tbuckley/cabot-search huggingface dataset:
Targeting signal transducer and activator of transcription 3 protein with arsenic trioxide: A phase I clinical trial
Authors: M. Wetzler, M. T. Brady, K. A. Donohue, S.-H. Lee, S. M. Tighe, L. A. Ford, E. S. Wang, M. R. Baer, H. Baumann
Journal: Journal of Clinical Oncology (2005)

6538 Background: Constitutive signal transducer and activator of transcription (STAT) 3 activity has been shown to be present in acute myeloid leukemia (AML) cells from 50% of patients and to correlate with shorter disease-free survival. We hypothesized that down-regulating constitutive STAT3 activity might improve outcome. In the absence of a specific STAT3 inhibitor, we studied arsenic trioxide (ATO) in vitro and showed that ATO at a concentration of 0.91 μM achieved 50% down-regulation of constitutive STAT3 activity in AML cells within 6 hours. We then conducted a phase I clinical trial to determine the biologically effective dose (BED) and/or the maximally tolerated dose of ATO in vivo in conjunction with induction chemotherapy. Methods: Untreated AML patients younger than age 60 received a single one-hour ATO infusion in escalating doses in 3-patient cohorts prior to high-dose cytarabine [3 gm/m2 (1.5 mg/m2 for age ≥ 50) every 12 hrs x 12 doses] and idarubicin (12 mg/m2 x 3 doses). The BED was defined by a 50% reduction in constitutive STAT3 activity in leukemia cells in vivo as determined by western blotting. ATO doses ranged from 0.01 to 0.25 mg/kg, the latter equivalent to 4 μM, the effective concentration in patients with acute promyelocytic leukemia. Results: Twenty-seven patients (17:10 female:male) were accrued, including 2 with secondary AML. Median age was 46 (range 22–57) years, and median white blood cell count at diagnosis was 13.2 (range 1.6–95.1) x 109/L. Karyotype was favorable in 3, normal in 14 and unfavorable in 10. Eighteen patients achieved complete remission, 5 had refractory disease, 3 were unevaluable and 1 is too early to assess. The BED was achieved at 0.25 mg/kg without dose-limiting toxicity and we are currently accruing 7 more patients at this dose level to study apoptosis and gene expression profiling in pre- and post-ATO samples. Conclusions: ATO down-regulates constitutive STAT3 activity in vivo in clinically tolerable doses. Its impact on treatment outcome will be studied in future trials. No significant financial relationships to disclose.
BEAC or BEAM Chemotherapy Followed by Autologous Stem Cell Transplantation in Non-Hodgkin’s Lymphoma Patients: Comparative Analysis on Efficacy and Toxicity.
Authors: Ja Eun Koo, Shin Kim, Ock Bae Ko, Danbi Lee, Young Pill Chong, Yoon-Koo Kang, Jooryung Huh, Cheolwon Suh
Journal: Blood (2005)
CEP-11981, a small molecule inhibitor of multiple angiogenic targets, in a preclinical system of urothelial carcinoma (UC).
Authors: Weiguo Jian, Jonathan M. Levitt, Seth P. Lerner, Guru Sonpavde
Journal: Journal of Clinical Oncology (2013)

293 Background: The systemic therapy of advanced UC has significant unmet needs. Angiogenesis appears to play a major tumorigenic role in UC, and inhibitors of the VEGF axis have demonstrated activity in clinical trials. Ang/Tie2 and FGFR1 are angiogenic pathways that may collaborate with the VEGF pathway to promote growth. Hence, we sought to examine the preclinical activity of CEP-11981, a small molecule inhibitor of Ang/Tie2, FGFR1 and VEGFR-1-2, in UC. Methods: The in vitro anti-tumor activity of CEP-11981 was evaluated in 4 human cell-lines (5637, TCC-SUP, RT4, RT112). In vivo examination of the anti-tumor activity of different doses of daily oral CEP-11981 for up to 4 weeks was examined in subcutaneous RT4 xenografts. Harvested xenograft tumors were subjected to immunohistochemistry (IHC) to evaluate apoptosis (cleaved-caspase [cc]-3) and angiogenesis (CD31). Results: In vitro activity was not detected at low micromolar concentrations in all 4 cell-lines (attainable in human subjects). Preliminary experiments suggested that both 5 mg/kg and 10 mg/kg orally once daily induced similar regressions of RT4 xenografts, which appeared greater than regressions with 2.5 mg/kg orally once daily. Given that the weight of mice was better maintained with 5 mg/kg dose, we performed the confirmatory experiment comparing placebo with CEP-11981 at 5 mg/kg orally once daily in RT4 xenografts. At this dose, CEP-11981 significantly arrested the growth of UC xenografts compared to control (p&lt;0.05). IHC of harvested RT4 xenografts demonstrated numerically lower angiogenesis (p=not statistically significant) but no change in cc-3. Modulation of Tie2 is being examined. Conclusions: CEP-11981 demonstrated significant preclinical cytostatic anti-tumor activity against human UC xenografts in a murine model, which was attributable to inhibition of angiogenesis. Clinical development of CEP-11981 in tolerable combination regimens and the discovery of tumor and host related biomarkers predictive for benefit are warranted.
Deepness of response: A quantitative analysis of its impact on post-progression survival time after first-line treatment in patients with mCRC.
Authors: Ulrich Robert Mansmann, Ute Sartorius, Ruediger Paul Laubender, Clemens Albrecht Giessen, Regina Esser, Volker Heinemann
Journal: Journal of Clinical Oncology (2013)

