New Combination of Chemoimmunotherapy for Systemic B-cell Lymphoma With Central Nervous System Involvement

Study Overview
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Brief Summary
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This is an open, non comparative, multicentre phase II trial, to evaluate the efficacy and feasibility of a new sequential combination of HD-MTX-AraC-based chemoimmunotherapy, followed by R-ICE regimen, and by high-dose chemotherapy supported by ASCT.

Detailed Description
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Treatment includes 6 courses of chemoimmunotherapy, the first three courses with an high dose methotrexate-based combination (MATRIX) followed by other three courses of R-ICE combination and finally a BCNU-thiotepa- containing conditioning and subsequent autologous stem cell transplantation. MATRIX (courses 1, 2, 3): Rituximab 375 mg/m2, Methotrexate 3.5 g/m2, Cytarabine 2 g/m2, Folinic rescue 15 mg/m2, Thiotepa 30 mg/m2, Intrathecal liposomial cytarabine 50 mg, rHuG-CSF 2,5 g/kg s.c. R-ICE (courses 4, 5, 6): Rituximab 375 mg/m2, Etoposide 100 mg/m2/d , Ifosfamide 5 g/m2, Intrathecal liposomial cytarabine 50 mg

Official Title
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An International Phase II Trial Assessing Tolerability and Efficacy of Sequential Methotrexate-Aracytin-based Combination and R-ICE Combination, Followed by HD Chemotherapy Supported by ASCT, in Patients With Systemic B-cell Lymphoma With CNS Involvement at Diagnosis or Relapse (MARIETTA Regimen)

