Rituximab, Methotrexate, Vincristine Sulfate, Procarbazine Hydrochloride, and Cytarabine With or Without Radiation Therapy in Treating Patients With Primary Central Nervous System Lymphoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Radiation Therapy Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier:
NCT01399372
First received: July 20, 2011
Last updated: July 28, 2014
Last verified: July 2014

July 20, 2011
July 28, 2014
September 2011
December 2022   (final data collection date for primary outcome measure)
Progression free survival (PFS) defined as the interval from randomization to progression or death, whichever occurs first [ Time Frame: From randomization to date of progression, death or last follow-up. Analysis occurs after 67 events (deaths or progression) have been reported. ] [ Designated as safety issue: No ]
PFS defined as the interval from randomization to progression or death, whichever occurs first [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01399372 on ClinicalTrials.gov Archive Site
  • Overall survival (OS) defined as the interval from randomization to death due to any cause [ Time Frame: From randomization to date of death or last follow-up. Analysis occurs at the same time as the primary outcome analysis. ] [ Designated as safety issue: No ]
  • Response rate (partial response or complete response) [ Time Frame: Analysis occurs at the same time as the primary outcome analysis. ] [ Designated as safety issue: No ]
  • Quality of life measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core/Brain Cancer Module (QLQ-C30/BCM20) [ Time Frame: From start of treatment to five years. ] [ Designated as safety issue: No ]
  • Neurocognitive function measured by the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test Part A, Trail Making Test Part B, Controlled Oral Word Association Test (COWAT) [ Time Frame: From start of treatment to five years. ] [ Designated as safety issue: No ]
  • OS defined as the interval from randomization to death due to any cause [ Designated as safety issue: No ]
  • Response rate (partial response or complete response) [ Designated as safety issue: No ]
  • Chemotherapy-related toxicity as measured by CTCAE, v 4.0 [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Rituximab, Methotrexate, Vincristine Sulfate, Procarbazine Hydrochloride, and Cytarabine With or Without Radiation Therapy in Treating Patients With Primary Central Nervous System Lymphoma
Phase II Randomized Study of Rituximab, Methotrexate, Procarbazine, Vincristine, and Cytarabine With and Without Low-Dose Whole-Brain Radiotherapy for Primary Central Nervous System Lymphoma

RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as methotrexate, vincristine sulfate, procarbazine hydrochloride, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x rays to kill cancer cells. It is not yet know whether rituximab and combination chemotherapy are more effective when given with or without radiation therapy in treating patients with primary central nervous system lymphoma.

PURPOSE: This randomized phase II trial studies how well giving rituximab and combination chemotherapy with or without radiation therapy works in treating patients with primary central nervous system lymphoma.

OBJECTIVES:

Primary

  • To determine median progression-free survival (PFS) in both arms on an intent-to-treat basis.

Secondary

  • To determine overall survival (OS) defined as the interval from randomization to death due to any cause.
  • To determine treatment-related neurotoxicity rates and disease-related cognitive deterioration in each arm, through the following methods: prospective formal neuropsychological evaluation, utilizing competing-risk methodology to account for death as a competing risk to neurotoxicity or cognitive deterioration from relapsed tumor burden/salvage treatment and incidence of clinically defined neurotoxicity as per investigator's assessment.
  • To determine if there exists differences between the two treatment arms in terms of health-related quality-of-life and symptoms over time.
  • To determine response (partial response (PR) and complete response (CR)) rate after methotrexate-based chemotherapy and after consolidation whole-brain radiotherapy (WBRT).
  • To determine chemotherapy-related toxicity, measured by Common Toxicity Criteria for Adverse Effects (CTCAE), v.4.0.

OUTLINE: This is a multicenter study. Patients are stratified according to Memorial Sloan-Kettering Cancer Center recursive-partitioning analysis (RPA) classification for primary central nervous system lymphoma on age and Karnofsky performance status (KPS) (Class 1: age ≤ 50 years vs Class 2: age > 50 years and KPS ≥ 70% vs Class 3: age > 50 years and KPS < 70%). Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive rituximab IV over 5 hours or per institutional guidelines on days 1 and 15, methotrexate IV over 2 hours on days 2 and 16, vincristine sulfate IV on days 2 and 16 (courses 1 and 2 only), and procarbazine hydrochloride orally (PO) on days 2-8. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive consolidation therapy comprising cytarabine IV over 3 hours on days 1-2. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive rituximab, methotrexate, vincristine sulfate, and procarbazine hydrochloride as in arm I. After completing chemotherapy (2-5 weeks later), patients without progressive disease undergo low-dose whole-brain radiotherapy once daily, 5 days a week, for approximately 2.5 weeks (13 fractions total). Patients then receive consolidation cytarabine as in arm I.

Patients may undergo blood and buccal sample collection for future correlative studies. Paraffin-embedded tissue block of primary tumor or a core tumor tissue punched from the tissue block, and cerebrospinal fluid may also be collected.

Patients may also complete the Hopkins Verbal Learning Test-Revised (HVLT-R), the Trail Making Test Part A and Part B, the Controlled Oral Word Association Test (COWAT), and the Quality of Life (QOL) questionnaires at baseline and periodically during study.

After completion of study therapy, patients are followed up every 2 months for 2 years and then every 6 months for 3 years.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Chemotherapeutic Agent Toxicity
  • Cognitive/Functional Effects
  • Lymphoma
  • Neurotoxicity
  • Radiation Toxicity
  • Biological: rituximab
    Given IV
  • Drug: cytarabine
    Given IV
  • Drug: methotrexate
    Given IV
  • Drug: procarbazine hydrochloride
    Given PO
  • Drug: vincristine sulfate
    Given IV
  • Radiation: whole-brain radiation therapy
    Undergo radiotherapy
  • Active Comparator: Arm I
    Patients receive rituximab IV over 5 hours or per institutional guidelines on days 1 and 15, methotrexate IV over 2 hours on days 2 and 16, vincristine sulfate IV on days 2 and 16 (of courses 1 and 2 only), and procarbazine hydrochloride orally (PO) on days 2-8. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive consolidation therapy comprising cytarabine IV over 3 hours on days 1-2. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: rituximab
    • Drug: cytarabine
    • Drug: methotrexate
    • Drug: procarbazine hydrochloride
    • Drug: vincristine sulfate
  • Experimental: Arm II
    Patients receive rituximab, methotrexate, vincristine sulfate, and procarbazine hydrochloride as in arm I. After completing chemotherapy, patients without progressive disease undergo low-dose whole brain radiotherapy once daily, 5 days a week, for approximately 2.5 weeks (13 fractions total). Patients then receive consolidation cytarabine as in arm I.
    Interventions:
    • Biological: rituximab
    • Drug: cytarabine
    • Drug: methotrexate
    • Drug: procarbazine hydrochloride
    • Drug: vincristine sulfate
    • Radiation: whole-brain radiation therapy
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
89
Not Provided
December 2022   (final data collection date for primary outcome measure)

DISEASE CHARACTERISTICS:

  • B-cell non-Hodgkin lymphoma (NHL) involving the brain, as demonstrated by contrasted MRI and histologic confirmation by one of the following within 6 weeks prior to registration:

    • A positive cerebral spinal fluid (CSF) cytology for lymphoma or a monoclonal lymphocyte population as defined by cell surface markers
    • A biopsy of the vitreous or uvea demonstrating NHL
    • Brain biopsy
    • Patients in whom the type of lymphoma could not be determined or is unknown (e.g., not enough tissue for further analysis) are assumed to have a B-cell lymphoma and are eligible
  • Patient must agree to submit tissue (i.e., the original H/E-stained slides and immunohistochemistry studies) for central pathology review post-registration
  • No evidence of systemic NHL as demonstrated by a CT scan of the chest, abdomen, and pelvis within 6 weeks prior to registration

    • Bone marrow biopsy is not required for registration but must be obtained prior to start of treatment

PATIENT CHARACTERISTICS:

  • History and physical examination within 6 weeks of registration
  • Karnofsky performance status (KPS) equal to 50% or higher, with the following exception:

    • KPS 30% to 50% are eligible if the reason for the poor performance status is neurologic deficit from primary central nervous system (CNS) lymphoma

      • Patients with KPS 30% to 50% due to reasons other than primary CNS lymphoma are ineligible
      • Patients with KPS under 30% for any reason are ineligible
  • Absolute neutrophil count (ANC) ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Hemoglobin (Hgb) ≥ 8.0 g/dL (transfusion or other intervention to achieve Hgb ≥ 8.0 g/dL is acceptable)
  • Bilirubin < 2.0 mg/dL
  • Aspartate aminotransferase (AST) < 2.5 times upper limit of normal
  • Serum creatinine < 1.5 mg/dL
  • Calculated creatinine clearance (CrCl) > 50 cc/min (CrCl from a 24-hour urine collection may also be used)
  • Women of childbearing potential and male participants must agree to practice adequate contraception during therapy
  • Patient must be able to swallow pills
  • Patient must have documentation of negative HIV-1 testing within 6 weeks prior to study registration
  • No prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
  • No severe, active co-morbidity, defined as follows:

    • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
    • Transmural myocardial infarction within the last 6 months
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

      • Laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
    • Known pre-existing immunodeficiency as seen in organ transplant recipient
  • No prior allergic reaction to any of the study drugs involved in this protocol

PRIOR CONCURRENT THERAPY:

  • No prior treatment with chemotherapy or radiotherapy for lymphoma or chronic lymphocytic leukemia

    • Prior chemotherapy for a different cancer is allowable
  • No prior cranial irradiation
  • No concurrent intensity-modulated radiotherapy
Both
18 Years and older
No
United States,   Israel
 
NCT01399372
RTOG 1114, CDR0000703682, NCI-2011-02678
Yes
Radiation Therapy Oncology Group
Radiation Therapy Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Antonio Omuro, MD Memorial Sloan-Kettering Cancer Center
Radiation Therapy Oncology Group
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP