bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tyme-88-Panc Part 2: A randomized phase II/III of SM-88 with MPS as third-line in metastatic PDAC.
Authors: Pant Shubham , Chawla Sant P. , Chung Vincent , Del Priore Giuseppe , Kim Dae Won , Noel Marcus Smith , Oberstein Paul Eliezer , Ocean Allyson J. , Philip Philip Agop , Picozzi Vincent J. , Simeone Diane M , Wang-Gillam Andrea 
Published: February 2020

TPS789 Background: Patients with metastatic pancreatic cancer who have progressed on two prior lines of therapy have a poor prognosis with an overall survival in the range of 2-2.5 months. (Manax, et al. J Clin Oncol 37, 2019 suppl 4; abstr 226). There is currently no standard of care for these patients that has demonstrated improved outcomes. SM-88 (D,L-alpha-metyrosine; racemetyrosine [USAN]) is a proprietary dysfunctional tyrosine derivative and is the backbone of SM-88 used with MPS (Methoxsalen 10mg, Phenytoin 50mg and Sirolimus 0.5mg; all administered daily). SM-88 monotherapy was relatively well tolerated, with improvement in survival in select patients with heavily pretreated PDAC who achieved stable disease on therapy (HR 0.08, p = 0.02). Circulating tumor cells (CTC’s) were prognostic and decreased on therapy with SM-88 potentially identifying a subgroup of PDAC that may be most likely to benefit from therapy (Noel et al. Annal Oncol V30, Suppl 4, 2019). Preliminary radiomic analysis of the largest metastases at baseline suggested the same benefits including a correlation with baseline CTCs, changes in CTCs on therapy and OS (Ocean et al, Annal Oncol, V30, Suppl 5, 2019). Here, we describe a randomized, open-label, phase 2/3 trial evaluating the efficacy of SM-88 + MPS vs physician’s choice treatment as third line therapy for patients with metastatic PDAC. Methods: This is a multi-center Phase 3 study of patients ≥18 years with metastatic PDAC that progressed after 2 lines of chemotherapy (gemcitabine [gem] and 5-fluorouracil [5-FU] based) with an ECOG <2. Randomization will be 1:1 with 250 patients being stratified by site, ECOG, and choice of chemotherapy. SM-88 will be administered at a dose of 460mg twice daily (920 mg/day). Primary end point is Overall Survival (OS). Secondary end points include progression free survival, response rate, duration of response, pharmacokinetics, safety and CTCs. Clinical trial information: NCT03512756.
Immune checkpoint inhibitor use in cancer patients with a pre-existing history of autoimmune disorders.
Authors: Tawagi Karine , Simenson Victoria , Yuan Helen , Velasco-Gonzalez Cruz , Johnson Daniel , Matrana Marc Ryan 
Published: February 2020

100 Background: Patients with a history of autoimmune disorders (AID) were generally excluded from immune checking inhibitor (CPI) trials because of concerns that these individuals might be at greater risk for developing serious immune-related adverse events (irAEs). This presents a knowledge gap, because a significant proportion of cancer patients also carry a diagnosis of AID. Methods: We retrospectively collected data from patients with AID treated with CPI at a single institution. irAEs were assessed using the CTCAEv5 criteria. Response was assessed using RECIST v1.1. Results: Of 47 cancer patients with a broad spectrum of malignancies and AIDs, 45% had active AID symptoms at the time of CPI initiation, of which 19% were on steroid-sparing agents (SSAs), 11% were on steroids, and 9% were on simultaneous steroids and SSAs. A total of 12 patients (25%) developed an AID flare, of which 100% were grade 1 or 2. Of these patients, 11 required systemic steroids, with 6 patients (55%) requiring greater than 12 weeks of oral steroids, and 3 patients required discontinuation of their CPI. Conventional irAEs developed in 10 patients (21%), of which 4 patients required systemic steroids, and 3 patients (27%) required discontinuation of their CPI. Efficacy outcomes for these patients, including radiographic response, will be available at time of data presentation. Conclusions: AID exacerbations or new irAES occurred in 25% and 21% of patients with a history of AID respectively, and were generally manageable. Only a minority of patients required cessation of their CPI due to toxicity.
A digital therapeutic for proactive monitoring of patients on immune checkpoint inhibitor therapy for early detection of immune-related adverse events.
Authors: Singhal Shyamali Mallick , Dormady Shane , Li Jiali , Singhal Shiva , Chin Lynda 
Published: February 2020

