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Targeted Oncology Apr 2019Peripheral T-cell lymphoma (PTCL) is associated with poor prognosis, particularly in patients with relapsed/refractory (R/R) disease. Pralatrexate, a folate analogue...
BACKGROUND
Peripheral T-cell lymphoma (PTCL) is associated with poor prognosis, particularly in patients with relapsed/refractory (R/R) disease. Pralatrexate, a folate analogue inhibitor, was the first drug approved to treat R/R PTCL.
OBJECTIVE
As the distribution of PTCL subtypes differs between populations and few patients in the pivotal trial of pralatrexate were Asian, this study investigated the safety and efficacy of pralatrexate as monotherapy in Chinese patients with R/R PTCL.
PATIENTS AND METHODS
In this single-arm, open-label, multicenter study, 71 patients with R/R PTCL (median [range] 2 [1-14] prior systemic treatments) were recruited from 15 centers in China and received pralatrexate IV 30 mg/m/week for 6 weeks in 7-week cycles (with vitamin B/folate). The primary endpoint was objective response rate (ORR) per central review (null hypothesis: ORR < 15%).
RESULTS
The study's primary objective was met: ORR (95% CI) was 52% (40-64%) (p < 0.001) and responses were observed across pre-specified patient subgroups. Median (95% CI) duration of response was 8.7 (3.3-14.1) months and first response was observed in Cycle 1 for most (84%) patients. Median (95% CI) progression-free survival and overall survival was 4.8 (3.1-8.1) months and 18.0 (10.4-NA) months, respectively. The most common treatment-emergent adverse events were stomatitis (68% [Grade 3/4: 20%]), anemia (49% [Grade 3/4: 24%]) and alanine aminotransferase increase (41% [Grade 3/4: 4%]).
CONCLUSIONS
These results demonstrate that pralatrexate may represent a promising treatment option for Chinese patients with R/R PTCL. The ORR of 52% compared favorably with prior studies of pralatrexate in other populations and there were no unanticipated side effects.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT03349333.
Topics: Adult; Aged; Aminopterin; Drug Resistance, Neoplasm; Female; Folic Acid Antagonists; Follow-Up Studies; Humans; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Salvage Therapy; Survival Rate; Young Adult
PubMed: 30904980
DOI: 10.1007/s11523-019-00630-y -
Leukemia & Lymphoma Feb 2021We present a retrospective multicenter study of pralatrexate treatment outcomes in an Australian practice setting for patients with relapsed/refractory T-cell lymphoma...
We present a retrospective multicenter study of pralatrexate treatment outcomes in an Australian practice setting for patients with relapsed/refractory T-cell lymphoma who had failed 1+ systemic therapies, treated a compassionate access program. Endpoints assessed included response rates, toxicities, and subsequent therapies. Progression-free survival (PFS), time to next treatment (TTNT), event-free survival (EFS), overall survival (OS), and time to best response, were assessed by Kaplan-Meier analysis. The study included 31 patients, with median age 69 years. We demonstrated ORR of 35.5% ( = 11), including 4 complete responses (13%) and 7 partial responses (23%). The predicted median OS was 10 months, with EFS of 9 months, and PFS of 9 months. Median TTNT was 8 months. Mucositis was the most commonly observed toxicity. This study - the second largest real-world cohort reported to date - underscores the importance of pralatrexate in relapsed/refractory T-cell lymphoma, as well as its acceptable toxicity profile.
Topics: Aged; Aminopterin; Australia; Humans; Lymphoma, T-Cell; Neoplasm Recurrence, Local; Retrospective Studies; Treatment Outcome
PubMed: 33026266
DOI: 10.1080/10428194.2020.1827241 -
Cancer Treatment Reviews Nov 2017Patients with relapsed or refractory peripheral T-cell lymphoma display a dismal prognosis and their therapy represents an unmet medical need, as the best treatment... (Review)
Review
Patients with relapsed or refractory peripheral T-cell lymphoma display a dismal prognosis and their therapy represents an unmet medical need, as the best treatment strategy is yet to be determined. Exciting data on novel targeted agents are now emerging from recently concluded and ongoing clinical trials in patients with relapsed and refractory PTCL. Four recently approved compounds are used as single agents: pralatrexate, a novel antifolate agent; romidepsin and belinostat, both histone deacetylase (HDAC) inhibitors; brentuximab vedotin, an anti-CD30 drug-conjugated monoclonal antibody. Several other molecules have demonstrated their activity in the same context: gemcitabine, bendamustine, lenalidomide, duvelisib, copanlisib, alisertib, mogamulizumab, selinexor and ARGX-110. Robust preclinical observations strongly support chemo-free combinations, which are expected to enhance the quality and duration of responses in pretreated patients and in those who are unable to receive a stem cell transplantation.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local
PubMed: 28946015
DOI: 10.1016/j.ctrv.2017.09.002 -
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 -
OncoTargets and Therapy 2018T-cell lymphoma is a rare hematologic malignancy with an incidence rate between 10% and 20% of that of non-Hodgkin lymphomas. Patients with peripheral T-cell lymphoma... (Review)
Review
T-cell lymphoma is a rare hematologic malignancy with an incidence rate between 10% and 20% of that of non-Hodgkin lymphomas. Patients with peripheral T-cell lymphoma (PTCL) generally have a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy; once relapse occurs, it is mostly regarded as an incurable disease. To overcome the chemorefractoriness of PTCL, several novel agents have been developed. Since the first approval of pralatrexate, a dihydrofolate reductase inhibitor, for relapsed/refractory PTCL by the US Food and Drug Administration, several new agents, such as romidepsin (histone deacetylase inhibitor), brentuximab vedotin (antibody-drug conjugate targeting CD30), chidamide (histone deacetylase inhibitor), and mogamulizumab (anti-CC chemokine receptor 4 monoclonal antibody), have been approved as a therapeutic option for relapsed/refractory PTCL in several countries, including the US, Europe, China, and Japan. Forodesine is a novel, potent purine nucleoside phosphorylase inhibitor that is effective against T-cell malignancies. Although the clinical development of forodesine was discontinued in the US and Europe, a multicenter Phase I/II study of oral forodesine for relapsed PTCL was recently completed in Japan. The overall response rate was 24% (10 of 41 patients), which included four patients with complete response. In general, the toxicity of forodesine is manageable. As the study met the primary end point, forodesine was approved for the treatment of relapsed/refractory PTCL in Japan in March 2017, which was the first approval of forodesine in the world. As forodesine is an oral formulation, it is more convenient than other novel intravenous agents approved for PTCL. However, it is necessary to appropriately manage opportunistic infections and secondary lymphomas possibly associated with long-lasting lymphocytopenia caused by forodesine. In this manuscript, we have summarized the currently available evidence for forodesine and discussed the clinical implications for PTCL treatment.
PubMed: 29719411
DOI: 10.2147/OTT.S140756 -
Cancer Treatment Reviews Dec 2017Patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL) display a dismal prognosis and their therapy represents an unmet medical need, as the best... (Review)
Review
Patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL) display a dismal prognosis and their therapy represents an unmet medical need, as the best treatment strategy is yet to be determined. Exciting data on novel targeted agents are now emerging from recently concluded and ongoing clinical trials in patients with relapsed and refractory CTCL. Three FDA approved compounds are used as single agents including the oral retinoid bexarotene and histone deacetylase inhibitors romidepsin and vorinostat. Brentuximab vedotin, an anti-CD30 drug-conjugated monoclonal antibody, has received from European Commission the orphan designation but has not been approved by EMA yet. Several other molecules have demonstrated their activity in the same context and combination strategies are being explored. Participation in a well designed clinical trial is encouraged, as the introduction of novel agents will continue to expand the therapeutics options available in the management of CTCL.
Topics: Animals; Antineoplastic Agents; Humans; Lymphoma, T-Cell, Cutaneous
PubMed: 29102679
DOI: 10.1016/j.ctrv.2017.10.007 -
Frontiers in Cell and Developmental... 2020Pralatrexate (Folotyn; PLX) and belinostat (Beleodaq; BLS) are registered for the treatment of patients with peripheral T-cell lymphoma (PTCL) and are being considered...
Pralatrexate (Folotyn; PLX) and belinostat (Beleodaq; BLS) are registered for the treatment of patients with peripheral T-cell lymphoma (PTCL) and are being considered for other lymphomas. In this study we investigated whether BLS had the ability to potentiate the cytotoxicity of PLX. A panel of lymphoma cell lines was used for the combination studies: the B-cell SUDHL-4, SUDHL-5, HT, Jeko-1 and T-cell Karpas-299 and Hut-78. Uptake of PLX was mediated by the reduced folate carrier (RFC). PLX showed a 6-fold better RFC substrate affinity compared to methotrexate, and 2-fold better than levoleucovorin (l-LV). Sensitivity expressed as the concentration that resulted in 50% growth inhibition (IC50) after 72 hr exposure to PLX varied from 2.8 to 20 nM and for BLS from 72 to 233 nM, independent of the background of the cell lines. The interaction between BLS and PLX was studied using the median-drug effect analysis. At a fixed molar ratio between the drugs based on the IC50 concentration the average combination index (CI) for all cell lines showed additivity (CI: around 1.0). In three selected cell lines (SUDHL-4, SUDHL-5, and HT) sequential exposure (24 h pretreatment with BLS, followed by 48 h to PLX + BLS), did not improve interaction (CI: 0.9-1.4). As an alternative approach a non-fixed ratio was used by exposing SUDHL-4, SUDHL-5, and HT cells to IC25 concentrations of either BLS or PLX in combination with the other drug. Exposure to IC25 of PLX did not decrease the IC50 for BLS (CI from 0.6-1.2), but exposure to IC25 of BLS markedly increased PLX sensitivity (low CIs from 0.40 to 0.66). Mechanistic studies focused on induction of apoptosis, and showed cleavage of predominantly caspase-9 in HT and SUDHL-4 cells for both drugs at their IC50s, being similar in the combination setting. Moreover, at these concentrations, the drugs were shown to confer an S-phase arrest. In conclusion, the combination of PLX and BLS showed additivity in various lymphoma cell lines, with a schedule-dependent synergism in B-cell lymphoma. Based on these data, proficient inhibition of HDAC activity by BLS holds promise in sensitization of tumor cells to PLX.
PubMed: 33163492
DOI: 10.3389/fcell.2020.577215 -
Leukemia & Lymphoma Sep 2020
Topics: Aminopterin; Humans; Immunoblastic Lymphadenopathy; Lymphoma, T-Cell
PubMed: 32729765
DOI: 10.1080/10428194.2020.1795164 -
Journal of Gastrointestinal Oncology Jun 2015The appropriate second-line therapy for patients with advanced gastroesophageal (GE) or esophageal (E) cancer after failure of first-line platinum-based therapy is...
A phase II study of biweekly pralatrexate and docetaxel in patients with advanced esophageal and gastroesophageal carcinoma that have failed first-line platinum-based therapy.
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. Pralatrexate 120 mg/m(2) and docetaxel 35 mg/m(2) were administered on day 1 of 14-day cycles. The primary end-point was to evaluate the overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and secondary end-points were to evaluate for progression-free survival (PFS) and overall survival (OS).
RESULTS
The study was halted prematurely due to loss of funding after the accrual of six patients. Two patients had stable disease (SD) and four patients had disease progression per RECIST. When applying PERCIST criteria in four evaluable patients, two had a partial response (PR) and two had SD. Median PFS was 1.9 months (95% CI, 0.8-7.2) and median OS was 5.5 (0.8-11.7) months.
CONCLUSIONS
Pralatrexate and docetaxel as therapy in refractory esophageal and GE adenocarcinoma did not demonstrate meaningful preliminary activity. PERCIST may prove to better assess the meaningfulness of anatomic SD.
PubMed: 26029462
DOI: 10.3978/j.issn.2078-6891.2015.011 -
Cancer Treatment Reviews Oct 2014Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on... (Review)
Review
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. In some of these, selected histologic subtypes have been evaluated in detail. As a consequence, numerous new therapies have been developed and shown activity in PTCL, including: agents targeting the immune system (e.g. brentuximab vedotin, alemtuzumab, lenalidomide); histone deacetylase inhibitors (romidepsin, belinostat); antifolates (pralatrexate); fusion proteins (denileukin diftitox); nucleoside analogs (pentostatin, gemcitabine); and other agents (e.g. alisertib, plitidepsin, bendamustine, bortezomib). A variety of interesting novel combinations is also emerging. It is hoped that these innovative approaches, coupled with a greater understanding of the clinicopathologic features, pathogenesis, molecular biology, and natural history of PTCL will advance the field and improve outcomes in this challenging group of diseases. This review summarizes the currently available clinical evidence on the various approaches to treating relapsed/refractory PTCL, including the role of stem cell transplantation, with an emphasis on potential new drug therapies.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Cyclophosphamide; Depsipeptides; Diphtheria Toxin; Doxorubicin; Folic Acid Antagonists; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Interleukin-2; Lenalidomide; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Peptides, Cyclic; Prednisolone; Recombinant Fusion Proteins; Stem Cell Transplantation; Thalidomide; Topoisomerase Inhibitors; Vincristine
PubMed: 25199959
DOI: 10.1016/j.ctrv.2014.08.001