427 Background: The extent of tumor shrinkage in patients (pts) receiving chemotherapy +/- monoclonal antibodies has prognostic value for PFS and OS. "Deepness of response (DpR)" is a new efficacy outcome measure that could explain the impact of tumor shrinkage on long-term survival outcome. If shrinkage takes place DpR is the percentage of tumor shrinkage observed at the nadir compared to baseline. DpR is 0 for no change and negative if the tumor load increases. Longest diameter (LD) based on RECIST or a calculated tumor volume (ASCO GI 2012 #635) can quantify the tumor load at distinct time points. A joint model was presented (ASCO GI 2012 #580, ASCO 2012 #3603) which allows us to relate DpR to individual post-progression survival (PPS) time. Methods: Based on the data from 2 randomized trials (CRYSTAL, n=1198; OPUS, n=337), 4 treatment regimens (FOLFIRI +/- cetuximab and FOLFOX4 +/- cetuximab) were studied. A joint model was used to quantify individual changes in tumor size over time and to relate these changes to PFS and OS. Relationships between baseline tumor load and DpR and PPS were studied. Proper scoring rules were used to assess whether the LD-based or the volume-based approach allowed a better prediction of individual prognosis. Results: Results are reported for the CRYSTAL study using LD-based measures for 663 pts with KRAS wild-type tumors and imaging data. The 348 pts treated with FOLFIRI alone had a mean DpR of 35.52% (Interquartile range [IR]:12.09%, 59.86%), minimum DpR -80%. The 315 pts treated with FOLFIRI + cetuximab had a mean DpR of 50.07% (IR: 22.87%, 79.55%) and a minimum DpR of -49%. The DpR was significantly different between the 2 groups (p&lt;0.00001). Individual DpR is a significant prognostic factor for PPS time in both the LD-based (p=0.0023) and volume-based (p=0.0003) models. Proper scoring rules provided evidence of a more precise estimation of individual PPS time based on volume algorithm-measured DpR. Results of the OPUS study will be presented. Conclusions: Our results emphasize the value of the variable DpR as a new efficacy outcome measure for clinical trials. The tumor-shrinking capacity of cetuximab was shown to be associated with its ability to prolong PPS.
BOLERO-2: Efficacy and safety of first-line everolimus plus exemestane in advanced breast cancer.
Authors: Hope S. Rugo, Mario Campone, Michael Gnant, Patrick Neven, Barbara Pistilli, Jose Baselga, Hounayda Bauly, Tanya Taran, Tarek Sahmoud, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2013)

152 Background: In the BOLERO-2 study, progression-free survival (PFS) was significantly longer with the combination of everolimus and exemestane (EVE + EXE) compared with placebo and exemestane (PBO + EXE; hazard ratio = 0.45; p &lt; .0001). Consistent efficacy results were observed in all subgroup analyses, such as in patients with visceral metastases and patients with disease recurrence during/after adjuvant therapy. This analysis of BOLERO-2 examines the efficacy of EVE + EXE in the subgroup of patients who received treatment immediately after recurrence during adjuvant therapy (i.e., as first-line therapy in the advanced setting). Methods: BOLERO-2 enrolled patients with hormone receptor–positive (HR+) advanced breast cancer with disease recurrence or progression after prior nonsteroidal aromatase inhibitors and compared EVE (10 mg/d) + EXE (25 mg/d) vs PBO + EXE. The primary end point was PFS by local investigator review. Results: A total of 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37) in the advanced setting. Of these patients, 74% of the EVE + EXE arm and 76% of the PBO + EXE arm had recurred after adjuvant endocrine therapy plus chemotherapy; 26% and 24%, respectively, had recurred after adjuvant endocrine therapy alone. Also, approximately 20% of patients entered the trial after recurring during or within 12 months of adjuvant therapy (21% EVE + EXE vs 16% PBO + EXE). The EVE + EXE group had significantly longer PFS compared with the PBO + EXE group (11.50 vs 4.07 months, respectively; hazard ratio = 0.39; 95% confidence interval, 0.25-0.62). Median PFS remained longer with EVE + EXE versus PBO + EXE, regardless of whether chemotherapy was included with the prior adjuvant hormonal therapy. Similar results were obtained from the analyses based on central review. The safety profile was consistent with the known profiles of each agent. Conclusions: EVE + EXE prolonged PFS in patients with HR+ advanced breast cancer who received treatment as first-line therapy. These results support the combination of EVE + EXE in patients with recurrence after adjuvant therapy. The recently initiated BOLERO-4 study is also evaluating the efficacy of EVE as a first-line therapy in patients with HR+ advanced breast cancer. Clinical trial information: NCT00863655.
Pathologic response rates between gemcitabine-cisplatin (GC) and methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin (MVAC) neoadjuvant chemotherapy in muscle-invasive urothelial cell carcinoma of the bladder.
Authors: Jonathan Lawrence Wright, Franklin Lee, William Proctor Harris, Heather H. Cheng, Song Zhao, Thomas Champion, John L. Gore, James Dean, Michael P Porter, Evan Y. Yu
Journal: Journal of Clinical Oncology (2013)

267 Background: Neoadjuvant chemotherapy for muscle invasive urothelial carcinoma (UC) of the bladder is associated with higher rates of pathologic complete response (CR) and improved disease-specific survival compared to those treated with radical cystectomy (RC) alone. Two standard regimens used are (1) gemcitabine and cisplatin (GC); and (2) methotrexate, vinblastine, adriamycin, and cisplatin (MVAC), with debate on whether there is a difference in clinical efficacy. In this analysis, we compare the pathologic outcomes at cystectomy between neoadjuvant GC and MVAC treatment. Methods: Data was retrospectively collected on patients with T2-T4 UC of the bladder who underwent RC between Sept 2003 and December 2011 at the University of Washington. Clinical and pathologic factors were recorded along with neoadjuvant chemotherapy and comorbidities. Pathologic outcomes included those with CR (pT0) and near CR (nCR = pT0/Ta/Tis). Odds ratio (OR) for CR and nCR were calculated using multivariate logistic regression adjusting for demographic (age, gender, race), medical (creatinine, diabetes mellitus, cardiac disease) and clinical factors (clinical T stage, prior BCG therapy, complete tumor debulking prior to chemotherapy). Results: A total of 78 patients received GC or MVAC neoadjuvant chemotherapy followed by RC, including 46 who received GC and 32 who received MVAC. There was no difference in gender, renal function, cardiac disease or clinical stage between the two groups. Patients over 70 years of age primarily received GC (17/18). CR was achieved in 30% and 25% (p = 0.15) of GC and MVAC patients, respectively (multivariate OR 0.42, 95% CI 0.11-1.63). nCR was more common in those receiving GC (50% vs. 38%, p = 0.04) although non-significant in the multivariate model (OR 0.30, 95% CI 0.07-1.16). Conclusions: We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of bladder cancer patients. These observations support the use of GC as an alternative regimen in the neoadjuvant setting.
Cetuximab and capecitabine as first-line treatment for elderly patients (pts) with metastatic colorectal cancer (mCRC): Preliminary results of TTD trial
Authors: C. Grávalos, F. Rivera, B. Massutí, J. Sastre, E. Marcuello, M. Valladares, S. Gil, A. Abad, E. Díaz-Rubio, E. Aranda
Journal: Journal of Clinical Oncology (2008)

15027 Background: Elderly pts are a special population due to comorbidity, drug altered metabolism and funcional capacity loss. We previously reported 15% overall response rate (OR) to cetuximab monotherapy as first line in elderly pts with mCRC (Sastre, ESMO 2006; Gravalos, ASCO 2007). Now we are doing this trial to determine the efficacy and tolerance of Cetuximab in combination with Capecitabine. Methods: Pts with age ≥70, histologically confirmed mCRC, measurable disease, KPS ≥80%, and adequate organs function were elegible. Not previous chemotherapy for mCRC, CNS involvement or geriatric syndromes were allowed. Treatment schedules: Cetuximab (400 mg/m2 loading dose and 250 mg/m2 weekly) and Capecitabine 1,250 mg/m2/12h [950 if creatinine clearance (ClCr) 30–50 mL/min] days 1–14, q3w (group A). After the first 22 pts, Capecitabine dose was reduced to 1,000 mg/m2/12h (750 if ClCr 30–50 mL/min) (group B) due to an early onset of severe nail toxicity. An ancillary study was designed to analyse prognostic/predictive factors. Results: From Aug/06 to Jul/07, 66 pts were included. Male/female 58/42%. Median age 77y. KPS 100/90/80: 31%/29%/40%. Main grade 3–4 toxicities are listed in table 1. Sixty pts are evaluable for efficacy: OR and control disease (OR + SD) were 32%/73% and 35%/93% for A and B groups, respectively. Progression free survival, duration of response, and analysis of predictive/prognostic factors will be presented at the meeting. Conclusions: In our study, Cetuximab in combination with Capecitabine (1,250 mg/m2/12h) is not well tolerated at this dose of capecitabine. A lower dose of Capecitabine (1,000 mg/m2/12h) is recommended. Preliminary results of Cetuximab plus Capecitabine suggest a higher activity than cetuximab alone but a randomized phase III trial is required. Toxicity Grade 3–4 % Acne-like rash % Nail Toxicity % Diarrhea %Hand-foot Syndrome (only G3) % Discontinuation due to Aes A (n=22) 23 32 14 18 27 B (n=44) 25 7 9 5 9 Overall Response (ITT) % OR (CR/PR) %SD %CD %PD %NE A (n=20) 32 (0/32) 41 73 18 9 B (n=40) 35 (5/30) 58 93 2 5 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck, Roche Roche
Frequency and predictors of insufficient chemotherapy use among stage I-III breast cancer patients by molecular subtype.
Authors: Lu Zhang, Tekeda Freeman Ferguson, Xiao-cheng Wu, Mei-Chin Hsieh, Elizabeth Fontham, Michelle Marie Loch, Qingzhao Yu, Vivien Chen
Journal: Journal of Clinical Oncology (2015)

154 Background: Identification of distinct molecular subtypes has expanded the treatment options for breast cancer, however, chemotherapy remains the common and effective treatment for each subtype. The objective is to compare the frequency and predictors of insufficient chemotherapy use among two subtypes of stage I-III breast cancer patients: luminal A and triple negative breast cancer (TNBC). Methods: We analyzed data from a CDC funded project - Enhancing Cancer Registry Data for Comparative Effectiveness Research (CER) collected by Louisiana Tumor Registry. Women aged &lt; = 70 years, diagnosed in 2011 with stage I-III luminal A or TNBC breast cancer, tumor size &gt; 1cm, were included (N = 1,189). Insufficient chemotherapy (i.e. no chemotherapy use, nonstandard regimen use, and low relative dose intensity (RDI &lt; 85%)) was evaluated respectively. Potential predictors included age, race, insurance, marital status, census tract-poverty, AJCC stage, grade, tumor size, lymph node status, and Charlson comorbidity. Stepwise model selection with p-value for entry at 0.2 and for stay at 0.25 was used to select the most relevant predictors. Results: The frequencies of no chemotherapy use were significantly different (p &lt; .0001) between luminal A (42%, N = 913) and TNBC patients (9%, N = 241). Older age, white race, no insurance, lower stage or grade, and without lymph node involvement were related with no chemotherapy for luminal A patients; older age, not married, and high poverty for TNBC. There were 36% of luminal A and 40% of TNBC patients receiving nonstandard regimen (p = 0.27). Predictors of nonstandard regimen use were increased age, insurance, stage, and grade for luminal A and high poverty level and stage for TNBC. Reduced RDI occurred in 9% luminal A and 10% TNBC patients (p = 0.61). Small cases precluded the prediction model for low RDI. Conclusions: Luminal A patients are less likely to receive chemotherapy than TNBC patients. Low social economic status factors are associated with no chemotherapy use and nonstandard regimens use, especially for TNBC patients.
Photodynamic therapy (PDT) of malignant biliary strictures using meso-tetrahydroxyphenylchlorin (mTHPC)
Authors: S. P. Pereira, L. Ayaru, A. R. W. Hatfield, A. Rogowska, S. Bown
Journal: Journal of Clinical Oncology (2005)

4176 Background: The palliation of patients with malignant bile duct obstruction with metal or plastic biliary stents is complicated by recurrent stent occlusion. The aim of this study was to determine the safety and efficacy of meso-tetrahydroxyphenylchlorin (mTHPC) PDT in the treatment of patients with irresectable malignant biliary strictures and recurrent stent occlusion. Methods: 13 patients (4M:9F; median age 70 yr, range 50–82 yr) with malignant biliary obstruction due to carcinoma of the biliary tract (n=5), ampulla (n=5), pancreas (n=2) or stomach (n=1), were studied. All had been initially palliated with metal (n=10) or polyethylene (n=3) biliary stents, and presented with recurrent obstructive jaundice. Patients received mTHPC 0.15mg/kg iv 72 hrs before endoluminal light activation with an endoscopically-placed optical fibre (4–5 cm diffusing tip, 652 nm light at 10–50 J, 100 mW/cm diffuser fibre), followed by polyethylene stent insertion in all but one patient. Results: Before PDT, patients had a median of 3 (0–5) stent occlusions over 13 (2–27) months, with a median patency of plastic stents placed inside metal stents for recurrent stent occlusion of 3.5 (0.5–13) months. After PDT, tumour necrosis and/or metal stent recanalisation was seen in all patients, with a median of 0 (0–3) stent occlusions during 17 (1–78) months follow-up. The median patency of plastic stents inside metal bile duct stents after PDT was 5 (1–52) months. The median survival after diagnosis and PDT administration was 21 (10–90) and 9 (1–27) months, respectively. PDT was generally well-tolerated but two patients developed significant haemobilia, one of whom died with a gallbladder empyema two weeks after treatment. Conclusions: In patients with malignant biliary obstruction mTHPC PDT is safe in the majority, can improve stricture patency and recanalise blocked metal stents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Association for International Cancer Research, St Andrews, UK, Scotia pharmaceuticals, Carlisle UK
Concurrent, 3-times daily ultrafractionated radiation therapy and temozolomide for newly inoperable glioblastoma: TEMOFRAC a phase II trial.
Authors: P. D. Beauchesnes, G. Faure, G. Noel, T. Schmitt, L. Martin, L. Taillandier, C. D. Carnin
Journal: Journal of Clinical Oncology (2011)

2073 Background: Ultrafractionation radiation therapy consists in irradiating cells or tumors several times daily, delivering low doses at which hyperradiosensitivity occur. We recently reported the efficiency of ultrafractionation radiotherapy regimen in newly inoperable glioblastoma. We are now conducting a phase II clinical trial to determine the effect of a concurrent ultrafractionation regimen and temozolomide for inoperable glioblastoma patients. Methods: A prospective, multicenter, phase II study has opened for accrual in February 2008. Patients over 18 years of age who are able to give informed consent and have histologically proven, newly inoperable diagnosed and supratentorial glioblastoma are eligible. Three doses of 0.75 Gy spaced by at least four hours are delivered daily, five days a week for six consecutive weeks for a total of 67.5Gy, and concomitant chemotherapy consisted of temozolomide given at dose of 75 mg/m2, 7 days per week during the ultrafractionated radiotherapy. After a 4-week break, chemotherapy is resumed up to 6 cycles of adjuvant temozolomide every 28 days, according to the standard 5-day regimen. Tolerance and toxicity is the primary endpoints; survival and progression- free survival are secondary endpoints. Results: To date 38 patients have been enrolled in this study, 29 men and 9 women, median age 62 (range from 29 to 77 years old), median Karnofsky performance status was 80. The concomitant ultrafractionated radiotherapy - temozolomide has been well tolerated; no acute grade 3 and/or 4 CNS toxicity has been observed. Complete responses were seen in 2 patients, partial response and stabilisation were reported in 8 patients. Median survival from initial diagnosis was not reached; half of patients included are alive at 12 months. Few long survival patients were noted. Conclusions: Concurrent ultrafractionated radiation therapy and temozolomide is safe and well tolerated. Preliminary results showed encouraging survivals for these patients with unfavorable factors.