Lymphoma
Conditions
Keywords
primary central nervous system non-Hodgkin lymphoma
Brief summary
RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and 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, leucovorin, vincristine, procarbazine, dexamethasone, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving rituximab together with combination chemotherapy may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving rituximab together with combination chemotherapy works in treating patients with primary central nervous system (CNS) lymphoma.
Detailed description
OBJECTIVES: Primary * Determine the complete response rate. Secondary * Determine the progression-free survival of these patients. * Determine the proportion of progression-free and overall survival in these patients. * Determine rituximab cerebrospinal fluid pharmacokinetics (only in patients requiring intrathecal chemotherapy). OUTLINE: This is a multicenter study. Patients receive rituximab IV 3 times weekly in weeks 1-4; high-dose methotrexate IV over 2 hours in weeks 1, 3, 5, and 9; oral or IV leucovorin calcium every 6 hours for 12 doses beginning 24 hours after the start of methotrexate in weeks 1, 3, 5, and 9; vincristine IV in weeks 1, 3, 5, 7, and 9; oral procarbazine hydrochloride daily on days 1-7 in weeks 1, 5, and 9; oral dexamethasone daily in weeks 1-6; and cytarabine IV over 2 hours twice weekly in weeks 11 and 14. Patients with positive cerebrospinal fluid also receive methotrexate intrathecally and oral leucovorin calcium every 12 hours for 8 doses beginning 24 hours after the start of methotrexate in weeks 2, 4, 6, 8, and 10. After completion of study treatment, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 43 patients will be accrued for this study.
Interventions
BIOLOGICALRituximab
Rituximab is administered intravenously. The initial rate is 50 mg/hr for the first hour. If no toxicity is seen, the rate may be escalated gradually in 50 mg/hour increments at 30-minute intervals to a maximum of 300 mg/hr. If the first dose is well tolerated, the initial rate for subsequent dose is 100 mg/hr, increased gradually in 100 mg/hr increments at 30-minute intervals, not to exceed 400 mg/hr.
DRUGCytarabine
3 g/m2/day in 500 cc D5W IV over 2 hrs. x 2 doses 24hrs. apart, Weeks 11, 14
DRUGDexamethasone
16mg (week 1) PO daily Weeks 1, 2, 3, 4, 5, 6 Taper by 4 mg/wk, weeks 2, 3, by 2 mg/wk week 4, 5, 6
DRUGLeucovorin
25 mg PO/IV every 6 hrs. x 12 doses, Weeks 1, 3, 5, 7, 9 For patients with meningeal involvement additionally 10 mg PO every 12 hrs. x 8 doses, Weeks 2, 4, 6, 8, 10
DRUGMethotrexate
3.5 g/m2In 500 cc D5W + 25 mEq NaHCO3 IV over 2 hours, Weeks 1, 3, 5, 7, 9 For patients with meningeal involvement additionally: 12 mg Intrathecally, in preservative-free sterile .9NS Weeks 2, 4, 6, 8, 10 Via Ommaya or lumbar puncture
DRUGProcarbazine
100 mg/m2 PO daily x 7 days Weeks 1, 5, 9
DRUGVincristine
1.4 mg/m2 IV push, Weeks 1, 3, 5, 7, 9 2m2 (2.8 mg) dose cap
Sponsors
Eastern Cooperative Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed non-Hodgkin's lymphoma by brain biopsy * Patients with inconclusive biopsy or patients who are not candidates for biopsy must have typical CT scan or MRI of the brain AND meet ≥ 1 of the following criteria: * Positive cerebrospinal fluid cytology for lymphoma OR a monoclonal lymphoid population as defined by cell surface markers or immunoglobulin gene rearrangement studies * Biopsy-proven involvement of the vitreous or uvea if cells are apparent in the posterior chamber or vitreous by ophthalmological examination * Bideminsionally measurable disease, defined as contrast-enhancing tumor ≥ 1 cm by pretreatment MRI/CT scan * Meningeal or vitreous involvement constitutes evaluable but not measurable disease * If an excisional, rather than a needle biopsy was done, measurable disease must be present on a postoperative scan (not a PET-CT scan) * ECOG performance status 0-3 * Absolute granulocyte count ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Bilirubin ≤ upper limit of normal (ULN) * SGOT ≤ 2.0 times ULN * Creatinine clearance ≥ 50 mL/min * Negative pregnancy test * Fertile patients must use effective contraception
Exclusion criteria
* Pregnant or nursing * HIV-1 positivity * Other malignancy within the past 5 years except basal cell skin cancer or any carcinoma in situ * Pre-existing immunodeficiency * Hepatitis B surface antigen positivity * Systemic lymphoma (as determined by pre-registration CT scans and physical examination) * Prior chemotherapy or radiotherapy for primary central nervous system lymphoma * Prior organ or bone marrow transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate - Locally Reviewed | For the primary endpoint, complete response will be based on disease status at three weeks post the end of therapy (week 17). | Assessed by the ECOG-ACRIN data manager based upon local review of images and data sent by the local sites. Treatment response was determined by calculating the sum of the maximal cross section in 2 separate axes using enhancing lesion(s) on CT or MRI imaging. The same imaging modality was to be used throughout assessment. Complete response was defined as the disappearance of all contrast enhancing tumor size on CT or MRI, patient was off all glucocorticoids, and resolution of all meningeal and vitreous involvement if present. Response must have lasted at least 4 weeks. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from ECOG-ACRIN member institutions starting 12/21/2006 and accrued its first patient on 08/23/2007. The study was suspended 2/24/2010 for interim analysis. After the interim analysis, it was determined that the goals of the study had been met and the study was closed on 4/12/2013.
Participants by arm
| Arm | Count |
|---|---|
| Rituximab + Standard Chemotherapy rituximab
cytarabine
dexamethasone
leucovorin calcium
methotrexate
procarbazine hydrochloride
vincristine sulfate | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 1 |
Baseline characteristics
| Characteristic | Rituximab + Standard Chemotherapy |
|---|---|
| Age, Customized Age Age < 60 years | 15 Participants |
| Age, Customized Age Age ≥ 60 years | 10 Participants |
| Cerebrovascular Disease Never | 21 Participants |
| Cerebrovascular Disease Symptomatic or on medication | 4 Participants |
| ECOG Performance Status 0 | 1 Participants |
| ECOG Performance Status 1 | 15 Participants |
| ECOG Performance Status 2 | 5 Participants |
| ECOG Performance Status 3 | 4 Participants |
| Neurologic Function Status Minor symptoms | 11 Participants |
| Neurologic Function Status Moderate symptoms/fully active | 5 Participants |
| Neurologic Function Status Moderate symptoms/less than fully active | 7 Participants |
| Neurologic Function Status No symptoms | 0 Participants |
| Neurologic Function Status Severe neurologic symptoms | 2 Participants |
| Other Medical Problems at Baseline Missing/unknown | 2 Participants |
| Other Medical Problems at Baseline Never | 9 Participants |
| Other Medical Problems at Baseline Past history of | 7 Participants |
| Other Medical Problems at Baseline Symptomatic or on medication | 7 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants |
| Race/Ethnicity, Customized Race White | 24 Participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 26 / 26 |
| serious Total, serious adverse events | 24 / 26 |
Outcome results
Primary
Complete Response Rate - Locally Reviewed
Assessed by the ECOG-ACRIN data manager based upon local review of images and data sent by the local sites. Treatment response was determined by calculating the sum of the maximal cross section in 2 separate axes using enhancing lesion(s) on CT or MRI imaging. The same imaging modality was to be used throughout assessment. Complete response was defined as the disappearance of all contrast enhancing tumor size on CT or MRI, patient was off all glucocorticoids, and resolution of all meningeal and vitreous involvement if present. Response must have lasted at least 4 weeks.
Time frame: For the primary endpoint, complete response will be based on disease status at three weeks post the end of therapy (week 17).
Population: Eligible, treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab + Standard Chemotherapy | Complete Response Rate - Locally Reviewed | 64 percentage of participants |