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Yardley D.A.,Tennessee Oncology PLLC | Hart L.,931 Colonial Center Drive | Waterhouse D.,Oncology Hematology Care Inc | Whorf R.,931 Colonial Center Drive | And 6 more authors.
Breast Cancer Research and Treatment | Year: 2013

Docetaxel-containing chemotherapy improves disease-free survival (DFS) and overall survival in patients with early stage breast cancer. Bevacizumab improves response rate and DFS in metastatic breast cancer. However, adding antivascular endothelial growth factor therapy to anthracycline-containing chemotherapy may increase cardiotoxicity. This trial evaluates the feasibility of adding bevacizumab to three standard adjuvant docetaxel regimens with a primary endpoint of grade ≥3 congestive heart failure (CHF). Phase IIb, randomized, non-comparative study of women with previously untreated node-positive or high-risk node-negative breast cancer. Human epidermal growth factor receptor 2 (HER2)-negative patients were randomized to: (arm A) doxorubicin + cyclophosphamide followed by docetaxel or (arm B) docetaxel + doxorubicin + cyclophosphamide. HER2-positive patients (arm C) received docetaxel + carboplatin + trastuzumab for 52 weeks. All patients received bevacizumab beginning on day 1 for 52 weeks. Safety data in 212 women (mean age = 53.1 years) show that 1 patient each in arm A (1.3 %) and arm C (1.7 %), and 3 patients in arm B (4.0 %) experienced clinical CHF grade ≥3. A decreased ejection fraction was observed in 1 patient each in arms A and C, and cardiac disorder was observed in 12.8, 22.7, and 8.5 % in arms A, B, and C, respectively. A grade 3/4 treatment-emergent adverse event was reported in 82.1, 84.0, and 52.5 % of participants in arms A, B, and C, respectively. Kaplan-Meier estimates of DFS show rates at 24 months of 85.5, 90.4, and 90.4 % in arms A, B, and C, respectively. Adding bevacizumab to three standard docetaxel-based chemotherapy regimens as adjuvant treatment in patients with node-positive and high-risk node-negative breast cancer resulted in a low rate of clinical CHF grade ≥3. Maintenance bevacizumab monotherapy did not identify any new safety signals. Breast cancer recurrence/relapse, secondary malignancies, and death were uncommon, although the follow-up time in this study was relatively short. © 2013 Springer Science+Business Media New York.

Langer C.J.,University of Pennsylvania | Albert I.,Matrai Gyogyintezet | Ross H.J.,Mayo Medical School | Kovacs P.,Debrecen University | And 11 more authors.
Lung Cancer | Year: 2014

Objective: This randomized phase II study assessed the efficacy and safety of obatoclax mesylate, a small-molecule Bcl-2 inhibitor, added to carboplatin/etoposide chemotherapy as initial treatment for extensive-stage small-cell lung cancer (ES-SCLC). Materials and methods: Chemotherapy-naïve subjects with ES-SCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 received carboplatin/etoposide with (CbEOb) or without (CbE) obatoclax for up to six cycles. Responders to CbEOb could receive maintenance obatoclax until disease progression. The primary endpoint was objective response rate (ORR). Results: 155 subjects (median age 62, 58% male, 10% ECOG PS 2) were treated with CbEOb (n = 77) or CbE (n = 78); 65% and 59% of subjects, respectively, completed six cycles. ORR was 62% with CbEOb versus 53% with CbE (1-sided p = 0.143). Clinical benefit (ORR+ stable disease) trended better with CbEOb (81% versus 68%; p = 0.054). Median progression-free survival (PFS) and overall survival (OS) were 5.8 months (95% confidence interval [CI]: 5.3-6.5) and 10.5 months (8.9-13.8) with CbEOb and 5.2 months (95% CI: 4.1-5.7) and 9.8 months (7.2-11.2) with CbE. Median OS was 10.5 months (95% CI: 8.9-13.8) and 9.8 months (7.2-11.2) with a nonsignificant hazard ratio for OS, 0.823; 1-sided p = 0.121. Grade 3/4 adverse events (AEs) were primarily hematologic and similar in frequency between treatment arms. Obatoclax-related somnolence and euphoria were grade 1/2, transient, and did not require treatment discontinuation. Conclusion: Obatoclax was well tolerated when added to carboplatin/etoposide in first-line treatment of ES-SCLC, but failed to significantly improve ORR, PFS, or OS. © 2014 Elsevier Ireland Ltd.

