tbuckley/cabot-search huggingface dataset:
Emergence of oral targeted agents in early clinical development: Experience at M. D. Anderson Cancer Center (MDACC) Clinical and Translational Research Center (CTRC).
Authors: K. S. Culotta, R. Kurzrock, C. D. Stewart, V. Dorsey, D. Harleaux-Grant, M. Wyles, M. A. Kramer, Y. Zhang, T. L. Madden, D. D. Karp
Journal: Journal of Clinical Oncology (2010)

3073 Background: Most of the 94 chemotherapeutic agents approved by the FDA since 1949 are given intravenously. Oral therapy is preferred by > 80% of patients because of convenience and ease of administration yet only 15 agents existed from the 1950s–1990s. Over the past decade, a new era has begun with 14 oral agents FDA-approved beginning with imatinib in 2001. The CTRC is a dedicated phase I/II research unit that has researched 30 cancer drugs FDA-approved since 2001. We analyzed the route of administration and class of all investigational agents studied in our unit over the past 6 years. Methods: 549 active clinical protocols were conducted from 2001–2009. All agents given were classified based on mechanism of action (eg. small molecules, antibody, cytotoxic, etc.). In addition, we also determined the number of patient accruals on each protocol type to elucidate any trends in registration rates. Results: From 2006 to 2008, we witnessed increases of 88% in protocols administering a small molecule oral agent and 32% for IV targeted antibodies. On the other hand, the number of protocols administering cytotoxic investigational agents decreased 28%. When comparing protocol activity, the percentage of patients on a protocol giving an oral small molecule increased from 15.4% in 2006 to 32.7% in 2008 and for IV targeted antibodies it slightly increased from 12.1% in 2006 to 13.1% in 2008. As for the cytotoxics, the percentage decreased dramatically from 28.8% in 2006 to 12.8% in 2008. Conclusions: Our data suggest a major shift in early clinical drug development from IV agents to oral small molecules. It has presented physicians and other healthcare providers involved in delivering anti-cancer treatment with challenges in the clinical research setting in terms of reorganizing patient care structures to deliver oral treatments. The effect of this emergence of oral targeted agents on the health-care system will not be for some time but it will most likely be significant. It is estimated that in 2002 almost $0.5 billion was spent on oral chemotherapy drugs in the United States whereas it is expected that at current trends this number could reach almost $6.0 billion by 2020. No significant financial relationships to disclose.
Consistency in reporting of primary endpoints (PEP) from registration to publication for modern randomized oncology phase III trials.
Authors: B. You, H. K. Gan, G. R. Pond, E. X. Chen
Journal: Journal of Clinical Oncology (2010)

6031 Background: To improve the quality of results reported in randomized clinical trials (RCTs), international registration has been recommended. We performed a review of oncology RCTs published over the past 5 years to assess the consistency of analysis and reporting of the primary endpoint (PEP) from registration to publication. Methods: All oncology RCTs published in Ann Oncol; Br J Cancer; Breast Cancer Res Treat; Cancer; Eur J Cancer; J Clin Oncol; J Natl Cancer Inst; Lancet; Lancet Oncol; N Engl J Med between 2005 and 2009 were reviewed. Data were collected by 2 independent reviewers. Relevant registration information was extracted from ClinicalTrials.gov and/or ISRCTN. Consistency of PEP reporting was assessed. Results: 346 RCTs (237,861 patients) were identified. The majority was published in J Clin Oncol (50%), Ann Oncol (11%) and N Engl J Med (9%). Number of published RCTs constantly decreased from 79 in 2005 to 57 in 2009. Industry sponsorship increased from 57% to 77%. Percentage of published RCTs without registration decreased from 59% in 2005 to 23% in 2009, while percentages of registered RCTs with clearly defined PEP increased from 14% to 65%. Registration rates were higher in journals with higher impact factors. Among registered RCTs with a clearly defined PEP, 17% reported a different PEP in publication (industry vs. nonindustry- sponsored trials:19% vs. 7%). Moreover methodological inconsistencies were found in 30% RCTs, mainly due to discordances between PEP nature defined in article statistical section and PEP discussed subsequently in the results section (68%). Inconsistencies between study results and authors' conclusions were found in 13% RCT: equivalence concluded on negative superiority trials (62%); trials deemed positive whilst statistical results were negative (17%) and use of an EP different from PEP for conclusion (20%). These discrepancies increased from 8% in 2005 to 19% in 2009. Conclusions: Whilst we noted increasing rates of international registration, there was a high rate of discordance in PEP between registration and publication. Moreover, author's published conclusions regarding PEP were frequently not supported by methodology or study results. No significant financial relationships to disclose.
Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study
Authors: Ivan Borbath, Antonio Ceratti, Chris Verslype, Anne Demols, Thierry Delaunois, Stéphanie Laurent, Amélie Deleporte, Philippe Vergauwe, Eric Van Cutsem, Jean-Luc Van Laethem
Journal: Journal of Clinical Oncology (2011)
R-HCVAD/R-MTX-ARAC is an effective regimen for untreated diffuse large B-cell lymphoma (DLBCL) with aggressive features: M. D. Anderson experience in 40 patients
Authors: L. Fayad, S. Temple, B. Pro, F. Hagemeister, F. Cabanillas, F. Samaiego, P. McLaughlin, M. Wang, L. Kwak, J. Romaguera, M. A. Rodriguez
Journal: Journal of Clinical Oncology (2007)

8058 Background: R-HCVAD (rituximab-cyclphosphamide, vincristine, dexamethasone, doxorubicin) alternating with R-MTX-ARAC (rituximab, methotrexate-cytarabine) is a chemoimmunotherapy regimen with activity in ALL, mantle cell, and Burkitt’s lymphomas (BL). Histological differentiation between BL, atypical BL, and DLBCL with high-grade features can be difficult. We thus have treated patients with DLBCL with high-grade histological features and/or poor-risk IPI with R-HCVAD. Methods: Forty consecutive patients with information collected prospectively in the NCCN database, treated between 7/2002 and 10/05 at M.D Anderson Cancer Center, and who received at least one cycle are included in this cohort analysis. Characteristics: 18 (45%) male; 18 (45%) HI and High IPI; 25 (62.5%) ↑LDH; 26 (65%) with Stage III/IV; 2 (5%) with PS&gt;1; 8 (20%) with &gt;60 years; 25 (62%) a Ki-67 &gt;90%. Four patients received less than 4 cycles of treatment. Results: ORR was of 100%, with 95% CR/CRu. With a median follow-up of 26 months, 6 patients failed: 1 died in CR of pulmonary embolism while on treatment; 1 patient who achieved CR, had PD before the end of treatment; 1 achieved a PR and was transplanted (is alive in remission); 1 achieved a PR and progressed died of disease; and 2 relapsed (one is in remission after an ASCT). Four patients have died: 3 of disease, 1 of pulmonary embolism. The 3-year OS is 88% (95% CI 77%-99%); 3-year FFS is 71% (95% CI 47%-95%). The 3-year FFS for patients with L/LI risk (3-failures of 22 pts) was 78% (95% CI 52%-100%); and for patients with HI/H IPI (3 failures of 18 pts) 65% (95% CI 27%-100%). Conclusions: R-HCVAD/R-MTC-ARAC is a very active regimen for DLBCL of high grade. Toxicity was mostly hematological. We are currently doing a prospective randomized phase II study comparing this regimen to standard R-CHOP in patients with poor-risk IPI scores. No significant financial relationships to disclose.
Bevacizumab (B) plus gemcitabine (G) in patient (pts) with advanced pancreatic cancer (PC): Updated results of a multi-center phase II trial
Authors: H. L. Kindler, G. Friberg, W. M. Stadler, D. A. Singh, G. Locker, S. Nattam, M. Kozloff, K. Kasza, E. E. Vokes
Journal: Journal of Clinical Oncology (2004)

4009 Background: Vascular endothelial growth factor (VEGF) and its receptors are overexpressed in PC. In preclinical models, anti-VEGF antibodies suppress PC growth and potentiate the activity of gemcitabine. High VEGF expression correlates with advanced stage and decreased survival in PC pts. These data suggest that anti-VEGF therapy may have utility in PC. Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody to VEGF. Methods: We are conducting a phase II trial of BG in advanced PC pts at 8 centers. Eligible pts have no prior chemotherapy (except 5-FU as a radiosensitizer); PS 0–2; measurable disease; no tumor invasion of major vessels; no bleeding or thrombosis. G 1000 mg/m2 is given over 30 minutes days (D) 1, 8, 15 every 28 D. B 10 mg/kg is given D 1, 15 every 28D. CT scans are obtained every 2 cycles. Plasma VEGF levels are obtained pretreatment. 45 pts enrolled 11/01–12/03. Pt characteristics: male 47%; median age 61 (range 42–83); PS: 0/1/2: 62%/36%/2%; stage IV 100%; liver metastases 80%; prior radiation 18%. Results: 182 cycles of BG have been administered (median 3, range <1–11). 42 pts are currently evaluable for response in this ongoing trial (median follow-up 5.7 months). There are 9 confirmed partial responses (21% PR) lasting a median of 9.4 months. 19 pts (45%) had stable disease lasting a median of 5.4 months. Median time to progression is 5.8 months (95% CI: 4.8, 9.1). Median survival is 9.0 months (95% CI: 7.4, 12.4); 6-month survival is 74%. Grade ¾ toxicities (% pts): neutropenia 33%; leukopenia 30%; thrombocytopenia 7%; thrombosis 12%; bowel perforation 5%; hypertension, proteinuria, and headache 2% each. Grade 5 toxicities: 1 gastrointestinal bleed, 1 bowel perforation. Pretreatment plasma VEGF levels in 32 pts (range 0–586 pg/ml) showed no correlation with either response (Fisher's exact test p=1.00) or survival (Log rank test p=0.70). Conclusion: BG is active and well-tolerated in advanced PC. The median survival of 9.0 months and the 74% 6-month survival are encouraging. A randomized phase III trial of BG vs. G is in development in the Cancer and Leukemia Group B. Supported by NCI grant N01-CM-17102. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech; Lilly Oncology Genentech Lilly Oncology Lilly Oncology
Phase I/II study (UKT-03) of CCNU/temozolomide chemotherapy in addition to radiotherapy as first-line therapy for glioblastoma: Status report
Authors: U. Herrlinger, J. Rieger, D. Koch, R.-D. Kortmann, T. Hundsberger, J. Schuth, M. Bamberg, M. Weller
Journal: Journal of Clinical Oncology (2005)

1566 Background: Primary chemotherapy with single agent temozolomide or nitrosourea-based chemotherapy in addition to radiotherapy prolongs survival in patients with glioblastoma. Previous studies in patients with recurrent gliomas have shown that BCNU, a nitrosourea compound, applied intravenously and oral temozolomide can be safely applied in combination chemotherapy. Methods: This two-center trial accrued patients between November 2002 and December 2003. Patients with newly diagnosed glioblastoma and a Karnofsky performance score of 70% or higher received first-line therapy with 6 courses CCNU 100 mg/m2 (day 1) and temozolomide 100 mg/m2 (days 2–6). The temozolomide dose could be increased to 125 mg/m2/d or 150 mg/m2/d if no myelosuppression had occurred in the previous course. Starting during course 1, all patients also received involved-field radiotherapy with 60 Gy in 2 Gy fractions. All patients were evaluated for toxicity, progression-free survival and overall survival. Results: Thirty-one patients with a median age of 51 years (29–68 years) were treated with a median of 4 courses (range 1–6 courses) of CCNU/temozolomide therapy. WHO grade 4 hematotoxicity was observed in 5 patients. WHO grade 3 or 4 hematotoxicity occurred in 12 patients. One patient died from myelosuppression-associated septicemia. One patient developed WHO grade 4 drug-induced hepatitis. One patient had WHO grade 2 lung fibrosis. After a median follow-up time of 12 months (range 1–25 months), 24 of 31 patients have suffered tumor progression. The median progression-free survival was 9 months with a progression-free survival rate of 61% at 6 months and of 34% at 12 months. So far, 9 patients have died and the median overall survival has not been reached yet. Conclusions: Chemotherapy with CCNU and temozolomide in combination with involved-field radiotherapy is feasible and the progression-free survival of 9 months suggests that this therapy is effective in the primary therapy of glioblastoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Essex Essex Essex Essex Essex
Phase II trial of weekly paclitaxel and carboplatin (wTJ) for endometrial cancer (EC): Results of a Kansai Clinical Oncology Group trial (KCOG0015) in Japan
Authors: K. Ito, S. Adachi, Y. Itani, T. Nobunaga, M. Shintani, H. Tsubamoto, K. Hosokawa, H. Fujita, Y. Nakata, N. Yamazaki
Journal: Journal of Clinical Oncology (2004)

5085 Background: The chemotherapy (CT) for recurrent or post operative high risk patients (pts) of EC has not been established. Previously, we reported the usefulness of wTJ in EC for preliminary results (Ito et al; Proc ASCO 2002). Here we report the final results. Methods: Eligibility criteria included: histologically confirmed primary advanced or recurrent EC (group A), post-operative pts having high risk factors (above FIGO stage IC, G3 histology, capillary space invasion) (group B). Each cycle considered of three-weekly drug administrations: paclitaxel 80mg/m2 on days 1, 8 and 15 and carboplatin AUC 5 on day 1 as a 1-hr infusion of each drug, and more than 3 cycles of administration were planned. Results: Between 05/2000 and 03/2002, a total of 40 pts (median age was 58, range:30 -70) were enrolled and administered 163 cycles. Thirty-six pts (93%) completed more than 3 cycles (median 4, range:1–9). ECOG performance status (PS) was 0–1 in 39 pts, PS 2 in 1 pt. Thirty-eight pts (95%) had no prior CT. Group A contained 17 pts (6 recurrent pts, 8 neo-adjuvant CT pts for bulky stage IIb –IV, and 3 pts had post operative residual tumor). Group B contained 23 pts (primary stage I:10, II:5, III:6, IV:2pts). Toxicity, response and QOL were assessed by NCI-CTC ver2.0J in all pts, RECIST in 15pts had measurable disease in group A and EORTC-QLQC30J in 19 pts obtained their approval, respectively. Hematological toxicities(G3/G4) were neutropenia (31%/33%), thrombocytopenia (6%/0%). Febrile neutropenia was not observed. Reversible G3 hypersensitivity (5%) and G2 cardiotoxicity (3%: reversible PVC) were observed. The response rate was 80% (12/15) with 3CR, 9PR and 3SD. No pts remarkably failed own QOL in this trial. Now the median follow up period of group A is 28 months (range 15–40). The median time to progression and survival are 15+ (range 5–32+) and 25+ months (range 5–40+), respectively. And the median follow up period of group B is 26 months (range 18–39). No pts relapsed and all pts are alive. Conclusions: This wTJ regimen was highly effective and feasible for EC pts. No significant financial relationships to disclose.
Abstract 14807: Tissue Doppler Imaging Predicts Long Term Outcome in Patients with ST-Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention
Authors: Tor Biering-Sorensen, Rasmus Mogelvang, Peter Sogaard, Sune Pedersen, Soren Galatius, Soren Hoffmann, Jan Skov Jensen
Journal: Circulation (2012)

Purpose: To investigate the prognostic value of Tissue Doppler Imaging (TDI) after an ST-elevation myocardial infarction (STEMI). Method: In total, 391 patients were admitted with a STEMI and treated with primary Percutaneous Coronary Intervention. Echocardiography was performed median 2 days after the STEMI. Longitudinal systolic (s'), early diastolic (e') and late diastolic (a') myocardial velocities were measured by color TDI at 6 mitral annular sites and averaged to provide global estimates. Treatment effect was assessed in relation to death (n=29), hospitalization with heart failure (CHF, n=49) and new myocardial infarction (MI, n=25). Follow-up was median 25 months. Results: Using the mean value of global s’, e’ and a’ as cutoff, the population was stratified according to high or low s’, e’ and a’ (see table). Patients with low global s’ or e’ had more than two times the risk of an adverse outcome (death, CHF or re-MI, n = 89) than patients with high global s’ or e’, respectively. Patients who had b...
