bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of early palliative care on the quality of life of patients with advanced pancreatic cancer: The IMPERATIVE study.
Authors: Lelond Stephanie , Chochinov Harvey , Daeninck Paul Joseph , Goldenberg Benjamin Adam , Lix Lisa , McClement Susan , Kim Christina 
Published: February 2020

TPS777 Background: Pancreatic cancer is lethal. Chemotherapy can improve survival by months; however, many patients experience an overwhelming burden of cancer-associated symptoms and poor quality of life (QOL). Early palliative care (EPC) alongside standard oncologic care results in improved QOL and survival in patients with lung cancer. Although international guidelines recommend EPC for patients with advanced pancreatic cancer (PANC), the benefit is not known. Objectives: The primary objective is to test for change in QOL between baseline (BL) and 16 weeks (wk). Secondary objectives are to test for change between BL and 16 wk in (a) symptom control; and (b) depression and anxiety. Methods: This prospective case-crossover study of patients with PANC provides EPC plus standard oncologic care. Primary oncology clinics refer patients to an EPC team led by a palliative care physician and a clinical nurse specialist. BL questionnaires are completed prior to initial EPC assessment, then every 4 wk until wk 16. EPC visits are every 2 wk for the first month, every 4 wk until wk 16, and then as needed. QOL, symptom control, anxiety and depression are measured using the FACT-Hep tool, ESAS-r, HADS and PHQ-9, respectively. A generalized linear model will test for statistically significant change in scores between BL and 16 wk; chemotherapy (yes/no) is included as a confounding covariate; model fit will be assessed. A sample size of 20 patients provides 80% power after controlling for covariate effects. 40 patients will be enrolled to account for missing data. To date, 28 patients have enrolled and 17 have completed the intervention. Significance: The benefit of EPC for patients with PANC is not known, however, EPC is increasingly recognized internationally by patients and stakeholders as a critical intervention which may improve both QOL and satisfaction with care. The Canadian Partnership Against Cancer’s report on the patient experience states “the best possible patient experience means all people with cancer have equitable access to high-quality person-centered palliative care”. This study offers access to EPC and provides an environment in which the benefit of an integrated approach is evaluated.
A phase II, open-label pilot study evaluating the safety and activity of Nal-IRI in combination with 5-FU and oxaliplatin in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI Study) (NCT03483038).
Authors: Parekh Hiral D. , Cioffi Jessica L. , Hitchcock Kathryn , Lee Ji-Hyun , Fan Z. Hugh , Allegra Carmen Joseph , Hughes Steven J. , Trevino Jose Gilberto , DeRemer David L. , George Thomas J. 
Published: February 2020

TPS790 Background: Neoadjuvant treatment for borderline resectable pancreatic cancer (PCa) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Irinotecan liposomal injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PCa. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with borderline resectable PCa without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board, adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive FOLFNal-IRINOX regimen as per Table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. Clinical trial information: NCT03483038 . [Table: see text]
Phase II study of nivolumab and relatlimab in advanced mismatch repair deficient (dMMR) cancers resistant to prior PD-(L)1 inhibition.
Authors: Bever Katherine M. , Wang Hao , Durham Jennifer N. , Petrie Susan , Hoare Jessica , Wilt Cara , Sharfman William Howard , Azad Nilofer Saba , Laheru Daniel A. , Anders Robert A , Pardoll Drew M. , Topalian Suzanne Louise , Jaffee Elizabeth M. , Le Dung T. 
Published: February 2020

