tbuckley/cabot-search huggingface dataset:
Retronectin and anti-CD3 monoclonal antibody actived T cell combined anti-PD-1 therapy in heavy-treated renal cell cancer.
Authors: Ling-Di Zhao, Tiepeng Li, Wei Li, Yonghao Yang, Quanli Gao
Journal: Journal of Clinical Oncology (2018)

e15053 Background: Metastatic renal cell carcinoma (MRCC) has a poor prognosis after failure of multitargeted kinase inhibitors. New immunomodulators, such as anti-programmed death (PD)-1 antibody, have made progress in the treatment of MRCC, but the objective response rate is only about 25%. Therefore, it is urgent to improve the efficacy of anti-PD-1 therapy. Methods: Patients with MRCC were eligible if they were failed to at least one kinase inhibitors, ECOG PS 0-2. Patients received nivolumab (2mg/kg, q2w) or keytruda ( 2mg/kg, q3w), followed by Retronectin and anti-CD3 monoclonal antibody actived T(RCAT) cell , and the total number of RCAT cell each time was about 5×109/L. The primary objective was to determine the objective response rate, secondary objectives included time to best efficacy, safety. Results: Until February 2018, 14 pts were enrolled (median age 59 [45-79], male 12). Pts had received a median of 2 (1-3) prior regimens. 3 pts received keytruda and 11 pts received nivolumab combined therapy. To date there is 3 patients that the efficacy can not be evaluated and one patient died at the 73th day after her first dose of nivolumab. During the other 10 pts 5 got complete remission(CR), 3 partial remission(PR) and 2 stable disease(SD), the objective response rate was 80 percent. The median time to CR for the 5 pts is 201 days (75 to 301 days). One patient with PR died at day386, one patient with SD died at day 142, another patient with SD experienced progressive disease at day366, after progressive he received axitinib as salvage therapy, one month late partial remission was got. 3 pts with CR stopped therapy and still kept CR at present, another 2 pts with CR was got at last followup. Time to best efficacy was 91 days (50-301 days). Grade 1 fever occurred in one patient, grade 1 hypothyroidism occurred in 3 pts, grade 1/2 elevated transaminase occurred in 4 pts, and there was no grade 3/4 adverse effects. Conclusions: RCAT cell might improve the efficacy of anti-PD-1 therapy without increasing the side effects in MRCC. This combination therapy has many implications in the age of combined immunotherapy, and should be explored across cancer types.
Anti-CD27 agonist antibody varlilumab (varli) with nivolumab (nivo) for colorectal (CRC) and ovarian (OVA) cancer: Phase (Ph) 1/2 clinical trial results.
Authors: Rachel E. Sanborn, Michael J. Pishvaian, Margaret K. Callahan, Amy M. Weise, Branimir I. Sikic, Osama E. Rahma, Daniel C. Cho, Naiyer A. Rizvi, Rhonda L. Bitting, Alexander Starodub, Antonio Jimeno, Michael Jay Yellin, Tracey Rawls, Laura Vitale, Abdel Halim, Hui Zhang, Tibor Keler
Journal: Journal of Clinical Oncology (2018)

3001 Background: Preclinical studies demonstrate synergistic antitumor activity of PD-1 blockade and varli, a CD27 agonist antibody. Ph1 results were previously presented from a Ph1/2 study assessing the safety of nivo with varli; we now report Ph1/2 results for CRC and OVA. Methods: Pts with advanced, treatment refractory (anti-PD-1/L1 naïve) solid tumors received nivo (Ph1: 3 mg/kg; Ph2: 240 mg) every two weeks (Q2W). Ph1 cohorts also received varli at 0.1, 1, or 10 mg/kg Q2W. Ph2 cohorts received varli at 3 mg/kg Q2W (CRC and OVA), 0.3 mg/kg Q4W (OVA), or 3 mg/kg Q12W (OVA). Primary study objectives: safety (Ph1) and overall response rate (Ph2). Results: 42 CRC and 66 OVA pts received nivo and varli. Toxicity was consistent with the safety profile of each agent; treatment-related serious events occurred for 3 pts with CRC (mixed motor sensory neuropathy, pneumonitis, elevated ALT) and 2 pts with OVA (acute kidney injury, hepatitis, small bowel obstruction). Of 49 (8 Ph1, 41 Ph2) evaluable OVA pts, 5 (10%; all Ph2) had RECIST 1.1 Partial Response (PR) and 19 (39%; 6 Ph1, 13 Ph2) had Stable Disease (SD). On-treatment biopsies revealed an increase in PD-L1 expression (p < 0.006), and CD8+ T cells (p < 0.005), which was more prevalent among pts with better outcome (PR or ≥ 16 weeks of SD), p < 0.017 and p < 0.002. Of 41 (21 Ph1, 20 Ph2) evaluable CRC pts, 2 (5%; 1 Ph1, 1 Ph2) had PR (Ph1 pt MSI-low, Ph2 pt MSI-high; both PD-L1 neg) and 7 (17%; 3 Ph1, 4 Ph2) had SD. 89% of CRC pts had PD-L1 neg tumors at baseline. In contrast to OVA, increase in tumor PD-L1 expression or CD8+ T cells during treatment in CRC patients was infrequent, correlating with less overall clinical impact. Conclusions: Varli with nivo was well tolerated without evidence of additive toxicity. In OVA pts, treatment induced significant tumoral changes that correlate with better outcome. Remaining analyses of OVA pts will examine the impact of varli dosing schedule on clinical outcome and biomarkers. The mechanisms that mediate the lack of T cell and PD-L1 increase in some pts are being explored by further tumor molecular profiling. Clinical trial information: NCT02335918.
Combined treatment of apatinib with docetaxel in non-small-cell lung cancer mice and its material basis of pharmacokinetics.
Authors: Fang Zhou, Siqi Feng, Jingwei Zhang, Jiye Aa, Guangji Wang
Journal: Journal of Clinical Oncology (2017)

e14069 Background: Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2, has attracted many attentions due to its encouraging anticancer activity in clinic third-line treatment across a broad range of malignancies, including gastric cancer, non-small-cell lung cancer (NSCLC) and colorectal cancer. Its usage in second-line with chemotherapeutic drugs is still under exploration. This study is focus on the antitumor effect of apatinib combined with docetaxel (DTX) on NSCLC and its pharmacokinetic material basis. Methods: Apatinib (150 mg/kg, every day, p.o.) with or without DTX (8 mg/kg, q3d for four times, i.p.) was administered in A549 xenograft nude mice. The antitumor effect, histopathology of important organs and serum transaminases for liver function were detected. The metabolomic changes in serum were profiled by GC/MS and analyzed for the treatment outcome. The effect of apatinib on DTX concentrations in plasma, tumor and other tissues were determined by LC-MS/MS. The expressions of multidrug resistant transporters were detected. Effects of apatinib on the uptake, efflux and subcellular distribution of DTX in A549 cell and A549/DTX (DTX resistant) cell were investigated. Results: Apatinib enhanced the antitumor effect of DTX with alleviated DTX-induced inflammatory cells infiltration in liver and decreased serum transaminases (ALT and AST). Metabolomic results showed that serum endogenic molecules of apatinib and DTX co-treatment mice were closer to that of normal nude mice when compared to the DTX group. Apatinib significantly increased DTX concentration in tumor (up to 1.82 times) without enhancement in serum, heart, liver, lung and kidney. Additionally, apatinib decreased the DTX-induced upregulation of P-glycoprotein in tumor. In vitro, apatinib increased the cell/subcellular accumulation (especially in cytosol) and decreased the efflux of DTX in A549/DTX cells, while apatinib exerted no significant effect on cellular pharmacokinetics of DTX in A549 cells. Conclusions: Apatinib has a potential application prospect in second-line therapy combined with DTX for NSCLC patients, especially for multidrug resistant patients.
Efficacy and safety results from a phase I/IIa study of dabrafenib in pediatric patients with <i>BRAF</i> V600–mutant relapsed refractory low-grade glioma.
Authors: Mark W. Kieran, Eric Bouffet, Alberto Broniscer, Kenneth J. Cohen, Birgit Geoerger, Jordan R. Hansford, Pooja Hingorani, Isabelle Aerts, Nicolas Andre, Anne-Isabelle Bertozzi-Salamon, Ira J. Dunkel, Trent Ryan Hummel, Sarah Leary, Lucas Moreno, Mark W. Russo, Lillian Tseng, Kohinoor Dasgupta, Noelia Nebot, James Whitlock, Darren R Hargrave
Journal: Journal of Clinical Oncology (2018)

10506 Background: The primary treatment for many pediatric patients (pts) with low-grade glioma (LGG) remains surgical resection with curative intent. However, pts whose tumors cannot be completely resected or recur may require additional treatment, eg, radiotherapy or chemotherapy. Pediatric pts with BRAF V600–mutant LGG may benefit from treatment with the BRAF inhibitor dabrafenib. We report 2-y follow-up data from a 2-part phase I/IIa study investigating dabrafenib in pediatric BRAF V600–mutant LGG (NCT01677741). Methods: Part 1 determined the recommended phase 2 dose (RP2D); the Part 2 disease expansion evaluated efficacy and safety of dabrafenib in 4 pediatric tumor–specific cohorts, including LGG. Efficacy for LGG was determined by investigator and independent (IND) review per Response Assessment in Neuro-Oncology [RANO] criteria. Adverse events (AEs) were assessed per NCI-CTCAE version 4.0 criteria. Results: Thirty-two pediatric pts with relapsed, refractory, or progressive BRAF V600–mutant LGG were enrolled (Dec 2013 to Jul 2015). Fifteen pts were treated in Part 1 (n = 7 at RP2D) and 17 in Part 2. RP2D is 4.5 mg/kg/d for pts ≥ 12 y of age and 5.25 mg/kg/d for pts < 12 y of age, each divided into 2 equal doses per day. Common histologies included pilocytic astrocytoma (n = 13; 41%), ganglioglioma (n = 7; 22%), and pleomorphic xanthoastrocytoma (n = 3; 9%). At interim analysis (Sep 2017), median duration of exposure was 25 mo (range, 0.1-42.6 mo), with 15 ongoing. Most frequent reason for discontinuation was elective, following ≥ 1 yr of treatment. Across all dose levels, the confirmed overall response rate (ORR, complete response [CR] + partial response [PR]) per IND review was 44% (95% CI, 26.4%-62.3%), including 1 CR and 13 PR. Eleven pts had stable disease, and 2 had progressive disease as best response. Median PFS by IND review was 35 mo (95% CI, 12.9 mo-NE). Common AEs of all grades, regardless of causality, included pyrexia (72%), vomiting (53%), and headache (47%). Conclusions: Dabrafenib demonstrated clinical activity with tolerability in pediatric pts with relapsed, refractory, or progressive BRAF V600E mutation–positive LGG and supports its further clinical evaluation. Clinical trial information: NCT01677741.
Trabectedin and olaparib in patients with advanced and non-resectable bone and soft-tissue sarcomas (TOMAS): an open-label, phase 1b study from the Italian Sarcoma Group
Authors: Giovanni Grignani, Lorenzo D'Ambrosio, Ymera Pignochino, Emanuela Palmerini, Massimo Zucchetti, Paola Boccone, Sandra Aliberti, Silvia Stacchiotti, Rossella Bertulli, Raimondo Piana, Sara Miano, Francesco Tolomeo, Giulia Chiabotto, Dario Sangiolo, Alberto Pisacane, Angelo Paolo Dei Tos, Luca Novara, Alice Bartolini, Emanuela Marchesi, Maurizio D'Incalci, Alberto Bardelli, Piero Picci, Stefano Ferrari, Massimo Aglietta
Journal: The Lancet Oncology (2018)
Various fashions of laparoscopic resection for gastrointestinal stromal tumors in esophagogastric junction.
Authors: Wenjun Xiong, Wei Wang, Jin Wan
Journal: Journal of Clinical Oncology (2017)

e22512 Background: Laparoscopic surgery for small (&lt;5 cm) gastric gastrointestinal stromal tumors (GIST) is now widely performed. However, laparoscopic resection of GIST in esophagogastric junction is technically difficult. Herein, we introduce various fashion of laparoscopic resection for small GIST in esophagogastric junction. Methods: Retrospective review of 40 consecutive patients with small GIST in esophagogastric junction who underwent attempted laparoscopic surgery. GIST in esophagogastric junction was defined as that the distance of the upper border of GIST from esophagogastric line was less than 2 cm. Three fashions of laparoscopic resection were performed: fashion A, laparoscopic wedge resection using linear stapler; fashion B, laparoscopic complete resection by opening the stomach wall and the stomach wall incision was closed with suture; fashion C, laparoscopic proximal gastrectomy with pyloroplasty. The data of clinicopathologic characteristics, operative course and short-term outcomes were analyzed. Results: All procedures were finished successfully and no operative relatively complication was recorded. Tumor in 24/40 (60%) patients was located in greater curvature. 70.1% (17/24) of them received fashion A and others (7/24) underwent fashion B. Tumor in 16/40 (40%) patients was located in lesser curvature. 18.8% (3/16) of them underwent fashion C and others (13/16) underwent fashion B. The mean operative time was 97.4±21.3 min and the mean estimated blood loss was 20.5±10.4 ml. The mean first time of flatus was 39.2±10.0 hours and the time of fluid intake was 40.1±11.7 hours. The mean hospital stay was 4.2±1.3 days. The mean diameter of tumor was 2.7±1.0 cm. Conclusions: Laparoscopic surgery for small GIST in esophagogastric junction is safe and feasible. The selection of various laparoscopic resection fashions was according to the tumor location.
Association of paclitaxel to lipid nanoparticles in the treatment of bone metastasis in patients with solid tumors.
Authors: Silvia Regina Graziani, Carolina Graziani Vital, Aleksandra Tiemi Morikawa, Hezio Jadir Fernandes, Fauzia de Fátima Naime, Ricardo Oliveira Da Fonseca, Carla Andressa Rodrigues Dias, Ligia Rabello De Almeida, Raphael Francisco Azuaga Neto, Karina Emi Yamada, Maria Stella Sa Granja De Abreu, Tatiana Caldeira Pontes, Thiago D'Alvia, Rafael Sanches Ferreira, Arianne Renata Eyzaguirre Velasquez, Valéria Urresti Orias, Fabiano Garcia Vanderlinde, Leandro Maritan de Almeida, Paula Calixto Batistela Diniz, Raul Cavalcante Maranhão
Journal: Journal of Clinical Oncology (2017)

e21631 Background: Bone metastasis occurs in more than 65-90% patients with hormone-dependent solid tumors, as breast and prostate cancer, with slow evolution, being not responsive to standard chemotherapeutic agents, which restricts treatment options. Previously, we have shown that lipid nanoparticles resembling LDL-cholesterol-like are uptake in malignant tissues and capable of delivery anti-cancer drugs, after intravenous injection. The delivery of drug drastically reduced toxicity. The objective of this study was to evaluate the clinical responses to treatment with paclitaxel associated to nanoparticles, laboratory toxicity and pain scale in patients with breast and prostate carcinoma, previously treated with conventional schemes chemotherapy and not eligible for subsequent treatment. Methods: We included six patients with prostate carcinoma, and ten patients with breast carcinoma (age 68 ± 4 and 55 ± 7 years, respectively). All patients had advanced clinical staging IV at diagnosis (TNM-UICC classification). Treatment consisted in the combination of paclitaxel to lipid nanoparticles (dose: 175 mg/m 2 body surface), intravenous, every 21 days, without premedications. Biochemistry determinations were performed before onset and every three weeks during treatment. To assess pain, we used the Verbal Analogue Scale (from zero to 10) and the use of opioids in the treatment period. Results: Total of 64 cycles were performed without clinical or laboratory toxicity. At the beginning of treatment the pain score was 8 (range 6-9), after six weeks it reduced to a mean of 6 (range 4-8) and after 18 weeks reduced to 4 (range 2-8). Six patients required 180 mg/day of morphine, but after 12 weeks the dose was reduced to 60 mg/day. Six patients progressed after three cycles requiring use of potent analgesic. Conclusions: The notable absence of toxicity and significant improvement in pain indicate paclitaxel associated to lipid nanoparticles as a promising option in chemotherapy regimens.
Improved survival in AYAs with NRSTS treated at specialized cancer centers in California.
Authors: Elysia Marie Alvarez, Sheri L. Spunt, Marcio H. Malogolowkin, Qian Li, Theodore Wun, Theresa Keegan
Journal: Journal of Clinical Oncology (2018)

e23551 Background: Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a heterogeneous group of soft tissue tumors whose management benefits from a multidisciplinary therapeutic approach, especially for patients with metastatic or unresectable disease. Published data suggest that cancer treatment at a specialized cancer center (SCC) can mitigate poor outcomes for other cancers. Therefore, we examined the impact of location of treatment, sociodemographic and clinical factors on survival in adolescents and young adults (AYAs) with NRSTS. Methods: We performed a retrospective, population-based analysis of patients (ages 15-39) hospitalized within one year of diagnosis with first primary NRSTS between 2000–2014 using the California Cancer Registry linked with state hospitalization data. Patients were divided into two groups based on receiving all inpatient treatment at a SCC (Children’s Oncology Group and/or National Cancer Institute-designated center) versus part/none. Multivariable Cox proportional hazards regression identified factors associated with overall and sarcoma-specific survival. Kaplan Meier survival analysis was stratified by location of treatment. Results are presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: Of the 1532 AYA patients with NRSTS, 40.4% percent received all their inpatient care at a SCC. Kaplan Meier analysis demonstrated a higher 5-year survival in patients who received all (vs part/none) care at a SCC (60.0% vs 51.8%; p = 0.0002). Multivariable analysis found that having all treatment at a SCC was associated with significantly better overall (HR 0.81, CI 0.68-0.96) and sarcoma-specific (HR 0.73, CI 0.58-0.92) survival. In addition, inferior survival was associated with African American race/ethnicity, nerve sheath tumor, tumor size > 5 cm, non-localized disease, comorbidities and body wall/visceral tumor location (vs extremity). Conclusions: Our findings demonstrate that treatment for NRSTS at a SCC independently predicts better survival in AYAs and confirms other known predictors of outcomes in this patient population. Eliminating barriers to treatment of AYAs with NRSTS at SCCs could improve survival.
Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia
Authors: Elad Jacoby, Bella Bielorai, Abraham Avigdor, Orit Itzhaki, Daphna Hutt, Vered Nussboim, Amilia Meir, Adva Kubi, Michal Levy, Dragoslav Zikich, Li‐at Zeltzer, Karin Brezinger, Jacob Schachter, Arnon Nagler, Michal J. Besser, Amos Toren
Journal: American Journal of Hematology (2018)

Abstract Autologous CD19 chimeric‐antigen receptor (CAR) T cells demonstrated remarkable remission rates in relapsed and refractory acute lymphoblastic leukemia (R/R ALL). Here, we report results from a phase 1b/2 study of in‐house produced CD19 CAR with a CD28 costimulatory domain. Twenty‐one patients with R/R ALL were enrolled, and 20 infused. The median age was 11 years (range, 5‐48). Patients had a median of 4 prior regimens, including blinatumomab in 6 and prior stem–cell transplantation in 10. In total 8 patients had extramedullary (EM) leukemic involvement, and prior to lymphodepletion and CAR 7 had active lesions, a group underrepresented in previous trials. In vivo expansion of CAR T cells was observed in 18 patients. In total 16 patients developed cytokine release syndrome, and 11 patients developed neurotoxicity, with no toxic deaths. All responding patients were referred to an allogeneic hematopoietic stem‐cell transplantation. The remission rate was 90%, including resolution of all refractory EM sites. Four responding patients relapsed, 3 who had a PCR‐MRD positive remission at 28 days following CAR‐T cells and 1 patient 21 months after an MRD‐negative response. The estimated 1‐year event‐free survival and overall survival are 73% and 90%, respectively. Patients with R/R EM ALL may also benefit from CAR‐T cell therapy.
Efficacy of sulbactam-cefoperazone as empirical monotherapy for febrile neutropenic children wıth solid tumors and lymphoma.
Authors: Inci Ilhan, Selma Cakmakci, Neriman Sari
Journal: Journal of Clinical Oncology (2018)

e22516 Background: Febrile neutropenia (FEN) is one of the major causes of morbidity and mortality in patients with cancer. The clinical effectiveness of sulbactam-cefoperazone (SC) was demonstrated in adult FEN patient but there are a few studies in pediatric FEN. With this retrospective study, we aimed to assess the efficacy of SC as emprical monotherapy for FEN in pediatric cancer patients. Methods: Children with neutropenic fever (age≤18years) hospitalized at our center for lymphomas or solid tumors between October 2004 and August 2016 were included in the study. Patients were assigned to receive SC (80 mg/kg/day, every 8 hours), reevaluated at 72 hours and in case of persistent fever, an aminoglycoside and/or a glycopeptide was added . The antibiotic therapy was modified if a resistant pathogen was isolated. Treatment responses was defined as success without modification, overall success or failure. Results: Three hundred and fifty episodes of FEN in 157 patients (F:73, M:84, median age:11.8 years (0.6-18)) were evaluated. The most common diagnosis were osteosarcoma (%35) and Ewing's sarcoma (%30) followed by Non-Hodgkin's lymphoma (%13) and rhabdomyosarcoma (%7). Absolute neutrophil count and duration of neutropenia were 60/mm3 (0–800) and 7 days (3–60). The median time of therapy was 7 days (3-30). Of the 350 episodes, 113 (32%) were during induction therapy, 114 (33%) were during partial remission, 87 (%25) were during the treatment for relapsed disease, and the remaining 36 (10%) were during remission treatment. The origin of fever could not be detected (FUO) in 220 (63%) episodes, microbiologically documented infection (MDI) was present in 81 (23%) episodes, and infection was clinically documented (CDI) in 60 (17%). The success rate without treatment modification was 70% (244) and the failure rate was 30% (106). Overall success rate was 100% as none of the patients died of infection. SC monotherapy failed in 60% of episodes with MDI, 43 % of episodes with CDI. However SC monotherapy was successful in 84% of episodes in which fever of origin could not be detected. Conclusions: Empiric SC monotherapy was found to be effective in FEN episodes with FUO, but episodes with MDI or CDI may need modifcation.
Abstract IA09: Inflammation and immunity in pulmonary premalignancy
Authors: Kostyantyn Krysan, Linh M. Tran, Brandon S. Grimes, Steven M. Dubinett
Journal: Clinical Cancer Research (2018)

Abstract Unleashing the immune response against pulmonary premalignancy could transform therapy and outcomes. We are evaluating the mutational landscape of pulmonary premalignancy and the associated premalignant microenvironment by whole-exome DNA sequencing and immunohistochemistry. Remarkably, we find putative neoepitopes and frequent immune-effector cell infiltration as well as evidence of immune suppression in pulmonary premalignancy. These findings suggest that premalignant-associated antigens are recognized and elicit immune responses at the earliest points of lung adenocarcinoma development. Identification of neoepitopes that can be targeted before the development of invasive lung cancer could eventually shift the approach to disease interception through immunoprevention and treatment of the very earliest phase of the disease. Citation Format: Kostyantyn Krysan, Linh M. Tran, Brandon S. Grimes, Steven M. Dubinett. Inflammation and immunity in pulmonary premalignancy [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA09.