tbuckley/cabot-search huggingface dataset:
THU0117 PHARMACOKINETICS AND SHORT-TERM SAFETY OF FILGOTINIB, A SELECTIVE JANUS KINASE 1 INHIBITOR, IN SUBJECTS WITH MODERATE HEPATIC IMPAIRMENT
Authors: Kacey Anderson, Hao Zheng, Oliver Medzihradsky, LI Yizhao, Ann Qin, Brian Kearney, Anita Mathias
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Filgotinib (FIL) is an oral selective Janus kinase 1 (JAK1) inhibitor being developed to treat inflammatory diseases. <h3>Objectives</h3> This phase 1 study evaluated the pharmacokinetics (PK) and short-term safety of FIL in subjects with hepatic impairment (HI) to guide safe and appropriate dosing in the presence of this comorbidity. <h3>Methods</h3> This study enrolled 20 subjects: 10 with moderate (Child-Turcotte-Pugh-B) HI and 10 healthy controls. All were matched for age, sex, and body mass index and received a single oral dose of FIL 100 mg followed by intensive plasma PK sampling over 120 hours. Plasma concentrations of FIL and its primary circulating metabolite were measured by validated LC-MS/MS methods; plasma protein binding was also evaluated. A parametric analysis of variance was applied to the natural logarithmic transformation of PK parameters (AUC and C<sub>max</sub>) for FIL and its metabolite. Geometric least squares means (GLSM) ratios and 90% confidence intervals (CIs) of PK parameters were evaluated in subjects with moderate HI relative to controls, with clinically relevant exposure change defined as ≥2-fold for FIL or its metabolite. Safety endpoints consisted of the incidence of adverse events (AEs), laboratory abnormalities, and vital sign and electrocardiogram changes monitored through day 15. <h3>Results</h3> All subjects completed the protocol-specified dosing and assessments. FIL and metabolite AUCs were increased by 1.6- and 1.2-fold, respectively, in subjects with moderate HI compared to controls. Protein bindings of FIL and its metabolite (f<sub>u</sub>: 41%–44% and 55%–61%, respectively) were unchanged in subjects with moderate HI. FIL was well tolerated, with no serious AEs reported. All treatment-emergent AEs were Grade 1 in severity. Serum and plasma markers did not show evidence of treatment-emergent hepatotoxicity or worsened liver function and were consistent with the use of FIL in a population with moderate HI. <h3>Conclusion</h3> In the setting of moderate HI, a single oral dose of FIL 100 mg was well tolerated. FIL can be administered without predefined dose adjustment to patients with mild to moderate HI. <h3>Disclosure of Interests</h3> Kacey Anderson Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Hao Zheng Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Oliver Medzihradsky Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Yizhao Li Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ann Qin Employee of: Gilead Sciences, Inc., Brian Kearney Employee of: Gilead Sciences, Inc., Anita Mathias Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc.&nbsp;
Phase II study of preoperative chemotherapy versus standard postoperative chemotherapy in HR-negative HER2-positive breast cancer patients.
Authors: Meng Xiu, Pin Zhang
Journal: Journal of Clinical Oncology (2019)

e12118 Background: HR-/HER2+ breast cancer is a subtype with aggressive characteristic and poor survival. More clinical evidence are needed for choice of therapeutic strategies. Methods: Patients with T1-3N0-3M0 received preoperative chemotherapy (PTX 175 mg/m 2 , CBP AUC 4, q2w*6) combined with trastuzumab (2mg/kg qw) or standard postoperative chemotherapy such as ddAC-PH, AC-PH, TCH. The primary endpoint was RFS. Results: 86 patients were enrolled, 43 received preoperative chemotherapy (pre arm) and the other 43 received postoperative chemotherapy (post arm). There was no significant difference in baseline between the two arms. 22.1% of patients were stage IIA, 25.6% IIB, 34.9% IIIA, and 18.6% IIIC. At a median follow-up of 33.4 months, 16 patients had relapsed (pre arm 8, post arm 8). The median time from diagnosis to relapse was 22.8 months (7.1-49.2) and 23.8 months (11.4-37.4) in pre and post arm. Kaplan-Meier survival analysis estimated that the 3-year RFS were similar (pre vs post: 73.4% vs 75.4%, p= 0.631). Only 1 death occurred in post arm. Table showed that in subgroups, there was no statistical difference in risk of recurrence between pre and post arms. In pre arm, ORR was 97.7% clinically, and pCR (ypT0/TisN0) was 39.0%. No patients achieved pCR relapsed, and the residual invasive lesions indicated poor prognosis. Table showed that Neo-Bioscore 4-5 was related to recurrence event significantly ( p= 0.021). The rate of breast-conserving in pre arm was higher (19.5% vs 9.3%), and PCb regiments every 2 weeks had similar adverse effects with standard chemotherapy, and less patients had dose reductions (18.6% vs 25.6%). Conclusions: Preoperative chemotherapy versus standard postoperative chemotherapy results in similar RFS among HR-/HER2+ patients. Preoperative chemotherapy can identify prognosis of patients early by Neo-Bioscore and adjuvant therapy should be strengthened for high-risk patients. PCb every 2 weeks combined with trastuzumab can be an option of preoperative therapy for HER2+ breast cancer. Clinical trial information: NCT02934828. [Table: see text]
Nimbus: A phase II study of nivolumab plus ipilimumab in metastatic hypermutated HER2-negative breast cancer.
Authors: Romualdo Barroso-Sousa, Lorenzo Trippa, Paulina Lange, Chelsea Andrews, Heather L. McArthur, Barbara B. Haley, Hope S. Rugo, Leisha A. Emens, Eric P. Winer, Elizabeth A. Mittendorf, Sara M. Tolaney
Journal: Journal of Clinical Oncology (2019)

TPS1115 Background: A previous study from our group showed that approximately 9% of metastatic breast cancer (MBC) is hypermutated, defined as a tumor mutational burden (TMB) ≥10 Mutations/Megabase (Mut/Mb). The aim of this study is to evaluate if patients with hypermutated HER2-negative MBC benefit from the combination of nivolumab plus ipilimumab. Methods: This is an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of nivolumab 3 mg/Kg intravenously (IV) every 14 days plus Ipilimumab 1 mg/Kg IV every 6 weeks in subjects with hypermutated metastatic HER2-negative breast cancer. Patients with measurable HER2-negative MBC, TMB ≥10 Mut/Mb assessed by a cancer-gene panel evaluating &gt; 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting are eligible. The primary objective is overall response rate according to RECIST 1.1. Secondary objectives include the safety and tolerability of the combination, progression-free survival, and overall survival. The study will follow a two-stage design. In the first stage 14 patients will be enrolled. If there is at least one patient with objective response, accrual will continue to the second stage where an additional 16 patients will be enrolled. If there are at least 4 patients with an objective response among the 30 patients, the regimen will be considered worthy of further study. If the true response rate is 5%, the chance the regimen is declared worthy of further study is less than 5%. If the true response rate is 25%, the chance that the regimen is declared worthy of further study is &gt; 90%. Tumor biopsies, peripheral blood, and stool collection are mandatory and will be obtained at baseline, on treatment (end of cycle 1), and at disease progression and will be assessed for potential biomarkers of treatment response. The trial was activated in February 2019, and accrual should be completed in 18 months. Clinical trial information: NCT03789110.
Pembrolizumab (Pem) in recurrent high-grade glioma (HGG) patients (PTS) with mismatch repair deficiency (MMRd): An observational study.
Authors: Giuseppe Lombardi, Mario Caccese, Matteo Simonelli, Matteo Fassan, Marta Padovan, Pasquale Persico, Luisa Bellu, Angelo Dipasquale, Marina Paola Gardiman, Stefano Indraccolo, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2019)

2043 Background: Pem, an immune checkpoint inhibitor, demonstrated to be active in various neoplasms with MMRd. No data exists about its efficacy in MMRd glioma PTS. Methods: MMRd HGG relapsed after receiving RT and CT were treated with Pem. MMR status was analyzed by immunohistochemistry, including the MLH1, MSH2, MSH6, and PMS2 markers. MMRd was defined as presence of a weak (wMMRd) or absent (aMMRd) signal for at least one MMR protein. Other inclusion criteria were: ECOG PS 0-2, histologically confirmed glioma, dexamethasone ≤4 mg. Pem was administrated at 200 mg every 3 weeks until disease progression or unacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeks according to the RANO criteria. OS and PFS were evaluated by Kaplan-Meier curves. Results: among 167 glioma PTS, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, all PTS had microsatellite stability. Tumor histologies included 5 anaplastic astrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2 deficiency was found in 6 cases , MSH6 deficiency in 9 cases, PMS2 and MLH1 deficiency in 2 cases. Median number of prior lines of chemotherapy was 1 (range 1-5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showed progressive disease (PD). PTS with anaplastic gliomas showed a statistically significant association with SD (p=0.03, OR=3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6 (deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1-13.8), PFS 2.4 ms (95% CI 1.8-2.9). OS was 2.8 ms and 5.6 ms (p=0.9), PFS was 1.8 ms and 3.1 ms (p=0.5) in PTS with wMMRd and aMMRd, respectively. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6-10.2) and 1.8 ms (95% CI 0.2-3.4), p=0.002; OS was “not reached” and 2.8 ms in PTS having SD vs PD (p=0.04), respectively. Grade ≥3 adverse events were reported in 8% of PTS. Conclusions: a subgroup of recurrent MMRd HGG might benefit from Pem, especially anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. The enrollment and analyses for identifying additional molecular predictive factors are ongoing.
Human papillomavirus genotype and prognosis of invasive cervical cancer: A nationwide cohort study.
Authors: Jiayao Lei, Alexander Ploner, Camilla Lagheden, Carina Eklund, Sara Nordqvist Kleppe, Bengt Andrae, Klara Miriam Elfström, Joakim Dillner, Pär Sparén, Karin Sundström
Journal: Journal of Clinical Oncology (2019)

5525 Background: The role of human papillomavirus (HPV) in development from oncogenic infection to invasive cervical cancer (ICC) has been well established. However, the association of HPV genotypes and prognosis of ICC is controversial. Methods: We identified all ICC diagnosed in Sweden during the years 2002-2011 (4254 confirmed cases after clinical and histo-pathological review), requested all archival formalin-fixed, paraffin-embedded blocks and subjected them to comprehensive HPV genotyping. Twenty out of twenty-five archives agreed to the study, contributing a total of 2845 confirmed cases with valid HPV results. Cases were followed up from date of cancer diagnosis to 31 December, 2015, migration from Sweden, or death; whichever occurred first. Five-year relative survival ratios (RSRs) were calculated and excess hazard ratios (EHRs) with 95% confidence intervals (CIs) were estimated using Poisson regression. Results: HPV was detected in 2365 tumors (83.1% of all cases). The five-year RSR by tumor HPV status was 0.54 (HPV negative), 0.76 (HPV16 positive), 0.73 (HPV18 positive), 0.72 (other high-risk HPV positive) and 0.56 (low-risk HPV positive) compared to the age-matched general female population. Compared to cases with HPV-negative tumor, a significantly lower excess mortality was seen if the tumor was positive for HPV16 (EHR:0.54, 95% CI 0.44-0.65), other high-risk HPV (EHR:0.47, 95% CI 0.37-0.60), and low-risk HPV (EHR:0.48, 95% CI 0.32-0.74), after adjustment for age, time since cancer diagnosis, International Federation of Gynecology and Obstetrics (FIGO) stage, educational level and histology. However, the mortality among women with HPV18 positive tumors were not statistically significantly different from cases with HPV-negative tumors. In women with a single HPV infection of either HPV16 or HPV18, those with HPV18-positive tumors had 56% (EHR:1.56, 95% CI: 1.13-1.97) higher excess mortality compared to women with HPV16-positive tumors. Conclusions: HPV genotype in cervical cancer tumor is associated with prognosis of ICC. Single HPV18 positivity indicated a poorer prognosis than single HPV16 positivity. This could add information of value beyond the established clinical prognostic factors for women diagnosed with ICC.
Correlation between innate cytokine levels and progression in men with biochemically recurrent prostate cancer treated with intermittent hormonal therapy.
