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T cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy, and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T cell infiltration to the tumor core. The spatial regulation of ANGPT2 in whole tumor cross-sections was analyzed in conjunction with T cell distribution, vascular integrity, and response to immunotherapy in syngeneic murine melanoma models. T cell exclusion was associated with ANGPT2 upregulation and elevated vascular leakage at the periphery of human and murine melanomas. Both pharmacological and genetic blockade of ANGPT2 promoted CD8+ T cell infiltration into the tumor core, exerting antitumor effects. Importantly, the reversal of T cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 immune checkpoint blockade therapy in immunogenic, therapy responsive mouse melanomas, but it also rendered non-responsive tumors susceptible to immunotherapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T cell infiltration to the tumor core, coincided with spatial TIE2 signaling activation and increased vascular integrity at the tumor periphery where endothelial expression of adhesion molecules was reduced. These data highlight ANGPT2/TIE2 signaling as a key mediator of T cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma.

Supplementary Data from A Phase 1 Dose-Escalation Study of Irinotecan in Combination with 17-Allylamino-17-Demethoxygeldanamycin in Patients with Solid Tumors

Purpose: Both heat shock protein 90 (Hsp90) and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors.Experimental Design: During the dose escalation phase, patients received i.v. irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity.Results: Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity at dose level 4 (100 mg/m2 irinotecan and 375 mg/m2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by the coadministration of irinotecan, and vice versa. There was no partial response, although tumor shrinkage was observed in six patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P = 0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G2-M cell cycle checkpoint, and cell death could be shown in tumor biopsy samples obtained at the MTD.Conclusions: The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m2 irinotecan and 300 mg/m2 17AAG.

Immune checkpoint inhibitors (ICI) have demonstrated limited success in patients with metastatic uveal melanoma (MUM) with liver involvement due to an immunosuppressive tumor microenvironment (TME) driven in part by myeloid-derived suppressor cells (MDSCs). Toll-like receptor-9 agonists (TLR-9A) have improved ICI response rates in cutaneous melanoma, but delivery challenges have limited their application for MUM. Hepatic arterial infusion (HAI) of TLR-9A using a pressure-enabled drug deliveryTM (PEDDTM) device has the potential to enhance responsiveness to ICI by optimizing delivery to intrahepatic tumors and reprogramming the TME, including elimination of MDSCs.PERIO-01 is an open-label first-in-human Phase 1 trial of SD-101 given by HAI using a PEDDTM in MUM (NCT04935229). The study consists of dose-escalation cohorts of single agent SD-101 alone and with ICI. SD-101 is delivered over 2 cycles, with 3 weekly doses per cycle. Research blood, tumor and normal liver biopsies are collected serially for correlative studies. At data cutoff, a total of 20 patients were enrolled, with 13 in the single agent dose escalation cohort (2, 4, and 8 mg) and 7 patients with SD-101 (2 mg) + nivolumab. The median age was 65.5 years with an equal gender distribution. Only 2 patients were treatment-naïve and the median number of liver metastases was 5.1. The average number of SD-101 infusions was 5.2. One patient in the combination cohort experienced a serious adverse event related to treatment - asymptomatic Grade 3 increase in liver enzymes. PEDDTM resulted in high drug levels in the liver (up to 2,340 ng/ml at 8mg) with only transient exposure in the periphery ( Citation Format: Sapna P. Patel, Cara Haymaker, Rahul A. Sheth, Joshua D. Kuban, Joshua Weintraub, Eric Wehrenberg-Klee, Paula Novelli, Carin Gonsalves, Robert Adamo, Virgina Honaker, Laura Timciuc, Tarin Hennegan, Juan C. Amador Molina, Dzifa Duose, Edwin R. Parras Cuenta, Anthony Lucci, Salyna Meas, Vanessa Sarli, Victor G. Prieto, Jason LaPorte, Ann-Marie Hulstine, Ashley Moody, Bryan Cox, David Geller, Diwakar Davar, Kamaneh Montazeri, Marlana Orloff, Steven C. Katz, Richard Carvajal. PERIO-01: Initial safety experience and immunologic effects of a Class C TLR9 agonist using pressure- enabled drug delivery in a phase 1 trial of hepatic arterial infusion of SD-101 +/- checkpoint inhibition in metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5881.

Combination treatment of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) produces remarkable response rates and is expected to prevent ERK activation in BRAF-mutant melanoma. However, sporadic ERK reactivation occurs in melanoma models, and efficacy is severely limited by the emergence of drug resistance. The underlying molecular mechanisms that drive ERK reactivation and adaptation to BRAFi/MEKi remain elusive. Here, using single-cell imaging and optogenetic approaches, we show that the strength and duration of receptor tyrosine kinase (RTK) activation determines ERK reactivation and the development of BRAFi/MEKi-resistant cells. Single-cell data reveal that despite global RTK activation by the same external stimuli, only small subsets of melanoma cells induce effective RTK and ERK activation to develop BRAFi/MEKi resistance. Furthermore, by directly controlling RTK activity, we demonstrate that the kinetics of RTK activation determine ERK signaling dynamics and the percentage of drug-resistant cells. While these drug-resistant cells are rare during early stages of drug treatment, they eventually become the dominant population through sustained RTK-mediated ERK activation that drives cell proliferation. Thus, RTK activation in established drug-resistant cells causes effective ERK activation and cell proliferation. Importantly, limiting RTK signaling activation reverses the BRAFi/MEKi-resistant state. We show that targeting SHP2, a mediator of RTK signaling, effectively suppresses RTK-mediated ERK activation and cell proliferation in BRAFi/MEKi-resistant cells. Our results provide mechanistic insights into the contribution of heterogeneity in RTK activation kinetics to ERK reactivation and BRAFi/MEKi resistance, also highlighting SHP2 activity as a promising target to overcome drug resistance in BRAF-mutant melanoma. Citation Format: Sungsoo Kim, Richard Carvajal, Minah Kim, Hee Won Yang. Kinetics of RTK activation determine ERK signaling dynamics and resistance to BRAF and MEK inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3876.

T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T-cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T-cell infiltration within tumor. We analyzed the spatial regulation of ANGPT2 in whole tumor cross-sections and its impact on CD8+ T-cell position, vascular integrity, and response to immunotherapy using syngeneic murine melanomas. We found that T-cell exclusion was associated with peritumoral expression of ANGPT2 and elevated vascular leakage in human and murine melanomas. Both pharmacological and genetic blockade of ANGPT2 promoted CD8+ T-cell infiltration to the tumor core, exerting antitumor effects. Importantly, the reversal of T-cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 therapy in immunogenic, therapy responsive mouse melanomas, but also rendered non-responsive tumors susceptible. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T-cell infiltration, coincided with TIE2 signaling activation and increased vascular integrity in the tumor periphery, indicating that maintenance of vascular integrity within tumors is necessary for robust response to immunotherapy. These data highlight ANGPT2/TIE2 signaling as a key mediator of T-cell exclusion and a promising target to potentiate checkpoint inhibitor efficacy in melanoma. Citation Format: Ha-Ram Park, Anahita Shiva, Portia Cummings, Richard Carvajal, Gavin Thurston, Joon-Yong An, Amanda W. Lund, Hee Won Yang, Minah Kim. Vascular regulation of T-cell exclusion in melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4588.

Extracutaneous melanomas (ECMs) represent a heterogeneous group of melanoma subtypes characterized by distinct clinical and biological features from cutaneous melanoma. These subtypes share an aggressive natural history with high mortalities compared with nonacral cutaneous melanoma (NACM). Although recent advances in NACM have made significant improvements in morbidity and mortality, ECMs continue to lag behind. As the pathogenesis and molecular features of these rare subtypes continue to emerge, therapeutic research has aimed to closing the gap.

BackgroundTebentafusp, a bispecific fusion protein consisting of affinity-enhanced T cell receptor targeting a gp100 derived peptide fused to anti-CD3 effector, has shown overall survival (OS) benefit in untreated metastatic uveal melanoma (mUM). The OS benefit derives from all RECIST response categories, even progressive disease (PD). In Ph2 trial of previously treated mUM (NCT02570308), one-third (35%) of 48 evaluable patients with best response of PD had ctDNA reduction (³0.5 log reduction) and longer OS (median 16.9 months) compared to the group without ctDNA reduction (median OS 8.5 months).Methods34 of 127 mUM patients from Ph2 trial1 were selected based on best response of PD and no ctDNA reduction (Group A, n=17) or 0.5 log ctDNA reduction (Group B, n=17). One patient per group were excluded due to poor image quality or limited CT/MRI sequences. Tumor lesions were manually segmented on CT and MRI. Radiomics features were extracted at baseline and Week-8 (first assessment). The objective was to use unsupervised machine-learning to develop two signatures using 16 features to classify the two groups. The per-patient analysis signature (n=32) combined 8 volumetric features on CT-scan at baseline and change by Week-8. The per-lesion analysis signature (n=148) combined 4 features (volume and 3 radiomics features previously associated with outcome to checkpoint immunotherapy in cutaneous melanoma) at two timepoints using CT and MRI. Performance was evaluated using area under the receiver operating characteristic curve (AUC).ResultsThe median OS for Groups A and B were 8.5 and 16.9 months, respectively. In the per-patient analysis, a volumetric signature classified patients into the groups with AUC 0.71 (95%CI: 0.53–0.90) with 63% specificity and 81% sensitivity at the optimal threshold (0.57). In the per-lesion analysis, a radiomic signature reached an AUC of 0.70 (95%CI: 0.58–0.81) with 66% specificity and 74% sensitivity at the optimal threshold (0.53). Group B had lower baseline tumor lesion volume (AUC=0.65), distinct baseline tumor heterogeneity (AUC=0.66), and distinct change in tumor heterogeneity by week 8 (AUC = 0.66/0.69 on CT/MRIConclusionsA radiomic analyses of a subset of PD patients was able to predict Group B, patients with ctDNA reduction and longer OS, at a patient and lesion level. The strongest radiomic predictor by CT/MRI was decrease on treatment in tumor heterogeneity. Confirmation in a larger dataset of these signatures is needed to identify which patients may be benefiting from tebentafusp despite radiographic progression.Trial RegistrationNCT02570308Reference1. Sacco JJ, Carvajal R, Butler MO, et al. A phase (ph) II, multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM). Ann Oncol 2020;31:S1442–S1143.Abstract 819 Figure 1Percent change in tumor measurement from baseline at week 8 per independent review committee by Group A and BAbstract 819 Figure 2Kaplan-Meier plot comparing overall survival rates in group A and group B patientsAbstract 819 Figure 3Blue color represents a high probability of the patient being in Group A while red color indicates high probability of being in Group B

Predicting tumor sensitivity to antineoplastics remains an elusive challenge, with no methods demonstrating predictive power. Joint analysis of tumors—from patients with distinct malignancies who had progressed on multiple lines of therapy—and drug perturbation transcriptional profiles predicted sensitivity to 28 of 350 drugs, 26 of which (93%) were confirmed in low-passage, patient-derived xenograft (PDX) models. Drugs were prioritized based on their ability to either invert the activity of individual Master Regulator proteins, with available high-affinity inhibitors, or of the modules they comprise (Tumor-Checkpoints), based on de novo mechanism of action analysis. Of 138 PDX mice enrolled in 16 single and 18 multi-protein treatment arms, a disease control rate (DCR) of 68% and 91 %, and an objective response rate (ORR) of 12% and 17%, were achieved respectively, compared to 6% and 0% in the negative controls arm, with multi-protein drugs achieving significantly more durable responses. Thus, these approaches may effectively complement and expand current precision oncology approaches, as also illustrated by a case study.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma, yet our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naïve MBM and 10 extracranial melanoma metastases (ECM), and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion, and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX(+)CD8(+) T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

Brain metastases are the most frequent malignancies in the brain and are associated with significant morbidity and mortality. Melanoma brain metastases (MBM) occur in most patients with advanced melanoma and are challenging to treat. Our understanding of the treatment-naïve landscape of MBM is still rudimentary, and there are no site-specific molecular therapies available. To gain comprehensive insights into the niche-specific biology of MBM, we performed multi-modal profiling of fresh and frozen samples using single-cell RNA-seq, single-cell TCR-seq, single-nuclei RNA-seq, and spatial transcriptional profiling. We evolved single-nucleus RNA-seq processing methods to enable profiling of minute amounts of archival, frozen specimens and compared data quality and structure between matched fresh and frozen MBM. We curated a treatment-naïve single-transcriptome atlas of MBM, collected either fresh samples over 1 year or profiled frozen samples dating back more than 15 years, and compared these samples to extracranial melanoma metastases (ECMM). In total, we profiled 25 samples with more than 114,000 transcriptomes. We identified more than 20 different cell types, including diverse tumor-infiltrating T-cell subsets and rare dendritic cell types, and tissue-specific cell types, such as activated microglia. Tumor cells in MBM showed an increase in copy number alterations (CNAs) compared to ECMM, which we validated using an external dataset of whole exome sequencing (WES) data including both MBM and ECMM. MBM-derived tumor cells show enrichment of genes involved in neuronal development and function, and site-specific metabolic programs (e.g., oxidative phosphorylation). Comparison with an external bulk RNA-seq dataset validated enriched key genes in MBM and ECMM as putative dependencies. We recovered cell-cell interactions between tumor and brain-resident cells involved in brain development, homeostasis, and disease. Similar to ECMM, the tumor microenvironment of MBM contained CD8+ T cells across a spectrum of differentiation, exhaustion and expansion, which was associated with loss of TCF7 expression and adoption of a TOX+ cell state. CD4+ T cells included T regulatory, T helper and T follicular-helper-like expression profiles. Plasma cells showed spatially localized expansion and limited heterogeneity. Myeloid cells largely adopted pro-tumorigenic cell states, including microglia, the brain-resident myeloid cells, which showed an activation trajectory characterized by expression of SPP1 (osteopontin). Spatial transcriptional analysis revealed restricted expression of antigen presentation genes with only a subset of these locations showing a type I interferon response. In summary, this work presents a multi-modal single-cell approach to dissect and compare the landscape of treatment-naïve MBM and ECMM. Citation Format: Johannes C. Melms, Jana Biermann, Amit Dipak Amin, Yiping Wang, Somnath Tagore, Massimo Andreatta, Ajay Nair, Meri Rogava, Patricia Ho, Lindsay A. Caprio, Zachary H. Walsh, Shivem Shah, Daniel H. Vacarro, Blake Caldwell, Adrienne M. Luoma, Joseph Driver, Matthew Ingham, Suthee Rapisuwon, Jennifer Wargo, Craig L. Slinguff, Evan Z. Macosco, Fei Chen, Richard Carvajal, Michael B. Atkins, Michael A. Davies, Elham Azizi, Santiago J. Carmona, Hanina Hibshoosh, Peter D. Canoll, Jeffrey N. Bruce, Wenya L. Bi, Gary K. Schwartz, Benjamin Izar. Dissecting the ecosystem of treatment-naïve melanoma brain metastasis using multi-modal single-cell analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 984.

Existing criteria to estimate the benefit of a therapy in patients with cancer rely almost exclusively on tumor size, an approach that was not designed to estimate survival benefit and is challenged by the unique properties of immunotherapy. More accurate prediction of survival by treatment could enhance treatment decisions.To validate, using radiomics and machine learning, the performance of a signature of quantitative computed tomography (CT) imaging features for estimating overall survival (OS) in patients with advanced melanoma treated with immunotherapy.This prognostic study used radiomics and machine learning to retrospectively analyze CT images obtained at baseline and first follow-up and their associated clinical metadata. Data were prospectively collected in the KEYNOTE-002 (Study of Pembrolizumab [MK-3475] Versus Chemotherapy in Participants With Advanced Melanoma; 2017 analysis) and KEYNOTE-006 (Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab [MK-3475] Compared to Ipilimumab in Participants With Advanced Melanoma; 2016 analysis) multicenter clinical trials. Participants included 575 patients with a diagnosis of advanced melanoma who were randomly assigned to training and validation sets. Data for the present study were collected from November 20, 2012, to June 3, 2019, and analyzed from July 1, 2019, to September 15, 2021.KEYNOTE-002 featured trial groups testing intravenous pembrolizumab, 2 mg/kg or 10 mg/kg every 2 or every 3 weeks based on randomization, or investigator-choice chemotherapy; KEYNOTE-006 featured trial groups testing intravenous ipilimumab, 3 mg/kg every 3 weeks and intravenous pembrolizumab, 10 mg/kg every 2 or 3 weeks based on randomization.The performance of the signature CT imaging features for estimating OS at the month 6 posttreatment landmark in patients who received pembrolizumab was measured using an area under the time-dependent receiver operating characteristics curve (AUC).A random forest model combined 25 imaging features extracted from tumors segmented on CT images to identify the combination (signature) that best estimated OS with pembrolizumab in 575 patients. The signature combined 4 imaging features, 2 related to tumor size and 2 reflecting changes in tumor imaging phenotype. In the validation set (287 patients treated with pembrolizumab), the signature reached an AUC for estimation of OS status of 0.92 (95% CI, 0.89-0.95). The standard method, Response Evaluation Criteria in Solid Tumors 1.1, achieved an AUC of 0.80 (95% CI, 0.75-0.84) and classified tumor outcomes as partial or complete response (93 of 287 [32.4%]), stable disease (90 of 287 [31.3%]), or progressive disease (104 of 287 [36.2%]).The findings of this prognostic study suggest that the radiomic signature discerned from conventional CT images at baseline and on first follow-up may be used in clinical settings to provide an accurate early readout of future OS probability in patients with melanoma treated with single-agent programmed cell death 1 blockade.

