-
Cancer Chemotherapy and Pharmacology Oct 2009This study evaluated mechanistic differences of pralatrexate, methotrexate, and pemetrexed. (Comparative Study)
Comparative Study
PURPOSE
This study evaluated mechanistic differences of pralatrexate, methotrexate, and pemetrexed.
METHODS
Inhibition of dihydrofolate reductase (DHFR) was quantified using recombinant human DHFR. Cellular uptake and folylpolyglutamate synthetase (FPGS) activity were determined using radiolabeled pralatrexate, methotrexate, and pemetrexed in NCI-H460 non-small cell lung cancer (NSCLC) cells. The tumor growth inhibition (TGI) was assessed using MV522 and NCI-H460 human NSCLC xenografts.
RESULTS
Apparent K ( i ) values for DHFR inhibition were 45, 26, and >200 nM for pralatrexate, methotrexate, and pemetrexed, respectively. A significantly greater percentage of radiolabeled pralatrexate entered the cells and was polyglutamylatated relative to methotrexate or pemetrexed. In vivo, pralatrexate showed superior anti-tumor activity in both NSCLC models, with more effective dose-dependent TGI in the more rapidly growing NCI-H460 xenografts.
CONCLUSIONS
Pralatrexate demonstrated a distinct mechanistic and anti-tumor activity profile relative to methotrexate and pemetrexed. Pralatrexate exhibited enhanced cellular uptake and increased polyglutamylation, which correlated with increased TGI in NSCLC xenograft models.
Topics: Aminopterin; Cell Line, Tumor; Dose-Response Relationship, Drug; Folic Acid Antagonists; Glutamates; Guanine; Humans; Kinetics; Methotrexate; Neoplasms; Pemetrexed; Polyglutamic Acid; Tetrahydrofolate Dehydrogenase; Xenograft Model Antitumor Assays
PubMed: 19221750
DOI: 10.1007/s00280-009-0954-4 -
Expert Opinion on Biological Therapy Sep 2017T-cell lymphoma is a relatively rare hematologic malignancy that accounts for 10-20% of non-Hodgkin lymphomas. Treatment strategies for T-cell lymphomas are different... (Review)
Review
T-cell lymphoma is a relatively rare hematologic malignancy that accounts for 10-20% of non-Hodgkin lymphomas. Treatment strategies for T-cell lymphomas are different from that for B-cell lymphomas and have poor prognoses. Among various subtypes of T-cell lymphomas, adult T-cell leukemia-lymphoma (ATL) has the worst prognosis. To achieve further improvement in the treatment outcome of T-cell lymphomas, several novel agents such as brentuximab vedotin, lenalidomide, romidepsin, and pralatrexate are actively being studied. Mogamulizumab, an anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, is one of the promising agents for CCR4-positive T-cell lymphomas, especially for ATL. Areas covered: First, basic information about the current treatment strategy of T-cell lymphomas including ATL is described. Then, the authors discuss the current clinical development of mogamulizumab and its clinical implications for T-cell lymphomas. Expert opinion: Mogamulizumab has potent clinical efficacy against CCR4-positive T-cell lymphomas, especially against ATL. Among various toxicities associated with mogamulizumab, skin eruptions are the most significant. Although there are several effective competitors, mogamulizumab has a unique mechanism and is expected to be a key agent for treating CCR4-positive T-cell lymphomas, especially ATL.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Clinical Trials as Topic; Half-Life; Humans; Immunohistochemistry; Leukemia-Lymphoma, Adult T-Cell; Lymphoma, T-Cell; Neoplasm Recurrence, Local; Receptors, CCR4; Skin Diseases; Treatment Outcome
PubMed: 28649848
DOI: 10.1080/14712598.2017.1347634 -
Blood Mar 2017Peripheral T-cell lymphoma, not otherwise specified, is a broad category of biologically and clinically heterogeneous diseases that cannot be further classified into any... (Review)
Review
Peripheral T-cell lymphoma, not otherwise specified, is a broad category of biologically and clinically heterogeneous diseases that cannot be further classified into any other of the existing entities defined by the World Health Organization classification. Anthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), nowadays represent the standard first-line treatment; for patients who achieve a satisfactory response, a consolidation by means of autologous stem cell transplantation may offer a greater chance of long-term survival. Several patients, however, display treatment refractoriness or relapse soon after obtaining a response, and just a few of them are suitable transplant candidates. This is why several new agents, with innovative mechanisms of action, have been investigated in this context: pralatrexate, romidepsin, belinostat, and brentuximab vedotin have been approved for relapsed and refractory peripheral T-cell lymphomas based on their activity, although they do not significantly affect survival rates. The incorporation of such new drugs within a CHOP backbone is under investigation to enhance response rates, allow a higher proportion of patients to be transplanted in remission, and prolong survival.
Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, T-Cell, Peripheral
PubMed: 28115372
DOI: 10.1182/blood-2016-08-692566 -
Gan To Kagaku Ryoho. Cancer &... Jan 2020Pralatrexate(PDX)has been approved for the treatment of relapsed/refractory peripheral T-cell lymphoma(PTCL), including angioimmunoblastic T-cell lymphoma(AITL). Oral...
Pralatrexate(PDX)has been approved for the treatment of relapsed/refractory peripheral T-cell lymphoma(PTCL), including angioimmunoblastic T-cell lymphoma(AITL). Oral mucositis is the most common and severe adverse effect of PDX that often leads to dose reduction or omission. Herein, we report a 65-year-old man with AITL, who received PDX treatment after a second relapse. This drug was effective; however, the adverse effects, such as oral mucositis, were severe. Therefore, leucovorin(LV)was administered to prevent the adverse effect, resulting in continuation of the PDX treatment for 8 months. LV administration minimizes adverse effects for patients receiving high-dose methotrexate. However, the optimal dose and schedule of LV in PDX treatment has not yet been established. In the future, clinical trials on the use of LV for PDX-induced oral mucositis are needed.
Topics: Aged; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Folic Acid Antagonists; Humans; Leucovorin; Lymphoma, T-Cell; Male; Neoplasm Recurrence, Local
PubMed: 32381871
DOI: No ID Found -
Leukemia & Lymphoma Dec 2019Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are rare, heterogeneous non-Hodgkin lymphomas with poor prognoses. Pralatrexate has demonstrated...
Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are rare, heterogeneous non-Hodgkin lymphomas with poor prognoses. Pralatrexate has demonstrated efficacy in T-cell lymphomas; however, mucositis has been reported as the most common dose-modifying adverse event. Leucovorin has been shown to minimize mucositis incidence, without sacrificing pralatrexate efficacy. We retrospectively studied 34 patients (7-PTCL/27-CTCL) treated with pralatrexate alone or pralatrexate and leucovorin. Leucovorin was administered preemptively prior to any mucositis occurrence. Pralatrexate dosing ranged from 10-30 mg/m and clinical response or disease stabilization was observed in 85.2%. The incidence of mucositis was reduced in CTCL patients to 17% and was ameliorated in all but one patient with PTCL. There was no change the incidence of skin reactions with the addition of leucovorin. The response rates were similar to those previously reported in CTCL and PTCL. The addition of leucovorin reduced the incidence of mucositis in patients with CTCL and PTCL.
Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Female; Humans; Leucovorin; Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Mucositis; Neoplasm Staging; Premedication; Retrospective Studies; Skin Diseases; Treatment Outcome
PubMed: 31119966
DOI: 10.1080/10428194.2019.1612061 -
Advances in Radiation Oncology 2019
PubMed: 30706007
DOI: 10.1016/j.adro.2018.10.001 -
Clinical Medicine Insights. Oncology 2012Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas, with generally poor prognosis. Historically, there has been...
Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas, with generally poor prognosis. Historically, there has been a lack of consensus regarding appropriate therapeutic measures for the disease, with conventional frontline chemotherapies being utilized in most cases. Following promising results obtained in 2009, the methotrexate analogue, pralatrexate, became the first drug to gain US FDA approval for the treatment of refractory PTCL. This antimetabolite was designed to have a higher affinity for reduced folate carrier (RFC) and folylpolyglutamate synthetase (FPGS). RFC is the principal transporter for cell entrance of folates and antifolates. Once inside the cell, pralatrexate is efficiently polyglutamated by FPGS. Pralatrexate has demonstrated varying degrees of efficacy in peripheral T-cell lymphoma, with response rates differing between the multiple subtypes of the disease. While phase III studies are still to be completed, early clinical trials indicate that pralatrexate is promising new therapeutic for PTCL.
PubMed: 23032692
DOI: 10.4137/CMO.S8536 -
Cancer Science Oct 2017Pralatrexate is a novel antifolate approved in the USA for the treatment of relapsed or refractory peripheral T-cell lymphoma. To assess its safety, efficacy, and...
Pralatrexate is a novel antifolate approved in the USA for the treatment of relapsed or refractory peripheral T-cell lymphoma. To assess its safety, efficacy, and pharmacokinetics in Japanese patients with this disease, we undertook a phase I/II study. Pralatrexate was given i.v. weekly for 6 weeks of a 7-week cycle. All patients received concurrent vitamin B and folic acid. In phase I, three patients received pralatrexate 30 mg/m and none experienced a dose-limiting toxicity. In phase II, we treated 22 additional patients with that dose. The median number of treatment cycles was 1 (range, 1-9). Nine of 20 evaluable patients (45%) achieved an objective response by central review, including two complete responses. All responses occurred within the first treatment cycle. At the time of data cut-off, median progression-free survival was 150 days. Median overall survival was not reached. In the total population, the most commonly reported adverse events included mucositis (88%), thrombocytopenia (68%), liver function test abnormality (64%), anemia (60%), and lymphopenia (56%). Grade 3/4 adverse events included lymphopenia (52%), thrombocytopenia (40%), leukopenia (28%), neutropenia (24%), anemia (20%), and mucositis (20%). The pharmacokinetic profile showed no drug accumulation with repeat dosing. These results indicate that pralatrexate is generally well tolerated and effective in Japanese patients with relapsed or refractory peripheral T-cell lymphoma. This trial was registered with ClinicalTrials.gov (NCT02013362).
Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Drug Administration Schedule; Female; Folic Acid; Humans; Japan; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Neoplasm Recurrence, Local; Survival Analysis; Treatment Outcome; Vitamin B 12
PubMed: 28771889
DOI: 10.1111/cas.13340 -
Investigational New Drugs Jun 2014Pralatrexate (Fotolyn(TM); Allos Therapeutics Inc.) is an antifolate dihydrofolate reductase (DHFR) inhibitor. We conducted a phase II study of pralatrexate with folic...
BACKGROUND
Pralatrexate (Fotolyn(TM); Allos Therapeutics Inc.) is an antifolate dihydrofolate reductase (DHFR) inhibitor. We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC).
PATIENTS AND METHODS
This was a single-arm, Simon optimal two stage phase II study. Patients with R/M HNSCC previously treated with chemotherapy were eligible. The study was initiated with a dosing schedule of pralatrexate 190 mg/m(2) biweekly on a 4-week cycle with vitamin supplementation. Due to toxicity concerns, the dosing was modified to 30 mg/m(2) weekly for 3 weeks in a 4-week cycle with vitamin supplementation. Radiologic imaging was to be obtained about every 2 cycles.
RESULTS
Thirteen subjects were enrolled; 12 were treated. Seven of the twelve patients had previously received ≥2 lines of chemotherapy. The most common grade 3 toxicity was mucositis (3 patients). Seven patients did not complete two cycles of therapy due to progression of disease (4), toxicity (1), death (1), and withdrawal of consent (1). Two deaths occurred: one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate. No clinical activity was observed. The median overall survival was 3.1 months. The study was closed early due to lack of efficacy.
CONCLUSIONS
Pralatrexate does not possess clinical activity against previously treated R/M HNSCC. Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted.
Topics: Adult; Aged; Aminopterin; Carcinoma, Squamous Cell; Disease Progression; Female; Folic Acid; Folic Acid Antagonists; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Squamous Cell Carcinoma of Head and Neck; Vitamin B 12; Vitamin B Complex; Young Adult
PubMed: 24566705
DOI: 10.1007/s10637-014-0073-x -
Annals of Hematology May 2019
Topics: Aged; Aminopterin; Humans; Intestinal Neoplasms; Lymphoma, T-Cell; Male
PubMed: 30173289
DOI: 10.1007/s00277-018-3491-6