Venetoclax and Obinutuzumab for Relapsed/Refractory Primary CNS Lymphoma

Inclusion criteria: 1. Age at inclusion ≥ 18 to 80 years, in case of ECOG 0 to 1 age up to 85 years 2. Eastern Cooperative Group performance status (ECOG) ≤ 3 3. Evaluable lymphoma manifestation in the CNS, either contrast-enhanced lesion in the brain parenchyma or measurable meningeal lesions. 4. Biopsy proven CD20 positive PCNSL at initial diagnosis or previous relapse/progression (re-biopsy at study inclusion is not mandatory for inclusion, but strongly recommended if time in remission is longer than 24 months). 5. At least one prior HD-MTX containing chemotherapy application (MTX dosed at ≥ 1 g/m2 body surface area) before progression or relapse. 6. Confirmed relapsed or refractory PCNSL according to the IPCG response criteria with the following definition: Evidence of disease recurrence following PR/CR or uCR or no radiological response (SD or PD) as per the IPCG criteria to prior chemotherapy regimen(s), at least one of them containing high-dose methotrexate. 7. Absolute neutrophil count (ANC) of at least 1'500/μl 8. Platelet count of at least 50'000/μl 9. Adequate liver (alanine aminotransferase \[ALAT\] and AST ≤ 3.0 x upper limit of normal \[ULN\] and total bilirubin ≤ 1.5 x ULN) and kidney function (estimated ≥ 30ml/min creatinine clearance according to Cockgroft-Gault formula) 10. Written informed consent 11. Recovery from toxicity from previous anti-lymphoma treatment to ≤ grade 2 Exclusion criteria: 1. Known allergy to venetoclax or other components of the formulation 2. Known allergy to obinutuzumab or other components of the formulation 3. Primary ocular lymphomas without brain parenchymal involvement 4. Lymphoma relapse outside the CNS; extra CNS relapse needs to be ruled out by body CT scans (neck till pelvis) or PET-CT scans. 5. Contraindications for lumbar puncture at the discretion of the clinical investigator 6. Prior exposure to obinutuzumab or venetoclax 7. Other additional anti-lymphoma treatment, e.g. chemotherapy or radiotherapy 8. Active hepatitis B or C 9. HIV seropositivity 10. Chronic use of immunosuppressive drugs, e.g. steroids for systemic autoimmune disease 11. Active infections requiring treatment 12. Other active malignancies (except non-melanoma skin cancer). Prior malignancies without evidence of disease for at least 5 years are allowed 13. Patient is pregnant or breastfeeding, or expecting to conceive or father children within one year of finishing venetoclax and 18 months for obinutuzumab. 14. Prior allogeneic haematopoietic stem cell or solid organ transplantation 15. Therapeutic intervention in setting of other former interventional clinical trial within 30 days before the first IMP administration in VENOBI study; simultaneous participation in registry and diagnostic studies or follow up of an interventional trial is allowed 16. Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial 17. Known or persistent abuse of medication, drugs or alcohol 18. Person who is in a relationship of dependence/employment with the sponsor or the investigator 19. Administration of moderate or strong CYP3A inhibitors or inducers within 1 week of initiation of venetoclax dosing.