Clinical trial NCT01399372: Rituximab, Methotrexate, Vincristine Sulfate, Procarbazine Hydrochloride, and Cytarabine With or Without Radiation Therapy in Treating Patients With Primary Central Nervous System Lymphoma
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chemotherapeutic Agent Toxicity
Cognitive/Functional Effects
Lymphoma
Neurotoxicity
Radiation Toxicity
Keywords: neurotoxicity
chemotherapeutic agent toxicity
radiation toxicity
cognitive/functional effects
primary central nervous system non-Hodgkin lymphoma
Lead sponsor: Radiation Therapy Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: NRG Oncology
First posted: 2011-07-21
Enrollment: 91
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Progression-free Survival
timeFrame: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.
Secondary outcomes:
measure: Overall Survival
timeFrame: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.
measure: Percentage of Participants Experiencing Partial Response or Complete Response
timeFrame: After 4th cycle of chemotherapy, approximately 4 months after randomization.
measure: Global Heath Status (GHS) Score of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
timeFrame: 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.
measure: Percentage of Participants With Neurocognitive Failure
timeFrame: 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.
measure: Distribution of Participants by Highest Grade Adverse Event Related to Protocol Treatment
timeFrame: 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.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Birmingham
country: United States
facility: The Kirklin Clinic at Acton Road
state: Alabama
city: Phoenix
country: United States
facility: Saint Joseph's Hospital and Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Arizona Oncology-Deer Valley Center
state: Arizona
city: Scottsdale
country: United States
facility: Arizona Oncology Services Foundation
state: Arizona
city: Fresno
country: United States
facility: Fresno Cancer Center
state: California
city: Rancho Cordova
country: United States
facility: Kaiser Permanente-Rancho Cordova Cancer Center
state: California
city: Rohnert Park
country: United States
facility: Rohnert Park Cancer Center
state: California
city: Roseville
country: United States
facility: The Permanente Medical Group-Roseville Radiation Oncology
state: California
city: Sacramento
country: United States
facility: South Sacramento Cancer Center
state: California
city: Santa Clara
country: United States
facility: Kaiser Permanente Medical Center - Santa Clara
state: California
city: South San Francisco
country: United States
facility: Kaiser Permanente Cancer Treatment Center
state: California
city: Colorado Springs
country: United States
facility: Penrose-Saint Francis Healthcare
state: Colorado
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Warrenville
country: United States
facility: Cadence Cancer Center in Warrenville
state: Illinois
city: Portland
country: United States
facility: Maine Medical Center-Bramhall Campus
state: Maine
city: Scarborough
country: United States
facility: Maine Medical Center- Scarborough Campus
state: Maine
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Las Vegas
country: United States
facility: Nevada Cancer Research Foundation CCOP
state: Nevada
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Cancer Center at Basking Ridge
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Cancer Center Commack
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: West Chester
country: United States
facility: University Pointe
state: Ohio
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: American College of Radiology Imaging Network
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Geisinger Wyoming Valley/Henry Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: M D Anderson Cancer Center CCOP Research Base
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Menomonee Falls
country: United States
facility: Community Memorial Hospital
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert and the Medical College of Wisconsin
state: Wisconsin
city: Waukesha
country: United States
facility: Waukesha Memorial Hospital
state: Wisconsin
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
Study officials:
affiliation: Yale University
name: Antonio Omuro, MD
role: PRINCIPAL_INVESTIGATOR
References: