Brain and Central Nervous System Tumors, Lymphoma
Conditions
Keywords
primary central nervous system non-Hodgkin lymphoma, primary central nervous system Hodgkin lymphoma
Brief summary
RATIONALE: Drugs used in chemotherapy such as methotrexate and temozolomide use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining methotrexate, temozolomide, and rituximab with radiation therapy may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of temozolomide when given together with methotrexate and rituximab followed by radiation therapy and to see how well they work in treating patients with primary central nervous system lymphoma.
Detailed description
OBJECTIVES: * To assess the maximum tolerated dose (MTD) of temozolomide (TMZ) in combination with methotrexate (MTX) and rituximab (RTX) when administered prior to twice daily fractionated whole brain radiation therapy (WBRT) in patients with primary central nervous system lymphoma. * To compare the two-year survival rate in patients receiving pre-irradiation chemotherapy, twice daily fractionated whole brain radiation therapy and post-irradiation temozolomide to the reported two-year survival rate of Radiation Therapy Oncology Group (RTOG) trial 93-10. RTOG 9310 does not fall within ClinicalTrials.gov registration/reporting requirements.) * To compare the pre-irradiation chemotherapy tumor response rates to the reported rate from RTOG 93-10. * To report progression-free survival. * To assess acute and long-term neurologic toxicity, and to collect quality of life data for this patient group. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Interventions
DRUGrituximab
375 mg/m2, intravenously three days prior to the first cycle of methotrexate
DRUGmethotrexate
Five cycles of methotrexate (MTX) at 3.5 gm/m2 administered every two weeks on weeks 1, 3, 5, 7, and 9 via intravenous infusion over four hours once per cycle. Calcium leucovorin 25 mg orally or intravenously every six hours initiated exactly 24 hours following the start of the MTX infusion. Methotrexate levels to be monitored daily, and calcium leucovorin discontinued when the MTX level is less than 10 micromolar.
DRUGtemozolomide 100 mg/m^2
Temozolomide 100 mg/m\^2 by mouth per day for five days on weeks 4 and 8.
DRUGtemozolomide 150 mg/m^2
Temozolomide 150 mg/m\^2 by mouth per day for five days on weeks 4 and 8.
DRUGtemozolomide 200 mg/m^2
Temozolomide 200 mg/m\^2 per day by mouth for five days on weeks 4 and 8.
RADIATIONradiation therapy
Whole brain irradiation (WBRT) during weeks 11, 12, and 13, five days per week (excluding weekends). A daily dose of 2.4 Gy delivered in two fractions of 1.2 Gy each with a minimum inter-fraction interval of 6 hours, with a total dose to brain and meninges of 36 Gy.
DRUGpost-radiation therapy temozolomide
Temozolomide (TMZ) 200 mg/m\^2 by mouth per day for 5 days on weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50 for a total of 10 cycles.
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Primary central nervous system (CNS) lymphoma \[B-cell, Cluster of Differentiation 20 (CD20) antigen positive\] based on positive biopsy or cerebrospinal fluid (CSF) or vitreous cytology (in association with measurable intraparenchymal tumor). Cytology must demonstrate lymphoma or have an immunohistochemical diagnosis of malignant lymphocytes with a monoclonal lymphocytic population. 2. Life expectancy ≥ 8 weeks; 3. Zubrod performance status of 0-2; 4. Absolute granulocyte count ≥1500/mm3; platelet count ≥ 100,000/mm3; creatinine clearance ≥ 50, calculated with the Cockcroft-Gault Equation: Cr Clearance = (140-age) x wt (kg)/(Cr\[mg/dl\]x 72); Bilirubin, serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (AST) ≤ 2 x institutional upper limits of normal; 5. Patients must sign a study-specific informed consent prior to study entry. 6. Age ≥ 18
Exclusion criteria
1. Evidence of systemic lymphoma; 2. Prior malignancy (excluding in situ carcinoma of the cervix or non-melanomatous skin cancer)unless disease free for at least five years; 3. Prior radiotherapy to the brain or head/neck; 4. Prior chemotherapy; 5. History of idiopathic sensitivity to any of the drugs to be used; 6. Active infectious process; 7. Seropositive for HIV, AIDS, or post-organ transplant; 8. Pregnant women are ineligible as treatment involves unforeseeable risks to the participant and to the embryo or fetus. 9. Active hepatitis B.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Phase I Participants Experiencing Toxicity | From start of treatment to 10 weeks if radiation therapy received, to 15 weeks if not. | A dose limiting toxicity (DLT) is defined as any grade 3 or 4 non-hematological toxicity (other than grade 3 nausea/vomiting) or any hematological toxicity resulting in the discontinuation of temozolomide. Toxicity evaluation for this dose escalation includes all toxicities occurring prior to the start of radiation therapy. If the patient did not receive radiation therapy, then toxicity evaluation included all toxicities occurring through week 15. Any grade 5 toxicity would result in immediate suspension of accrual. |
| Phase II: Overall Survival Rate at 2 Years (Including Phase I Patients at Same Dose) | Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years. | Survival time is defined as time from registration to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. (Please note that this outcome measure is considered the primary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. ) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose) | From start of treatment to 10 weeks if RT received, to 15 weeks if not. | Tumor response was centrally reviewed. Complete response: Disappearance of all enhancing tumor, the patient must be off steroid therapy and neurologically stable or improved; partial response: ≥ 50% decrease in enhancing tumor; progressive disease: ≥ 25% increase in a lesion, progressive or newly emergent meningeal or ocular disease. (Please note that this outcome measure is considered a secondary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. ) |
| Phase II: Progression-free Survival (Including Phase I Patients at Same Dose) | Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years. | Progression is defined as greater than 25% increase in enhancing tumor or the appearance of new lesions in the brain, eye, or the appearance of a new positive cerebrospinal fluid (CSF) cytology. The patient may be neurologically stable or worse and on stable or increasing doses of corticosteroid. Progression-free survival time is defined as time from registration to the date of progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. (Please note that this outcome measure is considered a secondary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. ) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I: Temozolomide 100 mg Rituximab, methotrexate, temozolomide 100 mg/m\^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m\^2. | 6 |
| Phase I: Temozolomide 150 mg Rituximab, methotrexate, temozolomide 150 mg/m\^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m\^2. | 6 |
| Phase II: Temozolomide 100 mg Rituximab, methotrexate, temozolomide 100 mg/m\^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m\^2. | 47 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase I: Dose Level 2 | Protocol Violation | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase I: Temozolomide 100 mg | Phase I: Temozolomide 150 mg | Phase II: Temozolomide 100 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 57 years | 62 years | 57 years | 57 years |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 24 Participants | 30 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 23 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 47 / 47 |
| serious Total, serious adverse events | 3 / 6 | 4 / 6 | 16 / 47 |
Outcome results
Primary
Number of Phase I Participants Experiencing Toxicity
A dose limiting toxicity (DLT) is defined as any grade 3 or 4 non-hematological toxicity (other than grade 3 nausea/vomiting) or any hematological toxicity resulting in the discontinuation of temozolomide. Toxicity evaluation for this dose escalation includes all toxicities occurring prior to the start of radiation therapy. If the patient did not receive radiation therapy, then toxicity evaluation included all toxicities occurring through week 15. Any grade 5 toxicity would result in immediate suspension of accrual.
Time frame: From start of treatment to 10 weeks if radiation therapy received, to 15 weeks if not.
Population: Eligible patients on Phase I arms who started study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: Temozolomide 100mg | Number of Phase I Participants Experiencing Toxicity | 1 Participants |
| Phase I: Temozolomide150 mg | Number of Phase I Participants Experiencing Toxicity | 3 Participants |
Primary
Phase II: Overall Survival Rate at 2 Years (Including Phase I Patients at Same Dose)
Survival time is defined as time from registration to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. (Please note that this outcome measure is considered the primary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. )
Time frame: Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years.
Population: Eligible patients on Temozolomide 100 mg arms who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Temozolomide 100mg | Phase II: Overall Survival Rate at 2 Years (Including Phase I Patients at Same Dose) | 80.8 percentage of participants |
Comparison: Null hypothesis: Two-year survival rate \<= 64%; Alternative hypothesis: Two-year survival rate \> 64%. The fixed survival rate for comparison comes from Radiation Therapy Oncology Group (RTOG) trial 9310. (RTOG 9310 does not fall within ClinicalTrials.gov registration/reporting requirements.)p-value: 0.006One-sample z-test
Secondary
Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose)
Tumor response was centrally reviewed. Complete response: Disappearance of all enhancing tumor, the patient must be off steroid therapy and neurologically stable or improved; partial response: ≥ 50% decrease in enhancing tumor; progressive disease: ≥ 25% increase in a lesion, progressive or newly emergent meningeal or ocular disease. (Please note that this outcome measure is considered a secondary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. )
Time frame: From start of treatment to 10 weeks if RT received, to 15 weeks if not.
Population: Eligible patients on Temozolomide 100 mg arms who started study treatment and have scans for central review
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I: Temozolomide 100mg | Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose) | Complete Response | 18 Participants |
| Phase I: Temozolomide 100mg | Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose) | Partial Response | 12 Participants |
| Phase I: Temozolomide 100mg | Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose) | Progressive Disease | 2 Participants |
| Phase I: Temozolomide 100mg | Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose) | Not evaluable | 3 Participants |
Comparison: RTOG 93-10 reported a pre-irradiation chemotherapy complete response rate of 59%. A chi-square test with a 0.20 one-sided significance level provides 81% power to detect the difference between a null hypothesis complete response rate of 59% and the alternative rate of 71% (a 20% increase) for the planned sample size of 52 patients.p-value: 0.82Chi-squared
Secondary
Phase II: Progression-free Survival (Including Phase I Patients at Same Dose)
Progression is defined as greater than 25% increase in enhancing tumor or the appearance of new lesions in the brain, eye, or the appearance of a new positive cerebrospinal fluid (CSF) cytology. The patient may be neurologically stable or worse and on stable or increasing doses of corticosteroid. Progression-free survival time is defined as time from registration to the date of progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. (Please note that this outcome measure is considered a secondary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. )
Time frame: Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years.
Population: Eligible patients on Temozolomide 100 mg arms who started study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Temozolomide 100mg | Phase II: Progression-free Survival (Including Phase I Patients at Same Dose) | 5.4 years |