tbuckley/cabot-search huggingface dataset:
Interference Of The Tumor Supportive Effects Of BCL2 and MCL1 Sensitize Malignant Plasma Cells To The Lethal Effects Of Lenalidomide and Dexamethasone Regimen: An Important Clinical Path For BCL2 Targeting Drugs
Authors: Aneel Paulus, Kasyapa S. Chitta, Sharoon Akhtar, Maja Kuranz, Shaji Kumar, Vivek Roy, Stephen M. Ansell, Joseph R. Mikhael, Angela Dispenzieri, Craig Reeder, Candido E. Rivera, James M. Foran, Francis Buadi, Vincent Rajkumar, Asher Chanan-Khan
Journal: Blood (2013)
Cost-effective treatment with half year of trastuzumab and chemotherapy as adjuvant treatment for overexpression of Her2/neu breast cancer patients: Two institutional experiences in Taiwan
Authors: C. J. Tai, C. K. Pan, C. H. Wu, C. S. Chen
Journal: Journal of Clinical Oncology (2006)

10765 Background: In this study, we are evaluating the utilizing trastuzumab as an adjuvant combination with chemotherapy in an half year interval for breast cancer (1–3). Methods: Patients after October 2000 with HER2-positive (3+ by immunohistochemistry; if 2+, should fit over expression by FISH) stage II/III breast cancer who received adjuvant trastuzumab (4mg/kg ×1, then 2mg/kg/wk ×22, equals 6 bottles of trastuzumab) in combination with chemotherapy. The chemotherapy utilized for stage II breast cancer patients received CEF only and for those patients with LN(+) but ER/PR(−/−) also added paclitaxel for another 4 cycles besides CEF with interval of 3 weeks, and for those with stage III breast cancer patient with ER or PR(+), the docetaxel was given with CEF for 6 cycles). Clinical response rates were followed by using imaging studies with chest films, CT scanning, bone scan and sonography. Results: Overall, there were 37 patients enrolled in this study. The median age was 43 years old (22–74 y/o). Two patients (including the youngest one) were found to have bilateral breast cancer on diagnosis but both were still alive without disease so far. There were 3 patients developed disease progression after adjuvant chemotherapy with trastuzumab and 2 of them died thereafter and all these 3 patients were stage III disease. The oldest patient was one of the exception without receiving adjuvant chemotherapy and received monotherapy of trastuzumab only and so far, she was still alive without disease. The side effect including chills (24.32%), dizziness (8.10%), cough (2.10%), cold sweating (2.10%). Conclusions: For her2/neu overexpression patients, trastuzumabwith chemotherapy may have positive role in adjuvant therapy. In this study, our main goal is to achieve patient’s treatment outcome in disease free status. Nonetheless, the cost was high if we applied trastuzumab as adjuvant therapy with 1- or 2-year interval (4–6). Even if this required further time to demonstrate this study’s final outcome, I suppose that utilization of trastuzumab as adjuvant treatment plus chemotherapy in a half interval will be a good alternative treatment option. No significant financial relationships to disclose.
WOMAC 20, 50 70 response levels in patients treated with hylan G-F 20 for knee osteoarthritis
Authors: N. Bellamy, M. J. Bell, C. H. Goldsmith, G.W. Torrance, J. Raynauld, P. Tugwell, R. Polisson, D. Pericak, V. Walker
Journal: Annals of the Rheumatic Diseases (2004)
Combined modality therapy for stage II and stage III pancreatic carcinoma.
Authors: A G Kamthan, J C Morris, J Dalton, J P Mandeli, M R Chesser, D Leben, A Cooperman, H W Bruckner
Journal: Journal of Clinical Oncology (1997)

PURPOSE To study the outcome achieved with three-drug chemotherapy and split-course external-beam radiotherapy as a treatment for unresectable stage II and III pancreatic carcinoma. PATIENTS AND METHODS Radiotherapy was given in three cycles of 2 Gy/d on days 1 to 5 and 8 to 12 (total dose, 54 Gy) concurrently with fluorouracil (FU) 1,000 mg/m2/d by continuous infusion for 4.5 days, streptozocin (STZ) 300 mg/m2 on days 1, 2, and 3 and cisplatin (P) 100 mg/m2 on day 3 of each every-28-day cycle. Subsequent treatment consisted of leucovorin (LV) 200 mg/m2 and FU 600 to 1,000 mg/m2 every 14 days. RESULTS The median survival time for the 35 patients was 15 months and 26% of patients were alive at 24 months. Fifteen patients (42.8%) had objective responses to therapy. Six (17%) had a complete response (CR). Three of nine patients with partial responses (PRs) achieved a radiographic CR within the next 3 months. Nine patients underwent attempts at surgical resection: five were resected (median survival time, 31 months; range, 12.8 to 44.7+), two had no residual disease found at complete resection, and three others also had a complete resection. Of four others who could not be resected, three underwent intraoperative radiotherapy and one had occult metastatic disease. Of primary tumors, 91% did not produce either back pain or local gastrointestinal complications for 2 years. The rates of severe side effects were stomatitis 15%, anemia 14%, granulocytopenia 6%, and thrombocytopenia 6%. CONCLUSION Palliation and survival compare favorably with other series, including many surgical series. The response findings encourage studies of both unresectable and (as neoadjuvant therapy) resectable tumors.
Phase II study of S-1 and docetaxel combination in advanced or recurrent gastric cancer
Authors: K. Yoshida, T. Toge, M. Ninomiya, N. Takakura, N. Hirabayashi, W. Takiyama, Y. Sato, M. Terashima, M. Goto, J. Sakamoto, M. Nishiyama
Journal: Journal of Clinical Oncology (2005)

4049 Background: Docetaxel (TXT) and S-1 are active agents against gastric cancer. A synergistic antitumor effect has been shown in a preclinical study, and our previous phase I trial demonstrated the safety and tolerability of the combination, and its potent activity (Yoshida et al, ASCO 2003). To prospectively evaluate toxicity and efficacy of TXT/S-1, we conducted the current phase II study in patients with advanced and recurrent gastric cancer. Methods: Patients (pts) with advanced or recurrent gastric cancer, who have not received any chemotherapy except one regime (not including Taxanes), were eligible for the trial, and were treated with docetaxel 40 mg/m2 one hour iv infusion on day 1 and S-1 at a full dose of 80 mg/m2/day for two weeks every three weeks, and corticosteroids were administered on day 1 and 2. Results: Forty-eight pts with measurable lesions (RECIST) (13 females, 35 males; performance status [PS] 0/1/2: 33/13/2, age 25–75, well differentiated/undifferentiated adenocarcinoma: 19/29) have been enrolled. A total of 195 cycles were administered (median 3, range 1–10), and all pts were assessable for toxicity and efficacy. Grade 3–4 toxicities were: neutropenia in 58.3% (grade 4: 22.9%) of patients, leukocytopenia in 35.4% (grade 4:6.3%), anemia in 6.3%, stomatitis in 10.4%, nausea-vomiting in 6.33% and diarrhea in 2.1%. All treatment related toxicities resolved, and no toxic death was reported. Twenty five partial responses (PR) were obtained, resulting in an overall response (OR) rate of 52.1% (95% CI: 0.38–0.66). Twenty pts (41.7%) had stable disease, and 3 pts (6.3%) progressed. The tumor control rate was 93.8% (95% CI: 0.83–0.98). The median survival time (MST) and time to treatment failure (TTF) were 434 and 221 days, respectively. Conclusions: The combination of TXT/S-1 is highly active in advanced or recurrent gastric cancer, and can be given safely with proper management of adverse events. TXT/S-1 is one of the most powerful candidates to become standard regimen for metastatic gastric cancer. No significant financial relationships to disclose.
Adherence to treatment with second-line therapies, dasatinib and nilotinib, in patients (pts) with chronic myeloid leukemia (CML).
Authors: M. Ulcickas Yood, S. A. Oliveria, I. Hirji, S. Phillips, M. J. Cziraky, C. C. Davis
Journal: Journal of Clinical Oncology (2011)

6589
A phase I-II study to assess the safety, pharmacokinetics, and potential efficacy of intravenous SB-743921 on days 1 and 15 of a 28-day cycle in patients with non-Hodgkin lymphoma
Authors: A. Goy, T. Feldman, M. Dessanti, J. Hainsworth, C. Weaver, R. Ungerleider, A. Wolff, R. Escandon
Journal: Journal of Clinical Oncology (2007)

18516 Background: Kinesin spindle protein (KSP) is required for mitotic spindle bipolarity and cell cycle progression. SB-743921 (SB- 921), a selective KSP inhibitor, blocks mitotic spindle assembly, causing cell cycle arrest in mitosis and subsequent cell death. Neutropenia was the dose-limiting toxicity (DLT) in the first-in-humans study of SB-921 given Q21 days. Methods: Cohort 1 of the Phase I portion of a study determining the safety, pharmacokinetics and MTD of SB-921 without prophylactic GCSF in patients (pts) with Non-Hodgkin’s Lymphoma (NHL) or Hodgkin’s Disease is reported. Pts with relapsed or refractory disease were eligible if they had received at least one prior chemotherapy regimen, had failed high-dose therapy with autologous stem cell transplant (ASCT), or were not candidates for ASCT. SB-921 is given to dose-escalating cohorts of 3 pts as a 1 hr IV infusion, Q14 days. Dosing began at 2 mg/m 2 and escalated in 1 mg/m 2 increments after 3 pts tolerated 1 cycle. Pts without dose-limiting toxicity (DLT) not completing Cycle 1 are replaced. Cohort expansion to 6 pts occurs if 1/3 pts experiences DLT, defined as any drug-related toxicity = grade 3 or drug-related grade 4 hematologic toxicity. Results: Cohort 1 (2 mg/m 2 ) enrolled 6 NHL pts (5 indolent, 1 aggressive). 4 were female; median age = 59 (52–73); 5 Caucasian, 1 African-American; median no. of cycles = 2 (1–6). 5/6 pts were evaluable; 1 dropped out before dosing. The most common Grade 1–2 AEs, in decreasing order, were fatigue, dysgeusia, paresthesia, leukopenia, and diarrhea. Grade 3 AEs of note were 1 each of hemolytic anemia, leukopenia, thrombocytopenia and dyspnea; 1 Grade 4 anemia was reported. Conclusions: SB-921 was well tolerated without prophylactic GCSF in Cohort 1 of the Phase I portion of this study, which continues to dose-escalate. If neutropenia is the DLT, dose escalation will continue with prophylactic GCSF. No significant financial relationships to disclose.
Phase II study of the histone deacetylase inhibitor belinostat in thymic malignancies
Authors: G. Giaccone, A. Rajan, C. Carter, R. Kelly, A. Berman, J. Spittler, I. Espinoza-Delgado, M. Lee, J. Trepel, P. Loehrer
Journal: Journal of Clinical Oncology (2009)

7589 Background: Thymic malignancies are rare tumors. Chemotherapy is used for advanced disease. There is no established role of second-line therapy in patients with refractory or recurrent disease. Belinostat is an HDAC inhibitor with activity in cutaneous and peripheral T cell lymphoma and is being investigated in several solid tumors. One prolonged minor response (31 m) was seen in a phase I study of this agent in a patient with thymoma. Methods: Patients with recurrent thymoma or thymic carcinoma, progressing after platinum-based chemotherapy were eligible. They were also required to have measurable disease, PS 0–2 and normal organ functions. Belinostat was given iv at 1.0 g/m 2 on days 1–5 of a 21-day cycle until disease progression or intolerable side effects. Correlative markers of activity in blood and tumor were performed. Results: From December 07 to December 08, 22 patients have been accrued from 2 institutions; 12 patients were males, median age 52 (23–72), 14 thymomas and 8 thymic carcinomas, mean number of prior regimens 3.5 (1–10), 16 prior tumor resection and 3 myasthenia gravis. A median of 4 cycles have been given (1–15+). Treatment was well tolerated, with nausea being the most common side effect and well controlled with prophylactic antiemetics. 21 patients are evaluable for response: 2 had a partial response (9+, 9+ m), 13 stable disease (3–11+ m) and 6 progression. No responses were seen in 8 evaluable patients with thymic carcinomas. Acetylated lysine and tubulin were analyzed in lymphocytes and monocytes by multiparameter flow cytometry. An increase of protein acetylation (2–10 fold) over baseline was observed at 1 hour post-infusion on day 3 of the first cycle in all patients analyzed. Other correlative markers are being investigated. Conclusions: The thymoma cohort has been expanded to the second stage of the study. Belinostat has activity in patients with recurrent or refractory thymoma. No significant financial relationships to disclose.
Effect of bortezomib, cyclophosphamide, and filgrastim on complete remission rates and CD34+ stem cell collections in multiple myeloma (MM)
Authors: R. Niesvizky, J. Stern, M. Manco, T. Mark, M. W. Schuster, T. B. Shore, J. G. Harpel, R. N. Pearse, F. Zafar, M. Coleman
Journal: Journal of Clinical Oncology (2008)

8587 Background: Typical stem cell mobilization regimens in MM include G-CSF alone or with high-dose cyclophosphamide. Given the known in vitro/in vivo synergy between bortezomib (Velcade [Vel]) and alkylating agents, we investigated the potential for concurrent cytoreduction by adding Vel to the mobilization regimen. Methods: Primary objectives of this open-label study were to maximize response pre-transplant and the successful mobilization and harvest of stem cells (goal ≥10 × 106/kg in <7 leukaphereses). Eligible patients (pts) had symptomatic, Durie-Salmon stage II/III MM. All pts received six 21-day cycles of Vel/dexamethasone ± liposomal doxorubicin. Mobilization comprised Vel 1.3 mg/m2 on days 1, 4, 8, and 11, cyclophosphamide 3 g/m2 on day 8, and filgrastim (rhG-CSF) for 10 days from day 9. Time to post-transplant ANC (>1.5 × 109/L) and platelet (>20 × 109/L) recovery were recorded. Results: Of 24 pts accrued, 14 have been mobilized, and 10 have completed transplant. CD34+ yields greatly exceeded the study goal (table). Median CD34+ collection was 21.3 ×106/kg in a median of 1.5 collection days. Of the 23 evaluable pts 70% had ≥ PR, with 48% CR/nCR. Pts who had not achieved a complete response (CR) prior to mobilization continued to respond positively to treatment during mobilization, including one transition from near-CR to CR and one from stable disease to partial response. Expected grade 3/4 toxicities occurred; no pts discontinued mobilization. Post-transplant, median time to ANC recovery was 11 days and to platelet recovery was 18 days. Correlative studies of biomarkers for stem cell mobilization comparing Vel mobilized to non Vel mobilized stem cells (CD34, gene array analysis, CXCR2–4) will be presented. Conclusion: Vel, cyclophosphamide, and filgrastim is a novel, well tolerated, and effective regimen for stem cell mobilization in MM. It results in high stem cell yields in a short collection time and provides the potential for further cytoreduction. CD34+ stem cell collection and engraftment data by patient Patient Days to collection Days to meet study goal (10 x 106/kg) * CD34+ stem cells (x 106/kg) Days to ANC recovery Days to platelet recovery 1 18 1 21.2 14 20 2 17 1 47.4 11 13 3 19 1 22.0 13 22 4 18 1 17.9 10 15 5 19 3 40.6** 11 21 6 18 1 19.9 10 16 7 19 1 294.2*** 10 17 8 17 2 13.8 13 24 9 18 5 9.3 11 18 10 17 2 21.4 16 15 11 17 1 50.0 12 21 1 66.1 13 18 1 30.4 14 17 1 43.6 * Median time to meet study goal was 1 day; ** Note: 20.4 x 106 cells collected after 2 days; *** Note: 86.3 x 106 cells collected after 1 day Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Millennium Millennium
The impact of brain metastases on overall survival (OS) in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) clinical trials (CT) in advanced non-small cell lung cancer (NSCLC)
Authors: P. A. Bradbury, P. Twumasi-Ankrah, K. Ding, N. B. Leighl, G. D. Goss, S. Laurie, F. A. Shepherd, L. Seymour
Journal: Journal of Clinical Oncology (2009)

8075 Background: NSCLC patients (pts) with brain metastases (BMet) commonly are excluded from participating in clinical trials (CTs), based on perceptions of inferior outcomes. We evaluated the validity of this exclusion criterion, by investigating the OS of stage IV NSCLC pts with (BMet) and without (non-BMet) a prior history of BMet recruited to NCIC CTG CTs. Methods: This pooled analysis utilized data from BR.18 (paclitaxel/ carboplatin [PC] ± MMPI [BMS275291]), BR.21 (erlotinib vs. placebo), BR.24 (PC± VEGFR TKI [AZD2171]). Each trial permitted entry of pts with neurologically stable BMet, provided they had been treated and off corticosteroids (BR.24), or either treated or not but without corticosteroids (BR.18), or on a stable corticosteroid dose (BR.21). The primary end-point of these analyses was OS, evaluated in the pooled pt cohorts stratified by treatment arm, and in each trial individually. Results: Of 1,349 stage IV pts, 131 had a history of BMet. Of these, 103 (78%) pts had cranial radiation prior to randomization and 15 (11%) prior craniotomy. The median age of the BMet cohort was 56yrs vs. 61yrs for non-BMet cohort. There was no difference in baseline PS (BMet: PS 0–1 vs. 2 vs. 3 =74% vs. 21% vs.5%; non-BMet: 81% vs. 16% vs. 4%, p=0.16), weight loss (p=0.73) or hemoglobin (p=0.80) between the two cohorts. Female gender (41% vs. 33%, p=0.04) and adenocarcinoma (66% vs. 51%, p=0.005) was more common in the BMet cohort. There was no OS difference between the BMet and non-BMet cohort in the pooled analysis, stratified by trial (HR 1.05, 95%CI 0.85–1.28, stratified log-rank p=0.67), or in multivariate analysis adjusted for baseline covariates (AHR 1.12, 95%CI 0.91–1.37, p=0.31). There was also no OS difference between BMet and non-BMet pts when evaluated in each individual trial separately. Conclusions: Pts with a prior history of BMet have a similar OS to those pts without BMet in NSCLC in NCIC CTG CTs. In neurologically stable pts, BMet, should not be an exclusion criterion, while discontinuation or stable dose of corticosteroids appears a reasonable eligibility requirement. No significant financial relationships to disclose.
Phase I trial of the mTOR inhibitor RAD001 (R) in combination with two schedules of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor PTK787/ZK 222584 (P) in patients (pts) with advanced solid tumors
Authors: G. K. Dy, G. A. Croghan, Y. Qi, J. Glockner, L. Hanson, M. Roos, A. D. Tan, J. R. Molina, A. A. Adjei
Journal: Journal of Clinical Oncology (2008)

2529 Background: There is synergistic antitumor effect between mTOR inhibitors and anti-angiogenesis agents. Methods: A phase I study was performed to define the maximum tolerated dose (MTD) and clinical activity of both QD dose and BID dose of P in combination with R (see table) q28 days in pts with advanced cancers. Correlative markers of response and therapy-induced hypertension were analyzed. Results: 24 pts at dose escalation phase and 24 pts at expanded MTD cohort received 233 cycles of therapy. Major toxicities (cumulative events, CTC grade) were ALT elevation (3 gr 3), diarrhea (6 gr 3), vomiting (5 gr 3), fatigue (5 gr 3), hypercholesterolemia (1 gr 3 and 1 gr 4 ), hypertriglyceridemia (6 gr 3), hypertension (6 gr 2 and 1 gr 3), proteinuria (10 gr 2), thrombosis (1 gr 3 and 1 gr 4). DLTs were gr 3 ALT elevation and diarrhea. Dose level 3 was used for the expanded MTD cohort due to better pharmacokinetic and toxicity profile with chronic dosing. PRs were seen in 6 pts: 2 neuroendocrine carcinoma (NEC), 2 treatment-naïve clear cell renal cell cancer (RCC), 1 uterine serous carcinoma, 1 melanoma. 9 pts had SD lasting >5 cycles. There was temporal decrease in plasma sVEGFR1 and increase in VEGF-A levels. There was no significant change in flow-mediated dilated (FMD) measured by brachial artery US. There was no correlation between BP change with VEGF-A, sVEGFR1 or FMD. DCE-MRI in 4 pts showed temporal reduction in maximal slope of increase and signal enhancement ratio (SER). Adjusting for normal control tissue, there was temporal increase in SER except in the pt with disease progression. Conclusions: The combination of P with R is effective and well tolerated. There is no correlation between BP change with VEGF-A, sVEGFR1 or FMD. Absolute temporal changes of vascular parameters in DCE-MRI do not predict for treatment response. We recommend the BID schedule of P with R for future evaluation in phase II studies for RCC and NEC. Dose Level R (mg, QD) P ( mg) No. pts (No. replaced) No. cycles No. DLTs 0* 5 1,000 QD 3 (3) 38 0 1 10 1,000 QD 3 14 0 2 10 1,250 QD 6 21 1 3 10 750 BID 6 (1) 45 1 4 10 1,000 BID 6 (2) 19 0 No significant financial relationships to disclose.
<sup>89 </sup>Zr-bevacizumab PET imaging in metastatic renal cell carcinoma patients before and during antiangiogenic treatment.
Authors: Sjoukje Oosting, Adrienne H. Brouwers, Suzanne C. Van Es, Wouter B. Nagengast, Thijs H. Oude Munnink, Marjolijn N. Lub-de Hooge, Harry Hollema, Johan R De Jong, Igle J. de Jong, Sanne de Haas, Stefan Scherer, Wim J. Sluiter, Rudi A Dierckx, A. H.H. Bongaerts, Jourik A. Gietema, Elisabeth De Vries
Journal: Journal of Clinical Oncology (2012)

10581 Background: Renal cell cancer (RCC) is characterized by high VEGF production leading to excessive angiogenesis. To visualize VEGF, we performed serial 89 Zr-bevacizumab-PET scans before and during antiangiogenic treatment in RCC patients. Methods: Metastatic (m) RCC patients who received sunitinib (50 mg once daily, 4 out of 6 weeks) or bevacizumab (10 mg/kg every 2 weeks) plus interferon (IFN 3-9 MU 3x/week), underwent 89 Zr-bevacizumab-PET scans at baseline and after 2 and 6 weeks, and CT scans at baseline and every 3 months. Tracer uptake in tumor lesions was quantified with maximum Standardized Uptake Value (SUVmax). Relationship between baseline and Δ SUVmax and time to progression (TTP) was analyzed. Wilcoxon test was used to compare scans, Kaplan-Meier method for survival analysis. Results: 22 out of 26 patients were evaluable, 11 per treatment. On 89 Zr-bevacizumab-PET, 131 out of 231 lesions ≥ 10 mm (detection limit) were visible and 125 quantifiable. Mean SUVmax at baseline was 10.1 (SD 8.4; range 2.3 - 46.9). During bevacizumab/IFN treatment, SUVmax consistently decreased (mean decrease 47.0% 95% CI 39.1-54.9, P&lt;0.0001) at 2 weeks with a further decrease of 9.7% (95% CI 0.86-18.5, P=0.016) at 6 weeks. After 2 weeks sunitinib, there was only a modest decrease in mean SUVmax (14.6%, 95% CI 1.57-27.63, P=0.0064) with a wide range (-80.4% to +269.9%) and an overshoot of 84.4% (95% CI 47.8-120.9, P=0.0001) after 2 drug free weeks. TTP was longer in (n=15) patients with baseline SUVmax &gt; 11.1 (highest normal tissue uptake) in the 3 most intense lesions than in those with a lower value (median 89.7 vs 22.8 weeks, HR 0.16, 95% CI 0.04 - 0.70). TTP was longer in patients (n=11) with an absolute Δ SUVmax &gt;6.00 in the most intense lesion at 2 weeks (HR 0.25, 95% CI 0.06-0.98). Conclusions: 89 Zr-bevacizumab-PET visualizes tumor lesions in mRCC patients. Different changes in tumor tracer uptake after start of bevacizumab/IFN versus sunitinib indicate that these drugs induce different angiogenic responses. High baseline SUVmax and large change in SUVmax corresponded with longer TTP, suggesting that 89 Zr-bevacizumab-PET may help to identify patients who benefit the most from antiangiogenic treatment.
Mitochondria and Caspase-Independent Cell-Death Triggered by GCS-100, a Novel Carbohydrate-Based Therapeutic in Multiple Myeloma (MM) Cells.
Authors: Dharminder Chauhan, Guilan Li, Klaus Podar, Teru Hideshima, Kenji Ishitsuka, Laurence Catley, Martin Sattler, Yu-Tzu Tai, Renate Burger, Paul Richardson, Yan Chang, Joanne Schindler, Bradley Carver, Kenneth C. Anderson
Journal: Blood (2004)