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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Drug: pralatrexate

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.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 135 mg/m^2 Pralatrexate 1/2 weeks; 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; Other Names: Folotyn; 10-Propargyl-10-Deazaaminopterin (PDX)
EXPERIMENTAL: 30 mg/m^2 Pralatrexate 3/4 weeks; 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; Other Names: Folotyn; 10-Propargyl-10-Deazaaminopterin (PDX)
EXPERIMENTAL: 30 mg/m^2 Pralatrexate 6/7 weeks; 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; Other Names: Folotyn; 10-Propargyl-10-Deazaaminopterin (PDX)
EXPERIMENTAL: 45 mg/m^2 Pralatrexate 6/7 weeks; 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; Other Names: Folotyn; 10-Propargyl-10-Deazaaminopterin (PDX)
EXPERIMENTAL: 270 mg/m^2 Pralatrexate 2/4 weeks; 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; Other Names: Folotyn; 10-Propargyl-10-Deazaaminopterin (PDX)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Spectrum Pharmaceuticals, Inc
• Collaborators: National Cancer Institute (NCI); Memorial Sloan Kettering Cancer Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2002
• Primary Completion (ACTUAL): March 1, 2009
• Study Completion (ACTUAL): March 1, 2009

Study Registration Dates

• First Submitted: January 24, 2003
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (ESTIMATE): January 27, 2003

Study Record Updates

• Last Update Posted (ACTUAL): August 25, 2021
• Last Update Submitted That Met QC Criteria: August 20, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: recurrent grade 3 follicular lymphoma; recurrent adult diffuse large cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult Burkitt lymphoma; recurrent adult Hodgkin lymphoma; recurrent adult diffuse mixed cell lymphoma; recurrent adult lymphoblastic lymphoma; recurrent mantle cell lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; 10-deazaaminopterin
• Other Study ID Numbers: CDR0000258425; MSKCC-02078; NCI-H02-0100