IB flow chart. Lenalidomide dose K: 20 mg per day D1 to 14; Lenalidomide dose K-1: 15 mg per day D1 to 21; Ibrutinib dose K: 420 mg per day (D3 to 14 and D17 to 28); Ibrutinib dose K + 1: 560 mg per day (D3 to 14 and D17 to 28); DLT: dose-limiting toxicity; E: evaluable; NE: not evaluable; Disc: discontinued

Fig. 3

Swimmer plots depicting patients’ responses to lenalidomide (A) or ibrutinib (B), in combination with R-MPV, over time. Lenalidomide dose K: 20 mg per day D1 to 14; Lenalidomide dose K-1: 15 mg per day D1 to 21; Ibrutinib dose K: 420 mg per day (D3 to 14 and D17 to 28); Ibrutinib dose K + 1: 560 mg per day (D3 to 14 and D17 to 28); CR: complete response; uCR: unconfirmed complete response; PR: partial response; SD: stable disease; PD: progressive disease; DLT: dose-limiting toxicity