tbuckley/cabot-search huggingface dataset:
A phase I study of TPI 287, a novel taxane, administered every 21 days in patients (pts) with advanced cancer
Authors: M. R. Modiano, P. Plezia, M. Basche, A. L. Cohn, Y. Baram, G. Tapolsky, S. Yancik, L. Pugliese, S. Silberman
Journal: Journal of Clinical Oncology (2008)

13510 Background: TPI 287 is a novel taxane engineered to overcome multi-drug resistance. In preclinical studies, TPI 287 suppressed the growth of multiple human tumor xenografts in nude mice, including xenografts that expressed mdr-1 and were resistant to other taxanes. The safety and tolerability of TPI 287 when administered every 21 days was examined in this Phase 1 dose escalation study in pts with advanced cancers. Methods: TPI 287 was administered over 1 hour every 21 days in ascending doses to groups of 3 pts. Treatment cohorts were expanded to 6 pts in the face of dose-limiting toxicity (DLT); pts could remain on study until the development of progressive disease or an intolerable adverse event. The maximum tolerated dose (MTD) was defined as the dose at which < 2/3 of pts experienced DLT. Results: 21 pts (M:F 5:9, median age 58.5, range 49 - 77) were enrolled in 5 dose levels ranging from 56 - 185 mg/m2. Pts’ cancers included colorectal (7 pts), pancreatic (2), NSCLC (2), breast (2) and one each carcinoid, cholangiosarcoma, esophageal, gastric, ovarian, and an unknown primary. Twenty pts had received prior chemotherapy (median #: 4 (range, 2 - 11). Pts received a median of 3 cycles (range 1–13). All patients experienced adverse events during the study, the most common being neuropathy (48%) anemia (38%), diarrhea (29%), nausea (29%), and neutropenia (24%). DLTs consisted of Gr 3 peripheral sensory neuropathy (3 pts) and neutropenia (2 Gr 3, 1 Gr 4). One pt with pancreatic cancer had a confirmed partial response (51% by RECIST) that lasted for 9 months and one patient with breast cancer had stable disease for over 6 months. Peak plasma concentrations (Cmax) and area under the curve (AUC) were generally dose linear at the 3 highest doses administered, and these parameters as well as the terminal elimination half life (HL) of TPI 287 were similar to values reported for paclitaxel infused for 1 or 3 hours at clinically relevant dose levels ranging from 135 to 175 mg/m2. Conclusions: TPI 287 can be safely administered in a dose of 160 mg/m2 every 21 days. The DLTs consisted of neuropathy and neutropenia. Anti-tumor activity was seen in two pts with pancreatic and breast cancers, respectively. PK is dose linear and predictable. Several Phase 2 studies using TPI 287 in this dose and schedule have been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Tapestry Pharmaceuticals, Inc. Tapestry Pharmaceuticals, Inc.
A phase II trial of radiation therapy with concurrent paclitaxel chemotherapy in high-risk endometrial cancer patients after staging operation: An interim analysis of a prospective multicenter trial (KGOG2001)
Authors: J. Kim, J. Jeong, B. Nam, S. Kim, C. Cho, B. Kim, J. Lee, Y. Kim, D. Bae, S. Kang
Journal: Journal of Clinical Oncology (2007)

16069 Background: This is an interim report of a prospective multicenter phase II trial to evaluate 2-year disease free survival rate, toxicity, overall survival rate and recurrence rate in high-risk endometrial cancer patients who received concurrent chemoradiotherapy after staging operation. Methods: Thirty four patients with endometrial cancer from 17 medical centers in Korea have enrolled the study. The cell types were all endometrioid type and they had no prior chemotherapy. They were in either stage III or IV and all received staging operation including total hysterectomy, bilateral salpingo-oophorectomy, pelvic and paraaortic lymph node dissection and washing cytology. Concurrent chemoradiotherapy was performed with paclitaxel (60 mg/m 2 /weekly, 6 cycles) and external field irradiation (5 fractions/week, total 4,500–5,040 cGy). Primary end point was 2-year disease free survival rate. Overall survival rate and recurrence rate were secondary end points. Toxicity of the treatment was also evaluated. Results: The expected number of subjects to complete the trial is 56. The trial was activated on 5 th June 2005 and median follow up period is 5.8 (0–11) months until December 2006. 19 patients (55.8%) have completed treatment regimen and 14 patients (41.1%) are still receiving treatment. 1 patient (2.9%) died during treatment of the disease and 1 patient (2.9%) was lost during the follow up period. Disease free survival is 94.1% (32/34) and no recurrence has occurred so far. Toxicities have occurred in 52.9% (18/34) with gastrointestinal symptoms (13/34, 38.2%) such as diarrhea and constipation being the most common ones. Conclusions: This interim report suggest a possibility that a concurrent chemoradiotherapy for high-risk endometrial cancer may be an optimal treatment option to improve disease free survival rate. [Table: see text]
Medicare D Subsidies and Racial Disparities in Persistence and Adherence With Hormonal Therapy
Authors: Alana Biggers, Yushu Shi, John Charlson, Elizabeth C. Smith, Alicia J. Smallwood, Ann B. Nattinger, Purushottam W. Laud, Joan M. Neuner
Journal: Journal of Clinical Oncology (2016)

Purpose To investigate the role of out-of-pocket cost supports through the Medicare Part D Low-Income Subsidy on disparities in breast cancer hormonal therapy persistence and adherence by race or ethnicity. Methods A nationwide cohort of women age ≥ 65 years with a breast cancer operation between 2006 and 2007 and at least one prescription filled for oral breast cancer hormonal therapy was identified from all Medicare D enrollees. The association of race or ethnicity with nonpersistence (90 consecutive days with no claims for a hormonal therapy prescription) and nonadherence (medication possession rate < 80%) was examined. Survival analyses were used to account for potential differences in age, comorbidity, or intensity of other treatments. Results Among the 25,111 women in the study sample, 77% of the Hispanic and 70% of the black women received a subsidy compared with 21% of the white women. By 2 years, 69% of black and 70% of Hispanic patients were persistent compared with 61% of white patients. In adjusted analyses, patients in all three unsubsidized race or ethnicity groups had greater discontinuation than subsidized groups (white patients: hazard ratio [HR], 1.83; 95% CI, 1.70 to 1.95; black patients: HR, 2.09; 95% CI, 1.73 to 2.51; Hispanic patients: HR, 3.00; 95% CI, 2.37 to 3.89). Racial or ethnic persistence disparities that were present for unsubsidized patients were not present or reversed among subsidized patients. All three subsidized race or ethnicity groups also had higher adherence than all three unsubsidized groups, although with the smallest difference occurring in black women. Conclusion Receipt of a prescription subsidy was associated with substantially improved persistence to breast cancer hormonal therapy among white, black, and Hispanic women and lack of racial or ethnic disparities in persistence. Given high subsidy enrollment among black and Hispanic women, policies targeted at low-income patients have the potential to also substantially reduce racial and ethnic disparities.
A phase I dose-escalation and pharmacokinetic (PK) study of a novel multiple-targeted receptor tyrosine kinase (RTK) inhibitor, XL647, in patients with advanced solid malignancies
Authors: H. Wakelee, A. A. Adjei, H. Keer, J. Halsey, L. Hanson, J. Reid, S. Hutchison, J. Piens, S. Lacy, B. I. Sikic
Journal: Journal of Clinical Oncology (2005)

3142 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple RTKs involved in tumor cell growth, angiogenesis, and metastasis including EGFR (erbB1), erbB2, VEGFR-2, and EphB4. Methods: Patients (pts) with advanced solid malignancies were enrolled in successive cohorts to receive XL647 orally as a single dose on day 1 with PK sampling, followed by 5 continuous daily doses starting on day 4 with additional PK sampling. Pts then continued to receive dosing for 5 continuous days followed by a break with cycles repeated every 14 days. Imaging was done at baseline, after the first 3 or 4 cycles and then after every 4 cycles. Pts with stable or improving disease were allowed to stay on study. Results: A total of 12 pts (5 non-small cell lung cancer (NSCLC), 3 colon cancer, 2 renal cell carcinoma, 1 chordoma, 1 adrenal cortical carcinoma) have been treated across 4 dose levels to date (3 per cohort): 0.06, 0.12, 0.19 and 0.28 mg/kg. No grade 3/4 toxicities have been recorded to date and no patterns of lower grade toxicity have emerged. The MTD has not yet been reached. Preliminary PK analysis indicate XL647 is absorbed after oral administration; mean time to maximum concentration (Tmax) for the first 3 cohorts is 17.1 hours with single dosing and 4.9 hours with repeated dosing. Elimination is linear and elimination half-life is long (mean 68.8 hours); significant accumulation occurs on repeated dosing. No objective responses have been seen but 1 pt (NSCLC) from cohort 1 has had a minor (22%) regression of tumor and continues with stable disease at 22 weeks. Conclusions: XL647 has been well tolerated with accrual to higher dose cohorts ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Exelixis Exelixis Exelixis Exelixis
Towards Equity in Service Provision for Gay Men and Other Men Who Have Sex with Men in Repressive Contexts
Authors: Chris Beyrer, Keletso Makofane, Ifeanyi Orazulike, Daouda Diouf, Stefan D. Baral
Journal: PLoS Medicine (2016)

