tbuckley/cabot-search huggingface dataset:
A phase I trial to assess the biologic effect of CBM588 (<i>Clostridium butyricum</i>) in combination with nivolumab plus ipilimumab (nivo/ipi) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Paulo Gustavo Bergerot, Nazli Dizman, Nora Ruel, Paul Henry Frankel, Joann Hsu, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2020)

TPS764 Background: The combination of the immune checkpoint inhibitors (ICIs) nivo/ipi is standard of care for pts with intermediate/poor-risk clear cell RCC. Although data are encouraging, less than 50% of pts will exhibit partial or complete response with nivo/ipi, and approximately 20% of pts will progress through this regimen. Studies have shown that response to ICIs may be modulated by the gut microbiome (Routy et al Science 2018), and that certain gut bacteria (e.g., Bifidobacterium spp) may predispose pts to response (Caitano et al ASCO GU 2017). CBM588 is a strain of Clostridium butyricum, a Gram-positive bacillus which produces short-chain fatty acids. It promotes the growth of commensal gut bacteria like Bifidobacterium, Lactobacillus and Bacteroides spp, and has been shown to enhance Th1 cells and IL-10 production with immunomodulatory effects. Here, we present the study design of an ongoing phase I trial to assess the biologic effect of CBM588 in combination with nivo/ipi in pts with mRCC. Methods: This is a single institution phase I trial. Pts will be randomized to one of two treatment arms. The experimental arm will receive the standard dose/schedule for nivo/ipi (3 mg/kg / 1 mg/kg Q3w for 12w, followed by nivo alone Q4w) plus CBM588 (60 mg PO 3x/d). The control arm will receive nivo/ipi at standard dose/schedule. Key eligibility criteria include intermediate/poor-risk mRCC, no concurrent antibiotic therapy and no prior systemic treatment. The primary objective is to determine the biologic effect of CBM588 + nivo/ipi in the modulation of the gut microbiome, measured by the change in Bifidobacterium spp and Shannon index (a measure of microbiome diversity). Secondary objectives include clinical efficacy (progression free survival by RECIST 1.1) and assessment of systemic immune-modulation effects through the analysis of circulating Tregs, MDSCs, and circulating cytokines/chemokines. Stool samples and serum correlatives will be collected on weeks 1 and 13 of treatment. A two-group t-test with a one-sided type I error of 0.05 will be used to assess the study primary endpoints. Clinical trial information: NCT03829111.
Impact of 68Ga-PSMA-11 PET/CT on staging and management of prostate cancer patients in various clinical settings.
Authors: Ida Sonni, Matthias Eiber, Wolfgang Fendler, Rejah M. Alano, Sitaram S. Vangala, Amar Upadhyaya Kishan, Nicholas George Nickols, Matthew Rettig, Robert Evan Reiter, Johannes Czernin, Jeremie Calais
Journal: Journal of Clinical Oncology (2020)

26 Background: The goal of this study was to determine the impact of 68 Ga-PSMA-11 PET/CT on initial and subsequent management decisions in a cohort of PCa patients referred for various indications excluding the two main classical indications: BCR and pre-surgical staging. Methods: This is a prospective study of 197 patients that aimed to determine the impact of 68 Ga-PSMA-11 PET/CT on PCa stage and management. Indications for PSMA PET/CT were initial staging of non-surgical candidates (30 patients) and re-staging after definitive treatment (n=168). The re-staging cohort comprised: patients re-staged with known advanced metastatic disease (n=103), after androgen deprivation therapy only (n=16), after surgery with serum PSA levels &lt;0.2 ng/ml (n=13), after radiation therapy (RT) not meeting the Phoenix criteria (n=22) and after other primary local treatments [i.e. HIFU, focal laser ablation, cryoablation, hyperthermia or irreversible electroporation] (n=13). Patients with BCR and candidates for curative surgery were excluded. Impact on management was assessed using pre- and post-PET questionnaires completed by referring physicians, electronic chart review and/or patient telephone encounters. Results: PSMA PET/CT changed disease stage in 135/197 (69%) patients (38% up-stage, 30% down-stage and no changes in stage in 32%). Management was affected in 104/182 (57%) patients. PSMA PET/CT had its greatest management impact in patients who were re-staged after RT. Conclusions: PSMA PET/CT has a profound impact on stage and management of PCa patients outside of the two main classical indications (BCR and presurgical staging) across all examined clinical scenarios. Clinical trial information: NCT04050215.
The emerging target <i>KRAS</i> G12C in genitourinary malignancies.
Authors: Petros Grivas, Andrea Necchi, Gennady Bratslavsky, Oleg Shapiro, Joseph Jacob, Julia Andrea Elvin, Jo-Anne Vergilio, Keith Killian, Erik Williams, Shakti H. Ramkissoon, Eric Allan Severson, Amanda Hemmerich, Alexa Betzig Schrock, Jon Chung, Kimberly McGregor, Prasanth Reddy, Brian Michael Alexander, Ethan Sokol, Natalie Danziger, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2020)

434 Background: KRAS has recently emerged as a druggable driver with novel agents targeting G12C genomic alteration (GA). Methods: FFPE tissue from 1453 renal clear cell carcinomas (RCCC), 3879 urothelial bladder carcinomas (UBC) and 8322 prostate acinar adenocarcinomas (PAAC) underwent comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on 0.8 to 1.2 Mbp of sequenced DNA and MSI was determined on 114 loci. PD-L1 expression (Dako 22C3) was measured by IHC. Results: KRAS GA were identified in 7 RCCC (&lt;1%), 202 UBC (5.2%), and 158 PAAC (1.9%). KRAS G12C mutations were observed in 0 RCCC, 24 (2%) of UBC, and 1 (&lt;1%) PAAC. Age/gender distributions were similar. VHL, SETD2, and PBRM1 mutations were the most frequent concurrent GA in the 7 RCCC with KRAS G12C GA. In KRAS G12C mutated UBC, co-mutations in TERT were significantly reduced and in KDM6A were significantly increased (both p&lt;0.05) in cases with KRAS G12C GA versus KRAS G12C negative tumors. Conclusions: KRAS G12C mutations are extremely rare in the major genitourinary malignancies. However, given the emerging interest in identifying KRAS G12C for potential basket-type clinical trials using novel anti-KRAS G12C targeted therapies, further study of these alterations in genitourinary malignancies, especially bladder and prostatic carcinomas, appears warranted.[Table: see text]
Principles and current strategies targeting metallo‐β‐lactamase mediated antibacterial resistance
Authors: Yu‐Hang Yan, Gen Li, Guo‐Bo Li
Journal: Medicinal Research Reviews (2020)

Abstract Resistance to β‐lactam antibacterials is commonly associated with the production of the serine β‐lactamases (SBLs) and/or metallo‐β‐lactamases (MBLs). Although clinically useful inhibitors for the SBLs have been developed, no equivalent inhibitors are available for the MBLs, which can hydrolyze almost all β‐lactam antibiotics, including the so‐called “last resort” carbapenems. It is still a challenging task to develop a clinically useful inhibitor that should be broad‐spectrum targeting multiple clinically relevant MBL enzymes that differ in their active site features. This review provides a detailed description of interaction modes of substrates and small‐molecule inhibitors with various MBL enzymes and highlights the importance of metal‐ and “anchor residue”‐binding features to achieve broad‐spectrum MBL inhibition. Recently emerging active site interference strategies include metal ion deprivation, metal ion replacement, and cysteine modification as challenging, but worth experimenting directions for inhibitor development. The metalloenzyme selectivity, metal‐binding pharmacophore, and cellular permeability and accumulation should be properly considered in the further development of clinically useful inhibitors to combat MBL‐mediated antibacterial resistance.
Plasma cell-free DNA (cfDNA) profiling of copy number variation (CNV) to identify poor prognostic biomarkers in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Edmond Michael Kwan, Heidi Fettke, Patricia Bukczynska, Nicole Ng, Christine Hauser, Lisa-Jane K. Graham, Kate Lynette Mahon, Chao Dai, Feng Xie, Xiaohong Wang, Zhixin Zhao, Kemin Zhou, Peter Du, Jianjun Yu, Shidong Jia, Winston Tan, Lisa Horvath, Manish Kohli, Arun Azad
Journal: Journal of Clinical Oncology (2020)

