tbuckley/cabot-search huggingface dataset:
Peri/post-operative chemotherapy of oxaliplatin combined with S-1 (SOX) versus post-operative oxaliplatin with capecitabine (XELOX) in locally advanced gastric cancer: RESOLVE Trial.
Authors: Jiafu Ji, Han Liang, Yingwei Xue, Lin Shen, Yanong Wang, Zhiwei Zhou, Jiren Yu, Yian Du, Guoli Li, Lin Chen, Gan Xiao, Dan Wu, Chengxue Dang, Yanbing Zhou, Yulong He, Zhongtao Zhang, Yong Li, Ziyu Li, Xiaotian Zhang
Journal: Journal of Clinical Oncology (2017)

e15519 Background: Peri-operative treatment of locally advanced gastric cancer (LAGC) has always been argued. We aim to compare the survival benefit and safety for SOX as peri-opertative therapy versus SOX or XELOX as postoperative therapy after D2 dissection. Methods: RESOLVE is a phase III trial investigating effects of post-operative SOX and XELOX, and peri-operative SOX on LAGC. RESOLVE is the first RCT investigating different therapeutic timeframes in gastric cancer patients with stratification by Lauren classification. Clinical trials JCOG 0501 and RESOLVE exploring optimal chemotherapy modalities are compared in the table below. Results: The study enrolled the first patient in Aug 2012. By Dec 31, 2016, a total of 1061 patients were recruited. Currently 136 patients have died (arm A: 54; arm B: 44; arm C: 37) and 187 patients are under treatment (arm A: 60; arm B: 61; arm C: 66). Conclusions: The patient recruitment has completed and events of DFS will be achieved in 2 years. Clinical trial information: NCT01534546. [Table: see text]
Use of QTc-prolonging medications among patients with lung cancer: implications for clinical trials and standard clinical care.
Authors: David E. Gerber, Tri Le, Hui Yang, Sawsan Rashdan, Carlos A Alvarez
Journal: Journal of Clinical Oncology (2018)

e20529 Background: Exclusion from cancer clinical trials is common for patients taking QTc-interval prolonging drugs. To estimate the potential impact on accrual, we determined the prevalence of QTc-prolonging medication prescriptions among individuals with lung cancer in a national cohort. Methods: We identified adult patients in the Veterans’ Affairs system diagnosed with lung cancer 2003-2016 (ICD-9 codes 162.0-162.9 and ICD-10 code C34.00-34.90). QTc-interval prolonging drugs and risk category were obtained from CredibleMeds®. We calculated prevalence of use (defined as a prescription for a known or possible risk drug in the 3 months up to and including date of diagnosis) across patient groups and time periods using Chi-square test. Results: 280,068 patients were included in the study. Mean age was 70 years, 98% were male, and 72% were white. Overall, 29.7% were using a QTc-prolonging medication. The most commonly prescribed QTc-prolonging medications were antimicrobials (14.0%), psychiatric agents (10.2%), antiemetics (2.6%), and cardiac meds (1.7%). Over the period of study, the rate of QTc-prolonging medication use increased from 25% to 29% (P < 0.0001). There was not a meaningful difference in characteristics between patients taking and not taking QTc-prolonging drugs. Expanding QTc-prolonging drugs to include those with conditional or undetermined risk, 57% of patients were using a QTc-prolonging medication, with 34% using multiple such agents. Conclusions: A substantial and growing proportion of individuals with lung cancer are taking QTc-prolonging medications at the time of their cancer diagnosis. These prescriptions may limit eligibility for clinical trials and complicate the administration of standard cancer therapies. Further research into the actual clinical risks and optimal management of QTc-prolonging drugs in cancer populations is warranted.
Molecular profile of lung adenocarcinoma in Brazilian never-smokers.
