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Owen A. O'connor - One of the best experts on this subject based on the ideXlab platform.
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The anti-tumor activity of Pralatrexate (PDX) correlates with the expression of RFC and DHFR mRNA in preclinical models of multiple myeloma.
Oncotarget, 2020Co-Authors: Cristina Kinahan, Michele Visentin, Enrica Marchi, Luigi Scotto, Michael Mangone, Hearn Jay Cho, Owen A. O'connorAbstract: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.
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Safety and efficacy of Pralatrexate in the treatment of patients with relapsed or refractory peripheral T-cell lymphoma
Therapeutic advances in hematology, 2012Co-Authors: Enrica Marchi, Owen A. O'connorAbstract:T-cell lymphomas (TCL) are a diverse and heterogeneous group of malignancies that represent less than 15% of all non-Hodgkin lymphomas. Initial refinements of the clinical classification of these complex diseases have been made, but a better understanding of their molecular pathogenesis is still needed. Even if the paucity of insights into the underlying pathogenesis of TCLs has hindered our ability to develop rational targeted therapies, significant advances have been made. Pralatrexate (10-propargyl 10-deazaaminopterin) is a unique antifolate that has been rationally designed to have high affinity for the reduced folate receptor (RFC) and the folylpolyglutamate synthetase (FPGS) and was the first drug ever approved for the treatment of relapsed and refractory peripheral T-cell lymphomas (PTCL). This review describes the preclinical development of Pralatrexate that led to early-phase clinical trials in lung cancer and lymphoma and its subsequent approval in PTCL. The review also describes how Pralatrexate has been combined with other agents in both the preclinical and clinical settings. FDA approval for the use of Pralatrexate in PTCL has been granted based on the results of the pivotal Phase II trial of this agent in relapsed and refractory PTCL patients. clinical development, Pralatrexate, preclinical data, T-cell lymphoma
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Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results From the Pivotal PROPEL Study
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2011Co-Authors: Owen A. O'connor, Barbara Pro, Kerry J. Savage, Nancy L. Bartlett, Mary Jo Lechowicz, Lauren Pinter-brown, Andrei R. Shustov, Leslie Popplewell, Bertrand Coiffier, Christian GisselbrechtAbstract:Purpose Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of Pralatrexate, a novel antifolate with promising activity. Patients and Methods Patients with independently confirmed PTCL who progressed following ≥ 1 line of prior therapy received Pralatrexate intravenously at 30 mg/m2/wk for 6 weeks in 7-week cycles. Primary assessment of response was made by independent central review using the International Workshop Criteria. The primary end point was overall response rate. Secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS). Results Of 115 patients enrolled, 111 were treated with Pralatrexate. The median number of prior systemic therapies was three (range, 1 to 12). The response rate in 109 evaluable patients was 29% (32 of 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median DoR of 10.1 mo...
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Pralatrexate Reverses the Trend to Progressive Resistance to Successive Systemic Treatment Regimens In Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL)
Blood, 2010Co-Authors: Owen A. O'connor, Francine M. Foss, Barbara Pro, Kerry J. Savage, Nancy L. Bartlett, Pier Luigi Zinzani, Christian Gisselbrecht, Corinne Haouin, Lauren C. Pinter-brown, Steven M. HorwitzAbstract:Abstract 4881 Background: In a wide range of malignancies, including nonHodgkin lymphoma (NHL), treatment-naive patients generally show a greater response to chemotherapy than patients receiving second-line or subsequent therapy. Furthermore, objective response rate (ORR) and progression-free survival (PFS) generally decrease with each subsequent line of therapy, the hallmark of acquired drug resistance. This trend would also be expected for PTCL, although there are no published studies or retrospective data analyses specifically in PTCL describing the pattern of response to successive treatments. The goal of the analysis presented here was to determine whether a trend of progressive resistance is observed in relapsed or refractory PTCL, and to identify the efficacy (PFS and ORR) of Pralatrexate (FOLOTYN®) as a subsequent therapy relative to previous treatments. The PROPEL (Pralatrexate in Patients with Relapsed Or Refractory Peripheral T-cell Lymphoma) study is the largest data set published for relapsed or refractory PTCL to date. As a part of the patients9 medical history, data were collected on response and PFS in previous lines of therapy. Patients had a median of 3 prior systemic therapies (range 1 to 12). Overall in the PROPEL study, Pralatrexate demonstrated a 39% ORR by investigator assessment and a 29% ORR by central review. The median duration of response was 8.1 months by investigator assessment and 10.1 months by central review. The median duration of PFS was 4.0 months by investigator assessment and 3.5 months by central review. Median overall survival was 14.5 months. Methods: Analyses were conducted on patients according to the number of prior systemic therapies. PFS and ORR of the third therapy prior to Pralatrexate (-3) were compared with those of the second prior therapy (-2); PFS and ORR of second prior therapy (-2) were compared with those of the last (most recent) line of therapy (-1) prior to Pralatrexate; and PFS and ORR of last line of therapy (-1) were compared with Pralatrexate therapy for these patients. These analyses utilized investigator assessment of PFS and response since review of tumor assessments on prior therapies was based on investigator assessment. Results: 57 patients had undergone at least 3 prior systemic therapies before entry into PROPEL. Of these 57 patients, 34 had > 3 previous treatments and 23 had exactly 3 previous treatments. As presented in the table below, a trend of reduced PFS and ORR with successive lines of therapy was observed. The hazard ratio (HR) for outcomes worsens with successive lines of therapy [-3 vs -2: HR 0.660 (0.450, 0.967); -2 vs -1: HR 0.823 (0.566, 1.195)]. Thus, patients with ≥3 prior lines of therapy (-3) had higher response rates and PFS vs the RR and PFS in the same patients with later lines of therapy (-2 or -1). According to this analysis, this trend was reversed with Pralatrexate treatment demonstrated by a higher response rate (40%) and longer PFS (median =134 days) than the previous line of therapy. The only HR >1 in this analysis, indicating a longer PFS for a more recent line of therapy vs the most recent prior line of therapy, is for Pralatrexate vs -1. The same analyses were performed on the 86 patients who had undergone at least 2 previous treatments. The trend for PFS and response rate to decrease with each subsequent treatment was again demonstrated and was again reversed with Pralatrexate (HR for PFS = 1.201 [-1 vs -0] vs 0.785 [-2 vs -1]). Conclusions: This is the first analysis to demonstrate that patients with PTCL exhibit the same pattern of progressive resistance as seen in most other tumor types. It is also the first to demonstrate that a drug, Pralatrexate, can reverse the pattern of progressive resistance in patients with drug-resistant PTCL. Pralatrexate demonstrated higher responses and longer PFS than would be expected in a later line of therapy setting, thus reversing the trend of progressive resistance. Disclosures: O9Connor: Allos Therapeutics, Inc.: Research Funding. Haouin: GlaxoSmithKline: Consultancy; Amgen Inc.: Consultancy. Gisselbrecht: Allos Therapeutics, Inc.: Research Funding. Foss: Allos Therapeutics, Inc.: Consultancy, Speaker. Savage: Allos Therapeutics, Inc.: Consultancy, Honoraria. Pro: Allos Therapeutics, Inc.: Research Funding. Pinter-Brown: Allos Therapeutics, Inc.: Consultancy. Horwitz: Allos Therapeutics, Inc.: Consultancy, Research Funding. Jacobsen: Allos Therapeutics, Inc.: Consultancy. Koutsoukos: Allos Therapeutics, Inc.: Employment. Fruchtman: Allos Therapeutics, Inc.: Employment.
