ALBERT

Description: Introduction: For patients with relapsed or refractory DLBCL with chemosensitive disease after 2nd line (salvage treatment), AutoHCT is considered the standard of care. Risk factors for progression following AutoHCT include primary refractory disease and early relapse (

Description: Introduction and Objectives: Mycosis fungoides and Sezary syndrome (MF/SS) represent a group of heterogeneous diseases. Recent studies demonstrated dysregulation of several signaling pathways in MF/SS, including PI3K/AKT, JAK/STAT, RAS and NFkB pathways. We performed a high throughput drug screen to determine the potential of novel agents targeting these pathways for the treatment of MF/SS. Materials and Methods: We compiled a libraryof 94 compounds targeting pathways known to be relevant in cancer biology. These included kinases involved in growth factor receptor signaling, HDACs, proteasome, DNA repair and regulators of apoptosis. The compounds were screened for anti-proliferative activity against four MF/SS cell lines in high throughput proliferation assays. Selected hits were further studied in xenograft models of MF/SS and in primary T cell lymphomas. Promising candidates from different classes were also tested in combination therapy assays using a matrix block method across dose gradients of each compound designed to detect synergistic activities. Results: From the high throughput screen, we identified 14 compounds with anti-proliferative activity in MF/SS, including multiple inhibitors of the PI3K pathway. PI3K inhibitors emerged as preliminary hits in this screen and secondary validation assays confirmed the class effect of PI3K inhibitors. From this class, the PI3K inhibitor BKM120 was selected for in vivo studies. In a xenograft model of MF, BKM120 exhibited striking anti-tumor activity measured by a marked suppression of tumor growth and prolonged survival of tumor-bearing mice compared with vehicle control. In a search for even more effective combination therapies, we identified that BKM120 and the HDAC inhibitor class of compounds exhibit synergistic anti-proliferative effects in MF/SS tumor cells. Each of three HDAC inhibitors including LBH, Romidepsin and Vorinosat showed synergistic activity with BKM120, most evident at the GI50 concentrations of each drug, and apparent in both growth inhibition and apoptotic assays. Conclusion: BKM120 is highly active in preclinical models of MF/SS. Furthermore, it synergistically potentiates the effect of HDAC inhibitors against MF/SS tumor cells. These are highly promising approaches for the treatment of MF/SS and warrant clinical investigation. Disclosures No relevant conflicts of interest to declare.

Description: 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.

Description: Background: Despite numerous treatment (Tx) options, follicular lymphoma (FL) remains incurable, and established common treatments such as chemoimmunotherapy combinations and kinase inhibitors can have significant morbidity, especially in older patients or in those with comorbidities. G100 is a TLR4 (toll-like receptor 4) agonist that activates both the innate and adaptive arms of the immune system. When given intratumorally (IT), G100 triggers an anti-tumor immune response that leads to systemic tumor shrinkage (Flowers ASCO 2017). Initial data from a randomized study of the combination of G100 and pembrolizumab (P) demonstrated that the addition of P resulted in more PRs, abscopal tumor shrinkage, and a trend to a better PFS than G100 alone. In addition, an association between baseline tumor TLR4 expression by immunohistochemistry (IHC) and clinical response was observed (Flowers ASH 2017). We now present updated response data and long-term follow-up of this randomized study. Methods: Previously treated or Tx naïve FL pts with ≥2 tumor sites were eligible. Pts received 6-9 doses of IT G100 (G) weekly to a site treated with low dose radiation (RT, 2 Gy x2 doses). A 2nd course of G could be given without additional RT to an additional site. Pts were randomized to IT G (10 µg/dose) or IT G + P 200mg IV on Day 14 then q3wks for up to 2 years. Responses were evaluated by IrRC criteria based on bidimensional measurements (Wolchok ClCanRes 2009). Untreated sites were followed for abscopal response. Results: As of 3July2018, 26 FL pts were treated (13, G vs. 13, G + P). 7 and 5 pts were Relapsed/Refractory (R/R) in G and G+P, respectively. Median number of prior therapies were 3 for G and 4 for G+P and included 5pts previously Tx with auto-SCT. Median duration of observation was 14.3 and 16.6 mos for the G and G+P, respectively. G was well tolerated; related AEs were all grade (Gr) 1/ 2 with no G-related DLTs or SAEs. For G+P, 1 pt experienced Gr 2 hypothyroidism and 1pt, Gr 3 colitis/lab abnormalities/adrenal insufficiency (SAE). No deaths were reported. Overall best responses (PRs) were: 23% in pts on G and 54% in pts on G+P. In the R/R population, PRs occurred in 29% of pts on G and in 80% of pts on G+P. Median time to response was 2.3 mos (range 1.7-18.1) for G and 3.7 mos (range 2.2-17.1) for G+P, and included delayed responses at ≥18mos. Among pts with baseline TLR4high (≥50%) tumor expression, ORR was 17% for G (n=6) vs 75% for G+P (n=8). Within the GELF high tumor burden pts, PRs occurred in 0% of pts in G and in 33% of pts in G+P. Likewise, in pts failing R-Chemo

Description: Background Although multiple studies have shown superiority of allogeneic hematopoietic cell transplantation (alloHCT) over autologous hematopoietic cell transplantation (autoHCT) for patients with "high-risk" acute lymphoblastic leukemia (ALL), these findings may be explained, in part, by contamination of the peripheral blood progenitor cell (PBPC) leukapheresis product by residual leukemic cells in patients undergoing autoHCT. Methods We retrospectively evaluated minimal residual disease (MRD) via next-generation sequencing (NGS) (Adaptive Biotechnologies, S. San Francisco, CA) in the PBPC leukapheresis products from 32 ALL patients who underwent autoHCT. All patients had "high-risk" ALL, as defined by B-lineage disease with WBC at diagnosis 〉30,000/uL; high-risk cytogenetics including t(9;22), t(4;11), other 11q23 abnormalities, or monosomy 7; or primary refractory disease. Peripheral hematopoietic cell mobilization consisted of cytarabine 2000mg/m2 IV every 12 hours (16,000mg/m2 cumulative) concurrent with etoposide 40mg/kg cumulative by continuous IV infusion over 4 days. The autoHCT conditioning consisted of 1320cGy total body irradiation (TBI) given in 11 fractions from day -8 to -5, etoposide 60mg/kg IV on day -4, and cyclophosphamide 100mg/kg IV on day -2. Tyrosine kinase inhibitors (TKI) were allowed for patients with Philadelphia chromosome-positive (Ph+) B-ALL. Seven patients (22%) participated in a multi-institutional trial in which the PBPC graft underwent ex vivo complement-mediatedpurging using monoclonal antibodies against CD9/CD10/CD19/CD20 for patients with B-lineage disease, or against CD2/CD3/CD4/CD5/CD8 for patients with T-lineage disease. Kaplan-Meier curves were generated using GraphPad Prism (GraphPad Software, La Jolla, CA) and statistical differences assessed via Log-Rank and Wilcoxon analyses, with a p-value of

Description: Cutaneous T cell lymphoma (CTCL) is an orphan disease and represents 3% of non-Hodgkin lymphomas. Mycosis fungoides and Sézary syndrome (MF/SS) are the most common subtypes of CTCL. The development of targeted therapies for orphan diseases is challenging, but particularly so in the case of MF/SS due to the lack of reliable preclinical models for this malignancy, which is limited to the skin at the early stage, but disseminated to lymph nodes and other organs as disease progresses. Here we report a novel patient-derived xenograft (PDX) mouse model of MF/SS that recapitulates the multi-compartmental nature of CTCL and a blood-based genetic biomarker assay for quantitative monitoring of systemic tumor burden in PDX mice. The PDX models were extensively characterized and exhibit cardinal clinical and histologic features of CTCL, including erythematous scaly skin lesions and eventual lymphomatous dissemination to the spleen and other organs, and maintain the molecular characteristics of their clinical counterparts. The malignant T cells harvested from spleen of PDX mice shared identical TCR sequences and immunophenotypes with corresponding MF/SS patient donor, which featured as losing CD7 and CD26 expression in CD4+ T cells. We also developed a quantitative assay of tumor burden in PDX mice by determining the amount of human β-actin cell-free DNA (cfDNA) in the plasma. The cfDNA levels in the plasma were increased in a linear fashion and correlated with the tumor growth post-implantation. To explore the utility of this PDX model for drug testing, we searched for novel agents for CTCL by performing a high-throughput screen of selected available targeted agents and identified phosphatidylinositol 3-kinase (PI3K) as a high value target. A PI3K inhibitor was advanced to our PDX model with favorable results including disease attenuation and survival prolongation. Further experiments using isoform-specific siRNA knockdowns and isoform-selective PI3K inhibitors identified PI3K-δ as the tumor-driving isoform. Additional studies showed synergistic combination of PI3K-δ inhibitors with histone deacetylase (HDAC) inhibitors. The particularly potent combination of copanlisib and panobinostat is proposed for further clinical development. Disclosures McCormick: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aduro BioTech,Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; BridgeBio Pharma,Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Stock;Ownership; Caris Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo Co., Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; NeuroTrials,LLC: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences,Inc.: Research Funding; Leidos Biomedical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Navire: Membership on an entity's Board of Directors or advisory committees, Other: Stock;Ownership; Riptide Bioscience: Membership on an entity's Board of Directors or advisory committees; Quadriga Biosciences: Membership on an entity's Board of Directors or advisory committees; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PMV Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer,Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ai:Nurix Inc: Research Funding; ADC Therapeutics: Honoraria; Bayer: Honoraria; BMS: Honoraria; Kirin: Honoraria; Immune Design: Honoraria; Seattle Genetics: Honoraria.