10-Propargyl-10-Deazaaminopterin in Treating Patients With Recurrent or Refractory Non-Hodgkin's Lymphoma or Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. PURPOSE: Phase II trial to study the effectiveness of 10-propargyl-10-deazaaminopterin in treating patients who have recurrent or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Determine the efficacy of 10-propargyl-10-deazaaminopterin, in terms of objective response rate, duration of response, and time to disease progression, in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma or Hodgkin's lymphoma. Determine the impact of pharmacokinetics on toxicity and drug elimination in patients treated with this drug. Determine the toxicity of this drug in these patients. Determine the effect of prior chemotherapy response duration on duration of response in patients treated with this drug. Correlate, if possible, the pharmacodynamics (area under the curve) of this drug with tumor response and toxicity (mucositis) in these patients. Correlate, if possible, intraerythrocytic folate or homocysteine levels with severity of mucositis in patients treated with this drug. Determine whether levels of the RFC-1 folate transporter, folylpolyglutamate synthetase, and folylpolyglutamate hydrolase are markers of response in patients treated with this drug. OUTLINE: This is an open-label study. Patients receive 10-propargyl-10-deazaaminopterin IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients achieving a complete response (CR) may receive 2 additional courses beyond the CR. PROJECTED ACCRUAL: A total of 39-72 patients (12-35 for cohort 1 and 17-37 for cohort 2) will be accrued for this study within 10-36 months.

Official Title
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A Phase II Study of 10-Propargyl-10-Deazaaminopterin (PDX) in Relapsed or Refractory Aggressive Non-Hodgkin's Lymphomas and Hodgkin's Disease

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: pralatrexate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed Hodgkin's lymphoma or, using the World Health Organization (WHO) classification, aggressive non-Hodgkin's lymphoma including: Large B- or T-cell lymphomas (including transformed lymphomas) Mantle cell lymphoma Immunoblastic lymphoma At least 1 unidimensionally measurable lesion At least 2 centimeter (cm) by conventional techniques OR At least 1 cm by spiral computerized tomography (CT) scan Lymph nodes no greater than 1 cm in the short axis are considered normal Relapsed or refractory disease after first-line chemotherapy Cohort 1: No more than 3 prior conventional cytotoxic chemotherapy regimens Must have had at least a partial response (PR) lasting no more than 6 months or refractory disease Patients with disease refractory to or relapsed less than 100 days from peripheral blood stem cell (PBSC) transplantation are not eligible Cohort 2: No limit on prior treatment Must have had at least a PR to the last therapy lasting at least 6 months Patients who have received high-dose chemotherapy as part of peripheral blood stem cells (PBSC) transplantation are eligible if relapse occurred at least 100 days after transplantation No clinically significant pleural effusions or ascites No active brain or leptomeningeal metastases Treated Central nervous system (CNS) disease allowed PATIENT CHARACTERISTICS: Age 18 and over Performance status Karnofsky 70-100% Life expectancy Not specified Hematopoietic Absolute neutrophil count greater than 1,000/mm^3 Platelet count greater than 75,000/mm^3 Hemoglobin at least 10 g/dL Hepatic Bilirubin less than 1.5 times upper limit of normal (ULN) Aspartate aminotransferase/alanine aminotransferase (AST/ALT) no greater than 2.5 times ULN (4 times ULN if liver involvement) Alkaline phosphatase no greater than 5 times ULN Renal Creatinine no greater than 1.5 mg/dL OR Creatinine clearance at least 50 mL/min Cardiovascular No symptomatic congestive heart failure No New York Heart Association class III or IV heart disease No unstable angina pectoris No cardiac arrhythmia No myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months No history of orthostatic hypotension No ECG evidence of acute ischemia or significant conduction abnormality (e.g., bifascicular block or 2nd or 3rd degree atrioventricular blocks) No uncontrolled hypertension requiring active manipulation of antihypertensive medications No grade III or IV edema Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No ongoing or active infection Febrile episodes up to 38.5° Celsius without signs of active infection allowed No other concurrent active cancer No other concurrent serious medical illness No psychiatric illness or social situation that would preclude study compliance PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics At least 3 months since prior monoclonal antibody therapy (e.g., rituximab) Chemotherapy See Disease Characterisitics At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for mitomycin or nitrosoureas) and recovered Endocrine therapy At least 7 days since prior steroids No concurrent steroids Radiotherapy See Disease Characteristics At least 4 weeks since prior radiotherapy and recovered Surgery More than 4 weeks since prior major surgery Other No prior antifolates No concurrent folic acid supplementation No other concurrent investigational agents No concurrent combination antiretroviral therapy for human immunodeficiency virus (HIV)-positive patients No other concurrent investigational or commercial agents or therapies with the intent to treat the malignancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 135 mg/m^2 Pralatrexate 1/2 weeks<br>Pralatrexate (PDX) 135 mg/m^2 administered as an intravenous (IV) infusion over one hour into a side arm of a running intravenous infusion of normal saline for 1/2 weeks. | Drug: pralatrexate<br> <br> * Other names: 10-Propargyl-10-Deazaaminopterin (PDX);|
| Experimental: 30 mg/m^2 Pralatrexate 3/4 weeks<br>PDX 30 mg/m^2 administered as an IV infusion over 15 minutes into a side arm of a running intravenous infusion of normal saline for 3/4 weeks. | Drug: pralatrexate<br> <br> * Other names: 10-Propargyl-10-Deazaaminopterin (PDX);|
| Experimental: 30 mg/m^2 Pralatrexate 6/7 weeks<br>PDX 30 mg/m^2 administered as an IV infusion over 15 minutes into a side arm of a running intravenous infusion of normal saline for 6/7 weeks. | Drug: pralatrexate<br> <br> * Other names: 10-Propargyl-10-Deazaaminopterin (PDX);|
| Experimental: 45 mg/m^2 Pralatrexate 6/7 weeks<br>PDX 45 mg/m^2 administered as an IV infusion over 15 minutes into a side arm of a running intravenous infusion of normal saline for 6/7 weeks. | Drug: pralatrexate<br> <br> * Other names: 10-Propargyl-10-Deazaaminopterin (PDX);|
| Experimental: 270 mg/m^2 Pralatrexate 2/4 weeks<br>PDX (270 mg/m^2) administered as an IV bolus over 3-5 minutes into a side arm of a running intravenous infusion of normal saline for 2/4 weeks. | Drug: pralatrexate<br> <br> * Other names: 10-Propargyl-10-Deazaaminopterin (PDX);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Per Response Evaluation Criteria in T-cell and B-cell Lymphoma for target lesions and assessed using computerized tomography (CT) and or Positron emission tomography CT (PET CT) by local investigators: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=50% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities of Pralatrexate | Adverse events; number of patients with at least one adverse events reported. | 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult Burkitt lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent mantle cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent grade 3 follicular lymphoma