tbuckley/cabot-search huggingface dataset:
Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with squamous cell carcinoma of the head and neck.
Authors: Khalil Saleh, Amaury Daste, Nicolas Martin, Elvire Pons-Tostivint, Anne Auperin, Ruth Gabriela Herrera-Gómez, Neus Baste, François Bidault, Joel Guigay, Christophe Le Tourneau, Esma Saada, Caroline Even
Journal: Journal of Clinical Oncology (2018)

6015 Background: Immune checkpoint inhibitors (ICI) have shown efficacy in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) with an overall response rate (ORR) ranging from 13 to 17%. Recent data suggest that exposure to ICI potentially improves ORR to salvage chemotherapy (SCT) in advanced non-small cell lung carcinoma. We evaluated responses to chemotherapy in R/M SCCHN patients after progression on ICI. Methods: A retrospective study was conducted at 4 French referral centers. Eligibility criteria were patients treated with ICI for R/M SCCHN, who progressed after treatment with ICI (primary or secondary resistant to ICI) and received SCT between September 2014 and January 2018 and for whom efficacy data were available. Clinical and radiological data were collected from review of medical records. Results: Of 232 patients treated with ICI (anti-PD-1, anti-PD-L1, anti-CTLA-4 and anti-KIR), 82 met eligibility criteria: 84% were male, median age was 60 years old. ICI was given as monotherapy in 45% of patients or as combination in 55%. SCT included taxane-based regimen (56%), platinum-based regimen (37%), and methotrexate (7%). Cetuximab was administered in combination with taxanes or platinum in 50% of patients. The median number of treatment lines prior to SCT was 2 (range 1-6). The ORR to SCT was 30% (95% confidence interval: 21%-40%). Three patients (4%) presented complete response and 22 patients (27%) had partial response. The disease control rate was 57%. The age at initiation of SCT, initial tumor location, number of prior chemotherapy regimens, type of chemotherapy prior to ICI, best response to ICI, site of relapse and ECOG at SCT were not significantly associated with response to SCT on univariate analysis. Conclusions: In R/M SCCHN pretreated with ICI, the ORR to SCT was 30% higher than figures of historical cohorts in this setting. This suggests that exposure to ICI may increase tumor sensitivity to chemotherapy. Further investigations are warranted.
Determination of the effect of target site density on the efficacy of CD22 chimeric antigen receptor t-cell therapy to treat acute lymphoblastic leukemia.
Authors: Sang Nguyen, Robbie G. Majzner, Christopher Chien, Haiying Qin, Terry Fry
Journal: Journal of Clinical Oncology (2016)

10536 Background: Across multiple phase I trials using CD19 chimeric antigen receptors (CARs), pediatric acute lymphoblastic leukemia patients have achieved remarkable complete response rates of 70-90%. However, up to 20% will relapse with leukemia lacking the CD19 target. To address this issue, CAR-T therapy targeting CD22 has been created. In 2014, a phase I clinical trial testing the CD22 CAR was initiated (NCI-15-C-0029). From preliminary data, we identified one patient achieving complete remission who relapsed with ALL retaining CD22 expression, but at a lower site density than prior to CAR treatment. Also, a CD22 site density analysis of 110 individual patient samples of BCP-ALL shows that 25% of these patients have less than 2000 copies per ALL blast. Therefore, we are interested in studying how low antigen density affects the efficacy of CD22 CAR-T treatment. Methods: In order to develop a pre-clinical model ALL with varying levels of CD22 expression, we used CRISPR/Cas9 editing to knock out endogenous CD22 in NALM6 cell line, and then lentivirally transduced, at different multiplicities of infection, full length human CD22. We tested a second-generation construct of CD22 CAR-T (scFv-41BB-CD3ζ) against these cell lines and patient-derived xenografts from post-CD19 CAR-T and pre/post-CD22 CAR-T treatments at different time points. Results: At 24 hours, CD22 CAR-T response against patient samples and NALM6 cell lines showed that induction of IL2, IFN-γ, granzyme B and perforin correlated with site density by a sigmoid curve. Also, IL2 and IFN-γ induction were more sensitive predictors of CD22 CAR-T efficacy than granzyme B and perforin induction. Conclusions: According to our preliminary results, the correlation between CD22 site density and CAR-T efficacy showed a sigmoid curve with low site density generating low to no response and high density generating a high to saturated response. Moving forward, we will incorporate different costimulatory domains into the construct to optimize CD22 CAR-T and study the CAR biology at low target site density.
Final results of a phase II of metformin plus irinotecan for refractory colorectal cancer.
Authors: Arinilda Bragagnoli, Rapahel Araujo, Kathia Abdalla, Fabiana Comar, Florinda Santos, Mauricio Ferraz, Lucas Vieira dos Santos, Jose Carvalheira, Joao PsDN Lima
Journal: Journal of Clinical Oncology (2018)

