A Phase 1b Dose Escalation Trial of Carfilzomib in Combination with Bendamustine and Rituximab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma
Authors: Kambhampati Swetha , Fakhri Bita , Ai Weiyun , Kaplan Lawrence D , Tuscano Joseph , Wieduwilt Matthew J. , Sudhindra Akshay , Hwang Jimmy , Reiner Jesika , Martinelli Michelle , Aoun Charlie , Ta Teresa , Le Diem , Padilla Michelle , Crawford Erika , Andreadis Charalambos 
Published: November 2019

Background
Despite advances in therapy, relapsed or refractory (RR) non-Hodgkin lymphoma (NHL) remains a major treatment challenge. Preclinical data support the activity of proteasome inhibitors against lymphoma through multiple mechanisms including activation of the endoplasmic reticulum (ER) stress response and reduction in the threshold for apoptosis in response to chemotherapy. Clinically, proteasome inhibiton with bortezomib added to bendamustine yielded promising results in patients (pts) with indolent NHL with limited additional toxicity. Compared to bortezomib, carfilzomib is a more target specific and potent proteasome inhibitor with less neurotoxicity. We embarked on a multicenter, phase 1b dose escalation trial to assess the combination of carfilzomib with bendamustine and rituximab in pts with RR aggressive or indolent NHL.
Methods
The primary objective of the study is to determine the maximum tolerated dose (MTD) and recommended phase II dose of carfilzomib when combined with bendamustine and rituximab. The secondary objective is to evaluate the preliminary antitumor activity of the combination in select NHL histologies. Correlative studies examine markers of ER stress and apoptosis in response to treatment. Here we report the preliminary results of the dose escalation phase expected to be completed in Fall 2019. We followed a standard 3+3 design with escalation of the carfilzomib dose in 4 dose level cohorts combined with bendamustine dosed at 90 mg/m2 IV on Days 1 and 2 and Rituximab dosed at 375 mg/m2 IV on Day 9 of cycle 1 and Day 1 of subsequent cycles. Initially, carfilzomib was dosed twice a week with dose level 1 at 15 mg/m2 IV on days 1,2,8,9, 15, and 16. Subsequently, we explored weekly dosing schedules with carfilzomib at 36 mg/m2 (dose level 2), 56 mg/m2 (dose level 3), and 70 mg/m2 (dose level 4) on days 9 and 16 with a 20 mg/m2 starting dose on day 2. Dose limiting toxicity (DLT) was defined as Gr4 or specific Gr3 events attributable to the combination. Pts are treated for up to 6 cycles with an interim PET/CT after cycle 3.
Results
To date, 10 pts have been treated on the dose escalation phase with one patient currently on study treatment. Overall, 5 pts had diffuse large B-cell lymphoma (DLBCL), 3 mantle cell lymphoma (MCL), 1 follicular lymphoma (FL), and 1 marginal zone lymphoma (MZL). Pts received a median of 3 prior lines of therapy. Four pts were treated on dose level 1, 3 on dose level 2, and 3 on dose level 3. Treatment-emergent Grade 2-4 adverse events included thrombocytopenia in 1 pt (Gr 4), neutropenia in 1 pt (Gr 4), febrile neutropenia in 1 pt (Gr 3), culture negative fevers in 1 pt (Gr 3), nausea/vomiting in 2 pts (Gr 2 and 3), other GI toxicities in 1 pt (Gr 2), lower back pain in 1 pt (Gr 2), arthralgias in 1 pt (Gr 2), and cerebrevoascular ischemia in 1 pt (Gr 2). Two pts had treatment related-SAEs (Gr3 culture negative fevers; Gr 3 febrile neutropenia and Gr 3 vomiting) at dose level 2 and 3 respectively. One patient experienced DLT (Gr 3 febrile neutropenia) at dose level 3. There were no treatment related deaths. Of 10 evaluable pts to date, the overall response rate (ORR) is 40% with 3 pts achieving complete remission (one with FL, one with DLBCL and one with MCL) and one pt with MCL achieving a partial remission. The responder with FL had relapsed disease after achieving prior complete remission with rituximab and bendamustine alone. For the 9 pts who completed study treatment, median duration of treatment was 2.4 months, median progression free survival was 1.9 months and median overall survival was 11.6 months. The median duration of response for the 3 responders who completed therapy was 21.8 months.
Conclusion
Carfilzomib in combination with bendamustine and rituximab is a safe and well-tolerated treatment for pts with RR NHL. The MTD has not been reached and enrollmemt continues, with dose escalation phase anticipated to complete in Fall 2019. Preliminary data indicate that this combination may have efficacy with an acceptable side effect profile in this heavily pre-treated patient population with limited treatment options.
Disclosure: This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program with general research support provided by Amgen.

Disclosures
Tuscano: Spectrum: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Honoraria; Amgen: Honoraria; Takada: Research Funding; Abbvie: Research Funding; Genentech: Research Funding. Wieduwilt:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership. Andreadis:Genentech: Equity Ownership, Other: Spouse is Employee; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy.