tbuckley/cabot-search huggingface dataset:
A phase I/II trial of BMS-247550 for patients with recurrent high-grade gliomas
Authors: D. Peereboom, K. Carson, D. Lawson, G. Lesser, J. Supko, S. Grossman
Journal: Journal of Clinical Oncology (2004)

1546 Background: BMS-247550 is a semi-synthetic analog of epothilone B, a novel non-taxane microtubule-stablizing agent. A phase I/II trial of this agent in patients with recurrent high-grade glioma is in progress. Methods: Patients (pts) receive BMS-247550 on a 1-hour infusion, daily x 5 every 3 weeks. In the phase I portion, cohorts of 3 pts are treated at each dose level starting at 5 mg/m2/day. Pts are stratified into groups A and B according to the use or non-use, respectively, of cytochrome P450 enzyme-inducing anticonvulsants. Dose escalation for each group occurs separately using the continual reassessment method (CRM) to calculate each dose level. The MTD is reached when the CRM assigns two consecutive dose levels within 10% of the previous level. Pharmacokinetic sampling (PKs) occurs on days 1–5 of cycle 1. The phase II portion of the study combines group A and B pts at their respective MTDs in a standard 2-stage design. Results: Ten pts have entered the study, all on the phase I portion: median age 55 (range 41–71); 3 male; 3 in group A. All had received radiation and 9 had received prior chemotherapy. Group A completed dose level 1 (5 mg/m2) with no dose-limiting toxicities (DLT). Group B pts have received drug on 3 dose-levels: 5 mg/m2 (3 pts), 7.5 (1) and 6 (3) with 1 treatment-related death (sepsis/typhlitis) at 7.5 mg/m2 necessitating a dose de-escalation to 6 mg/m2. No other DLTs have occurred. Grade 2–5 treatment-related toxicities: Group A - 0 pts; Group B - 1 pt had G2 fatigue and 1 pt had G3 abdominal pain/cramps, G4 neutropenia, and G5 sepsis. All 8 pts evaluable for response have progressed. PKs are being assessed. Conclusions: To date, BMS-247550 has not shown new toxicities in glioma pts with the possible exception of typhlitis for which BMS-247550 could not be excluded as the cause. The most severe toxicity has been hematological. Dose escalation in group B is near completion, and the MTD will be close to that (6 mg/m2) established in non-CNS pts. Because BMS 247550 is a substrate for the P450 system, pharmacodynamic differences between the groups A and B may emerge with further accrual to the study. No significant financial relationships to disclose.
Sexual behavior (SB) and relationship satisfaction after first distant recurrence (REC) in metastatic breast cancer (MBC): Preliminary results from prospective trials
Authors: C. L. Shapiro, K. M. Carpenter, B. L. Andersen
Journal: Journal of Clinical Oncology (2004)

623 Background: The median survival of MBC is 24–36 months (mo), but the effects of REC on SB and relationships are largely unknown. We hypothesized that SB would decline after first REC, but satisfaction with the relationship would not decrease. Methods: From 1994 to 2000, 227 women with localized BC were randomized (R) to a psychosocial intervention or assessment-only group. With 60 mo mean follow-up, 31/227 (14%) had REC, and 24 (77%) enrolled on this study. Additionally, 21 women at first REC enrolled in parallel non-R prospective trial. Outcome measures included the single satisfaction item in Dyadic Adjustment Scale (DAS) measuring relationship satisfaction[3=happy (average),4=very happy], frequency of kissing (K)[6=4–6/wk,7=1/day] and sexual intercourse (SI)[1=1/mo, 2=1–2/mo], and sexual satisfaction (SS)[3=somewhat inadequate, 4=average]. Assessments occurred within 12 weeks of REC, and at 4- and 8-months post REC. As the demographic, disease, and treatment variables, and the outcome measures were mostly comparable among R and non-R REC groups, these data were combined and compared to the non-REC group. ANOVA and Chi-square tests were used to test for differences within and between REC and non-REC groups. Results: Demographic[age=52 years (yr), education=15 yr, income=$66,000, Caucasian=93%, married=69% or cohabiting=74%], disease, and treatment variables were similar in the REC and non-REC groups. There were no statistically significant differences in DAS, K, SI, or SS within, or between the REC and non-REC groups, although frequency of SI and SS tended to be slightly lower in the REC-group (see Table). Conclusions: These preliminary results suggest that SB, sexual and relationship satisfaction do not change much within the first 8 months after REC. Accrual is ongoing and updated results will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis
Eliciting early-response signals from first-in-human clinical trials and validation of prognostic scores in aggressive biology bone cancers: The MD Anderson experience.
Authors: John Andrew Livingston, Kenneth R. Hess, Joanna Grace Fernandez, Aung Naing, David S. Hong, Shreyaskumar Patel, Peter Meade Anderson, Robert S. Benjamin, Joseph A. Ludwig, Cynthia E. Herzog, Siqing Fu, Jennifer J. Wheler, Gerald Steven Falchook, Apostolia Maria Tsimberidou, Sarina Anne Piha-Paul, Filip Janku, Eric Rohren, Funda Meric-Bernstam, Razelle Kurzrock, Vivek Subbiah
Journal: Journal of Clinical Oncology (2014)

10531 Background: There have been no new US FDA approved therapies for bone sarcomas (osteosarcoma, Ewing’s sarcoma, and chondrosarcoma) in the last three decades. Current treatment options are limited and the prognosis of aggressive bone cancers remains extremely poor. Rarity poses an additional challenge in developmental therapeutics for bone sarcoma. Advanced relapsed/ refractory bone cancer patients may be enrolled in targeted therapy phase 1 trials which may provide unique insight and an opportunity to elicit early response signals. Methods: We systematically analyzed the characteristics and outcomes for advanced bone sarcoma patients referred for treatment on phase I trials at MD Anderson Cancer Center (MDACC) from 7/2005 to 11/2013 with an emphasis on targeted agents. In addition we sought to validate the Royal Marsden Hospital (RMH) score and the MDACC score as survival stratification tools within this population. Results: Among the 92 patients analyzed [Ewing’s sarcoma N=47, osteosarcoma N=22, chondrosarcoma N=16, chordoma N=5, Other N= 2] median age at phase I trial referral was 24 (range 11 to 79), 58 (63%) were males; ECOG PS was zero in 25 pts (27 %), the number of metastatic sites were > 2 in 26 pts (28 %). The median number of prior chemotherapy regimens was 3 (range 0 to 11) and 57 pts (62 %) had prior radiation. Both RMH score (HR = 5.8 (2.9, 11), p < 0.0001) and MDACC score (HR = 3.2 (1.9, 5.6), p < 0.0001) were successfully validated. Responses were seen in IGF1R +/-mTOR therapy in Ewing’s sarcoma and Apo2L/TRAIL in chondrosarcoma. No responses were seen in osteosarcoma. Ten pts (11%) had stable disease. Clinical benefit rate (CR+ PR+SD > 6 mo) was 18% (17 pts). Conclusions: Both the RMH and MDACC prognostic scores were validated for predicting overall survival in patients with bone cancers who were referred for phase 1 trials. Responses were seen with targeted therapies in Ewing’s sarcoma and chondrosarcoma, however prognosis remains poor. Novel approaches are urgently needed for bone sarcomas.
Adjuvant chemotherapy containing oxaliplatin without radiotherapy to improve survival of local advanced low and middle rectal cancer.
Authors: Ke-Feng Ding, Jun Li, Yong-Mao Song, Jian-Wei Wang, Ying Yuan, Suzhan Zhang
Journal: Journal of Clinical Oncology (2012)

e14024 Background: In this study, the impact of oxaliplatin on survival of local advanced rectal cancer patients were analyzed by comparing the survival of patients accepted only radical surgery (group S) and patients accepted radical surgery following oxaliplatin-containing adjuvant chemotherapy (group SO). Methods: The data of patients, who accepted radical surgery in our center from Jan 2002 to Jun 2009, were reviewed. Inclusion criteria: carcinoma ≤12 cm from the anal verge; pathologically confirmed T3/4 or N1/2; without history of malignancy; neither transanal nor transsacral resection. Patients who accepted radiotherapy were excluded. The disease specific survival (DSS) and overall survival (OS) of patients in group S and SO were analyzed. Results: 236 patients were included in analysis (S 135 vs. SO 101), including 11 patients without survival information. The most of patients' basic characteristics were similar in two groups (P&gt;0.05). However, the ratio of stage II patients in group S was higher than that in group SO (51.9% vs. 27.0%, P&lt;0.001). The DSS of group SO were higher in patients with stage II, N1a or mucious adenocarcinoma than patients in group S (P&lt;0.05). The OS of group SO were higher in patients with N1a, N2 or mucious adenocarcinoma than patients in group S (P&lt;0.05). Conclusions: Adjuvant chemotherapy containing oxaliplatin improved survival of local advanced low and middle rectal cancer. Randomized perspective trials are needed to clarify the importance of oxaliplatin for rectal cancer. [Table: see text]
Antitumor activity of panRAF inhibition in BRAF V600E metastatic colorectal cancer.
Authors: Alex Sorokin, Lea Bitner, Ji Wu, David Menter, Scott Kopetz, Van Karlyle Morris
Journal: Journal of Clinical Oncology (2017)

616 Background: BRAF V600E mutations, present in &lt;10% of patients with metastatic colorectal cancer (mCRC), are associated with low responses to chemotherapy and poor survival outcomes. Targeted therapies against BRAF and EGFR have shown promising clinical activity. The panRAF inhibitor (PRI) LSN3074753 inhibits dimerization of all RAF isoforms to impede downstream MEK activation, with no reflexive MAPK reactivation common with other BRAF inhibitors. Anti-tumor activity of PRI has not been compared to BRAF + EGFR inhibition in patient-derived xenograft (PDX) models of BRAF V600E mCRC. Methods: Two PDX models of BRAF V600E mCRC (B1003 and C0999) were generated. C0999 featured a concomitant KRAS G12D mutation following resistance to the BRAF V600E kinase inhibitor vemurafenib. Mice were treated daily with oral PRI or with the combination of vemurafenib + intraperitoneal cetuximab. Tumor volumes were measured twice weekly. B1003 and C0999 cell cultures were established to test the interaction between PRI and palbociclib or BYL319 (PI3K inhibitor). Results: PRI was tolerated at a dose of 60 mg/kg and demonstrated a reduced tumor volume in the B1003 model after 28 days when compared to untreated controls (P=.03). No difference in tumor volume was seen between PRI and vemurafenib + cetuximab (P=.08). Assessment of anti-tumor activity by PRI in the vemurafenib-resistant BRAF V600E/KRAS G12D C0999 model will be reported. Cell culture from both the B1003 and C0999 models demonstrated synergism for PRI with palbociclib (ED50 .41 and .62 for the 2 models, respectively) and with BYL319 (ED50 .48 and .86, respectively). Conclusions: panRAF inhibition demonstrates similar anti-tumor activity to BRAF + EGFR inhibition in PDX models of BRAF V600E and represents a promising treatment strategy for further combination studies targeting additional critical signaling pathways in mCRC.
Pilot study of immunological factors in non-inflammatory bowel disease enterocutaneous fistulas
Authors: Goher Rahbour, Janindra Warusavitarne, Ailsa L Hart, Philip J Tozer, Mohammad R Ullah, Gregory P Thomas, Simon M Gabe, Stella C Knight, Hafid O Al-Hassi, Carolynne J Vaizey
Journal: International Journal of Surgery (2017)
Multifocal myxoid liposarcoma: Metastasis or second primary? A molecular biological analysis
Authors: R. S. de Vreeze, D. de Jong, P. M. Nederlof, H. J. Ruijter, L. Boerrigter, R. L. Haas, F. van Coevorden
Journal: Journal of Clinical Oncology (2009)

10576 Background: The metastatic or second primary nature of multifocal myxoid/round cell liposarcoma (MRLS), defined as tumor presentation in at least two separate sites before manifestation in the lungs, is a matter of debate with essential clinical consequences. Characteristic genetic alteration for MRLS include the t(12;16)(q13;p11) or t(12;22)(q13;q12), of which various exon fusion transcripts are described with highly varying incidences, permitting use as a marker for clonality. Moreover, in solid tumors, analysis of loss of heterozygozity (LOH) has proven its value for clonality analysis. Methods: Fifteen patients with features fitting to the criteria of multifocal MRLS with 2–5 metachronous (n= 12) or synchronous (n=3) localizations were investigated. Using RT-PCR, the detailed molecular characteristics of FUS-CHOP and EWS-CHOP breakpoints were determined. LOH analysis at 12 loci on 11 chromosomes was used to further analyze clonal relationships and a dedicated algorithm for interpretation in MRLS was developed. Results: In all patients, tumor sites showed identical FUS-CHOP exon fusion products. In six patients, identical rare fusion transcripts were found, strongly supporting clonal relation. Nine patients had the common exon5-FUS/exon2-CHOP fusion transcript, of which two were identified as clonally related by LOH analysis. In all other patients, LOH analysis was highly suggestive of clonal relation and no evidence for interpretation of a second primary tumor was found. Conclusions: This study supports the metastatic nature of apparent multifocal MRLS. Therefore, in these cases the optimal treatment should be chosen as for this metastasis is preferred, in which case all treatment modalities can be considered. No significant financial relationships to disclose.
Disease management: has it a future?
Authors: D. J Hunter
Journal: BMJ (2000)

Education and debate p 563, 566

Disease management, often known as integrated care or care pathways, has wide appeal for health care reformers keen to contain costs and improve outcomes. 1 2 Integrated care is a key plank in the government's NHS modernisation programme.3 It is also particularly relevant to chronic illness.

Disease management commands wide international support as the optimal approach to planning and delivering health care.4 It is welcomed as a structured systems response to a set of problems that are evident to some degree in all health services. These include uncoordinated arrangements for delivering care, a bias towards acute treatment, a neglect of preventive care, and inappropriate treatment. The theory behind disease management is that resources can be used more effectively if the patient becomes the pivot around which health care is organised.5 In place of functional divisions, such as those between primary care and hospitals or between different clinical specialties, the divisions …
A novel low molecular weight inhibitor of focal adhesion kinase and insulin-like growth factor-1 receptor, TAE226, inhibits glioma growth
Authors: J. N. Rich, Q. Shi, A. B. Hjelmeland, S. T. Keir, S. Wickman, G. Wu, D. Jackson, O. Ohmori, D. D. Bigner, H. S. Friedman
Journal: Journal of Clinical Oncology (2006)

11505 Background: Glioblastomas are highly lethal cancers that resist current therapies. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase overexpressed in glioblastoma patient specimens that may promote glioma growth and invasion by increasing cellular adhesion, migration, invasion, proliferation. TAE226 is a novel low molecular weight inhibitor of several kinases that demonstrates in vitro activity primarily against FAK with activity against insulin-like growth factor-1 receptor (IGF1R) at higher concentrations. Methods: As FAK and IGF1R are potential molecular targets in glioblastomas, we examined the efficacy of TAE226 against human glioma cell lines and xenografts. Results: TAE226 inhibited the activating phosphorylation of FAK at submicromolar concentrations with residue specific preference. Downstream effectors (Akt and ERK) were inhibited at slightly higher concentrations. TAE226 demonstrated a concentration-dependent decrease in cellular proliferation with an associated G 2 cell cycle arrest in multiple glioma cell lines, whereas TAE226 potently induced apoptosis in a concentration-dependent manner in only one of four cell lines tested. TAE226 also induced a concentration-dependent decrease in cellular adhesion, migration, and invasion. In preliminary animal studies, a limited course of orally administered TAE226 (100 mg/kg qd 5 days on/2 days off/5 days) was well tolerated with minimal weight loss. TAE226 induced a modest growth delay of human glioma xenografts grown in a subcutaneous location in athymic mice (3 to 4 days delay, p &lt; 0.001). In addition, mice bearing orthotopic intracranial human glioma xenografts demonstrated a modest increase in median survival (3.5 days, p = 0.078). Despite the modest degree of the tumor responses, these results are superior to other low molecular weight inhibitors, such as epidermal growth factor receptor (EGFR) inhibitors. As glioma xenografts often grow without invasion, these results may underestimate the efficacy of targeting FAK as FAK plays a major role in tumor invasion. Conclusion: TAE226 demonstrates modest activity as monotherapy against malignant gliomas and warrants further investigation, potentially in combination with other therapies. [Table: see text]
A pharmacokinetic (PK) and pharmacodynamic (PD) biomarker-driven phase I study of intermittent, low dose intensity schedules of the dual MEK/RAF inhibitor, RO5126766 (RO) in patients (pts) with advanced solid tumors.
Authors: Maria Jose de Miguel Luken, Desamparados Roda, Raquel Perez Lopez, Begona Jimenez, Hasina Hassam, Nitharsan Sathiyayogan, Mona Parmar, Alison Joanne Turner, Emma Hall, Nina Tunariu, L Rhoda Molife, Timothy Anthony Yap, Johann Sebastian De Bono, Udai Banerji
Journal: Journal of Clinical Oncology (2015)

104 Background: RO5126766 is a novel dual MEK-RAF inhibitor. A previous phase I study explored high dose intensity schedules that were limited by a t1/2 of 60 hours and a challenging toxicity profile. We hypothesised that schedules that achieve significant target modulation but a lower dose intensity due to intermittent dosing will lead to clinically effective and tolerable schedules of RO5126766. Methods: The aims of this investigator-initiated study (EudraCT: 2012-001040-22) were to determine the tolerability, PK, PD and preliminary antitumor activity of 2 dosing schedules: orally once daily on Mon-Wed-Fri (MWF) and Mon & Thu (MT). An expansion cohort mandated patients (pts) with K- or N-RAS/B-RAF mutations. Plasma PK and phosphorylated (p)-ERK in peripheral blood mononuclear cell (PBMCs) were analysed. Tumor PD was assessed in pre- and post-treatment tumor biopsies and diffusion-weighted MRI (DWI). Results: To date, 29 pts have been treated. MWF schedule; 3.2 mg and 4 mg (n = 7 each) and MT schedule; 4 mg (n = 8) and expansion cohort (n = 7). Dose-limiting toxicities (DLTs) on the MWF schedule were G3 blurred vision (n = 1) at 4 mg, and G3 skin rash and G4 creatine kinase (CK) elevation (n = 2) at 3.2 mg. No DLTs were recorded in the MT schedule. Most common toxicities were rash, CK elevation, fatigue, mucositis and diarrhea. PK profile at 4 mg MT showed a Cmax of 247 ng/mL and an AUC of 3,580 ng.hr/mL, consistent with growth inhibition in xenograft models. Maximal PD inhibition of p-ERK in PBMCs was 83% at 3.2 mg, thus both 3.2 mg and 4 mg were in the pharmacodynamically active range. Based on the tolerability, PK and PD profiles, 4 mg MT was declared the recommended phase 2 dose (RP2D). At the RP2D, 3/7 (42.9%) pts with KRAS mutations (NSCLC, ovarian and endometrial cancers) achieved RECIST confirmed partial responses and DWI showed increased apparent diffusion coefficient (ADC) at 15 days post-dose in these pts. Recruitment to the expansion cohort is ongoing. Conclusions: The RP2D of RO5126766 was defined as 4 mg orally, delivered twice a week, MT, and is associated with preliminary promising single agent activity in KRAS mutant tumors. Clinical trial information: 2012-001040-22.
Stimulating an immune response through bavituximab in a phase III lung cancer study.
Authors: David E. Gerber, Joseph Shan, Ulrich Keilholz, David R. Spigel, Leora Horn, Rebecca Suk Heist, Rachel E. Sanborn, Paul N. Mainwaring, Chandra Prakash Belani, Martin J. Edelman
Journal: Journal of Clinical Oncology (2014)

TPS8129 Background: Escape from immune surveillance is a frequent mechanism of tumor initiation, proliferation, and resistance to treatment. Bavituximab is a chimeric monoclonal antibody with immune modulating properties. Bavituximab targets exposed phosphatidylserine (PS) on tumor vascular endothelium, tumor cells and tumor derived exosomes. Exposed PS in the tumor microenvironment suppresses immune and inflammatory responses by binding to PS receptors on myeloid derived suppressor cells (MDSC) and M2 macrophages, which leads to production of anti-inflammatory cytokines such as TGF-β and IL-10which inhibits the development of an adaptive immune response. In preclinical models, PS-targeting antibodies counter these effects, resulting in production of pro-inflammatory cytokines such as TNF-α and IL-1β, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte immunity. Administration of docetaxel increases PS exposure within the tumor microenvironment and also suppresses MDSCs, thereby enhancing bavituximab's effects. In a double-blind Phase II clinical trial, bavituximab 3 mg/kg plus docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 month) in median overall survival (OS) compared to control. Methods: In this randomized, double-blind, global Phase III clinical trial, approximately 600 pts with second-line stage IIIb/IV non-squamous NSCLC will be randomized 1:1 to receive up to six 21-day cycles of docetaxel 75 mg/m2 with placebo or bavituximab 3 mg/kg weekly until disease progression or unacceptable toxicity. Patients must have one progression on platinum doublet therapy for advanced disease. Prior maintenance or targeted therapy is allowed if only 1 progression occurred. Within each geographic region, patients will be stratified by disease stage and prior maintenance/targeted therapy. The primary endpoint is overall survivaland secondary endpoints include overall response rate (modified RECIST 1.1), progression free survival (PFS) and safety. Clinical trial information: NCT01999673.