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Rituximab
* Drug: Cytarabine
* Drug: Thiotepa
* Drug: liposomial cytarabine
* Drug: Etoposide
* Drug: Ifosfamide
* Drug: Carmustine
* Radiation: whole brain radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of diffuse large B-cell lymphoma CNS involvement (brain, meninges, cranial nerves, eyes and/or spinal cord) at diagnosis (concomitant to extra-CNS disease) or relapse after conventional chemo(-immuno)therapy Diagnosis of CNS involvement either by brain biopsy or CSF cytology examination. Neuroimaging alone is acceptable when stereotactic biopsy is formally contraindicated or when the disease has been previously histologically documented in other areas and the CNS localization is concomitant with a diffuse progression of systemic disease. No previous treatment with high-dose methotrexate-based chemotherapy and/or brain irradiation. One-two courses of R-CHOP combination as upfront therapy are admitted in patients with large amount and/or extensive extra-CNS disease that could condition prognosis in an early phase of treatment. Local investigator decides if initial R-CHOP is needed based on patient's conditions Age 18-70 years ECOG performance status 0-3 Adequate bone marrow (Platelets count ≥100.000/mm3, hemoglobin ≥9 g/dL, neutrophils count≥1.500/mm3), renal (creatinine clearance ≥60 mL/min), cardiac (LVEF ≥50%), and hepatic function (total serum bilirubine ≤3 mg/dL, AST/ALT and GGT ≤2.5 per upper normal limit value), unless the abnormality is due to lymphoma infiltration Absence of HIV infection and of detectable HCV-RNA and/or HBsAg and/or HBV-DNA No concurrent malignancies. Previous malignancies are accepted if surgically cured or if there was no evidence of disease in the last 3 years at a regular follow-up Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Female patients must be non-pregnant and non-lactating. Sexually active patients of childbearing potential must implement adequate contraceptive measures during study participation No treatment with other experimental drugs within the 6 weeks previous to enrolment Given 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 any prejudice. Informed consent signed by a patient's guardian is acceptable if the patient is not able to decide inclusion in the study due to cognitive impairment Exclusion Criteria: Other lymphoma categories other than diffuse large B-cell lymphoma. In particular, patients with primary mediastinal lymphoma, intravascular large B-cell lymphoma or leg-type large B-cell lymphoma are excluded. Patients with positive flow cytometry examination of the CSF, but negative results in CSF conventional cytology, and without any other evidence of CNS disease. Patients with exclusive CNS disease at presentation (primary CNS lymphoma) are excluded Previous treatment with support of autologous or allogeneic stem cells/bone marrow transplantation. 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) Any other serious medical condition which could impair the ability of the patient to participate in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MATRIX - R-ICE - Conditioning and ASCT<br>MATRIX (courses 1,2,3): Rituximab 375 mg/m2 d0/Methotrexate 3.5 g/m2 d1/Cytarabine 2 g/m2 d2 & d3/Thiotepa 30 mg/m2 d4/Liposomial Cytarabine 50 mg* d5 R-ICE (courses 4,5,6):Rituximab 375 mg/m2 d1/Etoposide 100 mg/m2 d1,d2, d3/Ifosfamide 5 g/m2 d2/Carboplatin 5 AUC d2/Liposomial Cytarabine 50 mg* d4 *If liposomal cytarabine is not available, standard intrathecal chemotherapy with methotrexate 10 mg + cytarabine 40 mg + hydrocortisone 50 mg can be administered. Oral steroids are suggested for 2-3 days after intrathecal liposomial cytarabine delivery to prevent chemical or aseptic meningitis/ arachnoiditis. Conditioning and ASCT: BCNU (carmustine)** 400 mg/m2 d-6/Thiotepa 5 mg/kg d-5 & d-4 ASCT: 5 x 106 CD34+cells/kg d0 **In case of BCNU unavailability, the recommended conditioning regimen (Phase IV) is: Thiotepa 5 mg/kg d-6 & d-5/Busulfan 3.2 mg/kg d-4,d -3,d-2/Clonazepam 2 mg/d d-4,d -3,d-2 ASCT: 5 x 106 CD34+cells/kg d0 | Drug: Methotrexate<br>* methotrexate 3.5 g/m2 on day 1 courses 1, 2,3 of MATRIX regimen<br>Drug: Rituximab<br>* Rituximab 375 mg/m2 as conventional IV infusion on day 0 courses 1, 2,3 (MATRIX regimen) and on day 1 courses 4,5,6 (R-ICE)<br>Drug: Cytarabine<br>* Cytarabine 2 g/m2 every 12 hours, in 3-hr infusion on days 2,3 courses 1, 2,3 (MATRIX regimen)<br>Drug: Thiotepa<br>* Thiotepa 30 mg/m2 in 30 minutes infusion on day 4 courses 1, 2,3 (MATRIX regimen) and 5 mg/kg in 250 ml of saline sol. in 2-hrs infusion every 12 hours on day -5 and -4 of conditioning and ASCT<br>Drug: liposomial cytarabine<br>* Intrathecal liposomial cytarabine 50 mg on day 5 courses 1, 2,3 (MATRIX regimen) and on day 4 courses 4,5,6 (R-ICE)<br>Drug: Etoposide<br>* Etoposide 100 mg/m2/d in 500 mL saline sol. in 30 minutes on day 1-2-3 courses 4,5,6 (R-ICE)<br>Drug: Ifosfamide<br>* Ifosfamide 5 g/m2 in 1.000 mL saline sol. in 24-hour infusion on day 2 courses 4,5,6 (R-ICE)<br>Drug: Carmustine<br>* BCNU (carmustine) 400 mg/m2 in 500 mL glucose 5% sol. in 1-hr infusion on day-6 of conditioning and ASCT<br>Radiation: whole brain radiotherapy<br>* whole-brain irradiation 36 Gy + tumor- bed boost 10 Gy in patients with residual disease in the parenchymal brain/cerebellum.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression free survival |  | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission rate |  | at the end of chemoimmunotherapy (up to 22-24 weeks from treatment start) | 
| response duration |  | after the 2nd, 4th and 6th courses of chemoimmunotherapy and 45 days after ASCT. During follow up every 3 months for 2 years, than every 6 months for 3 years and yearly thereafter | 
| overall survival |  | from entry onto trial until death from any cause or date of the last visit of follow-up (5 years) | 
| number of participants with adverse events |  | from time informed consent is given until 30 days after end of treatment |