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Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2010Co-Authors: Enrica Marchi, Jasmine Zain, Luca Paoluzzi, Luigi Scotto, Venkatraman E. Seshan, Pier Luigi Zinzani, Owen A. O'connorAbstract:Purpose: Pralatrexate (10-propargyl-10-deazaaminopterin) is an antifolate with improved cellular uptake and retention due to greater affinity for the reduced folate carrier (RFC-1) and folyl-polyglutamyl synthase. Based on the PROPEL data, Pralatrexate was the first drug approved for patients with relapsed and refractory peripheral T-cell lymphoma. Bortezomib is a proteasome inhibitor that has shown some activity in patients with T-cell lymphoma. Experimental Design: Assays for cytotoxicity including mathematical analysis for synergism, flow cytometry, immunoblotting, and a xenograft severe combined immunodeficient-beige mouse model were used to explore the in vitro and in vivo activities of Pralatrexate alone and in combination with bortezomib in T-cell lymphoid malignancies. Results: In vitro , Pralatrexate and bortezomib exhibited concentration- and time-dependent cytotoxicity against a broad panel of T-lymphoma cell lines. Pralatrexate showed synergism when combined with bortezomib in all cell lines studied. Pralatrexate also induced potent apoptosis and caspase activation when combined with bortezomib across the panel. Cytotoxicity studies on normal peripheral blood mononuclear cells showed that the combination was not more toxic than the single agents. Western blot assays for proteins involved in broad growth and survival pathways showed that p27, NOXA, HH3, and RFC-1 were all significantly modulated by the combination. In a severe combined immunodeficient-beige mouse model of transformed cutaneous T-cell lymphoma, the addition of Pralatrexate to bortezomib enhanced efficacy compared with either drug alone. Conclusion: Collectively, these data suggest that Pralatrexate in combination with bortezomib represents a novel and potentially important platform for the treatment of T-cell malignancies. Clin Cancer Res; 16(14); 3648–58. ©2010 AACR.
Francine M. Foss - One of the best experts on this subject based on the ideXlab platform.
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Effect of leucovorin administration on mucositis and skin reactions in patients with peripheral T-cell lymphoma or cutaneous T-cell lymphoma treated with Pralatrexate*
Leukemia & lymphoma, 2019Co-Authors: Francine M. Foss, Terri L. Parker, Michael GirardiAbstract:AbstractPeripheral 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/m2 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 ...
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Clinical Activity of Pralatrexate in Patients With Cutaneous T-Cell Lymphoma Treated With Varying Doses of Pralatrexate.
Clinical lymphoma myeloma & leukemia, 2018Co-Authors: Francine M. Foss, Terri L. Parker, Michael GirardiAbstract:Summary Cutaneous T-cell lymphomas (CTCL) are rare, heterogeneous non-Hodgkin lymphomas with poor prognoses. Treatment options for CTCL are limited by the their efficacy and tolerability profile. Pralatrexate has demonstrated efficacy in T-cell lymphomas, however dose-modifying adverse events, such as mucositis have occurred. We retrospectively reviewed clinical responses and toxicity in 27 CTCL patients treated with Pralatrexate at doses ranging from 10-30mg/m 2 and clinical response or disease stabilization was observed in 85% even at lower doses. Administration of leucovorin resulted in no change in the incidence of skin reactions in CTCL patients but reduced the incidence of mucositis.
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Pralatrexate: treatment of T-cell non-Hodgkin’s lymphoma
Future oncology (London England), 2013Co-Authors: Terri L. Parker, Lisa Barbarotta, Francine M. FossAbstract:Pralatrexate is a folate analogue metabolic inhibitor manufactured by Allos Therapeutics, Inc., a wholly-owned subsidiary of Spectrum Pharmaceuticals, Inc. In both preclinical and clinical studies, Pralatrexate demonstrated activity in lymphoma. Pralatrexate was US FDA approved for the treatment of relapsed/refractory peripheral T-cell lymphoma in 2009. Approval was based on data from the PROPEL trial that demonstrated an overall response rate of 29% in a heavily pretreated patient population. The dose and schedule of Pralatrexate is 30-mg/m(2) weekly for 6 weeks, given in 7-week cycles. Folate and vitamin B12 supplementation are required to minimize toxicity. The most common toxicities are mucositis, thrombocytopenia, nausea and fatigue.
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Pralatrexate treatment of t cell non hodgkin s lymphoma
Future Oncology, 2013Co-Authors: Terri L. Parker, Lisa Barbarotta, Francine M. FossAbstract:Pralatrexate is a folate analogue metabolic inhibitor manufactured by Allos Therapeutics, Inc., a wholly-owned subsidiary of Spectrum Pharmaceuticals, Inc. In both preclinical and clinical studies, Pralatrexate demonstrated activity in lymphoma. Pralatrexate was US FDA approved for the treatment of relapsed/refractory peripheral T-cell lymphoma in 2009. Approval was based on data from the PROPEL trial that demonstrated an overall response rate of 29% in a heavily pretreated patient population. The dose and schedule of Pralatrexate is 30-mg/m(2) weekly for 6 weeks, given in 7-week cycles. Folate and vitamin B12 supplementation are required to minimize toxicity. The most common toxicities are mucositis, thrombocytopenia, nausea and fatigue.
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Cutaneous Toxicity Associated with Pralatrexate in Cutaneous and Peripheral T-Cell Lymphoma
Blood, 2012Co-Authors: Terri L. Parker, Michael Girardi, Lisa Barbarotta, Francine M. FossAbstract:Abstract 3660 Background: Pralatrexate is a folate analogue metabolic inhibitor that is approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) (O9Connor, O.A. et al. JCO. 2011 29: 1181–1189). More recently, Pralatrexate has been investigated for the treatment of relapsed or refractory cutaneous T-cell lymphoma (CTCL) (Horowitz, S.M. et al. Blood. 2012 119: 4115–4122). The most common adverse event (AE) observed with Pralatrexate has been mucositis with other reported AEs consisting of fatigue, nausea, and cutaneous toxicity. Methods: We retrospectively analyzed the data of 22 patients who had received Pralatrexate for a diagnosis of either PTCL or CTCL at our institution since 2010 in order to determine the incidence of cutaneous toxicity. Results: Of the 22 patients, 4 had a diagnosis of PTCL, 18 had CTCL. In the PTCL cohort, the median age was 66.5 with the median number of prior treatments (nonsystemic and systemic) being 2.75. One patient (25%) developed cutaneous toxicity which resulted in death. A skin biopsy revealed toxic erythema of chemotherapy and the skin lesions progressed to bullae and moist desquamation. In the CTCL cohort, the median age was 60 with the median number of treatments being 5. A total of 14 patients (78%) developed cutaneous toxicity. The toxicity included worsening erythema, skin breakdown, ulceration, and pain at the CTCL lesion sites. The majority of patients (n= 10; 71%) developed the toxicity following cycle 1 week 1 of treatment. The development of cutaneous toxicity was seen in 8 patients at a dose of 15mg/m2, in 3 patients at a dose of 10mg/m2, and in 2 patients who underwent dose escalations to 17.5mg/m2 and 20mg/m2respectively. Of those patients who developed cutaneous toxicity, 8 (57%) required the Pralatrexate to be held and 2 patients (14%) required hospitalization and treatment with intravenous antibiotics for superimposed skin infection. The cutaneous toxicity observed was not associated with any other adverse event. Seven patients (39%) in the entire CTCL cohort developed grade I/II mucositis and 3 (17%) developed grade I diarrhea. In 7 patients (50%) the Pralatrexate was restarted at a lower dose, 3 patients were changed to an every other week dosing schedule, and 2 patients continued on Pralatrexate with no change following resolution of their symptoms. Only 2 patients were not continued on Pralatrexate following the cutaneous toxicity. In all 12 patients who were retreated with Pralatrexate, cutaneous toxicity did not reoccur and the dose was able to be escalated. At the time of data analysis, 7 patients remained on treatment with Pralatrexate while the remainder had discontinued therapy secondary to disease progression. Conclusions: In this retrospective review, a high incidence of cutaneous toxicity was seen in CTCL patients who were treated with Pralatrexate. The cutaneous toxicity might be interpreted as a “skin flare” since it may be concentrated at sites of CTCL lesions. The majority of patients developed the toxicity with the first dose and were able to continue on Pralatrexate at a lower dose with eventual dose escalation. Based on data analysis, the “skin flare” is not dose dependent or associated with disease response. Disclosures: Off Label Use: Pralatrexate is FDA approved for the treatment of relapsed or refractory peripheral T-cell lymphoma. Our abstract discusses its use, specifically the cutaneous toxicity observed, in both peripheral and cutaneous T-cell lymphoma. The use of Pralatrexate in relapsed or refractory cutaneous T-cell lymphoma is off-label. Barbarotta:Genentech: Speakers Bureau; Allos: Speakers Bureau. Foss:Seattle Genetics: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Celgene: Study Grant, Study Grant Other; Merck: Study Grant, Study Grant Other; Allos: Consultancy.
