Tafasitamab Plus Lenalidomide in Relapsed CNS Lymphoma

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lenalidomide in combination with Tafasitamab in patients with relapsed central nervous system (CNS) lymphoma (Phase 1). II. To evaluate the clinical benefit rate of Tafasitamab in combination with lenalidomide in relapsed CNS lymphoma (Phase 2). SECONDARY OBJECTIVES: I. To describe the toxicities of Tafasitamab in combination with lenalidomide in relapsed CNS lymphoma. II. To describe the efficacy of Tafasitamab in combination with lenalidomide in relapsed CNS lymphoma. EXPLORATORY OBJECTIVES: I. To obtain pilot information about cerebral spinal fluid (CSF) penetration of Tafasitamab as well as CSF partition coefficient of lenalidomide in combination with Tafasitamab to evaluate possibility that Tafasitamab enhances CSF penetration of lenalidomide to an extent greater than CSF/plasma partition coefficient of lenalidomide which was 20% at 15 and 20 milligram (mg) dose levels. II. To evaluate the relationship between tumor mutational profile and response to Tafasitamab plus lenalidomide, via whole exome sequencing of diagnostic specimens. II. To evaluate change in immune cell phenotypes in CSF and blood in patients via flow-cytometry of natural killer (NK) cell, T-cells and CSF monocytes/macrophages in patients treated with combination Tafasitamab plus lenalidomide. IV. To evaluate the relationship between CSF cytokine microenvironment such as Interleukin-10 (IL-10), Chemokine ligand 13 (CXCL13), etc. as well as CSF metabolites, including energy metabolites and neurotransmitters, and response to combination Tafasitamab plus lenalidomide Tafasitamab, PFS, OS, and neurocognitive endpoints. V. To test the hypothesis that Tafasitamab in combination with lenalidomide impacts blood-brain barrier permeability associated with CNS lymphoma lesions, as assessed by albumin levels and MRI vascular permeability imaging metrics. VI. To explore the correlation between immune cell subsets and response and/or resistance to lenalidomide/Tafasitamab. VII. To evaluate the relationship between Minimal Residual Disease status (MRD) and response and PFS using either circulating tumor DNA or Clonoseq technologies. STUDY DESIGN: This is a single arm open-label multicenter phase I/II investigation of combination lenalidomide/Tafasitamab in patients with relapsed CNS lymphoma.During the phase 1 portion of the study, the investigators will examine three dose levels of Lenalidomide (10mg, 15mg and 20mg) in combination with Tafasitamab at a dose of 12 mg/kg. After MTD/RP2D is determined during phase 1, the phase 2 portion of the study will begin enrollment to the established dose. Participants will be followed for AEs 90 days after last dose/decision to discontinue treatment, or new treatments are administered and followed for overall survival/disease status for up to 1 year after last dose. Participants may continue study treatment until disease progression.