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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

Phase 2
18 Years
Open (Enrolling)
Chemotherapeutic Agent Toxicity, Cognitive/Functional Effects, Lymphoma, Neurotoxicity, Radiation Toxicity

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Trial Information

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



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


- 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

- 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.

Inclusion Criteria


- 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

- 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


- History and physical examination within 6 weeks of registration

- Karnofsky performance status (KPS) equal to 50% or higher, with the following

- 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

- 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


- No prior treatment with chemotherapy for CNS lymphoma

- Prior chemotherapy for a different cancer is allowable

- No prior cranial irradiation

- No concurrent intensity-modulated radiotherapy

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression free survival (PFS) defined as the interval from randomization to progression or death, whichever occurs first

Outcome Time Frame:

From randomization to date of progression, death or last follow-up. Analysis occurs after 67 events (deaths or progression) have been reported.

Safety Issue:


Principal Investigator

Antonio Omuro, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Federal Government

Study ID:

RTOG 1114



Start Date:

September 2011

Completion Date:

Related Keywords:

  • Chemotherapeutic Agent Toxicity
  • Cognitive/Functional Effects
  • Lymphoma
  • Neurotoxicity
  • Radiation Toxicity
  • neurotoxicity
  • chemotherapeutic agent toxicity
  • radiation toxicity
  • cognitive/functional effects
  • primary central nervous system non-Hodgkin lymphoma
  • Lymphoma
  • Neurotoxicity Syndromes
  • Radiation Injuries



Memorial Sloan-Kettering Cancer Center New York, New York  10021
Penrose Cancer Center at Penrose Hospital Colorado Springs, Colorado  80933
West Michigan Cancer Center Kalamazoo, Michigan  49007-3731
Case Comprehensive Cancer Center Cleveland, Ohio  44106-5065
Natalie Warren Bryant Cancer Center at St. Francis Hospital Tulsa, Oklahoma  74136
Medical College of Wisconsin Cancer Center Milwaukee, Wisconsin  53226
Kimmel Cancer Center at Thomas Jefferson University - Philadelphia Philadelphia, Pennsylvania  19107
Cleveland Clinic Taussig Cancer Center Cleveland, Ohio  44195
Maine Center for Cancer Medicine and Blood Disorders - Scarborough Scarborough, Maine  04074
James P. Wilmot Cancer Center at University of Rochester Medical Center Rochester, New York  14642
Baptist Cancer Institute - Jacksonville Jacksonville, Florida  32207
Greenebaum Cancer Center at University of Maryland Medical Center Baltimore, Maryland  21201
Robert H. Lurie Comprehensive Cancer Center at Northwestern University Chicago, Illinois  60611
Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center Boise, Idaho  83706
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida Tampa, Florida  33612
Arizona Oncology Services Foundation Phoenix, Arizona  85013
Integrated Community Oncology Network Jacksonville Beach, Florida  32250
Baptist Medical Center South Jascksonville, Florida  32258
Florida Cancer Center - Palatka Palatka, Florida  32177
Flagler Cancer Center Saint Augustine, Florida  32086
Integrated Community Oncology Network - Orange Park Orange Park, Florida  32073
Integrated Community Oncology Network at Southside Cancer Center Jacksonville, Florida  32207
Memorial Sloan-Kettering Cancer Center - Basking Ridge Basking Ridge, New Jersey  07920