Raza A.,Columbia University | Ravandi F.,University of Houston | Rastogi A.,University of California at Los Angeles | Bubis J.,Cancer Specialists of North Florida | And 6 more authors.
Cytometry Part B - Clinical Cytometry | Year: 2014

Background Paroxysmal nocturnal hemoglobinuria (PNH), a rare clonal hematopoietic stem cell disorder, is characterized by chronic, uncontrolled complement activation leading to intravascular hemolysis and an inflammatory prothrombotic state. The EXPLORE study aimed to determine the prevalence of undiagnosed PNH in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), and/or other bone marrow failure (BMF) syndromes and the effect of PNH clone size on hemolysis. Methods Patients, selected from medical office chart reviews, had blood samples collected for hematologic panel testing and for flow cytometry detection of PNH clones. Results Granulocyte PNH clones ≥ 1% were detected in 199 of all 5,398 patients (3.7%), 93 of 503 AA patients (18.5%), 50 of 4,401 MDS patients (1.1%), and 3 of 130 other BMF patients (2.3%). Higher-sensitivity analyses detected PNH clones ≥ 0.01% in 167 of 1,746 patients from all groups (9.6%) and in 22 of 1,225 MDS patients (1.8%), 116 of 294 AA patients (39.5%), and four of 54 other BMF patients (7.8%). Among patients with PNH clones ≥ 1%, median clone size was smaller in patients with AA (5.1%) than in those with MDS (17.6%) or other BMF (24.4%), and the percentage of patients with lactate dehydrogenase levels (a marker for intravascular hemolysis) ≥ 1.5 × upper limit of normal was smaller in patients with AA (18.3%) than in those with MDS (42.0%). Conclusions These results confirm the presence of PNH clones in high-risk patient groups and suggest that screening of such patients may facilitate patient management and care. © 2013 The Authors. Published by Wiley Periodicals, Inc. © 2013 The Authors. Published by Wiley Periodicals, Inc.

Von Pawel J.,Asklepios Fachkliniken | Jotte R.,Rocky Mountain Cancer Center | Spigel D.R.,Sarah Cannon Research Institute | O'Brien M.E.R.,Royal Marsden National Health Service NHS Foundation Trust | And 15 more authors.
Journal of Clinical Oncology | Year: 2014

Purpose: Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC. Patients and Methods: A total of 637 patients with refractory or sensitive SCLC were randomly assigned at a ratio of 2:1 to 21-day cycles of amrubicin 40 mg/m2 intravenously (IV) on days 1 to 3 or topotecan 1.5 mg/m2 IV on days 1 to 5. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival (PFS), and safety. Results: Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (hazard ratio [HR], 0.880; P = .170); in refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P = .047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P < .018). ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P < .001). Grade ≥ 3 treatment-emergent adverse events in the amrubicin and topotecan arms were: neutropenia (41% v 54%; P = .004), thrombocytopenia (21% v 54%; P < .001), anemia (16% v 31%; P < .001), infections (16% v 10%; P = .043), febrile neutropenia (10% v 3%; P = .003), and cardiac disorders (5% v 5%; P = .759); transfusion rates were 32% and 53% (P < .001), respectively. NQO1 polymorphisms did not influence safety outcomes. Conclusion: Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with SCLC. OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with amrubicin. © 2014 by American Society of Clinical Oncology.

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