FG-3019, a human monoclonal antibody to CTGF, with gemcitabine/erlotinib in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.
Authors: Vincent J. Picozzi, J. Marc Pipas, Albert Koong, Amato Giaccia, Nathan Bahary, Smitha S. Krishnamurthi, Charles D. Lopez, Peter J. O'Dwyer, Katharina Modelska, Vanessa Poolman, James Chou, Ming Zhong, Seth Porter, Tom Neff, Frank Valone
Journal: Journal of Clinical Oncology (2013)

213 Background: Connective tissue growth factor (CTGF) is overexpressed in PDAC and facilitates local desmoplasia, tumor survival and metastasis. FG-3019 is a CTGF-specific monoclonal antibody that decreases tumor growth and metastases and prolongs survival in orthotopic and KPC mouse models. This study evaluates safety and efficacy of FG-3019 with gemcitabine/erlotinib in patients with PDAC. Methods: In a nongoing open-label, dose-escalation study, FG-3019 was used in combination with gemcitabine and erlotinib in patients with previously untreated, measurable, locally advanced or metastatic PDAC. Cohorts 1−6 received FG-3019 Q2W at 3, 10, 15, 25, 35 or 45 mg/kg. Cohort 7 received 35 mg/kg on Day 1 and then 17.5 mg/kg QW. Cohort 8 received 45 mg/kg on Day 1 and then 22.5 mg/kg QW. Results: 75 patients were enrolled at 7 centers. Baseline data: Stage III= 15, Stage IV=60; ECOG=0 (n=32), ECOG=1 (N=43). No SAEs or DLTs related to FG-3019 occurred at any dose. In per protocol population (n=68) median PFS and OS were 4.3 and 9.4 months respectively. Baseline plasma CTGF levels correlated inversely with PFS and OS (p=0.0029) (ITT population). Median FG-3019 Cmax and Cmin increased linearly with dose. Because of considerable overlap between subjects across cohorts, outcomes are correlated with drug exposure. OS, but not PFS, correlated with exposure after the first FG-3019 dose (Day 1 Cmax, p=0.009; Day 15 Cmin, p=0.005; ITT population). 47% of evaluable subjects had &gt;50% decrease in CA19.9.The magnitude of reduction correlated with Day 1 Cmax (p=0.04) and inversely with baseline plasma CTGF (p=0.01). As FG-3019 accumulated over time, minimum FG-3019 exposure (Cmin) of 150 ug/mL on Day 43 appeared to be a threshold. Median OS was 7.7 and &gt;8.6 months for subjects &lt; (n=15) or ≥ (n=43) 150 ug/mL respectively on Day 43 (p=0.0034). Day 43 Cmin &lt; 150, none alive at 12 months: Day 43 Cmin &gt;150, 8 alive at 12 months, 17 alive 6.7-12 months. Conclusions: FG-3019 combined with gemcitabine/erlotonib is well tolerated. Interim results in this open-label study suggest OS improves with increasing exposure to FG-3019. Clinical trial information: NCT01181245.
Radium-223 dichloride (Ra-223) in U.S. expanded access program (EAP).
Authors: Nicholas J. Vogelzang, Daniel Celestino Fernandez, Michael J. Morris, Andrei Iagaru, Alan Brown, Fabio Almeida, Christopher Sweeney, Matthew Raymond Smith, Adam Dicker, Yu-Ning Wong, Neal D. Shore, Keith Bangerter, Oana Petrenciuc, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2015)

247 Background: The ALSYMPCA study (Parker, NEJM, 2013) was the basis for regulatory approval of Ra-223 for the treatment of castrate-resistant prostate cancer (CRPC) patients (pts) with symptomatic bone metastases. The aim of this prospective EAP was to monitor acute and long-term safety of Ra-223. Pt profiles and findings in the EAP setting are presented. Methods: In the EAP, CRPC pts with symptomatic bone metastases who either received or were not eligible for docetaxel received Ra-223 50 kBq/kg by injection q4wks for 6 cycles. Primary endpts: ECOG PS, symptomatic skeletal-related events (SSE), treatment-emergent adverse events [TEAEs], routine laboratory tests including PSA. Exploratory endpts: overall survival (OS), SSE rates, changes in total ALP (tALP)/PSA responses, time to tALP normalization, and to tALP and PSA progression. Descriptive statistics were used. Results: 184 pts entered treatment; baseline characteristics were similar as seen in ALSYMPCA (N=600) (exceptions in table); 67% had total ALP &lt;220 U/L and 47% mild/moderate pain. 81/184 (44%) received all 6 injections; 26 (14%) had a dose interruption/delay, 18 due to AEs. Median OS was 17m (50/184; 27% pts). TEAEs occurring at ≥10% were anemia, fatigue, diarrhea, and nausea. The most common Grade 3/4 hematologic TEAE was anemia (11%). Majority of pts had no change in ECOG PS within each trt cycle. 19 (10%) pts had an SSE, 13 received EBRT for bone pain. 33% of pts had a ≥30% confirmed ALP decline from baseline and 16% had a ≥50% decline. Median time to ALP progression was not reached. Median time to PSA progression was 4m and 6% had a confirmed PSA response. Conclusions: In heavily pretreated patients with CRPC and bone metastases and in an EAP setting, Ra-223 was well tolerated with no new safety concerns and a positive effect on efficacy parameters. Clinical trial information: NCT01516762. [Table: see text]
The application of Fuhrman Nuclear Grade to lung adenocarcinoma and correlation with the Iaslc/ats/ers Multidisciplinary Classification of Adenocarcinoma and Survival in stage 1 disease
Authors: E. E. Duhig, B. E. Clarke, D. Godbolt, A. Dettrick, J. Pauli, I. A. Yang, R. Bowman, K. M. Fong
Journal: Journal of Thoracic Oncology (2012)
Quality-Adjusted Survival After Treatment for Acute Myeloid Leukemia in Childhood: A Q-TWiST Analysis of the Pediatric Oncology Group Study 8821
Authors: S. K. Parsons, S. Gelber, B. F. Cole, Y. Ravindranath, A. Ogden, A. M. Yeager, M. Chang, J. Shuster, H. J. Weinstein, R. D. Gelber
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To describe quality-of-life considerations in postremission therapies for children with acute myelogenous leukemia. PATIENTS AND METHODS: A quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method, was applied to Pediatric Oncology Group Trial 8821, which compared randomized assignment with intensive consolidation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). Nonrandomized assignment to allogeneic bone marrow transplantation (allo BMT) on the basis of availability of a matched related donor was also evaluated. A 25-patient cohort provided data for modeling chronic graft-versus-host disease. The Q-TWiST analysis was performed based on the intent-to-treat principle. RESULTS: As previously reported, the 3-year event-free survival was not significantly different between the randomized arms (CC v ABMT). At a median follow-up of 5 years (of the censoring distribution), the CC group had less time in toxicity (TOX) and more time without symptoms or toxicity (TWiST), relapse-free time, and alive time than patients assigned to ABMT (none of these were statistically significant). Compared with the CC group, allo BMT patients spent more time in TOX (P &lt; .001), more time in TWiST (P = .06), and had more relapse-free time (P = .03) and time alive (P = .07). Allo BMT was superior to ABMT with greater time in TWiST (P = .02), relapse-free time (P = .01), and time alive P = .002). CONCLUSION: The Q-TWiST analysis is a powerful decision aid in choosing among alternative therapies. Prospective information on patient preferences will facilitate future trials evaluating treatment outcomes. Refinements in the Q-TWiST method could be included to further enhance the power of this patient care decision-making tool.