tbuckley/cabot-search huggingface dataset:
Safety and pharmacokinetics (PK) of AMG 479 in combination with erlotinib (E) or sorafenib (S) in patients (pts) with advanced solid tumors.
Authors: I. Puzanov, J. Sarantopoulos, J. Gilbert, D. Mahalingam, L. I. Chap, H. Deng, M. Zhu, I. McCaffery, G. R. Friberg, L. S. Rosen
Journal: Journal of Clinical Oncology (2010)

3018 Background: AMG 479, a fully human monoclonal antibody antagonist of IGF1R, showed activity in early clinical trials and additive effects with other therapies in preclinical models. This study examined adverse events (AEs), dose limiting toxicities (DLTs), PK, and WHO tumor response of AMG 479 combined with E, S, panitumumab (P), or gemcitabine (G). P and G results were shown previously (JCO 2008;26 abstr 3583). Methods: Eligible pts had advanced solid tumors, ECOG 0-2, and no hyperglycemia. A sequential 3+3 design was used. Pts received E (150 mg po QD) or S (400 mg po BID) with AMG 479 (6 or 12 mg/kg IV Q2W) until progression. CT scans were done every 8 weeks (wks). Results: A total of 25 pts enrolled and received AMG 479 + E (n = 12) or S (n = 13); median age (range) = 58 (41 to 74); 68% had ≥ 3 prior therapies; 44% were male. Most common emergent AEs are shown (Table). The S arm had no DLTs. There was 1 DLT (grade 4 thrombocytopenia) in the E arm at 12 mg/kg AMG 479. AMG 479 clearance (CL, mL/day/kg) was 10 ± 2.3 with E and 14 ± 5.4 with S, similar to monotherapy (10 ± 3.7). CL (L/h) for S (11 ± 4.8) and E (8.2 ± 5.8) were similar to published values. No anti-AMG 479 antibodies were detected. Partial responses occurred in a breast cancer pt (E cohort, ongoing at 32 wks) and an endometrial cancer pt (S cohort, lasting 39 wks), both with 6 mg/kg AMG 479. Four pts had stable disease > 4 months (HCC and carcinoid in S cohort; NSCLC and carcinoid in E cohort). Conclusions: AMG 479 at 12 mg/kg can be safely combined with full dose E or S and shows anti-tumor activity in combination in some pts with refractory disease. Serum biomarker (IGF-1 and IGF binding protein 3) and tumor-based analyses (PIK3CA and RAS mutation status) will be shown. Most common treatment emergent AEs (>25% incidence) AMG 479 dose Erlotinib (all grades) Erlotinib (grade ≥ 3) Sorafenib (all grades) Sorafenib (grade ≥ 3) 6 mg/kg (n = 3) 12 mg/kg (n = 9) 6 mg/kg (n = 3) 12 mg/kg (n = 9) 6 mg/kg (n = 3) 12 mg/kg (n = 10) 6 mg/kg (n = 3) 12 mg/kg (n = 10) Rash, n (%) 2 (67) 5 (56) 0 0 2 (67) 4 (40) 0 0 Fatigue, n (%) 2 (67) 2 (22) 1 (33) 1 (11) 2 (67) 6 (60) 0 2 (20) Diarrhea, n (%) 2 (67) 2 (22) 0 0 3 (100) 3 (30) 0 2 (20) Nausea, n (%) 0 5 (56) 0 0 2 (67) 1 (10) 0 0 Vomiting, n (%) 2 (67) 2 (22) 0 0 1 (33) 2 (20) 0 1 (10) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen
Comorbidity, age and stage at diagnosis in colorectal cancer (CRC)
Authors: Y. Zafar, A. P. Abernethy, D. H. Abbott, J. E. Herndon, K. Rowe, J. Kolimaga, L. Conner, M. Patwardhan, S. Grambow, D. Provenzale
Journal: Journal of Clinical Oncology (2007)

6554 Background: Stage at diagnosis is a crucial predictor of outcome in CRC. The purpose of this study is to determine if comorbidity and age affect the stage at which CRC is diagnosed. Identifying variables that influence stage might improve outcomes in CRC. Due to frequent contact with the health care system, we hypothesize that patients with greater comorbidity and older age are more likely to be diagnosed with early-stage disease. Methods: We present data from two distinct patient populations: using the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) database, we identified CRC patients treated at 15 Veterans Administration (VA) hospitals from 2003-present. We also identified CRC patients treated from 2003-present at 10 non-VA, fee-for-service (FFS) practices in North and South Carolina. Data were abstracted by retrospective chart review. Comorbidity was calculated by the Charlson comorbidity index (CCI) with high comorbidity defined as CCI =3. Older age was defined as age =70 years. Data were analyzed using logistic regression where the odds of late stage at diagnosis were modeled as influenced by older age, high CCI, and race. The analysis included estimation of adjusted and unadjusted odds ratios. Results: 347 VA and 282 FFS patients were included. 98% VA vs 50% FFS were male; 43% VA vs 27% FFS were aged =70; 56% VA vs 70% FFS were white; 26% VA vs 44% FFS presented with metastatic CRC; and 21% VA vs 6% FFS had a CCI =3. In both patient populations, regression analysis showed that older age, high CCI and white race were not significant predictors of stage at diagnosis. VA 95% confidence intervals (CI's) were 0.52–1.41 (age =70), 0.50–1.75 (CCI =3), and 0.42–1.11 (white race). FFS 95% CI's were 0.52–1.53 (age =70), 0.36–2.78 (CCI =3), and 0.74–2.11 (white race). Broader 95% CI's in the FFS analysis were due to smaller sample size. Conclusions: In CRC patients, age and comorbidity were not related to stage at diagnosis. The findings are similar whether the patients were treated in a fee-for-service or VA health system. While older age and greater illness might provide more contact with the health care system, this exposure did not result in earlier diagnosis of CRC. Future studies will examine the impact of comorbidity on CRC treatment and survival. No significant financial relationships to disclose.
Soluble iC3b as an early marker for pancreatic adenocarcinoma compared to CA 19.9 and radiology
Authors: A. Marten, M. W. Büchler, M. N. Wente, J. Schmidt
Journal: Journal of Clinical Oncology (2009)

4626 Background: Pancreatic adenocarcinoma as an aggressive tumor still lacks specific markers. Resection offers the only potential cure, and earlier diagnosis could benefit many patients. Here, we analyzed siC3b as a potential diagnostic marker.siC3b is generated in the fluid phase after binding of auto-antibodies to tumor cells and subsequent inactivation of the complement cascade by interaction with complement regulatory proteins. Methods: 232 plasma samples from subjects with adjuvant treatment after resection, from healthy volunteers and from vulnerable patients were collected prospectively and analyzed for siC3b. Every three months, patients underwent imaging and the results from siC3b ELISA were categorized according to radiological-defined recurrence within four months after blood withdrawal. Furthermore, regulatory factors of the complement system were analyzed on tumor cells and in urine. Results: The most important finding was that up to four months prior to radiological defined recurrence, siC3b plasma level is increased with a sensitivity and specificity resulting in an AUC of 0.85 which could be further increased by combining it with CA 19.9 (AUC = 0.92). Complement regulatory proteins are highly expressed on pancreatic carcinoma cells and detectable in patient's urine. Conclusions: In summary, screening for siC3b in subjects with an increased risk for PDAC (patients with chronic pancreatitis, hereditary pancreatitis, after curative resection and patients with a variety of familial cancer syndromes) allows for early detection with high sensitivity, as siC3b plasma levels are increased up to four months prior to radiological evidence. Sensitivity could be further increased by combining this approach with CA 19.9. No significant financial relationships to disclose.
Actions of a novel therapeutic formulation: Zn, Se and Mn plus <i>Lachesis Muta</i> venom (O-LM) on radiation deleterious immune effects
Authors: E. Rivera, G. Cremaschi, A. M. Genaro, M. Croci, L. Sambuco, G. Cricco, G. Martin, R. Bergoc, E. Crescenti
Journal: Journal of Clinical Oncology (2007)

14116 Background: We have previously reported that O-LM inhibits malignant cell proliferation and increases survival in rodent tumor models (Int J Cancer S13:183, 2002). Molecular and immunological basis of O-LM action were reported (J Clin Oncol 24:18S, 2006). As O- LM selectively protects normal tissues from high doses of ionizing radiation (Proc Int Cancer Congress,1495–9, 1998), we here investigated O- LM protective action upon radiation effects on immune cells. Methods: Balb/c mice (n=15 each group) were employed: control (C); 2Gy whole body irradiated (IR); treated with O-LM (Zn, Se, Mn 4μg/ml each; L. Muta 4 ng/ml; 0.1 ml/day, sc) for 15 days and 2Gy irradiated (O-LM+IR). Mice were sacrificed at day 3, 7 or 15 post-irradiation (PI). Proliferation was evaluated in lymphocytes by [ 3 H]- Thymidine incorporation after T- or B selective mitogen stimulation. In cell-free supernatants (SN) from mitogen-stimulated cultures cytokines involved in lymphocyte regulation and/or inflammation were determined by ELISA. Results: Irradiation induced a decrease in T lymphocyte proliferation at 3 and 7 days PI (% of decrease in IR: 47.6±9.0, p&lt;0.05; 42.0±7.2, p&lt;0.02 respectively). Pretreatment with O-LM recovered proliferation to basal values (day 3 PI 93.4±10.2%; day 7 PI 130.9±15.3%, O-LM+IR vs. C; p=NS). No modifications were observed in B cells. At day 3 PI, a marked decrease in IFN? levels was obtained in SN of IR mice that was reverted by O-LM treatment (pg/ml: IR 1653±419; C 10884±2783, p&lt;0.02; O-LM+IR 16924±4284, p&lt;0.05 vs C). Also, at day 7 PI, an important increase in TNFa was observed in IR mice, that were reverted by O-LM (pg/ml: IR: 300.7±62.3 vs O-LM+IR: 28.7±2.3, p&lt;0.02). No differences were found in IL-2 levels. Conclusions: The therapeutic action of O-LM is based on its ability of targeting simultaneously multiple pathways involved in cancer development. Present data demonstrate that O-LM protects animals from irradiation by recovering the immune function, improving T lymphocyte activity and modulating the production of key cytokines as IFN? and TNFa. The reported effect may represent a potential benefit for cancer patients undergoing radiotherapy. No significant financial relationships to disclose.
Randomized phase II study (GATE study) of docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer.
Authors: E. Van Cutsem, C. Boni, J. Tabernero, B. Massuti, D. A. Richards, H. Prenen, I. Steinberg, P. Rougier
Journal: Journal of Clinical Oncology (2011)

4018 Background: Docetaxel plus cisplatin and fluorouracil (TCF) improved time to progression and survival compared with CF in advanced gastric cancer (GC). We conducted a randomized phase II study of T plus oxaliplatin (E) with or without fluorouracil (F) or capecitabine (X) in advanced GC. Methods: The GATE study is a multinational, randomized, 3-parallel-arm, stratified study. Optimal doses for all regimens were determined in a pilot phase. Patients ≥18 of age, with a KPS >70 and histologically proven metastatic or locally advanced GC not treated with chemotherapy for advanced GC were randomized to TEF (T 50 mg/m² followed by E 85 mg/m² simultaneously with folinic acid 400 mg/m² followed by F 2400 mg/m² as a 46-hr continuous infusion on Day 1, q2w), TE (T 75 mg/m² followed by E 130 mg/m² on Day 1 q3w), and TEX (T 50 mg/m² followed by E 100 mg/m² Day 