tbuckley/cabot-search huggingface dataset:
Exposure-response (E-R) analysis of efficacy of pegvorhyaluronidase alfa (PEGPH20) in combination with nab-paclitaxel + gemcitabine (AG) in patients (Pts) with metastatic pancreatic ductal adenocarcinoma.
Authors: Yong Liu, Andrea J. Bullock, Julie Passarell, Sebastien Bihorel, Jill Fiedler-Kelly, Thomas C Heineman, Rose E. Sekulovich
Journal: Journal of Clinical Oncology (2019)

e15746 Background: PEGPH20 depolymerizes extracellular matrix hyaluronan (HA) and is an investigational agent for the treatment of pts with HA-accumulating tumors. HALO-109-202 (260 pts) was conducted to evaluate the effect of PEGPH20 + AG in pts with mPDA. Methods: E-R models were developed to evaluate the relationship between PEGPH20 exposure and efficacy, including time to PFS, time to OS, and overall response (OR). Results: The final E-R PFS model was a Cox proportional hazards model that included effects of PEGPH20 C max and baseline tumor biopsy HA (high or low). Higher PEGPH20 C max was associated with a lower risk of radiological progression. Pts with baseline HA≥ 50% (HA-high) tumor biopsy were at a lower risk of radiological progression with PEGPH20 treatment. A similar E-R model evaluated the effect of PEGPH20 on OS, including effects of dose-adjusted PEGPH20 concentration 7 days postdose (D7 Conc), liver metastases, and baseline tumor burden. The model-predicted influence of PEGPH20 D7 Conc on risk of death indicated that with increasing PEGPH20 D7 Conc, the predicted risk of death decreases. Pts with liver metastases and higher baseline tumor burden were predicted to have a higher risk of death. The final E-R efficacy model for OR probability was a linear function of dose-adjusted PEGPH20 AUC in Cycle 1, where increasing exposure was related to a higher predicted OR probability. Conclusions: The E-R analyses demonstrate that improvements in PFS and OS with PEGPH20 + AG is PEGPH20 exposure-dependent, supporting 3 µg/kg as an appropriate dose for further development and emphasizing the need for sufficient PEGPH20 exposure for improved therapeutic effect. Clinical trial information: NCT01839487. [Table: see text]
NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).
Authors: Eleftherios P. Mamounas, Hanna Bandos, Julia R. White, Thomas B. Julian, Atif J. Khan, Simona Flora Shaitelman, Mylin Ann Torres, Frank Vicini, Patricia A. Ganz, Susan Ann McCloskey, Soonmyung Paik, Nilendu Gupta, X. Allen Li, Dominic J. DiCostanzo, Walter John Curran, Norman Wolmark
Journal: Journal of Clinical Oncology (2019)

TPS600 Background: This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PPAx nodes that are pathologically negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease, and predictors for the degree of reduction in loco-regional recurrence. Methods: Clinical T1-3, N1 IBC PPAx nodes (FNA or core needle biopsy) pts complete ≥8 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC, BCS or Mx, sentinel node biopsy (≥2 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts may receive appropriate adjuvant systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI+RNRT. Statistics: 1,636 pts are to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 2-7-19 is 1,164 (71.1%). Contacts: Protocol: CTSU member website https://www.ctsu.org . Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org . Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. Support: U10 CA-2166; -180868, -180822; 189867; Elekta NCT01872975 Clinical trial information: NCT01872975.
A phase I dose-escalation and immune biomarker study of intravenous FF-10832, liposomal gemcitabine, in patients with advanced solid tumors.
Authors: Erkut Hasan Borazanci, Gerald Steven Falchook, Atif Abbas, Catherine A. Wheeler, Gary Maier, Mary Johansen, Paula Sedivy, Ruth Ann Subach, Shiraj Sen, Suzanne Fields Jones, Tadaaki Ioroi, Takeshi Matsumoto, Takeaki Suzuki, Timothy Madden, Erika Paige Hamilton
Journal: Journal of Clinical Oncology (2019)

TPS3163 Background: FF-10832 (832) is a liposomal formulation of gemcitabine (GEM) that demonstrates a prolonged half-life and preferential uptake in tumor vs normal tissues and marrow in pre-clinical models. Macrophage uptake has been shown in the tumor microenvironment (TME), with subsequent GEM release in tumor cells. This relative selectivity and anti-tumor immunological changes observed in the TME may lead to decreased toxicity and increased efficacy compared to GEM. Ferumoxytol (FMX) may be a surrogate for nanoparticle penetration into tissue and is being examined as a potential correlate for activity. Methods: This ongoing Phase 1, 3+3 dose-escalation study of 832 will determine the safety profile, maximum tolerated dose, dose-limiting toxicities (DLT) and recommended Phase 2 dose, and will be followed by expansion. Enrollment of up to 60 patients (pts) with advanced solid tumors is planned. Pre-treatment (tx) FMX MRI scans are performed, followed by 832 administration on Days 1 &amp;15 of each 28-day cycle until disease progression or unacceptable toxicity. In addition to standard biomarker and imaging evaluations, change in macrophage polarity, myeloid-derived suppressor cell (MDSC) and regulatory T cell populations are being investigatedin peripheral blood and tumor tissue. Clinical trial information: NCT03440450.
Lymphopenia and clinical significance associated with tyrosine kinase inhibitors in metastatic renal cell cancer in Guatemalan cohort.
Authors: Rixci Ramirez, Daniel Estuardo Rosales Lopez, Francisco Godinez Jerez, Alfredo Mansilla, Carolina Camey, Gustavo Oliva Vega
Journal: Journal of Clinical Oncology (2019)

e16117 Background: Lymphopenia is associated with toxicity and clinical outcomes in several types of cancer. Decrease in absolute lymphocyte count (ALC) has been observed in the treatment with sunitinib. Objective: characterize lymphopenia ( &lt; 1000/µL) associated with tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma (mRCC) and its relation to progression free survival (PFS). Methods: A retrospective review of the charts was performed in patients with sunitinib and/or sorafenib between April 2000 and May 2017 in Guatemalan Social Security Institute (IGSS). The Kaplan-Meier models, the Cox regression and the log-rank test are within the groups for progression-free survival. Results: Eighty-nine patients were analyzed, 56 men and 33 women. The age groups &lt; 50 from 51 to 75 and &gt; 75 being these 19, 34 and 34 respectively. Regarding treatment received 56 patients received sunitinib and 47 sorafenib. Lymphopenia was found in 55% and 8% of the treated with sunitinib and sorafenib, respectively (p &lt; 0.001). Focusing on patients treated with sunitinib for all subsequent analyzes, the median PFS was 11 months (95% CI, 6-19). The median PFS was 21 months (95% CI, 11-25) for patients who will not develop lymphopenia compared to 4 months (95% CI, 3-8) in patients with lymphopenia (p = 0, 0001). Conclusions: Lymphopenia related to sunitinib is associated with a decrease in PFS in mRCC. The decrease in lymphocytes can be used as a prognostic biomarker for patients treated with sunitinib in this context. [Table: see text]
An integrated analysis of elbasvir/grazoprevir in Korean patients with hepatitis C virus genotype 1b infection
Authors: Youn Jae Lee, Jeong Heo, Do Young Kim, Woo Jin Chung, Won Young Tak, Yoon Jun Kim, Seung Woon Paik, Eungeol Sim, Susila Kulasingam, Rohit Talwani, Barbara Haber, Peggy Hwang
Journal: Clinical and Molecular Hepatology (2019)

Background/Aims In the Republic of Korea, an estimated 231,000 individuals have chronic hepatitis C virus (HCV) infection. The aim of the present analysis was to evaluate the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) administered for 12 weeks in Korean patients who were enrolled in international clinical trial phase 3 studies. Methods This was a retrospective, integrated analysis of data from patients with HCV genotype (GT) 1b infection enrolled at Korean study sites in four EBR/GZR phase 3 clinical trials. Patients were treatment-naive or had previously failed interferon-based HCV therapy, and included those with human immunodeficiency virus coinfection or Child-Pugh class A cirrhosis. All patients received EBR 50 mg/GZR 100 mg once daily for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12, HCV RNA <15 IU/mL). Results SVR12 was achieved by 73 of 74 (98.6%) patients. No patients had virologic failure and one discontinued from the study after withdrawing consent. SVR12 rates were uniformly high across all patient subgroups. A total of 16 patients had nonstructural protein 5A resistance-associated substitutions at baseline (16/73, 22%), all of whom achieved SVR12. Adverse events (AEs) reported in >5% of patients were fatigue (6.8%), upper respiratory tract infection (5.4%), headache (5.4%), and nausea (5.4%). Thirteen patients (17.6%) reported drug-related AEs, two serious AEs occurred, and two patients discontinued treatment owing to an AEs. Conclusions In this retrospective analysis, EBR/GZR administered for 12 weeks was well-tolerated and highly effective in Korean patients with HCV GT1b infection. Keywords: Hepatitis C, Chronic; Antiviral agents; Sustained virologic response
ADAPTcycle: Adjuvant dynamic marker-adjusted personalized therapy (ADAPT) comparing endocrine therapy plus ribociclib versus chemotherapy in intermediate-risk HR+/HER2- early breast cancer (EBC).
Authors: Nadia Harbeck, Oleg Gluz, Matthias Christgen, Monika Graeser, Felix Hilpert, Katja Krauss, Marc Thill, Mathias Warm, Volkmar Müller, Michael Wilhelm Braun, Marianne Just, Hans Heinrich Kreipe, Ulrike Nitz, Ronald E. Kates, Timo Schinkoethe, Rachel Wuerstlein, Sherko Kuemmel
Journal: Journal of Clinical Oncology (2020)

TPS601 Background: The WSG ADAPT trial program represents the concept of individualization of (neo)-adjuvant decision-making in EBC in a subtype-specific manner. The first WSG ADAPT umbrella trial aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment. The goals of the WSG ADAPT trial program are early response assessment and subtype-specific therapy tailoring to those patients who are most likely to benefit. Methods: WSG-ADAPTcycle is a prospective, multi-center, interventional, two-arm, open-label, (neo)adjuvant, non-blinded, randomized, controlled phase III trial (NCT04055493). It investigates whether patients (pts.) with HR+/HER2- EBC identified during screening as intermediate risk (based on Oncotype DX and response to 3 weeks of preoperative endocrine therapy [ET]) derive additional benefit from 2 years of the CDK4/6 inhibitor ribociclib combined with ET compared to chemotherapy (CT) (followed by standard ET). Co-primary endpoints are disease-free survival (DFS) and distant DFS. It is planned to screen 5600 pts and to randomize 1670 pts in a 3:2 ratio (ribociclib + ET/CT). Study start was in July 2019 (80 sites, enrollment period 36 months) and until date of submission, 180 pts. have been screened and 40 randomized. Pts with HR+/HER2- EBC with clinically enhanced risk (cT2-4 or Ki67 20% or G3 or cN+) are eligible if they fulfill the ADAPT intermediate-risk group criteria: either Recurrence Score (RS) ≤25 and Ki67 postendocrine &gt;10%, RS &gt;25 and Ki67 postendocrine &lt;10% in p/cN0-1 pts, or RS ≤25 and Ki67 postendocrine &lt;10% in c/pN2-3 pts. Treatment duration is 2 years for the ribociclib + ET (premenopausal: AI + GnRH) arm and 16-24 weeks for the CT arm; treatment is possible either in the neoadjuvant (ET + ribociclib duration 16 – 32 weeks) or adjuvant setting. ePROs are collected using CANKADO; ECG monitoring is performed using a novel cardiology-supported CANKADO-based eHealth method. Translational analyses: Exploratory tissue biomarker research will be conducted to assess alterations in molecular markers. In addition, ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression. Conclusions: ADAPTcycle seeks to evaluate whether endocrine-based therapy with ET and a CDK 4/6 inhibitor is superior to CT followed by ET in patients with luminal EBC who may be undertreated with ET alone (based on either lack of endocrine responsiveness or high tumor burden). Clinical trial information: 2018-003749-40 .
Cognitive impairment and treatment effects among gastrointenstinal stromal tumor survivors: Results of a large online survey.
Authors: Robert J. Ferguson, Jessica Manculich, Beth E. Snitz, Dana H. Bovbjerg, Anette Duensing
Journal: Journal of Clinical Oncology (2019)

