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Clinical Nuclear Medicine Feb 2019Here we report on the treatment of a 38-year-old woman with primary cutaneous γδT-cell lymphoma, which is a rare subset of cutaneous T-cell lymphoma. She presented...
Here we report on the treatment of a 38-year-old woman with primary cutaneous γδT-cell lymphoma, which is a rare subset of cutaneous T-cell lymphoma. She presented with multiple subtle subcutaneous nodules, which were not clearly observed on computed tomography scans or after biopsy. However, F-fluorodeoxyglucose positron emission tomography (F-FDG-PET) accurately detected small cutaneous lesions. She achieved a second complete remission, as demonstrated by F-FDG-PET performed after pralatrexate infusion.
Topics: Adult; Aminopterin; Female; Fluorodeoxyglucose F18; Humans; Lymphoma, T-Cell, Cutaneous; Positron-Emission Tomography; Skin Neoplasms; Treatment Outcome
PubMed: 30516664
DOI: 10.1097/RLU.0000000000002409 -
Therapeutics and Clinical Risk... 2011Aggressive T cell lymphomas are a subgroup of lymphomas with a particularly poor prognosis. This is especially true for patients with recurrent or refractory disease,...
Aggressive T cell lymphomas are a subgroup of lymphomas with a particularly poor prognosis. This is especially true for patients with recurrent or refractory disease, who typically have limited response to salvage therapy and extremely poor overall survival. For this reason, there is a strong need to develop potentially active drugs for these malignancies. Pralatrexate is a novel antifolate designed to have high affinity for reduced folate carrier type 1. Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against T cell lymphomas. The dose-limiting toxicity for pralatrexate is mucositis, which can be abrogated with folic acid and vitamin B12 supplementation. Pralatrexate is the first single agent approved for the treatment of patients with relapsed or refractory peripheral T cell lymphoma. This approval was based on an overall objective response rate observed in the pivotal study. The overall response rate was 29%, with a median duration of 10.1 months. This article reviews the biochemistry, preclinical experience, metabolism, and pharmacokinetics of pralatrexate, including the clinical experience with this agent in lymphoma. Future areas of development are now focused on identifying synergistic combinations of pralatrexate with other agents and the evaluation of predictive markers for clinical benefit.
PubMed: 22076116
DOI: 10.2147/TCRM.S22834 -
Clinical Cancer Research : An Official... May 2007Pralatrexate is a rationally designed antifolate with greater preclinical antitumor activity than methotrexate. Pralatrexate was synergistic with paclitaxel and with...
PURPOSE
Pralatrexate is a rationally designed antifolate with greater preclinical antitumor activity than methotrexate. Pralatrexate was synergistic with paclitaxel and with docetaxel in mouse xenograft experiments. This phase 1 study was designed to determine the maximum tolerated dose and toxicity of pralatrexate plus paclitaxel or docetaxel in patients with advanced cancer.
EXPERIMENTAL DESIGN
Pralatrexate was administered i.v. every 2 weeks (days 1 and 15) in a 4-week cycle. Depending on the taxane used and dose being tested, the taxane was administered on days 1 and 15; days 2 and 16; or days 1, 8, and 15. In the latter part of the study, patients in the docetaxel arm were treated with vitamin B(12) and folic acid supplementation to mitigate toxicity and allow pralatrexate dose escalation.
RESULTS
For the combination of pralatrexate plus paclitaxel without vitamin supplementation, dose-limiting stomatitis and peripheral neuropathy were encountered at the lowest dose levels tested. For pralatrexate plus docetaxel plus vitamin supplementation, pralatrexate 120 mg/m(2) plus docetaxel 35 mg/m(2) administered on the same day every other week was defined as the maximum tolerated dose and schedule, with dose-limiting toxicities at higher dose combinations including stomatitis and asthenia. Significant antitumor activity was observed for this combination in patients with non-small-cell lung cancer.
CONCLUSIONS
Pralatrexate (120 mg/m(2)) plus docetaxel (35 mg/m(2)) plus vitamin supplementation is well tolerated with signs of efficacy against non-small-cell lung cancer that merit phase 2 testing.
Topics: Adult; Aged; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Dietary Supplements; Docetaxel; Female; Folic Acid Antagonists; Homocysteine; Humans; Male; Methylmalonic Acid; Middle Aged; Neoplasms; Paclitaxel; Taxoids; Vitamins
PubMed: 17473201
DOI: 10.1158/1078-0432.CCR-06-1754 -
PLoS Computational Biology Dec 2020The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No...
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008μM and 9.453 μM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19.
Topics: Aminopterin; Animals; Antiviral Agents; Azithromycin; Chlorocebus aethiops; Computer Simulation; Deep Learning; Drug Evaluation, Preclinical; Drug Repositioning; Molecular Dynamics Simulation; RNA-Dependent RNA Polymerase; SARS-CoV-2; Vero Cells; Virus Replication; COVID-19 Drug Treatment
PubMed: 33382685
DOI: 10.1371/journal.pcbi.1008489 -
Cancer Chemotherapy and Pharmacology May 2006The antifolate pralatrexate (10-propargyl-10-deazaaminopterin, PDX) demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate. Preclinical models...
PURPOSE
The antifolate pralatrexate (10-propargyl-10-deazaaminopterin, PDX) demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate. Preclinical models indicated that the efficacy of pralatrexate may be enhanced by coadministration with probenecid. The aim of this phase I study was to determine the maximum-tolerated dose of pralatrexate when combined with probenecid given every 2 weeks in humans.
METHODS
The starting dose was pralatrexate 40 mg/m(2) intravenously and probenecid 70 mg/m(2) intravenously administered every 14 days, where one cycle of treatment was every 28 days. The pralatrexate dose was initially fixed while probenecid dose escalation was explored. The pralatrexate area under the curve (AUC), terminal-half life (t1/2), and maximum plasma concentration (Cmax) were determined in cycle 1.
RESULTS
Seventeen patients with advanced solid tumors were treated with a median of two prior chemotherapy regimens. Stomatitis was dose-limiting with pralatrexate 40 mg/m(2) and probenecid 233 mg/m(2). Mean pralatrexate AUC and half life (t1/2) increased with increasing doses of probenecid. No objective responses were seen.
CONCLUSION
For patients with advanced solid tumors, the maximum-tolerated dose of this drug combination was pralatrexate 40 mg/m(2) and probenecid 140 mg/m(2). Vitamin B(12) and folate supplementation may allow for further dose escalation of pralatrexate and probenecid. This is a suitable question for a future study.
Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Probenecid; Treatment Outcome
PubMed: 16136310
DOI: 10.1007/s00280-005-0080-x -
Leukemia & Lymphoma Sep 2020Angioimmunoblastic T-cell lymphoma (AITL) is a histological subtype of peripheral T-cell lymphoma associated with a poor prognosis. This post-hoc pooled analysis aims to...
Angioimmunoblastic T-cell lymphoma (AITL) is a histological subtype of peripheral T-cell lymphoma associated with a poor prognosis. This post-hoc pooled analysis aims to provide insight about the efficacy of pralatrexate monotherapy in a subset of twenty-nine patients with relapsed or refractory (r/r) AITL drawn from two prospective registration trials completed in China and Japan. After a median of two prior lines of therapy, an overall response rate of 52% (15/29 patients; 95% CI 0.34, 0.70) was demonstrated. The estimated median duration of response, progression free survival (PFS) and overall survival (OS) were 6.4 months (196 days), 5.0 months (151 days), and 18.0 months (548 days), respectively. Grades 1-3 mucositis was observed in twenty-three patients (79.3%); and hemato-toxicity in twenty-six (89.7%) patients. Results of this analysis corroborate with data from two previously reported US retrospective cohorts, supporting the potential benefits of pralatrexate monotherapy in patients with r/r AITL.
Topics: Aminopterin; China; Humans; Japan; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Prospective Studies; Retrospective Studies
PubMed: 32536233
DOI: 10.1080/10428194.2020.1765232 -
British Journal of Haematology Nov 2007T-cell lymphomas (TCLs) are characterised by poor responses to therapy with brief durations of remissions. An early phase study of pralatrexate has demonstrated dramatic...
Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma.
T-cell lymphomas (TCLs) are characterised by poor responses to therapy with brief durations of remissions. An early phase study of pralatrexate has demonstrated dramatic activity in patients with relapsed/refractory disease. Of the first 20 lymphoma patients treated, 16 had B-cell lymphoma and four had refractory aggressive TCL. All four patients with TCL achieved a complete remission. Patients with B-cell lymphoma achieved stable disease at best. For each TCL patient, the response was more durable than their best response with chemotherapy. This early experience is the first to document this unique activity of pralatrexate in TCL.
Topics: Adult; Aged; Aminopterin; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Folic Acid Antagonists; Humans; Lymphoma, B-Cell; Lymphoma, T-Cell; Male; Membrane Transport Proteins; Middle Aged; Positron-Emission Tomography; Treatment Failure; Treatment Outcome
PubMed: 17910632
DOI: 10.1111/j.1365-2141.2007.06658.x -
Cancer Chemotherapy and Pharmacology May 2014To investigate the impact of 5-formyltetrahydrofolate on the activities of pralatrexate, as compared to methotrexate (MTX), in vitro.
PURPOSE
To investigate the impact of 5-formyltetrahydrofolate on the activities of pralatrexate, as compared to methotrexate (MTX), in vitro.
METHODS
Cells were exposed to (6S)5-formyltetrahydrofolate (5-formylTHF) for 24 h, before or after a 6-h exposure to antifolates following which the cellular accumulation and activities of the drugs were evaluated in HeLa cells.
RESULTS
A 24-h delay between a 6-h exposure to antifolates and a subsequent 24-h exposure to 4 μM 5-formylTHF sustained the full activities of both antifolates. A 72-h interval was required between a single exposure of up to 4 μM 5-formylTHF and subsequent exposure to drugs to sustain activities of the antifolates. When cells were incubated with 4 μM 5-formylTHF for 24 h weekly, for 4 weeks, there was no significant increase in the IC50 for pralatrexate, but the MTX IC50 increased 2.5-fold as compared to cells growing continuously in 25 nM 5-formylTHF. This cyclical exposure to 5-formylTHF increased the cell folate pool by 16 %, had no significant effect on the intracellular pralatrexate level, but decreased intracellular MTX by 15 %. An extracellular concentration of MTX 50-fold higher than that of pralatrexate was required to achieve an intracellular level, and growth inhibition, comparable to that of pralatrexate.
CONCLUSIONS
Cyclical exposures to 5-formylTHF at levels in excess of what is achieved in most clinical "rescue" regimens do not affect pralatrexate accumulation nor antitumor activity in HeLa cells, in contrast to MTX. An important element in preserving pralatrexate activity is achieving a sufficient interval between exposure to 5-formylTHF and the next dose of antifolate.
Topics: Aminopterin; Carbon-Nitrogen Ligases; Folic Acid Antagonists; HeLa Cells; Humans; Methotrexate; Neoplasms; Tumor Cells, Cultured
PubMed: 24682532
DOI: 10.1007/s00280-014-2441-9 -
Cancer Chemotherapy and Pharmacology Nov 2016Pralatrexate 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...
Phase 1 study evaluating the safety and pharmacokinetics of pralatrexate in relapsed/refractory advanced solid tumors and lymphoma patients with mild, moderate, and severe renal impairment.
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. Four cohorts of 6 patients were planned for a total of 24 patients. Patients with normal renal function (Cohort A), mild (Cohort B), and moderate renal impairment (Cohort C) received 30 mg/m pralatrexate once weekly for 6 weeks in 7-week cycles, and patients with severe renal impairment (Cohort D) were to be administered 20 mg/m once weekly for 6 weeks. Plasma and urine samples were collected at pre-specified time points to determine the PK profile of pralatrexate in each treatment cohort. Patients were followed for safety and tolerability.
RESULTS
A total of 29 patients were enrolled and 27 patients (14 male) received at least 1 dose of pralatrexate. Because of a qualifying toxicity in Cohort C, the starting dose for Cohort D was reduced to 15 mg/m. Chronic renal impairment led to a decrease in renal clearance of the pralatrexate diastereomers, PDX-10a and PDX-10b, but systemic exposure to these diastereomers was not dramatically affected by renal impairment. Pralatrexate exposure in Cohort D (15 mg/m) was similar to the exposure in other cohorts (30 mg/m). No apparent difference in toxicity between the four treatment cohorts was observed, except for an increase in cytopenias in patients with severe renal impairment.
CONCLUSION
Pralatrexate exposure, at a dose of 30 mg/m, in patients with mild or moderate renal impairment was similar to the exposure in patients with normal renal function. For patients with severe renal impairment only, a pralatrexate dose of 15 mg/m is recommended.
Topics: Adult; Aged; Aminopterin; Drug Resistance, Neoplasm; Endpoint Determination; Female; Folic Acid Antagonists; Humans; Kidney Failure, Chronic; Kidney Function Tests; Lymphoma; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Renal Insufficiency; Stereoisomerism
PubMed: 27638045
DOI: 10.1007/s00280-016-3142-3 -
Oncotarget May 2020Multiple myeloma (MM) is the second most common hematologic malignancy. While major advances have been made in the disease, it is still incurable. Although...
Multiple myeloma (MM) is the second most common hematologic malignancy. While major advances have been made in the disease, it is still incurable. Although antifolate-based drugs are not commonly used to treat myeloma, new generation analogs with distinct patterns of preclinical and clinical activity may offer an opportunity to identify new classes of potentially active drugs. Pralatrexate (PDX), which was approved for the treatment of relapsed or refractory peripheral T-cell lymphoma in 2009, may be one such drug. Pralatrexate exhibits a potency and pattern of activity distinct from its predecessors like methotrexate (MTX). We sought to understand the activity and mechanisms of resistance of multiple myeloma to these drugs, which could also offer potential strategies for selective use of the drug. We demonstrate that PDX and MTX both induce a significant decrease in cell viability in the low nanomolar range, with PDX exhibiting a more potent effect. We identified a series of myeloma cell lines exhibiting markedly different patterns of sensitivity to the drugs, with some lines frankly resistant, and others exquisitely sensitive. These differences were largely attributed to the basal RFC (Reduced Folate Carrier) mRNA expression levels. RFC mRNA expression correlated directly with rates of drug uptake, with the most sensitive lines exhibiting the most significant intracellular accumulation of pralatrexate. This mechanism explains the widely varying patterns of sensitivity and resistance to pralatrexate in multiple myeloma cell lines. These findings could have implications for this class of drugs and their role in the treatment of multiple myeloma.
PubMed: 32405334
DOI: 10.18632/oncotarget.27516