101 Background: Immune-related adverse events (irAEs) occur frequently in patients receiving immuno-oncology therapy. irAEs are heterogeneous and unpredictable. Experience at academic cancer centers has shown that (1) education of patients and families must be continuous; (2) experience of the care team can improve outcomes; and (3) close monitoring of patients in between visits translate into early detection and timely intervention. Most oncologists in lower volume community practices have not gained the experience nor have the resource for continuous education frequent proactive monitoring. Methods: In addition to self-monitoring by patients on chemotherapy to improve outcome (Basch ref), we hypothesized that adoption of evidence-based management is critical as well. Thus, we have developed ApricityRx, a digital therapeutic (DTx) for end-to-end irAE management, which not only engages patients in frequent self-nonitoring but also activates the oncology team for timely intervention. In brief, ApricityRx (i) enables intelligent monitoring by educating and guiding patients to track specific expert-prioritized symptoms in between clinic visits; (ii) facilitates early recognition by prompting triage at the right time and (iii) recommends evidence-based management based on consensus guidelines. Results: In a community cancer center, 16 patients have been enrolled (44% consent rate) in an IRB approved feasibility trial to evaluate the usability of ApricityRx as a tool for frequent monitoring and timely triage. Over 435 unique longitudinal records containing over 34K data points, including patient-reported outcome (PRO) and clinical care data (EMR), were generated. Interim analyses have shown that primary and secondary endpoints were met. Detailed results will be presented. Conclusions: ApricityRx has shown usability in a low-volume community-based oncology practice to facilitate proactive monitoring and tinely triage by the oncology team. Further, ApricityRx has enabled not only generation of high-resolution patient-reported outcome (PRO) data, but also aggregation of PRO and real-world EHRs data for downstream analyses.
Efficacy and safety of yttrium-90 ibritumomab tiuxetan in the treatment of non-Hodgkin lymphoma.
Authors: Doyle Catherine , Smith Johnna , Bello Celeste M. , Sokol Lubomir , El-Haddad Ghassan 
Published: February 2020

103 Background: Yttrium 90-labeled ibritumomab tiuxetan (Zevalin) is a radioimmunotherapy agent which combines the action of a beta-emitting isotope, yttrium-90, with the anti-CD20 monoclonal antibody, rituximab. The purpose of this study was to evaluate the efficacy of Zevalin in the treatment of Non-Hodgkin Lymphoma (NHL) in terms of response to therapy, overall survival (OS) and progression free survival (PFS). Methods: A total of 171 patients with NHL referred for treatment with Zevalin between September 2005 and January 2017 were identified for retrospective analysis. Clinical characteristics, treatments, and outcomes were extracted from clinical chart review. Survival rates and survival curves were generated using Kaplan-Meier analysis. Chi-square and independent student t test were used for comparison of categorical variables. Multivariate analysis (MVA) Cox proportional hazards ratios (HR) model was used to assess OS and PFS. Results: Of the 171 patients referred for treatment, median age was 70 years old, 54% were male (n = 93), and each patient had received a median of 2 prior chemotherapy regimens. The majority of patients were treated for follicular lymphoma (n = 107) and diffuse large B-cell lymphoma (n = 34). Seventy-three patients (53%) achieved complete response, and 23 patients achieved partial response (17%). One-year progression free survival was 71%, and median PFS was 31 months. Adverse events included cytopenic events, GI side effects, and mucocutaneous toxicity. Conclusions: Use of Zevalin for treatment of NHL demonstrated a significant improvement in PFS. In addition to improved efficacy, Zevalin was well-tolerated in this study and demonstrated an adequate safety profile. Further considerations will be given as to which treatment factors are associated with a complete response and improved PFS.
Immune monitoring of blood in advanced gastroesophageal adenocarcinoma patients treated with an anti-MMP9 monoclonal antibody in combination with nivolumab.
Authors: Kitano Shigehisa , Yamashita Makiko , Muro Kei , Satoh Taroh , Yamaguchi Kensei , Kadowaki Shigenori , Sakai Daisuke , Ichimura Takashi , Mitani Seiichiro , Kudo Toshihiro , Chin Keisho , Fukui Masato , Bhargava Pankaj , Brachmann Carrie , Zavodovskaya Marianna 
Published: February 2020

