tbuckley/cabot-search huggingface dataset:
Final analysis: A multicenter phase I study of EMD 525797 (DI17E6), a novel humanized monoclonal antibody to human αv integrins, in progressive castrate-resistant prostate cancer with bone metastases after chemotherapy.
Authors: Manfred Wirth, Axel Heidenreich, Jürgen E. Gschwend, Thierry Gil, Stefan Zastrow, Michael Laniado, Michael Zuehlsdorf, Joachim Gerloff, Wolfgang Uhl, Heinrich Lannert
Journal: Journal of Clinical Oncology (2012)

231 Background: EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting αv integrins involved in tumor progression. Methods: The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts). 24 pts (43–80 years) were treated with IV infusions of 250, 500, 1000, or 1500 mg EMD 525797 given over 1 h and received 3 doses (weeks 1, 3, and 5) before response assessment at the end of week 6. Pts without progressive disease could receive further doses every 2 weeks. Dose-limiting toxicities (DLTs) were assessed over the first 6 weeks and safety was monitored until 4 weeks after the last administration of EMD 525797. Results: Final analysis showed that 13 of 24 pts had a longer exposure time than expected (≥84 d): 7 pts had exposure times ≥126 d, 3 pts ≥280 d and 1 pt received EMD 525797 for 534 d (Table). All pts experienced adverse events (AEs), and in 11 pts AEs were considered related to EMD 525797. 4 pts had generalized pruritus, erythema, or rash and 3 pts experienced fatigue, mucosal inflammation, or peripheral edema, but no pt had administration site reactions. Changes in clinical lab values were consistent with basic disease. No DLTs occurred. EMD 525797 showed a dose-dependent, nonlinear PK profile in line with a target-mediated drug disposition. Pt 1 and 2 of the 500 mg cohort had a marked decrease in prostate specific antigen. Pt 1 also had primary tumor shrinkage and normalization of lymph node size. These pts had long-term anti-integrin treatment (297 and 534 d, respectively). Both patients showed additional pain relief. Conclusions: EMD 525797 showed clinical activity in mCPRC pts in salvage setting, pain relief, and tumor regression. EMD 525797 is well tolerated without any premedication and did not show clinically relevant dose-related changes in the safety parameters assessed. [Table: see text]
Phase I and pharmacologic study of enzastaurin HCl, gemcitabine and cisplatin
Authors: J. M. Rademaker-Lakhai, L. Beereport, E. O. Witteveen, S. A. Radema, C. M. Visseren-Grul, L. C. Musib, G. Van Hal, J. H. Beijnen, J. H. M. Schellens, E. E. Voest
Journal: Journal of Clinical Oncology (2004)

3129 Background: Enzastaurin HCl (LY317615, e-HCl), an acyclic bisindolylmaleimide, is a potent inhibitor of Protein Kinase C-β isozyme. The β isoform lies in the signal cascade of VEGF and inhibition of this pathway may lead to a block in tumor angiogenesis. In preclinical studies gemcitabine (G) and cisplatin (C) exerted synergistic effects in combination with e-HCl. The objective of the study is to investigate the feasibility and toxicities of e-HCl in combination with G and C in patients (pts) with advanced malignancies, to evaluate the pharmacokinetics (PK) of all 3 agents and to recommend the Phase II doses when given in combination.Methods: Pts received a lead-in treatment period of single-agent oral e-HCl administered daily for 14 days, followed by repeated 21 day (d) combination cycles. In each combination cycle, e-HCl was taken orally on d1 - d21, G was administered as a 30 min. intravenous (iv) infusion on d1 and d8, followed by C as a 3 hr iv infusion on d1. The starting dose of e-HCl was 350 mg once daily and of G and C 1000 and 60 mg/m2, respectively. Results: Currently, 17 pts have been treated at 5 dose levels. No dose limiting toxicities have been reported. Drug related adverse events to date include max. CTC grade 2 gastro-intestinal toxicities, vitiligo, anorexia, tinnitus and deafness, and max. CTC grade 3 fatigue, neutropenia, thrombocytopenia, anemia and leukopenia. PK data indicate that the geometric mean (%CV) exposures of e-HCl in Cycle 1 were 20500 (196) nM*h at 350 mg, 32100 (94.8) nM*h at 500 mg; in Cycle 2, 18500(161) nM*h at 350 mg and 25500(83.2) nM*h at 500 mg. No apparent differences in e-HCl exposures were seen when given in combination with G and C. G exposures were not altered when given in combination with e-HCl as compared to historical data. C data is pending. Due to less than dose proportional increase in e-HCl exposures in a previous study, dosing of e-HCl was changed to a bid-dosing regimen. Bid dosing started at the most recent dose level 5; 250 mg bid e-HCl, 1250 mg/m2 G and 75 mg/m2 C. 3 Pts showed a PR (prostate, papilla and head/neck cancer).Conclusions: Preliminary safety and PK data enable continued dose-escalation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly Eli Lilly
Many cancer drugs recently approved in US do not improve overall survival, study finds
Authors: Michael McCarthy
Journal: BMJ (2015)

In recent years most cancer drug approvals by the US Food and Drug Administration have been made on the basis of a surrogate endpoint, such as tumour response rate or progression-free survival. When such approvals are made the agency typically advises or requires that post-approval studies be conducted to clarify the drug’s effect on overall survival.

However, a new US study has found that, in most cases, cancer drugs that have recently secured FDA …
Factors predicting willingness to participate in cancer genetic epidemiologic research
Authors: J. S. Evans, B. M. Ford, J. Balmaña, E. M. Stoffel, R. J. Mayer, S. Syngal
Journal: Journal of Clinical Oncology (2005)

6007 Background: Previous studies have identified low patient accrual in large-scale cancer clinical trials, particularly for under-represented groups such as ethnic minorities, females, and patients older than 65 years. However, there have been few studies examining participation in cancer genetics research. Our objective was to identify the clinical and demographic factors that predict enrollment in a study exploring the genetic predisposition for colorectal cancer (CRC). Methods: A total of 1111 patients diagnosed with CRC presenting to a gastrointestinal oncology clinic were approached to enroll in a study investigating the role of the gene MSH6 in familial CRC. Patient consent was sought for: providing a blood specimen for DNA analysis, releasing medical records/tumor specimens, and contacting family members to confirm the family history of cancer. Patients also completed a questionnaire detailing demographic, medical, and family history information. Seven predictor variables for enrollment (age, sex, ethnicity, family history of CRC in a first-degree relative, presence of children, insurance type, and type of visit (first visit versus follow-up visit)) were analyzed using logistic regression analysis to determine the impact on decision to enroll. Results: Of the 1111 patients approached, 696 (62.6%) enrolled in the study. Of these individuals, 4.2% were of non-white ethnicity and 33.5% were aged 65 years and older. Patients of white ethnicity (OR 2.09, p = .016), males (OR 1.47, p<.002), those aged < 65 years (OR 1.42, p<.009), and those with a first-degree relative diagnosed with CRC (OR 1.42, p<.022) were more likely to enroll in the study. Presence of children in the patient’s family, type of clinic visit and type of insurance did not have a significant impact on enrollment (p>0.05). Conclusions: Our data suggest that overall participation in genetics research may be higher than enrollment in cancer clinical trials, but that trends of lower participation for ethnic minorities, females, and elderly patients are similar for both types of research. No significant financial relationships to disclose.
Development of a clinically feasible molecular assay to predict recurrence of Dukes’ B colon cancer
Authors: Y. Jiang, Y. Zhang, T. Briggs, D. Talantov, A. Mazumder, D. Atkins, Y. Wang, C. Deleany, M. Brown, G. Casey
Journal: Journal of Clinical Oncology (2006)

20110 Background: The 5-year survival rate of Dukes’ B colon cancer patients is approximately 75%. In our earlier genome-wide measurements of gene expression we have identified a 23-gene signature that sub-classifies Dukes’ B tumors and may provide better means of risk assessment on an individual basis for these colon cancer patients. The aim of this study is to validate this gene signature in an independent and more diverse group of patients, and further develop this prognostic signature into a clinical feasible test using formalin-fixed paraffin-embedded (FFPE) tissue samples. Methods: Using Affymetrix U133a GeneChip we analyzed the expression of the 23 genes in total RNA of frozen tumor samples from 123 Dukes’ B patients who did not receive adjuvant systemic treatment. Furthermore, we developed a quantitative RT-PCR assay for this gene signature in order to perform the test with standard clinical FFPE samples. Results: In the independent validation set of 123 patients, the gene signature proved to be informative in identifying patients who would develop distant metastasis (hazard ratio, HR 2.56; 95% confidence interval CI, 1.01–6.48), even when corrected for the traditional prognostic factors in multivariate analysis (HR, 2.73; 95% CI, 0.97–7.73). The RT-PCR assay developed for this gene signature was also validated in an independent set of 114 patients as a strong prognostic factor for the development of distant recurrence (HR, 6.38; 95% CI, 2.88–14.2) in univariate analysis and in multivariate analysis (HR, 13.3; 95% CI, 5.13–34.4). Conclusions: Our data provide not only a validation of the pre-defined prognostic gene signature for Dukes’ B colon cancer patients but also a clear feasibility of testing the gene signature using RT-PCR with standard FFPE specimens. The ability of such a test to identify patients that have an unfavorable outcome demonstrates potential clinical importance that could lead clinicians to choose a more aggressive therapeutic option for the high-risk patients. [Table: see text]
Vincristine, dactinomycin, cyclophosphamide (VAC) versus VAC/V plus irinotecan (VI) for intermediate-risk rhabdomyosarcoma (IRRMS): A report from the Children’s Oncology Group Soft Tissue Sarcoma Committee.
Authors: Douglas S. Hawkins, James Robert Anderson, Leo Mascarenhas, Geoffrey Brian McCowage, David A. Rodeberg, Suzanne L. Wolden, David Parham, Lynn Million, Sarah S. Donaldson, Andrea Anita Hayes-Jordan, Kenneth L.B. Brown, Lisa A. Teot, Sheri L. Spunt, William H. Meyer
Journal: Journal of Clinical Oncology (2014)

