tbuckley/cabot-search huggingface dataset:
The steroid sulfatase inhibitor BN83945 inhibits the E1S stimulated growth of DMBA induced mammary tumors in rat
Authors: G. P. Prevost, Z. Koob, F. Bichat, M. Hillairet de Boisferon, E. Bascompta, A. Perez, L. Woo, A. Purohit, B. V. Potter, M. Reed, T. Ali
Journal: Journal of Clinical Oncology (2008)

14683 Background: Steroid sulfatase (STS) is a new target for the treatment of steroid hormone-dependent diseases such as breast, prostate or endometrial cancer. In breast cancer, estrogens play a major role in the establishment of the disease and between one to two- thirds of tumours are estrogen receptor (ER) positive. Despite current hormonal treatments, improvement is still necessary to achieve better disease control & improve disease outcome. BN83495 is a non-steroidal, non-estrogenic, potent, irreversible STS inhibitor that blocks both the formation of E1 from estrone sulfate (E1S) and androstenediol from DHEAS. Methods: The ability of BN83495 to inhibit E1S- stimulated tumor growth in the rat was examined in a DMBA-induced mammary tumor model. Results: Based on median tumor volume and the interquartile range at the end of the treatment period, BN83495 displayed the greatest antitumor activity compared to Tamoxifen or Fulvestrant. Addition of Fulvestrant or Tamoxifen to BN83495 did not improve on the potent antitumor activity already observed with BN83495 alone. Pharmacokinetic data of BN83945 and estradiol levels were generated during this study and are discussed. Conclusions: Altogether, these preclinical results have supported the entry of BN83945 into further clinical trials for estrogen receptor- positive breast cancer patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ipsen
Paclitaxel and gemcitabine vs carboplatin and gemcitabine. A multicenter, phase III randomized trial in patients with advanced inoperable non-small cell lung cancer (NSCLC)
Authors: P. A. Kosmidis, C. Kalofonos, K. Syrigos, D. Skarlos, G. Fountzilas, C. Nicolaides, D. Bafaloukos, E. Samantas, C. Bakogiannis, A. M. Dimopoulos
Journal: Journal of Clinical Oncology (2005)

7000 Background: This phase III study was designed to compare the combination paclitaxel - gemcitabine (PG) versus carboplatin - gemcitabine (CG) in patients with advanced inoperable NSCLC. Methods: Chemotherapy - naïve patients with performance status (PS) of 0 or 1 were randomized to gemcitabine 1gm/m2 on days 1 and 8 plus either paclitaxel 200mg/m2 on day 1 (arm A) or Carboplatin at an area under the concentration - time curve of 6 on day 1 (arm B) every 3 weeks. Primary endpoint was overall survival (OS). Secondary endpoints included objective response (OR), time to progression (TTP) and toxicity. For a two-sided test at the 5% level of significance and power of 80%, the number of patients required to detect a 10% difference in survival rate was 417. Results: A total of 512 patients were enrolled and 445 evaluable (arm A, 222; arm B, 223) were analyzed. All characteristics were well balanced. As shown in the table below with a median follow-up time 23 mos (0.1 - 48.16) there was no difference in the OS, one-year survival, OR and TTP. However, statistically significant differences were seen in toxicity. Conclusions: The two regimens are equally active. Myelotoxicity is worse in the CG group whereas alopecia, myalgia and neurotoxicity worse in the PG group. No significant financial relationships to disclose.
Bevacizumab (B) plus erlotinib (E) for patients (pts) with recurrent ovarian (OC) and fallopian tube (FT) cancer: Preliminary results of a multi-center phase II trial
Authors: G. Friberg, A. M. Oza, R. J. Morgan, E. E. Vokes, D. R. Gandara, G. F. Fleming
Journal: Journal of Clinical Oncology (2006)

5018 Background: The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are commonly over-expressed in OC and correlate with poor prognosis. The anti-VEGF antibody B and the EGFR tyrosine kinase inhibitor E have each demonstrated activity in OC. Dual inhibition with BE may overcome mechanisms of resistance encountered with either agent alone. Methods: We are conducting a 2-stage phase II trial of BE in pts with recurrent OC, primary peritoneal, and FT cancer. Eligible pts had ≤ 2 prior chemo regimens for recurrent or refractory disease; no prior VEGF or EGFR inhibitors; ECOG performance status (PS) 0–2; measurable disease; normal organ function; no proteinuria (&lt;1000 mg/24 hours). B 15 mg/kg was given IV on day 1 every 21 days and daily E 150 mg PO was given continuously. CT scans were obtained every 9 weeks. 2 responses are required in the first stage to justify accrual into a second stage. Results: 13 pts enrolled at 3 centers from 7/05 to 10/05. Median age: 56 (range 45–70). PS (N with 0/1/2): 6/4/3. Primary site (N): OC 11, FT 2. Primary platinum response (N): refractory 4, resistant (&lt;12 mo PFS) 2, sensitive (≥12 mo) 7. Total prior chemo regimens (N with 1/2/3): 1/8/4. 55 cycles of BE have been delivered (median 4, range 1–8). 12 pts are evaluable for response (1 too early). There has been 1 major response (8%). 8 patients (67%) had stable disease (SD). 1 pt with SD met 75% CA-125 response criteria. 8 pts remain on study. Median PFS has not been reached (median f/u 2.2 months). Attributable toxicities (N with grade 1/2/3/4): rash 4/7/0/0, diarrhea 6/1/2/0, stomatitis 3/1/0/0, myalgias 4/0/0/0, proteinuria 3/0/0/0, bilirubin 0/2/0/0. There were 2 bowel perforations (grade 3/4): both had 2 prior regimens, peritoneal implants &gt;1 cm, 3 doses of B (last was 10 and 42 days prior), and small bowel obstructions in the preceding 28 days. Conclusions: The first stage of accrual is complete and further enrollment is on hold pending continued efficacy evaluation. There appeared to be an increased rate of bowel perforation, and identification of potential risk factors for this event would be critical for further development of this combination. Updated results will be presented. Supported by NCI Grant N01-CM-17102. [Table: see text]
Phase I/II study of taxane and estramustine with samarium in patients with hormone refractory prostate cancer
Authors: S. L. Arnsmeier, S. Spies, D. Shervin, M. Pins, R. C. Bergan
Journal: Journal of Clinical Oncology (2004)

4732 Background: Though metastatic prostate cancer (PCa) is a systemic disorder, bone disease predominates in its clinical management. Sm-153 lexidronam (Quadramet) is a bone seeking radioisotope. Though used for pain, preliminary data suggests that Quadramet may have direct anticancer activity. To evaluate the toxicity and efficacy of systemic therapy given in combination with Quadramet, we initiated a phase I/II study in patients with hormone refractory PCa. Methods: Patients with progressive disease were first treated with fixed doses of taxol/estramustine, and were then treated with Quadramet, in a dose escalation fashion. The first six patients received taxol 200 mg/m2 plus estramustine (280 mg TID, for 5 days) given q 3 wks X 3 cycles. Subsequent patients received taxol 90 mg/m2 plus estramustine (for 3 days) q wk X 6, given q 8 wks X 2 cycles. Quadramet was administered in dose escalating fashion, starting at 1.0 mCi/kg, increasing to MTD. In addition to measurement of response and toxicities, dosimetry was evaluated by performing serial body scans. Results: Eight of twelve patients (75%) enrolled in the phase I trial had partial responses. One patient who did not respond to the combination of taxol/estramustine, had a significant PSA response after Quadramet. Dose limiting toxicity, grade 3 leukopenia, was seen in 1 of 6 people treated at the 1.5 mCi/kg level, and MTD has not yet been determined. While myelosuppression was the most common adverse effect, it has been mild and self limiting. Detailed dosimetry estimates will be provided. Conclusions: The combination of taxol/estramustine followed by Quadramet is a well tolerated and effective regimen for hormone refractory PCa. Early anecdotal findings provide proof-of-principal results supporting the notion of the benefit of adding bone directed agents to systemic therapy. Myelosuppression with the combination is mild, manageable, and does not limit future therapeutic options. No significant financial relationships to disclose.
Anti-insulin-like growth factor-1 receptor (IGF-IR) monoclonal antibody cixutumumab plus mammalian target of rapamycin (mTOR) inhibitor temsirolimus in metastatic castration-resistant prostate cancer (CRPC).
Authors: D. E. Rathkopf, D. C. Danila, J. J. Chudow, M. J. Morris, S. F. Slovin, S. Fine, J. J. Fox, S. M. Larson, N. Rosen, H. I. Scher
Journal: Journal of Clinical Oncology (2010)

TPS242 Background: This is an ongoing study of cixutumumab (cix) and temsirolimus (tem) in chemo-naive patients with metastatic CRPC. Cix, a fully human IgG1 monoclonal antibody, specifically targets IGF-IR with high affinity and antagonizes IGF-I and IGF-II ligand binding and signaling. It inhibits the IGF-IR pathway by effecting internalization and degradation of IGF-IR. In vitro and in vivo, cix inhibits proliferation of a variety of human tumor cell lines (Cancer Res. 2003;63:8912; Clin Cancer Res. 2005;11:3065). Temsirolimus inhibits mTOR, (Oncogene 2007;26:1932) and has been shown to inhibit growth of histologically diverse tumor cells. Since activation of phosphatidylinositol 3-kinase (PI3K)/AKT/mTor signaling is associated with negative feedback on IGF-1R and other upstream pathways, it is hypothesized that relief of this negative feedback with a rapamycin-analog may paradoxically activate IGF/AKT signaling, thus attenuating antitumor effects. Inhibition using an IGF-1R antibody in addition to mTOR inhibition may restore antitumor activity (Cancer Res 2006;66:1500). Prostate cancer, despite a high frequency of PTEN loss (>50%) and AKT/mTOR signaling, is relatively insensitive to single agent mTOR inhibition and is an ideal setting to test an IGF-1R antibody in combination with mTOR inhibition. Methods: The starting dose of cix [6 mg/kg intravenous (i.v.)] and tem (25 mg i.v.) is based on phase I studies of the combination in advanced solid tumors. If not tolerated in the first 6 patients with CRPC, the dosage will be systematically decreased. The primary endpoint is tumor response rate and/or composite time to progression in 20 patients. If predetermined efficacy criteria based on reported results with cix alone in CRPC (J Clin Oncol 27:15s, 2009; abstr 5142) are met, the study will proceed to a randomized phase II study of cix alone vs cix with tem. Correlative studies include analysis of circulating tumor cells, FDG PET imaging, and optional FDHT PET and tumor biopsies. This study is a DOD/PCF PCCTC trial sponsored by CTEP. No significant financial relationships to disclose.
Evaluation of clinical use of darbepoetin alfa in patients with chemotherapy-induced anemia
Authors: A. Bustos, M. A. Cruz, P. Aramburo, F. Carabantes, N. Díaz, J. Florián, M. Lázaro, J. M. Martín de Segovia, J. A. Gasquet, A. Alegre
Journal: Journal of Clinical Oncology (2009)