13 Background: A phase 1b study was conducted in Japanese patients with >2nd line advanced gastroesophageal adenocarcinoma (GEA) to evaluate the safety, tolerability and explore efficacy and biomarkers, of andecaliximab (ADX), an anti-MMP9 monoclonal antibody, in combination with nivolumab (nivo). In this study, 5 of the 10 enrolled patients had a partial response and the remaining 5 had progressive disease. A larger parallel study in western patients showed no improvement in response or survival for the addition of ADX to nivo. A biomarker study is reported here which explored the hypothesis that baseline levels or early changes in the frequency of peripheral immune cells might identify responders to immunotherapy. Methods: Blood samples were collected at screen, C1D1, C1D8, C1D15, C2D1, C2D15 and then at CXD1 until end of treatment and processed to viably-frozen PBMCs. Immune cell analysis was conducted by flow cytometry (FCM), and included evaluation of T cells, B cells, myeloid derived suppressor cells, NK cells, monocytes, and dendritic cells (DCs). Baseline status and on treatment changes were explored. Results: FCM analysis of peripheral blood showed that the 5 responders had higher frequency of LAG3+CD8+ T cells and myeloid DCs, and lower frequency of plasmacytoid DC than non-responders at baseline. The number of CD8+ T cells decreased at C1D8 and then recovered in responders. In contrast, no CD8+ T cell changes were observed in non-responders. CTLA-4+ CD4+ T cells also increased after treatment in responders but not in non-responders. Changes in other evaluated cell populations were not observed. Conclusions: The observation that baseline levels of LAG3+CD8+ T cells and DCs were higher in responders is consistent with a prior anti-tumor immune response. Transient decreased peripheral CD8+ T cells might reflect T-cell trafficking into tumor in response to immunotherapy, and increased peripheral CTLA-4+ CD4+ T cells may also relate to tumor-localized response. Although in a very small number of patients, the observations are consistent with early changes in peripheral immune cells that may relate to response to immunotherapy. Clinical trial information: NCT02862535.
Phase I trial evaluating safety and efficacy of intratumorally administered allogeneic monocyte-derived cells (ilixadencel) in advanced gastrointestinal stromal tumors.
Authors: Karlsson-Parra Alex , Fröbom Robin , Berglund Erik , Berglund David , Nilsson Inga-Lena , Linder-Stragliotto Christina , Suenaert Peter , Branstrom Robert 
Published: February 2020

15 Background: Ilixadencel is a cell-based, off-the-shelf product based on allogeneic monocyte-derived inflammatory cells aimed to prime an anti-cancer immune response when injected intratumorally. The present single arm Phase I trial (ClinicalTrials.gov Identifier: NCT02686944) assessed the safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Methods: Three GIST patients were progressing while on sunitinib (second-line), one on regorafenib (third-line), and two on pazopanib (fifth-line). Treatment consisted of two intratumoral injections of ilixadencel two weeks apart. If further tumor progression was observed at the 3-month follow up, the TKI was withdrawn and the subject performed an end of study visit. If stable disease or objective response was observed, the subject continued with the TKI until progression of disease. Results: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. Two patients had stable disease as best response; one of these patients (on third-line regorafenib) progressed at 12 months and the other (a patient on second-line sunitinib) showed continued stable disease at end of study (12 months) as per RECIST 1.1. These two patients also developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. No serious adverse events were found to be possibly or probably related to ilixadencel administrtion. Conclusions: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial information: 02686944.
CXCR1/2 blockade to enhance response to immune checkpoint inhibition in an aggressive orthotopic pancreatic adenocarcinoma model.
Authors: Ullman Nicholas A. , Ruffolo Luis I. , Jackson Katherine M. , Chacon Alexander , Georger Mary , Jewell Rachel , Belt Brian A. , Maeda Dean , Zebala John , Linehan David 
Published: February 2020

19 Background: Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths, with the incidence expected to rise in the coming years. Despite conventional chemotherapy and advances in immune checkpoint blockade, 5 year survival remains a dismal 8%. Intratumoral accumulation of granulocytic myeloid derived suppressor cells (G-MDSC) pose a significant barrier to treatment as they contribute to immune evasion by PDAC and correlate with poor prognosis. The ELR+ CXC chemokine receptors CXCR1 and CXCR2 (CXCR1/2) contribute to peripheral neutrophil migration into tissues and have been implicated in tumor mediated G-MDSC recruitment to the tumor microenvironment. Here we present our findings using an orally dosed CXCR1/2 inhibitor, SX-682, in an orthotopic PDAC model. Methods: C57BL/6 mice underwent orthotopic injections with KP2 cells. Mice were randomized into five groups (Table) receiving three weeks of FOLFIRINOX with combinations of SX-682 and/or checkpoint inhibition (anti-PD1/anti-CTLA4). FOLFIRINOX was dosed weekly for three weeks. Checkpoint inhibition was administered twice weekly. Chow weights were monitored for consumption of SX-682. Results: The simultaneous administration of FOLFIRINOX with SX-682 combined with checkpoint inhibition (triple therapy) resulted in a significant increase in survival compared to other groups (p = 0.0001). Notably, there was a significant increase in survival with triple therapy versus FOLFIRINOX plus checkpoint alone (p = 0.0259). Median survival of the triple therapy group was 42.5 days, compared to 37 days with checkpoint inhibition (p = <0.05). There were no differences in chow consumption between the control and medicated chow groups. Conclusions: CXCR1/2 blockade combined with immune checkpoint inhibition and first line chemotherapy significantly enhanced survival in our PDAC mouse model. Thus, CXCR1/2 inhibition with SX-682 represents a promising target for clinical intervention in PDAC. [Table: see text]
Antibody blockade of semaphorin 4D to sensitize pancreatic cancer to immune checkpoint blockade.
Authors: Ruffolo Luis I. , Ullman Nicholas A. , Dale Benjamin , Jackson Katherine M. , Burchard Paul , Georger Mary , Jewell Rachel , Belt Brian A. , Galka Eva , Schoeniger Luke O. , Mallow Crystal L. , Evans Elizabeth E. , Fisher Terrence Lee , Zauderer Maurice , Linehan David 
Published: February 2020

26 Background: Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, and will soon become the second leading cause of cancer mortality. Unfortunately, T-cell directed immunotherapies have failed to demonstrate efficacy in PDAC. These failures may in part be mediated by an immunosuppressive tumor microenvironment (TME). Semaphorin 4D (Sema4D) is a glycoprotein which binds its cognate receptors Plexin B1/B2. Here we present our work in blocking Sema4D in a murine model of PDAC. Methods: C57b/6 mice were orthotopically injected with PDAC line (KP2) derived from KRASG12D,TP53Flox/Wt;P48-Cre autochthonous tumors and confirmed for disease by ultrasound. Mice were treated with FOLFIRINOX (5-FU, Irinotecan, Oxaliplatin, weekly), immune checkpoint blockade (ICB) (anti-PD1, anti-CTLA-4 mAbs bi-weekly), and anti-Sema4D mAB (bi-weekly). Human and mouse circulating and tumor infiltrating leukocytes were interrogated through flow cytometry (FACS) for immune subset and expression of Sema4D and Plexin receptors. Archived human PDAC tissues were assessed through quantitative immunohistochemistry (IHC) for presence of Sema4D positive infiltrate. Results: Both FACS and IHC analysis of human PDAC specimens confirm the presence and increased prevalence over normal pancreata of Sema4D lymphocytes and Plexin B1/B2 expressing tumor associated macrophages (TAMs). KP2 orthotopically injected mice exhibited longer survival when treated with the triple combination of FOLFIRINOX, ICB, and anti-Sema4D antibody, compared to FOLFIRINOX alone, FOLFIRINOX plus ICB, or FOLFIRINOX plus anti-Sema4D antibody (P < 0.02). Flow cytometric analysis of anti-Sema4D and ICB treated murine tumors show a doubling of penetration by CD 8+ effector T cells within tumors compared to control groups (P = 0.03). A loss in Sema4D fluorescence signal via FACS in tumor-infiltrating CD3+ leukocytes was observed in mice treated with anti-SEMA4D, confirming penetration and target blockade within the TME. Conclusions: Sema4D and Plexin B1/B2 leukocytes penetrate human PDAC tumors, and treatment with Sema4D blocking antibody improved response to ICB in combination with standard of care FOLFIRINOX in preclinical murine studies.
Network analysis to reveal BTK as a link between myeloid and T cells in TLR signaling in colorectal cancer.
Authors: Hummel Justin , Shen Yuanyuan , Innokenteva Iiulia , Papageorgiou Christos , Shyu Chi-Ren , Mitchem Jonathan B. 
Published: February 2020

30 Background: Colorectal cancer (CRC) is the second-leading cause of cancer mortality in the US today. Recent advances in immunotherapy have only been shown to benefit a limited subgroup of patients with CRC. In other malignancies, activation of Toll-like receptors (TLRs) has been shown to overcome resistance to immunotherapy, such as immune checkpoint inhibition (ICI). In this study, using publicly available data and informatics-based analysis, we identified BTK as a critical link between TLR signaling and T cells in the CRC tumor microenvironment. Methods: Using RNA-seq data from The Cancer Genome Atlas (TCGA) and the Microenvironment Cell Populations (MCP)-Counter, abundance scores were generated for the tumor microenvironment of each patient. A curated TLR gene panel was generated using Reactome and GO. Pearson analysis was used to evaluate each pairwise combination of genes and cell-types. Significance was determined by the correlation coefficient, r ≥ | 0.7 | with a p-value < 0.05. Network analysis was performed using the Girvan–Newman algorithm to establish critical connections across these features. Results: After establishing a 453 gene TLR panel and creating MCP-Counter scores, correlation analysis demonstrated strong correlations between 54 different genes and 7 cell-types. As expected the most genes were associated with monocytic lineage cells' (30) and 'myeloid dendritic cells' (7). Only 5 genes were significantly associated with 'T cells'. Genes and cell-types that were highly correlated were then further analyzed for network association. From this analysis, BTK was identified as a critical edge acting as the primary link between ‘myeloid cells’ and ‘T cells’. Conclusions: Developing novel strategies for the treatment of CRC is critical and immunotherapy represents an area ripe for advancement. Informatics based analysis combined with publicly available data provides us with an opportunity to shape pre-clinical and translational studies. Using this approach, we have identified BTK as a critical link between myeloid cells and T cells in the tumor microenvironment in CRC. Further studies in our laboratory will focus confirming these findings for translation into patients.
Avelumab flat dose regimen: Justification for use in advanced renal cell carcinoma (aRCC).
Authors: Haanen John B. A. G. , Masters Joanna C. , Huang Bo , Choueiri Toni K. , Motzer Robert J. , Khandelwal Akash , Dai Haiqing (Isaac) , di Pietro Alessandra , Brar Satjit , Rini Brian I. , Albiges Laurence , Larkin James M. G. 
Published: February 2020

32 Background: Avelumab, an anti–PD-L1 monoclonal antibody, was recently approved for the treatment of aRCC in combination with axitinib and was previously indicated for the treatment of metastatic Merkel cell carcinoma (MCC) and platinum-treated advanced/metastatic urothelial carcinoma (UC). Although avelumab was approved with weight-based dosing (10 mg/kg intravenously [IV] every 2 weeks [Q2W]), it was subsequently approved for flat dosing (800 mg IV Q2W) based on population pharmacokinetic (popPK), exposure-efficacy and exposure-safety modeling and simulations in MCC and UC (Novakovic AM, et al. Clin Pharmacol Ther. 2019). The justification for the recommended flat-dose regimen for avelumab as combination therapy with axitinib in aRCC is presented. Methods: Simulated exposure metrics (eg, area under the curve) from the previous popPK model (data from 1,827 patients with solid tumors across 3 clinical trials) for both weight-based and flat-dose regimens were compared with the exposure metrics obtained from treatment-naive patients with aRCC enrolled in 2 clinical studies (N = 488 from NCT02493751 and NCT02684006) who received avelumab (10 mg/kg Q2W) + axitinib (5 mg orally twice daily). Avelumab exposure-response relationships for safety and efficacy were also analyzed. Endpoints included grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions (IRRs) and immune-related (ir)AEs, and progression-free survival (PFS) by independent review. Results: The administration of weight-based dosing of avelumab in the aRCC population yielded similar PK exposures to simulated reference exposures of the flat-dose regimen in the solid tumor population. Avelumab exposure was not associated with increased probabilities of grade ≥3 TEAEs or IRRs, although there was a weak association with an increased probability of any-grade irAEs. Conclusions: The similar exposures observed for both avelumab dosing regimens in aRCC, and in prior studies in the MCC and UC populations, suggest that the 800 mg Q2W flat-dose regimen will maintain the benefit-risk ratio for avelumab + axitinib for treatment-naive patients with aRCC. Clinical trial information: NCT02493751 . Clinical trial information: NCT02684006.