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Phase 3 hematology

J J Zhao, Y L Zhang, S J Zhang, J Zhou, F K Yu, Y L Zu, H F Zhao, Z Li, Y P Song
Objective: To investigate the molecular-cytogenetic characterization and impact on tyrosine kinase inhibitors (TKIs) therapy in chronic phase of chronic myeloid leukemia (CML-CP) patients with variant Ph chromosome (vPh). Methods: The clinical data of 32 patients with vPh chromosomes were collected and compared with 703 patients with typical Ph chromosome in newly diagnosed CML-CP who were on first-line imatinib (IM) and with BCR-ABL transcript of P210. Results: There was no significant difference in demographic and hematological characteristics between vPh and classic Ph patients...
March 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Yaming Xi, Zhuanzhen Ma, Hao Zhang, Maowen Yuan, Lina Wang
The aim of the present study was to investigate the cytotoxic effect and multi-drug resistance (MDR) of Clostridium difficile toxin A (TcdA) on K562/A02 cells, and understand its underlying molecular pathways. K562/A02 cells were treated with TcdA at different concentrations for 24, 48 and 72 h, and the inhibition effect and drug resistance of TcdA on K562/A02 cell proliferation was assessed by methyl thiazolyl tetrazolium colorimetric assay. Furthermore, cell cycle-apoptosis was analyzed by flow cytometry, P-glycoprotein (P-gp) expression was determined by western blot analysis and caspase-3 activity was measured using a caspase-3 activity kit...
April 2018: Oncology Letters
John Mascarenhas, Ronald Hoffman, Moshe Talpaz, Aaron T Gerds, Brady Stein, Vikas Gupta, Anita Szoke, Mark Drummond, Alexander Pristupa, Tanya Granston, Robert Daly, Suliman Al-Fayoumi, Jennifer A Callahan, Jack W Singer, Jason Gotlib, Catriona Jamieson, Claire Harrison, Ruben Mesa, Srdan Verstovsek
Importance: Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib. Objective: To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia. Design, Setting, and Participants: For this phase 3 randomized international multicenter study-the PERSIST-2 study-of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 109/L or less were recruited for analysis...
March 8, 2018: JAMA Oncology
Nadia Khan, Brad Kahl
Resistance to apoptosis is one of the hallmarks of cancer and members of the B-cell lymphoma 2 (BCL-2) family of proteins are central regulators of apoptosis. Many cancers become resistant to chemotherapy and apoptosis by up-regulating BCL-2 and other family members, making these proteins attractive targets for cancer therapy. Venetoclax is an orally administered, small-molecule apoptosis stimulant that targets BCL-2 proteins by acting as a BCL-2 homology domain 3 (BH3) mimetic. The drug is approved in the USA and EU as a monotherapy for the for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and is in phase III clinical development for multiple myeloma (MM), and in phase II or I/II clinical trials for acute myeloid leukemia, and several B-cell malignancies, including diffuse large B-cell lymphoma, Waldenstrom's macroglobulinaemia, follicular lymphoma, and mantle-cell lymphoma...
March 8, 2018: Targeted Oncology
Anthony B El-Khoueiry, Robert O'Donnell, Thomas J Semrad, Philip Mack, Suzette Blanchard, Nathan Bahary, Yixing Jiang, Yun Yen, John Wright, Helen Chen, Heinz-Josef Lenz, David R Gandara
PURPOSE: The insulin-like growth factor (IGF) pathway is activated in hepatocarcinogenesis. Cixutumumab is a monoclonal antibody against human insulin-like growth factor-1 receptor (IGF-1R). Given the cross-talk between the IGF and VEGF pathways, we performed a phase I study of the combination of cixutumumab and sorafenib in hepatocellular cancer (HCC). METHODS: Eligible patients with no prior systemic therapy for advanced HCC and Child-Pugh A to B7 were treated with sorafenib 400 mg BID and escalating doses of cixutumumab (2, 4, or 6 mg/kg IV weekly) in a 3 + 3 design...
March 8, 2018: Cancer Chemotherapy and Pharmacology
Tsutomu Takeuchi, Hisashi Yamanaka, Masayoshi Harigai, Ryo Tamamura, Yuichi Kato, Yoshifumi Ukyo, Toshikazu Nakano, Benjamin Hsu, Yoshiya Tanaka
BACKGROUND: Sirukumab, a high-affinity human monoclonal antibody that selectively binds to interleukin-6, has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) in global phase 1 and phase 2 studies. The present study evaluated the safety and efficacy of sirukumab, as monotherapy in Japanese patients with RA refractory to methotrexate or sulfasalazine. METHODS: In this phase 3, double-blind study, 122 patients (age ≥ 20 years) were randomized (1:1, 61 patients in each arm) to sirukumab administered subcutaneously: 50 mg once every 4 weeks (q4w) or 100 mg once every 2 weeks (q2w) through 52 weeks...
March 7, 2018: Arthritis Research & Therapy
Makoto Nishio, Miyako Satouchi, Atsushi Horiike, Yoshitsugu Horio, Yoshinori Sunaga, Evelyne Ecstein-Fraisse, Toyoaki Hida
Background: The combination use of the vascular disrupting agent ombrabulin with chemotherapeutic agents was previously shown to be highly synergistic in preclinical models. Methods: In this dose-escalation study of ombrabulin (15.5-35 mg/m2) in combination with docetaxel (60 or 75 mg/m2) and cisplatin (75 mg/m2), agents were administered 24 h apart every 3 weeks to Japanese patients with advanced solid tumors. The study was designed and conducted in a 3 + 3 manner...
March 3, 2018: Japanese Journal of Clinical Oncology
Serafeim Katsavos, Alasdair Coles
Alemtuzumab, the first monoclonal antibody to be used as a therapy and the first to be humanized, was introduced into the treatment of multiple sclerosis in 1991 after its successful use in hematology, oncology, and transplantation medicine. One phase 2 and two phase 3 trials of this lymphocyte-depleting agent have established alemtuzumab's superior efficacy to interferon β-1a over the short term (2-3 years) with greater relapse rate reduction, reduced accumulation of disability, and more frequent sustained improvement in disability...
March 2, 2018: Cold Spring Harbor Perspectives in Medicine
Min-Hua Tseng, Shih-Hua Lin, Chao-Yi Wu, Hui-Ping Chien, Huang-Yu Yang, Yung-Chang Chen, Yu-Ching Chou, Jing-Long Huang
Although aberrant complement activation is involved in the pathogenesis of systemic lupus erythematosus (SLE), the role of complement regulatory proteins in disease activity of SLE remains limited. We enrolled the pediatric-onset SLE patients from our cohort study over 10 years. The clinical and laboratory data including SLEDAI disease activity score, and serum complement factor H (CFH), CFI, CD46, C5a, and C5b-9 in the active and remission phases were determined. Glomerular C5b-9 deposition as a complement activity marker was also examined...
February 2, 2018: Oncotarget
Germán Reyes-Botero, Stéphanie Cartalat-Carel, Olivier L Chinot, Maryline Barrie, Luc Taillandier, Patrick Beauchesne, Isabelle Catry-Thomas, Jérôme Barrière, Jean-Sebastien Guillamo, Michel Fabbro, Didier Frappaz, Alexandra Benouaich-Amiel, Emilie Le Rhun, Chantal Campello, Isabelle Tennevet, François Ghiringhelli, Marie-Laure Tanguy, Karima Mokhtari, Jérôme Honnorat, Jean-Yves Delattre
LESSONS LEARNED: Results suggest that the combination of bevacizumab plus temozolomide is active in terms of response rate, survival, performance, quality of life, and cognition in elderly patients with glioblastoma multiforme with poor performance status.Whether this combination is superior to temozolomide alone remains to be demonstrated by a randomized study. BACKGROUND: The optimal treatment of glioblastoma multiforme (GBM) in patients aged ≥70 years with a Karnofsky performance status (KPS) <70 is not established...
February 22, 2018: Oncologist
Tzu-Ching Huang, Pu-Rong Chiu, Wen-Tsan Chang, Bau-Shan Hsieh, Yu-Ci Huang, Hsiao-Ling Cheng, Li-Wen Huang, Yu-Chen Hu, Kee-Lung Chang
Epirubicin is an anthracycline and is widely used in tumor treatment, but has toxic and undesirable side effects on wide range of cells and hematopoietic stem cells (HSC). Osteoblasts play important roles in bone development and in supporting HSC differentiation and maturation. It remains unknown whether epirubicin-induced bone loss and hematological toxicity are associated with its effect on osteoblasts. In primary osteoblast cell cultures, epirubicin inhibited cell growth and decreased mineralization. Moreover, epirubicin arrested osteoblasts in the G2/M phase, and this arrest was followed by apoptosis in which both the extrinsic (death receptor-mediated) and intrinsic (mitochondrial-mediated) apoptotic pathways were evoked...
February 21, 2018: Apoptosis: An International Journal on Programmed Cell Death
Li Li, Qingqing Zhuang, Zeyi Cao, Rutie Yin, Yaping Zhu, Lirong Zhu, Xing Xie, Youzhong Zhang, Li Li, Qiang Wu, Jianhua Zheng, Qi Zhou, Xiaoping Li, Lingying Wu, Youji Feng, Changyu Wang
The multi-center, randomized, open-label, phase III trial discussed in the present study was performed to compare the clinical outcomes of nedaplatin (NDP) plus paclitaxel, and carboplatin (CBP) plus paclitaxel for the treatment of epithelial ovarian cancer (EOC). In the current study, 182 patients with International Federation of Gynecology and Obstetrics (FIGO) stage II-IV EOC were randomly assigned to receive NDP plus paclitaxel or CBP plus paclitaxel at 3-week intervals for a total of six courses. The primary endpoints were progression-free survival rate (PFS) and overall survival rate (OS)...
March 2018: Oncology Letters
Kiran Naqvi, Jorge E Cortes, Raja Luthra, Susan O'Brien, William Wierda, Gautam Borthakur, Tapan Kadia, Guillermo Garcia-Manero, Farhad Ravandi, Mary Beth Rios, Sara Dellasala, Sherry Pierce, Elias Jabbour, Keyur Patel, Hagop Kantarjian
Kinase domain (KD) mutations of ABL1 represent the most common resistance mechanism to tyrosine kinase inhibitors (TKI) in CML. Besides T315I, mutations in codon 255 are highly resistant mutations in vitro to all TKI. We aimed to study the incidence, prognosis, and response to treatment in patients with E255K/V. We evaluated 976 patients by sequencing of BCR-ABL1 fusion transcript for ABL1 KD mutations. We identified KD mutations in 381 (39%) patients, including E255K/V in 48 (13% of all mutations). At mutation detection, 14 patients (29%) were in chronic phase (CP), 12 (25%) in accelerated phase (AP), and 22 (46%) in blast phase (BP)...
February 20, 2018: International Journal of Hematology
Rizwan Romee, Sarah Cooley, Melissa M Berrien-Elliott, Peter Westervelt, Michael R Verneris, John E Wagner, Daniel J Weisdorf, Bruce R Blazar, Celalettin Ustun, Todd E DeFor, Sithara Vivek, Lindsey Peck, John F DiPersio, Amanda F Cashen, Rachel Kyllo, Amy Musiek, András Schaffer, Milan J Anadkat, Ilana Rosman, Daniel Miller, Jack O Egan, Emily K Jeng, Amy Rock, Hing C Wong, Todd A Fehniger, Jeffrey S Miller
New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin (IL)-15 is a cytokine that stimulates CD8+ T cell and NK cell anti-tumor responses, and we hypothesized this cytokine may augment anti-leukemia/lymphoma immunity in vivo. To test this, we performed a first-in-human multi-center phase 1 trial ( NCT01885897) of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT...