e15527 Background: Metformin (Met) may exert anticancer effects through activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling. Our preclinical studies have shown synergistic activity of Met when combined to irinotecan (Iri) in colorectal models. The current study (MetIri) assessed this hypothesis. Methods: MetIri (NCT01930864) is a two stage trial of Iri 125 mg/m2 IV on D1 and D8 Q3W + Met PO daily (escalating up to 2500 mg/day) for ECOG 0-1 patients with RECIST 1.1 measurable metastatic colorectal cancer (mCRC) who had previously progressed on fluropyrimidine, oxaliplatin, irinotecan, and anti-EGFR antibody (if KRAS wild type). We judged that Met+Iri could increase disease control rate at week 12 (DCR12) from historical 25% to 45%. With a beta of 80% and alpha of 5%, 5 patients out 17 with DCR12 would permit progress to stage 2 and the study would be positive if 14 out 41 had DCR12. Secondary endpoints were safety, progression-free (PFS) and overall survival (OS). Results: From Sep 2015 to Jan 2018, 40 patients were enrolled, 38 treated. Median age was 56 years (range 22-76), 42% were female, 70% ECOG 1, median body mass index was 27.10 (range 17.10-40.40), 60% harbored KRAS mutated mCRC. All KRAs wild-type patients had used anti-EGFR. Median number of previous therapy lines was 3, including oxaliplatn, fluoropyrimidine and Iri. On Jan 2018, 37 patients had follow up > 12 weeks. A total of 21 patients reached DCR at week 12 (57%; 95% CI 40%-73%), all with stable disease, rendering the study positive. Median PFS was 12.6 weeks and OS was 39 weeks. Met dose was reduced in 7 (18%) and not escalated in 8 (21%) patients with a average dose density of 1770 mg/day. Ten patients had any grade 3 toxicity, 1 grade 4 (neutropenic fever), and none grade 5. The commonest grade 3 event was diarrhea (21%) in spite of prophylactic therapy and vomit > G1 wasG2 or higher ocurred in 18%. Conclusions: The combination of metformin and irinotecan in this heavily pre-treated mCRC population seems safe and promising enough to merit further evaluation in randomized trials. Clinical trial information: NCT01930864.
Hyperpolarized C-13 pyuvate metabolic MR imaging of solid tumor liver metastases as a biomarker of PI3K/mTOR pathway activity.
Authors: Rahul Raj Aggarwal, Zihan Zhu, Michael Ohliger, Jeremy Gordon, Robert A. Bok, Jim Slater, John V. Kurhanewicz, Emily Boyd, Susan Calabrese, Christopher E. Sotto, Daniel B. Vigneron, Pamela N. Munster
Journal: Journal of Clinical Oncology (2018)

e24168 Background: The PI3K/mTOR pathway is a relevant therapeutic target yet real-time monitoring of pathway inhibition is challenging. Metabolic MR imaging using hyperpolarized 13C-pyruvate provides real-time assessment of pyruvate-to-lactate conversion, a process enhanced by PI3K/mTOR overactivation. We performed first-ever hyperpolarized 13C pyruvate MR imaging to detect solid tumor liver metastases and monitor drug treatment response using inhibitors of the PI3K/mTOR pathway. Methods: Patients (pts) with advanced cancer and at least one liver metastasis measuring ≥ 1 cm in long axis diameter were enrolled. 1.47g of [1-13C]pyruvic acid was hyperpolarized within the GE SPINlab system (5T, 0.77 K), and 0.43 ml/kg of the dissolved sterile pyruvate solution (250 mM) was injected IV immediately following dissolution. MR studies were performed using a whole-body 3T scanner. A custom 13C figure-8 coil was built for carbon signal acquisition. The HP lactate-to-pyruvate ratio and metabolic conversion rate from pyruvate to lactate within tumor and adjacent liver tissue was measured. Results: A total of 12 pts with liver metastases were enrolled (median age = 56; breast cancer, n = 4; prostate, n = 2; endometrial, n = 2; other, n = 4). The average liver metastasis diameter was 4.1 cm in long axis. High signal-to-noise for HP 13-C pyruvate (up to 241) and lactate (up to 39) was observed in the tumor voxels compared to normal liver. Dynamic time course shows mean tumor peak lactate signal = 29.6 seconds after the start of injection. A patient with colorectal cancer treated with PI3K inhibitor alpelisib demonstrated a decrease in the tumor lactate/pyruvate ratio from 0.13 to 0.08 in the target liver lesion, nearly a 40% reduction in metabolic activity, on post vs. pre treatment HP C-13 pyruvate MRI. Conclusions: Hyperpolarized C-13 pyruvate MRI of liver metastases is feasible. High lactate-to-pyruvate ratios and lower alanine levels were observed within tumors compared to adjacent tissue and was decreased in response to PI3K inhibition. Real time assessment of down-regulation of pyruvate-to-lactate flux may be a novel method to monitor pharmacologic blockade of the PI3K/mTOR pathway. Clinical trial information: NCT02913131.
Ibrutinib: A post-marketing safety analysis.
Authors: Rawad Elias, Anita Pudusseri, Oladimeji Akinboro, Paul S. White, Shayna Sarosiek
Journal: Journal of Clinical Oncology (2018)

e19559 Background: Patients taking ibrutinib are at increased risk of bleeding and atrial fibrillation / flutter (AFF). Data regarding safety of ibrutinib is mostly based on information from clinical trials. We aimed through this analysis to evaluate the real-life toxicity of ibrutinib. Methods: We reviewed data from FDA Adverse Event Reporting System (FAERS) for adverse events (AEs) associated with the use of ibrutinib between January 2010 and November 2017. We restricted our analysis to patients aged ≥ 18 years (y) and to reports that included only ibrutinib as an agent suspected as the cause of the AE. We performed a descriptive analysis of hospitalization and death outcomes, as well as select adverse events including bleeding and atrial fibrillation/flutter (AFF). We examined the associations between clinicodemographic variables, such as age and bleeding, and primary outcome variables with Chi-square tests of homogeneity. Results: A total of 11,801 FAERS safety reports were included in this analysis after exclusion of 2,426. Rates of hospitalization and death were 4,831 (41%) and 1,751 (15%) respectively. No significant difference in hospitalization (p = 0.389) or death (p = 0.072) rates were seen across age groups. A bleeding event was reported in 1,344 (11%). AFF was reported in 553 (5%). A minimal but statistically significant increased prevalence of bleeding (p = 0.004) and AFF (p = 0.031) was seen in older patients. Higher rate of hospitalization was noted in patients with AFF (p < 0.001). Bleeding was associated with higher prevalence of hospitalization in older adults (p = 0.047) but not in the general population (p = 0.144). An increased rate of death was seen in patients with bleeding (p < 0.001) or AFF (p = 0.002) who required hospitalization. Conclusions: Our analysis suggests that among patients with ibrutinib-related toxicity, older adults had an increased prevalence of bleeding and a higher rate of hospitalization secondary to a bleeding event. Although AFF was observed at a higher prevalence in older patients, it was not associated with an increased hospitalization prevalence. Clinicians prescribing ibrutinib should be diligent in monitoring patients, especially those aged ≥ 65 years, and decreasing the risk of treatment-related adverse events.
Prevalence of homologous recombination deficiency (HRD) mutations in localized prostate cancer according to Gleason grade: Implications for neoadjuvant clinical trial design.
Authors: Catherine Handy, Alexander S Baras, Tamara L. Lotan, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2018)

5062 Background: Approximately 5-10% of men with localized prostate cancer have homologous recombination deficiency (HRD) mutations, yet it is unknown if these vary by Gleason score. In order to help design neoadjuvant trials for the HRD+ population and to minimize the number-needed-to-screen, we sought to determine if the prevalence of HRD mutations is influenced by Gleason grade. Methods: 484 localized prostate adenocarcinoma cases with somatic DNA sequencing data and Gleason grade information were interrogated using The Cancer Genome Atlas (TCGA) repository. HRD mutations were defined as pathogenic lesions in the following genes: ATM, BRCA1/2, CDK12, CHEK1/2, FANCA, FANCD2, FANCL, GEN1, NBN, PALB2, RAD51 and RAD51C. A separate analysis was also conducted restricting the gene list to BRCA1/2 and ATM, since deficiencies in these genes have the strongest association with PARP-inhibitor response. R software was used for analyses. Results: The prevalence of (any) HRD mutation was 11.6%, 10.8%, 14%, 16.8% and 25.0% for Gleason sums 6, 7, 8, 9 and 10, respectively. When analyzed using Grade Groups, the prevalence of (any) HRD mutation was 11.6%, 6%, 17.8%, 14% and 17% for Grade Groups 1, 2, 3, 4 and 5, respectively (Table). Those in Grade Group 3 and greater had 2.5 times higher odds of harboring at least one HRD mutation compared to those in Grade Groups 1 and 2 (16.8% vs 7.3%,P= 0.002). When specifically considering only BRCA1/2 or ATM lesions, the mutation prevalence was 6.1 times higher in Grade Group 3 and above compared to Grade Groups 1 and 2 (8.9% vs 1.6%, P= 0.0006) (Table). Conclusions: HRD mutations in general, and BRCA1/2/ATM mutations specifically, are enriched in localized prostate cancers with Gleason Grade Group 3 and higher (i.e. primary pattern 4 and higher). We propose that these patients could be targeted for neoadjuvant (or adjuvant) clinical trials using PARP inhibitors in HRD+ populations. HRD mutation prevalence by gleason grade group. Grade Group At least 1 HRD mutation At least 1 BRCA1/2/ATM mutation N Total N Total 1 11.6 % 5 43 2.3% 1 43 2 6.0 % 9 149 1.3% 2 149 3 17.8 % 18 101 10.9% 11 101 4 14.0 % 7 50 8.0% 4 50 5 17.0 % 24 141 7.8% 11 141
First in human phase I study of chlorogenic acid injection in recurrent high grade glioma.
Authors: Wenbin Li, Ming Ji, Nina Xue, Zhuang Kang, Xun Kang, Shan Li, Xiaoguang Chen
Journal: Journal of Clinical Oncology (2018)

e14081 Background: Chlorogenic acid (CHA) is a natural product with good antitumor activity in preclinical study. A phase I clinical trial of CHA injection was conducted to determine tolerance, safety, pharmacokinetics in patients with recurrent high grade glioma. Methods: Patients received CHA injection intramuscularly once daily for 30 days of each cycle following continuous treatment extension based on clinical evaluation. A standard 3+3 design was used for dose-escalation. The primary endpoints were to evaluate the tolerance and safety of CHA, determine the maximum-tolerate dose (MTD) and dose-limiting toxicity (DLT). The secondary endpoints included:pharmacokinetics, preliminary antitumor efficacy and potential biomarkers. Results: Twenty-six patients were enrolled at five doses: 2mg/kg (3), 3mg/kg (9), 4mg/kg (9), 5.5mg/kg (3) and 7mg/kg (2). Two patients were discontinued during treatment due to muscle-related injection induration and one patient was discontinued due to compliance. Among 26 patients for DLT evaluation, two DLTs were observed muscle-related injection induration. The MTD was determined as 5.5mg/kg. Common adverse events included thrombocytopenia (3.84%), pain in flank, shoulder and arms (each 3.84%), and muscle-related injection induration (92.3%). The maximum plasma concentration of CHA was increased after administration at all doses . The elimination half-life ranged from 1.12 to 1.27 h on day 1 and from 1.19 to 1.39 h on day 30. The disease control rate of 1 month and 3 months were 52.17% (SD, 12) and 33.33% (SD, 6), respectively. By the end of Feb. 6th, 2018 , the median OS in dose 2mg/kg is 9.6 months, 9.4 months in dose 4mg/kg, 12.2 months in dose 5.5mg/kg. In 3mg/kg dose 7/9 patients are still alive, two of them survival over 18 months since adminstration. In 5.5mg/kg dose 2/3 patients are survival. Among over 13 serum cytokines, IL12p70, IL-28A and IL-27 were identified to predict for both T cell immune response to CHA and clinical outcome. The serum level of sLAG3 is positively correlated with patient prognosis. Conclusions: This study demonstrated that CHA injection in patients with recurrent high grade glioma, at the MTD of 5.5mg/kg, was safety and well tolerated with potential antitumor activity. Clinical trial information: NCT02245204.
Comparing outcomes of renal cell carcinoma diagnostic and treatment intervals within two different hospital systems in a single academic medical center.
Authors: Sung-Hee Choi, Joseph Allen Moore, Xin Luo, Yang Xie, Yull Edwin Arriaga
Journal: Journal of Clinical Oncology (2016)

e16093 Background: Renal cell carcinoma (RCC) diagnostic and treatment delays have been described for several patient populations. Few studies have analyzed these delays among patients treated in contemporary health care systems in the United States (U.S.). We studied the time interval between the diagnosis and treatment of patients with RCC and its association with overall survival at a U.S. medical center providing care to patients at a safety net and private hospital system. Methods: We performed a retrospective analysis of patients diagnosed with all stages of RCC from 2000 to 2013 at a safety net and private hospital affiliated with the University of Texas Southwestern Medical Center. Demographic, clinical and socioeconomic data were obtained from hospital tumor registries. Association between variables were assessed using univariate analysis, multivariate logistic regression, and Kaplan-Meier survival analysis. Results: A total of 2487 patients met criteria for analysis. Seventy-nine percent of patients were treated within 3 months of initial presentation for safety net versus 86% for private hospital. In univariate analyses, diagnosis-treatment interval was significantly associated with age, race, hispanic origin, disease stage at diagnosis, histology, tumor grade, hypertension, body mass index (BMI), tobacco use, insurance type, income, education level and hospital type (55 days for safety net versus 45 days for private, p < .000006). For patients between 35-44 years, median diagnosis-treatment interval was 63 days for safety net versus 37 days for private hospital (p = .024). In multivariate analyses, age, histology, tumor grade, hypertension, tobacco status and hospital type were not significantly associated with the diagnosis-treatment interval. Overall survival was not significantly different between two hospitals (p= .24). Conclusions: Time intervals between diagnosis and treatment of RCC vary widely among different patient populations. Health care system factors, such as hospital type , largely account for these discrepancies. In this study, these intervals do not appear to be associated with clinical outcomes.
Effect of hypertension (HTN) on progression-free survival (PFS) in patients (pts) receiving front-line bevacizumab (BEV) for primary advanced ovarian cancer (OC) in the NOGGO single-arm OTILIA study: A post hoc analysis in 808 pts.
Authors: Robert Armbrust, Pauline Wimberger, Alexander Mustea, Gülten Oskay-Özcelik, Maren Keller, Rolf Richter, Johanna Harde, Max Zortel, Andrea Wegenaer, Oliver Tome, Jalid Sehouli
Journal: Journal of Clinical Oncology (2018)

5546 Background: The efficacy and safety of front-line BEV-containing therapy for OC were demonstrated in two phase III trials. At the 3rd interim analysis of OTILIA (NCT01697488) evaluating front-line BEV in German clinical practice, median PFS was 21.3 months. The potential association between HTN and PFS was explored in the present analysis. Methods: Pts with newly diagnosed FIGO stage IIIB–IV OC received the EU-approved BEV-containing regimen. In exploratory analyses, outcomes were analyzed according to the presence or not of HTN at baseline (BL). Cox regression models in each subgroup explored the effect on PFS of HTN developing (no HTN subgroup) or worsening (pre-existing HTN subgroup) during treatment in a time-dependent manner. Results: Of 808 evaluable pts, 406 had BL HTN and 402 did not. Pts in the HTN subgroup were generally older (median 71.8 vs 61.8 years in the subgroup without HTN) with a higher BMI (median 25.7 vs 23.1 kg/m2) and more likely to have diabetes (16% vs 5%). Median BEV duration was similar in the two subgroups (13.5 vs 13.3 months, respectively). As of 31 Jan 2017, PFS events had been recorded in 364 pts (45%). Median PFS was 21.3 months in both subgroups. HTN worsened in 291 (72%) of 406 pts with pre-existing HTN and developed in 132 (33%) of 402 pts without BL HTN. Cox regression analysis suggested an association between onset of HTN and PFS in pts without BL HTN (hazard ratio [HR] 0.69, 95% CI 0.50–0.96) but not between worsening of HTN and PFS in those with pre-existing HTN (HR 1.18, 95% CI 0.82–1.70). Residual tumor burden was associated with worse PFS in both subgroups (HR 2.04; 95% CI 1.39–3.00 in pts without BL HTN; HR 2.42, 95% CI 1.56–3.74 in pts with pre-existing HTN). Conclusions: These exploratory analyses suggest no detrimental effect of HTN on PFS in BEV-treated pts. Based on these observations, in pts with HTN and ongoing clinical benefit, it seems reasonable to continue BEV therapy if HTN is managed appropriately. As this was an exploratory interim analysis, the observed more favorable PFS in pts with HTN developing during BEV should be validated in further prospective trials. Clinical trial information: NCT01697488.