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

Phase 2

Completed

• Conditions: Diffuse Large B-cell Lymphoma
• Interventions: Drug: Methotrexate; Drug: Rituximab; Drug: Cytarabine; Drug: Thiotepa; Drug: liposomial cytarabine; Drug: Etoposide; Drug: Ifosfamide; Drug: Carmustine; Radiation: whole brain radiotherapy

• Registration Number: NCT02329080
• Lead Sponsor: International Extranodal Lymphoma Study Group (IELSG)

Brief Summary

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

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):
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Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2014-12
• Study First Submitted: 2014-12-22
• Study First Submitted QC: 2014-12-29
• Study First Posted: 2014-12-31
• Primary Completion: 2019-08
• Study Completion: 2024-03-22
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-26
• Last Update Posted: 2024-07-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 76

Inclusion Criteria

1. Histologically confirmed diagnosis of diffuse large B-cell lymphoma
2. 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
3. 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.
4. 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
5. Age 18-70 years
6. ECOG performance status 0-3
7. 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
8. Absence of HIV infection and of detectable HCV-RNA and/or HBsAg and/or HBV-DNA
9. 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
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. 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

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Exclusion Criteria

1. 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.
2. Patients with positive flow cytometry examination of the CSF, but negative results in CSF conventional cytology, and without any other evidence of CNS disease.
3. Patients with exclusive CNS disease at presentation (primary CNS lymphoma) are excluded
4. Previous treatment with support of autologous or allogeneic stem cells/bone marrow transplantation.
5. 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)
6. Any other serious medical condition which could impair the ability of the patient to participate in the trial.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
MATRIX - R-ICE - Conditioning and ASCT	liposomial cytarabine	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
MATRIX - R-ICE - Conditioning and ASCT	whole brain radiotherapy	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
MATRIX - R-ICE - Conditioning and ASCT	Methotrexate	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
MATRIX - R-ICE - Conditioning and ASCT	Rituximab	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
MATRIX - R-ICE - Conditioning and ASCT	Thiotepa	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
MATRIX - R-ICE - Conditioning and ASCT	Cytarabine	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
MATRIX - R-ICE - Conditioning and ASCT	Ifosfamide	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
MATRIX - R-ICE - Conditioning and ASCT	Etoposide	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
MATRIX - R-ICE - Conditioning and ASCT	Carmustine	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

Primary Outcome Measures

Name	Time	Method
progression free survival	one year

Secondary Outcome Measures

Name	Time	Method
Complete remission rate	at the end of chemoimmunotherapy (up to 22-24 weeks from treatment start)
number of participants with adverse events	from time informed consent is given until 30 days after end of treatment
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)

Trial Locations

Locations (36)

IRST Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori; 🇮🇹 Meldola, Italy

Villa Sofia - Cervello; 🇮🇹 Palermo, Italy

Facultni nemocnice; 🇨🇿 Brno, Czechia

FNKV (Facultni Nemocnice Kralovske Vinohrady); 🇨🇿 Praha, Czechia

Vseobecna facultni nemocnice v Praze; 🇨🇿 Praha, Czechia

Spedali Civili; 🇮🇹 Brescia, Italy

Istituto Nazionale Tumori; 🇮🇹 Milano, Italy

UO Ematologia e CTMO, PO Businco; 🇮🇹 Cagliari, Italy

UO Ematoliga Ospedale dell'Angelo; 🇮🇹 Mestre, Italy

AOU Policlinico di Modena; 🇮🇹 Modena, Italy

San Raffaele H Scientific Institute; 🇮🇹 Milan, Italy

Ospedale Maggiore Policlinico; 🇮🇹 Milano, Italy

UO Oncoematologia Ospedale Tortora; 🇮🇹 Pagani, Italy

SCDU Ematologia; 🇮🇹 Novara, Italy

Ematologia ed Immunologia Clinica - AO di Padova; 🇮🇹 Padova, Italy

IRCCS Istituto Regina Elena (IFO); 🇮🇹 Roma, Italy

Ematologia AOU; 🇮🇹 Parma, Italy

Ematologia Ospedale S.Maria delle Croci; 🇮🇹 Ravenna, Italy

A.O. Bianchi-Melacrino-Morelli, Divisione di Ematologia; 🇮🇹 Reggio Calabria, Italy

Arcispedale Santa Maria Nuova, Azienda Ospedaliera di Reggio Emilia; 🇮🇹 Reggio Emilia, Italy

Ematologia Università La Sapienza; 🇮🇹 Roma, Italy

Policlinico Universitario Campus Bio-Medico; 🇮🇹 Rome, Italy

IRCCS Casa Sollievo Della Sofferenza; 🇮🇹 San Giovanni Rotondo, Italy

AOU Senese; 🇮🇹 Siena, Italy

AO S.Maria di Terni; 🇮🇹 Terni, Italy

UO Ematologia Ospedale Panico; 🇮🇹 Tricase, Italy

SC Ematologia AO Città della Salute e della Scienza; 🇮🇹 Torino, Italy

AOU Santa Maria della Misericordia; 🇮🇹 Udine, Italy

Beatson Cancer Center; 🇬🇧 Glasgow, United Kingdom

UOC Ematologia Policlinico Rossi; 🇮🇹 Verona, Italy

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

UCLH University College London Hospitals NHS foundation trust; 🇬🇧 London, United Kingdom

Ematologia Ospedale S. Bortolo; 🇮🇹 Vicenza, Italy

Liverpool Aintree; 🇬🇧 Liverpool, United Kingdom

The Christie Hospital; 🇬🇧 Manchester, United Kingdom

Southampton General Hospital; 🇬🇧 Southampton, United Kingdom