tbuckley/cabot-search huggingface dataset:
A randomized phase II study of vismodegib (V), a hedgehog (HH) pathway inhibitor, combined with FOLFOX in patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: A New York Cancer Consortium led study.
Authors: Deirdre Jill Cohen, Paul J. Christos, Joseph A. Sparano, Hedy Lee Kindler, Daniel Virgil Thomas Catenacci, Tanios B. Bekaii-Saab, Sanaa Tahiri, Yelena Yuriy Janjigian, Michael K. Gibson, Emily Chan, Lakshmi Rajdev, Susan Urba, James Lloyd Wade, Peter Kozuch, Erica Love, Katherine Vandris, Naoko Takebe, Howard S. Hochster
Journal: Journal of Clinical Oncology (2013)

67 Background: The HH pathway is overexpressed in gastroesophageal (GE) tumors. Pre-clinically, HH inhibitors have demonstrated a reduction in GE tumor growth, cell motility and invasiveness. V, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with FOLFOX chemotherapy. Methods: Pts with untreated, metastatic or locally advanced gastric or GEJ adenocarcinoma were randomized 1:1, stratified by institution and disease status (with or w/o distant mets) to FOLFOX (ox 85 mg/m 2 , LV 200 mg/m 2 , 5-FU bolus 400 mg/m 2 , 5-FU infusion 2400 mg/ m 2 over 48 hrs) q14d plus V or placebo (P) (150mg PO daily). Cycle defined as 2 weeks and no crossover allowed at progression. FFPET and blood were collected for biomarker analyses. Response assessed every 8 weeks (RECIST 1.1). Primary endpoint was progression-free survival (PFS), secondary objectives were overall survival (OS), response rate (RR), and toxicity. Results: 124 pts (V/P 60/64) enrolled at 20 sites between 10/09-2/12. Pt characteristics (V/P): median age 58/62; ECOG PS 0: 23 (40%) / 30 (47%); male 39 (65%) / 53 (83%); GEJ 37 (62%) / 39 (61%); diffuse histology 20 (43%) / 14 (30%). Median number of FOLFOX cycles 9.5/11. Most common Gr ≥3 toxicities: (% pts V/P) neutropenia 50.0/31.7 (p=0.07), neuropathy 23.1/14.3 (p=0.33), fatigue 15.4/9.5 (p=0.50), thrombosis 13.5/11.1 (p=0.92), anemia 9.6/9.5 (p=0.99), hypokalemia 9.6/4.8 (p=0.52), nausea 7.7/9.5 (p=0.99). Death on or within 30 days of treatment 6.7%/15.6% (p=0.20). Median PFS in ITT population 11.5/9.3 mo (95% CI 8.5-14.4/6.7-11.9; p=0.34) and median OS 12.2/13.9 mo (95% CI 10.2-14.3/11.5-16.3; p=0.48). Non-statistically significant trends toward improved PFS with V were noted in female pts, diffuse histology, and PS 1 (p≤ 0.08). RR (%) 33/27 (p=0.64). Conclusions: Addition of V to FOLFOX did not improve PFS in an unselected advanced GE carcinoma population. Blood and tissue biomarker analyses are ongoing to determine if there is a subset of patients who may derive benefit from V. Supported by: N01-CM-62204, -62201, -62207, -62206, -62209, -62208 and 2UL1 TR000457-06 Clinical trial information: NCT00982592.
Impact of obesity in patients with metastatic urothelial carcinoma.
