Polatuzumab Vedotin Plus Rituximab, Ifosfamide, Carboplatin and Etoposide (Pola-R-ICE) Versus R-ICE Alone in Second Line Treatment of Diffuse Large B-cell Lymphoma (DLBCL)

Inclusion Criteria:

1. The informed consent form must be signed before any study specific tests orprocedures are done

2. Adult male and female patients ≥18 years (≥16 years in the UK*) at the time ofinclusion in the study (* In the UK an "adult" means a person who has attained theage of 16 years, according to The Medicines for Human Use (Clinical Trials)Regulations 2004, Part 1 Point 2.)

3. Ability to understand and follow study-related instructions

4. Risk group: All patients with one of the following histologically defined entities:Histological diagnosis of primary refractory or relapsed aggressive B-cellnon-Hodgkin lymphoma (B-NHL), confirmed by a biopsy of involved nodal or extranodalsite. Patients with any of the following histologies can be included:

• DLBCL not otherwise specified (NOS)

• T-cell/histiocyte-rich large B-cell lymphoma

• Primary cutaneous DLBCL, leg type

• Epstein-Barr virus (EBV)-positive DLBCL, NOS

• DLBCL associated with chronic inflammation

• Primary mediastinal (thymic) large B-cell lymphoma

• High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements

• High-grade B-cell lymphoma, NOS Refractory disease is defined as no complete remission to first line therapy;subjects who are intolerant to first line therapy are excluded. Three groups ofpatients are eligible:

• Progressive disease (PD) as best response to first line therapy (biopsy notmandatory if diagnostic sample available).

• Stable disease (SD) as best response after at least 4 cycles of first linetherapy (e.g., 4 cycles of R-CHOP) (biopsy not mandatory if diagnostic sampleavailable).

• Partial response (PR) as best response after at least 6 cycles, andbiopsy-proven residual disease or disease Progression after the partialresponse. Relapsed disease is defined as complete remission to first line therapy followed bybiopsy proven disease relapse.

5. Performance Status ECOG 0-2 at time of randomization or ECOG 3 at screening if thisis DLBCL-related and has improved to ECOG 2 or less with a 7-day steroid treatmentduring the screening Phase (e.g. 1 mg/kg prednisone).

6. Information on all 5 International Prognostic Index (IPI) factors

7. Staging (PET-CT based-staging according to Lugano criteria 2014). Patients must havePET-positive lesions.

8. Subjects must have received adequate first line therapy including at a minimum: i)anti-CD20 monoclonal antibody unless Investigator determines that tumor is CD20negative, and ii) an anthracycline containing chemotherapy Regimen

9. Intent to proceed to high-dose therapy (HDT) and stem cell transplantation (SCT) ifresponse to second line therapy

10. Adequate hematological function, as defined by: hemoglobin ≥ 8 g/dL, absoluteneutrophil count (ANC) ≥ 1.0 x 109/L OR ≥ 0.5 x 109/L if neutropenia is attributableto underlying disease and before the administration of steroids, and platelet count ≥ 75 x 109/L OR ≥ 50 x 109/L if thrombocytopenia is attributable to Underlyingdisease

11. Women of childbearing potential must have a negative pregnancy test result within 7days prior to the first study drug Administration

12. For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive measures, and agreement to refrainfrom donating eggs

13. For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse contraceptive measures, and agreement to refrain from donating sperm

Exclusion Criteria:

(1) Serious accompanying disorder leading to impaired organ function causing significant clinical problems and reduced life expectancy of less than 3 months. In particular, patients with the following organ dysfunction caused by accompanying disorders are to be excluded:

• Heart failure with left ventricular ejection fraction (LVEF) < 45%

• Impaired pulmonary function with vital capacity (VC) or forced expiratory volume (FEV1) < 50% of normal (only in case of history of significant pulmonary disease)

• Impaired renal function with glomerular filtration rate (GFR) < 50 mL/min (calculated)

• Impaired liver function with alanine aminotransferase (ALAT), aspartateaminotransferase (ASAT) or Bilirubin > 1.5 x upper limit of normal (ULN). Ifelevation is caused by the disease, threshold of 2.5 x ULN is accepted

• Peripheral neuropathy > Grade II (2) Human immunodeficiency virus (HIV)-positivitywith detectable viral load and/or a CD4+ count below 0.3/nL

(3) Hepatitis B and C as defined by seropositivity (HBsAG and anti HBe/ anti HBc;anti-Hc); in case of false positive serology (transfused antibodies) negativePCR-results will allow patient inclusion. Patients with occult or prior HBVinfection (defined as negative HBsAg and positive hepatitis B core antibody [HBcAb])may be included if HBV DNA is undetectable, provided that they are willing toundergo DNA testing on Day 1 of every cycle and monthly for at least 12 months afterthe last cycle of study Treatment

(4) Known active bacterial, viral, fungal, mycobacterial, parasitic, or otherinfection (excluding fungal infections of nail beds) at study inclusion or anyunresolved major episode of infection (as evaluated by the investigator) within 1week prior to Cycle 1 Day 1

(5) Patients with suspected or latent tuberculosis. Latent tuberculosis needs to beconfirmed by positive interferon-gamma release Assay

(6) Primary or secondary central nervous system (CNS) lymphoma at the time ofrecruitment

(7) Richter's transformation or prior chronic lymphocytic leukemia (CLL)

(8) Vaccination with a live vaccine within 4 weeks prior to Treatment

(9) Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) otherthan for diagnosis

(10) Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressivetherapy, or any investigational agent for the purposes of treating cancer within 2weeks prior to Cycle 1 Day 1

(11) Received more than one line of therapy for DLBCL

(12) Received polatuzumab vedotin as part of the first line therapy

(13) Any other diseases, metabolic dysfunction, physical examination finding, orclinical laboratory finding giving reasonable suspicion of a disease or conditionthat contraindicates the use of an investigational drug or that may affect theinterpretation of the results or render the patient at high risk from treatmentcomplications

(14) Ongoing treatment or study procedures within any other InvestigationalMedicinal Product (IMP) clinical trial with the exception of follow-up. In case of apreceding clinical trial, last application of the respective IMP(s) must have beendone more than five elimination half-lives before start of study medication in thistrial.

(15) History of severe allergic or anaphylactic reactions to human, humanized,chimeric, or murine monoclonal antibodies

(16) History of hypersensitivity to any of the study drugs or their ingredients orto drugs with similar structure

(17) Contraindications according to the Investigator´s Brochure (IB) of polatuzumabvedotin or the local Summary of Product Characteristics (SmPCs) of the usedrituximab, ifosfamide, carboplatin or etoposide products

(18) Criteria which in the opinion of the investigator preclude participation forscientific reasons, for reasons of compliance, or for reasons of the subject'sSafety

(19) Pregnancy or breastfeeding, or intending to become pregnant during the study orwithin 12 months after the last dose of study drug

(20) Close affiliation with the investigator (e.g. a close relative) or personsworking at the study site

(21) Subject is an employee of the sponsor or involved Contract ResearchOrganization

At study inclusion, any organ impairment due to lymphoma infiltration is NOT regarded as an exclusion criterion.