TPS839 Background: Cancers deficient in DNA mismatch repair (dMMR) are highly immunogenic tumors exhibiting high rates of response to immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) interaction. These tumors are characterized by high levels of microsatellite instability (MSI-H) and an exceptionally high tumor mutation burden, thought to underlie responsiveness to immunotherapy, with higher predicted immunogenicity of mutation-associated neoantigens. However, primary and acquired resistance are observed and diversity in responses is not fully explained by variations in mutation burden. Other immune checkpoints may be acting in parallel with PD-1/PD-L1. In particular, lymphocyte activation gene 3 (LAG3) mediates exhaustion of activated T cells and may have a role in resistance to PD-(L)1 inhibitors (PD-(L)1i); therefore, we hypothesized that the addition of LAG3 inhibitor (relatlimab) to the PD-1i nivolumab may overcome resistance in these tumors. Methods: Patients with advanced dMMR/MSI-H cancer who have progressive disease (by RECIST 1.1) during or within 6 months of PD-(L)1i containing therapy, and after at least 12 weeks of therapy, and meet other eligibility will be enrolled. All patients will receive nivolumab 480mg + relatlimab 160mg every 4 weeks until intolerance or progression, or up to a maximum of 2 years. The primary endpoint is objective response rate. Key secondary endpoints include safety, progression free and overall survival, and other response endpoints as measured by RECIST 1.1 and iRECIST criteria. Exploratory objectives will include analysis of the tumor microenvironment on biopsies obtained at baseline and on-treatment, analysis of T cell populations in the tumor and in the periphery and functional characterization of mutation-associated neoantigen-specific T cells. Studies of the microbiome will be conducted on stool and oral wash samples. Enrollment of 21 patients is planned. Clinical trial information: NCT03607890.
First-in-human phase I study of intraperitoneally administered interferon-activated autologous monocytes in platinum-resistant or refractory ovarian cancer.
Authors: Cole Christopher Browning , Annunziata Christina M. 
Published: February 2020

1 Background: This phase I study evaluated the safety and tolerability of autologous intraperitoneal monocytes treated with SYLATRON (Peginterferon alfa-2b) and ACTIMMUNE (Interferon gamma-1b). Methods: For the dose escalation portion, 3-6 patients with platinum-resistant or refractory ovarian cancer were enrolled into 4 cohorts and treated intraperitoneally (IP) with Peginterferon alfa-2b (25-250 mcg) and Interferon gamma-1b (5-50 mcg), with or without autologous monocytes (75-750 x 106 cells), in order to determine the recommended phase II dose (RP2D). A total of six patients were treated at the RP2D. Patients received the combination of interferons+/- monocytes via IP catheter once every 28 days. Results: 18 patients were enrolled (median age, 61 years; median 5 prior therapies). 1 of 3 patients at the second dose level experienced a dose-limiting toxicity (DLT, grade 3 anemia) and so this cohort was expanded to 6 patients; no subsequent DLTs were observed. The RP2D was defined as 250 mcg/50/mcg/750 x 106 cells on the basis of overall safety and tolerability. The only treatment–related grade 3 or higher adverse events occurring in more than one patient were lymphocyte decrease (33.3%) and abdominal pain (11.1%). Preliminary assessment of efficacy is ongoing. The best response observed has been partial response (PR) in 2/11 evaluable patients, with one patient having a 61% reduction in target lesion size. An additional 4/11 patients had stable disease, and 3 patients remained on treatment for >6 cycles. Exploratory biomarker analyses are ongoing to to further elucidate changes in the immune cell population and correlate with response. An expansion cohort of 10 patients at the RP2D is currently enrolling. Conclusions: This is the first-in-human study of the combination of IP peginterferon alfa-2b, interferon gamma-1b, and autologous monocytes, and the combination displays good tolerability and antitumor activity in a heavily pretreated population, supporting further investigation. Clinical trial information: NCT02948426.
AABH (aspartyl [asparaginyl] β-hydroxylase) as a serum biomarker for breast cancer.
Authors: Moshiri Kiarash 
Published: February 2020

2 Background: Breast cancer accounts for 27% of female cancers. One in every eight women will develop breast cancer in their lifetime. More than 220,000 new cases of breast cancer will be diagnosed in the United States in 2020. Five-year survival rates for breast cancer are 98% for localized disease, 83% for regionally spread and 26% for distantly spread cancer. However, 25% of all metastases occur more than 5 years after the initial diagnosis and thus survival rates decrease as time goes out to 10 years due to disease recurrence. Current detection methods rely on imaging modalities, including mammography and MRI. No serum bio-markers have been approved for either breast cancer screening or monitoring for disease recurrence, yet. In asymptomatic women in remission from breast cancer the guidelines of the major oncologic organizations only suggest annual mammography for detection of new primary tumors. Methods: We have investigated the utility of aspartyl (asparaginyl) β-hydroxylase (AABH) as a serum bio-marker for cancer. AABH has been detected by immunohistochemical staining (IHC) in a broad range of cancers including breast cancer. It has been detected by IHC in > 99% of tumor specimens tested (n > 2000) but is absent in adjacent non-affected tissue, and in tissue samples from non-affected individuals. This led to the development of a sandwich ELISA that reliably measures AABH in serum. Results: In the current study we have utilized the assay to quantify AABH levels in the sera of patients diagnosed with Breast Cancer compared to women free of disease. Increased levels of AABH were found in the serum of 99% of patients with breast cancer (n = 189). In women not known to have cancer, AABH was essentially undetectable in serum (n = 65, specificity = 96%). Serum from several women currently in remission subsequent to treatment for breast cancer were also analyzed and found to be negative for AABH. Conclusions: Thus, measurement of serum AABH levels has great promise as a diagnostic tool for breast cancer with potential application in monitoring for disease recurrence. Elevated serum AABH in conjunction with mammography and MRI may greatly facilitate earlier diagnosis of both primary and recurrent Breast Cancer.
Results of a phase Ib trial of encapsulated rapamycin in prostate cancer patients under active surveillance to prevent progression.
Authors: Kemp Bohan Phillip M. , Cindass Jessica L. , Chick Robert Connor , Vreeland Timothy J. , Hale Diane F. , Hickerson Annelies , Clifton Guy Travis , Peoples George Earl , Liss Michael 
Published: February 2020

34 Background: At low doses, rapamycin inhibits cell proliferation and angiogenesis while augmenting CD8 T-cell responses, cumulatively producing an antitumor effect. Oral rapamycin is limited by variable bioavailability. Encapsulated rapamycin (eRapa) incorporates submicron rapamycin particles into a pH-sensitive polymer, improving bioavailability and allowing for consistent and lower dosing. Here, we present results of a phase Ib trial evaluating safety and treatment effects of eRapa in patients with low-grade prostate cancer (PCa). Methods: PCa patients with Gleason ≤7 (3+4) under active surveillance were enrolled in a 3+3 study with 3 dosing cohorts (0.5mg weekly, 1mg weekly, and 0.5mg daily) to determine the optimal dosing. Patients were treated for 3 months (m) and followed for 6m. Safety, labs (including PSA), pharmacokinetics, immune response, and quality of life (QOL) were assessed for each cohort. Results: 14 patients were enrolled; 3 in cohort 1, 3 in cohort 2, and 8 in cohort 3. 2 patients withdrew for non-dose limiting toxicity (DLT) (grade 1-2) adverse events (AEs) in cohort 3, leaving 6 evaluable. A single grade 3 DLT (neutropenia) occurred in cohort 3. No AEs > Grade 1 occurred in cohorts 1/2. Peak serum rapamycin concentration ([Rapa]) was 7 ng/mL after a 1 mg dose (2h after administration). Stable trough levels (2 ng/mL) were established after 48 hrs and persisted to 13wks. Central memory CD8 T cells and CD3+/CD56+ NK cells were more prevalent in cohort 3 than other cohorts at 1m (p = 0.027 and p = 0.041) and 3m (p = 0.023 and p = 0.049). There was no significant change in PSA level; no patients clinically progressed on therapy. In cohort 3, there were no differences between baseline and 3m QOL assessments but there was a suggestion of withdrawal effects at 6m. Conclusions: Treatment with low dose eRapa is safe and well-tolerated. The dose of 0.5mg daily produced stable serum [Rapa] through the duration of treatment and resulted in a positive immune impact. Further investigation with low dose and/or intermittent dosing of eRapa as a preventive agent in PCa and other indications will be required to establish clinical benefit. Clinical trial information: NCT03618355.
Tumor microenvironment (TME), longitudinal biomarker changes, and clinical outcome in patients (pts) with advanced BRAF V600–mutant melanoma treated with first-line spartalizumab (S) + dabrafenib (D) + trametinib (T).
Authors: Dummer Reinhard , Gusenleitner Daniel , Campbell Catarina D. , Lebbe Celeste , Atkinson Victoria , Mandalà Mario , Nathan Paul D. , Arance Ana , Richtig Erika , Yamazaki Naoya , Robert Caroline , Schadendorf Dirk , Tawbi Hussein Abdul-Hassan , Ascierto Paolo Antonio , Ribas Antoni , Flaherty Keith , Gasal Eduard , Brase Jan C. , Long Georgina V. 
Published: February 2020

39 Background: Although pts with both low tumor mutation burden (TMB) and T-cell–inflamed gene expression profiles (TI-GEPs) usually have poor outcomes with anti–PD-1 therapy, an analysis in the adjuvant melanoma setting suggested that these pts benefited from adjuvant D+T therapy. Here we analyze TMB/TI-GEPs and other biomarkers in pts receiving a combination of anti–PD-1 and D+T therapy. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating S in combination with D+T in previously untreated pts with BRAF V600–mutant unresectable/metastatic melanoma. In the safety run-in (part [p] 1) and biomarker (p2) cohorts, blood/tissue samples were collected at baseline (BL), after 2-3 and 8-12 wk of treatment, and at disease progression. TMB/circulating tumor DNA (ctDNA) and TI-GEPs were examined by targeted DNA-seq and RNA-seq, respectively. Results: At data cutoff, 6 of 22 pts with DNA- and RNA-seq data available had a PFS event. At BL, these pts had low TMB, low TI-GEPs (4 of 6), or high levels of immunosuppressive TME signatures (eg, fibroblast, M2 macrophages) vs pts without a PFS event. Elevated BL ctDNA was significantly associated with PFS events ( P< .001). Pts with a complete response (CR) on S+D+T had significantly lower levels of BL immunosuppressive TME signatures (eg, M2 macrophages; P< .01) than pts without a CR. We observed a consistent increase in TI-GEPs and decrease in MAPK pathway activity score (MPAS) from BL to biopsy at 2-3 wk in all pts regardless of subsequent progression. Pts with a PFS event and available longitudinal biomarker data were characterized by a subsequent decrease in TI-GEPs and an increase in MPAS per the 8- to 12- wk biopsy sample. Conclusions: These results suggest that S+D+T had an early impact on tumor cells and the TME, potentially promoting antitumor activity. The majority of PFS events occurred in the TMB-low/TI-GEP-low subgroup. An immunosuppressive TME might preclude early CRs. The predictive implications of coupling TMB/GEP subgroups with other TME marker subgroups need further validation. The randomized placebo-controlled p3 of COMBI-i is ongoing. Clinical trial information: NCT02967692.
Immunogenomic signatures to predict outcome in ovarian and endometrial cancers: Potential strategies in targeting the tumor immune microenvironment to improve response to immunotherapy.
Authors: Mahdi Haider , Ni Ying 
Published: February 2020

4 Background: Ovarian and MSS endometrial cancers are characterized by immunosuppressive microenvironment (TME) and low response to immunotherapy with checkpoint inhibitors (CPI). Targeting immunosuppressive factors within TMErepresents an attractive approach to enhance response to CPI. Therefore, we sought to investigate different immunogenomic signatures and immune cells within TME and correlate them with survival. Methods: We used whole transcriptome sequencing of matched tumor-normal samples from 38 uterine serous cancer and TCGA data of ovarian (n = 374) and endometrial cancers (n = 541). Immunogenomic signatures focusing on Transforming Growth Factor (TGFβ), 18-genes IFN-γ and myeloid signatures (CD47 and B7H4 expressions) and immune cell abundance were investigated. Gene expression score was calculated by averaging the normalized and log transformed individual gene read counts. The optimized score cut off was selected to best separate the survival in the pilot cohort. Then the score was tested in TCGA RNAseq datasets. Population abundance of tissue-infiltrating immune cells were estimated using MCPcounter R package from bulk transcriptome data. Results: Higher IFN-γ and lower TGF-β signatures predicted better survival for endometrial and ovarian cancers (p < 0.05). The impact of TGF-β was higher in MSI-H vs. MSS cancers (p = 0.013 vs. 0.09). High CD47 predicted poor survival in endometrial cancer. Combined IFN-γ and TGF-β signatures predicted survival in the ovarian and endometrial cohorts (p < 0.001). Combined IFN-γ and CD47 expression predicted survival in endometrial cancer (p = 0.033). Analysis of immune cell abundance revealed enrichment of monocytic lineage and neutrophils but paucity of cytotoxic T-cells, NK cells, dendritic cells and B-cells. Immune cell abundance is being correlated with survival. Conclusions: Our data support the role of immunogenomic markers in predicting survival. We are evaluating these markers in predicting response to CPI in a pilot cohort. Immunogenomic markers represent the tumor microenvironment, can potentially guide rationale combination immunotherapy.
Tumor inflammatory signature as a biomarker of response to immunotherapy in lung cancer.
Authors: Pabla Sarabjot , Van Roey Erik , Conroy Jeffrey M. , Glenn Sean , Wang Yirong , Nesline Mary , Burgher Blake , Giamo Vincent , Andreas Jonathan , Lenzo Felicia L. , Morrison Carl 
Published: February 2020

47 Background: Tumor Inflammation signatures (TIS) comprising multiple immune genes have been shown to enrich for response to ICI. To study this immune phenotype in a large cohort of clinically evaluated patients, we studied gene expression data for a stable pan-cancer tumor inflammation profile and clinical response to ICI. Methods: 1323 FFPE tumors from 35 histologies were tested by RNA-seq, PD-L1 IHC and DNA-seq for TMB. Unsupervised analysis of the RNA-seq data revealed a cluster of 160 genes which separated inflamed from non-inflamed tumor microenvironments (TME). A TIS, algorithmically defined as the mean mRNA expression of the 160 genes was developed with each tumor assigned into a weak, moderate or strong inflammation group. PD-L1 IHC was performed using DAKO 22C3 antibody and considered positive if TPS ≥1%. TMB > 10 mut/Mb was considered high. The TIS, PD-L1 and TMB were independently applied to 110 NSCLC cases for association with ORR to ICIs by RECIST criterion. Results: Unsupervised clustering identified 3 inflammation clusters in the 1323 samples; inflamed (n = 439; 33.2%), borderline (n = 467; 35.3%) and non-inflamed (n = 417; 31.5%). 160 genes are over-represented by T & B-cell activation, IFNg, chemokine, cytokine and interleukin pathways. The TIS algorithm results in an inflammatory score that leads to 3 distinct groups of strong (n = 384; 29.0%), moderate (n = 354; 26.8%) and weak (n = 585; 44.2%) inflammation. Strongly inflamed tumors are over-represented by PD-L1+ tumors (240/384) whereas weakly inflamed tumors are significantly under-represented by PD-L1+ tumors (369/585; p = 1.02e-14). Strongly inflamed tumors presented with improved ORR to ICI in NSCLC (36.6%; 16/44; p = 0.051). Similar results were observed for overall survival for strongly inflamed tumors (median = 16 months; p = 0.0012) vs. weakly inflamed tumors (median = 8 months). ORR for PD-L1+ 33.96% (p = 0.026) and TMB high 21.43% (p = 0.83) were observed. Conclusions: Concurrent measurement of multiple markers led to a comprehensive, stable TIS that predicts host immune response. A strongly inflamed TIS was associated with higher ORR versus single biomarker PD-L1 and TMB in NSCLC.
Pemetrexed (Pem) with pembrolizumab (Pembro) maintenance: A post hoc subgroup safety analysis of KEYNOTE-189.
Authors: Aerts Joachim , Garon Edward B. , Wang Chunxiao , Muehlenbein Catherine , Kim Jong Seok , Gadgeel Shirish M. 
Published: February 2020

51 Background: KEYNOTE-189 showed that Pembro+Pem and platinum (Plat) followed by Pembro+Pem improved survival vs Placebo(Plac)+Pem+Plat followed by Plac+Pem in nonsquamous metastatic non-small cell lung cancer. Real-world data suggest Pem is being discontinued after the first 4 cycles with Plat (data on file), perhaps due to toxicity concerns. This study evaluated changes in toxicities and renal impairment in patients (pts) receiving Pem maintenance. Methods: Using KEYNOTE-189 patient data, pts receiving ≥5 cycles of Pem (including the first 4 cycles with Plat) were selected, and a subgroup with renal adverse events were identified by system organ class and preferred term (MedDRA 20.1). Pts with treatment-emergent adverse events (TEAEs) and changes in serum creatinine (sCR) were summarized every 4 cycles. Results: 310 pts in the Pembro+Pem+Plat arm and 135 in the Plac+Pem+Plat arm received ≥5 cycles of Pem. 30 and 5 pts experienced renal events in each arm, respectively. Table shows pts with Gr. 3-5 TEAEs in each period of 4 cycles. Gr. 3-5 TEAEs generally decreased after cycle 4. Pts with renal events had increasing maximum sCR changes from baseline with every 4 cycles. Conclusions: The percentage of pts with renal and Gr. 3-5 TEAEs did not increase with prolonged treatment with Pembro+Pem. Toxicity increased moderately with Pembro+Pem vs Plac+Pem in later cycles. The incidence of Gr. 3-5 renal toxicity was consistently low across the cycles. These data support the safety of prolonged Pem and Pembro in pts after 4 cycles of Pembro, Pem, and Plat along with careful monitoring of renal function. Clinical trial information: NCT02578680 . [Table: see text]