tbuckley/cabot-search huggingface dataset:
Randomized Phase II Trial of Cisplatin and Etoposide in Combination With Veliparib or Placebo for Extensive-Stage Small-Cell Lung Cancer: ECOG-ACRIN 2511 Study
Authors: Taofeek K. Owonikoko, Suzanne E. Dahlberg, Gabriel L. Sica, Lynne I. Wagner, James L. Wade, Gordan Srkalovic, Bradley W. Lash, Joseph W. Leach, Ticiana B. Leal, Charu Aggarwal, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2018)

Veliparib, a poly (ADP ribose) polymerase inhibitor, potentiated standard chemotherapy against small-cell lung cancer (SCLC) in preclinical studies. We evaluated the combination of veliparib with cisplatin and etoposide (CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC).Patients with ES-SCLC, stratified by sex and serum lactate dehydrogenase levels, were randomly assigned to receive four 3-week cycles of CE (75 mg/m2 intravenously on day 1 and 100 mg/m2 on days 1 through 3) along with veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P). The primary end point was progression-free survival (PFS). Using an overall one-sided 0.10-level log-rank test, the study had 88% power to demonstrate a 37.5% reduction in the PFS hazard rate.A total of 128 eligible patients received treatment on protocol. The median age was 66 years, 52% of patients were men, and Eastern Cooperative Oncology Group performance status was 0 for 29% of patients and 1 for 71%. The respective median PFS for the CE+V arm versus the CE+P arm was 6.1 versus 5.5 months (unstratified hazard ratio [HR], 0.75 [one-sided P = .06]; stratified HR, 0.63 [one-sided P = .01]), favoring CE+V. The median overall survival was 10.3 versus 8.9 months (stratified HR, 0.83; 80% CI, 0.64 to 1.07; one-sided P = .17) for the CE+V and CE+P arms, respectively. The overall response rate was 71.9% versus 65.6% (two-sided P = .57) for CE+V and CE+P, respectively. There was a significant treatment-by-strata interaction in PFS: Male patients with high lactate dehydrogenase levels derived significant benefit (PFS HR, 0.34; 80% CI, 0.22 to 0.51) but there was no evidence of benefit among patients in other strata (PFS HR, 0.81; 80% CI, 0.60 to 1.09). The following grade ≥ 3 hematology toxicities were more frequent in the CE+V arm than the CE+P arm: CD4 lymphopenia (8% v 0%; P = .06) and neutropenia (49% v 32%; P = .08), but treatment delivery was comparable.The addition of veliparib to frontline chemotherapy showed signal of efficacy in patients with ES-SCLC and the study met its prespecified end point.
TCT-798 Evaluation of sex-differences in one-year clinical outcomes among patients treated with the dual-therapy COMBO stent: From the COMBO Collaboration
Authors: Jaya Chandrasekhar, Melissa Aquino, Samantha Sartori, Pier Woudstra, Usman Baber, Karel Koch, Antonio Colombo, George Dangas, Roxana Mehran
Journal: Journal of the American College of Cardiology (2018)
Association of delayed adjuvant therapy and overall survival in early stage endometrial cancer.
Authors: Leo Luo, Weiji Shi, Zhigang Zhang, C. Jillian Tsai
Journal: Journal of Clinical Oncology (2017)

5590 Background: The primary treatment for early stage endometrial cancer includes definitive surgical staging procedure followed by adjuvant therapy in women with high risk of recurrence. The optimal interval time between surgery and adjuvant therapy is unclear. Methods: 349,404 patients with primary uterine carcinoma diagnosed from 2004 and 2012 were extracted from National Cancer Database (NCDB). Study population was limited to patients with FIGO 2009 stage I and II endometrial cancer with endometroid, mucinous, clear cell, or serous histology. Adjuvant therapy included radiation therapy, chemotherapy, or a combination. A binary variable of interval time between surgery and adjuvant therapy (“early” vs. “delayed”) was created by using the median time as a cutoff. Analysis of relationship between the interval time and overall survival was performed. Results: Final analysis included 118,373 early stage endometrial cancer patients who had definitive surgical treatment. Median age was 61 (interquartile range 55-69). 87,189 patients (74%) had stage IA disease, 21,573 (18%) patients had stage IB disease, and 9,611 (8%) patients had stage II disease. 28,824 (24%) patients received adjuvant therapy after surgery. The median time from surgery to adjuvant therapy was 1.6 months (interquartile range 1.3-2.2 months). Of the patients that received adjuvant therapy, 48% received intra-vaginal brachytherapy alone, 31% received pelvic external beam radiation, and 7% received a combination of chemotherapy and brachytherapy. There was a significant difference in overall survival in patients who received adjuvant therapy within 1.6 months from surgery and 1.6 months after surgery (Log-rank test, p = 0.04). Patients with advanced age, African-American or Hispanic race, and uninsured status or government-sponsored insurance were associated with delayed treatments. Conclusions: In this large retrospective review of early stage endometrial cancer patients, delayed time between surgery and adjuvant therapy is associated with worse overall survival. Further analysis will be performed to determine an optimal timing between surgery and adjuvant therapy.
A phase 1/2 study of carfilzomib, bendamustine, and dexamethasone (CBD) in newly diagnosed multiple myeloma patients.
Authors: Siyang Leng, Alexander Wei, Amer Assal, Divaya Bhutani, Gregory Baliko, Julia Gould, Ryan J Shelton, Shannon Kelly, Daniel Otap, Markus Y Mapara, Suzanne Lentzsch
Journal: Journal of Clinical Oncology (2018)

8029 Background: Carfilzomib and bendamustine have demonstrated efficacy in relapsed refractory myeloma. In this phase 1/2 study, we evaluated the combination of carfilzomib, bendamustine and dexamethasone in newly diagnosed patients. Methods: This is an ongoing, open label, single center study. Phase 1 dose escalation followed an up-and-down dosing scheme (Storer’s Design D). Carfilzomib was administered at dose levels of 27, 36, 45 and 56 mg/m2 on days 1,2,8,9,15,16, bendamustine at 70 and 90 mg/m2 on days 1,2, and dexamethasone at 20 mg on days of carfilzomib and on day 22 of a 28 day cycle. Autologous stem cell transplant (ASCT) eligible patients received 4 cycles of CBD, underwent stem cell harvest, and then received an additional 4 cycles followed by ASCT. ASCT ineligible patients received 8 cycles of CBD. Both groups received maintenance with carfilzomib 36 mg/m2 on days 1,2,15,16 every 28 days for up to 2 years. Results: To date, 18 patients have been treated. Median age was 65 (range 51-74); 12 were male, 7 Hispanic, 2 African American and 2 Asian. One patient was treated at each dose level from 1-4, without DLTs; 14 patients were treated at the maximum dose level. The overall response rate was 100% – 16 (89%) had complete response (CR) / very good partial response (VGPR), with 3 being MRD-negative CR by flow, 3 stringent CR, 1 CR, and 9 VGPR; 2 had partial response (PR). 2 patients with VGPR and 1 with PR are still receiving induction. All patients showed response after 1 cycle. Of the 13 patients who have completed 8 cycles of CBD, 7 underwent ASCT. The 12-month PFS rate was 100%, and median follow-up was 14.8 months. G3/4 hematologic toxicities include neutropenia (28%), thrombocytopenia (22%), anemia (17%), lymphopenia (17%). Notable non-hematologic toxicities (all grades) include infection (44%), creatinine increase (33%), weight loss (28%), and thromboembolic event (22%). Stem cell collection was not impacted. Conclusions: CBD appears to be a safe and highly effective induction regimen for myeloma, with an 89% rate of CR/VGPR in our cohort. Clinical trial information: NCT02002598.
ADI-PEG 20 and FOLFOX6: A phase 1 study in pts (pts) with advanced hepatocellular carcinoma (HCC).
Authors: James J. Harding, Richard K. G. Do, Ellen Hollywood, Khrystyna Uhlitskykh, Emily Valentino, Peter Justin Wan, Casey R. Hamilton, Jessica Frick, Xiaoxing Feng, Amanda Johnston, John S. Bomalaski, Chien-Feng Li, Eileen Mary O'Reilly, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2018)

4085 Background: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways, and preclinical data indicate that pairing pegylated arginine deaminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. Methods: An open-label phase 1 trial of ADI-PEG 20 and FOLFOX6 for treatment-refractory HCC and other advanced gastrointestinal (GI) tumors was based on a 3 + 3 dose escalation design. The primary objectives were to define, safety, tolerability, and the recommended phase 2 dose (RP2D). An HCC expansion cohort was used to define best overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and exploration of pharmacodynamics and immunogenicity. Eligible patients were treated with intravenous FOLFOX6 biweekly at standard doses and ADI-PEG 20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m2 (Cohort 2 and RP2D expansion). Results: 27 pts enrolled—23 advanced HCC (and 4 other GI). HCC cohort: median age 64 (44-77) years old/70% male/100% Child Pugh A/57% non-viral/70% extrahepatic disease/39% portal vein involvement/43% ≥ 2 lines of treatment. No dose-limiting toxicities were observed and the RP2D for ADI-PEG 20 was 36 mg/m2 weekly with FOLFOX6. Common adverse events (AEs) any grade: thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. Among 23 HCC pts, the most frequent treatment related Grade ≥ 3 AEs were neutropenia (47.8%), thrombocytopenia (34.7%), leukopenia (21.7%), anemia (21.7%), and lymphopenia (17.4%). The ORR for 23 HCC pts was 21.7% (95% CI: 95 7.5-43.7). Median PFS and OS were 7.3 and 14.5 months. Arginine levels (Mean ± SEM, baseline 81.7 ± 8.2, week 1 0.8 ± 0.2µM) were depleted with therapy despite the emergence of low levels of anti-ADI-PEG 20 antibodies. The degree of arginine depletion, presence of antibodies, and archived tumoral argininosuccinate synthetase-1 levels did not correlate with response. Conclusions: Concurrent ADI-PEG-20 and FOLFOX6 is safe with favorable efficacy compared to historic controls. The HCC cohort has been expanded further into a phase II study of the combination in the third-line. Clinical trial information: NCT02102022.
Tumor suppressor P53 gene codon 72 polymorphism and imatinib cytogenetic response in chronic myeloid leukemia
Authors: E.A. Elkhouly, K.A. Khalifa, W.M. Radwan, Y.A. Younis
Journal: Annals of Oncology (2018)

Background: P53 polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this variation and response to treatment in cancer. This study aimed to study p53 codon72 polymorphism in relation to cytogenetic response to imatinib treatment in patients with chronic myeloid leukemia (CML). Methods: This study was conducted on 54 CML patients presented to Clinical Oncology Department, Menoufia University during the period from June 2013 and April 2015. They were classified according to their cytogenetic response to imatinib therapy into 40 CML patients cytogenetic responder to imatinib and 14 CML patients cytogenetic non responder to imatinib. Patients were genotyped for P53codon72 polymorphism using Polymerase Chain Reaction (PCR). Follow up of the patients should be done after 3, 6, 9, 12 and 18 months after diagnosis. And was done by CBC, conventional cytogenetic and FISH. Results: Age, gender, hematologic and cytogenetic response to imatinib in CML patients did not differ significantly among P53 codon72 genotypes (arg /arg, arg /pro and pro /pro) (P = 0.44, p = 0.45 and p = 0.11 respectively). P53 codon72 polymorphism did not significantly alter the risk to imatinib cytogenetic unresponsiveness (P = 0.9221). Conclusions: It could be concluded that P53 codon72 polymorphism is not associated with imatinib unresponsiveness in CML. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
3-D physiomimetic extracellular matrix hydrogels provide a supportive microenvironment for rodent and human islet culture
Authors: K. Jiang, D. Chaimov, S.N. Patel, J.-P. Liang, S.C. Wiggins, M.M. Samojlik, A. Rubiano, C.S. Simmons, C.L. Stabler
Journal: Biomaterials (2018)
Coexistence of MET exon 14 mutations with EGFR mutations in non-small cell lung cancer.
Authors: Wen-Feng Li, Jin Kang, Xu-Chao Zhang, Su Jian, Huajun Chen, Zhen Wang, Bin-Chao Wang, Qing Zhou, Hai-Yan Tu, Yi-Long Wu, Jin-Ji Yang
Journal: Journal of Clinical Oncology (2017)

e20636 Background: Activation of MET oncogene as the result of amplification or activation MET exon 14 mutations represents an emerging molecular target for non-small cell lung cancer (NSCLC) treatment. MET exon 14 mutations account for 1.0% in Chinese NSCLC patients. However, few data have been reported on the coexisting of MET exon 14 mutations and EGFR mutations in NSCLC. Moreover, the clinicopathological characteristics and targeted therapy of these MET/ EGFR-coexisting patients remain elusive. Methods: Next-generation sequencing was performed on the DNA of 969 patients and Sanger sequencing was conducted on cDNA of 621 patients for MET exon 14 mutations in NSCLCs. EGFR mutations were determined by direct DNA sequencing. Results: Fifteen patients harbored positive MET exon 14 mutations. Frequency of concomitant EGFR and MET exon 14 mutations was 0.2%(3/1590). 3 patients with concomitant MET exon 14 mutation and EGFR activating mutation were all female, never smokers and adenocarcinoma. Their stagings were stageⅠB (n = 1) and stage Ⅳ(n = 2). The stage ⅠB patient harboring concomitant MET exon 14 skipping and EGFR L858R mutation did not relapse 2 years after operation. The other two stage Ⅳ patients received first-line gefitinib. Case one harbored concomitant MET exon 14 point mutations (IVS13-36G &gt; A) and EGFR exon 19 deletion, and showed resistance to gefitinib with progression free survival(PFS) of 2 weeks and overall survival(OS) of 1 month. Case two had concomitant MET exon 14 point mutations (IVS13-36G &gt; A) and EGFR L858R mutation. Meanwhile, she also had both METamplification and c-Met overexpression at the baseline. She showed partial response (PR) to gefitinib with 3.8 months PFS. Then she was enrolled in a clinical trial (NCT02374645) to receive volitinib plus gefitinib on December 20, 2016. Initial response was good PR on January 24, 2017. Only grade 1 rash was observed. Conclusions: Coexisting MET exon 14 /EGFR mutation is an uncommon molecular event in NSCLC patients. Such coexisted patients might show relative resistance to EGFR inhibitor. However, combination of MET and EGFR inhibitors will be potentially a good strategy to overcome such a relative resistance for MET exon 14 /EGFR co-mutant patients.
A phase 1b, open label, single institution trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors.
Authors: Ankit Madan, Benjamin Scott Jones, Ravi Kumar Paluri, Mary Jerome, Debi Miley, Francisco Robert
Journal: Journal of Clinical Oncology (2017)

TPS2614 Background: Vascular endothelial growth factor (VEGF) is a potent factor in inducing angiogenesis. VEGF inhibitors have produced demonstrable but limited and transient clinical benefit for various cancers. One mechanism of resistance includes revascularization secondary to up-regulation of alternative pro-angiogenic signals such as platelet derived growth factor receptor (PDGF) and fibroblast growth factor receptor (FGFR) pathway. Nintedanib is an oral triple kinase inhibitor that blocks the VEGFR, PDGFR and FGFR pathways. Our study is using combination of Nintedanib (Nin) and Bevacizumab (Bev) which will block VEGF as well as salvage pathway of angiogenesis (PDGFR and FGFR). Phase I dose selection studies revealed that Nin is generally well tolerated (Clin Can Res 16:47, 2010). LUME-Lung 1 phase 3, international, double blind, placebo controlled trial using Nin and docetaxel in non-small cell lung cancer (NSCLC) showed significant improvement in progression free survival (PFS) regardless of histology and improvement in overall survival (OS) in lung adenocarcinoma (Lancet oncology 15:2, 2014). Methods: This is a phase 1b, open label, single institution trial with standard 3+3 design. Primary objective is to evaluate the safety and tolerability of combination of Nin and Bev. The secondary objective is to determine clinical efficacy (objective response), PFS, and evaluation of plasma levels of angiogenic and anti-angiogenic biomarkers like VEGF, PDGF, VEGF-R and FGF. Patients (pts) in cohort I will be treated with Bev 15 mg/kg day 1 intravenously every 3 weeks and Nin 150 mg orally (PO) twice daily (BID) from day 2-21. In the absence of dose limiting toxicities, Nintedanib dose will be increased to 200 mg PO BID in cohort II. Major inclusion criteria includes advanced solid tumors for which Bev has an indication (non-squamous, NSCLC, colon, ovarian, cervical and renal cancer), progression after at least 1 line of systemic treatment, and measurable disease. Pts with prior treatment with Bev can be enrolled. We will enroll 18 patients. Cohorts I has been completed without DLT (n = 3). Cohort II has enrolled 10 patients. Clinical trial information: NCT02835833.
Analysis of contrast-enhanced CT textures to predict survival of patients with primary esophageal cancer treated with definitive chemotherapy and radiation therapy.
Authors: Qifeng Wang, Jinyi Lang, Tao Li, Jiahua Lv, Bangrong Cao, Yu Fan, Yi Wang, Miyong Xiao
Journal: Journal of Clinical Oncology (2017)

e15559 Background: To determine the association between tumor heterogeneity, morphologic tumor response, and overall survival in primary esophageal squamous cell cancer (ESCC) treated with chemotherapy and radiation therapy (CRT). Methods: After an institutional review board waiver was obtained, 57 clinical stage III patients with CRT were analysis. All patients underwent contrast-enhanced CT before RT and after RT 40Gy between 2012 and 2015 were analyzed in terms of whole-tumor texture, with quantification of entropy, uniformity, max and mean gray-level intensity, kurtosis, standard deviation of the histogram, mass and skewness for fine to coarse textures (filters 1.0-2.5, respectively). Whole-tumor texture was analyzed using IBEX 1.0β. The association between texture parameters and survival time was assessed by using Kaplan-Meier analysis and a Cox proportional hazards model. Results: The median, 1 and 3 years overall survival (OS)were 20.2 months 75.4% and 32.1% .Only the clinical factor posttreatment volume (median OS, 28.4 vs 14 months; P = 0.016), pretreatment median entropy of 0.069 or greater (median OS, 31.6 vs 17.0 months; P = 0.022), and medium max gray-level intensity of 11 or greater (median OS, 33.2 vs 11.7 months; P = 0.034),Coarse kurtosis of 58.4122 or greater (median OS, 28.4 vs 15.0months; P = 0.036) were associated with improved survival time. Survival models that included a combination of pretreatment entropy and posttreatment volume. We used a 3-point risk classification index with equal weights given to entropy and volume predict OS and progression-free survival (PFS). The median OS for high-, medium-, and low-risk groups were12.2, 19.1, and 31.7 months,respectively (P = 0.013). Validated the risk model in PFS, The median PFS for high-, medium-, and low-risk groups were 8.0, 18.5, and not received months,respectively (P = 0.043). Conclusions: Pretreatment texture parameters are associated with survival time, and the combination of pretreatment texture parameters and post volume performed better in survival models.
Outcomes of metastatic melanoma (MM) patients (pts) after discontinuation of anti-Programmed-Death 1 (PD1) therapy without disease progression.
Authors: Gustavo Schvartsman, Junsheng Ma, Roland L. Bassett, Lauren Elaine Haydu, Rodabe Navroze Amaria, Patrick Hwu, Wen-Jen Hwu, Adi Diab, Sapna Pradyuman Patel, Michael K.K. Wong, Scott Eric Woodman, Michael A. Davies, Isabella Claudia Glitza, Hussein Abdul-Hassan Tawbi
Journal: Journal of Clinical Oncology (2018)

9549 Background: The optimal duration of PD1 therapy for MM pts that do not progress remains unknown. There is limited information available about long-term outcomes of patients that discontinue treatment due to toxicity. Methods: Our institutional database was queried to identify stage IV or unresectable stage III MM pts that received single-agent anti-PD1 from January 1, 2012, to July 31, 2016, with at least 6 months of clinical follow-up. Pts that discontinued PD1 therapy for reasons other than progression were identified, including maximal clinical benefit (MCB) and toxicity. MCB was defined as either completion of two years or discontinuation per physician’s discretion. Data on demographics, tumor characteristics, treatment variables and outcomes were collected. Results: From 580 MM pts treated with PD1, 41 pts discontinued treatment for MCB and 34 for intolerable toxicity (75 total). 56% of pts achieved a complete response (CR), 35% partial response (PR), and 9% stable disease (SD). Response rate was similar among patients discontinuing therapy due to MCB (93%) and toxicity (88%), but CR rates were higher in the MCB group (76% vs 32%, p < 0.001). Median time on PD1 was 19.5 months in the MCB group and 6.5 months in the toxicity group; median time to response was 2.9 months, and median time to CR was 7.3 months. With median follow-up of 16 months after discontinuation, 89% were disease-free and 93% were alive; 6 patients died; no deaths were due to disease progression, and 3 were due to PD1 treatment complications. 8 pts progressed (3 in the MCB group, 5 in the toxicity group). 2 out of 3 in the MCB group were successfully rechallenged with PD1 (1 CR, 1 PR) and one had surgery and is still off therapy. One pt in the toxicity group was rechallenged, 2 are receiving ipilimumab, one had a single brain lesion resected (still off therapy) and one died of cardiac arrest while on T-VEC. No baseline factors were associated with relapse. Conclusions: Anti-PD1 was safely discontinued in the majority of MM pts, and no deaths due to disease progression were seen. Further prospective validation of early discontinuation for MM pts achieving MCB is warranted to prevent unnecessary toxicity and financial costs.