Authors: Amanda Leiter, John Doucette, Susanne Krege, Chia-Chi Lin, Noah M. Hahn, Thorsten Ecke, Guru Sonpavde, Aristotelis Bamias, William K. Oh, Matt D. Galsky
Journal: Journal of Clinical Oncology (2015)

346 Background: Obesity has been associated with worse outcomes in patients with clinically localized urothelial cancer. However, the impact of obesity on outcomes of patients with metastatic disease has not previously been evaluated. Methods: Data from 537 patients were aggregated from eight phase II and phase III clinical trials investigating first-line cisplatin-based combination therapy in metastatic urothelial cancer. Chemotherapy regimen, adverse events, treatment response, and survival outcomes were compared across body mass index (BMI) and body surface area (BSA) categories. Results: BMI was classified according to WHO criteria (&lt;18.5 underweight (4.1 % of patients), 18.5-24.99 normal weight (42.8%), 25-29.99 overweight (41.0%), &gt;30 obese (12.1%)). BSA was classified as either below (56.8% of patients) or greater than or equal to (43.2%) the European average (1.91 m 2 for males and 1.71 m 2 for females). There was no significant difference in number of chemotherapy cycles across BMI and BSA categories. Patients’ treatment regimens significantly differed across BMI (p=0.02) and BSA (p&lt;0.01) categories, with patients with higher BMI category and average or above BSA more likely to receive gemcitabine-cisplatin-based therapy rather than MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin)-based or other therapy regimens. There was no significant difference in adverse events across BMI categories, but the incidence of embolic events was significantly higher in patients with an average or higher BSA (6.6%) than those with a lower than average BSA (2.7%) (p=0.03). There was no significant difference in response rate or survival outcomes (overall and progression-free) amongst BMI and BSA categories. Conclusions: Obese patients with metastatic urothelial cancer on cisplatin-based therapies have similar response rates and survival outcomes to non-obese patients. Toleration of cisplatin-based therapy is similar across BMI and BSA categories, with the exception of a higher incidence of embolic events in patients with an above average BSA.
Phase I study of ATI-1123, a novel human serum albumin-stabilized docetaxel liposomal formulation, in patients with advanced solid malignancies.
Authors: S. Vemulapalli, A. C. Mita, N. S. Gallegos, G. Anderson, J. Charles, J. M. Rogers, A. Kousba, K. K. Sankhala, J. J. Nemunaitis
Journal: Journal of Clinical Oncology (2011)

2609 Background: Liposomal (LIPO) docetaxel (DOCE) formulations may reduce hypersensitivity reactions, eliminate premedication requirements, have a broader therapeutic index, and enhance systemic DOCE exposure. ATI-1123 is a novel LIPO DOCE formulation utilizing human serum albumin that facilitates LIPO tumor targeting. We studied safety, tolerability, pharmacokinetics (PK) and tumor response of ATI-1123 in patients (pts) with advanced solid tumors. Methods: Pts enrolled had progressive disease after standard therapy, measurable disease (RECIST), ECOG ≤ 2, survival ≥ 3 mo. Dosing (1 hr infusion) began at 15 mg/m2 using an accelerated titration design, followed by a modified Fibonacci schema to MTD. Dosing was continued until pts had progressive disease or unacceptable toxicities. Plasma was analyzed for encapsulated / non-encapsulated DOCE using a validated assay. PK was determined by model independent methods. Results: To date, 19 pts were enrolled (median age 62 yr; range 40-80 yr; 58% male; 5 (26%) NSCLC; 5 (26%) pancreas; 4 (21%) prostate; 3 (16%) other and 2 (11%) ovary. Doses studied (mg/m2) were 15 (2 pts), 30 (1 pt), 60 (3 pts), 90 (7 pts) and 110 (5 pts). Two DLTs were noted at the 110 mg/m2 cohort (Gr 3 mucositis; Gr 3 neutropenic fever) and the 90 mg/m2 cohort expansion is ongoing. At Cycle 1, 5 (26%) pts had hypersensitivity reactions (all Gr 2). One reaction required ATI-1123 discontinuation; the remainder were managed with test dose, prolonged infusion time and/or premedication. No new toxicities were noted relative to standard DOCE. PR was seen in 1 NSCLC pt. SD was noted in 4 of 9 pts (44%) for which protocol-defined followup was available (prostate, 2; pancreatic, 1; cervix, 1). Two prostate ca pts had pronounced PSA (>95% reduction) response following multiple treatment cycles. PK results demonstrated linear and dose proportional PK. Compared with standard DOCE PK Cmax and AUC0-24 ratios were 1.60-3.32 and 1.80-4.11 fold higher, and DOCE clearance was 1.68-4.10 fold lower with ATI-1123. Conclusions: ATI-1123 exhibited acceptable tolerability, a favorable PK profile and antitumor activity that warrant exploration in larger Phase 2 trials.
