bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist.
Authors: Hidalgo Manuel M. , Epelbaum Ron , Semenisty Valeriya , Geva Ravit , Golan Talia , Borazanci Erkut Hasan , Stemmer Salomon M. , Borad Mitesh J. , Park Joon Oh , Pedersen Katrina , Wolpin Brian M. , Ramirez Robert A. , Becerra Carlos , Shaw Steven , Oberkovitz Galia , Vainstein Haras Abi , Sorani Ella , Lustig Tzipora M , Peled Amnon , Von Hoff Daniel D. 
Published: February 2018

88 Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.
Association of DNA repair gene-mutation, mutation burden and, neoantigen load in breast cancer.
Authors: Lin Po-Han 
Published: February 2018

9 Background: Anti-cancer therapy with immune checkpoint inhibitors demonstrated high efficacy in hypermutated tumors; Food and Drug Administration recently proved PD1/PDL-1 blockade therapy in solid tumors characterized with deficiency of mismatch repair (MMR). However, several malignancies contain less feature of MMR deficiency. Except MMR, it remains uncertain whether mutations of other DNA repair genes are associated with hypermutated status. We aim to analyze the relationship between DNA repair gene-mutation statuses, mutation burden and neoantigen load in breast cancer. Methods: Whole exome sequencing was performed on germline and tumor DNA in 82 patients with early-onset breast cancer (≤ 40 year-old). Calculation of mutation burden includes tumor-specific insertion/deletion (Indel) and single nucleotide variants. Missense mutations, frameshift mutations and uncorrected splicing were considered to generate new peptides (neopeptides). Binding affinity of neopeptide-major histocompatibility complex class I and their immunogenicity were predicted by NetMHC 4.0 and POPI 2.0. Results: A total of 18 pathogenic mutations were found, 4 in ATM (2 germline and 2 somatic), 3 in BRCA1 (germline), 4 in BRCA2 (germline), 1 in BRIP1 (germline), 1 in CHK2 (germline), 1 in ERCC8 (germline), 2 in MSH2 (1 germline and 1 somatic), 1 in RAD51C (somatic) and 1 in OGG1 (germline). The median number of exomic mutations (missense mutations and Indels) were 744 (min. 355; max. 3587) variants per sample. Tumors with mutations of homologous recombination (HR) and MMR genes contained a higher trend of exomic mutations than those without mutation. However, tumors with mutations of HR and MMR genes contained significantly higher numbers of neopeptides with high binding affinity and immunogenicity than those without mutation (p = 0.04). Conclusions: Tumors with mutations of HR and MMR genes contained higher numbers of neoantigens. This study showed that HR and MMR mutation may be a biomarker predicted clinical benefit of immune checkpoint blockade therapy in breast cancer.
Fever after anti-programmed cell death-1 treatment to predict the response in advanced hepatocellular carcinoma.
Authors: Chen San-Chi 
Published: February 2018

90 Background: Anti-programmed cell death (PD)-1, an immune checkpoint inhibitor, has been recently approved for the treatment of patients with HCC following prior sorafenib. However, a reliable predictor of treatment response has not been established. Patients who experienced immune-related adverse events (irAEs) of any grade yielded a significantly higher response rate than did those did not experience irAEs. Methods: Three cases of advanced HCC with or without previous sorafenib treatment, underwent anti-PD-1 treatment (pembrolizumab, 2 mg/kg, at 3-week interval) with or without combination of sorafenib (400mg daily). Results: Case 1 Fever (38.3°C) developed 2 days after anti-PD-1 treatment. The fever persisted for 2 months and gradually subsided (Figure 2B). Follow-up computed tomography (CT) revealed persistent tumor shrinkage and complete response at the latest time of examination (Figure 1B); the treatment is ongoing. Case 2 Spiking fever developed after each time of anti-PD-1 treatment. Follow-up CT revealed a remarkable decrease in the tumor size (3 cm), resulting in a partial response (Figure 1D); the treatment is ongoing. Case 3 Twelve days after the treatment, the patient complained of fever and general weakness. Laboratory data revealed tumor lysis syndrome and disseminated intravascular coagulopathy (DIC). HBV, hepatitis B virus; HCV, hepatitis C virus; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha-fetoprotein; TACE, transarterial chemoembolization; CR, complete response; PR, partial response. Conclusions: Fever may be an early predictor of response to anti-PD-1 treatment. The degree of fever seemed to be correlated with tumor burden. High fever may suggest cytokine storm and possible tumor lysis syndrome. Early detection is necessary for the immediate prescription of steroids and management of tumor lysis.[Table: see text]
Comprehensive analysis of tumor mutational load, genomic alterations, and PD-L1 status in gastrointestinal cancers using a multiplatform molecular profiling tool.
Authors: Suero-Abreu Giselle Alexandra , Gonzalez Velez Miguel , McKenna Marshall , Duma Narjust , Kothadia Sejal , Krishnasamy Shalini R , Liu Janice , Dong Ning , Sharif Khawaja Umar , Pievsky Daniel , Proverbs-Singh Tracy Ann , Gutierrez Martin 
Published: February 2018

93 Background: Tumor mutational load (TML) has been proposed as a biomarker of responsiveness to novel immune checkpoint inhibitors (ICIs) due its association with increased neoantigen formation and tumor immunogenicity. Gastrointestinal cancers (GICs) are generally insensitive to ICIs; therefore the aim of this study was to evaluate the TML, clinically relevant genomic alterations (CRGAs), and PDL-1 status of GIC patients (pts). Methods: We analyzed samples of pts with GICs using a multiplatform profiling tool (Caris Life Sciences, Phoenix, AZ). TML and CRGAs were calculated based on next generation sequencing and mutational load was stratified as high (≥17 mut/Mb), intermediate (8-16 mut/Mb), and low (≤ 7 mut/Mb). PD-L1 status was determined by IHC. Descriptive statistics and simple linear regression were used for analysis. Results: A total of 85 pts with GICs were analyzed. The median pt age was 65. 53% were males and 47% were females. Tumors were colorectal 51%, pancreatic 13%, esophageal 13%, gastric 9%, hepatobiliary 11%, anal canal 4%, and small intestine 1%. 80 cases (94%) had an adequate sample for profiling and TML was available in 59 cases (74%). Cases were 5% TML-high, 56% TML-intermediate, and 39% TML-low. The median TML was 9 mut/Mb and median CRGAs was 3. The most commonly detected CRGAs were TP53 (56%), APC (44%), KRAS (40%), ATM (18%) and PTEN (6%). A positive but very weak correlation was found between TML and number of CRGAs (R2 = 0.3). PD-L1 status was available in 74 cases (93%) with 86% being PD-L1 negative and 14% PD-L1 positive. PD-L1 expression was most commonly seen in esophageal (50%) and anal canal (30%) cancers. Among 57 tumors tested for both biomarkers, no correlation was found between a high TML and PD-L1 expression. Conclusions: TML varies among GICs, and higher TML scores were not associated with PD-L1 expression, but there was a weak correlation between TML and the number of CRGAs. Further analysis by stratification of GIC type and prognostic analysis to assess the correlation between TMB and response to ICIs is warranted.
Checkpoint inhibitors assessment in oropharynx carcinoma (CIAO).
Authors: Ferrarotto Renata , Glisson Bonnie S. , Bell Diana , Hutcheson Kate A. , Phan Jack , Tran Hai T. , Gibbs Dyanne L , Lee J. Jack , Gillison Maura L. , Sikora Andrew G. , Gross Neil D. 
Published: February 2018

TPS118 Background: Oropharyngeal squamous cell carcinoma (OPSCC) is classified by HPV status. Patients with HPV negative OPSCC have worse prognosis when compared to HPV positive. The epidemic of HPV associated OPSCC emphasizes the need to improve outcomes and reduce treatment related toxicities in this patient population. Taken together, there is an unmet need for novel treatment approaches to improve survival and/or quality of life in patients with OPSCC. Checkpoint inhibitors, particularly anti-PD-1/PD-L1, have shown encouraging activity in metastatic head and neck SCC. Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity. Durvalumab and tremelimumab are immune checkpoint inhibitors that target, respectively, PD-L1 and CTLA-4. The optimal integration of novel therapeutics into clinical practice requires a thorough understanding of the molecular effects of treatment that is best evaluated by longitudinal tumor sampling. Minimally invasive transoral robotic surgery (TORS) provides opportunities to leverage standard-of-care surgery to interrogate the tumor microenvironment after neoadjuvant treatment. Methods: This is a randomized, window of opportunity trial evaluating durvalumab single agent or combined with tremelimumab in OPSCC patients amenable to curative intent surgery. The primary objective is to quantify differences in CD8+ TILs between pre- and post-treatment surgical specimens in patients treated with durvalumab vs. durvalumab plus tremelimumab. Secondary objectives include assessing the safety and toxicity of durvalumab plus or minus tremelimumab in the preoperative setting; objective response rate by RECIST at 8 weeks; percentage of patients undergoing surgery at 8 weeks; percentage of viable tumor cells in the surgical specimen; and patient-reported outcomes. Pre- and post- treatment tumor and blood based immune biomarkers will be evaluated and correlated with HPV status, outcomes, and toxicity. Eligible patients must be ≥ 18 years old, have surgically resectable stage II-IVA newly diagnosed OPSCC or loco-regional recurrence from an OPSCC primary ≥ 6 months after completion of curative intent treatment, and have a performance status ECOG 0-1. Enrollment is ongoing. Clinical trial information: NCT03144778.
Phase I/II trial of pembrolizumab in combination with binimetinib in unresectable locally advanced or metastatic triple negative breast cancer.
Authors: Chumsri Saranya , Polley Mei-Yin , Anderson Sarah L. , O'Sullivan Ciara Catherine Maria , Colon-Otero Gerardo , Knutson Keith L , Thompson E Aubrey , Moreno-Aspitia Alvaro 
Published: February 2018

TPS17 Background: Emerging studies suggest that breast cancer, particularly triple negative breast cancer (TNBC), may be sensitive to immunotherapy. However, the response rate of single agent immune checkpoint blockade agent in TNBC is rather low. Previous genomic study in residual tumor after neoadjuvant chemotherapy showed inverse correlations between MEK activation signature and the amount of tumor infiltrating lymphocytes (TILs) in residual disease samples as well as poor outcome. Preclinical study also showed that the combination of MEK inhibitor and anti-PD-L1 antibody in mouse model can eradicate TNBC tumors. Methods: This is a single arm, Phase I/II trial of Pembrolizumab (P) in combination with Binimetinib (B) in patients with unresectable locally advanced or metastatic TNBC. This trial is currently opened for accrual at Mayo Clinic in Florida and Minnesota. Patients with TNBC defined as ER ≤ 10% and PR ≤ 10% who received ≤ 3 prior lines with measurable disease will be enrolled. The primary objective of the Phase I part is to determine the maximum tolerated dose of B in combination with P and for the Phase II part is objective response rate (ORR) by RECIST criteria. The secondary endpoints include ORR by irRECIST, progression free survival, and overall survival. The total sample size is 15-38 patients with 6-12 patients in Phase I with 2 dose levels and 9-26 patients in Phase II. Simon’s Two-Stage Optimal Design is used to test the null hypothesis that this two-drug combination has an ORR of at most 15% vs. the alternative hypothesis that it has an ORR of at least 35%. Patients will receive single agent B for 2 weeks prior to starting P. A mandatory biopsy will be performed before starting B and an optional biopsy will be performed after 2 weeks of B. Tumor tissue will be evaluated for the amount and phenotypes of TILs, PD-L1 expression, and gene expression analysis using PanCancer Immune Profiling Panel, and PDJ amplification. Peripheral blood will be evaluated for circulating immunoregulatory cells, cytokine profiling, circulating tumor cells (CTCs), as well as p-ERK and PD-L1 expression on CTCs. Clinical trial information: NCT03106415.
A prospective, randomized, blinded, placebo-controlled, phase IIb trial of an autologous tumor lysate + yeast cell wall particles (YCWP) + dendritic cells (DC) vaccine vs unloaded YCWP + DC and embedded phase I/IIa trial with tumor lysate particle only (TLPO) vaccine in stage III and stage IV (resected) melanoma to prevent recurrence.
Authors: Myers John W , Herbert Garth S , Clifton Guy T , Vreeland Timothy J , Brown Tommy A , Peace Kaitlin M. , Greene Julia M , Jackson Doreen O , Hale Diane F , Berry John S , Faries Mark B. , Peoples George Earl 
Published: February 2018

TPS201 Background: Melanoma is a potentially lethal skin malignancy; patients with stage III/IV resected disease have a recurrence rate of 50-90%. Adjuvant checkpoint inhibitor immunotherapy decreases the risk of recurrence but also causes significant immune-related toxicity. Vaccines are a promising strategy for patients with high risk melanoma. The optimal time to intervene may be in the adjuvant setting after attaining a disease-free state through standard of care therapies. Our strategy uses autologous tumor lysate (TL) in a yeast cell wall particle (YCWP) to load dendritic cells (DC) ex vivo. The tumor lysate particle loaded dendritic cell (TLPLDC) vaccine is then given to prevent melanoma recurrences. An alternate vaccine delivery method that we are evaluating utilizes the tumor lysate particle-only (TLPO) technique, in which tumor lysate is loaded into capped YCWP and injected intradermally, allowing an in vivo uptake by the patient’s dendritic cells. Methods: We are performing a prospective, randomized, blinded, placebo-controlled phase IIb trial in patients with resected stage III/IV melanoma who have been rendered disease-free but remain at high risk of recurrence. The study will utilize the TLPLDC strategy vs placebo (2:1) in 120 patients, followed by a bridging study of TLPO vs TLPLDC (2:1) in 60 patients. Both TLPLDC and TLPO inoculations will be monthly x3, followed by boosters at 6, 12, and 18 months. Primary endpoints will be disease free survival (DFS) at 24 months in the TLPLDC arm, and overall safety in the TLPO arm. We have completed enrollment in the phase IIb portion of the study. Clinical trial information: NCT02301611.
Phase 1/2 study of safety/efficacy using trabectedin, ipilimumab, and nivolumab as first-line treatment of advanced soft tissue sarcoma (STS).
Authors: Gordon Erlinda Maria , Chua-Alcala Victoria S. , Kim Katherine , Tseng William W. , Quon Doris M , Chawla Sant P 
Published: February 2018

TPS46 Background: Sarcoma cells are most immunogenic at the onset of cancer when the immune system can recognize and destroy them. Hence, immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To investigate the maximum tolerated dose of trabectedin, an alkylating agent, when given sequentially with ipilimumab, a CTLA4 inhibitor, and nivolumab, a PD-1 inhibitor, in advanced STS, (2) To investigate the objective response rate (ORR), progression free survival (PFS) and overall survival (OS) , and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: Forty patients ≥18 years of age with advanced STS will be enrolled. This is a phase 1/2 study using a defined dose of ipilimumab (1 mg/kg i.v. q 12 weeks), nivolumab (3 mg/kg i.v. q 2 weeks), and escalating doses of trabectedin (1.0, 1.3, 1.5 mg/m2 i.v. q 3 weeks). I. Dose Escalation Phase 1 (previously treated patients): The study will employ the standard “cohort of three” design. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. II. Expansion Phase 2 (previously untreated patients): An additional 22-28 patients will receive trabectedin at the MTD and defined doses of ipilimumab and nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients may continue treatment until significant disease progression or unacceptable toxicity occurs. Statistical Considerations: NIH CTCAE v4.03 and RECIST v1.1 will be used. Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. The analyses of all study objectives will be descriptive and hypothesis generating, for planning Phase 2/3 studies. Clinical trial information: NCT 03138161.
Testosterone nadir and PSA recurrence-free survival in men with intermediate and high-risk localized prostate cancer undergoing definitive radiotherapy and androgen deprivation therapy.
Authors: Alex Bryant , McKay Rana R. , Kader A. Karim , Parsons J Kellogg , Einck John Paul , Kane Christopher J. , Mundt Arno James , Murphy James Don , Rose Brent Shane 
Published: February 2018

100 Background: There is limited data on the relationship between testosterone level during androgen deprivation and clinical outcomes of localized prostate cancer treated with hormone therapy and radiation therapy (RT). Here we investigate the association between testosterone nadir during androgen deprivation therapy and prostate-specific antigen (PSA) response and survival. Methods: Using a nationwide Veterans Affairs database, we identified 899 patients with intermediate- or high-risk localized prostate adenocarcinoma diagnosed between 2000 and 2015 and treated with gonadotropin-releasing hormone agonists and RT. All patients had total testosterone measurements while receiving hormone therapy and between 6 weeks and 6 months after the start of hormone therapy. Using univariable and multivariable models we examined the effect of testosterone nadir on 3-month post-treatment PSA, PSA recurrence-free survival, and prostate cancer-specific survival. Multivariable models included age at diagnosis, Gleason score, tumor stage, anti-androgen therapy, hormone therapy duration, comorbidity, BMI, and pre-treatment PSA. Results: Of the 899 patients with testosterone data, 481 patients had a testosterone nadir of < 20 ng/dL, 305 had a nadir between 20 and 49 ng/dL, and 113 had a nadir ≥50 ng/dL. Higher testosterone nadir was associated with higher 3-month post-treatment PSA on univariable (Spearman rho = 0.22, p < 0.001, n = 651) and multivariable (ß = 0.03, 95% CI 0.01-0.05, p = 0.004) analysis. In multivariable Cox regression, higher testosterone nadir was associated with an increased risk of PSA recurrence (hazard ratio [HR] 1.43 per 10-fold increase in testosterone nadir, 95% CI 1.07-1.90, p = 0.01, n = 715) but not prostate cancer-specific mortality (HR 1.45, 95% CI 0.87-2.42, p = 0.16, n = 891). Conclusions: Higher nadir testosterone levels in intermediate- or high-risk localized prostate cancer patients undergoing hormone therapy is associated with higher 3-month post-treatment PSA and inferior PSA recurrence-free survival, though there was no significant effect on prostate cancer-specific mortality.
Can post-operative prostate fossa radiation be omitted in patients with high-risk features using a genomic classifier?
Authors: Marascio Joseph Anthony , Bloom Matthew , Hurwitz Mark , Gomella Leonard G. , Lallas Costas D. , Trabulsi Edouard John , Mann Mark , Mark James Ryan , Calvaresi Anne , Kelly W. Kevin , Hoffman-Censits Jean H. , Godwin James Luke , Dicker Adam , Den Robert Benjamin 
Published: February 2018

101 Background: At our institution, based upon the AUA/ASTRO guidelines, discussion of adjuvant radiation therapy (ART) for patients with adverse pathologic features (APF) (pT3/positive margins) occurs in a multidisciplinary setting. We had previously offered ART to approximately 50% of these patients. We describe our evaluation of Decipher genomic testing to select patients to offer observation following prostatectomy (RP). Methods: Since March 2014, patients at Thomas Jefferson University with APF and undetectable post-operative PSA underwent Decipher genomic testing. Collectively, we decided to offer observation with salvage radiation therapy (SRT) for patients with low or intermediate risk Decipher scores. The primary outcome of this analysis was biochemical progression free survival (bPFS) with failure defined as a PSA ≥0.1 ng/mL. Results: From March of 2014 through September of 2016, 47 patients met the above criteria. The median patient age was 64 and median follow up was 16 months. Median pre-treatment PSA was 6.0 ng/mL (2.94 to 22.7 ng/mL). With regard to pathologic stage: 19% had T2c, 68% had T3a, and 13% had T3b disease. Pathologic Gleason grouping was 6%, 49%, 34%, 6%, and 4% for groups 1-5, respectively. 51% of patients had positive margins, 36% had lymph-vascular space invasion, and 53% had perineural invasion. Four patients received ART and 1 patient was lost to follow up after his initial visit. Of the remaining 42 patients, 3 patients experienced biochemical failure at 8, 27, and 44 months. Conclusions: This is the first prospective report utilizing Decipher genomic testing to stratify men with undetectable PSA and adverse pathologic features into an observation cohort following RP. Despite the stringency of our definition of biochemical failure, our observed bPFS was 87% at 3 years. Historically, in an unselected population the 3 year bPFS was 90% in those receiving ART and 65% in those receiving SRT. While these initial findings are promising, longer follow up is warranted. Our findings demonstrate the utility of genomic classifiers in patient selection and provide a safe approach to reducing over treatment in the post RP setting.