Authors: Pedro Masson Domingues, Tatiane Caldas Montella, Clarissa Serodio Da Rocha Baldotto, Mauro Zukin, Carlos G. M. Ferreira, Luiz H. Araujo, Giovana Tardin Torrezan
Journal: Journal of Clinical Oncology (2016)

e20611 Background: Lung adenocarcinoma in never-smokers (LANS) is a disease largely defined by targetable oncogenic mutations. High frequency of actionable genomic alterations has been reported in cohorts from different regions worldwide. Particularly in Asian cohorts, rates of clinically relevant mutations reach almost 90% of LANS. However, great variance between different geographic regions was found. In Brazil, the molecular profile of LANS is unknown. Methods: Consecutive cases of never-smokers with lung adenocarcinoma treated at the Brazilian National Cancer Institute from 2011 to 2013 were selected. DNA was extracted from formalin-fixed paraffin-embedded tissue and genotyped for 409 cancer-related genes by Next Generation Sequencing (NGS). All patients had been previously tested for EGFRmutations in Exons 18-21 either by Sanger or RT-PCR in a clinical laboratory. In tumours without a targetable alteration, a gene fusion panel was performed. Results: Sixteen patients had tumour block available for genotyping. The 409 NGS gene-panel detected 53 individual actionable mutations (median 3 per sample; range 0-10) in 15 (out of 16) tumours. The most commonly mutated genes were EGFR (15%,n = 8 of 53), STED2 (9%,n = 5 of 53), TP53 (7%,n = 4 of 53) and ERBB3 (7%,n = 4 of 53). Six cases (37%) harboured EGFR sensitizing mutations (1 L858R; 5 exon 19 deletions), some of which had not been previously detected by other technologies. The fusion panel identified 2 additional EML4-ALK rearrangements. No overlap was found between classic driver alterations. Overall, twelve out of 16 patient samples tested (75%) harboured a genomic alteration with a target agent based on NCCN guidelines (2 EGFR L858R; 6 EGFR exon 19 deletions; 2 ERBB2 mutations, 2 EML4-ALK). All four remaining patients without a oncogenic mutation considered targetable by NCCN, had at least one actionable genomic alteration identified. Conclusions: A broad genomic testing approach revealed a high prevalence of clinically relevant genetic alterations in Brazilian never-smoker with lung adenocarcinoma.
Concordant extra-medullary and bone marrow disease (EMD-BM) of blastic transformation of chronic myeloid leukemia (CML-BP) in the tyrosine kinase (TKI) era: Characteristics, treatments and outcomes.
Authors: Ahmad Ghorab, Hagop M. Kantarjian, Preetesh Jain, Rashmi Kanagal-Shamanna, Elias Jabbour, Koji Sasaki, Tapan M. Kadia, Guillermo Garcia-Manero, Prithviraj Bose, Musa Yilmaz, Kiran Naqvi, William G. Wierda, Srdan Verstovsek, Nitin Jain, Zeev Estrov, Farhad Ravandi, Susan Mary O'Brien, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2018)

e19022 Background: Occasionally, patients with CML-BP present extramedullary disease (EMD), frequently concomitantly with bone marrow disease (EMD-BM). Characteristics, treatment and outcome of these patients (pts) is sparse. Methods: We identified 78 pts with EMD-BM diagnosed between 2/2000 and 6/2015 who received TKI at some point during the course of their CML. Failure free survival (FFS; failure = disease progression, discontinuation of CML-BP therapy (Rx) for any reason, or death) and overall survival (OS) were defined from time of CML-BP diagnosis to last follow up or failure/death, respectively. Results: Median age was 50 yrs (19-83); 53% were male. Immunophenotype was myeloid 72%, lymphoid 25% and bi-phenotypic 3%. At the time of EMD-BM diagnosis, EMD affected central nervous system in 36 pts (46%), skin 12 (15%), bones 10 (13%), pleura 9 (12%), soft tissues 7 (9%), lymph nodes 6 (8%), liver 2 (3%), spleen, stomach and lung (1 each); 5 pts had > 1 site involved. Sixty-four (82%) pts received Rx (Table1). Response to 1st line Rx for EMD-BM was complete remission in 23 (36%), partial remission in 1 (2%), progressive disease in 39 (61%), and lost to follow up 1 (2%). Median OS of pts with EMD-BM was 5 mo (23% alive at 1 year); significantly inferior to pts presented with either isolated EMD (n = 50; p = 0.005) or BM CML-BP (n = 349; p = 0.0003) and it was significantly better in pts treated with TKI than pts treated without TKI (median OS 7 and 2 mo, respectively; p = 0.0002). The median FFS was 3 months. Fourteen pts (22%) relapsed: 6 with isolated EMD, 4 with isolated BM and 4 with EMD-BM. At the time of last follow up, 11 pts were alive. Causes of death in pts with EMD-BM were CML progression (n = 57), unknown (n = 7) and other causes (n = 3). Conclusions: CML-BP pts present with concordant EMD-BM have poor clinical outcome. This group of pts have worse outcome than pts present with either isolated EMD or BM CML-BP. Further studies to understand the biologic features of EMD-BM are ongoing Table1: EMD-BM Rx modalities Modality With TKI (n = 53) Without TKI (n = 11) TKI alone 8 Systemic chemotherapy 36 2 Local therapy (Surgery and/or XRT) 3 8 Both systemic and local 6 1
Incidence of hyperlipidemia among patients with chronic myelogenous leukemia (CML) receiving first or second line therapy with dasatinib or nilotinib.
Authors: Meg Franklin, Leah Burns, Samuel Perez, Deepak Yerragolam, Dinara Makenbaeva
Journal: Journal of Clinical Oncology (2016)

e18108 Background: Lipid metabolism is affected to varying levels in patients receiving BCR-ABL tyrosine kinase inhibitor (TKI) therapy. Resultant hyperlipidemia (HLD) is not well documented in large, real-world studies. The purpose of this study was to determine incidence and risk for HLD occurrence in insured patients receiving dasatinib or nilotinib for CML. Methods: This was aretrospective cohort study using data from the MarketScan database from 2006-2014. Patients ≥ 18 years with ≥ 2 claims for CML (ICD-9 205.10-205.12) and ≥ 1 prescription for dasatinib or nilotinib were eligible. Patients had continuous enrollment for ≥ 6 months prior to the first TKI prescription; no minimum follow-up time was required. Patients with a diagnosis of HLD prior to index TKI were excluded. To identify HLD occurrence, patients were followed from index prescription until first occurrence of: discontinuation of therapy, switch in therapy, end of study period, or end of continuous enrollment. Patients who developed HLD were identified by ≥ 2 claims with an ICD-9 code for HLD, or 1 code and the presence of an anti-HLD medication. Incidence was calculated as number of events divided by sum of the person time at risk for all subjects in the cohort. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HR) for HLD while adjusting for baseline characteristics. Results: 1,466 patients met criteria (n = 960 dasatinib, n = 506 nilotinib). Half (50.2%) of patients received either drug as first-line therapy. Mean age was 50.6 years, and 50.9% were male. Median follow-up time was 193 days for dasatinib and 204 days for nilotinib. Incidence rate of HLD was 68.2 per 1000 person years (PY) (95% CI: 52.3, 87.4) for dasatinib, and 112.5 per 1000 PY for nilotinib (95% CI: 84.3, 147.2). The HR for occurrence of HLD (dasatinib as reference) was 1.6 (95% CI: 1.1, 2.4), indicating patients initiating nilotinib had a 1.6 times higher risk of developing HLD while adjusting for baseline characteristics. Conclusions: Patients receiving nilotinib for CML had a higher incidence rate and significantly higher adjusted risk for developing HLD than patients receiving dasatinib.
Expanded Access Program of GRASPA for treatment of patients with acute lymphoblastic leukemia unable to receive other form of L-Asparaginase: A status update (NCT02197650).
Authors: Yves Bertrand, Herve Dombret, Bruno Quesnel, Severine Lissandre, Claudine Schmitt, Emmanuel Plouvier, Christian Recher, Maryline Poiree, Cecile DUMESNIL de MARICOURT, Iman El-Hariry
Journal: Journal of Clinical Oncology (2016)

e18532 Background: L-asparaginase (L-ASP) is a key drug in the treatment of acute lymphoblastic leukemia (ALL). GRASPA is E-Coli L-ASP encapsulated into red blood cells (RBC). Asparagine is actively transported through the membrane of RBC where it is hydrolyzed by the encapsulated L-ASP. Recently, a Phase 2/3 study of GRASPA in pts with relapsed ALL demonstrated favorable safety profile and clinical activity. An expanded access program has been initiated to provide treatment with GRASPA in patients who are unable to receive L-ASPs. Methods: This is an open label study, currently initiated in France; its primary objective is to evaluate the tolerability of GRASPA. Patients < 55y of age presenting with de novo,relapsed or refractory ALL who are at risk to receive other L-ASP formulation are eligible. GRASPA (150 IU/KG) is administrated every 3 weeks combined to chemotherapy according to the Investigator’s choice. Patients are assessed regularly for safety and tolerability. The primary endpoint is tolerability; Key secondary endpoints include asparaginase activity, asparagine depletion, and complete remission rates. An independent Safety Monitoring Board (DSMB) is set up to assess toxicities. Results: As of time of June 2015, 13 patients were enrolled into the program. The first DSMB meeting reviewed the outcome of the first 7 patients enrolled into the program. Of the 7 pts (range 3 – 49 years), 5 males and 2 females were enrolled. Four pts presented with refractory disease and 3 with relapse. All patients had evidence of allergies to 2 E-Coli- and Erwinia-derived asparaginases. Two pts presented with myelosupression and infection, and G1 allergic reaction in 1pt. There were no treatment discontinuation due to toxicity or lack of clinical benefit. An updated safety and clinical activity information on all patients will be provided Conclusions: The EAP provides a potential treatment alternative for ALL patients, who are at risk of developing allergic reactions to prior L-ASP. The initial results suggest that GRASPA is well tolerated, and may have a potential benefit in patients with double allergies. The program may be expanded to other European countries Clinical trial information: NCT02197650.
CD62L expression in chronic lymphocytic leukemia patients
Authors: E.A. Elkhouly, W.M. Radwan, M.A. Soliman, S. Swelim
Journal: Annals of Oncology (2018)

Background: Chronic lymphocytic leukemia is the most common adult leukemia and often presents as early-stage disease. It could be stable for many years with no or minimal intervention. CD62L is a one of the selectin family of adhesion molecules which plays an important role in the trafficking/homing of lymphocytes to the lymph node. The objective of this study was to evaluate CD62L expression in chronic lymphocytic leukemia, and its effect on survival of malignant B-cells. Methods: This study was conducted on 35 patients of chronic lymphocytic leukemia and 15 age & sex matched healthy individuals as a control group. All patients were subjected to full history taking, clinical examination and laboratory investigations. CD62L/CD19 expression on lymphocytes was measured for all the study subjects using Flowcytometry technique before and after cell culture. Results: CD62L/CD19 expression increased minimally in control subjects at day 7 compared to day 0 (The mean ±SD 33.9±5.3 and 18.03±3.4 respectively) (P-Value < 0.001), while the diseased group showed marked elevation at day 7 than day 0 (The mean ±SD 90.7±6.4 and 36.9±17.2 respectively) (P-Value < 0.001). CD62L/CD19 expression in patients were higher than the control subjects at day 0 (The mean ±SD 36.9±17.2 and 18.03±3.4 respectively) and about three folds increase at day 7 (the mean ±SD 90.7±6.4 and 33.9±5.3 respectively) (P- Value < 0.001). Conclusions: There is high expression of CD62L on lymphocytic cells in chronic lymphocytic leukemia patients associated with increased survival of malignant B-cells. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Expanding enrollment of underrepresented populations on early phase clinical trials: An analysis of participation among adolescent and young adults (AYA) with advanced cancers on phase I clinical trials.