KRAS mutation in colorectal cancer and its association with a stromal-derived gene signature.
Authors: Raphael Pelossof, Moshe Elkabets, Oliver S Chow, Lauren Fairchild, Chin-Tung Chen, Manu Setty, Jesse Joshua Smith, Lukas E. Dow, Kevin P. O'Rourke, Scott W. Lowe, Christina S Leslie, Julio Garcia-Aguilar
Journal: Journal of Clinical Oncology (2015)

628 Background: KRAS mutation in colorectal cancer (CRC) is characterized by an altered transcriptional profile when compared to wild-type KRAS tumors. The list of differentially expressed genes overlaps significantly with a stromal fibroblast activation (SFA) signature present across multiple carcinomas. We have reported low expression of SFA genes in KRAS mutant CRC compared to KRAS wild type tumors. Here we sought to confirm the variation of the SFA signature with KRAS mutation and infer its origin in the stromal component of the tumor using experimental models. Methods: The SFA signature was assessed in an inducible-KRAS murine CRC model using RNA-sequencing, and in a CRC cell line with and without a transduced KRAS mutant vector by microarray analysis. Finally, RNA-sequencing of CRC patient-derived xenografts (PDXs) was used to determine whether the SFA signature was being expressed in the tumor epithelium or the surrounding stroma by leveraging the ability to align sequenced reads to the mouse and human genomes separately. Results: The SFA signature was identified in the inducible-KRAS mouse model, matching human cohort observations of decreased SFA gene expression in KRAS mutant CRC. On the other hand, KRAS transduction did not recapitulate the SFA signature in a CRC cell line, suggesting that the presence of stroma may be required for the expression of the SFA signature. Finally, RNA-seq reads for SFA signature genes in CRC PDXs immediately after implantation aligned primarily to the human genome but in later passages of the same PDXs aligned only to the mouse genome. These data suggest that the SFA transcriptional program is associated with the stroma rather than the epithelial tumor cells. Conclusions: KRAS mutation in CRC is associated with a gene expression signature derived from the tumor stroma. These findings suggest that KRAS mutation in the epithelial tumor cells may impact the tumor microenvironment in CRC.
Active surveillance as a treatment option for metastatic or recurrent renal cell carcinoma.
Authors: Inkeun Park, Jae-Lyun Lee, Jin-Hee Ahn, In Gab Jeong, Cheryn Song, Bum-Sik Hong, Jun Hyuk Hong, Choung-Soo Kim, Hanjong Ahn
Journal: Journal of Clinical Oncology (2014)

426 Background: Metastatic renal cell carcinoma (MRCC) often presents with very indolent course without any symptom, and treatment (Tx) for MRCC is mostly palliative rather than curative in a molecular target agents era. There exist several Tx options for MRCC, but all available agents have considerable toxicities, cause economic burden to patients (pts), and impair quality of life. We retrospectively evaluate outcomes of active surveillance for asymptomatic MRCC pts. Methods: We enrolled MRCC pts who was followed-up with deferred treatment in our institution between 2000 and 2012. Clinical characteristics, response to active surveillance, predictive factor for time-to-progression (TTP), and response to succeeding first line VEGFR TKIs were analyzed. Results: Of 58 pts, 42 had recurrent disease and 14 had initially metastatic disease. Most pts had good Karnofsty PS (KPS), 100% for 39 pts and 90% for 14 pts. Lung (47 pts) and lymph nodes (18 pts) were most common site of metastasis. During active surveillance, 83% of patients had stable disease (SD) as their best response. Only 17% of patients had progressive disease (PD) as their initial response. Ultimately, 47 pts had PD finally until data cut-off date. With a median F/U period of 31.4 months, 47 patients experienced disease progression with a median TTP of 12.4 months (95% CI, 8.4~16.5). A median OS was 91.1 months (95% CI, 30.7-151.6). Multivariate analysis revealed that KPS &lt; 100, presence of liver metastasis, time from diagnosis to active surveillance less than 1year, and neutrophilia were independent predictive factors for worse TTP. After PD, 30 pts proceeded to systemic treatment (14 sunitinib, 11 pazopanib, 4 immunotherapy, and 1 temsirolimus). Objective response rate were 71% for sunitinib, and 46% for pazopanib. Conclusions: This study suggests that active surveillance without any intervention could be a viable treatment option for the first-line approach in asymptomatic MRCC pts, especially for those who have good performance status without neurtrphilia or liver metastases. The possibility of disease stabilization should be considered before initiation of any active treatment and when assessing the activity of any treatment in terms of time to progression.
Hematopoietic Stem/Progenitor Cell Retention in the Bone Marrow Depends On Tissue Specific Heparan Sulfate Proteoglycans
Authors: Borja Saez, Francesca Ferraro, Rushdia Z. Yusuf, Colleen M Cook, Stephen M. Sykes, Ana Pardo, Vionnie W.C. Yu, Sutada Lotinun, Rahul Palchaudhuri, Dongjun Lee, Stefania Lymperi, Robyn Day, Radovan Vasic, Sanket S. Acharya, Roland Baron, Amy J. Wagers, David T. Scadden
Journal: Blood (2012)
Hypo-Albuminemia at Day+90 after Allogeneic Hematopoietic Cell Transplantation for Lymphoid Malignancies Independently Predicts for Inferior Overall Survival and Higher Non-Relapse Mortality
Authors: Josephine Emole, Mohamed A. Kharfan-Dabaja, Julio C Chavez, Taiga Nishihori, Marcie Riches, Asmita Mishra, Binglin Yue, Jongphil Kim, Ernesto Ayala, Claudio Anasetti, Frederick L Locke
Journal: Blood (2015)
Effect of antisense oligonucleotides targeting bcl-2 on addition proteins that regulate prostatic apoptosis and differentiation in LNCaP cells.
Authors: M. Bjurlin, M. Rubenstein, C. Chou, C. M. Hollowell, P. Guinan
Journal: Journal of Clinical Oncology (2011)

e13511 Background: Our lab has evaluated bispecific oligos targeting unrelated genes and reported inhibition of both growth and targeted protein expression. Mono- and bispecific oligos against bcl-2 were added to LNCaP cells and evaluated for expression of bcl-2 and a non-sequence related protein also associated with apoptosis. These oligos produce significant growth inhibition; the expression of proteins associated with prostate cancer progression was therefore evaluated. Methods: RT-PCR was used to evaluate extracted RNA for gene expression of apoptosis regulating proteins bcl-2 (targeted) and bax (not targeted); as well as prostate differentiation antigens PSA and PSMA (neither targeted by oligos). Results: All oligos suppressed (targeted) bcl-2 expression, but mono- and bispecific types produced no compensatory changes in bax. PSA was also not inhibited by oligos, but PSMA was significantly enhanced by both bispecifics. Conclusions: Although bcl-2 was suppressed by all oligos (and presumably apoptosis enhanced), no compensatory alterations in bax were noted to suppress apoptosis. Untargeted PSMA was enhanced by bispecific forms, possibly due to interferon induction know to enhance other surface antigen expressions.
A phase I/II study of pemetrexed in combination with carboplatin in patients with platin sensitive recurrent ovarian or peritoneal cancer (PSOC)
Authors: J. Sehouli, M. Kania, A. Zimmerman, K. Look, A. Mustea
Journal: Journal of Clinical Oncology (2008)

16513 Background: Carboplatin (Cb)-based combinations are used commonly in platin-sensitive recurrent ovarian or peritoneal cancer (PSOC) (Parmar 2003, Pfisterer 2006). Pemetrexed (Pem) is a multi-targeted antifolate whose primary mechanism of action is the inhibition of thymidylate synthase (TS). Methods: The primary objective of phase I was to determine the MTD, DLT, quantitative and qualitative toxicities of combination Pem and Cb. A standard 3-patient cohort dose escalation was planned starting at Cb AUC 5 and Pem 500 mg/m2. Inclusion criteria were: women age > 18 years, contraception use if still fertile, PSOC (defined as recurrence 6 months after first-line therapy), measurable (RECIST criteria) or evaluable disease (CA125 only), adequate organ function and ability to continue follow-up. Two dose levels of Cb (AUC 5, 6) and five levels of Pem (500, 600, 700, 800, 900 mg/m2) were evaluated. DLTs were defined based on cycle 1. Results: Twenty patients, median age 57.4 years (37.3–75.3) were enrolled. Three patients had a PS of 0 and the remaining 17 patients had a PS of 1. Three patients had measurable disease and the remaining 17 patients had CA125 - only evaluable disease. There were no deaths on study. There were no protocol-defined DLTs in cycle 1 and no serious adverse events (SAEs) related to study therapy. There were 2 SAEs noted, one at dose level 1 and one at dose level 6. The 20 patients completed 112 cycles of Cb including 104 as planned and 115 cycles of Pem, including 112 as planned. Five patients required dose adjustments. Dose level 6 was well tolerated. Conclusions: Combination Cb and pemetrexed is well tolerated. However, subsequent to data lock for this trial, data from a randomized Phase II comparing 500 vs. 900 mg/m2 pemetrexed in PSOC demonstrated numerically greater Grade 3 and 4 SAEs with the 900 mg/m2 dose (data on file). A Phase II trial utilizing pemetrexed 500 mg/m2 and Cb AUC 6 is underway. Dose Level Pem mg/m 2 Cb AUC Patients per Dose Level 1 500 5 4 2 600 5 3 3 600 6 4 4 700 6 3 5 800 6 3 6 900 6 3 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company, GlaxoSmithKline, Schering-Plough Eli Lilly and Company, GlaxoSmithKline, Schering-Plough
Surgery and adjuvant therapy in gallbladder cancer: A single-institution experience.
Authors: Nishi Kothari, Richard D. Kim, Gregory M. Springett, Sarah E. Hoffe, Khaldoun Almhanna, Pamela Joy Hodul, Jose Mario Pimiento, Mokenge Peter Malafa, William J. Fulp, Xiuhua Zhao, Ravi Shridhar
Journal: Journal of Clinical Oncology (2015)

405 Background: Gallbladder cancer is a highly fatal disease with a high rate of recurrence even when diagnosed at an early stage. Because of its relative rarity, there are currently no established algorithms to guide therapy after cholecystectomy. To explore the value of adjuvant therapy with chemotherapy and radiation, we evaluated patients with resected gallbladder cancer treated at our institution. Methods: Patients diagnosed with gallbladder cancer who underwent cholecystectomy (simple or radical) between 2000 and 2010 were identified using our cancer registry. Retrospective chart review was performed for clinicopathologic data, including age, stage, grade, type of surgery, margin status, and type and duration of adjuvant therapy. The primary endpoint was overall survival (OS). Univariate (UVA) and multivariate (MVA) analysis was performed with Cox logistic regression analyses. Results: We identified 73 patients with a median followup for all patients of 28.2 months. The majority of patients were female (74%) and underwent radical cholecystectomy (64%). Positive margins and adjuvant radiation therapy were documented in 21% and 37%, respectively. The majority of patients did not receive any adjuvant therapy (53.4%). Median OS for all patients was 41.3 months. There was a survival benefit associated with patients undergoing radical cholecystectomy followed by adjuvant radiation (median OS 48.4 months vs. 22.3 months; HR 0.35; 95% CI: 0.13–0.98; p=0.0448) compared to simple cholecystectomy alone. On UVA, increasing age and positive margins were significantly associated with worse OS, while radical cholecystectomy was associated with improved OS. On MVA, increasing age, male gender, poorly differentiated tumor, and positive margins were associated with worse OS, while adjuvant radiation was associated with improved OS (p=0.0113). Conclusions: Our analysis supports the role for adjuvant radiation therapy in resected gallbladder cancer. Multi-institutional prospective studies should be performed to evaluate the optimal treatment strategy. Biomarker analysis might also help determine the subset of patients who would benefit from combined chemoradiation.
A phase I trial with cohort expansion of BYL719 in combination with gemcitabine and nab-paclitaxel in locally advanced and metastatic pancreatic cancer.
Authors: Heloisa P. Soares, Danny Nguyen, Gregory M. Springett, Richard D. Kim, Irene Williams-Elson, Kara Miller, Nishi Kothari, Amit Mahipal
Journal: Journal of Clinical Oncology (2016)

TPS467 Background: The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway which is aberrantly stimulated in many tumors has emerged as a potential target for anticancer therapy. Although several class I PI3K inhibitors are under development, there is considerable evidence suggesting that targeting a single isoform of PI3K (p110α) would have sufficient antitumor activity and improved therapeutic window. The PI3K pathway is frequently activated and plays an important role in pancreatic cancer. Further, PI3KCA mutations, the gene encoding isoform p110α, are observed in this disease. BYL719 is an oral class I α-specific PI3K inhibitor that showed anti-tumor activity in different preclinical models. Recently, the first in human phase 1 trial of BYL719 defined the maximum tolerated dose (MTD) at 400 mg once daily. Methods: This is a single institution, open label, single group, phase I study with cohort expansion that utilizes the standard 3+3 design for dose. The primary objective is to determine the MTD of BYL719 in combination with gemcitabine and nab-paclitaxel as frontline therapy in patients with locally advanced, recurrent or metastatic pancreatic adenocarcinoma. Up to 24 patients will be enrolled in 4 dose escalation levels. The MTD is defined as the highest dose level at which 1 or less of 6 patients experience a dose limiting toxicity (DLT). Once the MTD is reached and/or the recommended dose for expansion is determined, an additional dose expansion cohort of 15 patients will be included. Secondary endpoints include characterizing the safety profile at the MTD and DLTs associated with it as well as obtaining pharmacokinetic data. Peripheral blood and pre-treatment tumor samples will be collected for evaluation of biomarkers that could predict treatment response, including levels of pAKT, p4EBP1 and pS6. BYL719 will be administered daily. Standard doses of gemcitabine and nab-paclitaxel will be given on days 1, 8 and 15 of the 28 days cycle. Patients will get restaging scans every 2 cycles. As per September 2015, twelve patients have been included in this study which is currently enrolling patients on cohort 3. Clinical trial information: NCT02155088 Clinical trial information: NCT02155088.
Factors predicting survival outcomes for patients with HPV-positive base of tongue cancer.
Authors: P. Attner
Journal: Journal of Clinical Oncology (2011)

5575 Background: Base of tongue cancer is the second most common oropharyngeal cancer in Sweden. We have previously demonstrated that the incidence of base of tongue cancer is increasing in Sweden and the proportion of human papillomavirus (HPV) positive cancer has increased in Stockholm, Sweden. Aims: This study aims to assess the impact of HPV status on prognosis for base of tongue cancer patients. Methods: All patients diagnosed with base of tongue cancer between 1998 and 2007 in Stockholm County and treated with the intention to cure was included in the survival analysis. Pre-treatment biopsies were obtained and tested for HPV both by general HPV PCR and HPV-16/HPV-33 type specific PCR. Age, sex, TNM-stage, stage, treatment and survival were recorded from patient charts. Kaplan-Meier curves were used to present survival data. In multivariable analyses, a Cox proportional hazards model was used to adjust for covariates. Results: Eighty-seven patients had available biopsies, were treated with intention to cure and could be included in the survival analysis. In total 68 (78%) tumor biopsies from the 87 included patients was HPV DNA positive. Kaplan-Meier estimates showed that the overall as well as disease free survival for patients with HPV-positive cancer was significantly better, (log-rank test) than that of patients with HPV-negative cancer. Conclusions: Survival for patients with HPV-positive base of tongue cancer was improved, regardless of oncological treatment and despite the fact that these patients were higher staged and with higher frequency of nodal metastases. These results further strengthen the option to consider HPV-status when planning prospective studies on treatment for base of tongue cancer.