tbuckley/cabot-search huggingface dataset:
A novel telomerase-specific oncolytic virotherapy for human cancer: preclinical evaluation of safety, biodistribution, and efficacy
Authors: T. Fujiwara, S. Kagawa, H. Kawamura, K. Nagai, R. Nohara, N. Tanaka, Y. Urata
Journal: Journal of Clinical Oncology (2006)

13057 Background: Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We constructed an adenovirus 5 vector (Telomelysin [OBP-301]), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an IRES. Methods: We examined the antitumor effect of Telomelysin as a single agent or in combination with systemic administration of chemotherapeutic drugs such as docetaxel in tumor xenograft models. IND-supporting preclinical toxicology and pharmacodynamic studies were also performed to characterize the safety, pharmacokinetics and biological activity of Telomelysin. Results: Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines derived from various organs, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. In nu/nu mice carrying subcutaneous human tumor xenografts, intratumoral injection of Telomelysin resulted in a significant inhibition of tumor growth, which was significantly enhanced in combination with systemic administration of docetaxel. Moreover, Telomelysin replication in the distant, un-injected tumors was demonstrated. Viral DNA was identified in tissues outside of the injection site; however, toxicology studies including pathological examinations in mice and cotton rats demonstrated that local injection of Telomelysin could be well-tolerated with an acceptable safety profile. Conclusions: The hTERT promoter confers competence for selective replication of Telomelysin in human cancer cells, an outcome that has important implications for the treatment of human cancers. Telomelysin has been already manufactured under GMP conditions for initial clinical trials. Upon FDA approval, a phase I dose-escalation study of intratumoral injection of Telomelysin for various solid tumors will be started. [Table: see text]
Treatment of Total-Body X-Irradiated Monkeys With Autologous and Homologous Bone Marrow&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: B G CROUCH, L van PUTTEN, D van BEKKUM, M de VRIES
Journal: JNCI Journal of the National Cancer Institute (1961)

Rhesus monkeys were given injections of autologous or homologous bone marrow after total-body X irradiation. After doses of 650 r or more, untreated monkeys survived for 12 to 16 days without recovery of the peripheral blood counts. Five of 6 animals treated with 2.2 to 12.9 × 108 autologous bone marrow cells after radiation doses of 850 to 950 r showed hematopoietic recovery and survived for over 100 days. After lethal radiation doses and treatment with more than 8 × 108 homologous bone marrow cells, recovery of hematopoiesis was observed in 14 monkeys. In most of these male animals the proliferation of female donor cells was demonstrated by the presence of typical “drumsticks” in the polymorphonuclear granulocytes of the peripheral blood. However, only 2 animals survived more than 30 days, and the average survival time, 21.6 days, was only slightly longer than that of the controls. A syndrome of anorexia, diarrhea, and wasting, often combined with dermatitis or jaundice, occurred only in the animals treated with foreign bone marrow. From the similarity of this syndrome and the autopsy findings (described in the following paper) to those of secondary disease in rodents, it is concluded that the monkeys which, after irradiation, were treated with homologous bone marrow died from severe and early development of secondary disease. The implications of these findings are discussed.
Capecitabine (X) and radiotherapy (RT) in locally advanced squamous carcinoma of the uterine cervix: Phase II results
Authors: E. Domingo, V. Lorvidhaya, R. De Los Reyes, T. Sy Ortin, P. Kamnerdsupaphon, C. Lertbutsayanukul, E. Vito-Cruz, E. Taravichitkul, N. Cupino, P. Lertsanguansinchai
Journal: Journal of Clinical Oncology (2008)

5513 Background: Uterine cervix cancer is the second most common female malignancy in the world. The oral fluoropyrimidine X is an established and effective radiosensitizer in the treatment of locally advanced rectal cancer, providing the rationale for evaluating X plus RT in locally advanced cervical cancer. Methods: We conducted a Simon’s two-stage design phase II trial (H1: overall response rate [ORR] ≥55%; H0: ORR ≤35%; α=5%, β=10%) in untreated patients with stage IIB-IIIB cervical cancer. Patients received X 825 mg/m2 bid (Monday-Friday) during RT (45 Gy per 25 fractions external beam and 26 Gy high-dose rate [HDR] brachytherapy to point A, maximum 8 weeks), followed by six adjuvant cycles of X 1,000 mg/m2 bid (days 1–14 every 21 days) for control of distant metastases. The primary endpoint was ORR using GOG RECIST based on clinical, histological and CT scan assessments. Results: Baseline characteristics (n=60) were median age 47 years (range 28–72); ECOG PS 0/1 95%/5%; and FIGO stage IIB/IIIA/IIIB 58%/2%/40%. All 60 patients were evaluable for efficacy and safety. Most adverse events were mild. Treatment-related grade 3/4 toxicities were diarrhea (n=1), hand-foot syndrome (n=1) and hypokalemia (n=1). 54 patients completed planned therapy; 6 withdrawals (unrelated to toxicity) occurred during adjuvant therapy (4 due to progressive disease). ORR was 88% (78% CR and 10% PR). At the time of this report, median follow-up was 13.9 months (range 2.1–24.6). At 23 months, progression-free survival rate was 78% (95% CI 66–91%). Conclusions: This non-platinum-based regimen demonstrated promising results, with an 88% ORR and CR rate of 78%. X simplified chemoradiation in locally advanced cervical cancer, offering convenient oral administration and a favorable safety profile. Adjuvant capecitabine was feasible and well tolerated. Long-term follow-up is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Hoffmann-La Roche
Phase II study of CP-4126, a gemcitabine-lipid conjugate, in patients with advanced pancreatic cancer.
Authors: T. Ikdahl, S. Dueland, A. Hendlisz, O. Dajani, P. Brunsvig, A. Awada, J. Rao, J. Farrell, W. Rasch
Journal: Journal of Clinical Oncology (2010)

e14674 Background: Uptake of hydrophilic nucleoside analogues into tumor cells is determined by membrane transporter expression. Clinical response to gemcitabine (gem) is correlated with expression of the nucleoside transporter hENT1. CP4126 (gemcitabine-5'-elaidic acid ester) is a novel gem analogue that, by virtue of a fatty acid conjugate, can enter cells in a transporter-independent manner. This ongoing study compares CP-4126 with gem and correlates activity with tumor cell hENT1 expression in pancreatic cancer patients. Methods: Treatment-naive patients with advanced or metastatic pancreatic adenocarcinoma, ECOG performance status ≤ 2, and adequate haematologic, renal and hepatic function are eligible. The study has a two stage design - a pilot stage in which all patients receive CP-4126, followed by a randomized stage comparing CP-4126 with gem (1:1). Both agents are administered as a 30-min IV infusion on days (d) 1, 8, 15 every 4 weeks. The doses of CP-4126 and gem are 1,250 mg/m2/d and 1,000 mg/m2/d, respectively. hENT1 expression on tumor cells (biopsies from primary or metastasis) is determined by immunohistochemistry. Results: 10 patients were enrolled in the pilot stage; enrollment continues in the randomized stage (n = 2, to date). The first 12 patients (m = 7; f = 5), median age 64.5 yrs (range 54-81), have received treatment in the range from 1 to 6 cycles. All pilot patients have been evaluated using RECIST criteria: 2 had partial remission (PR), 4 stable disease (SD), and 4 showed progressive disease. hENT1 expression was low in 3 patients and high in 6 (with one unknown). For the two PR patients, the hENT1 expression is high for one patient and unknown for the other, with CA19-9 reduction of 47% and 99% respectively. Toxicity was mainly grade 1-2 and included vomiting, infection, cholestasis, pleural effusion, ascites, brain metastases, hyperbilirubinemia, and flu-like symptoms. Conclusions: Preliminary efficacy for CP-4126 among 10 initial patients is promising and consistent with the hypothesis that a hENT1- independent nucleoside analog may improve antitumor efficacy. Results from the randomised comparison with gem will be presented with special reference to tumor cell hENT1 status. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Clavis Pharma Clavis Pharma
Laparoscopic extraperitoneal para-aortic lymphadenectomy in patients with locally advanced cervical cancer: Histopathologic findings and correlation with PET-CT imaging studies
Authors: R. L. Coleman, P. T. Ramirez, B. M. Slomovitz, C. Levenback
Journal: Journal of Clinical Oncology (2006)

