Polatuzumab Vedotin Combined with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP) for Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results of a Phase Ib Dose-Escalation
Authors: Bartlett Nancy L. , Chen Andy I , Kolibaba Kathryn S. , Lamy Thierry , Jones Surai , Hirata Jamie , Sharman Jeff P. 
Published: October 2019

Abstract
Introduction: Rituximab-CHOP (R-CHOP) has resulted in significantly improved outcomes for patients (pts) with untreated DLBCL. Despite this progress, approximately 30% of pts are not cured with R-CHOP, especially those with high risk disease as defined by the IPI. Polatuzumab vedotin (PoV) is an antibody drug conjugate (ADC) designed for the targeted delivery of the potent microtubule inhibitor MMAE to cells expressing CD79b. Because ADCs may possess a therapeutic index superior to that of many systemically administered chemotherapies, PoV has the potential to replace vincristine with a targeted agent and potentially increase the potency of the standard R-CHOP regimen. We report preliminary results from the dose-escalation portion of this Phase Ib/II study of PoV combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) (ClinicalTrials.gov NCT01992653).
Methods: This multicenter, open-label study will evaluate the safety, tolerability, and pharmacokinetics of escalating doses of PoV with standard doses of R-CHP. Adults, ages 60-80 years, with newly diagnosed or relapsed/refractory B-cell NHL were given PoV intravenously 1.0, 1.4, or 1.8 mg/kg with R-CHP every 21 days for a total of 6 or 8 cycles. Doses were escalated in a 3+3 design based on dose limiting toxicity assessment during cycle 1. Assessments for anti-tumor activity were performed following 4 cycles of study treatment (tx) and at the end of study tx (EOT).
Results: 13 pts (46% male) enrolled in the R-CHP + PoV dose-escalation phase of the study. Median age was 68 years (range 60-73). Pts had untreated DLBCL (n=10), relapsed FL (n=2), and untreated MZL (n=1). At baseline, pts had stage I/II (5), III/IV (8) disease and ECOG status of 1-2 (6). Of 10 DLBCL pts, 4 had age adjusted IPI (aaIPI) 2, and 6 had aaIPI 0-1. At the time of this report, all pts in the 1.0 mg/kg (n=3), 1.4 mg/kg (n=3) and 4 of 7 pts in the 1.8 mg/kg cohort completed study tx.
The most common adverse events (AEs) in >3 pts were nausea (8), fatigue (7), diarrhea (6), neutropenia (5), dizziness (4), peripheral neuropathy (PN; 4), and insomnia (4). Across all dose levels, 8 pts had a total of 18 grade (Gr) 3/4 AEs including neutropenia (10), thrombocytopenia (1), febrile neutropenia, pneumonia (2 each), DVT, PE, and ophthalmic herpes zoster (1 each).
Six pts experienced a serious AE (SAE). Four pts in the 1.8 mg/kg cohort had SAEs: 1 pt with Gr 2 dysphagia (not attributed to tx), 1 pt with Gr 4 pulmonary embolism (PE) and neutropenia and Gr 3 pneumonia (all tx-related), 1 pt with 2 episodes of Gr 4 neutropenia (tx-related that investigator deemed life-threatening), and 1 pt with Gr 4 pneumonia (not attributed to tx). The PE event was determined to be a DLT by the investigator. This pt had a concurrent event of deep vein thrombosis (non-serious). Seven of 13 pts experienced PN (Gr 1 [n=6] and Gr 2 [n=1]). The pt who had the Gr 2 PN received 2.4 mg/kg of PoV with R-CHP in error for 4 cycles and had additional risk factors for PN including history of diabetes mellitus, prior vincristine therapy. One tx discontinuation due to AE occurred due to Gr 2 PN in this pt who received PoV 2.4 mg/kg. One pt had a dose reduction for Gr 3 neutropenia. No deaths were reported.
Of the 10 pts with DLBCL, 8 were assessed for interim response by PET/CT: 5 CR [1 at 1.0 mg/kg, 3 at 1.4 mg/kg, and 1 at 1.8 mg/kg], 3 PR [1 at 1.0 mg/kg and 2 at 1.8 mg/kg]). Two of 10 had not completed 3 cycles of tx and therefore not assessable for interim response. At the EOT, 7 were assessed for response: 5 CR (1 at 1.0 mg/kg, 3 at 1.4 mg/kg, and 1 at 1.8 mg/kg), 1 PR (at 1.0 mg/kg), 1 unevaluable (at 1.8 mg/kg). The 3 other pts were not assessed because they did not have a PET scan at EOT.
Of the 2 pts with FL: one had SD (1.0 mg/kg) and one was not evaluable at the time of this report (2.4 mg/kg) at the EOT. One pt with MZL had CR at the EOT, then progressed at month 3 follow-up with biopsy proven transformed DLBCL.
Conclusions: Early results show that PoV plus R-CHP has an acceptable safety profile in pts with previously untreated DLBCL. The PoV doses tested (1.0, 1.4, and 1.8 mg/kg) in this study showed acceptable toxicity in previous studies with relapsed NHL pts. Although the protocol-specified MTD was not formally reached, the recommended phase 2 dose of PoV was established at 1.8 mg/kg based on the overall safety and tolerability profile at that dose. The study's Phase 2 PoV+R-CHP expansion and the Phase Ib PoV+obinutuzumab-CHP dose escalation are ongoing.

Disclosures
Bartlett: AstraZeneca: Research Funding; Janssen: Research Funding; ImaginAb: Research Funding; Pharmacyclics: Research Funding; Genentech, Inc.: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Medimmune: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy. Off Label Use: Polatuzumab vedotin is an investigational agent and not approved for DLBCL. Chen:Genentech, Inc.: Consultancy, Other: Advisory Board; Seattle Genetics: Consultancy, Other: Advisory Board; Janssen: Consultancy, Other: Advisory Board; Gilead: Consultancy, Other: Advisory Board. Kolibaba:Seattle Genetics: Research Funding; TG Therapeutics: Research Funding; GSK: Research Funding; Acerta: Research Funding; Genentech, Inc.: Research Funding; Novartis: Research Funding; Cell therapeutics: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Amgen: Research Funding; Pharmacyclics: Research Funding. Jones:Genentech, Inc.: Employment. Hirata:Genentech, Inc.: Employment, Equity Ownership. Sharman:TG Therapeutics, Inc.: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Janssen: Research Funding; Calistoga: Honoraria.