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R V R Prabhakara Sastry, C S Venkatesan, B S Sastry, K Mahesh
Pralatrexate (PTXT) is an antineoplastic folate analog and the chemical name is (2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl] benzoyl] amino] pentanedioic acid. Degradation products of PTXT drug product (DP) under different forced degradation conditions have been studied using LC-PDA and LC-MS techniques. PTXT DP was subjected to forced degradation under the conditions of hydrolysis, photolysis, oxidation, and heat in accordance with ICH guidelines. The LC-MS compatible HPLC method was developed and stressed solutions were chromatographed on reversed phase HPLC...
November 30, 2016: Journal of Pharmaceutical and Biomedical Analysis
Kevin R Kelly, Nashat Gabrail, Steven Weitman, John Sarantopoulos, Anthony J Olszanski, William Edenfield, Jurgen Venitz, Guru Reddy, Allen Yang, Steven J Hasal, A Craig Lockhart
PURPOSE: Pralatrexate is a folate analogue indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma. It has not been formally tested in patients with renal impairment. This study evaluated the pharmacokinetic (PK) profile of pralatrexate in patients with renal impairment and with relapsed/refractory advanced solid tumors and lymphoma. METHODS: This was an open-label, nonrandomized, phase 1 study. Eligible patients received pralatrexate administered as an IV push over 3-5 min once weekly for 6 weeks in 7-week cycles until progressive disease or intolerable toxicity...
September 16, 2016: Cancer Chemotherapy and Pharmacology
Marcela G Del Carmen, Jeff G Supko, Nora K Horick, J Alejandro Rauh-Hain, Rachel M Clark, Susana M Campos, Carolyn N Krasner, Tina Atkinson, Michael J Birrer
BACKGROUND: The objective of this phase 1 and 2 trial was to identify the appropriate dose of combined carboplatin and pralatrexate for patients with recurrent, platinum-sensitive ovarian, fallopian tube, and primary peritoneal cancer. METHODS: In phase 1, patients received carboplatin (at an area under the curve of 5) and increasing doses of pralatrexate until the maximum-tolerated dose (MTD) of pralatrexate was achieved. The primary endpoint was the response rate...
July 15, 2016: Cancer
Seung-Shin Lee, Sung-Hoon Jung, Jae-Sook Ahn, Yeo-Kyeoung Kim, Min-Seok Cho, Seung-Yeon Jung, Je-Jung Lee, Hyeoung-Joon Kim, Deok-Hwan Yang
Peripheral T cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with poor prognosis. Elderly (age ≥ 65years) patients generally have impaired bone marrow function, altered drug metabolism, comorbidities, and poor functional status. Thus, treatment of elderly patients with relapsed or refractory PTCL remains a challenge for clinicians. A recent study disclosed that pralatrexate has a synergistic effect in combination with bortezomib. Weekly pralatrexate and bortezomib were administered intravenously for 3 weeks in a 4-week cycle...
July 2016: Journal of Korean Medical Science
Tamara J Dunn, Shira Dinner, Elizabeth Price, Steven E Coutré, Jason Gotlib, Ying Hao, Caroline Berube, Bruno C Medeiros, Michaela Liedtke
Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles...
April 2016: British Journal of Haematology
Pier Luigi Zinzani, Vijayveer Bonthapally, Dirk Huebner, Richard Lutes, Andy Chi, Stefano Pileri
Peripheral T-cell lymphomas (PTCLs) tend to be aggressive and chemorefractory, with about 70% of patients developing relapsed/refractory disease. Prior to 2009, chemotherapies were the only options for relapsed/refractory PTCL, other than hematopoietic transplants. However, chemotherapy only improves survival by about 1 month compared with palliation. Four drugs are now approved in the US to treat relapsed/refractory PTCL: pralatrexate, romidepsin, belinostat, and brentuximab vedotin (for systemic anaplastic large cell lymphoma [sALCL])...
March 2016: Critical Reviews in Oncology/hematology
Jordan P McPherson, Alaina Vrontikis, Courtney Sedillo, Ahmad S Halwani, Jeffrey A Gilreath
Pralatrexate (PDX) is a folate antagonist structurally similar to methotrexate (MTX). Unlike MTX, it is currently not known whether PDX exhibits delayed clearance and heightened toxicity in the setting of fluid overload. A specific serum assay for PDX is not commercially available. To our knowledge, we report the first case using an MTX serum assay as a surrogate for PDX concentrations to avoid a potential drug-drug interaction with pralatrexate. We describe a 76-year-old man with refractory cutaneous T-cell lymphoma who began therapy with weekly PDX 15 mg/m(2) intravenous infusions on days 1, 8, and 15 of a 28-day cycle...
February 2016: Pharmacotherapy
Anne W Beaven, Louis F Diehl
Peripheral T-cell lymphomas (PTCL), with the exception of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), have a very poor prognosis. Although current first line chemotherapy continues to be a CHOP-like (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen there is now data suggesting that the addition of etoposide in younger patients improves outcomes. Even for those patients who do have a response to therapy, the risk of relapse remains quite high. Although autologous transplant in first remission is often used, its role as consolidation therapy in first remission remains unclear and may preferentially benefit low-risk patients...
2015: Hematology—the Education Program of the American Society of Hematology
Ranjana H Advani, Stephen M Ansell, Mary J Lechowicz, Anne W Beaven, Fausto Loberiza, Kenneth R Carson, Andrew M Evens, Francine Foss, Steven Horwitz, Barbara Pro, Lauren C Pinter-Brown, Sonali M Smith, Andrei R Shustov, Kerry J Savage, Julie M Vose
Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles...
February 2016: British Journal of Haematology
Catherine G Chung, Brian Poligone
Mycosis fungoides (MF) and its leukemic variant, Sézary syndrome (SS), are malignancies of skin-homing T cells that comprise the majority of cutaneous T cell lymphomas (CTCL). Treatment of CTCL is limited and can be approached by skin-directed therapy or systemic therapy. Recent investigations into the pathogenesis of MF and SS have broadened the therapeutic targets; here, we review emerging concepts in the pathogenesis of MF and SS as well as novel and traditional systemic therapies for MF and SS. These include histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, and belinostat), monoclonal antibodies (alemtuzumab, brentuximab vedotin, and mogamulizumab) and single-agent cytotoxic chemotherapeutic agents (e...
December 2015: Current Hematologic Malignancy Reports
Gary S Wood, Jianqiang Wu
This article reviews methotrexate and the more potent, related compound, pralatrexate, for the treatment of cutaneous T-cell lymphomas, including mycosis fungoides, Sézary syndrome, and CD30+ lymphoproliferative disorders. Although these folate antagonists are traditionally viewed as antiproliferative cell cycle inhibitors, it is recognized that they inhibit DNA methylation, providing a rationale for their use as epigenetic regulators and cell proliferation inhibitors. The underlying mechanisms are outlined, key supporting data presented, followed by brief mention of recent mathematical modeling supporting the general superiority of combination therapy...
October 2015: Dermatologic Clinics
Matthew A Lunning
Previously obscured within other designations of aggressive lymphomas, peripheral T-cell lymphoma (PTCL) now represents 23 different subtypes of non-Hodgkin lymphoma (NHL). Despite the many subtypes now recognized, PTCL represents only approximately 10% of all NHL cases diagnosed. Positron emission tomography/computed tomography has become essential to accurate staging and response-evaluation for PTCL. In comparison to aggressive B-cell NHL, patients with PTCL will more often be refractory to initial therapy, and chemosensitive patients will have shorter disease-free periods...
August 2015: Oncology (Williston Park, NY)
Jean L Grem, Mary E Kos, Ruby E Evande, Jane L Meza, James K Schwarz
BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). METHODS: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m(2) on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m(2) /48 hours every 2 weeks with folic acid and vitamin B12 supplementation...
November 1, 2015: Cancer
Brian Petullo, Lai Wei, Melissa Yereb, Alison Neal, Jeffrey Rose, Tanios Bekaii-Saab, Christina Wu
BACKGROUND: The appropriate second-line therapy for patients with advanced gastroesophageal (GE) or esophageal (E) cancer after failure of first-line platinum-based therapy is unclear. Pralatrexate and docetaxel have independently been shown to have efficacy in the treatment of these cancers. Thus, we performed a clinical trial examining the efficacy of the combination of these agents in the treatment of GE and E cancer. METHODS: A Fleming phase II design with a single stage of 32 patients was planned...