1, q3w and X 625 mg/m² BID continuously). The primary objective was time to progression (TTP) in the evaluable population; secondary objectives included response rate (RR), overall survival (OS), and safety. Results: 254 patients were randomized, and 248 received treatment (n=88 TEF, n=78 TE, n=82 TEX). Baseline characteristics were balanced among treatment groups. Most common Gr 3–4 adverse events across treatment arms were fatigue (20.6%), sensory neuropathy (13.7%), diarrhea (12.5%), and anorexia (6.0%); the febrile neutropenia rate was 8.1%. The proportion of deaths due to adverse events were 3.4% with TEF vs. 5.1% with TE and 13.4% with TEX. Conclusions: In patients with advanced GC, treatment with TEF was associated with improved TTP, RR and OS, with a better safety profile compared with TE and TEX. n TTP median (mos) (95% CI) RR (%) OS median (mos) (95% CI) Adverse events (%) grade 3-4 TEF 88 7.7 (7.0–9.4) 46.6 14.6 (11.7–21.8) 61 TE 78 4.5 (3.7–5.3) 23.1 9.0 (7.8–10.9) 77 TEX 82 5.6 (4.3–6.4) 25.6 11.3 (8.1–14.0) 67
Gene expression arrays for the prediction of response to doxorubicin and cyclophosphamide (AC) in human breast cancers
Authors: J. C. Chang, S. Cleator, A. Tsimelzon, A. Ashworth, M. Dowsett, T. Powles, H. Wong, C. K. Osborne, P. O’Connell, S. Hilsenbeck
Journal: Journal of Clinical Oncology (2005)

543 Background: Systemic chemotherapy for operable breast cancer significantly decreases the risk of death. Adriamycin and cytoxan (AC) combination is the standard regimen and has one of the highest response rates in breast cancer, but de novo resistance or incomplete response to this therapy is frequent. We hypothesize that gene expression profiles can predict optimal response to AC therapy. Methods: Core biopsies from 40 patients were obtained before treatment with neoadjuvant AC (6 cycles, 60/600 mg/m2 q3 weeks). Baseline and post-treatment bidimensional measurements of the primary breast cancers were recorded. Double-stranded cDNA was synthesized using an oligo-dT primer containing a T7 RNA polymerase promoter, followed by in vitro transcription with biotinylated ribonucleotides. The labeled cRNA was hybridized to Affymetrix U133A chips which comprise ∼22,200 genes to determine gene expression patterns. Results: To date, clinical complete responses (cCR) were observed in 22 patients (55%), partial responses in 7 (17.5%), and stable disease in 11 (27.5%). Sensitive tumors were defined as those with clinical complete disappearance of all palpable cancer, while resistant tumors were defined as those with at least 70% residual cancer after chemotherapy. We found differential expression of 233 genes between sensitive and resistant tumors with a low false discovery rate (FDR <5%). Of these differentially expressed genes, pathways up-regulated in sensitive tumors included oncogenes (AREG), survival (BCL2, BIRC3), stress-related (interleukins, interferons), metabolism (lipoprotein lipases), and estrogen-related pathways (ER, IRS1). Resistant tumors expressed genes promoting differentiation (FGF) and invasion (MMP1). This molecular portrait for AC differs from our published profile for docetaxel chemoresistance. Conclusions: Unique molecular profiles for neoadjuvant AC sensitivity and resistance exist and differ from docetaxel gene expression patterns. This new technology offers a potential predictive test for sensitivity to different chemotherapy treatments and may thereby allow selection of the most appropriate therapy for women with breast cancer. No significant financial relationships to disclose.
Use of adjuvant trastuzumab with chemotherapy in women with small, node-negative, HER2-positive breast cancers.
Authors: H. L. McArthur, K. Mahoney, P. G. Morris, S. Patil, L. M. Jacks, J. Howard, L. Norton, C. Hudis
Journal: Journal of Clinical Oncology (2010)

615 Background: Since several large, randomized trials reported benefits with adjuvant trastuzumab with chemotherapy, the adverse prognostic impact of HER2 overexpression and/or amplification has been overcome for most women with node-positive and high-risk node-negative breast cancer. Whether women with lower risk HER2-positive (HER2+) disease also derive benefit is unknown as these patients were largely excluded from the randomized studies. We conducted a retrospective, single institution study of women with small, node-negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab. Methods: Through an institutional (MSKCC) database, 485 women with ≤ 2 cm, node-negative, HER2+ (IHC 3+ or FISH ≥ 2) breast cancer diagnosed between 1/01/02 and 12/31/08 were identified. Two cohorts were described: 106 trastuzumab-untreated women diagnosed between 1/01/02 and 5/14/04 and 155 trastuzumab/chemotherapy-treated women diagnosed between 5/16/05 and 12/31/08. Survival and recurrence endpoints were estimated by Kaplan-Meier methods. Results: The cohorts were similar in age, median tumor size, histology, hormone receptor status, hormone therapy and locoregional therapy. Chemotherapy was administered in 66% and 100% of the “no-trastuzumab” and trastuzumab cohorts, respectively. The median follow-up for women without recurrence and for survivors was: 5.8y (0.7-7.6y) and 5.9y (0.7-7.6y), respectively, for the no-trastuzumab cohort and 2.1y (0.5-4.4y) and 2.2y (0.6-4.4y), respectively, for the trastuzumab cohort. The 2y locoregional invasive recurrence-free survival, distant recurrence-free survival and overall survival were 93% vs. 99%, 98% vs. 100% and 100% vs. 99% for the no-trastuzumab and trastuzumab cohorts, respectively. Conclusions: Women with small, node-negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab-chemotherapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech
Pharmacists' interventions on clinical asthma outcomes: a systematic review
Authors: Victoria Garcia-Cardenas, Carol Armour, Shalom I. Benrimoj, Fernando Martinez-Martinez, Inajara Rotta, Fernando Fernandez-Llimos
Journal: European Respiratory Journal (2015)

The objective of this systematic review was to evaluate the impact of pharmacists' interventions on clinical asthma outcomes on adult patients and to identify the outcome indicators used.PubMed, Scopus, Web of Science and Scielo were searched. Studies addressing pharmacists' interventions on adult asthma patients reporting clinical asthma outcomes were incorporated.11 clinical outcomes were identified in 21 studies. 10 studies measured the impact of the intervention on asthma control. Randomised controlled trials (RCT) and non-RCTs found positive results in percentages of controlled patients and Asthma Control Questionnaire (ACQ) scores. Discordant results were found for Asthma Control Test results. Asthma severity was assessed in four studies. One RCT found a significant decrease in the percentage of severe patients; two non-RCTs found significant improvements in severity scores. 11 studies reported pulmonary function indicators, showing inconsistent results. Eight studies measured asthma symptoms; three RCTs and four non-RCTs showed significant improvements.RCTs and non-RCTs generated similar results for most outcomes. Based on the evidence generated by RCTs, pharmacists' have a positive impact on the percentage of controlled patients, ACQ scores, severity and symptoms. Future research should report using the core outcome set of indicators established for asthma (PROSPERO CRD42014007019).
A phase II study of fixed-dose rate (FDR) gemcitabine plus cisplatin for metastatic pancreatic adenocarcinoma (PanCa)
Authors: A. H. Ko, E. Dito, B. Schillinger, A. P. Venook, E. K. Bergsland, J. Allen, M. A. Tempero
Journal: Journal of Clinical Oncology (2004)

4107 Background: Gemcitabine (gem) remains the standard of care for advanced PanCa, but recent studies have suggested that further improvement in patient outcomes may be realized by (1) optimizing drug delivery using pharmacokinetic principles such as FDR infusion, and (2) combining gem with other cytotoxic agents for which preclinical evidence of synergy exists. The objectives of this study are to determine safety and efficacy in a cohort of patients with metastatic PanCa treated with FDR gem plus low-dose cisplatin (CDDP). The primary study endpoint is overall survival. We present here interim results of the first 48 patients. Methods: Chemotherapy naive pts with histologically confirmed PanCa and documented extrapancreatic disease were eligible to participate. Pts received a combination of gem 1000 mg/m2 at 10 mg/m2/min and CDDP 20 mg/m2, both given on dd 1 and 8 of a 21 dd-cycle, with periodic monitoring by CT scans and serial CA19–9 measurements. Results: As of 12/2003 a total of 48 pts have been enrolled, with median f/u time of 188 dd (range, 6–595 dd). Major toxicities have been primarily hematologic (see table). 17/35 pts (48.6%) with baseline serum CA19–9 levels ≥ 2X ULN have demonstrated a ≥ 50% biomarker decline. 8/41 pts (19.5%) with measurable disease have had an unconfirmed minor or partial response. Preliminary Kaplan-Meier analyses show an estimated median time to disease progression of 4.0 months. More updated survival data will be presented at the meeting. Conclusions: The combination of FDR gem + CDDP is generally well-tolerated in pts with untreated metastatic PanCa. Thus far, clinical outcomes appear comparable to those reported in studies of other FDR gem regimens. Longer follow-up and more mature survival data will dictate whether this regimen deserves further investigation in a randomized phase III trial or as a platform on which to add newer targeted therapies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly
Randomized phase II trial of S-1 and cisplatin versus gemcitabine and cisplatin in advanced biliary tract adenocarcinoma.
Authors: M. Kang, J. Lee, T. Kim, S. Lee, D. Park, D. Seo, M. Kim
Journal: Journal of Clinical Oncology (2010)

4029 Background: Gemcitabine plus a platinum has been reported to be the most effective treatment against advanced biliary tract adenocarcinoma (ABTA). S-1 has also shown potent antitumor activity as monotherapy or in combination with platinum. The aim of this study was to evaluate the efficacy and safety of combination chemotherapy with S-1 and cisplatin (SP) versus gemcitabine and cisplatin (GP) as first-line therapy in ABTA. Methods: Patients with ABTA including gallbladder cancer, intrahepatic cholangiocarcinoma (IHCCC), extrahepatic bile duct carcinoma, and ampulla of Vater cancer were randomized to receive either S-1 (40 mg/m2 bid orally D1-14) and cisplatin (60 mg/m2 IV D1) or gemcitabine (1,000 mg/m2 IV fixed dose rate of 10 mg/m2/min on D1,8) and cisplatin (60 mg/m2 IV on D1). Cycles were repeated every 3 weeks. The primary end point was 6-month progression-free survival (PFS) and randomized phase II trial design was used to select the better regimen for further investigation. Secondary endpoints was the response rate (RR) and overall survival (OS). Results: Between March 2008 and March 2009, a total of 96 eligible patients (SP = 47, GP = 49) were enrolled. Overall response rates for patients assigned to GP and SP were 18.4% (95% CI 7.5-29.2%) and 21.3% (95% CI, 9.6-33%, p = 0.721), respectively. With a median follow-up duration of 14.1 months for all patients (95% CI, 12.7-15.5 months), 6-months PFS was 44.0% in GP and 35.3% in SP [unadjusted HR (GP/SP) = 0.85, 95% CI, 0.52-1.36, p = 0.488]. The median OS and estimated 1-year survival rate were 10.1 months and 42.2% in GP and 9.9 months and 21.9% in SP (unadjusted HR [GP/SP] = 0.72, 95% CI = 0.45-1.17, p = 0.187). Grade 3 to 4 toxicities for SP vs. GP were: neutropenia (31.8% vs. 49%), anemia (2.3% vs. 22.4%), thrombocytopenia (4.5% vs. 22.4%), asthenia (2.1% vs. 4.1%), and diarrhea (4.3% vs. 0%). Febrile neutropenia developed only in GP arm (4.1%). Conclusions: Despite of more frequent hematologic toxicities and inconvenience associated weekly visit, GP showed better 6-months PFS and OS based on statistical design, gemcitabine in combination with cisplatin was selected over SP for further investigation in ABTA. No significant financial relationships to disclose.