Study of Pralatrexate to Treat Participants With Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether pralatrexate, given with vitamin B12 and folic acid, is effective in the treatment of relapsed or refractory B-cell Non-Hodgkin's lymphoma (NHL). The study will also investigate the safety of pralatrexate with vitamin B12 and folic acid in this participant population. Additionally, this study includes the collection of blood samples to investigate the pharmacokinetics (PK) of pralatrexate in this participant population (PK is the activity of a drug in the body over a period of time, including how the drug is absorbed, distributed in the body, localized in the tissues, and excreted from the body).

Official Title
-----------------
A Phase 2, Single-arm, Open-label, Multi-center Study of Pralatrexate in Patients With Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma

Conditions
-----------------
Lymphoma, B-Cell

Intervention / Treatment
-----------------
* Drug: Pralatrexate
* Dietary Supplement: Vitamin B12
* Dietary Supplement: Folic Acid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically/cytologically confirmed, measurable (lesion or node =2 cm by CT [at least 1 cm if by spiral CT]) B-cell Non-Hodgkin's Lymphoma, using the Revised European American Lymphoma (REAL) World Health Organization (WHO) disease classification Progressive or persistent disease after ≥ 1 prior treatment(s) Recovered from toxic effects of prior treatment At least 4 weeks since most recent cytotoxic therapy Easter Cooperative Oncology Group (ECOG) performance status ≤ 2 Adequate blood, liver, and kidney functions as defined by laboratory levels 1.0 mg/day orally of folic acid for at least 7 days prior & 1 mg intramuscular of vitamin B12 within 10 weeks of the planned start of pralatrexate Females of childbearing potential must agree to use medically acceptable birth control from start of pralatrexate until at least 30 days after the last administration of pralatrexate and must have a negative serum pregnancy test within 14 days prior to the first day of study treatment Males who are not surgically sterile must agree to use medically acceptable birth control from start of pralatrexate until at least 90 days after the last administration of pralatrexate Available for repeat dosing and follow-up Able to give written informed consent Exclusion Criteria: Relapsed participants with diffuse large B-cell lymphoma (DLBCL) who are candidates for high-dose therapy and autologous stem cell transplantation (SCT) and for whom high-dose therapy and autologous SCT is a standard curative option Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix). If there is a history of prior malignancies other than those exceptions listed above, the participant must be disease-free for ≥ 5 years. Participants with other prior malignancies < 5 years before study entry may still be enrolled if they have received treatment resulting in complete resolution of the cancer and currently have no clinical, radiologic, or laboratory evidence of active or recurrent disease Congestive heart failure Class III/IV according to the New York Heart Association Functional Classification Uncontrolled hypertension Known human immunodeficiency virus (HIV)-positive diagnosis Symptomatic central nervous system (CNS) metastases or lesions for which treatment is required. Participants who received prophylactic CNS treatment are eligible. Participants who have undergone an allogeneic SCT Participants who have relapsed < 100 days from the time of an autologous SCT Participants with disease refractory to peripheral blood SCT or who have relapsed < 100 days from the time of transplant Active uncontrolled infection, underlying medical condition, or other serious illness that would impair the ability of the participant to receive protocol treatment. Major surgery within 14 days of enrollment Receipt of any conventional chemotherapy or radiation therapy (encompassing a substantial [> 10%] amount of bone marrow) within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study treatment or planned use during the course of the study Receipt of systemic corticosteroids within 1 week of study treatment, unless participant has been taking a continuous dose of no more than 10 mg/day of prednisone or its equivalent for at least 1 month Use of any investigational drugs, biologics, or devices within 4 weeks prior to study treatment or planned use during the course of the study Previous exposure to pralatrexate Females who are pregnant or breastfeeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pralatrexate<br>Participants received pralatrexate at an initial dose of 30 mg/m^2, as IV push over 30 seconds to 5 minutes via a patent free-flowing IV line containing normal saline on Days 1, 8 and 15 of a 4-week cycle (weekly for 3 weeks with 1 week of rest) until criteria for discontinuation per protocol were met. The initial dose of 30 mg/m^2 may be reduced to 20 mg/m^2 weekly, permitted per protocol defined criteria. If pralatrexate 20 mg/m^2/week was not tolerated, pralatrexate had to be discontinued. Dose re-escalation was not allowed once dose reduction was done. Participants had dietary supplement of vitamin B12 and folic acid along with pralatrexate. Vitamin B12, given as 1mg IM, within 10 weeks of start of pralatrexate dosing, every 8-10 weeks throughout the study and for at least 30 days post last dose of pralatrexate. Folic acid was given 1mg daily, orally, for at least 7 days prior to start of pralatrexate, throughout the study and for at least 30 days post last dose of pralatrexate. | Drug: Pralatrexate<br>* Pralatrexate injection administered as intravenous (IV) push<br>* Other names: (RS)-10-propargyl-10-deazaaminopterin;Dietary Supplement: Vitamin B12<br>* 1 mg intramuscular (IM) injection<br>* Other names: Cyanocobalamin;Dietary Supplement: Folic Acid<br>* Oral 1 mg tablet<br>* Other names: Folacin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective response rate was defined as the percentage of participants with a complete response (CR) or a partial response (PR). Tumor response was evaluated on the basis of clinical and radiological criteria, assessed according to International Workshop Criteria (IWC) with or without positron emission tomography (PET) scans. Per IWC criteria CR is defined as complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities definitely assignable to non-Hodgkin's lymphoma (NHL) and PR is defined as >= 50% decrease in sum of the product of the perpendicular diameters (SPD) of the six largest dominant nodes or nodal masses and no increase in size of other nodes, liver or spleen. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | The Duration of Response was defined as the time (in months) from the date the measurement criteria were first met for CR or PR (whichever status was recorded first) until the first subsequent date that relapse or progression was documented. It was assessed according to IWC with or without PET, subject to its availability. Per IWC, progression was defined as a ≥50% increase from the nadir in the individual sum of the products of the diameters of any index lesion; the reappearance of pathology, enlargement of liver/spleen, or unequivocal progression of non-measurable disease or appearance of any new lesions. | Up to 24 months | 
| Progression Free Survival (PFS) | Progression-free survival (PFS) was the duration of time (in months) from first administration of study treatment to date of first documented progression or death from any cause. It was based on tumor assessments made according to the IWC with or without PET scans, subject to their availability. Per IWC, progression was defined as a ≥50% increase from the nadir in the individual sum of the products of the diameters of any index lesion; the reappearance of pathology, enlargement of liver/spleen, or unequivocal progression of non-measurable disease or appearance of any new lesions. | Up to 24 months | 
| Overall Survival (OS) | Overall Survival was the time (in months) from first administration of study treatment until the date of death. | Up to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Relapsed, Refractory, Non-Hodgkin's