Andrei R. Shustov - One of the best experts on this subject based on the ideXlab platform.
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Management of Mucositis with the Use of Leucovorin As Adjunct to Pralatrexate in Treatment of Peripheral T-Cell Lymphomas (PTCL) — Results from a Prospective Multicenter Phase 2 Clinical Trial
Blood, 2018Co-Authors: Andrei R. Shustov, Michi M. Shinohara, Shaker R. Dakhil, Gajanan Bhat, Jasmine ZainAbstract:Background: A frequent complication of Pralatrexate therapy is development of oral mucositis. In a recent pivotal trial of Pralatrexate (PROPEL, O9Connor et al. J Clin Onc 2011) the incidence of ≥ Grade 2 mucositis was 52%, occurring primarily in the first treatment cycle. Mucositis often leads to dose reduction or omission and possibly, diminished efficacy of Pralatrexate in relapsed/refractory (R/R) PTCL. Leucovorin (d,l-folinic acid) is an approved rescue therapy for high-dose methotrexate (MTX) therapy, mitigating gastrointestinal lining, and bone marrow cell toxicity and has been used adjunctively with Pralatrexate to manage mucositis. The objective of this prospective Phase 2, single-arm study was to evaluate the effect of leucovorin on the incidence of Pralatrexate-induced mucositis in patients with R/R PTCL, including primary cutaneous T-cell lymphomas. Methods: Eligible patients had diagnosis of PTCL, including CTCL, confirmed by local hematopathologist or dermatopathologist and were deemed appropriate for Pralatrexate therapy by investigator. Study treatment consisted of two cycles of Pralatrexate, (6 weekly doses (30 mg/m2) followed by 1 week of rest per cycle, currently approved label). All patients received vitamin B12 and folic acid supplementation; oral leucovorin, 25 mg TID was self-administered for 2 consecutive days (a total of 6 doses) beginning 24 hours after each dose of Pralatrexate. Patients underwent in-clinic oral mucositis assessment at baseline and at each visit prior to Pralatrexate administration by healthcare professional. Patients also completed a daily oral mucositis questionnaire (OMDQ) from Day 1 of Cycle 1 to the end of treatment visit. Mucositis was assessed by the investigator and recorded as an AE along with grade and causality. Toxicities were assessed using Common Terminology Criteria (CTCAE V4.03). Responses were assessed by the investigator per revised Response Criteria for Malignant Lymphoma (Cheson 2007) and Modified SWAT Criteria for CTCL.The primary endpoint was the incidence of Grade 2 or higher oral mucositis in Cycle 1. Secondary endpoints included the incidence of ≥ Grade 3 mucositis, and overall response rate. Results: A total of 30 patients have been enrolled as of time of data analysis. The majority of patients were male, white, with the median age of 63 yrs (range, 31-85). To date (5 July 2018) 11 patients have completed the study treatment, 12 patients discontinued (1 AE, 9 PD, 1 death, and 1 withdrawal) and 7 patients remain in the trial. All 30 subjects reached the assessment of the primary endpoint. The primary endpoint of the study has been met. Twenty (67%) patients have reported TEAEs, of which 11 (37%) have been ≥Grade 3 AEs. Overall toxicity profile was consistent with previously reported in the PROPEL trial. Most common Pralatrexate-related AEs were fatigue in 6 (20%) patients and diarrhea that occurred in 4 (13%) patients. SAEs occurred in 9 patients (only pyrexia in >1 pt; N=2), none were treatment-related. The rate of ≥2 mucositis was 4% (95% C.I. = 0, 20%). No Grade 3 or higher mucositis occurred; Grade 1 mucositis was observed in 4 patients. Assessment of treatment response rate (secondary endpoint) is ongoing and will be reported at the meeting. Conclusions: Overall safety profile of the study treatment was consistent with pivotal trial of Pralatrexate in R/R PTCL. Leucovorin as adjunctive treatment resulted in a significant reduction in rates of both ≥Grade 2, and ≥Grade 3 mucositis and should be considered in patients treated with Pralatrexate. Disclosures Shustov:SPECTRUM PHARMACEUTICALS: Consultancy, Research Funding. Bhat:SPECTRUM PHARMACEUTICALS: Employment.
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management of mucositis with the use of leucovorin as adjunct to Pralatrexate in treatment of peripheral t cell lymphomas ptcl results from a prospective multicenter phase 2 clinical trial
Blood, 2018Co-Authors: Andrei R. Shustov, Michi M. Shinohara, Shaker R. Dakhil, Gajanan Bhat, Jasmine ZainAbstract:Background: A frequent complication of Pralatrexate therapy is development of oral mucositis. In a recent pivotal trial of Pralatrexate (PROPEL, O9Connor et al. J Clin Onc 2011) the incidence of ≥ Grade 2 mucositis was 52%, occurring primarily in the first treatment cycle. Mucositis often leads to dose reduction or omission and possibly, diminished efficacy of Pralatrexate in relapsed/refractory (R/R) PTCL. Leucovorin (d,l-folinic acid) is an approved rescue therapy for high-dose methotrexate (MTX) therapy, mitigating gastrointestinal lining, and bone marrow cell toxicity and has been used adjunctively with Pralatrexate to manage mucositis. The objective of this prospective Phase 2, single-arm study was to evaluate the effect of leucovorin on the incidence of Pralatrexate-induced mucositis in patients with R/R PTCL, including primary cutaneous T-cell lymphomas. Methods: Eligible patients had diagnosis of PTCL, including CTCL, confirmed by local hematopathologist or dermatopathologist and were deemed appropriate for Pralatrexate therapy by investigator. Study treatment consisted of two cycles of Pralatrexate, (6 weekly doses (30 mg/m2) followed by 1 week of rest per cycle, currently approved label). All patients received vitamin B12 and folic acid supplementation; oral leucovorin, 25 mg TID was self-administered for 2 consecutive days (a total of 6 doses) beginning 24 hours after each dose of Pralatrexate. Patients underwent in-clinic oral mucositis assessment at baseline and at each visit prior to Pralatrexate administration by healthcare professional. Patients also completed a daily oral mucositis questionnaire (OMDQ) from Day 1 of Cycle 1 to the end of treatment visit. Mucositis was assessed by the investigator and recorded as an AE along with grade and causality. Toxicities were assessed using Common Terminology Criteria (CTCAE V4.03). Responses were assessed by the investigator per revised Response Criteria for Malignant Lymphoma (Cheson 2007) and Modified SWAT Criteria for CTCL.The primary endpoint was the incidence of Grade 2 or higher oral mucositis in Cycle 1. Secondary endpoints included the incidence of ≥ Grade 3 mucositis, and overall response rate. Results: A total of 30 patients have been enrolled as of time of data analysis. The majority of patients were male, white, with the median age of 63 yrs (range, 31-85). To date (5 July 2018) 11 patients have completed the study treatment, 12 patients discontinued (1 AE, 9 PD, 1 death, and 1 withdrawal) and 7 patients remain in the trial. All 30 subjects reached the assessment of the primary endpoint. The primary endpoint of the study has been met. Twenty (67%) patients have reported TEAEs, of which 11 (37%) have been ≥Grade 3 AEs. Overall toxicity profile was consistent with previously reported in the PROPEL trial. Most common Pralatrexate-related AEs were fatigue in 6 (20%) patients and diarrhea that occurred in 4 (13%) patients. SAEs occurred in 9 patients (only pyrexia in >1 pt; N=2), none were treatment-related. The rate of ≥2 mucositis was 4% (95% C.I. = 0, 20%). No Grade 3 or higher mucositis occurred; Grade 1 mucositis was observed in 4 patients. Assessment of treatment response rate (secondary endpoint) is ongoing and will be reported at the meeting. Conclusions: Overall safety profile of the study treatment was consistent with pivotal trial of Pralatrexate in R/R PTCL. Leucovorin as adjunctive treatment resulted in a significant reduction in rates of both ≥Grade 2, and ≥Grade 3 mucositis and should be considered in patients treated with Pralatrexate. Disclosures Shustov:SPECTRUM PHARMACEUTICALS: Consultancy, Research Funding. Bhat:SPECTRUM PHARMACEUTICALS: Employment.
