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

J Hematol Oncol. 2024 Sep 19;17(1):86. doi: 10.1186/s13045-024-01606-w.

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.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Adenine* / administration & dosage
  • Adenine* / analogs & derivatives
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols* / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Central Nervous System Neoplasms* / drug therapy
  • Female
  • Humans
  • Lenalidomide* / administration & dosage
  • Lenalidomide* / adverse effects
  • Lenalidomide* / therapeutic use
  • Lymphoma / drug therapy
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / therapeutic use
  • Middle Aged
  • Piperidines* / administration & dosage
  • Piperidines* / adverse effects
  • Piperidines* / therapeutic use
  • Prednisone / administration & dosage
  • Prednisone / adverse effects
  • Prednisone / therapeutic use
  • Pyrazoles* / administration & dosage
  • Pyrazoles* / adverse effects
  • Pyrazoles* / therapeutic use
  • Pyrimidines* / administration & dosage
  • Pyrimidines* / adverse effects
  • Pyrimidines* / therapeutic use
  • Rituximab / administration & dosage
  • Rituximab / adverse effects
  • Rituximab / therapeutic use
  • Vincristine / administration & dosage
  • Vincristine / adverse effects
  • Vincristine / therapeutic use

Substances

  • ibrutinib
  • Lenalidomide
  • Adenine
  • Piperidines
  • Pyrimidines
  • Pyrazoles
  • Vincristine
  • Rituximab
  • Methotrexate
  • Prednisone

Associated data

  • ClinicalTrials.gov/NCT04446962