STUDY TITLE
A Randomized, Phase 2, Two-Arm, Open-Label, Multicenter, Study of Folotyn® (Pralatrexate Injection) with and without Oral Leucovorin to Prevent or Reduce Mucositis in Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL)
BACKGROUND
1.a Defining Peripheral T-Cell Lymphomas (PTCL)
Peripheral or mature T-cell lymphomas are subset of aggressive non-Hodgkin lymphomas (NHL) that comprise approximately 10-15% of all newly diagnosed cases of NHL in the United State. According to the 2008 World Health Organization (WHO) Classification schema, there are 18 subtypes of mature T- and natural killer (NK) cell neoplasms (Swerdlow 2008). Various subtypes of T- and NK-cell lymphomas are known to express the cell surface marker CD30; most notably, sACLC, in which CD30 expression is a hallmark of the diagnosis (Savage 2008). These difficult-to-treat lymphomas are often grouped together for enrollment in clinical trials based on their universal dismal outcomes. Five-year overall survival (OS) in the over 1,300-patient International Peripheral T-Cell and Natural Killer/T-Cell lymphoma Study was poor and ranged from 12 to 49% depending on histologic subtype (Vose 2008). Five-year failure-free survival, defined as time from any cause, ranged from 6 to 36%. In contrast to B-cell NHL, PTCLs are more resistant to conventional chemotherapy and are generally associated with an inferior outcome except for anaplastic lymphoma kinase (ALK) + anaplastic large-cell lymphoma. While the precise biologic reasons for the differences between B- and T-cell lymphomas are not clear, many explanations have been advanced, including differences in intrinsic chemosensitivity, the fact that patients with PTCL typically have a higher International Prognostic Index (IPI) at presentation, and the absence of drugs with unique activity in PTCL. Importantly, all regimens presently employed for PTCL are derived from B-cell lymphoma experiences.12-14 (art 2) These data underscore the urgent need for new treatment options for patients with PTCL, especially those with recurrent or refractory disease, who typically have limited responses to salvage therapy and extremely poor OS.9 (art 2) 1.b Options of Therapies for Peripheral T-Cell Lymphomas Frontline treatment of peripheral T-cell and NK-cell neoplasms is dependent on the subtype of disease and often includes clinical trials as the preferred therapeutic options (NCCN 2013). For most subtypes, anthracycline-based multiagent chemotherapy regimens such as CHOP are commonly utilized. The notable exception is extranodal NK/T-cell lymphomas, nasal and non-nasal types, where concurrent chemoradiotherapy regimens are employed. Although no randomized studies have been conducted to establish the use of CHOP in patient with PTCL, it is the most commonly used regimen in the frontline treatment of these patients. The International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study results indicate that over 85% of patients were treated with an anthracycline-based multiagent chemotherapy regimen (Vose 2008). In published studies that have compared new treatment approaches to an established standard of care, CHOP administered every 3 weeks (CHOP-21) has been used as the control arm (Simon 2010). In addition, published guidelines recommend enrollment into clinical trial or CHOP as appropriate frontline treatment options for patients with a diagnosis of PTCL (NCCN 2013). Guidelines support administration of 6 cycles of CHOP therapy for patients with Stage I-II disease and International Prognostic Index (IPI) score of 0-2, and 6-8 cycles of CHOP therapy for Stage I-II patients with an IPI score of 3-5 and all Stage III-IV patients (Schmitz 2010; NCCN 2013). Comparison of non-randomized clinical trials does not support a difference in activity between 6 or 8 cycles of CHOP, with 6-8 cycles commonly employed in clinical practice (Coiffier 2002; Schmitz 2010). …show more content…
This mechanism of action results in a potential for broad spectrum cytotoxic activity against tumor cells and rapidly dividing nucleated cells. The improved antitumor effects of Pralatrexate are likely due to the more effective internalization by the 1-carbon reduced folate carrier (RFC-1), and the subsequent accumulation in tumor cells through the formation of polyglutamylated metabolites. 75,77 RFC-1 is a fetal oncoprotein that is predominantly expressed on fetal and malignant tissue, and is felt to be the principal means through which Pralatrexate, though not necessarily other anti-folates, enters the cell. This carrier protein has evolved to efficiently transport reduced natural folates into highly proliferative cells, in order to meet he demands for purine and pyrimidine nucleotides during deoxyribonucleic acid (DNA)
A Randomized, Phase 2, Two-Arm, Open-Label, Multicenter, Study of Folotyn® (Pralatrexate Injection) with and without Oral Leucovorin to Prevent or Reduce Mucositis in Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL)
BACKGROUND
1.a Defining Peripheral T-Cell Lymphomas (PTCL)
Peripheral or mature T-cell lymphomas are subset of aggressive non-Hodgkin lymphomas (NHL) that comprise approximately 10-15% of all newly diagnosed cases of NHL in the United State. According to the 2008 World Health Organization (WHO) Classification schema, there are 18 subtypes of mature T- and natural killer (NK) cell neoplasms (Swerdlow 2008). Various subtypes of T- and NK-cell lymphomas are known to express the cell surface marker CD30; most notably, sACLC, in which CD30 expression is a hallmark of the diagnosis (Savage 2008). These difficult-to-treat lymphomas are often grouped together for enrollment in clinical trials based on their universal dismal outcomes. Five-year overall survival (OS) in the over 1,300-patient International Peripheral T-Cell and Natural Killer/T-Cell lymphoma Study was poor and ranged from 12 to 49% depending on histologic subtype (Vose 2008). Five-year failure-free survival, defined as time from any cause, ranged from 6 to 36%. In contrast to B-cell NHL, PTCLs are more resistant to conventional chemotherapy and are generally associated with an inferior outcome except for anaplastic lymphoma kinase (ALK) + anaplastic large-cell lymphoma. While the precise biologic reasons for the differences between B- and T-cell lymphomas are not clear, many explanations have been advanced, including differences in intrinsic chemosensitivity, the fact that patients with PTCL typically have a higher International Prognostic Index (IPI) at presentation, and the absence of drugs with unique activity in PTCL. Importantly, all regimens presently employed for PTCL are derived from B-cell lymphoma experiences.12-14 (art 2) These data underscore the urgent need for new treatment options for patients with PTCL, especially those with recurrent or refractory disease, who typically have limited responses to salvage therapy and extremely poor OS.9 (art 2) 1.b Options of Therapies for Peripheral T-Cell Lymphomas Frontline treatment of peripheral T-cell and NK-cell neoplasms is dependent on the subtype of disease and often includes clinical trials as the preferred therapeutic options (NCCN 2013). For most subtypes, anthracycline-based multiagent chemotherapy regimens such as CHOP are commonly utilized. The notable exception is extranodal NK/T-cell lymphomas, nasal and non-nasal types, where concurrent chemoradiotherapy regimens are employed. Although no randomized studies have been conducted to establish the use of CHOP in patient with PTCL, it is the most commonly used regimen in the frontline treatment of these patients. The International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study results indicate that over 85% of patients were treated with an anthracycline-based multiagent chemotherapy regimen (Vose 2008). In published studies that have compared new treatment approaches to an established standard of care, CHOP administered every 3 weeks (CHOP-21) has been used as the control arm (Simon 2010). In addition, published guidelines recommend enrollment into clinical trial or CHOP as appropriate frontline treatment options for patients with a diagnosis of PTCL (NCCN 2013). Guidelines support administration of 6 cycles of CHOP therapy for patients with Stage I-II disease and International Prognostic Index (IPI) score of 0-2, and 6-8 cycles of CHOP therapy for Stage I-II patients with an IPI score of 3-5 and all Stage III-IV patients (Schmitz 2010; NCCN 2013). Comparison of non-randomized clinical trials does not support a difference in activity between 6 or 8 cycles of CHOP, with 6-8 cycles commonly employed in clinical practice (Coiffier 2002; Schmitz 2010). …show more content…
This mechanism of action results in a potential for broad spectrum cytotoxic activity against tumor cells and rapidly dividing nucleated cells. The improved antitumor effects of Pralatrexate are likely due to the more effective internalization by the 1-carbon reduced folate carrier (RFC-1), and the subsequent accumulation in tumor cells through the formation of polyglutamylated metabolites. 75,77 RFC-1 is a fetal oncoprotein that is predominantly expressed on fetal and malignant tissue, and is felt to be the principal means through which Pralatrexate, though not necessarily other anti-folates, enters the cell. This carrier protein has evolved to efficiently transport reduced natural folates into highly proliferative cells, in order to meet he demands for purine and pyrimidine nucleotides during deoxyribonucleic acid (DNA)