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Pralatrexate in Combination with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Previously Untreated Patients with Peripheral T-Cell Lymphoma (PTCL): A Phase 1 Dose-Escalation Study
Blood, 2017Co-Authors: Andrei R. Shustov, Stefan K. Barta, Patrick B. Johnston, Gajanan Bhat, Reddy, Yasuhiro OkiAbstract:Background: The prognosis of patients with PTCL remains poor after standard CHOP therapy - the most commonly used combination regimen. Relapses occur in the majority of patients, and curability rates of the relapsed disease are very low. Hence, advances in front-line therapy of PTCL are long overdue. Pralatrexate, a second-generation antifolate, demonstrated a single agent activity in patients with relapsed and refractory PTCL with a response rate of 27%, including complete remissions in 11% of patients (O9Connor et al. J Clin Onc 2011). We conducted a Phase 1 multi-center dose-escalation study of Pralatrexate in combination with standard CHOP (Fol-CHOP) in treatment-naive PTCL patients. Objectives: The primary objective of the study was to determine the maximum tolerated dose (MTD) of Pralatrexate when administered with a standard CHOP regimen to patients with newly diagnosed PTCL. The secondary objectives included safety, tolerability, efficacy and pharmacokinetics of Pralatrexate in combination with CHOP (Fol-CHOP). Methods: In Part 1 of this 3+3 dose-escalation study, Pralatrexate was administered at 10, 15, 20, 25, or 30 mg/m2 as an IV push on days 1 and 8 of a standard 21-day CHOP regimen (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1 and oral prednisone 100 mg on days 1-5). In Part 2 of the study patients were treated at the MTD of Pralatrexate established in Part 1, with standard CHOP. In both parts of the study patients were treated with up to 6 cycles of therapy, or until toxicity or disease progression. Patients received antimicrobial prophylaxis, myeloid growth factor support, and "leucovorin rescue" throughout 6 cycles of therapy. Dose-limiting toxicities (DLT) were considered during the 1st cycle of Fol-CHOP and included: Grade 4 infections, treatment-related non-hematological toxicity ≥Grade 3, platelet count 7 days despite G-CSF administration. Responses were assessed by the investigator per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: A total of 31 patients have been enrolled (19 in Part 1; 12 in Part 2). MTD was not reached and Pralatrexate dose of 30 mg/m2 in combination with CHOP was selected for Part 2 of the study as predefined by the protocol. The majority of patients were male, White, with the median age of 66 yrs (range, 18-78) at the time of enrolment. PTCL diagnoses included: anaplastic large cell lymphoma, anaplastic lymphomakinase-negative (ALCL, ALK-, n=5), peripheral T-cell lymphoma, not-otherwise specified (PTCL-NOS, n=18), and angioimmunoblastic T-cell lymphoma (AITL, n=5). Fol-CHOP was generally well tolerated with median RDI of 98%. Common (≥ 30%) adverse events (AEs) of any grade were fatigue (n=23), constipation (n=20), nausea (n=16), mucositis (n=14), diarrhea (n=12), anemia (n=9), vomiting (n=10) and oral pain (n=10). Most common (≥ 10%) AEs ≥ grade 3 were anemia (n=6), fatigue (n=4) and neutrophil count decreas (n=5). The only Grade >3 treatment-related AEs (≥10%) was neutrophil count decrease (n=4). SAEs were observed in 13 patients, treatment related SAEs were anemia, febrile neutropenia, dehydration, mucositis and nausea. Five patients withdrew from study: 2 due to disease progression, 1 due to AE and 2 due lapse >28 days between doses. In the 27 patients avaluable for response, the investigator assessed objective response (OR) and complete response (CR) rates were 89% wand 67%, respectively. Conclusions: The combination of Pralatrexate and CHOP was well tolerated in treatment-naive PTCL patients. MTD of Pralatrexate was not reached, and the protocol-defined maximum dose of 30 mg/m2 on days 1 and 8 of a 21-day CHOP cycle was recomended for future studies. The observed OR and CR rates warrant further evaluation of this regimen in newly diagnosed PTCL patients. Disclosures Shustov: Celgene: Other: Publication assistance; Spectrum Pharmaceuticals: Consultancy, Research Funding. Bhat: Spectrum Pharmaceuticals: Employment. Reddy: Spectrum Pharmaceuticals: Employment.
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CHOP in Combination with Pralatrexate, a Novel Folate Analogue Metabolic Inhibitor in Patients with Previously Untreated Peripheral T-Cell Lymphoma (PTCL): Interim Results of the Phase 1 Trial
Blood, 2016Co-Authors: Andrei R. Shustov, Yasuhiro Oki, Stefan K. Barta, Patrick B. Johnston, Pankaj Sharma, Tao Song, Sanjay MouryaAbstract:Background: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell and natural-killer-cell aggressive non-Hodgkin lymphomas associated with poor prognosis with current therapies. Numerous studies have reported poor survival for PTCL patients with a median Overall Survival (OS) shorter than 2 years and 5-year survival rates of Pralatrexate (Folotyn) is a folate analogue metabolic inhibitor that was the first drug approved in the US for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 PROPEL study (O9Connor et al, JCO, 2011) of Pralatrexate in R/R PTCL, in which Pralatrexate monotherapy demonstrated a durable clinical benefit (objective response rate of 29%). Pralatrexate is administered intravenously (IV) at a dose of 30 mg/m2 weekly for 6 weeks of a 7-week treatment cycle. Since Pralatrexate and each of the components of the CHOP regimen target different aspects of tumor cell growth and proliferation, there is a potential for synergistic anti-tumor effect, and limited additive toxicities. Objectives: The primary endpoint of the study is the determination of the MTD of Pralatrexate in combination with CHOP (Fol-CHOP) in previously untreated PTCL patients. Secondary endpoints included safety, tolerability and ORR (complete response [CR] + partial response [PR]) and pharmacokinetics. Methods: In this study, patients with PTCL received CHOP in combination with Pralatrexate, repeated every 3-weeks for up to 6 cycles. Part 1 of the study was to determine the Maximum Tolerated Dose (MTD) of the Fol-CHOP combination. Once the MTD was determined, an additional 10 patients were treated in the Expansion Phase (Part 2). The cohort schema followed a traditional "3+3" design. Pralatrexate was to be administered as 10, 15, 20, 25, or 30 mg/m2 IV push over 3 to 5 minutes on Days 1 and 8 of each cycle. The starting cohort was CHOP + 10 mg/m2 of Pralatrexate. Patients received prophylaxis with acyclovir and sulfamethoxazole/trimethoprim during the study and primary prophylaxis with growth factor (filgrastim or pegfilgrastim) support. Dose-limiting toxicities (DLT) were considered during the 1st cycle and included: Severe infections, study treatment-related non-hematological toxicity Grade 3-4, platelet count Results: A total of 12 patients have been enrolled in Part 1 of the study at the time of abstract submission. Nine patients have completed Cycle 1 and no DLT was reported. Among these nine patients, three patients each were treated at CHOP + 10 mg/m2, 15 mg/m2 and 20 mg/m2 of Pralatrexate. One patient (11%) treated with CHOP + 10 mg/m2 had one serious adverse event (SAE) of febrile neutropenia that was deemed unrelated to any study drug. Only four Grade 3 AEs (anemia, constipation, mucosal inflammation, and nausea) were reported, in one patient (11%). The enrollment into the study continues. Conclusions: These interim results demonstrate that the combination of Pralatrexate with CHOP (Fol-CHOP) is well tolerated, with all components of CHOP as well as Pralatrexate being given at close to or at standard doses. The rates of AEs are comparable to those typically reported with CHOP alone. The study is ongoing to confirm the MTD and to assess preliminary efficacy of the Fol-CHOP combination. Updated results will be presented at the meeting. Disclosures Oki:Novartis: Research Funding. Barta:Celgene, Merck, Seattle Genetics: Research Funding; Janssen: Honoraria, Speakers Bureau. Sharma:Spectrum Pharmaceuticals: Employment. Song:Spectrum Pharmaceuticals: Employment. Mourya:Spectrum Pharmaceuticals: Employment.
