A Phase II Study Evaluating Safety and Efficacy of Polatuzumab Vedotin in Combination with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone in Patients with Previously Untreated Double and Triple Hit Lymphoma

Background: Double hit lymphoma (DHL) accounts for approximately 10-14% of diffuse large B cell lymphoma (DLBCL) and is characterized by the presence of rearrangements affecting MYC and either BCL2 and/or BCL6 by FISH. The complete response (CR) rate with standard R-CHOP is very poor at 20%, with dismal long-term progression-free (PFS) and overall survival (OS). Aggressive chemotherapy regimens including R-EPOCH, R-HyperCVAD/MA, and R-CODOX-M/IVAC have been evaluated in retrospective studies and have demonstrated better PFS compared to R-CHOP. However, no OS benefit is noted. Moreover, these regimens are associated with significant toxicity and cannot be used in a substantial proportion of patients due to advanced age and comorbidities, and have not been evaluated in prospectively studies. Therefore, new therapeutic modalities, which are better tolerated, are indeed needed to improve outcomes in this high-risk population.

Polatuzumab vedotin (PoV) is a CD79b-directed antibody-drug conjugate delivering monomethyl auristatin E (MMAE). PoV either as a single agent or with bendamustine and rituximab (BR) demonstrated encouraging activity in relapsed refractory DLBCL with an overall response rate (ORR) of approximately 50%. Given the promising activity, PoV has been combined with rituximab, cyclophosphamide, doxorubicin, prednisone (R-CHP) in a phase 1b/2 trial, and has shown a favorable safety and tolerability profile.

Study design and Methods: This is a phase II, multicenter, open label study of PoV 1.8 mg/kg in combination with standard doses of R-CHP in patients with untreated double or triple hit lymphoma. One cycle of R-CHOP prior to enrollment is allowed. Key eligibility criteria include patients aged > 18 years with previously untreated double or triple hit lymphoma, ECOG PS 0 to 2, measurable FDG-avid disease. Key exclusion criteria are DLBCL NOS subtype, primary mediastinal or Burkitt's lymphoma, and CNS involvement. A total of 49 patients will be enrolled. All patients will receive PoV with R-CHP every 3 weeks for a total of 6 cycles with intrathecal methotrexate for CNS prophylaxis. The primary endpoint is CR rate. Key secondary endpoints are PFS, OS, ORR, duration of response, and safety and tolerability of the combination. Disease response will be assessed by the Lugano response criteria. The study is currently enrolling. ClinicalTrials.gov Identifier: NCT04479267.