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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01399372
Recruitment Status : Completed
First Posted : July 21, 2011
Results First Posted : May 13, 2021
Last Update Posted : June 21, 2022
Sponsor:
Collaborators:
National Cancer Institute (NCI)
NRG Oncology
Information provided by (Responsible Party):
Radiation Therapy Oncology Group

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Chemotherapeutic Agent Toxicity Cognitive/Functional Effects Lymphoma Neurotoxicity Radiation Toxicity Biological: Rituximab Drug: Cytarabine Drug: Methotrexate Drug: Procarbazine Drug: Vincristine Radiation: low-dose whole-brain radiation therapy Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 91 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : September 2011
Actual Primary Completion Date : March 19, 2020
Actual Study Completion Date : May 20, 2022


Arm Intervention/treatment
Active Comparator: Chemotherapy
Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 3-5 weeks later by two 28-day cycles of cytarabine.
Biological: Rituximab
One 28-day cycle = 500 mg/m^2 intravenously on day 1 and day 5.

Drug: Cytarabine
One 28-day cycle = 3 g/m^2 intravenously on day 1 and day 2.

Drug: Methotrexate
One 28-day cycle = 3.5 g/m^2 intravenously (standard hydration/leucovorin support) on day 2.
Other Name: MTX

Drug: Procarbazine
One 28-day cycle = 100 mg/m^2 orally on days 2-8.

Drug: Vincristine
One 28-day cycle = 1.4 mg/m^2 intravenously, dose capped at 2.4mg, on day 2 and day 16.

Experimental: Chemotherapy + Low-Dose WBRT
Rituximab, methotrexate, procarbazine for four 28-day cycles with vincristine for the first two cycles, followed 2-5 weeks later by 3 weeks of low-dose whole-brain radiotherapy (WBRT), followed 3-5 weeks later by two 28-day cycles of cytarabine.
Biological: Rituximab
One 28-day cycle = 500 mg/m^2 intravenously on day 1 and day 5.

Drug: Cytarabine
One 28-day cycle = 3 g/m^2 intravenously on day 1 and day 2.

Drug: Methotrexate
One 28-day cycle = 3.5 g/m^2 intravenously (standard hydration/leucovorin support) on day 2.
Other Name: MTX

Drug: Procarbazine
One 28-day cycle = 100 mg/m^2 orally on days 2-8.

Drug: Vincristine
One 28-day cycle = 1.4 mg/m^2 intravenously, dose capped at 2.4mg, on day 2 and day 16.

Radiation: low-dose whole-brain radiation therapy
Total dose of 2340 cGy administered as 13 daily fractions of 180 cGy over 3 weeks. Participants with progressive disease on magnetic resonance imaging (MRI) do not receive WBRT.
Other Name: WBRT




Primary Outcome Measures :
  1. Progression-free Survival [ Time Frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years. ]
    Progression is defined as any of the following: more than 25% increase in the contrast-enhancing lesion seen on magnetic resonance imaging (MRI) compared with baseline or best response; new site of disease (central nervous system or systemic); recurrent or new ocular disease; recurrent or positive cerebrospinal fluid (CSF) cytology. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method.


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years. ]
    Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.

  2. Percentage of Participants Experiencing Partial Response or Complete Response [ Time Frame: After 4th cycle of chemotherapy, approximately 4 months after randomization. ]
    Response was evaluated using the international criteria proposed by the International Primary Central Nervous System Lymphoma (PCNSL) Study Group criteria. Complete Response was defined as no contrast brain enhancement on magnetic resonance imaging (MRI), no corticosteroid use for at least 2 weeks, a normal eye exam, and negative CSF cytology. Partial response was defined as at least 50% decrease in enhancing tumor on MRI compared with baseline imaging, no or minor retinal pigment epithelium (RPE) abnormality, and negative CSF cytology.

  3. 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. ]
  4. 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. ]
  5. Distribution of Participants by Highest Grade Adverse Event Related to Protocol Treatment [ Time Frame: At the end of each chemotherapy 28-day cycle, then every 2 months for two years starting 4 weeks after treatment, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 7.3 years. ]
    Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. Adverse events reported as definitely, probably, or possibly related to protocol treatment are considered to be related to treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. B-cell non-Hodgkin's lymphoma(NHL) involving the brain, as demonstrated by contrast-enhanced Magnetic resonance imaging (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 non-Hodgkin's lymphoma
    • Brain biopsy

    Note: Patients in whom the type of lymphoma could not be determined or is unknown (eg, not enough tissue for further analysis) are assumed to have a B cell lymphoma and are eligible.

  2. The patient must agree to submit tissue (i.e., the original H/E stained slides and immunohistochemistry studies) for central pathology review post-registration.
  3. No evidence of systemic non-Hodgkin lymphoma as demonstrated by a computed tomography (CT) scan of the chest, abdomen and pelvis within 6 weeks prior to registration (Note: Bone marrow biopsy is not required for registration but must be obtained prior to start of treatment.)
  4. Age ≥ 18
  5. History and physical examination within 6 weeks of registration
  6. Karnofsky performance status (KPS) equal to 50 or higher, with the following exception

    • Patients with 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)

  7. Patient must have documentation of negative HIV-1 testing within 6 weeks prior to study registration (Separate counseling and consent as per institutional guidelines)
  8. Complete blood count (CBC)/differential obtained within 2 weeks prior to study registration, with adequate bone marrow function defined as follows:

    • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;
    • Platelets ≥ 100,000 cells/mm3;
    • Hemoglobin (Hgb) ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.);
  9. Adequate liver function within 2 weeks prior to study registration, defined as follows:

    • Bilirubin < 2.0 mg/dl
    • Aspartate aminotransferase (AST) <2.5 times upper limit of normal
  10. Adequate renal function within 2 weeks prior to study registration, defined as follows

    • Serum creatinine < 1.5 mg/dl
    • Calculated creatinine clearance (CrCl) > 50cc/min/1.73m2, using the Cockcroft-Gault equation, as follows:

    Male: CrCl (ml/min) = (140-age) X (Actual weight in kg) / 72 x serum Creatinine (mg/dl).

    Female: CrCl (ml/min) = (140-age) X (Actual weight in kg) X 0.85 / 72 x serum Creatinine (mg/dl).

    Note: A measured CrCl from a 24 hour urine collection may also be used.

  11. Women of childbearing potential and male participants must agree to practice adequate contraception during therapy
  12. Patient must provide study-specific informed consent prior to study registration
  13. Patient must be able to swallow pills.

Exclusion Criteria:

  1. 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)
  2. Prior treatment with chemotherapy or radiotherapy for lymphoma or chronic lymphocytic leukemia; note that prior chemotherapy for a different cancer is allowable; see section 1
  3. Prior cranial irradiation
  4. 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; note, however, that 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.
  5. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
  6. Prior allergic reaction to any of the study drugs involved in this protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01399372


Locations
Show Show 45 study locations
Sponsors and Collaborators
Radiation Therapy Oncology Group
National Cancer Institute (NCI)
NRG Oncology
Investigators
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Principal Investigator: Antonio Omuro, MD Yale University
  Study Documents (Full-Text)

Documents provided by Radiation Therapy Oncology Group:
Informed Consent Form  [PDF] September 19, 2019

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Responsible Party: Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier: NCT01399372    
Other Study ID Numbers: RTOG 1114
CDR0000703682
NCI-2011-02678 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: July 21, 2011    Key Record Dates
Results First Posted: May 13, 2021
Last Update Posted: June 21, 2022
Last Verified: May 2022
Keywords provided by Radiation Therapy Oncology Group:
neurotoxicity
chemotherapeutic agent toxicity
radiation toxicity
cognitive/functional effects
primary central nervous system non-Hodgkin lymphoma
Additional relevant MeSH terms:
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Lymphoma
Neurotoxicity Syndromes
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Nervous System Diseases
Poisoning
Chemically-Induced Disorders
Cytarabine
Rituximab
Methotrexate
Vincristine
Procarbazine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists