Brentuximab Vedotin (BV) Plus Rituximab (R) As Frontline Therapy for Patients (Pts) with Epstein Barr Virus (EBV)+ and/or CD30+ Lymphoma: Phase I Results of an Ongoing Phase I-II Study
Authors: Gandhi Mitul , Ma Shuo , Smith Sonali M. , Nabhan Chadi , Evens Andrew M. , Winter Jane N. , Gordon Leo I. , Petrich Adam M. 
Published: October 2019

Background
Although there is no standardized frontline therapy for pts with post transplant lymphoproliferative disorder (PTLD), aggressive induction with chemoimmunotherapy (CIT) is associated in this population with excess toxicity (Choquet, 2007). Recent data support a risk-stratified sequential therapy approach, in which pts receive single-agent R, with aggressive CIT reserved for those not achieving complete response (CR; Trappe, 2012). However, only about 25-30% of pts treated by this method are spared aggressive CIT. Furthermore, elderly pts (eg, EBV-related DLBCL of elderly) and those with autoimmune disorders are prone to lymphoma sharing clinicopathological characteristics with PTLD, such as EBV, CD30, and CD20 coexpression. BV is a novel antibody-drug conjugate that received accelerated FDA approval based on high response rates in pts with relapsed/refractory CD30+ lymphoma. We hypothesized that a combination of BV and R would yield higher response rates than R alone, would limit exposure to CIT, and its attendant toxicity, in these pts.
Methods
We initiated a Phase I-II trial of the combination of BV and R in adults with previously untreated CD20+ NHL, with co-expression of EBV and/or CD30 (all at any level). Pts with central nervous system involvement, HIV infection, and those lacking history of immunodeficiency, were excluded. Induction consisted of R 375 mg/m2 days 1, 8, 15 22, and BV 1.2 mg/kg, days 1, 8, and 15, followed by restaging. Those with progressive (PD) or stable disease (SD) were removed from protocol and treated per local investigator (CIT recommended). Pts with partial response (PR) or CR could receive a second identical induction, followed by maintenance therapy (MT), or move directly to MT without consolidation. MT consisted of BV 1.8 mg/kg every 3 weeks and R 375 mg/m2 every 6 weeks for up to one year of total therapy. A standard 3 + 3 design was employed for Phase I, with provisional dose reduction in BV to 0.8 mg/kg. Toxicity data was defined using CTCAE 4.0. Response (Cheson, 2007) was assessed, at the end of induction, consolidation (if given), and after cycles 4 and 7 of BV. The primary objective in the phase I portion was to evaluate the safety of the combination of BV and R and to determine the recommended phase II dose (RP2D) of the combination.
Results
Toxicity and response data are available on seven pts (six treated in Phase I). Four were female, and median age was 61. Five pts had PTLD, diagnosed between 2 and 26 years from transplant, and two had pre-existing autoimmune disease with histories of iatrogenic immunosuppression. Patient characteristics and response data are summarized in Table 1. Five patients (71%) had a CR as best response. At median follow up of 9 months, no pts had PD or had died. One pt with SD as best response achieved CR after CIT, and another with SD declined further therapy but had not progressed at last follow up. Both pts with EBV+ serum by PCR at baseline cleared the virus during therapy. The most frequent Grade 3/4 adverse events (AE) observed were lymphopenia and neutropenia. The most frequent AE of any grade were anemia, transaminitis, and lymphopenia (Table 2). A dose reduction was not required after treatment of the first cohort, but an expansion cohort was requested by the Data/Safety Monitoring Committee for an episode of hyperbilirubinemia (primarly indirect and attributed to blood transfusion). No dose reductions were required during phase I, and the starting dose was the RP2D.
Conclusions
The combination of BV and R has an acceptable safety profile, appears efficacious and capable of sparing pts exposure to CIT, and warrants further evaluation in patients with CD30+ and/or EBV+ lymphomas with the RP2D idenfitied above.
TABLE 1 Characteristics & Outcomes Pt Histology Stage IPI EBV (Serum) CD30 (IHC) Response(Induction) Best Response(Induction or MT) 1 P 4 2 + + CR CR 2* M 1 0 - + PR CR 3 M 3 3 - + PR CR 4 HL 3 1 - + CR CR 5* TCL 1 2 + - SD SD 6 M 4 1 - + SD SD 7 M 3 3 - + CR CR
P: Polymorphic; M- Monomorphic large B cell like; TCL- T cell lymphoma; HL- Hodgkin's Like Lymphoma
* Immunosuppression Related Lymphoma without history of solid organ transplant
TABLE 2 Adverse events occurring in 50% or more of patients (total n=7) Adverse Event Grade 1 & 2 (n) Grade 3 & 4 (n) Anemia 5 1 Abdominal Pain 4 0 Diarrhea 3 0 Nausea 3 0 Fatigue 4 0 Elevated AST 3 2 Hyperbilirubinemia 2 1 Lymphopenia 1 4 Neutropenia 1 3 Anorexia 3 0 Hypoalbuminemia 5 0 Peripheral neuropathy 2 2

Disclosures
Nabhan: Celgene: Honoraria, Research Funding. Petrich:Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics : Consultancy, Honoraria, Research Funding, Speakers Bureau.