176 Background: Multiple tumour tissue studies have demonstrated the prognostic utility of CNVs in mCRPC. However, accurate assessment of CNVs in plasma cfDNA remains challenging, and prognostic significance has not been well characterized. Using a large customized panel, we correlated plasma CNVs with clinical outcomes in a contemporary cohort of mCRPC patients. Methods: Deep targeted sequencing was performed using a 180-gene cfDNA panel (Predicine) in 56 patients commencing AR pathway inhibitors (enzalutamide or abiraterone; n = 34) or taxane chemotherapy (n = 22) at two Australian institutions. Kaplan-Meier estimates and Cox proportional-hazards models were used to correlate CNVs with progression-free survival (PFS) and overall survival (OS). Significant results were validated in an independent cohort (Mayo Clinic, n = 144). Results: Median follow-up was 19.4 months (mo; IQR 11.3-31.9). The most common CNVs in the Australian cohort are shown (Table). OS was significantly decreased in patients with PI3KCA gain (median 21.7 mo vs 6.6 mo, p &lt; 0.0001), PTEN loss (24.8 mo vs 11.7 mo, p = 0.0019) and AR gain (21.7 mo vs 12.0 mo, p = 0.0083). Furthermore, all three alterations independently predicted for poor survival in multivariable analyses (MVA; Table). Findings in the independent cohort showed similar OS results in MVA: PIK3CA gain (HR 2.0, p = 0.07), PTEN loss (HR 1.7, p = 0.08) and AR gain (HR 1.7, p = 0.03). Conclusions: Sequencing of plasma cfDNA revealed that PTEN loss, and PIK3CA and AR gain are associated with inferior clinical outcomes in patients commencing contemporary systemic treatment. These data support therapeutic strategies co-targeting the PI3K and AR pathways in mCRPC.[Table: see text]
Phase III study of first-line pembrolizumab (pembro) plus lenvatinib (len) in patients (pts) with advanced urothelial carcinoma (UC) ineligible for platinum-based chemotherapy: LEAP-011.
Authors: Yohann Loriot, Arjun Vasant Balar, Ronald De Wit, Jorge A. Garcia, Petros Grivas, Nobuaki Matsubara, Blanca Homet Moreno, Eric Sbar, Xieyang Calvin Jia, Corina E. Dutcus, Arlene O. Siefker-Radtke
Journal: Journal of Clinical Oncology (2020)

TPS597 Background: KEYNOTE-052 (NCT02335424) results led to pembro, a PD-1 inhibitor, to become the standard of care for cisplatin-ineligible pts with locally advanced or metastatic UC with tumors expressing PD-L1 and for pts unable to receive platinum-based chemotherapy regardless of PD-L1 status. Len, a potent, multiple-receptor, tyrosine kinase inhibitor has activity in multiple solid tumors. KEYNOTE-146 (NCT02501096) results showed promising efficacy and manageable safety with pembro+len in previously treated pts with advanced UC, regardless of PD-L1 status. Methods: LEAP-011 (NCT03898180) is a randomized phase 3 study to assess efficacy and safety of pembro+len, compared with pembro+placebo, in pts with advanced UC. An estimated 694 pts will be enrolled. Adults (≥18 years) with histologically confirmed locally advanced unresectable or metastatic UC who are either cisplatin-ineligible with tumors expressing PD-L1 (combined positive score [CPS] ≥10) or ineligible to receive any platinum-based chemotherapy are eligible. Pts are required to have an ECOG PS of 0-2 and provide tumor tissue for PD-L1 analysis. Previous treatment with systemic chemotherapy for advanced UC is not permitted, except in cases of recurrence after 1 year of platinum-based chemotherapy for either muscle-invasive bladder cancer (neoadjuvant) or after radical cystectomy (adjuvant). Pts will be randomly assigned 1:1 to receive pembro 200 mg IV every 3 weeks for up to 35 cycles (~2 y) plus either len 20 mg or placebo orally once daily. Pts will be stratified as follows: ineligible for any platinum containing chemotherapy and ECOG PS 2 (CPS ≥10 vs &lt;10); cisplatin ineligibility and CPS ≥10 (ECOG 0-1 vs 2). Radiologic assessment will include CT/MRI of the chest, abdomen, and pelvis, and bone imaging. Responses will be assessed per RECIST v1.1 by blinded independent central review (BICR). Coprimary end points are PFS and OS. Secondary end points are objective response rate, duration of response, and disease control rate per RECIST v1.1 by BICR; patient-reported outcomes; and safety. Tissue-and blood-based biomarkers will be explored. Accrual began May 6, 2019. Clinical trial information: NCT03898180.
Window of opportunity trial to characterize the safety, pharmacokinetics, and pharmacodynamics of fosciclopirox (CPX-POM) in cisplatin-ineligible muscle invasive bladder cancer patients.
Authors: John Arthur Taylor, Robyn Wood, Tammy Ham, Crista Casey, Prasad Dandawate, Greg Reed, Benjamin L. Woolbright, Michael Jay Baltezor, Roy A. Jensen, Michael Dalton, Valentina Zhukova-Harrill, William McCulloch, Shrikant Anant, Scott James Weir
Journal: Journal of Clinical Oncology (2020)

TPS604 Background: Fosciclopirox (Ciclopirox Prodrug, CPX-POM) is being developed for the treatment of non-muscle invasive and muscle invasive (MIBC) bladder cancer. CPX-POM selectively delivers its active metabolite, ciclopirox (CPX), to the entire urinary tract following systemic administration. In a validated, chemical carcinogen mouse model of bladder cancer, CPX-POM treatment results in significant decreases in bladder weight, a clear migration to lower stage tumors, dose-dependent reductions in Ki67 and PCNA staining, and inhibition of Notch 1 and Wnt signaling. The safety, dose tolerance, pharmacokinetics and pharmacodynamics of IV CPX-POM have recently been characterized in 19 patients with advanced solid tumors (CPX-POM-001, NCT03348514). The safety and dose tolerance of IV CPX-POM was characterized across a dose range of 30 to 1200 mg/m 2 . The CPX-POM Recommended Phase 2 Dose (PR2D) of 900 mg/m 2 administered IV over 20 minutes on Days 1-5 every 21 days was selected. Methods: Twelve cisplatin ineligible MIBC patients (Stage &gt;T2, NO-N1, M0), scheduled for radical cystectomy (RC) will be enrolled in this window of opportunity study. Patients will receive two 21-day treatment cycles followed by RC within 14 days of completion of the second cycle. Safety and tolerability assessments will be made based on observed adverse and serious adverse events, physical examination, vital signs, electrocardiogram, clinical laboratory tests, and concomitant medications. Assessment of complete and partial pathologic response will be determined at RC. Ki67, Notch and Wnt signaling, and CD8+ lymphocyte tumor infiltration will be determined by immunohistochemistry. An unbiased approach to characterizing CPX-POM mechanisms of action will also be employed using RNAseq and ChIPseq. Serial blood (plasma) and complete urine specimens will be collected on Days 5-6 of Cycle 1 for determination of drug and metabolite concentrations by LC-MS/MS. Plasma and urine steady-state pharmacokinetics of CPX-POM, CPX and ciclopirox glucuronide will be characterized. Urine ß-glucuronidase activity is also being determined by ELISA. Clinical trial information: NCT03348514.
The relationship between socioeconomic status and treatment for prostate cancer in a universal healthcare system: A population-based analysis.
Authors: Justin Oake, Oksana Harasemiw, Navdeep Tangri, Thomas Ferguson, Jeff W. Saranchuk, Rahul K. Bansal, Darrel Drachenberg, Jasmir G. Nayak
Journal: Journal of Clinical Oncology (2020)

361 Background: A large body of research has shown that there are strong socioeconomic disparities in access to cancer treatment. However, whether these inequalities persist among men with prostate cancer has not been previously explored in the equal-access, universal Canadian health care system. The aim of this study is to compare whether socioeconomic status is associated with the type of treatment received (radical prostatectomy (RP) versus radiation therapy (RT)) for men diagnosed with nonmetastatic prostate cancer in Manitoba, Canada. Methods: Men who were diagnosed with non-metastatic prostate cancer between 2004 and 2016 and subsequently treated with RP or RT were identified using the CancerCare Manitoba Registry and linked to provincial databases. SES was defined as neighbourhood income by postal code and divided into income quintiles (Q1-Q5, with Q1 the lowest quintile and Q5 the highest). Multivariable logistic regression nested models were used to compare whether socioeconomic status was associated with treatment type received. Results: We identified 4,560 individuals between 2004-2016 who were diagnosed with non-metastatic prostate cancer. 2,554 men were treated with RP and 2,006 with RT.As income quintile increased, men were more likely to undergo RP than RT (Q3 vs Q1: aOR 1.45 (1.09-1.92); Q5 vs. Q1: aOR 2.17, 95% CI 1.52-2.86). Conclusions: Despite a universal health care system, socioeconomic inequities are present for men seeking primary treatment for prostate cancer. Further investigation into the decision making process among patients diagnosed with prostate cancer may inform decision making to ameliorate these disparities.
Factors associated with clinical trial participation for patients with renal cell carcinoma.
Authors: Brian Shinder, Sinae Kim, Arnav Srivastava, Hiren V. Patel, Tina M. Mayer, Biren Saraiya, Eric A. Singer
Journal: Journal of Clinical Oncology (2020)

670 Background: Clinical trials are critical for the development of new treatment paradigms for renal cell carcinoma (RCC). The primary objective of this study was to characterize the factors associated with clinical trial participation for patients with RCC. The secondary objective was to examine survival outcomes in the clinical trial and control cohorts. Methods: The National Cancer Database (NCDB) was queried for patients with RCC who were coded as having enrolled in a clinical trial. Trial patients were matched in a 1:5 ratio to controls from the same institution based on clinical stage. Sociodemographic variables were compared between the two groups and univariate and multivariate logistic regression models evaluated factors associated with clinical trial participation. Kaplan-Meier product limit estimate was used to compare overall survival (OS) between the groups. Results: From 2004-2015, 681 patients enrolled in clinical trials were included for analysis. The mean age of trial patients was 56.4 compared to 62 in the matched cohort (p&lt;0.0001). More patients in the trial group had a Charlson-Deyo comorbidity score of 0 (81.6% vs. 73.9%, p&lt;0.0001). On multivariate analysis, male patients (OR 1.27; 95%CI 1.06-1.54, p=0.012) and white patients (OR 1.88, 95%CI 1.23-2.87; p=0.003) were more likely to participate in a trial. Having Medicaid (OR 0.42; 95%CI 0.27-0.64; p&lt;0.0001) or Medicare (OR 0.6; 95%CI 0.46-0.77; p&lt;0.0001) was negatively associated with clinical trial participation. Median OS was greater among clinical trial participants than that the control cohort (106.61 vs 87.62 months, p&lt;0.0001). Conclusions: In this contemporary analysis of RCC patients from a national hospital registry database, we found that patient sociodemographic factors remain associated with clinical trial participation and that clinical trial participants experienced superior OS. Further work, both qualitative and quantitative, is necessary to identify clinical and non-clinical barriers to research participation in order to improve the validity of RCC trials.
Evaluation of Durability of a Single Dose of the Bivalent HPV Vaccine: The CVT Trial
Authors: Aimée R Kreimer, Joshua N Sampson, Carolina Porras, John T Schiller, Troy Kemp, Rolando Herrero, Sarah Wagner, Joseph Boland, John Schussler, Douglas R Lowy, Stephen Chanock, David Roberson, Mónica S Sierra, Sabrina H Tsang, Mark Schiffman, Ana Cecilia Rodriguez, Bernal Cortes, Mitchell H Gail, Allan Hildesheim, Paula Gonzalez, Ligia A Pinto
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background The authors investigated the durability of vaccine efficacy (VE) against human papillomavirus (HPV)16 or 18 infections and antibody response among nonrandomly assigned women who received a single dose of the bivalent HPV vaccine compared with women who received multiple doses and unvaccinated women. Methods HPV infections were compared between HPV16 or 18-vaccinated women aged 18 to 25 years who received one (N = 112), two (N = 62), or three (N = 1365) doses, and age- and geography-matched unvaccinated women (N = 1783) in the long-term follow-up of the Costa Rica HPV Vaccine Trial. Cervical HPV infections were measured at two study visits, approximately 9 and 11 years after initial HPV vaccination, using National Cancer Institute next-generation sequencing TypeSeq1 assay. VE and 95% confidence intervals (CIs) were estimated. HPV16 or 18 antibody levels were measured in all one- and two-dose women, and a subset of three-dose women, using a virus-like particle-based enzyme-linked immunosorbent assay (n = 448). Results Median follow-up for the HPV-vaccinated group was 11.3 years (interquartile range = 10.9–11.7 years) and did not vary by dose group. VE against prevalent HPV16 or 18 infection was 80.2% (95% CI = 70.7% to 87.0%) among three-dose, 83.8% (95% CI = 19.5% to 99.2%) among two-dose, and 82.1% (95% CI = 40.2% to 97.0%) among single-dose women. HPV16 or 18 antibody levels did not qualitatively decline between years four and 11 regardless of the number of doses given, although one-dose titers continue to be statistically significantly lower compared with two- and three-dose titers. Conclusion More than a decade after HPV vaccination, single-dose VE against HPV16 or 18 infection remained high and HPV16 or 18 antibodies remained stable. A single dose of bivalent HPV vaccine may induce sufficiently durable protection that obviates the need for more doses.