tbuckley/cabot-search huggingface dataset:
Gemcitabine plus paclitaxel (GT) versus paclitaxel (T) as first-line treatment for anthracycline pre-treated metastatic breast cancer (MBC): Quality of life (QoL) and pain palliation results from the global phase III study
Authors: C. Moinpour, J. Wu, G. Donaldson, A. Liepa, A. Melemed, J. Oshaughnessy, E. Rappold, K. Albain
Journal: Journal of Clinical Oncology (2004)

621 Background: At ASCO 2003, interim results of GT vs T in MBC patients (pts) were presented (#25), demonstrating significantly longer time to disease progression for GT with manageable toxicity. Here we present the results of the pain and QoL assessments. Methods: Pts with MBC with prior (neo)adjuvant anthracyclines were randomized to GT (G 1250 mg/m2 d1,8; T 175 mg/m2 d1) or T (175 mg/m2 d1) q21d. Pts completed the Brief Pain Inventory (BPI) and Rotterdam Symptom Checklist (RSCL) prior to each cycle; only data from validated translations were included. Analgesic level was assessed prior to each cycle. Mixed effect repeated-measure analysis was used to study overall and cycle-specific differences. This abstract presents the results of sensitivity analyses with five longitudinal models (e.g., pattern mixture models) that were performed to study potential bias due to informative dropout. Results: 529 pts were randomized (267 GT and 262 T). Arms were balanced; 70% had visceral metastases and 72% had KPS 90. Median cycles were 6 for GT (range, 0–20) and 5 for T (range, 0–16). 291 pts completed BPI and 350 completed RSCL. 85% of expected questionnaires were completed. The mean RSCL global QoL score for patients receiving GT was significantly and consistently better than that reported by T arm patients; this difference was also clinically significant. No consistent differences were seen in the other RSCL scales. Mean changes and trends in pain intensity and interference were similar across treatment arms. Data from the sensitivity analyses consistently supported these findings. Of pts requiring analgesics at baseline (n=216), more GT pts were able to decrease analgesic level for >1 cycle (25 vs 15%). Conclusions: For pts with MBC, the addition of gemcitabine to paclitaxel extended time to progression and resulted in a better global rating of QoL. The combination palliated pain as well as monotherapy in the predominantly asymptomatic population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Eli Lilly & Co. Eli Lilly & Co. Eli Lilly & Co.
Evidence against a role for simian virus 40 in malignant mesothelioma in Japan
Authors: A. Hiraki, K. Aoe, T. Murakami, S. Toyooka, N. Shivapurkar, A. Gazdar, N. Sueoka, K. Sugi, H. Ueoka, T. Kishimoto
Journal: Journal of Clinical Oncology (2006)

10040 Background: Malignant mesothelioma is a highly aggressive tumor arising from serosal membranes, most commonly the pleura. Worldwide incidence is increasing because of widespread exposure to asbestos, the major causal agent. Incidence of this disease also is increasing dramatically in Japan. Association of simian virus 40 (SV40) with malignant mesothelioma has been reported, suggesting that SV40 plays an important role in the origin of a subset of these tumors. Most recently, evidence against any role for SV40 in this disease has been also reported. The role of SV40 in malignant mesothelioma remains still controversial. In addition, it has been argued that differences in the reported frequency of SV40 detection in malignant mesothelioma may be related to geographic variation in populations exposed to the virus. Whether SV40 is associated with malignant mesothelioma in Japan therefore is an important issue. However, no study concerning SV40 in malignant mesothelioma has been reported from Japan. Methods: To address this, we studied 35 malignant mesotheliomas including 32 men and 3 women with a median age of 61 years (ranges 34 to 85) and examined the presence of SV40 large T antigen DNA with real time PCR based on TaqMan technology using primers that PCR amplified a specific 156-bp region of the large Tag of SV40 as well as its expression with immnohistological methods using anti-SV40 large T antigen antibody (pAb101, Santa Cruz Biotechnology, Inc., CA). Results: Two of 35 mesotheliomas were considered positive for the presence of SV40 large T antigen DNA, showing ratios of 36.0 and 4.9. The ratio in the positive control was 199.0. The two positive cases consisted of one epithelioid tumor and one biphasic tumor. In addition, none of 35 malignant mesothelioma specimens were positve for staining with SV40 large T antigen antibody; in contrast, diffuse staining for SV40 large T antigen was observed in the cytoplasm and on the cell membranes in the positive control. Conclusions: Taken together, these findings strongly argue against any role of SV40 in the etiology of the majority of malignant mesothelioma in Japan. No significant financial relationships to disclose.
LAQ824 is a novel histone deacetylase inhibitor with significant activity against multiple myeloma: Results of a pre-clinical evaluation in vitro and in vivo.
Authors: L Catley, E Weisberg, YT Tai, B Lin, N Mitsiades, T Hideshima, R LeBlanc, R Shringapure, R Burger, C Mitsiades, D Chauhan, R Schlossman, N Munshi, P Richardson, J Griffin, K Anderson
Journal: Blood (2002)
Validation of a genomic classifier for predicting biochemical failure following postoperative radiation therapy in high-risk prostate cancer.
Authors: Robert Benjamin Den, Felix Yi-Chung Feng, Timothy Norman Showalter, Mark Vikas Mishra, Edouard John Trabulsi, Costas D. Lallas, Leonard G. Gomella, Ruth C. Birbe, Peter McCue, Mercedeh Ghadessi, Karen E. Knudsen, Adam Dicker
Journal: Journal of Clinical Oncology (2014)

10 Background: Radiation therapy (RT) is commonly offered in the post radical prostatectomy (RP) setting, however response varies. We hypothesized that the genomic classifier ([GC] Decipher) score would predict biochemical failure (BF) and distant metastasis (DM) in men receiving post−RP RT. Methods: Under an institutional review board approved protocol, 223 men who underwent post−RP RT at the Kimmel Cancer Center of Thomas Jefferson University for pT3 or margin positive disease from 1990 to 2009 were identified. RNA was extracted from 143 patients with paraffin−embedded specimens and expression quantified from the highest Gleason grade tumor focus using a high−density oligonucleotide microarray. Excluding men who received neo−adjuvant therapy, 139 patients remained for GC calculation. Area under the receiver operating curve (AUC), decision curves, cumulative incidence accounting for competing risks, and multivariable Cox regression analyses were used to assess GC for predicting BF and DM after RT in comparison to nomograms. Results: The AUC of CAPRA-S was 0.67 (95% CI 0.58−0.77) and 0.65 (95% CI 0.44−0.86) for BF and DM, respectively. Integration of GC improved AUC to 0.75 (95% CI 0.66−0.84) and 0.77 (95% CI 0.64−0.91) for BF and DM, respectively. Cumulative incidence of BF at 8 years post-RT was 21%, 48%, and 81% for low (less than 0.4), intermediate (0.4 to 0.6), and high (more than 0.6) GC, respectively (p&lt;0.00001). In multivariable analysis, patients who received RT early (pre−RT prostate-specific antigen [PSA] less than 1 ng/mL) had a BF benefit with a significantly reduced hazard ratio (HR) of 0.32 (95% CI 0.11−0.96, p&lt;0.042). Patients with high GC had an HR of 14.73 for BF (95% CI 4.90−44.31, p&lt;0.00001). Earlier PSA recurrence was observed in patients with high GC score that received salvage compared to adjuvant RT with median BF survival post-RT of 4.67 versus 8.78 years (p&lt;0.04). This held true after adjusting for CAPRA-S score. Conclusions: This is the first validation of the GC in the post−RP RT setting. GC improved risk stratification above clinical classifiers. Patients with high GC received significant benefit from early RT intervention. For those patients with high pre-RT PSA and high GC, exploration of intensified therapy is warranted.
Phase I dose optimization trial of patupilone in previously treated patients (pts) with advanced colon cancer (ACC)
Authors: B. Melichar, J. Tabernero, E. Casado, J. Bridgewater, J. Hamm, I. Sklenar, J. Holland, W. Cheung, S. Zaknoen, A. Johri
Journal: Journal of Clinical Oncology (2005)

3688 Background: Patupilone, a natural epothilone, is a microtubule-targeting cytotoxic drug with activity in a wide range of tumors, including colon cancer. Because in earlier studies with a weekly regimen, diarrhea was the dose-limiting toxicity, and patients (pts) with colon cancer are more susceptible to diarrhea, the optimal dosing regimen of patupilone in this pt population needs to be defined. Methods: Pts with advanced colon cancer who had progressed after first-line combination chemotherapy received patupilone once every 3 weeks (q3w) via IV bolus on day 1 (bolus IV×1), via continuous 24-hr IV infusion on day 1 (24hCIV×1), or via 16-hr CIV on days 1 to 5 (16hCIV×5). Patupilone was started at 6.5 mg/m2 and escalated in 0.5-mg/m2 increments. Pts received proactive antidiarrheal treatment according to standard recommendations and a proprietary glutamine-containing nutritional supplement (NS). The lactulose-mannitol ratio (LAMA) was measured to characterize intestinal permeability. Pharmacokinetic parameters were followed. Results: To date, 24 pts have been enrolled. Median age was 62 yrs (range, 28 - 81 yrs). Thirteen pts received bolus IV×1 patupilone (4 pts at 6.5 mg/m2; 3 pts at 7.0 mg/m2; 3 pts at 7.5 mg/m2; 3 pts at 8.0 mg/m2), 8 pts received 24hCIV×1 patupilone (4 pts at 6.5 mg/m2; 4 pts at 7.0 mg/m2), and 3 pts received 16hCIV×5 patupilone at 6.5 mg/m2. The most common adverse events were diarrhea (42%), asthenia (17%), and abdominal pain (13%). Hematologic toxicity and peripheral neuropathy were rare (< 5%). There was only 1 case of peripheral neuropathy (grade 1) and no cases of alopecia. No dose-limiting diarrhea has been reported with the bolus IV×1 or 24CIV×1 q3w schedules. In contrast, 2 of 3 pts receiving 16hCIV×5 patupilone experienced grade 3 dose-limiting diarrhea. Clinical benefit (stable disease) was observed in 12 pts principally in the bolus IV×1 and 24CIV×1 arms, including 2 pts with a minor response. An increase in LAMA was observed in most pts and in some cases was associated with diarrhea. Conclusions: These preliminary data suggest that the q3w bolus dosing with proactive diarrhea management is better tolerated than the previous weekly regimen of patupilone. The study is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis
Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion [FDR]) versus gemcitabine + oxaliplatin (GEMOX) in patients with advanced pancreatic cancer (E6201)
Authors: E. Poplin, D. E. Levy, J. Berlin, M. L. Rothenberg, P. J. O’Dwyer, D. Cella, E. Mitchell, S. Alberts, A. Benson
Journal: Journal of Clinical Oncology (2006)

LBA4004 Background: Gemcitabine (GEM) is the cornerstone of treatment of metastatic pancreatic cancer (PANCA). FDR GEM or GEMOX are promising, but have yet to convincingly demonstrate a survival advantage over GEM alone. E6201 compares overall survival (OS) of standard GEM 1000 mg/m 2 /30 min wkly ×7 over 56 days then wkly ×3 q28 d (ARM A) vs. FDR GEM 1500 mg/m 2 /150 min wkly ×3 q28 days (ARM B) or GEM 1000 mg/m 2 /100-min/d1 + oxaliplatin 100 mg/m 2 /d2 q14d (ARM C). Secondary endpoints are the comparison of the experimental regimens, toxicity, response, patterns of failure, progression-free survival and quality-of-life. Methods: This multi-institutional trial included patients (pts) with measurable and non-measurable advanced, unresectable PAN CA, normal organ function and PS 0–2. Pts were chemonaive, although prior adjuvant radiosensitizing 5FU was permitted. Pts were stratified by PS 0–1 vs 2 and locally advanced vs metastatic disease The study was designed to detect a 33% difference in median survival (hazard ratio 1.33) with 81% power while maintaining a significance level of 2.5% in a two-sided test for each of the two primary comparisons, assuming exponential failure and median survival of 6 mo for Arm A and 8 mo for Arm B and C (N = 750 eligible). Results: Accrual started in 3/03 and completed in 3/05. Median follow up is 5.8 mo. 833 pts (53% men; 88% PS 0–1; 88% metastatic), were randomized with 280, 277 and 276 pts in Arms A, B and C. The third interim analysis was conducted with 89.5% information on 3/2006. The predominant toxicity, available for 758 pts, was grade 3/4 myelosuppression and fatigue. Two deaths from ARDS and infection occurred. Median OS for ARMS A, B, and C are 4.96, 6.01 and 6.47 months, respectively. Hazard ratio A vs B is 1.21 with stratified log rank of 0.053 and for A vs C is 1.22 with stratified log rank of 0.045, neither statistically significant. Conclusion: E6201 final OS results will be available in June, 2006. [Table: see text] [Table: see text]
A phase II trial of erlotinib monotherapy in pretreated patients (pts) with non-small cell lung cancer (NSCLC) who do not possess active <i>EGFR</i> mutations
Authors: H. Yoshioka, H. Hayashi, K. Kiura, N. Takigawa, K. Hotta, S. Harita, H. Kamei, A. Bessho, M. Tabata, M. Tanimoto
Journal: Journal of Clinical Oncology (2009)

8067 Background: Efficacy of gefitinib therapy strongly depends on the presence of active EGFR mutations in Asian NSCLC pts, with objective response rates (ORR) of 71.2% and only 1.1% in active mutant-positive (EGFR mt+ ) and -negative (EGFR mt- ) tumors, respectively [Mok T, ESMO2008]. Recently, the survival advantage of erlotinib, another TKI, is observed even in pts with EGFR mt- tumors (HR=0.74, p=0.09 [Zhu C, JCO2008]), indicating such subpopulation might also benefit from this TKI. The aim of this trial was to evaluate its efficacy and toxicity in Japanese pts with relapsedEGFR mt- tumors. Methods: Primary endpoint was ORR. Patients with EGFR mt- -NSCLC previously treated with one to three chemotherapy regimens were enrolled in this trial. The mutation status was assessed by the PCR clamp methods. Erlotinib was administered at a dose of 150mg/day until disease progression or unacceptable toxicities. Results: Thirty pts were enrolled between Jan and Dec 2008. Median duration of erlotinib treatment was 60 days. All pts were assessable for efficacy and safety. Demographics of the pts were as follows: M/F:24/6, Ad/others:20/10, ECOG-PS 0/1/2:7/19/4, and smoker/non-smoker:22/8. Platinum-based regimens were commonly used as the prior chemotherapy. Objective response was obtained in one pt (3.3%; RECIST). Seventeen pts obtained SD (56.7%). Toxicity profiles were almost tolerable with the treatment interruption in 11 pts (median duration; 10 days). Skin rash was common (grades 1, 2 and 3 in 7, 15, and 7 pts, respectively; NCI-CTCAE ver3). One pt developed grade 4 pulmonary embolism, but it seemed due to disease progression. Other 2 pts developed interstitial lung disease (grades 2 and 3 in one pt each). No treatment-related deaths (TRD) occurred. With a median follow-up time of 6.4 months, MST and MPFS time were 8.6 and 2.1 months, respectively. Conclusions: This is a first prospective biomarker study showing that erlotinib therapy for pretreated pts with EGFR mt- tumors seems as almost effective and safe as the standard docetaxel therapy (PR: 5.8%, SD: 42.7%, MST: 7.0 months, MTTP: 2.5 months and TRD: 4.9% [Shepherd JCO2000]). No significant financial relationships to disclose.