Chris Beyrer and colleagues reflect on an underappreciated trend in multiple African, Asian, and Caribbean settings, in which the provision of HIV and other essential health services for sexual and gender minorities is expanding despite challenging legal and social environments.
Veterans with prostate cancer talking about life experiences (VA T.A.L.E.S.)—A pilot study
Authors: E. McCarthy, N. A. Dandade, C. L. Bennett
Journal: Journal of Clinical Oncology (2008)

16124 Background: Trends suggest that more men are living many years with the sequelae of prostate cancer and its treatment. Health- related quality of life (QOL) issues become especially important to these patients. There are myriad means of psychological support available, including the use of written narrative. Recognizing the limits of a written narrative intervention among patients with low functional literacy, we evaluated the feasibility of conducting an oral narrative intervention on a low-literacy population. Methods: The first phase of the study was designed to evaluate whether veterans would participate in an oral history intervention. 52 veterans were interviewed by students at Columbia College in Chicago about their war experiences and completed an anonymous survey indicating their satisfaction with the oral narrative process. In the second phase, 9 pilot interviews were conducted at the oncology clinic at the Jesse Brown VAMC in Chicago. Subjects were asked questions stemming form the moment each interviewee received his draft notification to the process of readjustment after returning home. Patients were also asked to expound on experiences unrelated to their military service, particularly their cancer care. Results: 83% of patients interviewed in the phase 1 “looked forward to the interview,” 84% agreed that “participation [in the project] made them feel better,” and none of the participants had issues with PTSD. The patients interviewed in phase 2 openly discussed their satisfaction with treatment at the VA, issues relating to their sexuality, anxiety over sexual function after prostate cancer treatment, and concern that they were not well informed about issues important to prostate cancer care. Conclusions: The positive response from subjects in phase 1 indicates that oral history methods can be used to interview veterans without causing trauma. Results from phase 2 indicate that oral history can be used to add a humanistic level to cancer treatment at the Jesse Brown VA. Patient sexuality and treatment-related anxiety rarely emerge during clinical examination. Oral history can be used to connect with patients on a humanistic level. No significant financial relationships to disclose.
Oral delivery of leuprolide in a rat model using poly-lactide-glycolic acid (PLGA) nanoparticles coated with active-transport peptides derived from phage libraries
Authors: Vernon Alvarez, Imelda Lambkin, Daniel O'Mahony
Journal: Cancer Research (2007)

1497   Oral delivery of macromolecules, including proteins and peptides, is challenging because of the harsh intestinal environment and the lack of absorption of macromolecules through the gastro-intestinal tract (GIT). In a novel approach to search for peptides that would be actively transported across the GIT, we used complex random peptide phage libraries to select phage that would bind to selected cloned GIT receptors. We further screened these selected phage using an  in vivo  rat intra-duodenal model, and then finally used lead peptides to coat PLGA nanoparticles containing leuprolide to demonstrate  in vivo  delivery of this peptide hormone. The phage peptide libraries were long, 38- or 43-amino acids in length, and had the potential for complex folding. The long length of these libraries may contribute to novel interactions and binding motifs.  In vitro  screening was performed against four cloned GIT recombinant receptors, hPEPT1, HPT1, hSI, and D2H, and specifically-binding phage were then injected into a closed intra-duodenal loop in a rat model. Samples were taken from the portal and systemic circulation as well as the intestinal wall at various time points, and the samples plated out and sequenced to identify the sequences of the phage which crossed the GIT. A control phage, with no insert, was not transported into the blood in this model. Eight peptides from this screen were then used for further analysis, including identification of small binding motifs and the effect of D-amino acids. BLAST searches were performed on these sequences to determine any similarity to known proteins. Preliminary studies showed that two peptides, designated PAX2 and P31, were most effective; these were used to coat PLGA nanoparticles containing leuprolide, and the particles were then injected into the intra-duodenal loop in the  in vivo  rat model, along with uncoated nanoparticles and “free” leuprolide. In a study with 8 rats per group, analysis of leuprolide in the blood of these rats showed that peptide P31 was most efficient, resulting in the highest level of leuprolide in the blood, with a peak concentration of 19,500 pg/100 μL at 45 minutes after injection. Corresponding values at the 45 minute time-point were as follow: “free” = 3, 500 pg/100 μL, uncoated particles = 2,400 pg/100 μL and PAX2 coated = 5,200 pg/100 μL. These peptides are candidates for oral drug delivery of macromolecules using this technology.
Direct Determination of the Mutation Rate in the Bumblebee Reveals Evidence for Weak Recombination-Associated Mutation and an Approximate Rate Constancy in Insects
Authors: Haoxuan Liu, Yanxiao Jia, Xiaoguang Sun, Dacheng Tian, Laurence D. Hurst, Sihai Yang
Journal: Molecular Biology and Evolution (2016)

Accurate knowledge of the mutation rate provides a base line for inferring expected rates of evolution, for testing evolutionary hypotheses and for estimation of key parameters. Advances in sequencing technology now permit direct estimates of the mutation rate from sequencing of close relatives. Within insects there have been three prior such estimates, two in nonsocial insects (Drosophila: 2.8 × 10
Abstract IA26: Regulation of epithelial versus mesenchymal polarity and malignant progression
Authors: Diwakar Pattabiraman, Diwakar Pattabiraman, Tsukasa Shibue, Tsukasa Shibue, Xin Ye, Xin Ye, Robert A. Weinberg, Robert A. Weinberg, Robert A. Weinberg
Journal: Cancer Research (2016)

Abstract The ability of carcinoma cells to acquire cell-biological phenotypes associated with advanced malignancies is increasingly associated with activation of the EMT (epithelial-mesenchymal transition) program. Among the acquired phenotypes are those of motility, invasiveness, the ability to disseminate, and the ability to form increased numbers of tumor-initiating cells/cancer stem cells (CSCs). We have investigated the regulation of the EMT program and found that a key intracellular determinant is the levels of the cAMP second messenger molecule. When elevated, it causes exit of more mesenchymal carcinoma cells into an epithelial state. The formation of the CSCs within tumors has long been posited to arise following the conversion of normal tissue SCs into CSCs. However, in our hands, in a transgenic model of breast carcinoma formation, the SCs reside in one cell layer of the mammary ducts while the CSCs arise in another, making the direct derivation of CSCs from normal SCs unlikely, at least in this experimental model of mammary carcinogenesis. Once the EMT program is activated, carcinoma cells are able to acquire attributes that not only enable their dissemination from the primary tumor but also affect their subsequent post-extravasation proliferation in the lung parenchyma. The basis of this proliferation derives from the EMT-induced ability of extravasated carcinoma cells to form mature focal adhesions and activate the mitogenic signaling pathway via focal adhesion kinase (FAK). Additional consequences of EMT action will be discussed. Citation Format: Diwakar Pattabiraman, Diwakar Pattabiraman, Tsukasa Shibue, Tsukasa Shibue, Xin Ye, Xin Ye, Robert A. Weinberg, Robert A. Weinberg, Robert A. Weinberg. Regulation of epithelial versus mesenchymal polarity and malignant progression. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA26.
Phase I-II study of IV vinorelbine (VRL) and oxaliplatin (OXP) every two weeks (q2w) in metastatic breast cancer (MBC): Results of the phase I trial
Authors: A. Rodriguez-Lescure, A. Llombart, R. Colomer, G. Gutierrez, J. Gayo, I. Tusquets
Journal: Journal of Clinical Oncology (2006)

10691 Background: The combination of VRL and OXP was shown to be effective for the treatment of NSCLC. We designed a scheme for first line MBC consisting of administering IV VRL and OXP q2w to explore potential synergistic effects, to determine the maximal tolerated dose (MTD), recommended doses (RDs) and safety of the combination. Methods: Twelve patients (pts) entered the study. Four dose levels were established: A) VRL 25 mg/m 2 with OXP 80 mg/m 2 , B) 25/90, C) 25/100 and D) 30/90, both drugs q2w. Patients/cycles analyzed were: A) 3/15, B) 3/21, C) 3/15, D) 3/19. Results: Median age 58 y (range; 39–78), 10 pts (83%) received prior (neo)adjuvant CT. No dose limiting toxicities were found at any of the dose levels. RD was established at IV VRL 30 mg/m 2 and OXP 90 mg/m 2 /d both administered every 2 weeks. A total of 71 cycles were analyzed. Grade 3 neutropenia occurred in 4 pts (44%) and 13% of cycles, grade 4 in 1 pt (11%) and 1% of cycles. No complications were observed. No grade 4 non-haematological toxicity was seen. Grade 3 neurotoxicity occurred in 1 pt and 2 cycles, grade 3 fatigue occurred in 1 pt and 3 cycles. 2 partial responses were observed among the 6 evaluable patients for response. Conclusions: The combination of VRL and OXP is safe in the palliative setting of MBC. Phase II study explores the efficacy and safety of the combination of VRL 30 mg/m 2 and OXP 90 mg/m 2 q2w. Recruitment is ongoing. No significant financial relationships to disclose.
Druggable aberrations in solid tumors: an overview on ALK and ROS-1 status
Authors: M.S. Cona, A. Indini, A. Testi, S. Cresta, D. Signorelli, M.C. Garassino, V. Sinno, S. Sesana, G. Pelosi, F.G. de Braud, S. Damian
Journal: Annals of Oncology (2015)
A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors
Authors: C. S. Higano, E. Y. Yu, S. H. Whiting, M. S. Gordon, P. LoRusso, F. Fox, T. L. Katz, J. M. Roecker, J. D. Schwartz
Journal: Journal of Clinical Oncology (2007)

3505 Background: IMC-A12 is a fully human IgG1 monoclonal antibody directed against the human insulin like growth factor-I receptor. The safety and maximum tolerated dose (MTD) of IMC-A12 are being evaluated in an on-going a phase I trial. Methods: Patients (pts) with ECOG PS = 2 and advanced refractory solid tumors receive IMC-A12 weekly for 4 infusions per cycle until progression. After cycle one only, there is a two week observation period. Six cohorts of IMC-A12 are planned at 3, 6, 10, 15, 21, 27mg/kg. Sampling for PK and human anti-human antibodies directed against IMC-A12 occurs before and after the first and fourth doses of each cycle. Results: Fifteen pts have been treated, 7 at 3 mg/g, 4 at 6 mg/kg, 3 at 10 mg/kg and 1 at 15 mg/kg. Data is available for the first 11 pts: 7 male, 4 female, median age 56 years (range: 45–70). Treatment related toxicities for the first 11 pts include: grade 1 pruritis, rash, discolored feces; grade 2 anemia, psoriasis, hyperglycemia, infusion-related reaction; grade 3 hyperglycemia. Four of 11 pts have stable disease: 2 at the 3 mg/kg dose remain stable for &gt;9 months (1 male breast cancer,1 hepatocellular cancer) and 2 at the 6 mg/kg dose (1 bladder, 1 endometrial) were stable after cycle 1. One pt with prostate cancer had &gt;25% decline in PSA and stable radiographic disease at time of study discontinuation (week 5) for DLT. Non-compartmental PK analysis reveals a mean t1/2 of 148 and 209 hrs, mean Cmax of 333 and 415 ug/mL, and mean AUC0-Inf of 51317 and 80727 hr*ug/mL at the 3 and 6 mg/kg dose levels, respectively. Target trough levels have been achieved. Conclusions: Weekly administration of IMC-A12 appears to be well tolerated and the MTD has not been reached. The PK profile is consistent with that of other Mab’s. There is early evidence of clinical activity and correlative IGF biomarker data will be available. IMC-A12 will be further evaluated in prostate, breast, and other cancers. No significant financial relationships to disclose.