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

NCT ID: NCT01399372

Last Updated: 2023-07-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 91 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2022-05-20

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.

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.

Conditions

Chemotherapeutic Agent Toxicity; Cognitive/Functional Effects; Lymphoma; Neurotoxicity; Radiation Toxicity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Rituximab

Intervention Type: BIOLOGICAL

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

Cytarabine

Intervention Type: DRUG

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

Methotrexate

Intervention Type: DRUG

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

Procarbazine

Intervention Type: DRUG

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

Vincristine

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Rituximab

Intervention Type: BIOLOGICAL

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

Cytarabine

Intervention Type: DRUG

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

Methotrexate

Intervention Type: DRUG

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

Procarbazine

Intervention Type: DRUG

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

Vincristine

Intervention Type: DRUG

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 therapy

Intervention Type: RADIATION

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.

Interventions

Rituximab

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

Intervention Type: BIOLOGICAL

Cytarabine

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

Intervention Type: DRUG

Methotrexate

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

Intervention Type: DRUG

Procarbazine

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

Intervention Type: DRUG

Vincristine

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

Intervention Type: DRUG

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.

Intervention Type: RADIATION

Other Intervention Names

MTX; WBRT

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

NRG Oncology

OTHER

Sponsor Role: collaborator

Radiation Therapy Oncology Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Antonio Omuro, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, United States

The Kirklin Clinic at Acton Road

Birmingham, Alabama, United States

Saint Joseph's Hospital and Medical Center

Phoenix, Arizona, United States

Arizona Oncology-Deer Valley Center

Phoenix, Arizona, United States

Arizona Oncology Services Foundation

Scottsdale, Arizona, United States

Fresno Cancer Center

Fresno, California, United States

Kaiser Permanente-Rancho Cordova Cancer Center

Rancho Cordova, California, United States

Rohnert Park Cancer Center

Rohnert Park, California, United States

The Permanente Medical Group-Roseville Radiation Oncology

Roseville, California, United States

South Sacramento Cancer Center

Sacramento, California, United States

Kaiser Permanente Medical Center - Santa Clara

Santa Clara, California, United States

Kaiser Permanente Cancer Treatment Center

South San Francisco, California, United States

Penrose-Saint Francis Healthcare

Colorado Springs, Colorado, United States

Moffitt Cancer Center

Tampa, Florida, United States

Saint Alphonsus Cancer Care Center-Boise

Boise, Idaho, United States

Northwestern University

Chicago, Illinois, United States

Rush University Medical Center

Chicago, Illinois, United States

Loyola University Medical Center

Maywood, Illinois, United States

Cadence Cancer Center in Warrenville

Warrenville, Illinois, United States

Maine Medical Center-Bramhall Campus

Portland, Maine, United States

Maine Medical Center- Scarborough Campus

Scarborough, Maine, United States

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, United States

Saint Joseph Mercy Hospital

Ann Arbor, Michigan, United States

West Michigan Cancer Center

Kalamazoo, Michigan, United States

Nevada Cancer Research Foundation CCOP

Las Vegas, Nevada, United States

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, United States

Memorial Sloan Kettering Cancer Center at Basking Ridge

Basking Ridge, New Jersey, United States

Memorial Sloan Kettering Cancer Center Commack

Commack, New York, United States

Columbia University Medical Center

New York, New York, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

University of Rochester

Rochester, New York, United States

University of Cincinnati

Cincinnati, Ohio, United States

Case Western Reserve University

Cleveland, Ohio, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

University Pointe

West Chester, Ohio, United States

Geisinger Medical Center

Danville, Pennsylvania, United States

American College of Radiology Imaging Network

Philadelphia, Pennsylvania, United States

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, United States

Geisinger Wyoming Valley/Henry Cancer Center

Wilkes-Barre, Pennsylvania, United States

M D Anderson Cancer Center CCOP Research Base

Houston, Texas, United States

M D Anderson Cancer Center

Houston, Texas, United States

Community Memorial Hospital

Menomonee Falls, Wisconsin, United States

Froedtert and the Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Waukesha Memorial Hospital

Waukesha, Wisconsin, United States

Tel Aviv Sourasky Medical Center

Tel Aviv, , Israel

Countries

United States; Israel

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

CDR0000703682

Identifier Type: -

Identifier Source: secondary_id

NCI-2011-02678

Identifier Type: REGISTRY

Identifier Source: secondary_id

RTOG 1114

Identifier Type: -

Identifier Source: org_study_id