tbuckley/cabot-search huggingface dataset:
Phase II trial of enzalutamide in patients with androgen receptor positive (AR+) ovarian, primary peritoneal or fallopian tube cancer and one, two or three prior therapies.
Authors: Rachel N. Grisham, Dilip D. Giri, Alexia Iasonos, Qin Zhou, Jeffrey Girshman, Sean Patrick McGrath, Oana-Paula Orodel, Roisin Eilish O'Cearbhaill, Nancy E. Mills, Tiffany A. Troso-Sandoval, Paul Sabbatini, William P. Tew, David Michael Hyman, Martee Leigh Hensley, Dmitriy Zamarin, Jason A. Konner, Alexandra Snyder Charen, Karen Anne Cadoo, Gopa Iyer, Carol Aghajanian
Journal: Journal of Clinical Oncology (2016)

TPS5602 Background: Approximately 75% of women with epithelial ovarian cancer (OC) present with advanced disease. The majority of these women will ultimately recur and require life-long treatment for their disease. Well tolerated therapies for treatment in the recurrent setting are needed. The AR is expressed in greater than 60% of cases of OC and is more prevalent than the estrogen or progesterone receptor. All past clinical studies of androgen inhibition in OC have treated an unselected population of heavily pretreated women; however preclinical data suggests that AR expression decreases in OC cells with increasing lines of therapy. Enzalutamide is a small molecule androgen receptor-antagonist that is FDA approved for the treatment of prostate cancer and is currently being investigated as a treatment for breast and ovarian cancer. (NCT01974765) Methods: This is a phase II, single-institution trial of enzalutamide 160mg po QD in patients with AR+ ovarian, fallopian tube or primary peritoneal cancer. Eligible patients must be found to have greater than or equal to 5% AR staining by IHC on FFPE tumor tissue and been treated with only 1,2 or 3 prior cytotoxic therapies. Patients must have RECIST 1.1 defined measurable disease. Enrolled patients are treated with enzalutamide until progression of disease or unacceptable toxicity. The primary endpoint is to estimate the proportion of women who achieve a complete or partial response by RECIST 1.1 criteria or survive progression free for at least 6 months. Secondary objectives include the retrieval of optional tumor biopsies at time of progression to evaluate for effect of enzalutamide on androgen receptor expression and to observe the effect of enzalutamide on serum testosterone and estradiol levels in treated patients. This study will enroll 58 patients at Memorial Sloan Kettering Cancer Center and its regional sites. During the safety lead-in phase if less than 5 of the first 15 patients treated develop a dose limiting toxicity then enrollment will proceed following a two-stage design. The first patient enrolled on the study in April 2015 and 9 patients have been treated to date. Clinical trial information: NCT01974765.
Comparison of rural versus urban residence for symptoms and quality of life in recurrent ovarian cancer: Baseline analysis of GOG-0259, an NRG Oncology/GOG study.
Authors: Sarah M. Belcher, Susan M. Sereika, Zan M. Dodson, Meghan K. Mattos, Teresa Hagan, Heidi AS Donovan
Journal: Journal of Clinical Oncology (2017)

e18083 Background: Women with recurrent ovarian cancer (OC) experience a wide range of cancer- and treatment-related symptoms that negatively impact quality of life (QOL). Studies have reported healthcare disparities by geographic residence related to distance, time, and financial barriers to accessing high quality care. However, no studies have evaluated the impact of residence on symptoms and QOL in women with OC. Therefore, our objectives were to evaluate whether geographic residence (urban versus rural) is associated with symptoms and QOL in a sample of women with recurrent OC. Methods: The Center for Health Equity Research and Promotion conceptual framework guided analyses of baseline GOG-0259 data. We mapped zip codes to RUCA commuter codes and compared sociodemographic and clinical variables between rural and urban groups using two-sample t and chi-square tests. We used MANCOVA, adjusted for age and marital status, to test for associations between residence and symptoms (Symptom Representation Questionnaire) and QOL (Functional Assessment of Cancer Therapy-Ovarian). Results: Rural (n = 122, 25%) and urban (n = 374, 75%) women were similar in all sociodemographic and clinical comparisons except for marital status (83% vs. 70% married, p = .003). Women reported moderate symptom severity (M = 5.5, SD = 2.3) and QOL scores similar to other OC studies (M = 108.4, SD = 19.5). In multi-variate analyses, age and marital status were both associated with symptoms; marital status was associated with QOL. Geographical residence was not associated with either symptoms or QOL. Conclusions: Counter to previous research, there were no symptom or QOL disparities based on geographic residence in this sample. Possible explanations to be explored in future research include a) cooperative group selection bias for women with good access to care regardless of geographic residence and b) protective effects of marital status on symptoms and QOL.
Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer
Authors: Hua Jiang, Zhimin Shi, Peng Wang, Cong Wang, Linlin Yang, Guoxiu Du, Honghong Zhang, Bizhi Shi, Jie Jia, Qixiang Li, Huamao Wang, Zonghai Li
Journal: JNCI Journal of the National Cancer Institute (2018)