Authors: Ishwaria Mohan Subbiah, Chad Tang, Arvind Rao, Vivek Subbiah, David S. Hong
Journal: Journal of Clinical Oncology (2018)

e18714 Background: Patients with cancer aged 15-39 years, the Adolescent and Young Adults (AYA), are significantly underrepresented on late phase clinical trials overall particularly in comparison to their pediatric (age < 15y) and middle age (40-64y) counterparts. With the rapid proliferation of novel anticancer therapies brought to early phase trials, we sought to characterize the participation of AYAs on phase I trials with investigational agents to better understand this unique and vulnerable with advanced cancer. Methods: We retrospectively identified pts w advanced cancers who received therapy on a phase I trials bw Dec 2004-July 2013. We subdivided pts by age as AYA (15-39y) or middle age (40-64y) and obtained their demographics and clinical characteristics, time to treatment failure (TTF), and RECIST response to therapy per imaging (complete response CR, partial response PR, stable disease SD). Results: Overall we identified 1489 pts, of whom 991 (67%) were middle age and 220 (15%) were AYAs. The median age in AYA group was 32.6y, with 63% being female, 33% male, and having a median of 3 prior therapies. Most common primary malignancy in the AYA subgroup was gyn (41, 19%), sarcoma (39, 18%), GI (35, 16%), thoracic/H/N (31, 14%), melanoma (27, 12%), & breast (20, 9%) cancers. Both mid age and AYA pts had a similar TTF (3.5m v 3.3m, respectively). Regarding disease response to therapy per imaging, AYAs had 93 (42%) SD inc 42 (19%) prolonged SD (median duration 9.7m), 34 (15%) PR (median duration 9.5m), and 2 pts with a CR lasting 36.2m and 50.1m. To date, none of these trials have reported on patient reported symptoms and outcomes or quality of life metrics. Conclusions: Adolescent and young adults remain underrepresented on phase I clinical trials with the trials providing little to no information on the needs unique to the AYA population such as psychosocial, family, educational and economic needs. Thorough characterization of barriers and addressing these barriers in the clinical trial design will be crucial to improving trial participation in this vulnerable group.
Biomarker modulation in patients treated with TRC105 in combination with anti-VEGF therapy.
Authors: Yingmiao Liu, Zhenhua Yuan, Dadong Zhang, Mark D. Starr, John C. Brady, Manoj A. Jivani, Bonne J. Adams, Delia Alvarez, Steven Attia, Toni K. Choueiri, Charles P. Theuer, Kouros Owzar, Herbert Hurwitz, Andrew B. Nixon
Journal: Journal of Clinical Oncology (2017)

11546 Background: TRC105, an endoglin-targeting monoclonal antibody with anti-angiogenic and anti-tumor activity, is being evaluated in multiple diseases. Here we report on pharmacodynamic and prognostic biomarkers in patients (pts) treated with both TRC105 and anti-VEGF agents. Methods: Plasma samples were collected from pts on three phase 2 trials combining TRC105 with an anti-VEGF agent: axitinib in metastatic renal cell carcinoma (mRCC), pazopanib in advanced soft tissue sarcoma, and bevacizumab in glioblastoma (GBM). Baseline and on-treatment levels of 22 soluble protein biomarkers were assessed. Results: Soluble endoglin markedly increased after TRC105 treatment in all pts ( p&lt; 0.001) as previously reported. BMP9 (a ligand for endoglin) and TGFβR3 (a type III TGFβ receptor) decreased in sarcoma pts at Cycle 2 Day 1 (C2D1) and generally remained below baseline throughout the course of treatment (BMP9, p= 0.004; TGFβR3, p= 0.003). Although TGFβR3 was decreased at C2D1 in mRCC (p = 0.030), no clear patterns were observed over