Summary

This phase II trial studies the effect of polatuzumab vedotin, rituximab, ifosfamide, carboplatin, and etoposide as initial salvage therapy in treating patients with diffuse large B-cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Polatuzumab vedotin is a monoclonal antibody, polatuzumab, linked to a toxic agent called vedotin. Polatuzumab attaches to CD79b positive cancer cells in a targeted way and delivers vedotin to kill them. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Chemotherapy drugs, such as ifosfamide, carboplatin, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy with immunotherapy may kill more cancer cells in patients with diffuse large B-cell lymphoma.

Objectives

PRIMARY OBJECTIVES:
I. Evaluate the safety and tolerability of polatuzumab vedotin (Pola) added to rituximab, ifosfamide, carboplatin, and etoposide (PolaR-ICE) as first salvage therapy for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). (Safety Lead-in)
II. Evaluate the anti-tumor activity of PolaR-ICE as first salvage therapy for R/R DLBCL as assessed by the complete response rate after 2 cycles. (Phase 2)

SECONDARY OBJECTIVES:
I. Evaluate the overall response rate to PolaR-ICE as first salvage therapy for R/R DLBCL.
II. Evaluate the progression-free and overall survival of patients who received PolaR-ICE as first salvage therapy for R/R DLBCL followed by autologous stem cell transplantation (ASCT) and single-agent Pola consolidation after ASCT.
III. Evaluate the CR rate after Pola consolidation among those who were partial response (PR) at ASCT.
IV. Evaluate the toxicity of PolaR-ICE salvage therapy and that of Pola consolidation after ASCT.
V. Assess the rate of stem cell mobilization and collection failure in patients with R/R DLBCL who receive PolaR-ICE as first salvage therapy.

EXPLORATORY OBJECTIVES:
I. Assess the kinetics of circulating tumor deoxyribonucleic acid (DNA) after PolaR-ICE as first salvage therapy for R/R DLBCL followed by ASCT and single-agent Pola consolidation after ASCT.
II. Assess possible biomarkers of response to PolaR-ICE in patients with R/R DLBCL.
III. Examine the association between clinical outcomes (response, progression-free survival [PFS]) and pathological tumor characteristics.
IV. Examine the association between clinical outcomes (response, PFS) and circulating tumor (ct)DNA characteristics (mutation profile, kinetics of clearance).

OUTLINE:

SALVAGE THERAPY: Patients receive polatuzumab vedotin intravenously (IV) on day 1, rituximab IV on day 1, etoposide IV on days 1-3, carboplatin IV on day 2, and ifosfamide IV on day 2 or days 1-3. Treatment repeats every 21 days for up to 2-3 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response, partial response or stable disease by cycle 2 day 15 (C2D15) may receive 1 additional cycle of PolaR-ICE IV.

CONSOLIDATION THERAPY: Within 30-60 days after ASCT, patients receive polatuzumab vedotin IV on day 1. Treatment repeats every 21 days for up to 3-4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then periodically for up to 2 years.

Eligibility

1. Documented informed consent of the participant and/or legally authorized representative * Assent, when appropriate, will be obtained per institutional guidelines
2. Be willing to provide archival tissue of a biopsy that was performed after the frontline systemic therapy * If unavailable, exceptions may be granted with study principal investigator (PI) approval
3. Eastern Cooperative Oncology Group (ECOG) =< 2
4. Histologically confirmed diagnosis of diffuse large B-cell lymphoma according to the World Health Organization (WHO) classification, with hematopathology review at the participating institution. Subtypes of DLBCL including transformed indolent lymphomas (TIL), primary mediastinal large B-cell lymphoma (PMBCL), and aggressive B-cell lymphoma unclassified (BCL-U) are eligible
5. Biopsy-proven relapsed or refractory disease after 1 line of frontline CD20-directed immunotherapy with anthracycline- or anthracenedione-based multi-agent chemotherapy. Monotherapy with rituximab or other CD20-directed immunotherapy prior to frontline chemotherapy or as maintenance therapy, and radiation therapy in a limited field or as a part of the frontline treatment plan are permitted
6. Prior lymphoma therapy should be completed at least 2 weeks before start of protocol therapy
7. Measurable disease by computed tomography (CT) or positron emission tomography (PET)/CT scan with one or more sites of disease >= 1.5 cm in longest dimension
8. Considered eligible for high-dose chemotherapy followed by ASCT
9. Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 to prior anti-cancer therapy
10. Absolute neutrophil count (ANC) >= 1,000/mm^3 (without bone marrow involvement) * NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement
11. ANC >= 750/mm^3 (with bone marrow involvement) * NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement
12. Platelets >= 100,000/mm^3 (without bone marrow involvement) * NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement
13. Platelets >= 75,000/mm^3 (with bone marrow involvement) * NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement
14. Hemoglobin >= 8 g/dL (no erythropoietin and/or packed red blood cells (pRBC) transfusion allowed within 7 days prior to screening) * Exception: unless cytopenia is secondary to disease involvement
15. Total bilirubin =< 1.5 X upper limit of normal (ULN). If hepatic involvement by lymphoma, or Gilbert’s disease: =< 3 X ULN
16. Aspartate aminotransferase (AST) =< 2.5 x ULN. If hepatic involvement by lymphoma: AST =< 5 x ULN
17. Alanine aminotransferase (ALT) =< 2.5 x ULN. If hepatic involvement by lymphoma: ALT =< 5 x ULN
18. Creatinine clearance of >= 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula
19. If not receiving anticoagulants: international normalized ratio (INR) OR prothrombin (prothrombin time [PT]) =< 1.5 x ULN. If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
20. If not receiving anticoagulants: activated partial thromboplastin time (aPTT) =< 1.5 x ULN. If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
21. Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
22. Agreement by females and males of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 12 months after the last dose of polatuzumab vedotin or rituximab for women, at least 5 months following the last dose of polatuzumab vedotin or 3 months following the last dose of rituximab for men, and at least 6 months following the last dose of ifosfamide, carboplatin, or etoposide for both women and men * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)