Claudin18.2 (CLDN18.2), a gastric-specific membrane protein, has been regarded as a potential therapeutic target for gastric cancer and other cancer types. The aim of our study was to elucidate whether chimeric antigen receptor T (CAR T) cells redirected to CLDN18.2 have the potential to be used in the treatment of this deadly disease. CLDN18.2-specific humanized antibodies were developed using hybridoma and humanization technology. CLDN18.2-specific CAR T cells were prepared by lentiviral vector transduction. In vitro antitumor activities and cytokine production of the CAR T cells to gastric cancer cell lines were examined by cytotoxicity and ELISA assay. In vivo antitumor activities of CAR T cells were evaluated in mice bearing gastric cancer cell line and patient-derived tumor xenograft (PDX) models (n ≥ 6 mice per group). All statistical tests were two-sided. Humanized CLDN18.2-specific hu8E5 and hu8E5–2I single-chain fragment variables (scFv) were successfully developed. CLDN18.2-specific CAR T cells were developed using hu8E5 or hu8E5–2I scFv as targeting moieties. Both hu8E5–28Z and hu8E5–2I-28Z CAR T cells comprising the CD28 costimulatory domain potently suppressed tumor growth in a cancer cell line xenograft mouse model (mean [SD] tumor volume: hu8E5–28Z = 118.0 [108.6] mm3 and hu8E5–2I-28Z group = 75.5 [118.7] mm3 vs untransduced T cell group = 731.8 [206.3] mm3 at day 29 after tumor inoculation, P < .001). Partial or complete tumor elimination was observed in CLDN18.2-positive gastric cancer PDX models treated with the hu8E5–2I-28Z CAR T cells (P < .001), which persist well in vivo and infiltrate efficiently into the tumor tissues. Although the CLDN18.2 CAR T cells could lyse target cells expressing murine CLDN18.2 (mCLDN18.2), no obvious deleterious effect on the normal organs including the gastric tissues was observed in the mice. CLDN18.2-specific CAR T cells could be a promising treatment strategy for gastric cancer and potentially other CLDN18.2-positive tumors.
Population pharmacokinetics (pop PK) and exposure-safety analysis to reveal patient factors that affect AMG 900 tolerability.
Authors: Vincent F-S. Chow, Joanna Z. Peng, Florian D. Vogl, John P. Gibbs
Journal: Journal of Clinical Oncology (2016)

e14125 Background: AMG 900 is an orally administered, highly potent, selective, pan-aurora kinase inhibitor that has shown promising single-agent activity in drug-resistant solid tumors. In a phase 1 study (NCT00858377), grade 4 neutropenia was the primary dose limiting toxicity of AMG 900 treatment. In this dose/exposure/safety analysis, we assessed risk factors associated with high exposure and neutropenia. Methods: Key eligibility criteria: age ≥ 18 years, advanced solid tumors refractory to standard treatment, measurable disease, ECOG ≤ 2, adequate organ function, no treatment with strong CYP3A4 inducers or inhibitors or strong CYP2C substrates or inhibitors. AMG 900 was administered 4 d on/10 d off; dose escalation: 1–50 mg/d, dose expansion: 40 mg/d with G-CSF (the maximum tolerated dose). Cycle 1 PK data from all pts in the dose escalation and available pts in the dose expansion were included in a non-linear mixed-effect pop PK model. Patient demographics, disease characteristics, lab values, and concomitant medications were evaluated as potential PK covariates. A stepwise backward procedure was used for model selection. Individual AUC predicted by the PK model and corresponding absolute neutrophil count (ANC) values were explored to assess the relationship between exposure and neutropenia risk. Results: Overall, 105 pts were enrolled (escalation: N = 50; expansion: N = 55). A two-compartment model with first order absorption was used to describe AMG 900 PK. The estimated typical oral clearance (CL/F) and oral central volume of distribution (Vc /F) were 2.71 L/h and 26 L, respectively. Only gender and body weight (BW) were found to be significant covariates. The final pop PK model included the influence of BW on CL/F and Vc /F and the influence of gender on Vc /F. Both CL/F and Vc /F increased with BW. Males had 29% higher Vc /F values than females after adjusting for BW. Pts with BW < 60 kg tended to have higher drug exposure (measured as AUC0-24h ) and higher risk of grade 4 neutropenia. In addition, pts with low baseline ANC also had an increased risk of grade 4 neutropenia. Conclusions: A reduced dose of AMG 900 (30 mg/d with G-CSF) is recommended in patients with low body weight/low ANC in further studies. Clinical trial information: NCT00858377.
Single intravenous preoperative administration of the oncolytic virus Pexa-Vec to prime anti-tumor immunity.
Authors: Alan Anthoney, Adel Samson, Emma West, Samantha Jane Turnbull, Karen Scott, Emma Tidswell, Jennifer Kingston, Michelle Johnpulle, Samantha Noutch, Kaidre Bendjama, Michel Homerin, Nicolas Stojkowitz, Giles Toogood, Chris Twelves, Christy Ralph, Alan Melcher, Fiona Jane Collinson
Journal: Journal of Clinical Oncology (2018)

3092 Background: Oncolytic viruses (OV) constitute a promising modality of cancer therapy. Intra-tumoral administration has yielded encouraging clinical results, but restricted the use of OV to tumors that are readily accessible. Pexa-Vec, a Thymidine Kinase-Deactivated Vaccinia Virus expressing GM-CSF, has been shown previously to successfully target tumor tissue after intravenous administration (Breitbach C.J. et al., 2011). Herein, we report data on the immunostimulatory effects of a single intravenous (i.v.) administration of Pexa-Vec prior to surgical resection in patients with advanced solid tumors. Methods: Patients with operable tumors received a single i.v. administration of 1x109 plaque forming units of Pexa-Vec, 14 days prior to surgical resection. Up to six blood samples were collected pre- and post-injection for each patient. Tumor tissue was collected at surgery for histologic and translational assessments. Results: The study included 3 patients with metastatic melanoma and 5 with colorectal cancer metastases to the liver (CRLM). Pexa-Vec injection was well tolerated in all cases. Histologic examination of tumor tissue indicates the presence of virus in tumor at the time of surgery. Of the 3 evaluable CRLM, 2 showed signs of inflammation and fibrosis, within a normal background liver. Phenotyping of peripheral blood mononuclear cells showed robust activation of Natural Killer (NK) and professional antigen presenting cells (CD14+), as well as CD4+ and CD8+ cells, with high CD69 expression. Functional assays revealed increased patient NK cell degranulation in the presence of tumor cell lines. Consistent with cellular markers, Pexa-Vec induced a significant elevation of serum cytokines associated with immune response including IFNα, IL3, IL12p40, IL16, IL18. Conclusions: When administered intravenously, Pexa-Vec exhibited a selective persistence in tumor tissues suggesting a targeted oncolytic action in the tumor. Concurrently, Pexa-Vec triggered a robust immune activation of both innate and adaptive immune cells. These data strongly support the rationale for sequential JX-594 and anti-PD-1 viro-immunotherapy, which is the focus of the ongoing study, NCT03071094. Clinical trial information: ISRCTN13913966.
Multicenter Phase II Study of Sequential Brentuximab Vedotin and Doxorubicin, Vinblastine, and Dacarbazine Chemotherapy for Older Patients With Untreated Classical Hodgkin Lymphoma
Authors: Andrew M. Evens, Ranjana H. Advani, Irene B. Helenowski, Michelle Fanale, Sonali M. Smith, Borko D. Jovanovic, Gregory R. Bociek, Andreas K. Klein, Jane N. Winter, Leo I. Gordon, Paul A. Hamlin
Journal: Journal of Clinical Oncology (2018)