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Pralatrexate is an effective treatment for relapsed or refractory transformed mycosis fungoides: a subgroup efficacy analysis from the PROPEL study.
Clinical lymphoma myeloma & leukemia, 2012Co-Authors: Francine M. Foss, Barbara Pro, Nancy L. Bartlett, Steven M. Horwitz, Lauren Pinter-brown, Andrei R. Shustov, Leslie Popplewell, Richard R. Furman, Bertrand Coiffier, Corinne HaiounAbstract:Abstract Background Transformed mycosis fungoides (tMF) is an aggressive disease, with poor prognosis and a median survival of 24 months. Patients And Methods In the Pralatrexate in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma (PROPEL) study, 12 patients with tMF were treated with a median of 10 Pralatrexate doses (starting dose of 30 mg/m 2 ) administered weekly for 6 weeks in a 7-week cycle. The median number of prior systemic therapies was 3. Results This retrospective analysis showed that the objective response rate in this subgroup was 25% (n = 3) per independent central review and 58% (n = 7) per investigator assessment, with this discrepancy likely attributed to challenges with photodocumentation of cutaneous lesions. The median duration of response and the median progression-free survival were 2.2 and 1.7 months, respectively, per central review, whereas median duration of response was 4.4 months, and median progression-free survival was 5.3 months per investigator assessment. Median survival was 13 months. Grade 1-3 mucositis was reported in 7 (58%) patients. Grade 4 adverse events were fatigue (n = 1) and thrombocytopenia (n = 1). Pralatrexate was well tolerated, with no toxicity-related discontinuations. Conclusions Based on these results, Pralatrexate may be a treatment option for patients with relapsed or refractory tMF.
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Results from a Phase I/II Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-cell Lymphoma.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017Co-Authors: Madeleine Duvic, Pier Luigi Zinzani, Youn H. Kim, Steven M. HorwitzAbstract:Purpose: Pralatrexate is a folic acid analogue metabolic inhibitor similar to methotrexate, which has shown tolerability and efficacy with an overall response rate of 45% in a phase I dose deescalation study of patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL).Experimental Design: The object of this phase I/II open-label, multicenter clinical trial was to determine the MTD and recommended dose of Pralatrexate plus oral bexarotene in 34 patients with relapsed/refractory CTCL who had failed prior systemic therapies. Pralatrexate was administered by intravenous push at 15 mg/m2 given weekly 3 weeks out of 4 weeks with daily oral bexarotene (150 or 300 mg/m2), levothyroxine, atorvastatin, folate, and with B12 every 2 months.Results: At the MTD of 15 mg/m2 bexarotene and 15 mg/m2 Pralatrexate, the response rate was 60% [4 complete responses (CR), 14 partial responses (PR)], the maximum observed response duration was 28.9+ months, and duration of response for 4 CRs ranged from 9.0 to 28.3 months. The median progression-free survival was 12.8 months (0.5-29.9). Mucositis was the most common adverse event.Conclusions: The combination of Pralatrexate (15 mg/m2) and oral bexarotene (150 mg/m2) is active with high response rates and minimal toxicity for cutaneous T-cell lymphomas. Clin Cancer Res; 23(14); 3552-6. ©2017 AACR.
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Pralatrexate in Relapsed/Refractory HTLV-1 Associated Adult T-Cell Lymphoma/Leukemia: A New York City Multi-Institutional Experience.
Blood, 2012Co-Authors: Matthew A. Lunning, Jason Gonsky, Jia Ruan, Adrienne A. Phillips, Melissa Pulitzer, Alison J. Moskowitz, Christiane Querfeld, Patricia L. Myskowski, Ariela Noy, Steven M. HorwitzAbstract:Abstract 2735 Introduction: Adult T-cell lymphoma/leukemia (ATLL) is a mature T-cell malignancy associated with human T-cell lymphotropic virus -1 (HTLV-1) infection, which presents as aggressive (acute/lymphomatous) or indolent (chronic/smouldering) subtypes. The aggressive subtypes have a median survival of 6 months. Further, there is no established therapy for patients with relapsed/refractory disease. Pralatrexate is a dihydro-folate reductase inhibitor with high affinity for the reduced folate carrier type 1, a protein involved in trafficking of native folates. Pralatrexate given weekly at 30 mg/m2 for six of seven weeks was the first drug approved for use in relapsed/refractory peripheral T-cell lymphoma (PTCL) after demonstrating an overall response rate (ORR) of 29%. However, only one patient in the pivotal PROPEL study had ATLL. Approaches for relapsed/refractory PTCL are often applied to ATLL, as there is little data for this subtype. Here, we report a multi-institutional retrospective experience of Pralatrexate in relapsed/refractory ATLL focusing on efficacy, durability, and toxicity. Methods: To investigate the therapeutic benefit and toxicity profile of Pralatrexate we reviewed all patients with relapsed/refractory ATLL treated with Pralatrexate on published trials or treated off study between 2005 and 2012 at three New York City institutions. Individual chart review was performed to report clinicopathologic features, treatment outcomes, and toxicity assessments. An event was defined as toxicity from Pralatrexate resulting in discontinuation, progression, or death. Results: We identified 21 patients with relapsed/refractory ATLL treated with Pralatrexate. Patient characteristics were: median age 52 (range 37–74); male:female 9:12; Region of origin was Caribbean-18, non-Caribean-3. Subtype at diagnosis of ATLL was: Acute/Lymphomatous-17 and Smouldering/Chronic-4. The median number prior treatments were 1 (range 0–5). Seven patients were treated on Pralatrexate developmental clinical trials with one patient on the pivotal phase II PROPEL study. The median dose and number of treatments administered were 30 mg/m2 (range 15–45) and 4 (range 1–53) respectively. The ORR in patients evaluable for response (N=16) was 19% (2:PR; 1:CR) with an intent-to-treat (N=20) ORR was12% in patients with any exposure to Pralatrexate. The median duration of response was 15 weeks (range 11–83). The median event free survival (EFS) was 6 weeks (range 1 to 90). One patient continues on Pralatrexate without toxicity and has yet to be evaluated for response. Four patients (19%) developed findings consistent with Stevens-Johnson Syndrome (SJS) after 1 (N=2) or 2 (N=2) doses of Pralatrexate. One additional patient developed a papular rash after Pralatrexate; no biopsy was obtained. In the four patients with SJS, one had skin involvement of ATLL at diagnosis and at the time of Pralatrexate, two had cutaneous ATLL lesions at the time of Pralatrexate, and one did not have any cutaneous ATLL. Dermal apoptosis of tumor was not assessed in any of the cases. Seven patients (33%) developed clinically significant mucositis with two cases in patients with SJS. Conclusion: ATLL is a rare and difficult disease to manage. In our retrospective experience in relapsed/refractory ATLL, Pralatrexate appears to have inferior ORR and much shorter EFS when compared to other PTCL subtypes. Notably, the risk of SJS, even without cutaneous involvement by lymphoma, may be higher in ATLL. In early phase studies of Pralatrexate skin erosions were also seen in patients with PTCL with cutaneous involvement, including one cases of an ATLL patient with in vivo evidence of apoptosis of cutaneous tumor cells, but no cases of SJS were reported. A dedicated phase II study of Pralatrexate in relapsed/refractory ATLL is planned by the Japan Clinical Oncology Group. Disclosures: Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding.
