tbuckley/cabot-search huggingface dataset:
Simultaneous targeting of CD44 and EpCAM with a bispecific aptamer effectively inhibits intraperitoneal ovarian cancer growth
Authors: Jingying Zheng, Shuhua Zhao, Xiaolin Yu, Shuang Huang, Hong Yan Liu
Journal: Theranostics (2017)

CD44 and EpCAM play crucial roles in intraperitoneal ovarian cancer development. In this study, we developed an RNA-based bispecific CD44-EpCAM aptamer that is capable of blocking CD44 and EpCAM simultaneously by fusing single CD44 and EpCAM aptamers with a double stranded RNA adaptor. With the aid of a panel of ovarian cancer cell lines, we found that bispecific CD44-EpCAM aptamer was much more effective than either single CD44 or EpCAM aptamer in the ability to inhibit cell growth and to induce apoptosis. When these aptamers were tested in intraperitoneal ovarian cancer xenograft model, bispecific CD44-EpCAM aptamer suppressed intraperitoneal tumor outgrowth much more significantly than single CD44 and EpCAM aptamer either alone or in combination. The enhanced efficacy of bispecific CD44-EpCAM aptamer is most likely to be attributed to its increased circulation time over the single aptamers. Moreover, we showed that bispecific CD44-EpCAM aptamer exhibited no toxicity to the host and was unable to trigger innate immunogenicity. Our study suggests that bispecific CD44-EpCAM aptamer may represent a promising therapeutic agent against advanced ovarian cancer.
Extension of overall survival (OS) beyond objective responses (OR) in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with high dose interleukin-2 (HD IL-2).
Authors: David D. Stenehjem, Michael Toole, Joseph Merriman, Kinjal Parikh, Stephanie Daignault, Sarah Scarlett, Peg Esper, Katherine Skinner, Aaron Udager, Srinivas Kiran Tantravahi, Alli M. Straubhar, Archana M. Agarwal, Joan Van Atta, Kenneth F. Grossmann, Wolfram E. Samlowski, Bruce G. Redman, Neeraj Agarwal, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2015)

4565 Background: The aim of this study is to determine if achievement of stable disease as a best response to HD IL-2 may improve survival outcomes. Recent data suggest that immunotherapy may improve survival even in those pts who do not experience objective responses (CR+PR). Methods: All sequential mRCC pts treated with HD IL-2 at the University of Utah (1988-2013) and University of Michigan (1997-2013) were included. Best responses to HD IL-2 were correlated with survival outcomes using landmark analysis at 2 months—the median time to first disease assessment. Results: A total of 391 pts (75% male; median age 55 yrs, range 13-77) were included and belonged to the following risk categories: 80 (20%) good, 251 (64%) intermediate, and 60 (15%) poor. A CR was identified in 35 (9%), PR in 39 (10%), SD in 125 (32%), progressive disease (PD) in 164 (42%), and not evaluable for response (NE) in 28 (7%) pts. Median OS for the favorable, intermediate and poor risk groups were 53.8 (p=0.0015 vs intermediate), 26.4 (p<0.0001 vs poor), and 12.2 (p<0.0001 vs favorable) months, respectively. Table shows correlation of response to survival. Conclusions: Stable disease as best response to HD IL-2 was achieved in 32% of pts and survival outcomes were not statistically different in these pts from those achieving PR, however significantly greater than those with PD. Stable disease is an important response criterion for treatment with HD IL-2, and may be discussed with the pts. Correlation of best responses with survival outcomes in mRCC pts treated with HD IL-2: Landmark analysis at 2 months. Median PFS, months Median OS, months Overall 6.9 49.2 CR vs PR 113.8 vs 11.8 (HR 0.18, CI 0.09-0.37) 156.7 vs 37.8 (HR 0.21, CI 0.09-0.47) CR vs SD 113.8 vs 9.0 (HR 0.13, CI 0.06-0.23) 156.7 vs 38.4 (HR 0.13, CI 0.05-0.26) SD vs PD 9.0 vs 3.9 (HR 0.19, CI 0.12-0.31) 38.4 vs 19.9 (HR 0.41, CI 0.24-0.72) OR vs (SD and PD) 26.4 vs 4.9 (HR 0.26, CI 0.18-0.36) 101.2 vs 24.1 (HR 0.24, CI 0.15-0.37) (CR, PR, SD) vs PD 10.4 vs 2.6 (HR 0.10, CI 0.07-0.14) 53.9 vs 12.2 (HR 0.23, CI 0.16-0.33) PR vs SD 11.8 vs 9.0 (HR 0.69, CI 0.44-1.04) 37.8 vs 38.4 (HR 0.60, CI 0.34-1.01)
Gefitinib in patients with non-small cell lung cancer (NSCLC): The Royal Marsden experience
Authors: M. Parton, N. Maisey, S. Banerjee, C. Harper-Wynne, K. Sumpter, S. Ashley, T. Eisen, M. Obrien
Journal: Journal of Clinical Oncology (2004)

7099 Background: Gefitinib (Iressa), an inhibitor of the intracellular tyrosine kinase domain, has demonstrated useful activity in advanced pre-treated NSCLC (IDEAL I / II). The clinical efficacy of gefitinib was assessed as part of an Expanded Access Programme. Methods: Patients (pts)were treated with gefitinib 250mg/day. Endpoints included overall survival (OS)and time to treatment failure (TTF). Objective and symptom response (OR, SR) were assessed at 1 month intervals. Results: 140 patients were assessed: median age (range), 65 (35–88) years; male/female, 80/60; performance status (PS)0/1/2/3, 1/45/37/17%; advanced disease (IIIB/IV), 123pts; median number of prior chemotherapy regimens (range), 1 (0–4). 124 patients were evaluable for OR: partial responses (PR) 6%; stable disease (SD) 55%; progressive disease (PD) 39%. Median duration of disease control (PR + SD) was 13 weeks (95% CI 9–17). 130 patients were evaluable for SR: symptom improvement (SI) 30%; No change (NC)33%; worsening symptoms (WS) 37%. Median duration of symptom control (SI+NC) was 11 weeks (95% CI 9–13). The most common toxicity was diarrhoea (Grade 3: 4.5%; Grade IV: 1%). 1 patient died of suspected pneumonitis. Median OS and TTF was 20 weeks (95% CI 15–25) and 8 weeks (95% CI 7–9) respectively. Patients (n=12) with bronchoalveolar adenocarcinoma (BAC) had significantly longer TTF than adenocarcinoma and squamous-cell carcinoma (median duration was 13, 8 and 9 weeks respectively, p=0.04). OR and SI for patients with BAC was 9.1% and 50% respectively. Pts with a PS of 3 had significantly lower OS and TTF (8 and 5 weeks respectively), and OR and SI was 0% and 13.3% respectively. Number of prior chemotherapy regimens did not significantly alter survival. Conclusions: This large series of patients treated with gefitinib at 250mg/day, demonstrated similar survival and symptom response to published phase II data. Pts with BAC appeared to benefit more than other histological subtypes. Despite low toxicity, gefitinib does not benefit those with poor PS. However, gefitinib can benefit heavily pre-treated patients, since the number of prior chemotherapy regimens did not influence survival. No significant financial relationships to disclose.
An educational program to improve cancer survivorship research.
Authors: Guadalupe R. Palos, Patricia Chapman, Katherine Ramsey Gilmore, Paula A. Lewis-Patterson, Maria Alma Rodriguez
Journal: Journal of Clinical Oncology (2017)

94 Background: ASCO has recognized the need to expand its educational portfolio to focus on long-term care of cancer survivors. Academic programs across health care professions overlook this topic in their curricula. To address this gap, we developed a survivorship research internship for undergraduate students enrolled in public health or health education programs. Here we present the results of an evaluation to assess the level of satisfaction of trainees and improve the curriculum. Methods: All students who completed the internship were eligible to participate in the evaluation. The authors conducted the survey using an electronic data system. Respondents were asked to rate their level of satisfaction with the curriculum and specific assignments, i.e. conducting their own survivorship research project, taking classes about PubMed or EndNotes, and abstracting data from medical records to use in survivorship care plans. Other measures were whether a trainee had written/published an abstract/manuscript, pursued an advanced degree, or obtained a job in health care after completing the program. Descriptive statistics were used to summarize results. Results: An 85% response rate was achieved (34/40 respondents). The majority were female (82.4%), Caucasian (56.3%), and enrolled in public health programs (41.2%). Almost all respondents (90.9%) strongly agreed or agreed they had a better understanding of the process needed to conduct survivorship research. 50.0% reported being most satisfied with the internship experience. 36.4% reported data abstraction and participating in PubMed or EndNotes classes were least useful. 35.3% reported observing health care professionals in the clinical setting was the most useful. 88.2% strongly agreed or agreed that the training was useful in their current work position.18.8% have achieved advanced degrees in medicine, nursing, or public health. Two of the 34 trainees have published a paper in a peer-reviewed journal or presented a poster at a scientific conference. Conclusions: Results indicated the vast majority of trainees had a positive experience engaging in the survivorship research internship. This strategy is one method that can be used to build and enhance education in survivorship care and research.
Population pharmacokinetics and dosing implications for cobimetinib in patients with solid tumors.
Authors: Kelong Han, Jin Jin, Mathilde Marchand, Steve Eppler, Nicholas W. Choong, Stephen Paul Hack, Mika A. Sovak, Nalin Tikoo, Rene Bruno, Mark J. Dresser, Luna Musib, Nageshwar R. Budha
Journal: Journal of Clinical Oncology (2015)

2573 Background: Cobimetinib (COBI), an inhibitor of mitogen-activated protein kinases, when combined with vemurafenib (VEM) has been shown to significantly improve PFS (p < 0.001) over VEM alone in patients with BRAF V600 mutated melanoma in the Phase 3 study, coBRIM. This analysis aimed to characterize COBI PK and evaluate impact of clinically relevant covariates on COBI PK and exposure to inform dosing. Methods: Plasma samples (n = 4886) were collected from 487 patients with various solid tumors (mainly melanoma) in 3 clinical studies (MEK4592g, NO25395, GO28141). COBI was administered orally, once daily on a 21-day-on/7-day-off, 14-day-on/14-day-off or 28-day-on schedule in a 28-day dosing cycle as a single agent or in combination with VEM. COBI doses ranged from 2.1 to 125 mg. Nonlinear mixed effect modeling was used for PK analysis. Results: A linear two-compartment model with first-order absorption, lag time and first-order elimination described COBI PK. The typical estimates (inter-individual variability) of apparent clearance (CL/F), central volume of distribution (V/F) and terminal half-life were 322 L/day (58%), 511 L (49%) and 2.2 days, respectively. Inter-occasion variability on relative bioavailability (F) significantly improved the fitting and was estimated at 46%. CL/F decreased with age. V/F increased with body weight (BWT). However, the impact of age and BWT on COBI steady-state exposure (peak and trough concentrations and AUC following 60 mg 21-day-on/7-day-off) was limited ( < 25% changes across the distribution of age and BWT in the population studied). No significant difference in COBI PK parameters or steady-state exposure was observed between patient subgroups by gender, renal function, ECOG score, hepatic function tests, race, region, cancer types, V600 mutation subtype and co-administration of moderate and weak CYP3A inducers or inhibitors and VEM. Conclusions: A population PK model was developed for COBI in cancer patients. Age and BWT were the only statistically significant variables influencing COBI PK, but showed minimal impact on steady-state exposure, suggesting no need for dose adjustment and supporting the recommended daily dose of 60 mg 21-day-on/7-day-off for all patients.
The efficacy of metronomic thalimomide and methotrexate for refractory/relapsed non-Hodgkin lymphoma.
Authors: Jing-yun Wen, Xiao-kun Ma, Dan-Yun Ruan, Jie Chen, Qu Lin, Min Dong, Xing Li, Xiang-yuan Wu
Journal: Journal of Clinical Oncology (2014)

e19508 Background: Relapsed and refractory non-Hodgkin’s lymphomas (NHL) have a poor prognosis and represent a major treatment challenge. There is no standard of care for salvage regimens. Metronomic therapy offers a novel therapeutic strategy for cancer treatment endowed with an antiangiogenic effect. The aim of the present research was to evaluate the clinical efficacy and toxicity of metronomic administration of low-dose methotrexate and thalimomide in relapsed and refractory NHL. Methods: Data were collected from ninety-eight patients with the diagnosis of relapsed and refractory NHL who were admitted to the Third Affiliated Hospital of Sun Yat-Sen University from January 2009 to June 2013. The median age was 42 years (range, 14-78years).Of the ninety-eight patients treated, 28(28.6%) had follicular lymphoma; 17 (17.3 %) had marginal zone lymphoma; 35 (35.7 %) had diffuse large cell lymphoma; and 18 (18.3 %) had T-cell lymphoma. All had received at least two or more prior therapies. They received thalimomide tab (50mg p.o b.i.d) and methotrexate tab (10-12.5mg p.o per week) until disease progression. Results: Mean time on therapy was 18 months (range 3-37 months). At a median follow-up of 36.2 months (range 6-48months), 64.2% achieved an objective response (OR) with 29.5% complete responses (CR) and 34.6% partial responses (PR). The median overall and progression-free survivals were 23.4 and 10.6 months, respectively. The overall 1- and 3-year survival rates were 86.0% and 41.9%, respectively. The regimen was generally well tolerated. The most common toxicity was skin rash (n=18, 18.3%) ,vertigo (n=19, 19.4%) and fatigue (n=23, 23.5%). Myelosuppression and gastrointestinal side effects were uncommon. Conclusions: Our results suggested that metronomic administration of low-dose methotrexate and thalimomide presented significant effects in treating relapsed and refractory NHL with acceptable side effects profile.
Pharmacologic advantage (PA) of intraperitoneal (IP) nab-paclitaxel in patients with advanced malignancies primarily confined to the peritoneal cavity.
Authors: Mihaela C. Cristea, Timothy W. Synold, Paul Henry Frankel, Saul E. Rivkin, Dean Lim, Vincent M. Chung, Joseph Chao, Mark Tsuneo Wakabayashi, Isaac Benjamin Paz, Ernest Soyoung Han, Paul Lin, Lucille A. Leong, Amy Hakim, Mary I. Carroll, Henry Openshaw, Neal Prakash, Thanh Hue Dellinger, Min S. Park, Robert Morgan
Journal: Journal of Clinical Oncology (2015)

2553 Background: nab-Paclitaxel is albumin-bound paclitaxel that achieves higher intratumoral concentrations and undergoes receptor-mediated transcytosis across cell membranes. Previous clinical trials have demonstrated an advantage to IP chemotherapy. A phase I study was undertaken to evaluate the safety, tolerability and pharmacokinetics of IP nab-paclitaxel. Methods: Eligible pts received IP nab-paclitaxel on D1, 8, 15 of a 28-day cycle with a 3+3 dose-escalation design. Plasma and peritoneal pharmacokinetic (PK) samples were drawn prior to dose, immediately upon completion of infusion, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose on C1D1 and C1D15. Results: The trial is complete with 27 pts with peritoneal carcinomatosis secondary to GYN (n=14), GI (n=12) malignancies and 1 pt with peritoneal mesothelioma. The starting dose level was 35mg/m2 and escalated to 170mg/m2. The MTD of IP nab-paclitaxel was established at 140 mg/m2. DLTs included grade 3 neutropenia resulting in treatment delay >15 days, grade 3 abdominal pain and grade 4 neutropenia > 7 days. Plasma and IP PK data are summarized below in the Table. Over the four dose levels, the data show a ~150-fold PA to IP nab-paclitaxel with low intra-pt variability. The lowest PA was 50-fold. Conclusions: PK results suggest a significant PA to IP nab-paclitaxel (i.e. higher peritoneal exposure compared to plasma).The inter- and intra-patient variability appears to be low. The plasma AUC's resulting from IP nab-paclitaxel at the MTD of 140 mg/m2 are similar to plasma AUC's associated with IV nab-paclitaxel at 100 mg/m2. In addition to achieving high local drug levels in the peritoneum, patients are also exposed to therapeutic systemic drug levels. This study was funded by the National Comprehensive Cancer Network (NCCN) with support from Celgene Corporation. Clinical trial information: NCT00825201. nab-Paclitaxel Dose (mg/m2) N Treatment Day Plasma AUC (mg/L x hr) Peritoneal AUC (mg/L x hr) Ratio (%) 35 1 Cycle 1 Day 1 0.6 89 160 Cycle 1 Day 15 0.5 93 172 70 1 Cycle 1 Day 1 1.5 299 194 Cycle 1 Day 15 1.6 321 199 90 1 Cycle 1 Day 1 1.1 207 94 Cycle 1 Day 15 1.1 194 72 112.5 3 Cycle 1 Day 1 3.0 (0.8-4.2) 305 (210-427) 134 (50-389) Cycle 1 Day 15 2.5 (0.6-3.2) 290 (230-358) 118 (88-403)
Discovery of new gene expression predictors for adjuvant tamoxifen outcome for breast cancer patients
Authors: D. C. Sgroi, X. J. Ma, P. Ryan, Z. Wang, J. Younger, S. Isakoff, B. Smith, J. Brugge, T. M. Baer, M. G. Erlander
Journal: Journal of Clinical Oncology (2004)

9503 Background: A better understanding of tamoxifen resistance and accurately targeting tamoxifen therapy to responsive patients remain critical challenges in breast cancer treatment. Tamoxifen acts primarily by competing with estrogens for binding to the estrogen receptor (ER). Consequently, the presence of ER and PR (progesterone receptor) is currently the best predictor for tamoxifen response. However, 25%, 66% and 55% of ER+/PR+, ER+/PR- and ER-/PR+ tumors, respectively, fail to respond or develop resistance to tamoxifen through mechanisms that remain largely unclear. Therefore, it is currently an unmet medical need to better predict response to tamoxifen. Methods: Using high-density oligonucleotide microarrays, we analyzed gene expression profiles of hormone receptor-positive breast cancers from 60 patients with similar tumor size, nodal status, and tumor grade. These 60 patients were uniformly treated with systemic adjuvant tamoxifen only. In addition, we validated gene expression differences in an independent cohort of 20 hormone-receptor positive, patients treated only with tamoxifen. Results: We identified 19 genes (gene names will be disclosed at the presentation) whose expression levels were correlated with treatment outcome. Expression ratios of pairs of these genes were simple and powerful predictors of treatment outcome both in the 60 patients used for discovery and in the independent cohort of 20 patients. Expression of one of the genes in the mammary epithelial cell line MCF10A resulted in increased cell motility and invasion in a manner that is synergistic with EGF, suggesting functional interaction with the EGFR signaling pathway. Conclusions: These results demonstrate the potential for a gene expression-based test for selecting patients for tamoxifen treatment and provide new insight into the mechanisms of tamoxifen resistance. No significant financial relationships to disclose.
