tbuckley/cabot-search huggingface dataset:
Phase II study of panitumumab with irinotecan for patients with <i>KRAS</i> wild-type metastatic colorectal cancer (MCRC) refractory to standard chemotherapy: A GERCOR study.
Authors: B. Chibaudel, C. Tournigand, M. Mabro, M. Bennamoun, P. Artru, S. Nguyen, J. Bachet, N. Aissat, H. Blons, P. Laurent-Puig, A. De Gramont, T. Andre
Journal: Journal of Clinical Oncology (2011)

3573 Background: Panitumumab alone in third-line chemotherapy increased objective response rate (ORR) from 0 to 17% (95% CI 11%-25%) and prolonged progression-free survival (PFS) versus best supportive care in patients (pts) with chemorefractory KRAS wild-type (WT) MCRC (Amado et al, J Clin Oncol 2008). This trial (NCT00655499) was evaluating the combination of panitumumab and irinotecan in the same population. Methods: Main inclusion criteria were: pts with KRAS WT MCRC refractory to standard FOLFOX or XELOX ± bevacizumab and irinotecan alone or FOLFIRI or CAPIRI ± bevacizumab, PS 0-2, age 18-80 years, bilirubin level ≤1.5xULN, no prior therapy with EGFR inhibitors. KRAS status was assessed in each center for inclusion and a central assessment was done for confirmation after inclusion (allelic discrimination on tumor DNA). BRAF, NRAS and PTEN expression were evaluated. Pts received panitumumab (day 1: 6 mg/kg) and irinotecan (day 1: 180 mg/m²) Q2W until disease progression or unacceptable toxicity. Tumor evaluation was performed every 2 months (RECIST 1.0). The primary endpoint was ORR, with an anticipated rate of 30% and an expected CI between 18.2%-41.8%. Results: Sixty-nine pts were included in 12 centers. Seven pts were not eligible (3 with KRAS mutation at central assessment, 1 did not receive irinotecan, 2 received EGFR inhibitor, and 1 for other reason). The ORR was 32.3% (95%CI 20.7-43.9) (CR: N=3, 4.8%, PR: N=17, 27.4%); 22 (35.5%) pts had stable disease, 19 (30.6%) pts had a progressive disease, and 1 (1.6%) was not evaluable (unacceptable skin toxicity). Median PFS was 5.5 months (95%CI: 4.1-8.7). Three (4.8%) pts stopped treatment for limiting toxicity without toxic death. Most frequent grade 3/4 toxicities were: acneiform rash 19.0%, diarrhea 14.3%, and neutropenia 12.7%. There were no infusion reactions. Conclusions: This trial reached its primary endpoint with an ORR of 32.3%. These results suggest that the combination of panitumumab and irinotecan in third-line chemotherapy should be preferred to panitumumab monotherapy in pts with KRAS WT MCRC refractory to standard chemotherapy.
A phase Ib/II study of BBI608 combined with weekly paclitaxel in advanced pancreatic cancer.
Authors: Tanios S. Bekaii-Saab, Sameh Mikhail, Adrian Langleben, Carlos Becerra, Derek J. Jonker, Timothy R. Asmis, Gregory Michael Cote, Christina Sing-Ying Wu, Eunice Lee Kwak, Alexander I. Spira, Fadi S. Braiteh, Stephen Lane Richey, Stephanie Hume, Matthew Hitron, Chiang Li
Journal: Journal of Clinical Oncology (2016)

196 Background: Cancer stemness is thought to be associated with resistance to chemotherapies. BBI608, a first-in-class cancer stemness inhibitor that works through inhibiting the Stat3 pathway, has shown potent synergistic anti-tumor activity with paclitaxel in vivo. In a phase Ib dose escalation study in patients with advanced solid tumors, BBI608 plus weekly paclitaxel was well tolerated and a RP2D of BBI608 480 mg BID was determined. Methods: Patients with heavily pretreated metastatic pancreatic adenocarcinoma were enrolled in a phase Ib/II extension study to assess safety, tolerability, and preliminary anti-cancer activity in patients with this diagnosis. BBI608 was administered orally at a starting dose of 480 mg or 500 mg twice daily along with paclitaxel 80 mg/m 2 IV weekly 3 of every 4 weeks. A sample size of 40 set the bounds of the 90% CI at ±10% to 14%, assuming a DCR of 60% to 80%. Safety and efficacy results for the cohort will be presented as late breaking data. Results: 41 patients were enrolled. Patients had received a median of 2 prior lines of treatment including FOLFIRINOX (71%), gemcitabine/nab-paclitaxel (44%), or both (37%). Overall, prior therapy included gemcitabine in 90%, a thymidylate synthetase inhibitor (eg 5FU, capecitabine) in 81%, platinum in 76%, irinotecan in 73%, and taxane in 44%. Protocol therapy was well tolerated. Related grade 3 AE included diarrhea (N = 2, 4.9%), abdominal pain (N = 2, 4.9%), and nausea (N = 1, 2.4%), and were rapidly reversible. For evaluable patients (N = 31), response rate (PR+CR) was 7% and disease control rate (SD+PR+CR) was 52%. In evaluable taxane-naïve patients (N = 19), response rate was 11%, disease control rate was 63%, and 16% were progression free at 24 weeks. Overall (ITT, N = 41) mPFS was 10 weeks and mOS was 24 weeks. For the taxane-naïve patients (ITT, N = 23) mPFS was 16 weeks and mOS was 30 weeks. Conclusions: BBI608 plus weekly paclitaxel has demonstrated safety, tolerability, and promising activity in patients with refractory, heavily pretreated pancreatic cancer; particularly in taxane-naïve patients. Durable disease control and prolonged overall survival in this pre-treated population are notable. Clinical trial information: NCT01325441.
Does the diagnosing urologist influence choice of initial active treatment versus observation in older men with favorable prostate cancer?
Authors: Karen Elizabeth Hoffman, Jiangong Niu, Yu Shen, Jing Jiang, Jay Bakul Shah, Grace L. Smith, John W. Davis, Jeri Kim, Robert Volk, Deborah A. Kuban, Sharon Hermes Giordano, Benjamin D. Smith
Journal: Journal of Clinical Oncology (2013)

15 Background: Upfront treatment of older men with favorable prostate cancer yields substantial morbidity but does not improve survival. Deferring treatment in favor of observation promises to reduce morbidity without compromising survival, yet few patients select observation. Prior literature focuses on patient factors contributing to active treatment but the influence of the patient’s urologist on treatment choice remains uncertain. Methods: We identified men age 66 and older with favorable prostate cancer (cT1c or cT2; Gleason 6) diagnosed from 2004-2007 in the SEER-Medicare and Texas Cancer Registry-Medicare databases whose catchments include 34% of the United States (US). Diagnosing urologist, practice setting and cancer-directed treatment within 12 month of diagnosis (prostatectomy, radiotherapy, cryotherapy or androgen deprivation) were determined from claims data. Physician characteristics were obtained from the AMA Master File. Fixed effect and random effect hierarchical multivariate models evaluated physician variation and factors associated with observation. Results: 17,468 patients received care from 2,613 urologists. 64% of patients had T1c cancer. 85% received active treatment and 15% had observation. Even among men 80 and older, 67% received active treatment. The diagnosing urologist accounted for 10% of the variance in choice of active treatment versus observation. After adjusting for patient factors, urologists practicing in an office setting (vs. hospital; p&lt;0.001) and not trained in the US (vs. US-trained; p=0.006) were less likely to manage patients with observation. With adjustment for case mix, only 3.5% of urologists demonstrated a higher than average likelihood of managing their patients with observation; 34% of men diagnosed by these urologists were observed. Conclusions: The vast majority of older men, even those over 80, received active treatment for favorable prostate cancer. The diagnosing urologist contributed to variation in the choice of treatment versus observation. Less than 5% of urologists demonstrated higher than average use of observation suggesting widespread bias against observation during the study era.
Adolescent and young adult (AYA) survivors of childhood cancers: A challenge in after completion of therapy (ACT) clinic in resource-constrained country.
Authors: Purna Arun Kurkure, Saroj Prasad Panda, Maya Prasad, Savita Goswami
Journal: Journal of Clinical Oncology (2016)

19 Background: To assess the evaluation of late effects in childhood cancer survivors who have transitioned to AYA age group on longitudinal follow up in After Completion of Therapy (ACT) clinic at Tata Memorial Hospital, Mumbai. Methods: ACT clinic database was analyzed for childhood cancer survivors who have attained age 15-30 yrs at last follow up in the clinic for demographics, grade of late effects &amp;pattern of follow up. Results: Of 1720 childhood cancer Survivors ( &gt; , 2 yrs off therapy &amp; disease free) registered in ACT clinic from Feb 91-Feb15, 976(56.7%) are in AYA group, M.F = 707/269 (2.6:1), Hematolymphoid : Solid tumours = 543/433 (1.3:1), Mumbai based: Non Mumbai = 306/670 (1:2.2).Median age at diagnosis 8 yrs, current median age 20 yrs, median duration of ACT clinic follow up is 6 yrs. At registration 448 (47%) had no late effects. 230(24%) had grade I, 81(8.4%) grade II 195 (20%) had grade III. Only 9(1%) had grade IV late effects which increased to 53 (6%) at last follow up due to recurrence &amp; second neoplasia. Only 29(3%) were at low risk of developing potential late effects. 466(48.5%) were in intermediate risk &amp; 48.5% (466) fell in high risk category requiring at least annual follow up. 72% of survivors registered in ACT clinic from 1991-2001 had stopped follow up as compared to 36% registered in subsequent decade (p &lt; 0.01). Conclusions: AYA survivors of childhood cancers form major (56.7%) group in Long Term Follow up clinic. The increasing incidence of life threatening late effects on longitudinal follow up combined with statistically significant increasing trend of stopping follow up over period of time since ACT registration is alarming &amp; calls for innovative approaches for maintaining good follow up through survivor centric approaches such as use of IT based communication technologies &amp; formation of childhood cancer survivors support groups like Ugam.
Effect of targeting tumor-infiltrating myeloid cells on tumor progression in pancreatic adenocarcinoma.
Authors: Timothy M. Nywening, Brian Belt, Brian M Cusworth, Roheena Z. Panni, Dominic E. Sanford, Peter S. Goedegebuure, David Linehan
Journal: Journal of Clinical Oncology (2015)

298 Background: Human pancreas cancer (PC) is associated with a heavy desmoplastic reaction and influx of bone marrow derived myeloid cells. Recruitment of these cells by the tumor allows for PC to create a favorable microenvironment that is immunosuppressive. Our work demonstrates that the most abundant type of myeloid cell in PC is granulocytes, which are positive for the chemokine receptor CXCR2. This receptor is vital for the trafficking of granulocytes from the peripheral blood to the tumor, therefore selective targeting of these cells via CXCR2 blockade may lead to potential clinical benefit in patients with PC. Methods: Human samples were obtained under IRB approved protocol at Washington University.C57BL/6 mice were injected subcutaneously or orthotopically with syngeneic PC (KCKO) cells and treated with vehicle or inhibitor daily. Tumor size was determined by caliper measurements and weight. Flow cytometry was performed and samples analyzed for myeloid markers. Results: Human PC patients have elevated levels of CXCR2+ granulocytes in the peripheral blood (p=0.02) and tumor microenvironment (p=0.002) compared to controls. In a murine model, CXCR2 inhibition reduces tumor infiltrating granulocytes (p=0.02) which was associated with a reduction in tumor growth in both a subcutaneous and orthotopic model (p=0.03). Our group has previously demonstrated that targeting the monocytic subset of myeloid cells in PC is an effective treatment strategy (p=0.02). Surprisingly, neither antagonist alone was effective at significantly decreasing the total tumor myeloid infiltrate and treatment with CCR2 inhibitor alone increased tumor infiltrating granulocytes (p=0.03). However, both therapies in combination resulted in a significant reduction in total tumor myeloid infiltrate (p&lt;0.05) and was synergistic in regards to tumor reduction compared to either therapy alone (p&lt;0.05). Conclusions: Human PC has an abundant CXCR2+ granulocytic infiltrate and blockade of CXCR2 may translate to potential clinically useful therapies.
FLT3-ITD Signaling Induces Oncogenic Mir-155 by NF-κB and STAT5 Pathways In Acute Myeloid Leukemia Thereby Targeting Transcription Factor PU.1,
Authors: Dennis Gerloff, Daniela Braeuer-Hartmann, Christiane Katzerke, Jens-Uwe Hartmann, Carsten Mueller-Tidow, Daniel G. Tenen, Dietger Niederwieser, Gerhard Behre
Journal: Blood (2011)
Regulation of STAT3 activity by DARPP-32 in gastric cancer.
Authors: Zheng Chen, Shoumin Zhu, Mohammed Soutto, Jun Hong, Abbes Belkhiri, Alexander Zaika, Wael El-Rifai
Journal: Journal of Clinical Oncology (2014)

47 Background: Dopamine and cAMP regulated phosphoprotein MW 32 kDa (DARPP-32) and its truncated form (t-DARPP) are overexpressed in two-thirds of gastric adenocarcinomas. STAT3 is a member of STAT family. It mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. It has anti-apoptotic as well as proliferative effects. The relationship and interaction between DARPP-32 and STAT3 remain unknown. Methods: DARPP-32 was stable or transient overexpressed in gastric cancer cell lines. STAT3 expression and transcriptional activity were investigated by immunofluorescence and STAT3 luciferase reporter assay. DARPP-32 mRNA level was detected in 63 gastric cancer samples. Results: Using stable and transient expression of DARPP-32 and t-DARPP in AGS gastric cancer cell line, lacking endogenous DARPP-32, led to a significant increase of the phosphorylation of STAT3 as compared to empty vector control. Consistent with these findings, immunofluorescence assay also showed the up-regulation of nuclear p-STAT3 in AGS cells following transient expression of DARPP-32, as compared to empty vector control. Using the STAT3 luciferase reporter assay, AGS cells with stable overexpression of DARPP-32 showed higher luciferase activity than empty vector stable cells with and without IL-6 stimulate (p&lt;0.01). Using qPCR in 63 gastric cancers, we found that DARPP-32 is frequently overexpressed in gastric cancer samples (p=0.018). We have also shown that DARPP-32 has a progressive increase in expression from normal to metaplasia, dysplasia, and adenocarcinoma (p&lt;0.001). The relationship between DARPP-32 and STAT3 in these tissues will be examined. Conclusions: Our results suggest that DARPP-32 overexpression may participate in regulating the STAT3 phosphorylation and activating STAT3 signaling pathway in gastric cancer. The precise signaling mechanisms that mediate this activation and its functional impact on gastric tumorigenesis are under investigation.
A phase II trial design with direct assignment option for initial marker validation.
Authors: Sumithra J. Mandrekar, Ming-Wen An, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2012)

34 Background: Phase II clinical trials aim to identify promising experimental regimens for further testing in phase III trials. Testing targeted therapies with predictive biomarkers mandates efficient trial designs. Current biomarker-based trial designs, including the enrichment, all-comers, and adaptive designs, randomize patients to receive treatment or not throughout the entire duration of the trial. Recognizing the need for randomization yet acknowledging the possibility of promising but nonconclusive results after a preplanned interim analysis (IA), we propose a two-stage phase II design that allows for the possibility of direct assignment (i.e., stop randomization and assign all patients to the experimental arm in stage II) based on IA results. Methods: Using simulations, we compared properties of the direct assignment option design to a 1:1 randomized phase II design and assessed the impact of the timing of IA (after 33%, 50%, or 67% of accrual) and number of IA (one versus two with option for direct assignment at the first and second) over a range of response rate ratios (between 1.0 and 3.0). Results: Between 12% and 30% of the trials (out of 6,000 simulated trials) adopt direct assignment in stage II, with direct adoption depending on the treatment effect size and specified type I error rate (TIER). The direct assignment option design has minimal loss in power (&lt;1.8%) and minimal increase in T1ER (&lt;2.1%) compared to a 1:1 randomized design. The maximum loss in power across possible timings of IA was &lt;1.2%. For the direct assignment option design, there was a 20%-50% increase in the number of patients treated on the experimental (vs. control) arm for the 1 IA case, and 40%-100% increase for the 2 IA case. Conclusions: Testing predictive biomarkers in clinical trials requires new design strategies. In the spectrum of phase II designs from adaptive to balanced randomized all-comers or enrichment designs, the direct assignment design provides a middle ground with desirable statistical properties that may appeal to both clinicians and patients.
Correlation of <i>KRAS </i>mutational state with the expression of the hedgehog pathway in patients with pancreatic ductal adenocarcinoma.
Authors: Matteo Santoni, Alessandro Bittoni, Kalliopi Andrikou, Andrea Lanese, Cristian Loretelli, Alessandro Conti, Marco d'Arenzo, Alessandra Mandolesi, Italo Bearzi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2014)

227 Background: Pancreatic ductal adenocarcinoma (PDAC) is commonly associated with mutations in the KRAS gene. However, how KRAS mutations promote pancreatic carcinogenesis has not been fully established. Here we examine the association between KRAS mutational state and the expression of different tumor markers in PDAC samples. Methods: Immunohistochemical analysis was performed on PDAC specimens to identify the levels of expression of 28 surface and nuclear proteins: BRCA1, BRCA2, NOTCH1, SPARC, SHH, DHH, IHH, SMO, PTCH1, PTCH2, ALCAM, OCT3.4, PROM1, CD44, CD24, LGR5, BMP4, KDR, FLT1, PDGFRB, VEGFA, VEGFB, PGF, CDKN2A, SMAD4, MET, HGF, MUC6. All samples were also tested for identification of KRAS isoforms (wild type (WT) vs mutated type (MT)) expression by means of RT-PCR. Levels of mRNA expression were matched with a common standard tissue marker. Expression levels of PDAC markers were compared between MT and WT KRAS groups. Differences between groups were tested using Mann-Whitney U test for unpaired samples. Exploratory univariate logistic regression was also performed to evaluate possible correlations between increasing levels of each marker and KRAS mutational state. Results: 110 samples were collected. Of them, data on KRAS were provided for 86 samples; 40 and 46 samples expressed the WT and MT KRAS isofo rms, respectively. Preliminary analysis showed that the expression of SHH and IHH resulted significantly higher in KRAS MT samples (U=1097 p= 0.013 and U=1072 p= 0.028 respectively), whereas higher levels of SMAD4 (U=634, p= 0.012) and HGF (U= 655, p= 0.03) were expressed in the KRAS WT group. A weak difference between groups was found for the MUC6 pathway (U= 666, p= 0.056). No differences of VEGFA, VEGFB and VEGFRB expression were found between MT and WT groups. At univariate logistic regression we found that increased levels of SHH correlated with the expression of KRAS MT phenotype (OR 57.5, p= 0.011), while IHH showed only a weaker significance level (OR 13.1, p= 0.069). Conclusions: These results indicate that oncogenic KRAS is directly associated with SHH expression in PDAC tissues. They also mark Hedgehog pathway components as relevant therapeutic targets for KRAS-mutant patients.
Predictors of early response and event-free survival in Hodgkin lymphoma (HL): PET versus CT imaging.
Authors: C. L. Schwartz, D. L. Friedman, K. McCarten, S. L. Wolden, S. Voss, L. S. Constine, L. Chen
Journal: Journal of Clinical Oncology (2011)

8006 Background: Early PET imaging has emerged as a predictor of EFS in HL, but comparisons of early response assessment by PET vs. CT are limited. Children’s Oncology Group (COG) study AHOD0031 was designed to evaluate the paradigm of early-response-based treatment intensity. PET and CT scans were obtained after 2 cycles of ABVE-PC, allowing direct comparison of imaging modalities. We examined predictors of early response to 2 ABVE-PC as defined by CT scan and by PET. We also evaluated the 2-cycle CT and PET as predictors of EFS. Methods: Patients (< age 21) had intermediate risk HL (excluding non-bulky IA/IIA, IIIB/IVB). Rapid early response (RER) by CT was defined as >60% 2-dimensional tumor reduction. RER by PET was defined as a negative (vs. equivocal/positive) scan. Predictors of RER and EFS were derived from clinical and pathologic factors available in the COG database. Continuous variables were made categorical based on quartiles associated with abnormal values. Results: 1,136 patients with CT-based assessment of early response who had protocol-mandated, concurrent PET were included in an analysis of predictors of early response. 770 of these patients were assigned to treatment with 4 ABVE-PC/21Gy involved field radiation and included in the analysis of predictors of EFS. Multivariable predictors of RER by CT after 2 ABVE-PC included a large mediastinal mass (OR 0.41), NS (OR 0.45), age<13 (OR 1.48), and stage I (OR 2.31). Multivariable predictors of RER by PET included large mediastinal mass (OR 0.78), ESR<20 (OR 1.37), and albumen <3.5 (OR 1.36). A Cox regression including both early CT and PET found them to be independent predictors of EFS. CT was predictive (HR=0.49, p=0.01); PET was of borderline significance(HR=0.69 , p=0.10). Stage 4 (HR 2.41, p=0.0014) and B symptoms (HR=2.05, p=0.008) were strong predictors. Conclusions: Predictors of CT (anatomical) response differ from predictors of PET (functional) response. Each modality may thus represent different aspects of the biology of response and perhaps should inform the decision re: therapeutic intensity. As a predictor of EFS, RER based on the 2-cycle CT was more significant than RER defined by 2-cycle PET scans.