time. Overall BMP9 levels did not change in response to therapy in either mRCC or GBM. Osteopontin (OPN) levels, a downstream effector of TGFβ signaling, were increased in sarcoma pts [ p= 0.002 at C2D15, p&lt; 0.001 at C4D1 and end of study (EOS)]; however, in mRCC ( p= 0.010) and GBM ( p= 0.003), OPN was only elevated at EOS. Increases in PlGF and VEGFD, and decreases in VEGFR2 were observed across all studies, as previously noted for VEGF inhibitors. In the mRCC trial, 5 of 18 pts exhibited a ≥30% tumor reduction. Lower OPN ( p= 0.026) and higher TGFβR3 ( p= 0.003) levels at baseline correlated with radiographic response to treatment. In the sarcoma trial, 6 of 19 pts responded (CHOI criteria) in which lower baseline levels of ICAM1 ( p= 0.018) and TSP2 ( p= 0.042) correlated with stable disease. Conclusions: In these trials, increases of soluble endoglin in response to TRC105 were observed, independent of the presence of any specific VEGF inhibitor. Differential regulation of BMP9, TGFβR3, and OPN suggests potential disease-specific modulation of key TGFβ signaling molecules in response to dual therapy. Baseline levels of OPN and TGFβR3 showed potential prognostic value in mRCC. Confirmation in larger trials is needed.
Pooled analysis of aprepitant for carboplatin-based chemotherapy in advanced non-small-cell lung cancer.
Authors: Koji Nishimoto, Masato Karayama, Naoki Inui, Hideki Kusagaya, Shigeki Kuroishi, Tomoyuki Fujisawa, Noriyuki Enomoto, Yutaro Nakamura, Hiroyuki Matsuda, Koshi Yokomura, Naoki Koshimizu, Mikio Toyoshima, Shiro Imokawa, Takashi Yamada, Toshihiro Shirai, Masafumi Masuda, Kazumasa Yasuda, Hiroshi Hayakawa, Takafumi Suda, Kingo Chida
Journal: Journal of Clinical Oncology (2016)

e20557 Background: Chemotherapy-induced nausea and vomiting (CINV) remains a challenging issue in cancer treatment. Carboplatin is widely used in multi-organ cancers; however, clinical benefit of aprepitant for carboplatin-based chemotherapy has not fully been elucidated. In a pooled analysis, we evaluated the efficacy and safety of aprepitant in patients with advanced non-small-cell lung cancer (NSCLC) receiving carboplatin-based chemotherapy. Methods: We integrated our data from two randomized phase II studies that compared the efficacy and safety of the doublet antiemetic therapy with 5-HT3 antagonist and dexamethasone versus the triple antiemetic therapy with 5-HT3 antagonist, dexamethasone, and aprepitant in advanced NSCLC patients receiving carboplatin-based chemotherapy. One study used 1st generation 5-HT3 antagonists and another study used a 2nd generation 5-HT3 antagonist, palonosetron. Results: A total of 214 patients (106 in the doublet group and 108 in the triple group) were evaluated. One hundred sixty-seven (77.3%) were male, and the median age was 69 years (range, 39-90). One hundred thirty-four (62.6%) patients received 1st generation 5-HT3 antagonists and 80 (37.4%) received palonosetron. The triple antiemetic therapy demonstrated a non-significant trend toward a higher complete response rate (no vomiting and no rescue therapy) during the 5 days after administration of chemotherapy (80.6%, 95% CI: 71.8-87.5) than the doublet antiemetic therapy (69.8%, 95%CI: 60.1-78.3, odds ratio: 0.49, 95% CI: 0.28-1.10, p = 0.08). In multivariate analysis, antiemetic therapy without aprepitant, and aged < 70 years were independent risk factors for CINV. Conclusions: Compared with the doublet antiemetic therapy, the triple antiemetic therapy with aprepitant demonstrated a trend toward a better control of CINV in NSCLC patients receiving carboplatin-based chemotherapy. Clinical trial information: 10056.