Authors: Jessica Hawley, Samuel Pan, William Douglas Figg, Zoila Lopez Bujanda, Jonathan Strope, Antonio Tito Fojo, Matthew Dallos, David Henry Aggen, Emerson A. Lim, Mark N. Stein, Jianhua Hu, Charles G. Drake
Journal: Journal of Clinical Oncology (2019)

e16554 Background: Suppressive cytokines have the potential to drive prostate cancer progression with consequent decreased survival. Assessing longitudinal cytokine changes may shed light on mechanisms of disease progression, resistance to therapy, and suggest new therapeutic targets. Methods: Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time of PSA progression (TTPP) were identified from a previously conducted phase III trial (NCT00020085). Serum samples were archived at baseline, three months after administration of ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay (MesoScale Discovery). Wilcoxon signed rank sum test was used to compare paired observations between time points. Kaplan-Meier analysis was used to calculate progression function (TTPP) dichotomized by above or below the median value of cytokines with Bonferroni adjustment. Pearson’s rank correlation coefficient was used to compare continuous variables. Results: Median TTPP was 399 days (range, 114 - 1641). Median PSA at baseline and progression were 8.5 ng/ml, (range, 1.0 - 76.6) and 5.3 ng/mL (range, 1.2 - 19.4), respectively. Twenty-three patients (62%) achieved undetectable PSA with ADT. TNF-α (P = 0.002), IL-23 (P = 0.002), and IP-10 (P = 0.001) significantly increased from baseline to post ADT. Patients with a detectable PSA after ADT had moderately elevated levels of IL-6 (P = 0.049) and IL-8 (P = 0.013) at PSA progression as compared to those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = 0.042). TNF-α was strongly correlated with IL-23 (r = 0.72, P &lt; 0.001) and IL-8 (r = 0.59, P &lt; 0.001) from baseline to after ADT and to PSA progression. NLR correlated strongly with IL-27 (r = 0.57, P &lt; 0.001) and MIP-3α (r = 0.56, P &lt; 0.001). Conclusions: Cytokines associated with the innate immune response were associated with an unfavorable clinical outcome in early prostate cancer. These data suggest cytokine blockade combined with ADT may warrant future investigation.
A modeling and simulation study of less frequent dosing of nivolumab 480 mg.
Authors: Cody J. Peer, Daniel A. Goldstein, Mark J. Ratain, William Douglas Figg
Journal: Journal of Clinical Oncology (2019)

3115 Background: Nivolumab was originally approved at 3 mg/kg q2w. However, there is abundant evidence that doses as low as 0.1 mg/kg q2w are effective, and a randomized trial in RCC demonstrated equivalence across a dose range of 0.3-10 mg/kg q3w. Modeling and simulation have been used to amend the labeled dosage to 240 mg q2w or 480 mg q4w, with the latter yielding an estimated steady-state trough concentration (C trough ) of ~50 ug/mL. Given the high cost of nivolumab and the lack of a dose-response relationship, we hypothesized that less frequent dosing of 480 mg would maintain therapeutic serum concentrations. The objective of this study was to use modeling and simulation to develop alternative dosing strategies. Methods: A simulation model was built from a published population pharmacokinetic model, incorporating time-dependent clearance. Various alternative dosing schedules were simulated, beginning with the third dose (doses 1 and 2 were 480 mg at wk 1 and 5). We conservatively chose 4.5 mg/mL as the target concentration (TC), slightly above the mean simulated C trough at 0.3 mg/kg q3w (4.1 ug/mL), although even lower levels are likely efficacious. The simulated dose schedules were q8w, q10w, q12w and q14w, beginning with the third dose. Simulations were performed on 50 simulated patients, with each simulation replicated 5 times. Results: The simulated C trough following doses 2-4 are presented in the table below. Dosing q12w should maintain TC in &gt; 70% of patients, and q14w dosing should achieve TC in &gt; 55% of patients. Conclusions: Modeling and simulation provide evidence that nivolumab can be effectively dosed q8-14w (after the first 2 doses), resulting in a potential 70% cost savings. As responding patients generally have a 35-45% decrease in clearance over the first 6 months of treatment, even less frequent dosing may be required for subsequent doses. Randomized trials of this interventional pharmacoeconomic strategy are indicated. Similar opportunities may exist for other checkpoint inhibitors. [Table: see text]
Evaluation of inpatient cancer rehabilitation by routine electronic patient-reported outcome measures (ePROM): Improvement of quality of life (QoL) and psychological distress.
Authors: Thomas Licht, Alain Nickels, David Riedl, Gerhard Rumpold, Bernhard Holzner
Journal: Journal of Clinical Oncology (2019)

e18294 Background: Many cancer survivors suffer from psychological distress and poor QoL. Cancer rehabilitation is aimed at improving their condition but the benefit remains controversial, we have thus investigated the outcome. Methods: ePROM were routinely integrated into the inpatient program of a cancer rehabilitation center in Austria. Hospital Anxiety and Depression Scale (HADS) was used to assess distress, and EORTC QLQ-C30 questionnaire for analysis of cancer-related symptoms and functions. Patients answered questions via internet prior to admission (T0). This allowed for allocation of physical therapies and 4-8 psychological counseling sessions according to their needs. Following informed consent, the outcome was investigated likewise by the time of discharge after 3 weeks (T1). Data were analyzed with SPSS software using ANOVA repeated measures. Results: 4198 patients (age 59.2±11.7 yr; range 18-91 years; 61.5% female) participated between January 2015, and August 2018. HADS identified a marked reduction of anxiety and depression, with distress levels similar to the normal population by T1. QLQ-C30 revealed significant increases for global QoL; physical, social, emotional and role functions. All recorded symptoms were improved, in particular fatigue, pain and insomnia. Moreover, subgroup analyses confirmed improvement for 11 investigated entities. Of notice, decrease of anxiety was most prominent in survivors of breast, head/neck and lung cancer patients (p &lt; 0.001). No significant differences were observed between a subgroup of 1122 elderly ( &gt; 70 yr), and younger patients except for the physical function, which improved significantly in older patients (p = 0.003). Conclusions: Our study shows that inclusion of ePROM into inpatient cancer rehabilitation helps allocate therapies according to individual needs. This large series demonstrates significant reduction of psychological distress and improvement of all parameters of QoL. [Table: see text]
Utilization of surgery and its impact on survival in elderly patients with localized colon cancer in the United States.
Authors: Lubina Arjyal, Amir Bista, Michael Olayiwola Ojelabi
Journal: Journal of Clinical Oncology (2019)

e15179 Background: For patients with localized colon cancer, surgical resection is the only curative treatment modality. Old age may be an independent factor associated with decreased receipt of surgery. We conducted this study to evaluate the utilization of surgery and its impact on survival in older patients with colon cancer in the United States. Methods: Surveillance, Epidemiology and End Results Database (SEER-18) was utilized to identify elderly patients (≥65 years) diagnosed from 2004-2013 with non-metastatic colon cancer (stage≤ III). Study population was divided into various cohorts based on race (Caucasian, African Americans, others), sex and age (&lt; 80 years and ≥80 years), histology grade, tumor side, and stage. Multivariate logistic regression model was utilized to assess factors associated with receipt of surgery. Kaplan-Meier estimators with the log rank test was used to compare median overall survival (Md OS) between the surgery arm and non-surgery arm. Statistical significance was defined for p &lt; 0.05. Results: Database identified 89,467 patients (54.7% female, 82.7% Caucasian; Median age 77 years). 94.6% (n = 84,656) of patients received surgery. On multivariate-analysis, left sided disease, lower grade tumor, lower stage, female gender, residents of lower median household income county, African Americans and age ≥80 years were less likely to receive surgery. The Md OS in the surgery arm was 87 months vs 69 months for non-surgery arm, p &lt; 0.001. This benefit was seen in all the three stages (stage I: Md OS 104 vs 75 months; stage II: Md OS 88 vs 50 months; stage III: Md OS 74 vs 37 months, p &lt; 0.001 for all comparisons). Additional analysis for octogenarians (age≥ 80 years) showed Md OS of 68 months in the surgery arm vs 48 months in the non-surgery arm, p &lt; 0.001). Conclusions: Our study showed significant utilization of surgery (94.6%) in elderly patients with localized colon cancer. There is a clear survival benefit to surgery even in patients with age≥ 80 years. Surgical resection with curative intent should be strongly considered in patients with good performance status irrespective of age.