June 2015: Journal of Gastrointestinal Oncology
Philip M Tedeschi, Yamini K Kathari, Nadine Johnson-Farley, Joseph R Bertino
PURPOSE: To investigate the effectiveness of a combination of 6-thioguanine (6-TG) and pralatrexate (PDX) in methylthioadenosine phosphorylase (MTAP)-deficient T-cell acute lymphoblastic leukemia (T-cell ALL). METHODS: CCRF-CEM (MTAP(-/-)) and Molt4 (MTAP(+/+)) T-cell ALL cell lines were treated with 6-TG or PDX and evaluated for efficacy 72 h later. NOD/SCID gamma mice bearing CEM or Molt4 xenografts were treated with 6-TG and PDX alone or in combination to evaluate antitumor effects...
June 2015: Cancer Chemotherapy and Pharmacology
Kelly M Zullo, Yige Guo, Laurence Cooke, Xavier Jirau-Serrano, Michael Mangone, Luigi Scotto, Jennifer E Amengual, Yinghui Mao, Renu Nandakumar, Serge Cremers, Jimmy Duong, Daruka Mahadevan, Owen A O'Connor
PURPOSE: Aurora A kinase (AAK) is expressed exclusively during mitosis, and plays a critical role in centrosome duplication and spindle formation. Alisertib is a highly selective AAK inhibitor that has demonstrated marked clinical activity of alisertib across a spectrum of lymphomas, though particularly in patients with T-cell lymphoma (TCL). We sought to compare and contrast the activity of alisertib in preclinical models of B-cell lymphoma (BCL) and TCL, and identify combinations worthy of clinical study...
September 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Salvia Jain, Xavier Jirau-Serrano, Kelly M Zullo, Luigi Scotto, Carmine F Palermo, Stephen A Sastra, Kenneth P Olive, Serge Cremers, Tiffany Thomas, Ying Wei, Yuan Zhang, Govind Bhagat, Jennifer E Amengual, Changchun Deng, Charles Karan, Ronald Realubit, Susan E Bates, Owen A O'Connor
PURPOSE: T-cell lymphomas (TCL) are aggressive diseases, which carry a poor prognosis. The emergence of new drugs for TCL has created a need to survey these agents in a rapid and reproducible fashion, to prioritize combinations which should be prioritized for clinical study. Mouse models of TCL that can be used for screening novel agents and their combinations are lacking. Developments in noninvasive imaging modalities, such as surface bioluminescence (SBL) and three-dimensional ultrasound (3D-US), are challenging conventional approaches in xenograft modeling relying on caliper measurements...
May 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
M Gooptu, R Rhoades, B Pro
Peripheral T-cell lymphomas (PTCLs) are an uncommon group of lymphoproliferative disorders accounting for approximately 10-15 % of all non-Hodgkin lymphomas (NHL) in Western countries. Although PTCLs are associated with poor prognosis, outcomes vary with disease subtype. The standard of care has been anthracycline-based induction combination chemotherapy, however, with the exception of low-risk ALK-positive anaplastic large cell lymphoma, relapse rates are high. Therefore, consolidation with autologous stem cell transplantation is usually recommended for patients deemed candidates, and with aggressive subtypes...
2015: Cancer Treatment and Research
Philip M Tedeschi, Yamini K Kathari, Iqra N Farooqi, Joseph R Bertino
PURPOSE: To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo. METHODS: H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV. RESULTS: In vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed...
November 2014: Cancer Chemotherapy and Pharmacology
Bertrand Coiffier, Massimo Federico, Dolores Caballero, Claire Dearden, Franck Morschhauser, Ulrich Jäger, Lorenz Trümper, Emanuele Zucca, Maria Gomes da Silva, Ruth Pettengell, Eckhart Weidmann, Francesco d'Amore, Hervé Tilly, Pier Luigi Zinzani
Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on historical regimens for aggressive B-cell lymphomas, have resulted in insufficient patient outcomes. The majority of patients relapse rapidly, and current 5-year overall survival rates are only 10-30%. It is evident that new approaches to treat patients with PTCL are required. In recent years, prospective studies in PTCL have been initiated, mainly in patients with relapsed/refractory disease...
October 2014: Cancer Treatment Reviews
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