tbuckley/cabot-search huggingface dataset:
Affecting quality of life in ovarian cancer: encouraging results from a randomized phase II trial of gemcitabine ± pertuzumab in women with platinum-resistant disease
Authors: D. Lalla, V. Paton, C. Y. Lin, D. S. Dizon
Journal: Journal of Clinical Oncology (2008)

5550 Background: Pertuzumab, a humanized monoclonal antibody inhibits HER2 receptor heterodimerization by binding to the dimerization domain of the HER2 receptor, and it has shown promising activity in studies of women with platinum resistant ovarian cancer. We report the impact of pertuzumab on patient-reported symptoms evaluated as part of a completed randomized trial of gemcitabine given with pertuzumab versus placebo in this population. Methods: Patients received study treatment (study drug on Day 1 with Gem on Day 1, Day 8, every 3 weeks) until 17 cycles, disease progression, or unmanageable toxicity. Patients completed FOSI questionnaires at baseline and at Day 1 of each 3-week cycle. The FOSI score was derived from 8 items with higher scores indicating better health status (range 0–32). Symptom deterioration was defined as a ≥3 point decrease in FOSI from baseline. Results: A total of 130 patients participated with a median age of 59 years. The majority of women had ECOG PS=0 at baseline. The median time to symptom deterioration was 1.7 months in the Gemcitabine+placebo arm vs. 3.8 months in the gemcitabine+pertuzumab arm (HR=0.62, 95% CI: 0.36–1.05). Symptom improvement (≥3 point increase in FOSI) occurred in 28 women (43%) given Gemcitabine+pertuzumab, compared to 18 (28%) in those receiving Gemcitabine+placebo. Conclusions: In addition to encouraging activity of pertuzumab in this population (PFS HR=0.66, 95% CI: 0.43–1.03), the addition of pertuzumab to gemcitabine may stabilize symptom burden and delay the time to deterioration of symptoms. Due to small sample size and exploratory nature of this trial, further studies are needed to confirm the clinical benefit of gemcitabine+pertuzumab in ovarian cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc.
Effect of Btk inhibitor PCI-32765 monotherapy on responses in patients with relapsed aggressive NHL: Evidence of antitumor activity from a phase I study.
Authors: R. Advani, J. P. Sharman, S. M. Smith, D. A. Pollyea, T. E. Boyd, B. W. Grant, K. S. Kolibaba, J. J. Buggy, A. Hamdy, N. H. Fowler
Journal: Journal of Clinical Oncology (2010)

8012 Background: Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor signaling. Based on promising preclinical data in B cell NHL, a study was conducted to test the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of PCI-32765, a potent, selective oral inhibitor of Btk. Methods: Multiple histologic subtypes of B cell NHL were enrolled in this dose escalation study. Cohort I was dosed at 1.25 mg/kg/day, and further dose escalation (2.5, 5.0, 8.3, 12.5, 17.5 mg/kg) based on safety evaluation. In the absence of DLTs, dose escalation was to proceed to three dose levels above the cohort that achieved >90% occupancy of Btk by PCI-32765 assessed using a PD probe assay. Blood was collected for determination of PK and PD of PCI-32765 and responses assessed every two cycles. Results: 29 pts (12 follicular, 7 CLL/SLL, 4 DLBCL, 4 mantle, 2 marginal) with a median of 3 prior therapies have been enrolled on cohorts 1-4. Therapy was well tolerated with most adverse events < grade 2. One protocol defined DLT (dose delay > 7 d due to neutropenia) was observed. 19/22 pts from cohorts 1-3 are evaluable. The ORR is 42%; 1 CR (SLL), 7 PR (4 CLL/SLL, 2 MCL and 1FL). In cohort 2, PD demonstrate complete occupancy of Btk by PCI-32765, with >95% enzyme occupancy 4 hours post dose in all pts. Basophil degranulation, a Btk-dependent cellular process, was completely inhibited up to 24 hrs. T- cell responses were not affected, and no significant depletion of peripheral blood B, T or NK cell counts was observed. Positive correlation (R2 = 0.93) was found between Btk active-site occupancy in PBMCs (mean of Days 1 and 8) and PCI-32765 plasma AUC 0-° (Day 1) at the 1.25 mg/kg dose. Conclusions: PCI-32765 is a novel oral agent that selectively targets Btk, with favorable safety data, and encouraging antitumor activity. Dose escalation to subsequent cohorts is ongoing. Phase II studies of single-agent Btk are planned in relapsed and refractory CLL/SLL and MCL. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacyclics Pharamacyclics
CCL2 release by airway smooth muscle is increased in asthma and promotes fibrocyte migration
Authors: Shailendra Singh, Amanda Sutcliffe, Davinder Kaur, Sumit Gupta, Dhananjay Desai, Ruth Saunders, Christopher Brightling
Journal: European Respiratory Journal (2014)

Asthma is characterized by variable airflow obstruction, airway inflammation, airway hyper-responsiveness and airway remodeling. Airway smooth muscle hyperplasia is a feature of airway remodeling and contributes to bronchial wall thickening.

We sought to investigate the expression levels of chemokines in primary cultures of airway smooth muscle cells from asthmatics and healthy controls and to assess whether differentially expressed chemokines a)promote fibrocyte migration and b)are increased in blood from subjects with asthma and in sputum samples from those asthmatics with bronchial wall thickening.

Chemokines released by healthy and asthmatic primary airway smooth muscle were measured by MesoScale Discovery platform and the chemokine most highly expressed was confirmed by ELISA. Expression of its cognate chemokine receptor by fibrocytes was examined by immunofluorescence and flow cytometry. The role of this chemokine in fibrocyte migration towards airway smooth muscle was investigated by chemotaxis assays.

CCL2 levels were elevated in primary airway smooth muscle supernatants from asthmatics compared to healthy controls (1880±329 versus 947±203 pg/106 cells,p=0.02). CCR2 was expressed on fibrocytes. Fibrocytes migrated towards recombinant CCL2 and airway smooth muscle supernatants. These effects were inhibited by CCL2 neutralisation. CCL2 levels were increased in blood from asthmatics compared to healthy controls (136±14 versus 78±11 pg/mL,p=0.002) and sputum CCL2 was elevated in asthmatics with bronchial wall thickening (p=0.008).

Airway smooth muscle-derived CCL2 mediates fibrocyte migration and potentially contributes to the development of airway smooth muscle hyperplasia in asthma.
A multicenter phase II, open-label trial of multiple doses of cancer vaccine candidate IGN101 to evaluate efficacy against disseminated tumor cells in blood
Authors: H. Samonigg, G. Himmler, M. Gnant, G. Gastl, H. Loibner, K. Possinger, T. Bauernhofer, N. Dandachi, M. Balic, G. Steger, A. Obwaller
Journal: Journal of Clinical Oncology (2005)

2557 Background: IGN101 is a vaccine designed for therapeutic immunization against cancers of epithelial origin. It consists of 0.5 mg alum-adsorbed murine monoclonal antibody 17-1A as vaccine antigen to trigger an immune response which has been shown in a phase I study with 18 patients to significantly reduce the number of circulating EpCAM-positive tumor cells in peripheral blood. Methods: An open-label, single treatment arm, uncontrolled study with at least 45 evaluable patients in at least four centers is being conducted. Patients are male or female, ≥18 years of age, with biopsy proven carcinoma likely to express EpCAM, with a Karnofsky Performance Score ≥70 at baseline and a life expectancy > 4 months. Vaccinations with IGN101 are given by subcutaneous injection on days 1, 15, 29 and 57. Analyses of circulating tumor cells (EpCAM-positive, cytokeratin-positive, CD45-negative) in peripheral blood are performed for screening of patients and on days 1, 29, 57 and 71 (study end) utilizing the method described by Cristofanilli et al., NEJM (2004) 351:781. Primary objective is to assess the effect of IGN101 on the number of circulating tumor cells in peripheral blood. Secondary objectives are safety and tolerability of multiple injections of IGN101 and to obtain data for several immunological parameters. Results: 16 patients have completed the study until November 2004, the median number of circulating tumor cells has been reduced from 10.5 at day 1 to 5 cells per blood sample after 4 vaccinations at day 71. This difference is not yet statistically significant. Conclusions: In a number of patients with colorectal, ovarian and breast cancer a reduction of circulating tumor cells is being observed after conclusion of approximately one third of the study. It has been shown that in metastatic breast cancer patients an elevated number of circulating tumor cells predicts short survival (Hayes et al., J. Clin. Oncol., ASCO Annual Meeting Proceedings (2004) 22: 509). This parameter could potentially be used to probe for surrogate efficacy in patients at an early stage of development of immunotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration igeneon AG igeneon igeneon AG igeneon AG
Utilization of 5HTT-gene polymorphism as a prognostic indicator in cancer.
Authors: N. M. Awad, M. Farouk, H. Elshafei, S. Ghobashy, M. Elbordiny, A. A. Elsaid, A. Omar
Journal: Journal of Clinical Oncology (2010)

TPS139 Background: Clinical studies show an association between depression and cancer outcomes as decreased desire for life- sustaining treatment and increased mortality. Neurotransmitters are capable of altering immune function whereas immune-derived mediators regulate neuroendocrine and autonomic outflow from the brain. Host cellular defenses against cancer involve immune-mediated mechanisms that can be influenced by neurotransmitter activity. Recent studies on polymorphism of the 5-HTT gene explain why some individuals develop psychological morbidities on exposure to stressful life events while others exposed to the same conditions do not. This offers a screening criterion for identifying patients at risk for psychological morbidity that might be detrimental to their treatment outcome and may be used as a prognostic indicator in which case, starting anticancer treatment of this group of patients with concurrent psychological intervention may improve their treatment outcomes. Aim: To study the role of 5HTT gene as a prognostic indicator in cancer and its utilization for clinical selection of patients for concurrent psychotherapy with anticancer treatment. Methods: A simultaneous two study program. Study I: a longitudinal observational study in which cancer outcomes are compared in two independent cohorts of cancer patients grouped by 5HTT genotype (patients with two long alleles versus those with at least one short allele). In Study II, patients with at least one short allele will be randomized into either an intervention arm receiving anticancer treatment accompanied by supportive psychiatric care program or control arm receiving standard care (anticancer treatment without psychotherapy). Outcomes: Primary outcome is progression-free survival. Secondary outcomes are response to treatment, functional and psychological status of the patient as expressed by Quality of Life measurement using FACT-G questionnaire and the Hospital Anxiety and Depression Scale, and overall survival. No significant financial relationships to disclose.
Phase I and pharmacokinetic (PK) Study of CP-724,714, an oral human epidermal growth factor receptor-2 (HER-2) selective tyrosine kinase inhibitor
Authors: P. N. Munster, M. Mita, C. Britten, S. Minton, S. Moulder, D. Noe, B. Roedig, L. Denis, D. Slamon, A. Tolcher
Journal: Journal of Clinical Oncology (2004)

3082 Background: The substituted quinazoline CP-724,714 is a reversible, highly selective HER-2 tyrosine kinase inhibitor (TKI) for oral administration. Methods: This Phase 1 study seeks to evaluate the safety, tolerability and PK of continuous daily oral administration in 3-week cycles of CP-724,714 in patients with advanced malignant solid tumors that express HER-2. Safety evaluations include weekly visits, safety labs, ECG and MUGA scans. Blood specimens for PK were collected following a single dose in Cycle 1 and following the first dose in Cycle 2. Serum CP-724,714 concentrations were measured by LC/MS/MS following solid phase extraction. PK parameter values were estimated using standard noncompartmental techniques. Results: To date, 15 female patients (pts)[median age 51 (37–71); median PS 1 (0–1)] have received 36 cycles at 3 dose levels; 250 mg QD (4 pts), 250 mg BID (6 pts) and 400 mg BID (5 pts). Chronic treatment at 400 mg BID was not feasible due to reversible, cholestatic liver dysfunction [NCI-CTC Grade 3 conjugated hyperbilirubinemia (n=2), Grade 3 elevated gamma-glutamyl transpeptidase (GGT) (n=1)]. Preliminary safety data reveal the most common treatment-related adverse events to be mild nausea (54%), mild fatigue (46%) and hyperbilirubinemia (31%). No treatment-related skin rash, diarrhea or cardiomyopathy was observed. No objective responses were observed in patients with HER-2 overexpressing breast cancer, all of whom were heavily pretreated with trastuzumab. The mean (CV) PK parameter values are AUC0-Tlast 8740 (45%) and 14300 (43%) h.ng/ml, Cmax 3760 (55%) and 4930 (48%) and Tmax 1.25 and 1.33 h, respectively for a single dose of 250 mg and 400 mg. Conclusion: The preliminary safety profile indicates that daily administration of CP-724,714 is feasible with reversible dose limiting cholestatic liver dysfunction without toxicity associated with HER-1 (EGFR) TKIs. CP-724,714 is rapidly absorbed. AUC and Cmax are dose proportional over the range studied. Drug exposure (AUC0–4) exceeds the threshold for efficacy as determined in preclinical studies. Enrollment is continuing at 250 mg BID Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Inc. Pfizer, Inc. Pfizer, Inc. Pfizer, Inc.
Balanced chromosome aberrations in leukemias following chemotherapy with DNA-topoisomerase II inhibitors.
Authors: J Pedersen-Bjergaard, M K Andersen, B Johansson
Journal: Journal of Clinical Oncology (1998)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1998.16.5.1897 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9586907 Balanced chromosome aberrations in leukemias following chemotherapy with DNA-topoisomerase II inhibitors. J Pedersen-BjergaardxJ Pedersen-BjergaardSearch for articles by this author , M K AndersenxM K AndersenSearch for articles by this author , B JohanssonxB JohanssonSearch for articles by this author Show More Laboratory for Cancer Genetics and Cytogenetics, the Finsen Center, Rigshospitalet, the University Hospital of Copenhagen, Denmark. https://doi.org/10.1200/JCO.1998.16.5.1897 PDF "Balanced chromosome aberrations in leukemias following chemotherapy with DNA-topoisomerase II inhibitors.." Journal of Clinical Oncology, 16(5), pp. 1897–1898© 1998 by American Society of Clinical Oncology
A randomised, placebo-controlled, double-blind phase II study of raltitrexed and gefitinib vs raltitrexed alone as 2nd line chemotherapy in subjects with advanced colorectal cancer (CRC). GON group study (Grupo Oncologico del Norte)
Authors: J. Vieitez, M. Valladares, I. Pelaez, L. Gonzalez-de-Sande, C. García-Girón, J. García-López, A. Jimenez-Lacave, M. Reboredo, H. Bovio, J. Garcia-Foncillas
Journal: Journal of Clinical Oncology (2007)

14523 Background: Second-line monotherapy activity in patients with metastatic CRC is low with an objective response rate of 9% in phase II-III studies (Viéitez et al, Am J Clin Oncol 2003; Rougier y cols., 1998). Gefitinib has shown activity in vitro and in animal models against colon cancer cell lines, and has shown to increase the activity of raltitrexed (Cardiello et al, Clin Cancer Res 2000). Methods: A multi-center randomized, double blind, phase II study was initiated in patients with metastatic CRC who failed prior therapy based on 5-FU LV plus OXL or/and CPT and measurable disease. Patients were randomized to received Raltitrexed, 3 mg/m2 IV q3w, (arm A) or Raltitrexed plus Gefitinib, 250 mg PO OD (arm B). Primary end-point was time to progression (TTP); Secondary end-point was objective tumour response rate (ORR) based on the RECIST criteria at six month, overall survival (OS) and safety. Results: Between Dec 2003 and Oct. 2005, 76 patients were recruited in 7 centers. Median age was 65.0 (range 75–31) and 63.5 (range 76–40) years for arm A and B respectively; demographics characteristics were well balanced between both arms including sex, race or other previous mayor conditions. Both treatment arms were well tolerated. Grade 3/4 toxicity in Arm A was: anorexia 10.5% (4), asthenia 10.5% (4), liver toxicity 10.5% (4), nausea 5.3% (2), diarrhea 5.3% (2), abdominal pain 2.6% (1), neutropenia 2.6% (1), thrombopenia 2.6% (1), renal failure 2.6% (1). Grade 3/4 toxicity in Arm B included: anemia 2.6% (1), liver toxicity 7.9% (3), diarrhea 5.3% (2), skin rash 2.6% (1), melenas/upper digestive bleeding 2.6% (1), fever 2.6% (1). ORR was 5.3% (2/38) (95%CI: 0.64–17.75) and 7.9% (3/38) (95%CI: 1.66–21.38) for arm A and B. Median TTP was 72 (95%CI: 59–132) and 63 (95%CI: 57–84) days; median OS was 291 (95%CI: 255–539) and 361 (95%CI: 283–533) days; and median duration of treatment was 74.5 (range 21–274) and 63.5 (range 12–324) days for arm A and B. Conclusions: Addition of Gefitinib to Raltitrexed in pretreated patients with advanced CRC is well tolerated, with manageable toxicity profile, but not increases Raltitrexed efficacy. No significant financial relationships to disclose.
Phase I, pharmacokinetic, and pharmacodynamic study of carboplatin and topotecan administered in two different schedules
Authors: D. S. Boss, W. S. Siegel-Lakhai, N. E. Schoemaker-van Egmond, D. Pluim, H. Rosing, W. W. Ten Bokkel-Huinink, J. H. Beijnen, J. H. Schellens
Journal: Journal of Clinical Oncology (2009)

2561 Background: Preclinical studies showed sequence dependent synergy of the combination of topoisomerase I inhibitors and platinum agents. This trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) of carboplatin (carbo) and topotecan (topo) in patients (pts) with solid malignancies in two different schedules. Methods: In part 1, pts received carbo as a 60 min IV infusion on day 1 and topo as a 30 min IV infusion on days 1, 2 and 3 (C→T). The sequence of drug administration was reversed in part 2 of the study (T→C): topo on days 1, 2, and 3, followed by carbo on day 3. In both schedules, the PK was determined of each agent in plasma and the TopI catalytic activity and Pt-DNA adducts in white blood cells (WBC) and tumor tissue. Results: 41 pts were included in this trial. Dose-limiting toxicities (DLTs) during C→T included grade (G) 4 thrombocytopenia and febrile neutropenia. The MTD was reached at carbo target AUC 4 min.mg/mL and topo 0.5 mg/m 2 /day. DLTs during T→C included G4 neutropenia, thrombocytopenia and neutropenic fever, G3 nausea and G4 vomiting. Carbo target AUC 6 min.mg/mL and topo 0.9 mg/m 2 /day was the MTD in this schedule. No schedule dependent differences in PK were found (clearance (Cl) of unbound carbo: 0.6 vs 0.7 mL/min, p=0.14; Cl of total topo: 24.1 vs 29.6 L/h, p=0.08; Cl of topo lactone: 84.5 vs 83.7 L/h, p=0.96). WBC and tumor samples were collected from 30 and 27 pts, respectively. Pt-DNA levels were not schedule dependent in WBC (range C→T = 0.44–4.13, and T→C = 0.22–6.07 fmol*h/μg DNA) and in tumor tissue (range C→T = 0.20–0.96, and T→C = 0.62–1.8 fmol/μg DNA). Also, no schedule dependent effects were seen in TopI catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C→T schedule. One pt with ovarian cancer had a complete response (T→C schedule), 2 pts with ovarian cancer (C→T schedule) and 3 pts treated in the T→C schedule (ovarian, SCLC and gastric cancer) had a partial response. Conclusions: T→C was better tolerated as both hematological and non-hematological toxicities were milder. Other than the investigated PD factors must explain the schedule dependent differences in toxicities. No significant financial relationships to disclose.
Survival benefit of oral UFT for adjuvant chemotherapy after completely resected non-small-cell lung cancer
Authors: C. Hamada, M. Ohta, H. Wada, S. Fujimura, K. Kodama, M. Imaizumi, Y. Nakanishi, N. Matsuoka
Journal: Journal of Clinical Oncology (2004)

7002 Background: Survival rate should be used as the primary endpoint in clinical trials assessing the response of non-small-cell lung cancer to postoperative adjuvant chemotherapy. Single studies usually do not provide clear-cut conclusions because of limited sample size. We therefore performed a meta-analysis of all properly randomized clinical trials comparing long-term adjuvant chemotherapy with UFT, an oral fluorinated pyrimidine, to surgery alone in patients with completely resected non-small-cell lung cancer, and a number of subgroup analyses and tests for interaction were performed to evaluate generalizability of drug effect. Methods:Six such trials were identified. The analysis was based on individual patient data provided by the principal investigator of each trial. Data from 2,003 eligible patients were analyzed on an intention-to-treat basis. The endpoint of interest was overall survival at 5 years after surgery. Major prognostic factors were well balanced between the UFT group and surgery alone group. Results: The results of meta-analysis demonstrated that adjuvant chemotherapy with UFT significantly improved overall survival (5-year OS, HR, 0.77; 95%CI, 0.63–0.94; p=0.011, 7-year OS, HR, 0.74; 95%CI, 0.61–0.88; p=0.001). The 5-year OS rates and 7-year OS rates were 81.8%, 76.5% for the UFT arm and 77.2%, 69.5% for the surgery alone arm. Conclusions: We conclude that postoperative adjuvant chemotherapy with UFT has a beneficial effect uniformly in patients with completely resected early-stage non-small-cell lung cancer. No significant financial relationships to disclose.