Clinical trial NCT00052442: 10-Propargyl-10-Deazaaminopterin in Treating Patients With Recurrent or Refractory Non-Hodgkin's Lymphoma or Hodgkin's Lymphoma
Official title: A Phase II Study of 10-Propargyl-10-Deazaaminopterin (PDX) in Relapsed or Refractory Aggressive Non-Hodgkin's Lymphomas and Hodgkin's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Lymphoma
Keywords: 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
Lead sponsor: Spectrum Pharmaceuticals, Inc
Sponsor class: INDUSTRY
Collaborators: name: National Cancer Institute (NCI)
name: Memorial Sloan Kettering Cancer Center
First posted: 2003-01-27
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Response Rate
timeFrame: 3 weeks
Secondary outcomes:
measure: Toxicities of Pralatrexate
timeFrame: 3 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Owen A. O'Connor, MD, PhD
role: STUDY_CHAIR
References:
citation: O'Connor OA, Horwitz S, Hamlin P, Portlock C, Moskowitz CH, Sarasohn D, Neylon E, Mastrella J, Hamelers R, Macgregor-Cortelli B, Patterson M, Seshan VE, Sirotnak F, Fleisher M, Mould DR, Saunders M, Zelenetz AD. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol. 2009 Sep 10;27(26):4357-64. doi: 10.1200/JCO.2008.20.8470. Epub 2009 Aug 3.