AzTrials
AzTrials

Chemotherapeutic Agent ToxicityPhase 2NCT01399372

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

A Phase 2 study testing Rituximab, Cytarabine and Methotrexate in people with Chemotherapeutic Agent Toxicity and Cognitive/Functional Effects, run by Radiation Therapy Oncology Group at 45 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Rituximab, Cytarabine and Methotrexate
Could I receive a placebo?
No, everyone receives an active treatment
How many people
91 participants
Where
45 sitesin 2 countries
Study dates
Sep 2011to 20 May 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • The patient must agree to submit tissue (i.e., the original H/E stained slides and immunohistochemistry studies) for central pathology review post-registration.
Show all 28Show fewer
  • 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.)
  • Age ≥ 18
  • History and physical examination within 6 weeks of registration
  • 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)
  • Patient must have documentation of negative HIV-1 testing within 6 weeks prior to study registration (Separate counseling and consent as per institutional guidelines)
  • 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.);
  • 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
  • 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.
  • Women of childbearing potential and male participants must agree to practice adequate contraception during therapy
  • Patient must provide study-specific informed consent prior to study registration
  • Patient must be able to swallow pills.

Who cannot join

  • 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)
  • 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
  • Prior cranial irradiation
  • 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;
Show all 12Show fewer
  • 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.
  • 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.
  • Prior allergic reaction to any of the study drugs involved in this protocol.

Trial locations and contacts

45 sites in 2 countries.

45 sites in 2 countries

United States44 sites

  • Saint Joseph Mercy Hospital

    Ann Arbor, Michigan, 48106-0995

  • University of Maryland/Greenebaum Cancer Center

    Baltimore, Maryland, 21201

  • Memorial Sloan Kettering Cancer Center at Basking Ridge

    Basking Ridge, New Jersey, 07920

  • University of Alabama at Birmingham Cancer Center

    Birmingham, Alabama, 35233

  • The Kirklin Clinic at Acton Road

    Birmingham, Alabama, 35243

  • Saint Alphonsus Cancer Care Center-Boise

    Boise, Idaho, 83706

  • Northwestern University

    Chicago, Illinois, 60611

  • Rush University Medical Center

    Chicago, Illinois, 60612

  • University of Cincinnati

    Cincinnati, Ohio, 45267

  • Case Western Reserve University

    Cleveland, Ohio, 44106

  • Cleveland Clinic Foundation

    Cleveland, Ohio, 44195

  • Penrose-Saint Francis Healthcare

    Colorado Springs, Colorado, 80907

  • Memorial Sloan Kettering Cancer Center Commack

    Commack, New York, 11725

  • Geisinger Medical Center

    Danville, Pennsylvania, 17822

  • Fresno Cancer Center

    Fresno, California, 93720

  • M D Anderson Cancer Center CCOP Research Base

    Houston, Texas, 77030

  • M D Anderson Cancer Center

    Houston, Texas, 77030

  • West Michigan Cancer Center

    Kalamazoo, Michigan, 49007

  • Nevada Cancer Research Foundation CCOP

    Las Vegas, Nevada, 89106

  • Dartmouth Hitchcock Medical Center

    Lebanon, New Hampshire, 03756

  • Loyola University Medical Center

    Maywood, Illinois, 60153

  • Community Memorial Hospital

    Menomonee Falls, Wisconsin, 53051

  • Froedtert and the Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • Columbia University Medical Center

    New York, New York, 10032

  • Memorial Sloan-Kettering Cancer Center

    New York, New York, 10065

  • American College of Radiology Imaging Network

    Philadelphia, Pennsylvania, 19103

  • Thomas Jefferson University Hospital

    Philadelphia, Pennsylvania, 19107

  • Saint Joseph's Hospital and Medical Center

    Phoenix, Arizona, 85013

  • Arizona Oncology-Deer Valley Center

    Phoenix, Arizona, 85027

  • Maine Medical Center-Bramhall Campus

    Portland, Maine, 04102

  • Kaiser Permanente-Rancho Cordova Cancer Center

    Rancho Cordova, California, 95670

  • University of Rochester

    Rochester, New York, 14642

  • Rohnert Park Cancer Center

    Rohnert Park, California, 94928

  • The Permanente Medical Group-Roseville Radiation Oncology

    Roseville, California, 95678

  • South Sacramento Cancer Center

    Sacramento, California, 95823

  • Kaiser Permanente Medical Center - Santa Clara

    Santa Clara, California, 95051

  • Maine Medical Center- Scarborough Campus

    Scarborough, Maine, 04074

  • Arizona Oncology Services Foundation

    Scottsdale, Arizona, 85260

  • Kaiser Permanente Cancer Treatment Center

    South San Francisco, California, 94080

  • Moffitt Cancer Center

    Tampa, Florida, 33612

  • Cadence Cancer Center in Warrenville

    Warrenville, Illinois, 60555

  • Waukesha Memorial Hospital

    Waukesha, Wisconsin, 53188

  • University Pointe

    West Chester, Ohio, 45069

  • Geisinger Wyoming Valley/Henry Cancer Center

    Wilkes-Barre, Pennsylvania, 18711

Other trials in United States

Israel1 site

  • Tel Aviv Sourasky Medical Center

    Tel Aviv, 64239

Other trials in Israel

About this study

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

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.

Read the 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.

Being tested
Rituximab, Cytarabine, Methotrexate, Procarbazine, Vincristine
Keywords
neurotoxicity, chemotherapeutic agent toxicity, radiation toxicity, cognitive/functional effects, primary central nervous system non-Hodgkin lymphoma
Medical subject headings
Lymphoma, Neurotoxicity Syndromes, Radiation Injuries

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RituximabBiological

    One 28-day cycle = 500 mg/m^2 intravenously on day 1 and day 5.

  • CytarabineDrug

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

  • MethotrexateDrug

    Also called MTX

    One 28-day cycle = 3.5 g/m^2 intravenously (standard hydration/leucovorin support) on day 2.

  • ProcarbazineDrug

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

  • VincristineDrug

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

  • low-dose whole-brain radiation therapyRadiation

    Also called WBRT

    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.

Study groups in NCT01399372
Study groupRoleWhat they receive
ChemotherapyActive comparatorRituximab, 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.
Receives: Biological: Rituximab; Drug: Cytarabine; Drug: Methotrexate; Drug: Procarbazine; Drug: Vincristine
Chemotherapy + Low-Dose WBRTExperimentalRituximab, 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.
Receives: Biological: Rituximab; Drug: Cytarabine; Drug: Methotrexate; Drug: Procarbazine; Drug: Vincristine; Radiation: low-dose whole-brain radiation therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free Survival

    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.

    Measured: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.

Secondary outcomes (5)

  1. Overall Survival

    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.

    Measured: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.

  2. Percentage of Participants Experiencing Partial Response or Complete Response

    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.

    Measured: After 4th cycle of chemotherapy, approximately 4 months after randomization.

  3. Global Heath Status (GHS) Score of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)

    Global Health Status is calculated from two questions on the EORTC QLQ-C30. The question responses range from 1 "very poor" to 7 "excellent" such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Data through five years after end of protocol treatment is included in the analysis, while summary data is provided only through three years due to very few participants after that timepoint.

    Measured: EORTC QLQ-C30 was administered at baseline, after cycle 4 of treatment (4 months), then every six months after end of treatment (7 months) for five years.

  4. Percentage of Participants With Neurocognitive Failure

    Neurocognitive failure is defined as cognitive failure on two or more of the following tests: Hopkins Verbal Learning Test - Revised (HVLT-R) Free Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Trail Making Test Part A, Trail Making Test Part B, and Controlled Oral Word Association. Cognitive failure for each test is defined as a change from baseline in raw score (post baseline score - baseline score) at or exceeding the minimally important difference reported in the literature [determined by the reliable change index (RCI) method] of -5, -3, -2,12, 26, and -12, respectively, indicating a worsening of neurocognitive function. Time to neurocognitive failure is defined as time from randomization to date of first failure, last known follow-up (censored), or death without failure (competing risk). Failure rates are estimated using the cumulative incidence method and the distributions of failure times are compared between the arms. Two-year estimates are provided here.

    Measured: Neurocognitive function tests were administered at baseline, after cycle 4 of treatment (4 months), then every six months after end of treatment (7 months) for five years. Two-year rates are provided here.

  5. Distribution of Participants by Highest Grade Adverse Event Related to Protocol Treatment

    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.

    Measured: 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.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jul 2011 (estimated)
  2. Study startSep 2011
  3. Primary completion19 Mar 2020
  4. Study completion20 May 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
91 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01399372
Sponsor's protocol ID
RTOG 1114
Other IDs
CDR0000703682, NCI-2011-02678
Status last verified
May 2023
First submitted
20 Jul 2011
Last updated
20 Jul 2023
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Rituximab, Cytarabine and Methotrexate in people with Chemotherapeutic Agent Toxicity and Cognitive/Functional Effects, run by Radiation Therapy Oncology Group at 45 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 28 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 45 sites in United States, Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 May 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free Survival (time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01399372.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Jul 2023.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in