February 20, 2018: Blood
Michael R Savona, Daniel A Pollyea, Wendy Stock, Vivian G Oehler, Mark A Schroeder, Jeffrey E Lancet, James McCloskey, Hagop M Kantarjian, Weidong Wendy Ma, M Naveed Shaik, A Douglas Laird, Mirjana Zeremski, Ashleigh O'Connell, Geoffrey Chan, Jorge E Cortes
PURPOSE: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). EXPERIMENTAL DESIGN: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Marcin Waligora, Malgorzata M Bala, Magdalena Koperny, Mateusz T Wasylewski, Karolina Strzebonska, Rafał R Jaeschke, Agnieszka Wozniak, Jan Piasecki, Agnieszka Sliwka, Jerzy W Mitus, Maciej Polak, Dominika Nowis, Dean Fergusson, Jonathan Kimmelman
BACKGROUND: Pediatric Phase I cancer trials are critical for establishing the safety and dosing of anti-cancer treatments in children. Their implementation, however, must contend with the rarity of many pediatric cancers and limits on allowable risk in minors. The aim of this study is to describe the risk and benefit for pediatric cancer Phase I trials. METHODS AND FINDINGS: Our protocol was prospectively registered in PROSPERO (CRD42015015961). We systematically searched Embase and PubMed for solid and hematological malignancy Phase I pediatric trials published between 1 January 2004 and 1 March 2015...
February 2018: PLoS Medicine
Sumimasa Nagai, Keiya Ozawa
Background As relapsed disease is frequently the first target of newly developed therapies, it is vital to address the difficulty in demonstrating the efficacy of new drugs for relapsed malignancy in randomized phase 3 trials. Methods We analyzed the approved indications, target populations, and development status of post-marketing confirmatory trials of all oncology-related drugs that were granted accelerated approval for both hematological and solid malignancies. Furthermore, we searched for randomized phase 3 trials for adult patients with relapsed lymphoid malignancy, other than chronic lymphocytic leukemia (CLL) and multiple myeloma (MM)...
February 17, 2018: Investigational New Drugs
Rie Kondo, Satoshi Watanabe, Satoshi Shoji, Kosuke Ichikawa, Tetsuya Abe, Junko Baba, Junta Tanaka, Hiroki Tsukada, Masaki Terada, Kazuhiro Sato, Yoshie Maruyama, Masato Makino, Akira Hirata, Hiroshi Tanaka, Toshiyuki Koya, Hirohisa Yoshizawa, Toshiaki Kikuchi
OBJECTIVE: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. METHODS: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression...
February 14, 2018: Oncology
W Jurczak, P L Zinzani, G Gaidano, A Goy, M Provencio, Z Nagy, T Robak, K Maddocks, C Buske, S Ambarkhane, M Winderlich, M Dirnberger-Hertweck, R Korolkiewicz, K A Blum
Background: This two-stage, phase IIa study ( NCT01685008) investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells. Patients and methods: Patients aged ≥18 years, with R-R NHL progressing after ≥1 prior rituximab containing regimen were enrolled into subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent (i)NHL and mantle cell lymphoma (MCL)...
February 9, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Shoichiro Ohtani, Takahiro Nakayama, Tetsuhiro Yoshinami, Ken-Ichi Watanabe, Fumikata Hara, Yasuaki Sagara, Hidetoshi Kawaguchi, Kenji Higaki, Nobuki Matsunami, Yoshie Hasegawa, Masato Takahashi, Makiko Mizutani, Takashi Morimoto, Masako Sato, Mitsuya Itoh, Satoshi Morita, Norikazu Masuda
BACKGROUND: This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule. METHODS: Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle...
February 12, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
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