Phase II trial of paclitaxel/cisplatinum concomitant with adjuvant radiotherapy for treatment of bladder cancer.
Authors: W. O. Arafat, A. Darwish, W. Sameh, G. Elhossiny
Journal: Journal of Clinical Oncology (2010)

e15084 Background: Radical cystectomy is still considered a standard management for muscle-invasive bladder cancer. Yet, bladder sparing approach by concomittant chemoradiotherapy is gaining acceptance. Methods: 63 patients having T2-4a N0M0 transitional cell carcinoma of the bladder were enrolled in this study. All patients had complete TURBT as possible followed by chemo-radiotherapy (44 Gy radiation plus weekly paclitaxel/cisplatinum for 4 weeks). Complete responders, by biopsy, received chemoradiation (20 Gy plus weekly paclitaxel/cisplatinum for 2 weeks). Eight weeks later, those who maintained complete response received adjuvant chemotherapy (four-monthly cycles of paclitaxel/cisplatinum). Results: Three patients could not tolerate the induction chemoradiation and were excluded from the study. Sixty patients (38 T2 and 22 T3-4a) completed the induction course. Complete response was observed in 45 patients (75%) of them, 41 patients (68.3%) kept their complete response after the consolidation course and received the adjuvant chemotherapy. After a median follow up of 29 months (6-41 months), superficial recurrence of the disease was observed in 7 patients (11.7%) and 36 patients were alive and free of muscle invasive disease (60%). All these 36 patients kept their intact bladder although 17 (47.2%) had dysuria, 12 (33.3%) had frequency and 5 had bothering nocturnal enuresis (13.9%). Three patients could not tolerate the chemo radiation and were excluded from the study. Sixty patients (43 males and 17 females) (38 T2 and 22 T3-4a) completed the induction course. Complete response was observed in 45 patients (75%) of them, 41 patients (68.3%) kept their complete response and received the adjuvant chemotherapy. After a median follow up of 29 months (6-41 months), recurrence of the disease was observed in 7 patients (11.7%) and 36 patients were alive and free of disease (60%). All these 36 patients kept their intact bladder although 17 (47.2%) had dysuria, 12 (33.3%) had frequency and 5 had nocturnal enuresis (13.9%). Conclusions: Paclitaxel/cisplatinum chemotherapy concomitant with &adjuvant to radiotherapy can offer a satisfactory oncologic outcome while keeping an intact bladder. No significant financial relationships to disclose.
Preclinical evaluation of combined treatments in xenograft model of gastrointestinal stromal tumors (GISTs) using small animal PET.
Authors: M. A. Pantaleo, A. Maleddu, G. Nicoletti, C. Nanni, C. Gnocchi, M. di Battista, M. Nannini, L. Landuzzi, C. Quarta, G. Biasco
Journal: Journal of Clinical Oncology (2010)

e20502 Background: Primary and secondary drug resistance to imatinib and sunitinib in the treatment of patients with GISTs has led a progressively growing urgency to develop new strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib (I) and nilotinib (N) directly inhibit the kinase activity of KIT, RAD001(Everolimus)(E) inhibits mTOR. We report a preclinical study on combinations of drugs in xenograft model of GIST in which effects were assessed with tumor dimensions and metabolic activity using small animal PET imaging. Methods: Tumor xenografts were induced into ADKO mice by s.c injection of GIST882 cells into the right leg. After 30 days, tumors grew in all animals (volume 0,2-0,3 cm3). Animals were randomised into 7 groups of 6 animals each for different treatment regimens: * No therapy (control) * I (150 mg/kg b.i.d.) oral gavage for 6 days, then once/day because of toxicity * E (10 mg/kg/d.) oral gavage * E (10 mg/kg/d.) + I (150 mg/kg b.i.d.) * N (75 mg/kg/d.) oral gavage * N (75 mg/kg/d.) + I (150 mg/kg b.i.d) * I (300 Mg/kg q.d.) i.p. injection. Small animal PET (GE Explore tomography) was performed in one animal per group at base-line, after 7 and 13 days of treatment. The base-line FDG uptake was positive in all evaluated animals. Results: After 3 days of treatment all animals of the I i.p. treatment group died. In other groups, treatments were administered for 13 days and only 3 animals out of 36 died during the study (two in the I group, one in E + I group). Tumor volume (cm3) after 13 days of treatment: * Control: 1,2 * E, E + I, N + I: < 0,5 * N alone and I alone: 0,5-0,8. Micro-PET (FDG / SUV / TBR): * E: FDG was strongly reduced by E both as a single agent and in combination with I respectively: 3,1 > 2,3 > 1,9 and 2,5 > 2,3 > 0 * N also reduced FDG: 2,2 > 1,4 > 1,7 * N + I: 2,7> 3,2> 2,8 * I: 2,9 > 2, however, the mouse subjected to the first 2 PET scans died before the third scan. Conclusions: We report the in vivo evaluation of combined treatments vs single agent in GIST. All drugs showed activity as single agents. The combination E plus I appeared to be more active regimen in comparison to the others, both in terms of inhibiting tumor growth and FDG Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis
Phase I evaluation of SF1126, a vascular targeted PI3K inhibitor, administered twice weekly IV in patients with refractory solid tumors
Authors: E. G. Chiorean, D. Mahadevan, W. B. Harris, D. D. Von Hoff, A. E. Younger, D. M. Rensvold, C. F. Shelton, B. T. Hennessy, J. R. Garlich, R. K. Ramanathan
Journal: Journal of Clinical Oncology (2009)

2558 Background: SF1126 is composed of the pan PI3K inhibitor LY294002 conjugated to an RGD targeting peptide. It is designed to increased solubility and binding to integrins expressed on tumor vasculature. This targeted prodrug enhances tumor delivery of the active inhibitor, improving antitumor efficacy and tolerability in xenograft models. LY294002 inhibits other kinases including mTOR, DNA-PK, PIM1, PLK1, and CK2, and induces oxidative stress in cancer cells independent of its PI3K inhibition. Methods: Pts with advanced solid tumors are enrolled in sequential cohorts in standard 3+3 design. SF1126 is administered days 1, 4 weekly by 90 minute IV infusion in cycles of 4 weeks. Pharmacodynamic (PD) evaluations of PI3K pathways are being measured in PBMC, skin/hair and tumor samples as well as by 18FDG PET scans. Primary objectives are safety, establish MTD and recommended phase 2 dose. Results: 28 pts have been treated with SF1126126 across 7 dose levels of 90, 140, 180, 240, 320, 430, and 630 mg/m 2 . One dose limiting toxicity (DLT) was seen at the 180 mg/m 2 dose, consisting of transient G3 diarrhea. No other grade 3/4 drug related toxicities have been reported. No consistent effects on blood glucose levels noted. Eleven pts showed stable disease for ≥ 8 wks, including durations of 20 wks for one GIST, 1 endometrial, and 1 prostate; 15 wks for 1 pancreatic; 11 wks for 2 GIST, 2 ovarian, and 1 CRC pt. PK: SF1126 is rapidly cleared after infusion termination. PK of active hydrolysis product (LY294002) shows t 1/2 ∼1.6–2 hrs; dose proportional C max , achieving ∼ 21uM at 630 mg/m 2 ; and AUC (0-t) nearly dose proportional. Mean AUC values at doses ≥ 140 mg/m 2 exceed those found effective in mouse xenograft studies. PD: Compared to baseline biopsy, we observed significant inhibition of pS6 by IHC in a tumor biopsy 20 hours after the 8 th dose in a pancreatic cancer pt at 240 mg/m 2 . Conclusions: SF1126 is well tolerated at doses up to 630 mg/m 2 given twice weekly. MTD has not been reached; dose escalation continues. Clinical activity includes disease stabilization in multiple pts with refractory tumors. There is early evidence of target pathway inhibition. [Table: see text]