Background PARP is overexpressed in many malignancies, and can protect tumor cells from genetic damage. The PARP inhibitor ABT-888 (A) enhances the cytotoxicity of several alkylating agents. Since bendamustine (B) is an alkylator with promising clinical activity in a variety of lymphoid malignancies and some solid tumors, we have executed a phase 1b trial combining ABT-888 with bendamustine in patients with solid tumors, lymphomas and multiple myeloma. The primary aim of this study is to determine the safety and MTD of ABT-888 in combination with bendamustine, with secondary aims of establishing response rates and pharmacokinetic parameters of ABT-888 in this combination. We report here the results of the dose escalation portion of this study. Methods Patients with relapsed solid tumors, lymphoma and multiple myeloma with no standard curative options were eligible for enrollment to the dose escalation portion of this trial. Patients were treated with escalating doses of bendamustine (70 to 90mg/m2 IV days 1 and 2) and ABT-888 (30 to 400 mg PO bid x7) over 7 days each 28 day cycle. Planned treatment duration was 6 cycles, with the option of additional cycles in cases of clinical benefit. Results 29 patients are evaluable for study endpoints to date, including 21 with solid tumors and 8 with lymphoma. 4 DLTs were seen: one grade 4 anemia (at A=100/B=90), one grade 3 nausea (at A=300/B=90), one grade 3 hypertension and one grade 3 hyperhidrosis. The latter 2 DLTs were seen at the Maximum Administered Dose (MAD : A=400/B=90), and the Maximum Tolerated Dose (MTD) was therefore A=300mg/B=90mg/m2. Grade 3/4 toxicities to date that have occurred in more than one patient and are possibly related to treatment include anemia (n=3), thrombocytopenia (n=3), neutropenia (n=2), hematuria (n=2), nausea (n=2), abdominal pain (n=2), hypertension (n=2), pneumonia (n=2) and sepsis (n=2). There was one death due to sepsis on trial that was deemed possibly related to treatment due to its development during a possible neutropenic period after cycle 4 of treatment. There were no objective responses seen in patients with solid tumors. Of the 8 patients with relapsed/refractory lymphoma, best responses were: 3 HL (1CR, 2PR), 1 DLBCL (PD), 1 transformed FL (SD), 2 FL (1 CR, 1 pending), 1 MCL (CR). The one patient with multiple myeloma studied on trial achieved a PR. Pharmacokinetic analysis has shown no significant affect of bendamustine on Cmax, Tmax, AUC or volume of distribution of ABT-888 compared with historical single-agent analyses. Data will be updated in the final presentation, as the last patients enrolled have not yet completed their full safety and efficacy assessments. Conclusions ABT-888 plus bendamustine is tolerable in patients with solid tumors, myeloma and lymphoma, with an MTD of ABT-888 300mg bid days 1-7 plus bendamustine 90mg/m2 days 1 and 2 of each 28-day cycle. This regimen has shown efficacy in lymphoma and myeloma, although it is unclear if ABT-888 adds benefit to bendamustine alone. A cohort expansion is planned to assess the safety and preliminary efficacy of this regimen at the MTD in combination with rituximab in patients with B-cell non-Hodgkin Lymphomas. Disclosures: Off Label Use: novel drug combination.