10004 Background: The long-term event free survival (EFS) for IRRMS is 65%. Since VI had significant activity in metastatic and recurrent RMS, we tested whether adding VI to VAC would improve EFS for IRRMS. Methods: Patients (pts) with alveolar (A)RMS or incompletely resected (Group III) embryonal (E)RMS arising in an unfavorable primary site (Stage 2/3), both without distant metastases, < 50 years, and adequate organ function were eligible to be randomized to 42 weeks of VAC (V=1.5 mg/m2, A=0.045 mg/kg, C=1.2 g/m2 every 3 weeks) vs VAC/VI (I=50 mg/m2/day x 5 days) intravenously; doses were adjusted for children < 3 years; radiation therapy (36-50.4 Gy) was started at week 4, with individualized local control for children < 2 years allowed. The primary study endpoint was EFS. The study was designed with 80% power (5% 1-sided alpha level) to detect an increase in 5 yr EFS from 65% to 76%, a relative risk of 0.64. Results: 481 pts were entered between 12/2006-12/2012, with 461 confirmed eligible. Clinical features included ERMS 53%, ARMS 43%; age < 1 year 6%, 1-9 years 62%, 10+ years 32%; Group III 85%; Stage 3 61%. The most common primary tumor sites were parameningeal (44%), extremity (13%), and bladder/prostate (13%). With median follow up of 2.46 years in surviving pts, EFS and overall survival (OS) with 95% confidence intervals (CI) were similar overall and by histologic subtypes (Table). Grade 3/4 febrile neutropenia, anemia, and thrombocytopenia were less common with VAC/VI, particularly after the first 15 weeks of therapy, while diarrhea was more common with VAC/VI. Conclusions: The addition of VI to VAC did not significantly improve EFS or OS compared to VAC alone for IRRMS. The lower rate of hematologic toxicity and cumulative C dose with VAC/VI (8.4 g/m2 vs 16.8 g/m2) support the use of VAC/VI as the standard arm in future IRRMS trials. Clinical trial information: NCT00354835. Treatment n 2-year EFS (95% CI) 2-year OS (95% CI) VAC 227 64% (56%, 70%) 84% (78%, 89%) VAC/VI 234 64% (56%, 70%) 86% (80%, 90%) ERMS: VAC 118 67% (56%, 76%) 86% (76%, 92%) ERMS: VAC/VI 128 68% (58%, 76%) 89% (81%, 93%) ARMS: VAC 102 58% (48%, 69%) 81% (71%, 88%) ARMS: VAC/VI 95 57% (45%, 67%) 83% (72%, 90%)
Weight changes in breast cancer survivors who received adjuvant antiestrogen therapy
Authors: B. M. Harris, A. C. Broxson, L. A. Anderson, J. G. Engelbrink, M. A. Zalewski, K. R. Broglio, G. N. Hortobagyi, M. C. Green
Journal: Journal of Clinical Oncology (2009)

6588 Background: Antiestrogen therapy has dramatically improved breast cancer survival rates but weight gain may be problematic. Studies evaluating antiestrogen therapy-related weight gain have yielded mixed results. Our primary objective was to evaluate weight changes in female breast cancer survivors (BCS) who received adjuvant anti-estrogen therapy for stage 0-III breast cancer. Methods: A retrospective chart review was conducted to evaluate weight changes in female chemo naive BCS receiving anti-estrogen therapy. Weights at initiation of hormonal therapy and at 6, 12, 24, and 36 months of follow-up were recorded. Median weight changes were calculated and were compared with Wilcoxon's signed rank test or the Kurskall-Wallis test. Results: A total of 622 women were included. The majority were white (77%), had stage I disease (78%), and were postmenopausal (82%). The median age at diagnosis was 59 years (range, 26–87). Median weight at initiation of hormonal therapy among premenopausal women was 65 kg (range 45.4–122.9). Median weight gain in this group was 0.4 kg (p = 0.009), 0.7 kg (p = 0.013), 1.9 kg (p = 0.0001), and 2.4 kg (p &lt; 0.0001) at 6, 12, 24, and 36 months respectively. Among post-menopausal women, median weight at initiation of therapy was 71.7 kg (range 41.5–152.0) and median weight gain was 0.5 kg (p &lt; 0.0001), 1 kg (p &lt; 0.0001), 0.85 kg (p = 0.001), and 0.85 kg (p = 0.004) at 6, 12, 24, and 36 months respectively. Premenopausal patients had significantly more weight gain at 24 (p = 0.041) and 36 months (p = 0.005), as compared to postmenopausal patients. Among premenopausal women, 110/111 were treated with tamoxifen. Among post-menopausal women (n = 510), hormonal therapy was as follows: unknown n = 28 patients, tamoxifen n = 312, and AI n = 170. Overall, BCS treated with tamoxifen vs an AI had significantly more weight gain at 24 (p = 0.003) and 36 months (p = 0.009). Conclusions: Premenopausal patients are at higher risk for weight gain than postmenopausal patients. Further prospective research is warranted examining weight gain as a long-term side effect of anti-estrogen therapy in BCS. No significant financial relationships to disclose.
Can racial and financial disparities be overcome in the surgical treatment of NSCLC?
Authors: Jordan R. Sasson, Gary Schwartz, Sadiq Rehmani, Hassan S Moghaddas, Sarah Almubarak, Andrew Evans, Daniel Jacob Becker, Benjamin Philip Levy, Andy Nabong, Nadia Rush, Faiz Y. Bhora, Cliff P. Connery
Journal: Journal of Clinical Oncology (2013)

208 Background: Considerable data exists examining disparities in the treatment of non-small cell lung cancer (NSCLC) patients. Black patients, in particular those of lower socioeconomic status (SES), are less likely to receive appropriate care, including induction therapy and resection of surgically treatable lesions. We analyzed the outcomes of resection of NSCLC among a racially and financially diverse patient population at a large urban hospital network with a comprehensive thoracic oncology program. In this system, a patient navigation support team helped overcome barriers to preoperative preparation and multidisciplinary referral. Methods: A retrospective review of 345 patients who underwent lobectomy at our institution from 2002 - 2011 was performed. Data was retrieved from the Society of Thoracic Surgeons (STS) database and patient charts. Patient demographics, payor information and preoperative characteristics were noted. Postoperative complications, 30-day survival and 3-year survival were compared. Statistical analysis was performed using SPSS 17.0 (SPSS Inc, Chicago, IL). Chi-square test was used to compare categorical variables and Student's t-test was used to compare continuous variables. Results: Demographics of black and non-black patients were similar. There were more black patients within the Medicaid group than non-Medicaid (48.9% and 25.3%, p=0.001). Physiologic characteristics, risk factors and use of pre-operative RT and chemotherapy were similar. Post-operative complications were comparable in Medicaid vs. non-Medicaid (11.1% and 14.7%, p=0.524), however black patients had a lower rate of complications vs. non-black (6.1% and 17.4%, p=0.007). 3-year survival was similar in the black vs. non-black (82.3% and 78.6%, p=0.879) and Medicaid vs. non-Medicaid (66.7% and 78.8%, p=0.342) groups. Conclusions: We demonstrated equivalent surgical outcomes for NSCLC in addition to the similar use of induction therapy. Surprisingly, complications were lower in the black cohort. Our results reveal that appropriate treatment is being provided regardless of race or SES, and postulate that our system of preoperative patient support eliminates potential barriers to care.
Combination of gefitinib, cisplatin and 5-FU chemotherapy, and radiation therapy (RT) in newly-diagnosed patients with esophageal carcinoma
Authors: P. Sunpaweravong, S. Sunpaweravong, D. Sangthawan, P. Puttawibul, W. Mitarnun
Journal: Journal of Clinical Oncology (2007)

