Brain and Central Nervous System Tumors, Drug/Agent Toxicity by Tissue/Organ, Lymphoma, Thrombocytopenia
Conditions
Keywords
drug/agent toxicity by tissue/organ, thrombocytopenia, intraocular lymphoma, primary central nervous system non-Hodgkin lymphoma, primary central nervous system Hodgkin lymphoma
Brief summary
RATIONALE: Monoclonal antibodies, such as rituximab, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as carboplatin, cyclophosphamide, etoposide, etoposide phosphate, and cytarabine, use different ways to stop cancer cells from dividing so they stop growing or die. Osmotic blood-brain barrier disruption uses certain drugs to open the blood vessels around the brain and allow anticancer substances to be delivered directly to the brain tumor. Chemoprotective drugs such as sodium thiosulfate may protect normal cells from the side effects of carboplatin-based chemotherapy. Combining rituximab with chemotherapy given with osmotic blood-brain barrier disruption plus sodium thiosulfate may kill more cancer cells. PURPOSE: Phase II trial to study the effectiveness of combining rituximab with combination chemotherapy given with osmotic blood-brain barrier disruption plus sodium thiosulfate in treating patients who have refractory or recurrent primary CNS lymphoma.
Detailed description
OBJECTIVES: Primary * Determine the efficacy of rituximab, carboplatin, cyclophosphamide, etoposide or etoposide phosphate and cytarabine administered in conjunction with osmotic blood-brain barrier disruption and high-dose sodium thiosulfate, in terms of complete response rate, in patients with refractory or recurrent primary CNS lymphoma. Secondary * Determine the overall survival and 2-year progression-free survival of patients treated with this regimen. * Determine the quality of life and cognitive function of patients treated with this regimen. * Determine the neurotoxicity of this regimen in these patients. * Determine the percentage of patients with ototoxicity over time after treatment with this regimen. * Determine the effect of delayed administration of sodium thiosulfate on granulocyte and erythrocyte counts in these patients. OUTLINE: This is a multicenter study. Patients receive rituximab IV on day 1. On days 2 and 3, patients receive carboplatin intra-arterially over 10 minutes, cyclophosphamide IV over 10 minutes, and etoposide or etoposide phosphate IV over 10 minutes in conjunction with blood-brain barrier disruption. Patients also receive high-dose sodium thiosulfate IV over 15 minutes administered 4 and 8 hours after carboplatin on days 2 and 3 and intraventricular or intrathecal cytarabine on day 14. Beginning 48 hours after the last dose of chemotherapy, patients receive filgrastim (G-CSF)\* subcutaneously (SC) daily for 7-10 days or until blood counts recover. Treatment repeats every 4 weeks for up to 12 courses. NOTE: \* Alternatively, patients may receive a single dose of pegfilgrastim SC, administered 48 hours after the completion of chemotherapy Patients with intraocular lymphoma also receive methotrexate intravitreally twice weekly until the vitreous is clear of cells by slit lamp exam; once weekly for 1 month; and then monthly for 1 year. Quality of life is assessed at baseline, every 3 months during treatment, within 30 days of final treatment, then every 6 months for 1 year, and then annually thereafter. Patients are followed monthly for 3 months, every 2 months for 8 months, every 3 months for 1 year, and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 11-25 patients will be accrued for this study within 7-10 years.
Interventions
DRUGRituxan
Total dose: 375mg/m2 infused IV; Every 4 weeks for up to one year.
DRUGCyclophosphamide
Dose 330mg/m2 x 2 days infused IV; Every 4 weeks for up to 1 year
DRUGEtoposide
Dose 200mg/m2 x 2 days infused IV; Every 4 weeks for up to one year. Etoposide phosphate may be given instead.
DRUGEtoposide phosphate
Dose 200mg/m2 infused IV x 2 days; Every 4 weeks for up to one year. Etoposide may be given instead.
DRUGCarboplatin
Dose: 200mg/m2 x 2 days infused IA with BBBD; Every 4 weeks for up to one year.
DRUGSodium thiosulfate
Dose: 4 hrs post carboplatin = 20gm/m2; Dose: 8 hrs post carboplatin = 16gm/m2 Infused IV x 2 days
DRUGNeupogen
48 hours after chemotherapy, QD x 7-10 days until WBC greater than 5000. Neulasta (Pegfilgrastim) may be given instead.
DRUGNeulasta
Dose: 6mg, 24-72 hours after chemotherapy. Neupogen may be given instead.
DRUGCytarabine
Dose: 40mg on Day 14 following chemotherapy
Sponsors
National Cancer Institute (NCI)
OHSU Knight Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Months to 75 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent form in accordance with institutional guidelines * Histologically or cytologically confirmed primary CNS lymphoma documented by brain biopsy or cerebrospinal fluid or vitrectomy analysis * CD20 positive disease * Progressive or relapsed disease during or after completion of prior methotrexate-based chemotherapy * Aged 18 months to 75 years * Performance status ECOG 0-3 OR Karnofsky 30-100% * Hematocrit at least 25% (transfusion or epoetin alfa allowed) * Absolute granulocyte count at least 1,200/mm\^3 * Platelet count at least 100,000/mm\^3 OR at least lower limit of normal * Bilirubin no greater than 2.0 times upper limit of normal * Creatinine less than 1.8 mg/dL * Calculated Creatinine clearance (CrCl) at least 50 mL/min * Adequate cardiac function to tolerate general anesthesia * Adequate pulmonary function to tolerate general anesthesia * Available for follow-up for 1 year post therapy * Fertile patients must use effective contraception for a minimum of 2 months before and during study participation
Exclusion criteria
* Radiographic signs of intra-cranial herniation and/or spinal block * HIV positive * Systemic lymphoma * Positive serum HCG, pregnant or lactating * Allergy to study agents * Hepatitis B or hepatitis C positive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Complete Response Rate to Chemotherapy Regimen Assessed by Radiographic Response at 2 Years. | 2 years | Per RECIST criteria (v1.1) and assessed by magnetic resonance imaging (MRI): Complete response (CR), Disappearance of all target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Survival Assessed by Clinical and Radiographic Response | 5 years | Overall survival is measured from entry onto study until death from any cause or until death or progression of disease, respectively. |
| Progression-free Survival Assessed by Clinical and Radiographic Response From First Day of Treatment Until Tumor Progression | 5 years | — |
| Quality of Life Assessed by EORTC QOL Before Treatment and Then Every 3 Months | 5 years | — |
| Ototoxicity Assessed by Audiology Hearing Test Done Monthly During Treatment | 2 years | — |
| Effect of Sodium Thiosulfate (STS) on Granulocytes and Erythrocytes Assessed by Complete Blood Count Lab Values Done Weekly During Treatment | 2 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab and Carboplatin Rituximab: (i.v.) 375 mg/m\^2 given the evening before blood brain barrier disruption(BBBD) procedure day 1 Carboplatin: (i.a.) 200 mg/m\^2 /day x 2 days = 400 mg/m\^2 | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Rituximab and Carboplatin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 55.235 years STANDARD_DEVIATION 12.799 |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 17 |
| other Total, other adverse events | 1 / 17 |
| serious Total, serious adverse events | 16 / 17 |
Outcome results
Primary
Number of Participants With a Complete Response Rate to Chemotherapy Regimen Assessed by Radiographic Response at 2 Years.
Per RECIST criteria (v1.1) and assessed by magnetic resonance imaging (MRI): Complete response (CR), Disappearance of all target lesions.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab and Carboplatin | Number of Participants With a Complete Response Rate to Chemotherapy Regimen Assessed by Radiographic Response at 2 Years. | 1 Participants |
Secondary
Effect of Sodium Thiosulfate (STS) on Granulocytes and Erythrocytes Assessed by Complete Blood Count Lab Values Done Weekly During Treatment
Time frame: 2 years
Population: Data not collected due to low accrual and early termination.
Secondary
Number of Participants With Overall Survival Assessed by Clinical and Radiographic Response
Overall survival is measured from entry onto study until death from any cause or until death or progression of disease, respectively.
Time frame: 5 years
Population: Data not collected due to low accrual and early termination.
Secondary
Ototoxicity Assessed by Audiology Hearing Test Done Monthly During Treatment
Time frame: 2 years
Population: Data not collected due to low accrual and early termination.
Secondary
Progression-free Survival Assessed by Clinical and Radiographic Response From First Day of Treatment Until Tumor Progression
Time frame: 5 years
Population: Data not collected due to low accrual and early termination.
Secondary
Quality of Life Assessed by EORTC QOL Before Treatment and Then Every 3 Months
Time frame: 5 years
Population: Data not collected due to low accrual and early termination.