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

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01399372
• Other study ID #: RTOG 1114
• Secondary ID: CDR0000703682NCI
• Status: Completed
• Phase: Phase 2
• Start date: September 2011
• Est. completion date: May 20, 2022

Study information

• Verified date: May 2023
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 91
• Est. completion date: May 20, 2022
• Est. primary completion date: March 19, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chemotherapeutic Agent Toxicity
• Cognitive/Functional Effects
• Lymphoma
• Neurotoxicity
• Neurotoxicity Syndromes
• Radiation Toxicity

Intervention

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.
• Methotrexate
One 28-day cycle = 3.5 g/m^2 intravenously (standard hydration/leucovorin support) on day 2.
• Procarbazine
One 28-day cycle = 100 mg/m^2 orally on days 2-8.
• 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.

Locations

Country	Name	City	State
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Memorial Sloan Kettering Cancer Center at Basking Ridge	Basking Ridge	New Jersey
United States	The Kirklin Clinic at Acton Road	Birmingham	Alabama
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
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	University of Cincinnati	Cincinnati	Ohio
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Memorial Sloan Kettering Cancer Center Commack	Commack	New York
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Fresno Cancer Center	Fresno	California
United States	M D Anderson Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center CCOP Research Base	Houston	Texas
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	Loyola University Medical Center	Maywood	Illinois
United States	Community Memorial Hospital	Menomonee Falls	Wisconsin
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Columbia University Medical Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	American College of Radiology Imaging Network	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Arizona Oncology-Deer Valley Center	Phoenix	Arizona
United States	Saint Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	Maine Medical Center-Bramhall Campus	Portland	Maine
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	University of Rochester	Rochester	New York
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	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	Arizona Oncology Services Foundation	Scottsdale	Arizona
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	Moffitt Cancer Center	Tampa	Florida
United States	Cadence Cancer Center in Warrenville	Warrenville	Illinois
United States	Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	University Pointe	West Chester	Ohio
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Radiation Therapy Oncology Group	National Cancer Institute (NCI), NRG Oncology

Countries where clinical trial is conducted

United States,  Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.
Secondary	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.	From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.
Secondary	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.	After 4th cycle of chemotherapy, approximately 4 months after randomization.
Secondary	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.	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.
Secondary	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.	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.
Secondary	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.	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.