5014 Objective: To evaluate the safety and feasibility of laparoscopic extraperitoneal para-aortic lymphadenectomy and to correlate histopathologic findings and preoperative PET-CT imaging in patients with locally advanced cervical cancer. Methods: We performed a prospective study of patients with locally advanced cervical cancer. Patients enrolled underwent laparoscopic extraperitoneal para-aortic lymphadenectomy prior to chemoradiation at our tertiary cancer center from April 2004 to June 2005. All patients had a preoperative CT scan and PET-CT scan. Results: 12 patients were enrolled. One patient did not undergo surgery. No patient had evidence of metastatic disease to the para-aortic area by preoperative CT scan. The median age was 48 years (range, 35–67). 10 patients were diagnosed with squamous cell carcinoma, one patient with adenocarcinoma, and one patient with transitional cell carcinoma. The stage distribution was: IB2 (3), IIA (1), IIB (4), IIIA (1), IIIB (3). The median BMI was 26 (range, 18.6–29.7). Two (18%) of 11 patients had a positive preoperative PET-CT imaging study for disease in the para-aortic lymph nodes. The median time of surgery was 162 minutes (range, 52–247). The median blood loss was 25 mL (range, 10–100). There were no intraoperative complications. No patient required intraoperative blood transfusions. The median length of postoperative stay was 1 day (range, 1–2). There were two patients who developed postoperative lymphocysts requiring drainage. The median number of lymph nodes removed was 11 (range, 4–17). A total of 2 (18%) of 11 patients had evidence of histologically confirmed lymph node metastases. Of these, only one patient had evidence of disease by PET-CT scan. Only one of the two patients with a positive PET-CT scan for disease in the para-aortic nodes, actually had disease confirmed histopathologically. The sensitivity and specificity of PET-CT scan is 50% and 89%, respectively. Conclusions: Laparoscopic extraperitoneal para-aortic lymphadenectomy is safe, feasible and appears to increase the precision of identifying occult metastasis. Further patient accrual will be needed to evaluate the ultimate utility of PET-CT imaging in this setting. No significant financial relationships to disclose.
Costs of treatments for local/regional prostate cancer
Authors: C. F. Snyder, K. D. Frick, A. L. Blackford, R. J. Herbert, B. A. Neville, M. A. Carducci, C. C. Earle
Journal: Journal of Clinical Oncology (2009)

6527 Background: Men with prostate cancer have a variety of treatment options, including surgery, radiation, hormonal therapy, combinations thereof, or active surveillance. Treatment choice may have important cost implications. Methods: Using the SEER-Medicare database, we examined the Inpatient, Outpatient, Emergency, and Other costs of men diagnosed with local/regional prostate cancer in the year 2000 who were 66+ years old and enrolled in the fee-for-service Medicare program. Based on the treatments received in the first 9 months from diagnosis, men were assigned to these treatment groups: active surveillance, radiation, hormonal, hormonal+radiation, surgery (might also include radiation and hormonal therapy). We matched the prostate cancer cases to noncancer controls on age, race, sex, SEER region, comorbidity, and survival. We estimated the costs of prostate cancer care from 1 month pre- to 12 months post-diagnosis by calculating the incremental costs of care for cases vs. controls. Costs of care were estimated using Medicare payments. Results: 13,769 prostate cancer cases were matched with 13,769 controls and allocated to these treatment groups: active surveillance (n=2,805), radiation (n=2,582), hormonal (n=2,190), hormonal+radiation (n=3,992), and surgery (n=2,200). The most expensive treatment group was hormonal+radiation, with cases having a total average incremental cost of $17,795 vs. controls, followed by surgery ($15,467), radiation ($12,326), and hormonal therapy ($10,804). Active surveillance was the least expensive ($4,152). Outpatient costs were the major driver of increased costs for the hormonal+radiation group. Increased costs for surgery patients were driven by both Outpatient and Inpatient costs. Emergency Department and Other costs were generally similar between prostate cancer cases and controls. Conclusions: The treatment choice of men with local/regional prostate cancer has important implications for cost in the year following diagnosis. Additional analyses exploring long-term costs are needed. [Table: see text] No significant financial relationships to disclose.
Anti-neuroblastoma activity of hu14.18-IL2 against minimal residual disease in a Children’s Oncology Group (COG) phase II study
Authors: S. Shusterman, W. B. London, S. D. Gillies, J. A. Hank, S. Voss, R. C. Seeger, T. Hecht, R. A. Reisfeld, J. M. Maris, P. M. Sondel
Journal: Journal of Clinical Oncology (2008)

3002 Background: The hu14.18-IL2 fusion protein consists of IL2 linked to a humanized mAb that recognizes the GD2 disialoganglioside expressed on neuroblastoma (NB) cells. Hu14.18-IL2 has preclinical activity in mouse models of NB and melanoma, particularly when given to mice with a smaller tumor burden. Using the dosing and schedule developed in our phase I study, we determined the antitumor activity of hu14.18-IL2 in two strata of patients with recurrent or refractory NB. Methods: Hu14.18-IL2 was given intravenously at a dose of 12 mg/m2/day over 4 hours for three consecutive days every 28 days. Responses were evaluated every 2 cycles for patients with disease measurable by standard radiographical criteria (stratum 1) and for patients with disease evaluable only by MIBG and/or bone marrow histology (stratum 2). In each stratum, a one-stage design was powered to conclude efficacy with 4 or more responders (CR or PR) out of 20. Response was established by independent radiology review as well as bone marrow histology and immuno-cytochemistry, and durability assessed by repeat evaluation after >3 weeks. Results: 39 patients were enrolled (37 evaluable). No responses were seen in stratum 1 (n=13). In stratum 2, response rate was 21% (5/24 overall; 95% CI: 5%,37%), all 5 in first 20. All 5 responders had CR (3/5 bone marrow disease only at study entry, 1/5 MIBG-avid disease only and 1/5 marrow and MIBG-avid disease) of 12, 8, 8+, 7+ and 3+ mo duration. Two additional stratum 2 patients had partial improvement, but did not meet criteria for a PR. Two patients required dopamine for hypotension; 1 patient required ventillatory support for capillary leak and hypoxia. Other grade 3 and 4 non- hematologic toxicities included pain, rash, allergic reaction, fever and transaminitis. Most toxicities were reversible within 1–2 days of completing a treatment course and were expected based on phase 1 results. Correlative lab studies are being analyzed. Conclusions: Patients with MIBG and/or bone marrow only disease had a 21% CR rate to hu14.8-IL2 while patients with bulky disease did not respond. These results warrant further study of hu14.8-IL2 in recurrent or refractory NB patients with minimal residual disease. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration EMD-Lexigen Research Center EMD-Lexigen EMD-Lexigen EMD-Lexigen
Impact of nail toxicity on survival of patients with hormone-refractory prostate cancer (HRPC) treated with docetaxel
Authors: F. Scotte, E. Banu, J. Medioni, M. Boudraoui, J. M. Tourani, A. Banu, S. Oudard
Journal: Journal of Clinical Oncology (2009)

e16122 Background: Docetaxel is the standard first-line treatment for patients (pts) with metastatic HRPC. Taxanes are a well known cause of nail toxicity but docetaxel-related nail toxicity is rarely explored. Methods: Eligible HRPC pts included in the current analysis were from a phase II, multicentre, case-control study (Scotte F et al, J Clin Oncol 2005). Pts were treated with docetaxel 75 mg/m 2 every 3 weeks and oral prednisone 10 mg daily. Nail toxicity was graded according to NCI CTC version 2 (0: absence of toxicity; 1: minor changes; 2: onycholisis). The endpoint of interest was the impact of nail toxicity on overall survival (OS) using Cox regression analysis as the main statistical method. OS was the time from the start of chemotherapy to death or last follow-up. Results: Data from 23 HRPC pts treated in two French centres were analyzed. The median age was 68 years, 91% of pts had bone metastases, 84% had a single metastatic site, 49% had a Gleason score of ≥ 8 and 91% had an ECOG performance status (PS) of 0 or 1. Median OS was 16.7 months [95% confidence interval (CI), 5.7–27.6 months], all pts died. There were differences in OS between nail toxicity categories (see Table). Median OS was 10.6 months (95% CI, 9.5–11.7) and 22.7 months (95% CI, 15.1–30.3) for pts without and with nail changes, respectively. Nail changes severity was significantly related to OS: hazard ratio (HR)=0.50 (95% CI, 0.28–0.92), P=0.027 (univariate analysis). The multivariate analysis adjusted by ECOG PS (the second covariate associated with prognosis) showed a 63% reduction in the risk of death for pts with nail toxicities: HR=0.29 (95% CI, 0.09–0.82), P=0.049. Conclusions: Our results suggest that pts with docetaxel-related nail toxicity have a better OS than those with no nail toxicity. This demonstrates that nail changes in HRPC pts treated with docetaxel are predictive of OS; these findings should be validated in a large cohort of pts. [Table: see text] No significant financial relationships to disclose.
First evaluation of the French cancer clinical research projects funding program (PHRC)
Authors: I. Pauporte, E. G. Brain, C. Hennequin, G. R. Auleley, J. Reiffers
Journal: Journal of Clinical Oncology (2009)

6601 Background: Data on success and failure rates of clinical studies are cruelly missing, especially for public funded programs. The French Cancer Plan 2003–2007 has launched such program as a specific extension of the wider ‘Programme Hospitalier de Recherche Clinique‘ (PHRC). Grant applications are submitted yearly. Funding is competitively based, projects being selected by a national committee supported by independent experts. A substantial financial support for the recruitment of clinical research associates (CRA) was launched simultaneously.We performed a preliminary analysis of the projects’ outcome 5 years after their funding. Methods: We carried out a survey of the projects funded in 2003 and 2004. A questionnaire was sent to the principal investigator. Data on project status, number of patients recruited per project, reasons for delay or failure, and publication results were collected. Projects were classified as failure (not started or closed for lack of inclusions) or success (ongoing or completed). Results: Of 257 projects submitted, 85 (33%) were selected. Of them, 24 failed (28%). Higher failure rates were observed for breast (5/11, 45%), gastrointestinal tract (6/16, 38%), genitourinary tract (4/11, 36%), and immune or cell therapy (8/15, 53%) projects. In contrast, haematological malignancies projects showed a low failure rate (3/20, 15%) as well as studies associated with translational research (6/34, 18%) or led by cooperative groups. The main reason for trials delay or failure was recruitment difficulties, due to overestimation of recruitment potential or restrictive inclusion criteria. Very few (&lt; 5%) mentioned difficulty raised by the evolution of the scientific question or competing studies. No financial issue was reported. With 4-year of follow-up, 25% and 52% of projects have been respectively published in a peer-reviewed journal or presented at scientific meetings. Conclusions: In this first set of trials funded by the French Cancer Plan 2003–2007, more than a quarter failed despite apparent adequate funding. Main cause was a discrepancy between inclusion potential announced and real accrual. Application processes should evaluate more carefully this issue in order to improve the effectiveness of public health funding interventions in the future. No significant financial relationships to disclose.
Population pharmacokinetics (PPK) of eribulin mesylate in patients with locally advanced or metastatic breast cancer (MBC)
Authors: M. Jansen, M. Vernaz-Gris, C. DesJardins, N. Wong, M. Campone, J. Cortes, J. Wanders, D. Shuster, E. Fuseau
Journal: Journal of Clinical Oncology (2009)

2524 Background: Eribulin mesylate (E7389) is a non-taxane microtubule dynamics inhibitor with a novel mechanism of action. A study was conducted to evaluate efficacy, safety and pharmacokinetics of eribulin at a dose of 1.4 mg/m 2 for locally advanced or MBC in patients previously treated with an anthracycline, a taxane, and capecitabine. Methods: Eribulin was administered intravenously over 2–5 minutes at a dose of 1.4 mg/m 2 on days 1 and 8 of a 21- day cycle to 291 patients. Four plasma samples were collected between 5 min and 120 hours after the first dose. Plasma eribulin concentrations were determined by LC/MS/MS. A total of 774 samples, from 209 patients with complete dose and sampling information were included in the PPK analysis, which was conducted using nonlinear mixed effects modeling (NONMEM). Results: Eribulin PKs were best described by a three-compartment model, with elimination from the central compartment. Distribution was rapid and elimination slow. For a typical patient with AST&lt;ULN and CLCR=101mL/min (Cockroft-Gault), clearance (CL) was 2.98 L/h and central volume of distribution 3.72 L (V1). Volumes and inter-compartmental clearances for the two peripheral compartments were 3.60 L (V2), 126 L (V3), 2.7 L/h (Q2) and 5.6 L/h (Q3). Inter-patient variability on CL was 57%, and ranged from 26- 98% for other parameters. Residual error was 21% (proportional). CL was on average 38% lower in patients with AST&gt;ULN and positively correlated with renal function. The covariate effects only explained a minor fraction of inter-patient variability in this single study dataset. Conclusions: Eribulin PKs were described by a three-compartment model with rapid distribution and slow elimination. Appreciable interpatient PK variability exists, a minor fraction of which was explained by measures of liver and renal function. [Table: see text]