To improve the curability of older patients with newly diagnosed Hodgkin lymphoma.We conducted a multicenter phase II study that administered brentuximab vedotin (Bv) sequentially before and after standard doxorubicin, vinblastine, and dacarbazine (AVD) for untreated patients with Hodgkin lymphoma age 60 years or older. After two lead-in doses of single-agent Bv (1.8 mg/kg once every 3 weeks), patients received six cycles of AVD chemotherapy followed by four consolidative doses of Bv in responding patients.Patient characteristics included median age of 69 years (range, 60 to 88 years), 63% male, median Eastern Cooperative Oncology Group performance status 1, 81% stage III to IV disease, 60% International Prognostic Score 3 to 7, median Cumulative Illness Rating Scale-Geriatric comorbidity score of 7 (52% grade 3 to 4); and 12% had loss of instrumental activities of daily living at diagnosis. Thirty-seven (77%) of 48 patients completed six cycles of AVD, and 35 patients (73%) received at least one Bv consolidation. Overall response and complete remission rates after initial Bv lead-in dose were 18 (82%) of 22 and 8 (36%) of 22, respectively, and 40 (95%) of 42 and 34 (90%) of 42, respectively, after six cycles of AVD among 42 response-evaluable patients. Twenty (42%) of 48 patients experienced a grade 3 to 4 adverse event, most commonly neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%); 33% had grade 2 peripheral neuropathy, which was reversible in a majority of patients. By intent-to-treat, the 2-year event-free survival, progression-free survival, and overall survival rates were 80%, 84%, and 93%, respectively. Furthermore, 2-year progression-free survival rates for patients with a Cumulative Illness Rating Scale-Geriatric comorbidity score of ≥ 10 versus < 10 were 45% versus 100%, respectively (P < .001), and with baseline loss versus no loss of instrumental activities of daily living were 25% versus 94% (P < .001), respectively, the latter persisting on multivariable analyses.Altogether, sequential Bv-AVD was well tolerated and was associated with robust outcomes. Furthermore, geriatric-based measures were strongly associated with patient survival.
Comprehensive molecular and immune profiling of non-small cell lung cancer and matched distant metastases to suggest distinct molecular mechanisms underlying metastasis.
Authors: Won-Chul Lee, Daniel Richard Gomez, Jianhua Zhang, Ali Jalali, Whijae Roh, Alexandre Reuben, Wei Lu, Chi-Wan Chow, Chia Chin Wu, Junya Fujimoto, Mara Antonoff, Cesar Moran, Erik P. Sulman, Ganesh Rao, Stephen Swisher, John Heymach, Ignacio Ivan Wistuba, Andrew Futreal, Jianjun Zhang
Journal: Journal of Clinical Oncology (2017)

8541 Background: Despite complete resection, many non-small cell lung cancer (NSCLC) patients still develop and succumb to distant metastases. Previous studies suggested distant metastasis may be due to genomic evolution and/or suppressed immune surveillance. However, the relationship between specific genomic alterations and immune surveillance has not been systemically studied. Methods: We performed whole exome sequencing, RNA-Seq, methylation microarray, immunohistochemistry using multiple immune markers, and T cell receptor sequencing on 7 pairs of NSCLC primary tumors and matched metastases including 6 metachronous brain and 1 synchronous liver metastases. Results: On average, 84% of all somatic mutations (54% to 97%) and all 28 canonical cancer gene mutations were shared between primary tumors and paired distant metastases. Metastases also resembled paired primary tumors closely in regard to somatic copy number aberration profiles, methylation profiles. Subclonal analysis showed almost identical clonal architectures in 4 of 7 pairs of primary tumor and metastasis comparable to the similarity observed between different regions within the same tumors. The other 3 pairs, however, displayed clear evidence of clonal evolution. We validated these findings in a published dataset consisting of 38 pairs of primary NSCLC tumors and matched distant metastases. The RNA-Seq data showed that 25 of the top 35 significantly down-regulated signaling pathways in metastases relative to primary tumors were related to immune activation, which was validated in an independent cohort of 41 primary NSCLC tumors and distant metastases using NanoString’s PanCancer Immune Profiling Panel. Conclusions: Our data suggest that molecular mechanisms underlying postsurgical distant metastasis may be variable among NSCLC patients. While genomic evolution may play a role in development of metastasis in some patients, distant metastasis may be early event during carcinogenesis without further genomic evolution in a substantial proportion of NSCLC patients. Furthermore, immune suppression may be a characteristic of cancer cells of metastatic capacity.
Allogeneic hematopoietic stem celltransplant (HSCT) after checkpoint inhibitors (ChIs) in classic Hodgkin lymphoma (cHL): Outcome and safety in pooled analysis.
Authors: Reyad Dada, Binyam Swamimandathil Mohamed Usman
Journal: Journal of Clinical Oncology (2018)

e19020 Background: ChIs are highly effective in relapsed and refractory cHL. Patients undergoing HSCT after ChIs are at risk of developing severe Graft-versus-Host disease (GVHD) due to blockage of program death inhibitors on host tissue. The data on HSCT after ChIs is limited and controversial. Lethal complications have been reported. Methods: Purpose of this study was to evaluate outcome and safety of HSCT in patients with cHL previously treated with ChIs. We collected published data in PubMed, EMBASE, Google Scholar and Cochrane Library using the key words “Nivolumab”, “Pembrolizumab”, “Hodgkin lymphoma” and “allogeneic transplantation”. Abstracts of recent conferences (2015-2017) of ASCO, ASH and EBMT were also incorporated in analysis. Only serial reports of 3 patients and more were included. Publications from same group/author were rescanned and in case of duplication the concerning cohort was disregarded. Studies reporting on ChIs in different diseases/settings underwent special analysis and only cases fulfilling inclusion criteria were included. Two reviewers studied the publications independently and matched extracted data. Results: 259 records were screened. Eight publications with total of 155 patients (age range 18-70 years) fulfilled the inclusion criteria. Vast majority received nivolumab with median previous lines of 4 (range 1-18). Median ChIs cycles received prior to HSCT was eight. Matched sibling, matched unrelated, haplo-identical and mismatched unrelated donors were 43, 43, 58 and 11 respectively. Grade 3-4 GVHD was reported in 27%. Chronic GVHD was observed in 25% of the cohort. Non-relapse mortality (NRM) was 21% which remained unchanged after 6 months of HSCT. Other detailed, interesting results will be presented at ASCO meeting. Conclusions: Rate of grade 3-4 GVHD in patients undergoing HSCT after ChIs was higher than historical data (10-15%) in the pre-ChIs era. However, our results indicate similar NRM in comparison with historical data (10-30%). Taking all together HSCT after ChIs is feasible and not associated with higher mortality. However, more measures of GVHD prevention are required.
TCT-354 Pre-Procedural Left Heart Debris Identified by TEE Does Not Appear to be a Risk Factor for Stroke During TAVR
Authors: Addis Asfaw, Timothy Woods, Manavjot Sidhu, Neeraja Yedlapati, Nadish Garg, Uzoma Ibebuogu, Michael McDonald, Beverly Danley
Journal: Journal of the American College of Cardiology (2018)
Premedication for Neonates Requiring Nonemergency Intubation—Reply
Authors: Xavier Durrmeyer, Pierre Tourneux, Agnes Dechartres
Journal: JAMA (2018)

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TCT-113 Effectiveness of Atherectomy Vs. Balloon Angioplasty for Limb Salvage in Occlusive Tibioperoneal Arterial Disease
Authors: Payal Sharma, Tonga Nfor, Daniel Ortiz, M. Fuad Jan, Jayant Khitha, Suhail Q. Allaqaband, Tanvir Bajwa, Mark W. Mewissen
Journal: Journal of the American College of Cardiology (2018)