A phase I study of sequential vaccinations with recombinant Fowlpox-PSA (L155)-TRICOM (rF)alone, or in combination with recombinant vaccinia-PSA (L155)-TRICOM (rV), and the role of GM-CSF, in patients (Pts) with prostate cancer
Authors: P. M. Arlen, J. Gulley, W. Dahut, L. Skarupa, S. Morin, M. Pazdur, N. Todd, D. Panicali, K. Y. Tsang, J. Schlom
Journal: Journal of Clinical Oncology (2004)

2522 Background: Vaccine strategies targeting PSA represent a novel approach in the treatment of prostate cancer. Since PSA is a “self” antigen, vaccine strategies utilizing this as a target must be developed to enhance its immunogenicity. Previous studies have shown that the induction of T-cell responses directed against a self-antigen is associated with anti-tumor activity but not toxicity. Two novel vaccines have been developed: (a) a recombinant vaccinia virus containing the entire PSA transgene with a modified agonist epitope and three costimulatory molecule transgenes rV and (b) a similar recombinant fowlpox virus rF. Methods: This Phase I study evaluated the safety of a diversified prime/boost vaccine strategy: priming with rV and monthly boosts using rF. All pts had progressive metastatic prostate cancer. This trial also examined the combination of these agents with recombinant GM-CSF (rG) as well as two doses of fowlpox-GM-CSF (rF-G). The first of 5 cohorts utilized a fixed dose of rF alone, the second cohort tested the safety of a priming vaccination with rV followed by monthly rF boosting. Cohorts 3,4, and 5 provided safety data combining cohort 2 with rG or two doses of rF-G respectively. Results: Accrual (n=15) has been achieved. Thirteen pts remain on study. No dose limiting toxicities have been observed. Pt characteristics: median age = 64 years (range 48–80), median PSA = 191.7 ng/ml (range 2.6–2943), median Gleason score = 8 (range 7–9). Seven of 9 evaluable pts treated for at least 3 months have not demonstrated progression on CT or bone scan and remain on study. One pt in cohort 2 has a PSA decline of >35%. Immunologic studies are ongoing to measure changes in PSA specific T cells. Conclusions: Based on the safety data from this clinical trial, we have initiated the randomized Phase II component of this study to compare the immunologic effects of the above vaccine strategy alone, with r-G, or with either of 2 doses of rF-G. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Therion Biologics
Characteristics, outcomes, prognostic factors and treatment of patients with T-cell prolymphocytic leukemia (T-PLL)
Authors: P. Jain, E. Aoki, M. Keating, W.G. Wierda, S. O’Brien, G.N. Gonzalez, A. Ferrajoli, N. Jain, P.A. Thompson, E. Jabbour, R. Kanagal-Shamanna, S. Pierce, A. Alousi, C. Hosing, I. Khouri, Z. Estrov, J. Cortes, H. Kantarjian, F. Ravandi, T.M. Kadia
Journal: Annals of Oncology (2017)
An economic evaluation of anastrozole versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer (EBC) from a US healthcare perspective
Authors: G. Y. Locker
Journal: Journal of Clinical Oncology (2004)

590 Background: Results from the ATAC trial (Lancet 2002;359:2131) at a median follow-up of 33 months, indicated that anastrozole (n=3125) was superior to tamoxifen (n=3116) for disease free survival (DFS) in the adjuvant treatment of postmenopausal women with hormone receptor-positive (HR+) early breast cancer. Updated data (median follow-up 47.2 months for efficacy) confirmed these findings (Cancer 2003;98:1802). Using the updated data, the incremental cost effectiveness ratio (ICER) per life year gained (LYG) for managing this group was calculated for anastrozole vs tamoxifen from the US healthcare perspective. Methods: A probabilistic Markov model was developed using updated ATAC data to project outcomes for anastrozole and tamoxifen to 25 yrs by extrapolating pooled Kaplan-Meier curves using parametric statistical methods. It was assumed that recurrence rates after the maximum 5 yr treatment period would be equivalent in anastrozole and tamoxifen groups, a conservative approach. General mortality data were from US Census 2000. Resource utilization data was obtained from published literature and structured interviews with 9 US oncologists. Drug costs were based on average wholesale price and generic cost of tamoxifen. Other unit costs (2002 US$) from standard national sources and literature were used. Costs and benefits were discounted at 3%. Sensitivity analyses were conducted. Results: In a cohort of 1000 patients modeled over 25 yrs, anastrozole was estimated to lead to 145 discounted life years gained at an additional cost of $3.6 million. The discounted ICER of anastrozole compared to tamoxifen was estimated to be $25,169/LYG (95% CI $5,925–$48,593). Acceptability curves showed that the estimated cost/LYG at 25 yrs was below $50,000 with a probability >90%. The result compared favorably with commonly accepted thresholds for cost-effectiveness and was robust to all parameters, including AEs, tested in sensitivity analysis. Conclusions: Anastrozole is a cost-effective alternative to tamoxifen for the adjuvant treatment of postmenopausal women with HR+ early breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca