Lymphoma
Conditions
Keywords
primary central nervous system non-Hodgkin lymphoma
Brief summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving rituximab with combination chemotherapy may kill more cancer cells. PURPOSE: This phase II trial is studying how well rituximab given with combination chemotherapy works in treating patients with newly diagnosed primary CNS lymphoma.
Detailed description
OBJECTIVES: Primary * Determine the complete response rate after remission induction therapy with the combination of high-dose methotrexate (HDMTX), temozolomide, and rituximab at 4 months. Secondary * Determine the safety and feasibility of consolidation therapy comprising cytarabine and etoposide administered after induction therapy in these patients. * Determine the percentage of patients who achieve durable (complete and partial) remission when treated with this regimen. * Determine relapse-free survival after complete response in patients treated with this regimen. * Correlate molecular markers with outcome in patients treated with this regimen. * Determine the effects of this regimen on neurological function in these patients. OUTLINE: This is a multicenter study. * Induction Chemotherapy: All induction therapy courses repeat every 28 days. * Courses 1-3: Patients receive high-dose methotrexate IV over 4 hours on days 1 and 15, leucovorin calcium IV or orally every 6 hours beginning on days 2 and 16 and continuing until blood levels of methotrexate are in a safe range, and oral temozolomide on days 7-11. Patients also receive rituximab\* IV on days 3, 10, 17, and 24 of course 1 and days 3 and 10 of course 2 (total of 6 doses). NOTE: \*Patients diagnosed with T-cell primary CNS lymphoma do not receive rituximab. * Course 4: Patients receive oral temozolomide on days 7-11, high-dose methotrexate IV over 4 hours on day 15, and leucovorin calcium IV or orally every 6 hours beginning on day 16 and continuing until blood levels of methotrexate are in a safe range. Patients achieving a complete response or a complete response unconfirmed proceed to consolidation therapy. * Consolidation therapy I (course 5): Beginning 4 weeks after the start of course 4, patients receive high-dose methotrexate IV over 4 hours on day 1, leucovorin calcium IV or orally every 6 hours beginning on day 2 and continuing until blood levels of methotrexate are in a safe range, and oral temozolomide on days 7-11. * Consolidation therapy II (course 6): Beginning 3-5 weeks after the start of course 5, patients receive cytarabine IV over 2 hours twice daily and etoposide IV over 12 hours twice daily on days 1-4 and filgrastim (G-CSF) or sargramostim (GM-CSF) subcutaneously beginning on day 14 and continuing until blood counts recover. Treatment continues in the absence of disease progression. After completion of study treatment, patients are followed periodically for 3 years. PROJECTED ACCRUAL: A total of 27-45 patients will be accrued for this study within 2-3 years.
Interventions
BIOLOGICALfilgrastim
5 mcg/kg subQ injection daily Day 14 until ANC \> or = 500 uL for 2 days or 1500 uL for 1 day (Cycle 6)
BIOLOGICALrituximab
375 mg/sq m IV infusion (max rate of 400 mg/hr) on Days 3, 10, 17, & 24 of Cycle 1 nad Days 3 & 10 of Cycle 2
DRUGcytarabine
2 g/sq m IV infusion over 2 hours q 12 hrs x 8 doses Days 1-4 of Cycle 6
DRUGetoposide
5 mg/kg IV infusion over 12 hrs q 12 hrs x 8 doses Days 1-4 of Cycle 6
DRUGleucovorin calcium
100 mg/sq m IV infusion q 6 hrs starting 24 hrs after ea MTX dose until serum MTX \< or = 0.05uM Cycles 1-5.
DRUGmethotrexate
8 g/sq m IV infusion over 4 hrs Days 1 & 15 Cycles 1, 2, & 3; Day 15 Cycle 4 and Day 1 Cycle 5.
DRUGtemozolomide
150 mg/sq m PO Days 7-11 Cycles 1-5.
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed newly diagnosed primary CNS lymphoma confirmed by 1 of the following methods: * Brain biopsy or resection * Cerebrospinal fluid (CSF) cytology * Positive CSF cytology with or without measurable intracranial disease * No evidence of systemic non-Hodgkin's lymphoma * CT scan or MRI of the chest, abdomen, and pelvis AND bilateral bone marrow biopsy or unilateral biopsy with a 2cm core biopsy specimen that is negative for extracerebral source of lymphoma * Measurable contrast-enhancing disease by MRI of the brain and spine (plus gadolinium) unless CSF cytology positive * No evidence of pleural effusions or ascites PATIENT CHARACTERISTICS: Age * Any age Performance status * ECOG 0-2 Life expectancy * Not specified Hematopoietic * Absolute neutrophil count ≥ 1,500/mm\^3 Hepatic * ALT and AST ≤ 2 times upper limit of normal * Bilirubin ≤ 2 mg/dL Renal * Creatinine clearance ≥ 50 mL/min Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for at least 6 months after study participation * HIV negative PRIOR CONCURRENT THERAPY: Biologic therapy * Not specified Chemotherapy * Not specified Endocrine therapy * Concurrent steroids for the management of symptoms related to lymphoma allowed Radiotherapy * No concurrent palliative radiotherapy Surgery * Not specified
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate After Remission Induction | 4 months | Response is assessed by investigator according to Revised Response Criteria for Malignant Lymphoma. Complete response requires disappearance of all evidence of disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 4 Year Progression Free Rate | 4 years | Percentage of patients who were progression free at 4 years. The 4-year progression free rate was estimated using the Kaplan Meier method. Relapse was assessed by investigator according to Revised Response Criteria for Malignant Lymphoma. Progression required a 25% increase of previous area of gadolinium enhancement, appearance of new areas of T1 gadolinium enhancement or new appearance of malignant cells in the spinal fluid or new tumor appearance in other sites of the body |
| Change From Baseline in Mini-Mental Status Evaluation at 4 Months | Baseline & month 4 | Neurologic functioning will be assessed using the Mini-Mental Status Evaluation (MMSE), a standardized, bedside tool for evaluation of higher mental function. This assessment is based on a 30-point scale (0-30) with higher scores associated with better performance. |
| 4 Year Overall Survival Rate | 4 years | Percentage of patients who were alive at 4 years. The 4-year survival rate was estimated using the Kaplan Meier method. |
Countries
United States
Participant flow
Recruitment details
Between October 2004 and November 2009, 47 participants were recruited at 12 CALGB sites.
Pre-assignment details
Three participants were excluded from analysis because of failure to meet eligibility criteria or to receive protocol therapy.
Participants by arm
| Arm | Count |
|---|---|
| Intensive Combination Chemo & Immunotherapy Induction Cycles 1-3: Methotrexate 8gm/m\^2 days 1 & 15; Leucovorin 100 mg/m\^2 days 2 & 16; Rituximab 375 mg/m\^2 days 3, 10, 17 & 24 of cycle 1, days 3 & 10 of cycle 2; Temozolomide 150 mg/m\^2/day PO days 7-11
Induction Cycle 4: Temozolomide 150 mg/m\^2/day PO days 7-11; Methotrexate 8gm/m\^2 day 15; Leucovorin 100 mg/m\^2 day 16
Consolidation Cycle 5: Methotrexate 8gm/m\^2 days 1; Leucovorin 100 mg/m\^2 days 2; Temozolomide 150 mg/m\^2/day PO days 7-11
Consolidation Cycle 6: Cytarabine 2 g/m\^2 (x 8 doses) days 1-4; Etoposide 5 mg/kg (x 8 doses) days 1-4; G-CSF 5 mcg/kg/day or GM-CSF 250 mcg/m\^2/day starting day 14 until ANC recovers (\>= 500 for 2 consecutive days or \>= 1500 for one day) | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Disease Progression | 9 |
| Overall Study | Failed (to respond) during induction | 4 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Intensive Combination Chemo & Immunotherapy |
|---|---|
| Age, Continuous | 61 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 40 Participants |
| Region of Enrollment United States | 44 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 43 / 44 |
| serious Total, serious adverse events | 15 / 44 |
Outcome results
Primary
Complete Response Rate After Remission Induction
Response is assessed by investigator according to Revised Response Criteria for Malignant Lymphoma. Complete response requires disappearance of all evidence of disease.
Time frame: 4 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intensive Combination Chemo & Immunotherapy | Complete Response Rate After Remission Induction | 66 percentage of participants |
Secondary
4 Year Overall Survival Rate
Percentage of patients who were alive at 4 years. The 4-year survival rate was estimated using the Kaplan Meier method.
Time frame: 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intensive Combination Chemo & Immunotherapy | 4 Year Overall Survival Rate | 65 percentage of participants |
Secondary
4 Year Progression Free Rate
Percentage of patients who were progression free at 4 years. The 4-year progression free rate was estimated using the Kaplan Meier method. Relapse was assessed by investigator according to Revised Response Criteria for Malignant Lymphoma. Progression required a 25% increase of previous area of gadolinium enhancement, appearance of new areas of T1 gadolinium enhancement or new appearance of malignant cells in the spinal fluid or new tumor appearance in other sites of the body
Time frame: 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intensive Combination Chemo & Immunotherapy | 4 Year Progression Free Rate | 48 percentage of participants |
Secondary
Change From Baseline in Mini-Mental Status Evaluation at 4 Months
Neurologic functioning will be assessed using the Mini-Mental Status Evaluation (MMSE), a standardized, bedside tool for evaluation of higher mental function. This assessment is based on a 30-point scale (0-30) with higher scores associated with better performance.
Time frame: Baseline & month 4
Population: Only 14 participants had both baseline and 4 month MMSE evaluations reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Intensive Combination Chemo & Immunotherapy | Change From Baseline in Mini-Mental Status Evaluation at 4 Months | Baseline Score | 27 units on a scale |
| Intensive Combination Chemo & Immunotherapy | Change From Baseline in Mini-Mental Status Evaluation at 4 Months | 4 month Score | 28 units on a scale |
| Intensive Combination Chemo & Immunotherapy | Change From Baseline in Mini-Mental Status Evaluation at 4 Months | Change from Baseline | 1 units on a scale |