tbuckley/cabot-search huggingface dataset:
A first-in-man phase I study of R306465, a histone deacetylase (HDAC) inhibitor exploring pharmacokinetics (PK) and pharmacodynamics (PD) utilizing an electrochemiluminescent immunoassay in patients (p) with advanced tumours
Authors: P. C. Fong, S. Settatree, R. Sinha, A. Hardcastle, P. W. Hellemans, J. Arts, K. H. Brown, M. Janicot, W. Aherne, J. S. De Bono
Journal: Journal of Clinical Oncology (2007)

3578 Background: R306565 is an aromatic hydroxamic acid with predominant inhibitory effects on Class 1 HDAC enzymes (with IC 50 ∼10 nM). HDAC inhibitors (HDACi) affect gene expression at the transcriptional level, leading to cell cycle arrest and induction of apoptosis. Methods: P with solid tumours or lymphoma were given R306465 orally daily for 3 weeks (w) out of 4 in an escalating schedule. Objectives include safety, tolerability, PK (including food effect exploration), PD evaluation and circulating tumour cell (CTC) quantitation. Results: Four dose levels (100, 200, 300 and 400 mg) have been evaluated involving 15 p (7 male), age range 29–72 (median 59 y) and ECOG PS 0–2. A total of 37 cycles have been administered. Most common adverse events (AE) were Grade (G) 1–3 fatigue (87%), G1–2 nausea (66%), G1–2 vomiting (33%), G1–2 diarrhoea (40%), and G1–2 anorexia (40%). Dose limiting toxicity of G3 fatigue was seen in 1/6 p in the 400mg cohort. PK parameters were approximately dose proportional. Plasma concentrations increased in the fed state. PD effect of histone H3 acetylation (AcH3) in peripheral blood mononuclear cells (PBMC) was determined quantitatively with a novel validated electrochemiluminescent immunoassay developed in-house (applying Mesoscale Discovery technology). Although some interpatient variability exists, increased AcH3 was observed in 2/6 p in the 400 mg cohort, while the percentage rise in AcH3 was minimal for cohorts 1–3. Peak AcH3 achieved in 2 p dosed at 400 mg was approximately 5–10 fold increase over baseline. Using CellSearch technology for quantitation of CTCs, 8/14 p had detectable CTCs at baseline; the CTC trend will be presented. 4 p had stable disease (SD) for = 4 months. Conclusions: R306465 could be safely administered on a daily dosing schedule for 3 of 4 w up to 400 mg. Common toxicities seen were gastrointestinal and fatigue. Maximum tolerated dose has not been reached. PK suggests dose proportionality. Promising PD data showing increased acetylation in PBMC at 400 mg, further supports the utilization of the immunoassay platform in HDACi clinical trials. No significant financial relationships to disclose.
Preoperative FU-based chemoradiation with or without weekly oxaliplatin in locally advanced rectal cancer: Preliminary safety findings of the STAR (Studio Terapia Adiuvante Retto)-01 randomized trial
Authors: C. Aschele, C. Pinto, S. Cordio, G. Rosati, A. Bonetti, O. Alabiso, S. Siena, S. Pucciarelli, L. Boni, L. Cionini
Journal: Journal of Clinical Oncology (2007)

4040 Introduction: Oxaliplatin (OXA) significantly enhances the efficacy of 5-Fluorouracil (FU)-based chemotherapy (CT) in metastatic and radically resected, early stage colon cancer. Weekly OXA, at systemically active doses, can be added to preoperative FU-based pelvic chemoradiation (CRT) (Aschele, Ann Oncol 2005). Methods: An open-label, multicenter, randomized, phase III trial was launched to compare the efficacy (disease-free and overall survival) and activity (pathological response rate) of infused FU (225 mg/msq/day) concomitant to external-beam pelvic radiation (50.4 Gy in 28 daily fractions) (Arm A) to that of the same regimen plus weekly OXA (60 mg/msq weekly x 6) (Arm B). TME surgery is scheduled 6–8 weeks after completing CRT. FU-based adjuvant CT (4 cycles) is planned in both arms. Eligible patients (pts) have resectable tumors located within 12 cm from the anal verge and radiological evidence of perirectal fat or regional nodes involvement. Results: 410 pts (median age 63 years; males/females: 66/34 %; cT3/cT4: 66/18 %; cN+: 56 %; median distance from the anal verge: 6 cm) were randomized between 11/2003 and 10/2006 at 40 Italian centers. Toxicity data from the first 250 randomized pts are reported in the table . CRT was completed by 89 % and 74 % of pts in arm A and B, respectively. The median cumulative dose of delivered radiotherapy was 50.4 Gy in both arms. 120 of 123 pts in arm A and 109 of 112 pts in arm B were operated with a median interval from the end of treatment to surgery of 7.3 and 7.4 weeks, respectively. Conclusions: This analysis provides the first comparative toxicity data showing that OXA, at systemically active doses, can be safely added to standard FU-based CRT with an increased frequency and severity of acute toxicity but without major unexpected adverse events and without affecting the ability to deliver full RT doses and to perform surgery. [Table: see text] No significant financial relationships to disclose.
A randomized phase II study of Xcellerated T Cells with or without prior fludarabine therapy in patients with multiple myeloma (MM)
Authors: R. Vij, J. R. Berenson, I. M. Borrello, G. Spitzer, A. Bashey, T. Martin, R. V. Boccia, A. Simic, D. Siegel, M. W. Frohlich
Journal: Journal of Clinical Oncology (2005)

2582 Background: T cells from MM pts can be activated & expanded ex vivo using the Xcellerate Process, in which peripheral blood mononuclear cells (PBMC) are incubated with anti-CD3 & anti-CD28 antibody-coated magnetic beads (Xcyte Dynabeads). In a previous study (Siegel et al., ASH 2004), Xcellerated T Cells (XTC) administered to MM pts following autologous transplant led to accelerated lymphocyte recovery & clinical responses in the majority of pts. In the current study, pts with relapsed/refractory MM were randomized to XTC ± 1 cycle of fludarabine prior to XTC. Fludarabine was used to assess the influence of lymphoablation on T cell therapy; it has been reported to have no significant anti-tumor activity in MM (Kraut et al., Invest. New Drug, 1990). Methods: Pts underwent leukapheresis for collection of PBMC for the Xcellerate Process. All pts received a single dose of 60–100 x 109 XTC. Pts on the fludarabine arm received a single cycle (5 days at 25 mg/m2/day), completed 4 days prior to T cell infusion. Results: Of 30 planned pts, 28 have been enrolled, 19 treated & 16 are evaluable to date. 7 pts had received prior transplant. The median # infused cells was 77.1 x 109 (range 57.8–96.4 x 109), which were 98.9% CD3+. No serious adverse events related to XTC were reported. In the fludarabine arm (n=10), lymphocytes decreased from 1,212 ± 222/mm3 (mean ± SEM) to 444 ± 147 following fludarabine, & then increased to 1,840 ± 216 on Day 14 following T cell infusion. In the non-fludarabine arm (n=7), lymphocyte counts increased from 1,204 ± 148 to 3,218 ± 404 on Day 14. NK cells increased from 64 ± 17 to 104 ± 18 on Day 14 (n=17). On the fludarabine arm, 4 pts developed Grade 3 or 4 neutropenia & 2 developed Grade 3 or 4 thrombocytopenia. The fludarabine schedule was therefore decreased from 5 to 3 days. No significant decreases in M-protein have been observed to date. Conclusions: XTC were well-tolerated & led to increases in T lymphocytes. Fludarabine was lymphoablative, as anticipated, but caused neutropenia & thrombocytopenia. Additional follow-up & pts will be required to determine the activity of XTC in relapsed myeloma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Xcyte Therapies Xcyte Therapies Xcyte Therapies
Results of high-dose rate iridium-192 brachytherapy boost to external beam radiation therapy for prostate cancer in Japanese men
Authors: T. Satoh, M. Kitano, H. Ishiyama, S. Egawa, T. Arakawa, H. Okusa, K. Matsumoto, T. Fujita, K. Hayakawa, S. Baba
Journal: Journal of Clinical Oncology (2005)

4776 Background: Afterloading brachytherapy is the sole modality of interstitial radiotherapy currently available in Japan for treating prostate cancer. This technique has several advantages over permanent seed implantation, including absence of radiation protection and safety issues for patient. Also dosimetry can be based on images with the needles in situ, making it easy to optimize the dose. Currently several clinical trials reported that HDR brachytherapy is also appropriate for high risk (unfavorable) prostate cancer. To aim of this study is to evaluate treatment outcome of HDR brachytherapy and EBRT combined with or without neoadjuvant/adjuvant androgen ablation for patients with prostate cancer. Methods: From June 1999 to April 2003, 108 patients with clinically localized or locally extensive prostate carcinoma (T1N0M0-T3N0M0) were treated with HDR iridium-192 brachytherapy followed by 30 Gy EBRT. The whole prostate and any tumor extension beyond the capsule were irradiated five times over 3 days using an HDR Ir-192 source with a nominal activity of 370 GBq and each single dose was 7.5 Gy. Three days after HDR fraction, 3D conformal radiation was given using a fractionation of five times 3.0 Gy per week, specified at the isocenter, for 2 weeks. After June 2000, patients in the high risk group were given 6 months’ of neoadjuvant endocrine therapy followed by 36 months’ of adjuvant endocrine therapy following radiation therapy. The recommendations of the consensus panel of the ASTRO were followed for assessing biochemical failure. Results: The median age of the 108 patients was 70.5 years (range 50–84 years). Low risk patient was found in 20, intermediate risk in 30 and high risk in 58 patients, with a median follow-up was 31.5 months (range: 12–58months). The overall actuarial biochemical control rate (bNED) was 81.5%. The bNED in 36 months for low risk, intermediate risk, and high risk patient was 95.0%, 77.4% and 74.7%, respectively. Conclusions: HDR brachytherapy and EBRT combined with or without neoadjuvant/adjuvant androgen ablation is an effective treatment modality for prostate cancer and encouraging biochemical control rates after a median follow-up of 31.5 months. No significant financial relationships to disclose.
Observations on the General Effects of Injury in Man, with Special Reference to Wound Shock
Authors: R T GRANT, E B REEVE
Journal: JAMA (1952)

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A phase II study of paclitaxel and capecitabine combination chemotherapy in patients with advanced gastric cancer as a first-line therapy
Authors: H. J. Kang, T. W. Kim, H. M. Chang, M.-H. Ryu, J. H. Yook, S. T. Oh, B. S. Kim, J. S. Lee, W. K. Kim, Y.-K. Kang
Journal: Journal of Clinical Oncology (2004)

4051 Background: Paclitaxel and capecitabine, which have distinct mechanisms of action and toxicity profiles, showed considerable single-agent activity in gastric cancer. Synergistic interaction between these two drugs was also suggested by taxane-induced upregulation of thymidine phosphorylase. Therefore, we evaluated antitumor activity and toxicities of paclitaxel and capecitabine combination in patients with advanced gastric cancer (AGC) as a first-line therapy. Methods: Patients with histologically confirmed AGC with unresectable or metastatic diseases, measurable lesions, PS 0–2, age between 18 and 75, and no contraindication to chemotherapy were eligible in this study. Prior adjuvant chemotherapy finished at least 6 months before enrollment was allowed. Treatment included capecitabine 825 mg/m2 p.o. twice daily on days 1–14 and paclitaxel 175 mg/m2 i.v. on day 1 every 3 weeks until disease progression or unacceptable toxicities. Results: Between June 2002 and December 2003, total 40 pts were enrolled in this study. The median age was 57.5 years (range, 38–73). Twenty-nine pts were male. Nine pts had recurrent disease after previous curative gastrectomy and 8 had previous adjuvant chemotherapy. After a median 4 (range, 1–9) cycles of chemotherapy, thirty-four pts were evaluable for toxicity and 33 pts for response (6 pts too early for evaluation, 1 pt loss to follow-up). In intention-to-treat analysis, the overall response rate was 52.9% (95% C.I., 36.2–69.6%), including 0 CR, 18 PRs, 9 SDs, and 6 PDs. After a median follow-up of 8.6 months (range, 0.9–17.9), median time to progression was 5.3 months (95% C.I., 3.6–6.9) and median overall survival was 14.6 months (95% C.I., 8.5–20.7). The actual dose intensity was well maintained over 95% of planned during the first 4 cycles in both drugs. Commonly observed grade 3/4 adverse events were neutropenia (41.1% of patients), hand-foot syndrome (11.8%), arthralgia (8.8%). There was no neutropenic fever or treatment-related death. Conclusions:Paclitaxel and capecitabine combination chemotherapy was active and highly tolerable as a first-line therapy for AGC. No significant financial relationships to disclose.
Retrospective analysis of 24 synovial cell sarcoma patients treated with doxorubicin and ifosfamide.
Authors: S. J. Park, K. D. Glinert, A. P. Staddon
Journal: Journal of Clinical Oncology (2010)

e20508 Background: Synovial cell sarcoma (SS) has been reputed to be more responsive to treatment with doxorubicin and ifosfamide (AI) than to other treatments. However, a study by Gupta et al from ASCO 2009 suggests that SS patients experienced a minimal response to AI treatment. Therefore, we conducted a retrospective study at our outpatient oncology clinic of SS patients treated with AI. Methods: Between 2000 and 2009, 24 SS patients (10 female, 14 male) received at least 3 cycles of AI treatment. For these 24 patients, we determined the individual response to AI, progression-free survival (PFS), and overall survival (OS). PFS was measured from the date of the first cycle of AI treatment to the date of progression. OS was measured from the date of diagnosis to the date of death or until the writing of this abstract. Results: Of the 24 patients treated with AI, the median age was 36 (range: 16-67). At diagnosis, 3 patients (12.5%) were stage II, 17 (70.8%) were stage III, and 4 (16.7%) were stage IV. The median size of tumor at diagnosis was 8 cm (range: 3-30cm). 23 patients (95.8%) underwent surgery, and 18 patients (75.0%) received radiotherapy (RT). 10 patients (41.7%) received additional chemotherapy after AI treatment for recurrence of disease. As of the writing of this abstract, 5 patients (20.8%) have expired (4 with metastases, 1 with NED), 9 (37.5%) have evidence of disease (8 with metastases, 1 with local disease), and 10 (41.7%) have NED. In response to AI treatment, 12 patients (50.0%) had stable disease, 7 (29.2%) showed partial response (PR), 1 (4.2%) showed complete response (CR), 1 (4.2%) had progressive disease, and 3 (12.5%) had adjuvant treatment only. Of the 23 patients that did not have progressive disease during AI treatment, the median PFS was 26 months (range: 8-86 + months). The median OS was 52.5 months (range: 9-243 + months). Conclusions: The objective response (PR and CR) of the AI treatment was 33.3%. This compares favorably to the Gupta et al study which had an objective response of 20.0%. Previous studies of patients with soft tissue sarcomas show that AI treatment produces response rates of 20%-34%. Our study demonstrates that synovial cell sarcomas are more responsive to AI treatment than the average soft tissue sarcoma. No significant financial relationships to disclose.
Subpopulations with Iron Deficiency, Liver Disease, or HFE Mutations Revealed by Statistical Mixture Modeling of Transferrin Saturation and Serum Ferritin Concentration in Asians, African Americans, Hispanics, and Whites.
Authors: Christine E. McLaren, Victor R. Gordeuk, Wen-Pin Chen, James C. Barton, Ronald T. Acton, Mark Speechley, Oswaldo Castro, Paul C. Adams, Beverly M. Snively, Emily L. Harris, David M. Reboussin, Geoffrey J. McLachlan, Richard Bean, Gordon D. McLaren
Journal: Blood (2007)
The safety of BEMA (BioErodible MucoAdhesive) Fentanyl for breakthrough pain (BTP) in cancer patients
Authors: D. Blum, I. Breithaupt, S. Hackett, R. Kapoor, A. Finn
Journal: Journal of Clinical Oncology (2008)

20586 Background: The BEMA drug delivery system was designed for rapid oral transmucosal drug delivery with dose to dose reliability of plasma concentrations and ease of patient use. BEMA Fentanyl consists of a small, dissolvable, polymer disc formulated with the opioid narcotic fentanyl for application to the buccal membranes. The mucoadhesive polymers adhere and rapidly deliver fentanyl into the bloodstream. Methods: Subjects with cancer-related breakthrough pain (BTP) who were receiving concomitant chronic opioid therapy were enrolled in two studies: a double-blind, randomized, placebo-controlled, multiple crossover study (FEN-201) and an open-label study (FEN-202). In FEN-201, subjects entered a titration period followed by a double-blind period and received BEMA Fentanyl or placebo in random order. In FEN-202, subjects successfully completing FEN-201 and a second group of subjects meeting the same entry criteria as for FEN-201 were enrolled to receive open-label BEMA Fentanyl. Subjects in both studies were titrated to an effective dose (starting at 200μg and increasing to 1200μg in FEN-201 and 2400μg in FEN-202) and then continued with dosage adjustment as required. Results: In FEN-201, 141 subjects received an average of 14 doses of study medication over the course of the study. In FEN-202, a total of 220 subjects (70 from FEN-201 and 150 additional subjects) entered the study and received an average of 2.9 doses/day for 111.9 days (maximum duration of 531 days) in the open-label period. The most commonly reported treatment-related adverse events (AEs) during the titration and double-blind periods of FEN-201 were somnolence (6.0%), nausea (5.3%), dizziness (4.6%), and vomiting (4.0%). In the long-term safety study (FEN-202), these 4 events and constipation were the most commonly reported treatment-related AEs. There were no reports of treatment-related respiratory depression or death in either study. No unexpected findings or adverse trends were noted in vital signs or physical examination findings. Conclusions: BEMA Fentanyl administered in doses of 200 to 2400μg was shown to be safe and well-tolerated with no unexpected safety concerns. The AE profile of BEMA Fentanyl was consistent with the use of an opioid in patients with cancer and chronic pain. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration BioDelivery Sciences International BioDelivery Sciences International BioDelivery Sciences International BioDelivery Sciences International
Extremity soft tissue sarcoma: The need for a differential surgical approach to primary tumor and local recurrence?
Authors: A. Gronchi, R. Miceli, L. Mariani, M. Fiore, F. Grosso, P. Collini, P. Olmi, C. Mussi, P. G. Casali
Journal: Journal of Clinical Oncology (2006)

9565 Background: To explore the prognostic implications of local recurrence in extremity adult soft tissue sarcoma (eSTS). Methods: From January 1983 to December 2002, 1,017 patients with localized eSTS were treated at Istituto Nazionale Tumori, Milan, Italy. First local recurrence, re-operated with a curative intent, was investigated as a predictor of further recurrence, distant metastasis and cause specific mortality. Such a task was carried out considering recurrent patients earlier operated for primary disease at our institution (Group A, N=88) or elsewhere (Group B, N=150). The follow up of the above patients after recurrence was compared to that of the overall group of 738 patients operated for primary disease at our institution. Analyses were performed by multiple Cox models, in which local recurrence was entered as a time dependent factor, and tumour size, depth, histotype, grade, margins, RT and CT as covariates for the purpose of adjustment. Event-times were computed from the date of diagnosis, with “left censoring” on the time when patients entered our cohort (date of surgery). Results: The hazard ratio estimates of second recurrence, distant metastases and disease-specific mortality in groups A and B were 5.39 vs 2.95 (p&lt;0.001), 3.96 vs 1.54 (p&lt;0.001), and 2.93 vs 1.43 (p&lt;0.001), respectively. The prognostic effect of the covariates on mortality turned out to be not significantly affected by disease local relapse, but a trend for surgical margins in group A could be observed (HR 1.71). Conclusions: Local recurrence correlates with a worse prognosis, in terms of further local recurrence, distant metastases, and death. Such an effect is stronger following surgery at a referral center for eSTS if compared to local recurrence following surgery done elsewhere, i.e. at institutions less likely to perform adequate local treatment for this rare group of tumors. Possibly, this means that “true” local recurrences, not simply due to inappropriateness, single out pts carrying an inherently more aggressive disease. Consistently, these data cannot confirm, but neither rule out that more aggressive surgery (ie, at the cost of a higher amputation rate, in order to avoid contaminated surgical margins) may be needed in pts locally recurring after initial adequate surgery. No significant financial relationships to disclose.