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Pralatrexate in relapsed refractory htlv 1 associated adult t cell lymphoma leukemia a new york city multi institutional experience
Blood, 2012Co-Authors: Matthew A. Lunning, Jason Gonsky, Jia Ruan, Adrienne A. Phillips, Melissa Pulitzer, Alison J. Moskowitz, Christiane Querfeld, Patricia L. Myskowski, Ariela Noy, Steven M. HorwitzAbstract:Abstract 2735 Introduction: Adult T-cell lymphoma/leukemia (ATLL) is a mature T-cell malignancy associated with human T-cell lymphotropic virus -1 (HTLV-1) infection, which presents as aggressive (acute/lymphomatous) or indolent (chronic/smouldering) subtypes. The aggressive subtypes have a median survival of 6 months. Further, there is no established therapy for patients with relapsed/refractory disease. Pralatrexate is a dihydro-folate reductase inhibitor with high affinity for the reduced folate carrier type 1, a protein involved in trafficking of native folates. Pralatrexate given weekly at 30 mg/m2 for six of seven weeks was the first drug approved for use in relapsed/refractory peripheral T-cell lymphoma (PTCL) after demonstrating an overall response rate (ORR) of 29%. However, only one patient in the pivotal PROPEL study had ATLL. Approaches for relapsed/refractory PTCL are often applied to ATLL, as there is little data for this subtype. Here, we report a multi-institutional retrospective experience of Pralatrexate in relapsed/refractory ATLL focusing on efficacy, durability, and toxicity. Methods: To investigate the therapeutic benefit and toxicity profile of Pralatrexate we reviewed all patients with relapsed/refractory ATLL treated with Pralatrexate on published trials or treated off study between 2005 and 2012 at three New York City institutions. Individual chart review was performed to report clinicopathologic features, treatment outcomes, and toxicity assessments. An event was defined as toxicity from Pralatrexate resulting in discontinuation, progression, or death. Results: We identified 21 patients with relapsed/refractory ATLL treated with Pralatrexate. Patient characteristics were: median age 52 (range 37–74); male:female 9:12; Region of origin was Caribbean-18, non-Caribean-3. Subtype at diagnosis of ATLL was: Acute/Lymphomatous-17 and Smouldering/Chronic-4. The median number prior treatments were 1 (range 0–5). Seven patients were treated on Pralatrexate developmental clinical trials with one patient on the pivotal phase II PROPEL study. The median dose and number of treatments administered were 30 mg/m2 (range 15–45) and 4 (range 1–53) respectively. The ORR in patients evaluable for response (N=16) was 19% (2:PR; 1:CR) with an intent-to-treat (N=20) ORR was12% in patients with any exposure to Pralatrexate. The median duration of response was 15 weeks (range 11–83). The median event free survival (EFS) was 6 weeks (range 1 to 90). One patient continues on Pralatrexate without toxicity and has yet to be evaluated for response. Four patients (19%) developed findings consistent with Stevens-Johnson Syndrome (SJS) after 1 (N=2) or 2 (N=2) doses of Pralatrexate. One additional patient developed a papular rash after Pralatrexate; no biopsy was obtained. In the four patients with SJS, one had skin involvement of ATLL at diagnosis and at the time of Pralatrexate, two had cutaneous ATLL lesions at the time of Pralatrexate, and one did not have any cutaneous ATLL. Dermal apoptosis of tumor was not assessed in any of the cases. Seven patients (33%) developed clinically significant mucositis with two cases in patients with SJS. Conclusion: ATLL is a rare and difficult disease to manage. In our retrospective experience in relapsed/refractory ATLL, Pralatrexate appears to have inferior ORR and much shorter EFS when compared to other PTCL subtypes. Notably, the risk of SJS, even without cutaneous involvement by lymphoma, may be higher in ATLL. In early phase studies of Pralatrexate skin erosions were also seen in patients with PTCL with cutaneous involvement, including one cases of an ATLL patient with in vivo evidence of apoptosis of cutaneous tumor cells, but no cases of SJS were reported. A dedicated phase II study of Pralatrexate in relapsed/refractory ATLL is planned by the Japan Clinical Oncology Group. Disclosures: Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding.
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Pralatrexate is an effective treatment for relapsed or refractory transformed mycosis fungoides: a subgroup efficacy analysis from the PROPEL study.
Clinical lymphoma myeloma & leukemia, 2012Co-Authors: Francine M. Foss, Barbara Pro, Nancy L. Bartlett, Steven M. Horwitz, Lauren Pinter-brown, Andrei R. Shustov, Leslie Popplewell, Richard R. Furman, Bertrand Coiffier, Corinne HaiounAbstract:Abstract Background Transformed mycosis fungoides (tMF) is an aggressive disease, with poor prognosis and a median survival of 24 months. Patients And Methods In the Pralatrexate in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma (PROPEL) study, 12 patients with tMF were treated with a median of 10 Pralatrexate doses (starting dose of 30 mg/m 2 ) administered weekly for 6 weeks in a 7-week cycle. The median number of prior systemic therapies was 3. Results This retrospective analysis showed that the objective response rate in this subgroup was 25% (n = 3) per independent central review and 58% (n = 7) per investigator assessment, with this discrepancy likely attributed to challenges with photodocumentation of cutaneous lesions. The median duration of response and the median progression-free survival were 2.2 and 1.7 months, respectively, per central review, whereas median duration of response was 4.4 months, and median progression-free survival was 5.3 months per investigator assessment. Median survival was 13 months. Grade 1-3 mucositis was reported in 7 (58%) patients. Grade 4 adverse events were fatigue (n = 1) and thrombocytopenia (n = 1). Pralatrexate was well tolerated, with no toxicity-related discontinuations. Conclusions Based on these results, Pralatrexate may be a treatment option for patients with relapsed or refractory tMF.
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Identification of an active, well-tolerated dose of Pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma
Blood, 2012Co-Authors: Steven M. Horwitz, Francine M. Foss, Jasmine Zain, Nancy L. Bartlett, Mary Jo Lechowicz, Patricia L. Myskowski, Andrei R. Shustov, Youn H. Kim, David C. Fisher, Maria L. DelioukinaAbstract:Systemic treatment for cutaneous T-cell lymphoma (CTCL) involves the use of less aggressive, well-tolerated therapies. Pralatrexate is a novel antifolate with high affinity for reduced folate carrier-1. A dose de-escalation strategy identified recommended Pralatrexate dosing for patients with CTCL that demonstrated high activity, good rates of disease control, and an acceptable toxicity profile for continuous long-term dosing. Eligibility included mycosis fungoides, Sezary syndrome, or primary cutaneous anaplastic large cell lymphoma, with disease progression after ≥ 1 prior systemic therapy. The starting dose and schedule was 30 mg/m2/wk intravenously for 3 of 4 (3/4) weeks. Subsequent starting doses were 20, 15, and 10 mg/m2/wk for 3/4 or 2 of 3 (2/3) weeks. Response was evaluated by the modified severity-weighted adjustment tool. Fifty-four patients were treated. The recommended regimen was identified as 15 mg/m2/wk for 3/4 weeks and was explored in the expansion cohort. In 29 patients treated overall with the recommended dosing regimen, the median number of prior systemic therapies was 4. Pralatrexate was administered for a median of 4 cycles; response rate was 45%. The most common grade 3 adverse event (AE) was mucositis (17%); the only grade 4 AE was leukopenia (3%). Pralatrexate 15 mg/m2/wk for 3/4 weeks shows high activity with acceptable toxicity in patients with relapsed/refractory CTCL.
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Pralatrexate is an effective treatment for relapsed or refractory transformed mycosis fungoides: a subgroup efficacy analysis from the PROPEL study.
Clinical lymphoma myeloma & leukemia, 2012Co-Authors: Francine M. Foss, Barbara Pro, Nancy L. Bartlett, Steven M. Horwitz, Lauren Pinter-brown, Andrei R. Shustov, Leslie Popplewell, Richard R. Furman, Bertrand Coiffier, Corinne HaiounAbstract:Abstract Background Transformed mycosis fungoides (tMF) is an aggressive disease, with poor prognosis and a median survival of 24 months. Patients And Methods In the Pralatrexate in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma (PROPEL) study, 12 patients with tMF were treated with a median of 10 Pralatrexate doses (starting dose of 30 mg/m 2 ) administered weekly for 6 weeks in a 7-week cycle. The median number of prior systemic therapies was 3. Results This retrospective analysis showed that the objective response rate in this subgroup was 25% (n = 3) per independent central review and 58% (n = 7) per investigator assessment, with this discrepancy likely attributed to challenges with photodocumentation of cutaneous lesions. The median duration of response and the median progression-free survival were 2.2 and 1.7 months, respectively, per central review, whereas median duration of response was 4.4 months, and median progression-free survival was 5.3 months per investigator assessment. Median survival was 13 months. Grade 1-3 mucositis was reported in 7 (58%) patients. Grade 4 adverse events were fatigue (n = 1) and thrombocytopenia (n = 1). Pralatrexate was well tolerated, with no toxicity-related discontinuations. Conclusions Based on these results, Pralatrexate may be a treatment option for patients with relapsed or refractory tMF.
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Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results From the Pivotal PROPEL Study
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2011Co-Authors: Owen A. O'connor, Barbara Pro, Kerry J. Savage, Nancy L. Bartlett, Mary Jo Lechowicz, Lauren Pinter-brown, Andrei R. Shustov, Leslie Popplewell, Bertrand Coiffier, Christian GisselbrechtAbstract:Purpose Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of Pralatrexate, a novel antifolate with promising activity. Patients and Methods Patients with independently confirmed PTCL who progressed following ≥ 1 line of prior therapy received Pralatrexate intravenously at 30 mg/m2/wk for 6 weeks in 7-week cycles. Primary assessment of response was made by independent central review using the International Workshop Criteria. The primary end point was overall response rate. Secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS). Results Of 115 patients enrolled, 111 were treated with Pralatrexate. The median number of prior systemic therapies was three (range, 1 to 12). The response rate in 109 evaluable patients was 29% (32 of 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median DoR of 10.1 mo...
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Pralatrexate Is Effective In Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL) with Prior Ifosfamide, Carboplatin, and Etoposide (ICE)-Based Regimens
Blood, 2010Co-Authors: Andre Goy, Barbara Pro, Kerry J. Savage, Nancy L. Bartlett, Mary Jo Lechowicz, Eric D. Jacobsen, Faith Young, Michael Crump, Hossein Borghaei, Brian K. LinkAbstract:Abstract 1753 Background: Peripheral T-cell lymphoma (PTCL) is a group of aggressive T- and NK-cell lymphomas with a poor prognosis, with most patients progressing within 6 to 12 months after first-line therapy. Despite a paucity of data in PTCL, combination chemotherapy such as ifosfamide/carboplatin/etoposide (ICE)-based regimens (eg, ICE, rituximab-ICE [RICE] and dexamethasome-ICE [DICE]), are often used in the salvage setting. These regimens can induce responses allowing some patients to proceed to a stem cell transplant (SCT), yet most patients relapse quickly (Horwitz et al, Blood. 2005;(106:a2679; Zelenetz et al Annals Oncol. 2003;14:i5-i10.). Pralatrexate (FOLOTYN®), a rationally-designed folate analog, was granted accelerated approval in the United States for the treatment of relapsed or refractory PTCL, based on results of the pivotal study, PROPEL (Pralatrexate in Patients with Relapsed Or Refractory Peripheral T-cell Lymphoma). The present exploratory analysis of PROPEL data was conducted to assess the efficacy of Pralatrexate postfailure of ICE-based regimens. Methods: Of the 109 patients enrolled in PROPEL and evaluable for efficacy, a subset of 20 patients had received an ICE-based regimen as their second-line therapy and progressed at some point prior to treatment with Pralatrexate (30 mg/m2 weekly for 6 of 7 week cycles). Results: The median age of the 20 patients with a prior ICE-based regimen was 45 years. A summary of Pralatrexate efficacy data is presented in the table below. Pralatrexate demonstrated ORR of 40% in ICE-pretreated patients (n=20). Nine of the 20 patients received ICE-based regimens as their most recent therapy prior to Pralatrexate. Of these, 2 patients did not respond to these aggressive combination chemotherapies, but did respond to Pralatrexate (1 CR and 1 PR). Two of the 20 patients achieved a CR on Pralatrexate and proceeded to SCT; DoR to Pralatrexate in these patients was censored (at 1.3 and 4.9 months). However, these 2 patients remain in CR and the current disease-free period (DoR: Pralatrexate + transplant) is 10.9 and 30.8 months. The most common grade 3 adverse events (AEs) were anemia (8 patients) and mucositis (5 patients), and grade 4 AEs was thrombocytopenia (6 patients). Five patients discontinued treatment with Pralatrexate due to AEs. From a safety perspective, this compares favorably with ICE-based regimens, recognized for their intensity and their need for hospitalization for administration (Hertzberg et al, Ann Oncol. 2003;14[suppl 1] i11-i16). The PROPEL study also collected information on response to therapies administered prior to study entry. In the 20 patients included in the analysis, the ORR to prior ICE-based regimens was 25% with 3 patients achieving CR (15%) and 2 PR (10%). An additional 3 patients had SD (15%), 7 had PD (35%), and 5 patients had nonassessable response. The median duration on treatment for responders to ICE-based regimens was Conclusions Pralatrexate was highly active in patients with PTCL who received prior ICE-based chemotherapy, with an ORR of 40% including CRs leading to SCT in some patients. Of note, is the long duration of Pralatrexate responses in marked contrast to the short response duration of the combination chemotherapy regimens. Taken together, the efficacy of single-agent Pralatrexate compared favorably with ICE-based regimens, a finding that is consistent with other exploratory analyses, showing that Pralatrexate can reverse the characteristic progressive resistance of PTCL patients to second-line chemotherapy, and that Pralatrexate is an effective second-line treatment for patients with PTCL. Disclosures: Goy:Allos Therapeutics, Inc.: Consultancy, Honoraria. Pro:Allos Therapeutics, Inc. : Research Funding. Savage:Allos Therapeutics, Inc.: Consultancy, Honoraria. Lechowicz:Allos Therapeutics, Inc.: Consultancy; Celgene Corporation: Consultancy. Jacobsen:Allos Therapeutics, Inc.: Consultancy. Fruchtman:Allos Therapeutics, Inc.: Employment. O9Connor:Allos Therapeutics, Inc.: Research Funding.
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Pralatrexate Is Effective as Second-Line Treatment Following Cyclophosphamide/Doxorubicin/Vincristine/Prednisone (CHOP) Failure In Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)
Blood, 2010Co-Authors: Andrei R. Shustov, Jasmine Zain, Barbara Pro, Nancy L. Bartlett, Mary Jo Lechowicz, Faith Young, Christian Gisselbrecht, Leslie Popplewell, Richard R. Furman, Steven M. FruchtmanAbstract:Abstract 4882 Background: The most common therapy for first-line treatment of peripheral T-cell lymphoma (PTCL) is cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP). However, most patients progress within 6 to 12 months and there is no standard of care for second-line treatment. Despite a paucity of data in PTCL, B-cell lymphoma salvage regimens are regularly employed as a second-line treatment for PTCL. Pralatrexate was granted accelerated approval in the United States for the treatment of patients with relapsed or refractory PTCL, based on the results of the pivotal study, PROPEL (Pralatrexate in Patients with Relapsed Or Refractory Peripheral T-cell Lymphoma). All patients in PROPEL had received at least 1 prior therapy for PTCL, with a median of 3 prior systemic therapies (range 1 to 12). The objective response rate (ORR) was 29% (by central review) and 39% (by investigator assessment), with a median duration of response (DoR) of 8.1 months (by investigator) and 10.1 months (by central review). The present analysis was conducted to assess the efficacy of Pralatrexate as a second-line treatment post-CHOP. Methods: Of the 109 patients who were treated with Pralatrexate and evaluable for efficacy in the PROPEL study, a subset of 15 patients received Pralatrexate (30 mg/m2 intravenously weekly for 6 of 7 week cycles) as their second-line treatment post-CHOP. Results: The demographics and disease characteristics of the 15 patients treated with Pralatrexate in the second-line setting post-CHOP were reflective of the overall PROPEL patient population. Nine of 15 patients (60%) were male. Median age was 60 years. Eleven of the 15 patients had a prior response to CHOP (7 CR and 4 PR). The additional 4 patients had 1 SD and 3 PD, respectively. A summary of Pralatrexate efficacy as second-line treatment post-CHOP is presented in the table below. CR=complete response; CRu=complete response unconfirmed; PR=progressive disease; SD=stable disease; PD=progressive disease; DoR=duration of response; PFS=progression-free survival; OS=overall survival. The 15 patients treated in second-line post-CHOP received a median of 16 doses of Pralatrexate, for a median of 134 days. Only 1 patient had a grade 4 adverse event (AE) (sepsis) and the only grade 3 AEs to occur in >1 patient were thrombocytopenia (4 patients), and mucosal inflammation (3 patients). Two patients discontinued treatment with Pralatrexate due to AEs. Two of the 15 patients remained on treatment (time on treatment = 12.9 and 18.5 months) and in response as of the data cut-off (August 2009), and their DoR data were censored. An additional 2 patients proceeded to stem cell transplant (SCT) after response to Pralatrexate, and thus were censored for DoR (at 2.3 and 3.3 months). These 2 patients remain in CR and their current disease-free period (DoR: Pralatrexate + SCT) is 20.1 and 21.7 months. The PROPEL study also collected information on response to therapies administered prior to study entry. Of note, 33 patients received combination chemotherapy as their second-line systemic treatment post-CHOP (ICE and DHAP being the most common regimens): the ORR for combination therapy was 33% and the median duration on treatment for responders was 4 months, which is substantially shorter compared with the DoR to Pralatrexate (median 12.5 months, per investigators assessment). Conclusions: Pralatrexate administered as second-line treatment (post-CHOP) to patients with PTCL demonstrated high activity with durable responses, including CRs leading in some patients to SCT. Pralatrexate efficacy and safety profile compared favorably with combination chemotherapy in this disease setting. Taken together, this data suggests that Pralatrexate is a highly effective, single-agent, second-line therapeutic option for patients with PTCL, including those who are candidates for bone marrow transplantation. Disclosures: Shustov: Allos Therapeutics, Inc.: Honoraria, Research Funding. Pro: Allos Therapeutics, Inc.: Research Funding. Gisselbrecht: Allos Therapeutics, Inc.: Research Funding. Lechowicz: Allos Therapeutics, Inc.: Consultancy; Celgene Corporation: Consultancy. Zain: Allos Therapeutics, Inc.: Speakers Bureau. Furman: Allos Therapeutics, Inc.: Research Funding. Fruchtman: Allos Therapeutics, Inc.: Employment. Horwitz: Allos Therapeutics, Inc.: Consultancy, Research Funding. O9Connor: Allos Therapeutics, Inc.: Research Funding.
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Pralatrexate is effective as second line treatment following cyclophosphamide doxorubicin vincristine prednisone chop failure in patients with relapsed or refractory peripheral t cell lymphoma ptcl
Blood, 2010Co-Authors: Andrei R. Shustov, Jasmine Zain, Barbara Pro, Nancy L. Bartlett, Mary Jo Lechowicz, Faith Young, Christian Gisselbrecht, Leslie Popplewell, Richard R. Furman, Steven M. FruchtmanAbstract:Abstract 4882 Background: The most common therapy for first-line treatment of peripheral T-cell lymphoma (PTCL) is cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP). However, most patients progress within 6 to 12 months and there is no standard of care for second-line treatment. Despite a paucity of data in PTCL, B-cell lymphoma salvage regimens are regularly employed as a second-line treatment for PTCL. Pralatrexate was granted accelerated approval in the United States for the treatment of patients with relapsed or refractory PTCL, based on the results of the pivotal study, PROPEL (Pralatrexate in Patients with Relapsed Or Refractory Peripheral T-cell Lymphoma). All patients in PROPEL had received at least 1 prior therapy for PTCL, with a median of 3 prior systemic therapies (range 1 to 12). The objective response rate (ORR) was 29% (by central review) and 39% (by investigator assessment), with a median duration of response (DoR) of 8.1 months (by investigator) and 10.1 months (by central review). The present analysis was conducted to assess the efficacy of Pralatrexate as a second-line treatment post-CHOP. Methods: Of the 109 patients who were treated with Pralatrexate and evaluable for efficacy in the PROPEL study, a subset of 15 patients received Pralatrexate (30 mg/m2 intravenously weekly for 6 of 7 week cycles) as their second-line treatment post-CHOP. Results: The demographics and disease characteristics of the 15 patients treated with Pralatrexate in the second-line setting post-CHOP were reflective of the overall PROPEL patient population. Nine of 15 patients (60%) were male. Median age was 60 years. Eleven of the 15 patients had a prior response to CHOP (7 CR and 4 PR). The additional 4 patients had 1 SD and 3 PD, respectively. A summary of Pralatrexate efficacy as second-line treatment post-CHOP is presented in the table below. CR=complete response; CRu=complete response unconfirmed; PR=progressive disease; SD=stable disease; PD=progressive disease; DoR=duration of response; PFS=progression-free survival; OS=overall survival. The 15 patients treated in second-line post-CHOP received a median of 16 doses of Pralatrexate, for a median of 134 days. Only 1 patient had a grade 4 adverse event (AE) (sepsis) and the only grade 3 AEs to occur in >1 patient were thrombocytopenia (4 patients), and mucosal inflammation (3 patients). Two patients discontinued treatment with Pralatrexate due to AEs. Two of the 15 patients remained on treatment (time on treatment = 12.9 and 18.5 months) and in response as of the data cut-off (August 2009), and their DoR data were censored. An additional 2 patients proceeded to stem cell transplant (SCT) after response to Pralatrexate, and thus were censored for DoR (at 2.3 and 3.3 months). These 2 patients remain in CR and their current disease-free period (DoR: Pralatrexate + SCT) is 20.1 and 21.7 months. The PROPEL study also collected information on response to therapies administered prior to study entry. Of note, 33 patients received combination chemotherapy as their second-line systemic treatment post-CHOP (ICE and DHAP being the most common regimens): the ORR for combination therapy was 33% and the median duration on treatment for responders was 4 months, which is substantially shorter compared with the DoR to Pralatrexate (median 12.5 months, per investigators assessment). Conclusions: Pralatrexate administered as second-line treatment (post-CHOP) to patients with PTCL demonstrated high activity with durable responses, including CRs leading in some patients to SCT. Pralatrexate efficacy and safety profile compared favorably with combination chemotherapy in this disease setting. Taken together, this data suggests that Pralatrexate is a highly effective, single-agent, second-line therapeutic option for patients with PTCL, including those who are candidates for bone marrow transplantation. Disclosures: Shustov: Allos Therapeutics, Inc.: Honoraria, Research Funding. Pro: Allos Therapeutics, Inc.: Research Funding. Gisselbrecht: Allos Therapeutics, Inc.: Research Funding. Lechowicz: Allos Therapeutics, Inc.: Consultancy; Celgene Corporation: Consultancy. Zain: Allos Therapeutics, Inc.: Speakers Bureau. Furman: Allos Therapeutics, Inc.: Research Funding. Fruchtman: Allos Therapeutics, Inc.: Employment. Horwitz: Allos Therapeutics, Inc.: Consultancy, Research Funding. O9Connor: Allos Therapeutics, Inc.: Research Funding.