e23092 Background: Cancer-related cognitive impairment (CRCI) is chronic and negatively affects quality of life (QOL) for a large portion of cancer survivors. To date, no studies have exclusively examined CRCI among gastrointestinal stromal tumor (GIST) survivors. Tyrosine kinase inhibitors (TKI), such as imatinib mesylate, have greatly increased median survival of individuals with GIST, so evaluating CRCI for this group is important. We report results of a large online survey of GIST survivors to ascertain prevalence, course and features of CRCI. Methods: A web-based survey utilizing validated patient reported outcomes (PRO’s) and de-identified demographic questions was developed. Respondents answered questions on age, gender, education, medical/cancer history and treatment. Estimated IQ was derived from demographic indexing. The FACT-Cog V3 and PROMIS Short Forms 8a assessed cognitive complaints, fatigue, mood, and anxiety. The survey was distributed through GIST Support International, the GIST Cancer Research Fund, Sarcoma Patients EuroNet and the Life Raft Group. Results: Across 4 continents, 485 adult GIST survivors (median age = 59 years, 71.8% female, 88.7% Caucasian) completed the survey. Respondents were 6.29 (sd = 5.19) years post-diagnosis with 88.0% percent on, or at least having started, imatinib. A majority (63.9%) indicated significant negative QOL impact as assessed by FACT-Cog Perceived Cognitive Impairments scale (PCI). PCI did not correlate with emotional distress or fatigue, as in other cancer samples. Type of surgery, current use/non-use of imatinib or other therapy was not associated with PCI. However, GIST survivors ≥ 5 years post-diagnosis had significantly worse PCI scores than survivors &lt; 5 years post-diagnosis (p &lt; 0.05). No differences between survivors with/without B12 deficiency or anemia were found and PCI did not correlate with cognitive reserve (years of education or IQ). Conclusions: Nearly two-thirds of GIST survivors report significant QOL impact of CRCI. Those with ≥ 5 year survival report worse cognitive symptoms, regardless of being on or off current TKI and cognitive symptoms do not appear associated with emotional distress or fatigue. CRCI among GIST survivors appears long term but further research to objectively determine CRCI magnitude and trajectory is warranted.
Immune signatures associated with response to neoadjuvant PD-1 blockade in oral cavity cancer.
Authors: Hannah Knochelmann, Joshua Dean Horton, Megan Meek, Carsten Krieg, Cynthia Dawn Timmers, Martin Romeo, John M. Wrangle, Mark P. Rubinstein, M Rita I Young, David Neskey, Chrystal Paulos
Journal: Journal of Clinical Oncology (2019)

6055 Background: PD-1 inhibition therapy has revolutionized clinical medicine as it can mediate durable responses in a small cohort of patients. Yet, it remains incompletely understood why these patients respond. To address this question, we studied patients with oral cavity squamous cell carcinoma (OCSCC) to elucidate immune phenotypes associated with response to nivolumab. Methods: We defined the immune profile from the blood and tumor of patients on neoadjuvant nivolumab. We tested if tumor-infiltrating lymphocytes (TIL) could be preferentially expanded ex vivo from nivolumab-responsive patients versus those who were either non-responsive or had never received nivolumab. During the course of therapy, we comprehensively profiled a number of surface markers on patients’ T cells to define their activation status, cytotoxic capacity and memory phenotype. Moreover, the immune profile of the peripheral blood was assessed pre- and post-nivolumab using high dimensional mass cytometry. Results: Regardless of PD-1 therapy, TIL were successfully expanded from 11 of the 12 patients. TIL were comprised of both CD4 + and CD8 + T cells. Additional investigation revealed that the frequency of CD4 + T cells and effector memory T cells in TIL correlated with disease progression (CD4: p = 0.04, r = 0.74, effector memory: p = 0.046, r = 0.74). TILs from responders expressed higher CD26 (p = 0.007, r = -0.88) and Tim3 (p = 0.045, r = -0.74) while PD-1, Lag3, and Ox40 were not differentially expressed based on response. Spearman correlation and Mann Whitney U test were used to assess phenotypic differences. Conclusions: We demonstrate, for the first time, that TIL can be reliably expanded from OCSCC patients on neoadjuvant nivolumab. Moreover, individuals who were responsive to PD-1 blockade had TIL expressing high levels of CD26 and Tim3. Future studies will explore if these markers are predictive of responses and if they contribute to treatment outcome.
A phase I dose escalation (DE) study of ERK inhibitor, LY3214996, in advanced (adv) cancer (CA) patients (pts).
Authors: Shubham Pant, Johanna C. Bendell, Ryan J. Sullivan, Geoffrey Shapiro, Michael Millward, Gu Mi, Eunice Yuen, Melinda D. Willard, Dan Wang, Sajan Joseph, William T. McMillen, Shripad V. Bhagwat, Ramon Velasquez Tiu, Manish R. Patel
Journal: Journal of Clinical Oncology (2019)

3001 Background: LY3214996 is a selective and potent ERK1/2 inhibitor that has demonstrated tumor growth inhibition in several pre-clinical tumor models with BRAF, RAS, or MAP2K1 mutations. This is the first-in-human Phase 1 Study of LY3214996 in adv CA pts. Methods: The goals of this DE study were to determine a recommended Phase 2 dose (RP2D), safety, pharmacokinetic (PK), and preliminary efficacy of LY3214996 (NCT02857270; I8S-MC-JUAB; Eli Lilly &amp; Co.). Pts with adv CA, ≥18 yrs of age, ECOG ≤1, and with adequate organ function were eligible. Pharmacodynamic (PD) biomarkers including pRSK were evaluated in blood and paired tumor tissue. The DE phase evaluated PO doses using the Bayesian model-based toxicity band method. Results: A total of 51 pts with median age of 62 yrs (range: 21-81) received at least 1 dose of LY3214996 with a median of 3 cycles (range: 1-12). Most pts had a mutation in RAS (N = 33) or BRAF (N = 16) and had a median of 4 prior lines of treatment. The DLTs observed in the study include grade (G) 3 cough and fatigue, G3 dehydration, increased creatinine (Cr), G3 increased CPK, G3 rash &gt; 7 days, and 1 pt with renal failure. TRAEs to LY3214996 occurring in ≥10% of pts included nausea, vomiting, diarrhea, dermatitis acneiform, fatigue, pruritus, and blurred vision. LY3214996 exposures increased with dose. Tumor regression was observed in 7 pts with BRAF/non -BRAF mutant CA including 5 pts who failed prior IO/MAPK inhibitors. Four pts achieved stable disease (2 BRAF, 1 RAS and 1 CRAF mutation) that lasted &gt; 4 mos. Up to 100% pRSK decrease from baseline in tumor was observed. Conclusions: LY3214996 had an acceptable safety profile, favorable PK, and potent tumor PD inhibition at RP2D. This supports further exploration of LY3214996 as monotherapy and in combination in CA pts with activating MAPK pathway alterations. Clinical trial information: NCT02857270.
Phase 3 (COSMIC-312) study of cabozantinib (C) in combination with atezolizumab (A) versus sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy.
Authors: Robin Kate Kelley, Ann-Lii Cheng, Fadi S. Braiteh, Joong-Won Park, Fawzi Benzaghou, Steven Milwee, Anne Borgman, Anthony B. El-Khoueiry, Zeid K Kayali, Andrew X. Zhu, Lorenza Rimassa
Journal: Journal of Clinical Oncology (2019)

TPS4157 Background: C inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). C is approved for treatment of aHCC after prior S based on improved overall survival (OS) vs placebo in the phase 3 CELESTIAL trial (Abou-Alfa NEJM 2018). Standard of care for first-line treatment of aHCC is tyrosine kinase inhibition with S or lenvatinib, and phase 3 trials of immune checkpoint inhibitors (ICIs) in first- and second- line aHCC are ongoing. C may promote an immune-permissive tumor environment, which could enhance response to ICIs. C is being evaluated in combination with the anti-PD-L1 antibody A in multiple tumor types including HCC in a phase 1 study; and dose, preliminary clinical activity, and safety have been established in aRCC (Agarwal Ann Oncol 2018). A in combination with bevacizumab, an anti-VEGF antibody, has shown preliminary clinical activity in first-line aHCC (Pishvaian Ann Oncol 2018). Here, we present the study design of a phase 3 trial of C+A vs S in pts with aHCC who have not received prior systemic therapy. Methods: This international, randomized, open-label phase 3 trial (NCT03755791) is evaluating the efficacy and safety of C+A vs S as first-line treatment for aHCC. Eligibility criteria include age ≥18 years, BCLC stage B or C, Child-Pugh A, ECOG PS 0 or 1, and measurable disease per RECIST 1.1. Patients are randomized 6:3:1 to an experimental arm of C (40 mg qd) + A (1200 mg infusion q3w), a control arm of S (400 mg bid), and an exploratory arm of C monotherapy (60 mg qd). 640 pts are planned at ~200 sites globally. Randomization is stratified by disease etiology (HBV [with or without HCV], HCV [without HBV], or other), region (Asia, other), and the presence of extrahepatic disease and/or macrovascular invasion (yes, no). OS and progression-free survival are coprimary endpoints and objective response rate is a secondary endpoint. Additional endpoints include safety, pharmacokinetics, and correlation of biomarker analyses with clinical outcomes. Enrollment in COSMIC-312 is ongoing. Clinical trial information: NCT03755791.