4605 Background: Efficacy of chemotherapy and RT in patients with esophageal carcinoma has been established in addition to surgical treatment. EGFR protein expression is prevalent in esophageal carcinoma; adding gefitinib to chemoradiotherapy may improve treatment outcome in this less favorable cancer. Methods: In this phase II study, untreated ECOG PS 0–2 patients with stage 2–4 esophageal carcinoma were recruited. Stage 2–4a patients were given gefitinib in combination with concurrent chemoradiation whereas stage 4b patients received only gefitinib and chemotherapy. Gefitinib 250 mg was taken daily in combination with cisplatin 80 mg/m 2 D1 and 5-FU 1,000 mg/m 2 , 24 hour CI, D1–5 every 3 weeks to the maximum of 6 cycles. Concurrently with chemotherapy, stage 2–4a patients received RT, 2 Gy single daily dose to the total of 60 Gy. After a cohort of 10 patients, initial daily chemotherapy dose was reduced to cisplatin 65 mg/m 2 and 5- FU 800 mg/m 2 in pts who received concurrent RT due to gr 3–4 neutropenia and mucositis. Results: Thirty-seven patients, 33 esophageal squamous cell carcinoma (ESCC) and 4 adenocarcinoma (EAC) were accrued between August 2005 and November 2006. Twenty- seven patients were stage 2–4a and 10 patients were stage 4b. Twenty-five (93%) stage 2–4a patients completed chemoradiation. In stage 2–4a patients, 4 (15%) CR, 17 (63%) PR, 3 (11%) SD, and 3 (11%) PD were achieved. Four (15%) stage 2–4a patients thereafter underwent esophagectomy and 1 (25%) achieved pathological complete response. In stage 4b patients, 5 (50%) PR, 3 (30%) SD, and 2 (20%) PD were observed. Twenty-three (62%) ESCC responded whereas 3 (75%) EAC did. Major grade 3–4 toxicities included neutropenia (19%), leukopenia (19%), and anemia (16%). Diarrhea occurred in 70%, dry skin in 30%, mucositis/esophagitis in 27%, and rash in 14% of patients, mostly grade 1- 2. One patient had a chemotherapy-related death due to neutropenic septicemia. Conclusions: This combined EGFR inhibitor and chemoradiation regimen was feasible and efficacious in patients with newly-diagnosed esophageal carcinoma. Further investigation in Phase III trial is encouraged to better assess the benefit of this approach in comparison to conventional treatment. No significant financial relationships to disclose.
A prospective randomized phase III trial of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with stage II colon cancer
Authors: W. Schippinger, H. Samonigg, R. Greil, J. Tschmelitsch, G. Steger, R. Jakesz, M. Gnant, F. Hofbauer, H. Rabl, J. Thaler
Journal: Journal of Clinical Oncology (2007)

4052 Background: Whereas several studies showed adjuvant chemotherapy to improve survival of patients with stage III colon cancer, survival benefit from adjuvant treatment in patients with stage II disease is a matter of controversy. Methods: Patients with curatively resected stage II colon cancer (T3–4, N0, M0) according to UICC were randomized to either adjuvant chemotherapy with 5-FU/LV (100 mg/m 2 LV + 450 mg/m 2 5-FU weekly, w 1–6, in 8 w cycles x 7) or surveillance only. Primary endpoint was overall survival (OS) with 636 patients originally planned to demonstrate a difference in OS of 10% with 85% power and alfa =0.05 in a final analysis 7 years after study initiation. After accrual of 535 patients between 11/1993 and 6/2003, recruitment was stopped ahead of schedule for low accrual rates. Results: 505 patients were eligible and evaluable for analyses. After a median follow-up of 96 months, 56 (21.8%) patients have died in the 5-FU/LV arm and 58 (23.4%) in the surveillance arm. There was no statistically significant difference in OS between the two treatment arms (HR 1.137, 95% CI 0.787–1.641, p=0.4947, chi square), thus the primary endpoint of the study was not met. Disease relapse was documented in 35 (13.6%) patients of the chemotherapy arm and in 48 (19.4%) patients of the control arm. The relative risk for disease relapse was higher for patients in the surveillance arm compared to patients in the 5-FU/LV arm, however, this difference was statistically not significant (HR 1.506, 95% CI 0.974–2.328, p=0.0657, chi square). Subgroup analysis including in the chemotherapy arm only patients who received at least one cycle of 5-FU/LV (n=250), showed a statistically significantly lower risk for relapse in patients treated with 5- FU/LV (HR 1.559, 95% CI 1.001–2.429, p=0.0477, chi square). Conclusions: Results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, adjuvant chemotherapy did not significantly improve DFS and OS. No significant financial relationships to disclose.