e20585 Background: Chemotherapy-induced anemia (CIA) is a frequent complication of patients (pts) with cancer and could be treated with erythropoiesis-stimulating agents such darbepoetin alfa (DA). The aim of this study was to investigate the patterns of use and effect of DA to treat CIA in clinical practice conditions. Methods: This was an observational, retrospective, multicenter study performed in 58 Spanish centres. Eligible pts were ≥18 yrs, diagnosed with non-myeloid malignancies and treated with chemotherapy (CT) and DA from October 2005 to October 2006. Data on demographic and clinical characteristics, CT and radiotherapy (RT), DA administration, red blood cell (RBC) transfusions, and haemoglobin (Hb) levels were collected from DA treatment initiation up to a maximum of 16 weeks or until treatment discontinuation. Results: A total of 685 pts were included in the study. Median age was 64.66 years (range 18.54–88.95), 50.7% were women, 74.11% had ECOG status 0–1 and 71.38% had stage III/IV cancer. Solid tumours represented 72.55% of the cases. The CT regimen included platinum derivates in 33.58% of the pts. At DA initiation, mean (SD) Hb was 10.00 g/dL (1.05) Administration of DA every three weeks occurred in 54.01% of the pts. Mean (SD) DA administration was 9.20 weeks (5.31). Hematopoietic response (defined as Hb ≥ 12 g/dL or Hb rise from baseline &gt;2 g/dL in the absence of RBC transfusions during the previous 28 days) occurred in 63.24% (95% CI 59.49–66.83) of pts. A total of 88 pts (12.85%) required RBC transfusions from week 5 to end of treatment. Mean Hb (SD) at the end of treatment with DA was 11.36 g/dL (1.73). Adverse event (AE) potentially related to DA were reported in 20 pts (2.92%) and considered severe in 6 cases (0.88%). Conclusions: The findings of this study indicate that the use of DA for the treatment of CIA in real-life, daily oncology and haematology practice, is well-tolerated and effective for increasing haemoglobin to reduce the need of RBC transfusions. [Table: see text]
HER2 overexpression is associated with shorter disease-free survival (DFS) following neoadjuvant systemic therapy (NST) of primary breast cancer (PBC) patients with gemcitabine (G), epirubicin (E) and docetaxel (Doc)
Authors: F. Marmé, J. Rom, F. Schütz, M. Eichbaum, P. Sinn, C. Sohn, A. Schneeweiss
Journal: Journal of Clinical Oncology (2007)

11087 Background: To evaluate prognostic factors for disease-free survival (DFS) following NST with G, E and Doc of patients with PBC. Methods: From 1/02 to 12/04 113 patients with T2–4 N0–2 M0 PBC received either six cycles of GEDoc (G 800 mg/m 2 day (d) 1+8, E 60–90 mg/m 2 d 1, Doc 60–75 mg/m 2 d 1 every three weeks; 63 patients) or five cycles of GE (1,250 mg/m 2 d 1, E 90–100 mg/m 2 d 1 every two weeks) sequentially followed by four cycles of Doc (80–100 mg/m 2 d 1every two weeks) with prophylactic filgrastim. 71% of tumours were hormone receptor positive, 24% HER2 positive (3+ by immunohistochemistry), 46% grade 3. 28 patients (25%) achieved a pathologic complete response (pCR) defined as no invasive tumour residue in the removed breast tissue at surgery. 9 of these patients had non-invasive cancer residues in the breast, one patient showed persisting axillary lymph node involvement. Results: With a median follow up of 3.2 years there is no statistically significant difference in DFS, distant DFS (DDFS) and overall survival (OS) rates between patients with and without pCR (DFS 79 versus (vs) 81 %, p=0,61; DDFS 82 vs 84 %, p=0.69; OS 86 vs 91%, p=0.33). In a Cox proportional hazards model HER2 3+ before NST (hazard ratio (HR)= 4.7; 95% confidence interval (CI) 1.9 - 11.3; p=0.0006), positive hormone receptors before NST (HR=0.27; 95% CI 0.11 - 0.65; p=0.003) and clinically nodal involvement before NST (HR=3.3; 95% CI 1.2–9.1; p=0.02) were statistically significant prognostic factors for recurrence whereas tumour size and grade before NST, the achievement of pCR, nodal status at surgery and response after 6 weeks of NST did not reach statistical significance. Thus far, in multivariate analysis only Her2 3+ before NST retained its prognostic significance (HR= 2.8; 95% CI 1.03 - 7.5, p=0.04). Conclusions: With a median follow-up of 3.2 years in multivariate analysis only HER2 3+ is associated with shorter DFS following NST containing G, E and Doc for PBC. Thus far, there is no statistically significant prognostic value for pCR. No significant financial relationships to disclose.
Phase II study of irinotecan (CPT-11) and cisplatin (CDDP) with concurrent split-course thoracic radiotherapy (TRT) in stage III non-small cell lung cancer (NSCLC)
Authors: S. Nagashima, M. Fukuda, A. Kinoshita, M. Fukuda, T. Kasai, H. Takatani, T. Rikimaru, H. Soda, M. Oka, S. Kohno
Journal: Journal of Clinical Oncology (2004)

7169
Could green tea extract inhibit the tumor growth and invasiveness of 5-FU and MMC-resistant metastatic and remetastatic cell lines in a hamster pancreatic cancer model?
Authors: C. Y. Morioka, F. P. Costa, S. Saito, A. Watanabe, C. C. Huang
Journal: Journal of Clinical Oncology (2008)

15621 Background: Polyphenolic compounds present in tea may reduce risk of a variety of illnesses,including cancer. Chemopreventive potential of tea polyphenols has been shown. Therapy of cancer includes the therapy of the metastatic disease and properties of the metastatic cells may vary condiderably from those observed in the primary tumor. Additionally, some reports attribute fail of the chemotherapy regimens to acquired chemoresistance to the drugs. However, there is a hypothesis that metastases have heterogeneous populations,and because of this they already have a resistant phenotype to the drug. Aim: To elucidate whether the same drugs, which could inhibit the tumor growth in the parental pancreatic cancer cell line, could inhibit in the metastatic pancreatic cell line. Moreover, whether it could inhibit in a remetastatic one, i.e., metastases from metastasis in a hamster pancreatic cancer model, comparing the inhibition with green tea extract. Methods: HaP-T1: a cell line derived from nitrosamine induced pancreatic cancer, MS-PaS-1: a pancreatic metastatic cell line established from a “return trip” metastases of liver implanted tumor, which showed pancreatic metastases, and MS-PaS-2: a pancreatic remetastatic cell line established from metastases of MS-PaS-1 from the same method were used for the experiments. 5-Fluorouracil (5FU), Mytomicin C (MMC) and green tea extract (GTE) were used. MTT assay and MTT agarose assay were performed. In vitro chemoinvasion assay was done. Results: The inhibitory concentration (IC50) of 5FU, which inhibited the HaP-T1, had to be increased in 50 folds to inhibit MS-PaS-1, and 100 folds to inhibit MS-PaS-2. MMC had to be increased 10 folds to inhibit MS-PaS-1, and 50 folds to inhibit MS-PaS-2. However, IC50 of GTE had to be increased 3 folds to inhibit MS-PaS-1, and 5 folds to inhibit MS- PaS-2. GTE inhibited the invasiveness of all 3 cells lines in a dose dependent manner. Conclusions: Green tea extract may be a new cancer strategy for pancreatic cancer because it could inhibit tumor growth and invasiveness in metastatic and remetastatic cells as well as in primary tumor cells in small doses when compared to 5FU and MMC, leading to the fact that side effects could be decreased. No significant financial relationships to disclose.
A placebo-controlled trial of Sertraline's effects on symptoms, well-being and survival in advanced cancer: The ZEST Trial
Authors: N. R. Wilcken, D. Goldstein, A. K. Nowak, P. J. Beale, M. Jefford, H. Dhillon, R. O'Connell, S. Heritier, R. J. Simes, M. Stockler
Journal: Journal of Clinical Oncology (2007)

9002 Background: Depression, anxiety, fatigue and impaired well-being are common, important and closely related in advanced cancer. We sought to determine the effects of sertraline (a well-tolerated, SSRI antidepressant) on these symptoms and survival in a broad cross-section of people with advanced cancer but without major depression. Methods: 189 participants (pts) were randomly allocated to sertraline 50 mg daily or placebo. Assessments were at baseline; months 1, 2, 4, 6, 9, 12; and, then 3-monthly. Outcome measures rated by pts included the: Centre for Epidemiologic Studies Depression scale (CES-D); Hospital Anxiety and Depression Scale (HADS-A, HADS-D); and the Functional Assessment of Cancer Therapy General and Fatigue scales (FACT-G and FACT-F). Clinicians completed Spitzer's Quality of Life Index (SQLI). Outcomes on all scales are expressed from 0 (worst) to 100 (best). The primary analyses of sertraline's effects on quality of life were based on scores at 4 and 8 weeks adjusted for baseline scores using generalised estimating equations. Efficacy analyses are by intention to treat; toxicity analyses by treatment received. P-values and 95% confidence intervals (CI) are 2-sided. Results: Recruitment was stopped after the first planned interim analysis of 150 pts showed a trend in overall survival favouring placebo (univariable logrank p=0.04; multivariable Cox model hazard ratio 1.61, CI 1.1 to 2.5, p=0.02). This trend was weaker at the final analysis including all 189 patients and longer follow-up (univariable logrank p=0.09); and, after accounting for baseline factors (multivariable Cox model hazard ratio 1.27, CI 0.87 to 1.8, p=0.2). Sertraline had no significant effects (scale: benefit over placebo, 95% CI) on depression (CES-D: 0.4, −2.6 to 3.4), anxiety (HADS-A: 2.0, −1.5 to 5.5), fatigue (FACT-F: 0.3, −4.3 to 4.9), overall quality of life (FACT-G: 1.7, −1.3 to 4.7) or clinicians’ ratings (SQLI: 2.0, −2.5 to 6.5). Subgroup and sensitivity analyses also excluded significant benefits. Sertraline was discontinued more often and earlier than placebo (logrank p = 0.03). The trial was closed for lack of benefit. Conclusions: Sertraline did not improve symptoms, well-being or survival and should be reserved for those with a proven indication. No significant financial relationships to disclose.
Results of G004, a phase IIb actively controlled clinical trial with the TGF-b2 targeted compound AP 12009 for recurrent anaplastic astrocytoma
Authors: P. Hau, G. Stockhammer, M. Kunst, A. Mahapatra, K. V. Sastry, V. E. Parfenov, V. G. Leshinsky, P. Jachimczak, U. Bogdahn, K. Schlingensiepen
Journal: Journal of Clinical Oncology (2006)

1566 Background: In 3 phase I/II dose-escalation studies the TGF-β2 specific compound AP 12009 proved to be well tolerated and revealed an excellent safety profile. Furthermore, antitumor activity including complete tumor remissions was observed. Methods: G004 is an international open-label, actively controlled, dose finding phase IIb trial in adult patients with histopathologically confirmed recurrent high-grade glioma. 145 patients with recurrent anaplastic astrocytoma (AA, WHO grade III) or glioblastoma (GBM, WHO grade IV) were enrolled into the study. Objective of the current phase IIb study is to compare the efficacy and safety of two doses of AP 12009 and standard treatment. Patients were randomized to receive either one of two doses of AP 12009 (10 μM or 80 μM) or standard chemotherapy (TMZ or PCV). AP 12009 was administered intratumorally by CED. 134 patients received treatment and all of them have completed active treatment. Primary endpoint is tumor response by local and central MRI reading and survival. Results: Here we report on patients with recurrent AA (for GBM see separate Abstract). 38 patients with AA (68% male, 32% female; median age 39, range 22–60; median Karnofsky performance status: 90, range 70–100) were treated. 26 patients received AP 12009 (10 μM or 80 μM), 12 patients were treated with TMZ or PCV. Up to now, in 89 patients treated with AP 12009 (both AA and GBM patients) 6 SAEs possibly related to the study drug and 37 procedure related SAEs (92% mild or moderate) were documented. Partial and complete tumor responses were observed. Exact response rates will be determined after central MRI reading is completed. Responses in the AP 12009 groups are long lasting. The results confirm the good safety profile of AP 12009 as well as the efficacy data seen in phase I studies. The median overall survival is not yet reached. Conclusions: The long-term tumor free survival of several patients may actually hint towards a potential to cure some patients with this devastating disease. Phase III clinical trials in both AA and GBM patients are currently in preparation. [Table: see text]