Gouill, Steven Le

TPS7575 Background: Approximately 50% of patients (pts) with advanced DLBCL are refractory to or relapse following first line R-CHOP therapy. Pts with R/R DLBCL have limited treatment options and a poor prognosis. This study assesses immunotherapy-based regimens containing avelumab (a fully human IgG1 anti–PD-L1 antibody) in combination with utomilumab (a novel 4-1BB agonist), azacitidine, rituximab, and/or conventional chemotherapy (CT; bendamustine) in pts with R/R DLBCL. Methods: JAVELIN DLBCL (NCT02951156) is a global, multicenter, randomized, open-label, 2-component(phase 1b followed by phase 3) study of avelumab-based combination regimens in R/R DLBCL. In phase 1b, up to 84 pts will be randomized 1:1:1 to receive avelumab/rituximab/utomilumab, or avelumab/azacitidine/utomilumab, or avelumab/rituximab/bendamustine. The primary phase 1b objectives are preliminary assessments of dose-limiting toxicities (n = 6 per arm) and efficacy (objective response [OR]; n = 28 per arm). One regimen from phase 1b will be selected for phase 3 evaluation in 220 additional pts randomized 1:1 to the chosen regimen or investigator’s choice CT (rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin). The primary phase 3 objective is to demonstrate progression-free survival (PFS) superiority of the avelumab-based regimen over CT. Overall survival is a key secondary endpoint. Eligible pts have completed up to 4 lines of prior rituximab/multiagent CT, and/or have failed autologous stem cell transplantation (ASCT), or are not eligible for intensive CT or ASCT. Other eligibility criteria include ECOG PS ≤1 and no prior therapy with a checkpoint inhibitor. Treatment with avelumab, utomilumab, and azacitidine will be continued until the pt no longer receives clinical benefit; rituximab and bendamustine are limited to 8 and 6 cycles, respectively. OR and PFS will be assessed per Lugano disease classification criteria. Other secondary efficacy endpoints include disease control, duration of response, time to response, and minimal residual disease burden. Safety, PK, immunogenicity, pt-reported outcomes, and biomarkers will also be evaluated. Clinical trial information: NCT02951156.

TPS7574 Background: The PD-1/PD-L1 pathway is an important immune checkpoint used by tumor cells to evade immune cell detection and inhibit antitumor responses. PD-1/PD-L1 expression in multiple hematologic malignancies may provide an effective target for enhancing anticancer immune response. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal Ab that selectively blocks PD-L1 binding to PD-1 and CD80, and has shown preliminary evidence of antitumor activity across multiple tumor types. Study objectives are to evaluate durvalumab monotherapy and combinations to determine dose and safety, as well as identify histologies and combinations that show the best complementary antitumor signals for future study. Methods: This is a phase I/II open-label, global, multicenter study of durvalumab as a monotherapy and in combination in relapsed/refractory B-cell lymphoma or CLL (MEDI4736-NHL-001; EUDRA CT 2015-003516-21; NCT02733042). Patients must have histologically-confirmed FL, MCL, splenic or nodal MZL, T-cell/histiocyte rich BCL, PMBCL, ALK+ large BCL, transformed large BCL, Richter’s transformation, DLBCL (NOS), CLL/SLL, or classical HL during the dose-finding part. Inclusion criteria are ECOG PS 0-2, and ≥1 prior antilymphoma therapy. Up to 253 patients may enroll in 4 treatment arms, which include fixed-dose durvalumab 1500 mg Q4W monotherapy or combinations with lenalidomide/rituximab, ibrutinib, or bendamustine/rituximab. The study has 3 parts: dose finding, dose confirmation, and dose expansion. The monotherapy arm does not have a dose finding or expansion part; upon progression, patients may receive combination therapy or involved-field radiation to a single nodal site (evaluating for systemic abscopal antitumor effect). Primary endpoints are safety, identification of recommended phase II dose (phase I, 3+3 design), and overall response rate (ORR; phase II); secondary endpoints include DOR, PFS, and PK/PD. ORR is measured by 2014 IWG criteria for lymphoma or modified 2008 iwCLL criteria for CLL; safety is assessed per NCI CTCAE v4.03 criteria. Recruitment is ongoing, with a target enrollment of 253 patients across 60-80 centers globally. Clinical trial information: NCT02733042.

A critical role for vascular endothelial factor (VEGF) has been demonstrated in multiple myeloma (MM) pathogenesis. Here, we characterized the effect of the small-molecule VEGF receptor inhibitor pazopanib on MM cells in the bone marrow milieu. Pazopanib inhibits VEGF-triggered signaling pathways in both tumor and endothelial cells, thereby blocking in vitro MM cell growth, survival, and migration, and inhibits VEGF-induced up-regulation of adhesion molecules on both endothelial and tumor cells, thereby abrogating endothelial cell-MM cell binding and associated cell proliferation. We show that pazopanib is the first-in-class VEGF receptor inhibitor to inhibit in vivo tumor cell growth associated with increased MM cell apoptosis, decreased angiogenesis, and prolonged survival in a mouse xenograft model of human MM. Low-dose pazopanib demonstrates synergistic cytotoxicity with conventional (melphalan) and novel (bortezomib and immunomodulatory drugs) therapies. Finally, gene expression and signaling network analysis show transcriptional changes of several cancer-related genes, in particular c-Myc. Using siRNA, we confirm the role of c-Myc in VEGF production and secretion, as well as angiogenesis. These preclinical studies provide the rationale for clinical evaluation of pazopanib, alone and in combination with conventional and novel therapies, to increase efficacy, overcome drug resistance, reduce toxicity, and improve patient outcome in MM.

AbstractPrevious studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3′-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.