B-cell Lymphomas
Conditions
Keywords
B-cell lymphomas, lymphomatous meningitis, liposomal cytarabine, autologous transplant, CNS involvement, Secondary CNS lymphomas
Brief summary
This prospective trial will assess the activity and feasibility of a new high-dose methotrexate-based high-dose sequential chemotherapy combination in patients with B-cell lymphomas and CNS involvement at diagnosis or relapse. Selected drugs, with a well-documented anti-lymphoma activity, will be administered at high doses to increase blood-brain barrier penetration and CNS bioavailability as well as to reduce potential cross-resistance.
Detailed description
Patients with aggressive B-cell lymphoma and involvement of the central nervous system at diagnosis or relapse will be treated with a combination of high-dose methotrexate and high-dose cytarabine, rituximab, and intrathecal depocyte followed by rituximab-high-dose sequential chemotherapy supported by autologous tsem cell transplantation.
Interventions
DRUGHigh-dose sequential chemotherapy and autologous transplant
Two courses of methotrexate 3.5 g/mq day 1 and cytarabine 2 g/mq twice a day, for two days, Rituximab 375 mg/mq days 3 & 11 and Intrathecal liposomal cytarabine 50 mg day 6(Phase I) followed in case of response by cyclophosphamide 7 g/mq plus Rituximab 375 mg/mq and Intrathecal liposomal cytarabine 50 mg Leukapheresis A and cryopreservation (Phase II), Cytarabine 2 g/mq twice a day for 4 days, Rituximab 375 mg/m2 and Reinfusion of stem cells (Phase III), etoposide 2 g/mq, Intrathecal liposomal cytarabine 50 mg (Phase IV) and high-dose Thiotepa-BCNU supported by autologous stem cell transplant (Phase V), and whole-brain radiotherapy in patients who do not achieve a complete remission after chemotherapy (Phase VI)
Sponsors
Mundipharma Pte Ltd.
Andrés José Maria Ferreri
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed diagnosis of diffuse large-cell, follicular or mantle cell lymphoma 2. CNS involvement (brain, meninges, cranial nerves, eyes, and/or spinal cord) at diagnosis or relapse after conventional chemotherapy 3. Diagnosis of CNS involvement either by brain biopsy or CSF cytology examination. Neuroimaging alone is acceptable only when stereotactic biopsy is formally contraindicated. 4. Age 18-70 years 5. ECOG performance status 0-3 6. Adequate bone marrow (PLT \> 100000 mm3, Hb \> 9 g/dl, ANC \> 2.000 mm3), renal (creatinine clearance \> 60 mL/min), cardiac (VEF \> 50%), and hepatic function (total serum bilirubin \< 3 mg/dL, AST/ALT and gammaGT \< 2.5 per upper normal limit value), within 1 week prior to study start (unless the abnormality is due to lymphoma involvement) 7. Absence of symptomatic coronary artery disease, cardiac arrhythmias not well controlled with medication or myocardial infarction within the last 6 months (New York Heart Association Class III or IV heart disease) 8. Absence of HIV infection 9. No previous or concurrent malignancies with the exception of surgically cured carcinoma in-situ of the cervix and carcinoma of the skin and of other cancers without evidence of disease at least from 5 years 10. Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule 11. Female patients must be non-pregnant and non-lactating. Sexually active patients of childbearing potential must implement adequate contraceptive measures during study participation 12. No treatment with other experimental drugs within the 6 weeks previous to enrolment 13. Give written informed consent prior to any study specific procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice
Exclusion criteria
* NA
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | 2-year | No new pathological events in a 2 ys follow-up period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tolerability OF THE TREATMENT | 2-year | For the 38 patients enrolled the number of chemotherapy administered / expected during treatment period |
| Time to Progression (TTP) | 2-year | Time elapsed from Lymphoma diagnosis and CNS involvement |
| Overall Survival | 5 Years | Patients alive after 5 years long follow-up |
| Neurotoxicity | 2-year | Total number of patients with neurotoxic events during treatment |
Countries
Italy
Participant flow
Pre-assignment details
40 patients were registered, but only 38 patients met the inclusion critaria and was treatted
Participants by arm
| Arm | Count |
|---|---|
| High-dose Sequential Chemoimmunotherapy Two courses of methotrexate 3.5 g/mq day 1 and cytarabine 2 g/mq twice a day, for two days, Rituximab 375 mg/mq days 3 & 11 and Intrathecal liposomal cytarabine 50 mg day 6(Ph I) followed in case of response by cyclophosphamide 7 g/mq plus Rituximab 375 mg/mq and Intrathecal liposomal cytarabine 50 mg Leukapheresis A and cryopreservation (Ph II), Cytarabine 2 g/mq twice a day for 4 days, Rituximab 375 mg/m2 and Reinfusion of stem cells (Phase III), etoposide 2 g/mq, Intrathecal liposomal cytarabine 50 mg (Ph IV) and high-dose Thiotepa-BCNU supported by autologous stem cell transplant (Phase V), and whole-brain radiotherapy in patients who do not achieve a complete remission after chemotherapy (Ph VI)
High-dose sequential chemotherapy and autologous transplant: Two courses of methotrexate 3.5 g/mq day 1 and cytarabine 2 g/mq twice a day, for two days, Rituximab 375 mg/mq days 3 & 11 and Intrathecal liposomal cytarabine 50 mg day 6(Phase I) followed in case of response by cyclophosphamide 7 g/mq plus Rituximab 375 mg/mq and Intrathecal liposomal cytarabine 50 mg Leukapheresis A and cryopreservation (Phase II), Cytarabine 2 g/mq twice a day for 4 days, Rituximab 375 mg/m2 and Reinfusion of stem cells (Phase III), etoposide 2 g/mq, Intrathecal liposomal cytarabine 50 mg (Phase IV) and high-dose Thiotepa-BCNU supported by autologous stem cell transplant (Phase V), and whole-brain radiotherapy in patients who do not achieve a complete remission after chemotherapy (Phase VI) | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Screening Failure | 2 |
Baseline characteristics
| Characteristic | High-dose Sequential Chemoimmunotherapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Age, Continuous | 59 years |
| Region of Enrollment Italy | 38 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 22 / 38 |
| other Total, other adverse events | 3 / 38 |
| serious Total, serious adverse events | 4 / 38 |
Outcome results
Primary
Event-free Survival
No new pathological events in a 2 ys follow-up period
Time frame: 2-year
Population: No Event registered at a 2ys follow-up of the population included
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High-dose Sequential Chemoimmunotherapy | Event-free Survival | 16 Participants |
Secondary
Neurotoxicity
Total number of patients with neurotoxic events during treatment
Time frame: 2-year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High-dose Sequential Chemoimmunotherapy | Neurotoxicity | 2 Participants |
Secondary
Overall Survival
Patients alive after 5 years long follow-up
Time frame: 5 Years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High-dose Sequential Chemoimmunotherapy | Overall Survival | 16 Participants |
Secondary
Time to Progression (TTP)
Time elapsed from Lymphoma diagnosis and CNS involvement
Time frame: 2-year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High-dose Sequential Chemoimmunotherapy | Time to Progression (TTP) | 1 Months |
Secondary
Tolerability OF THE TREATMENT
For the 38 patients enrolled the number of chemotherapy administered / expected during treatment period
Time frame: 2-year
Population: Number of Chemotherapy cycles planned
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High-dose Sequential Chemoimmunotherapy | Tolerability OF THE TREATMENT | 123 Number of Chemotherapy cycles |