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

• ClinicalTrials.gov Identifier: NCT02329080
• Recruitment Status: Active, not recruiting
• First Posted: December 31, 2014
• Last Update Posted: March 1, 2019
• Sponsor: International Extranodal Lymphoma Study Group (IELSG)
• Information provided by (Responsible Party): International Extranodal Lymphoma Study Group (IELSG)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Diffuse Large B-cell Lymphoma	Drug: Methotrexate; Drug: Rituximab; Drug: Cytarabine; Drug: Thiotepa; Drug: liposomial cytarabine; Drug: Etoposide; Drug: Ifosfamide; Drug: Carmustine; Radiation: whole brain radiotherapy	Phase 2

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):

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 76 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: December 2014
• Estimated Primary Completion Date: December 2019
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: MATRIX - R-ICE - Conditioning and ASCT; 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; methotrexate 3.5 g/m2 on day 1 courses 1, 2,3 of MATRIX regimen; Drug: Rituximab; 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); Drug: Cytarabine; Cytarabine 2 g/m2 every 12 hours, in 3-hr infusion on days 2,3 courses 1, 2,3 (MATRIX regimen); Drug: Thiotepa; 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; Drug: liposomial cytarabine; Intrathecal liposomial cytarabine 50 mg on day 5 courses 1, 2,3 (MATRIX regimen) and on day 4 courses 4,5,6 (R-ICE); Drug: Etoposide; Etoposide 100 mg/m2/d in 500 mL saline sol. in 30 minutes on day 1-2-3 courses 4,5,6 (R-ICE); Drug: Ifosfamide; Ifosfamide 5 g/m2 in 1.000 mL saline sol. in 24-hour infusion on day 2 courses 4,5,6 (R-ICE); Drug: Carmustine; BCNU (carmustine) 400 mg/m2 in 500 mL glucose 5% sol. in 1-hr infusion on day-6 of conditioning and ASCT; Radiation: whole brain radiotherapy; whole-brain irradiation 36 Gy + tumor- bed boost 10 Gy in patients with residual disease in the parenchymal brain/cerebellum.

Outcome Measures

Primary Outcome Measures :

1. progression free survival [ Time Frame: one year ]

Secondary Outcome Measures :

1. Complete remission rate [ Time Frame: at the end of chemoimmunotherapy (up to 22-24 weeks from treatment start) ]
2. response duration [ Time Frame: 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 ]
3. overall survival [ Time Frame: from entry onto trial until death from any cause or date of the last visit of follow-up (5 years) ]
4. number of participants with adverse events [ Time Frame: from time informed consent is given until 30 days after end of treatment ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

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.

Contacts and Locations

Locations

Czechia

Facultni nemocnice

Brno, Czechia

FNKV (Facultni Nemocnice Kralovske Vinohrady)

Praha, Czechia

Vseobecna facultni nemocnice v Praze

Praha, Czechia

Italy

Spedali Civili

Brescia, Italy

UO Ematologia e CTMO, PO Businco

Cagliari, Italy

IRST Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Meldola, Italy

UO Ematoliga Ospedale dell'Angelo

Mestre, Italy

Istituto Nazionale Tumori

Milano, Italy

Ospedale Maggiore Policlinico

Milano, Italy

San Raffaele H Scientific Institute

Milan, Italy

AOU Policlinico di Modena

Modena, Italy

SCDU Ematologia

Novara, Italy

Ematologia ed Immunologia Clinica - AO di Padova

Padova, Italy

UO Oncoematologia Ospedale Tortora

Pagani, Italy

Villa Sofia - Cervello

Palermo, 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

IRCCS Istituto Regina Elena (IFO)

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

SC Ematologia AO Città della Salute e della Scienza

Torino, Italy

UO Ematologia Ospedale Panico

Tricase, Italy

AOU Santa Maria della Misericordia

Udine, Italy

UOC Ematologia Policlinico Rossi

Verona, Italy

Ematologia Ospedale S. Bortolo

Vicenza, Italy

Netherlands

Erasmus MC

Rotterdam, Netherlands

United Kingdom

Beatson Cancer Center

Glasgow, United Kingdom

Liverpool Aintree

Liverpool, United Kingdom

UCLH University College London Hospitals NHS foundation trust

London, United Kingdom

The Christie Hospital

Manchester, United Kingdom

Southampton General Hospital

Southampton, United Kingdom

Sponsors and Collaborators

International Extranodal Lymphoma Study Group (IELSG)

Investigators

• Study Chair: Andrés JM Ferreri, MD; IELSG

More Information

• Responsible Party: International Extranodal Lymphoma Study Group (IELSG)
• ClinicalTrials.gov Identifier: NCT02329080 History of Changes
• Other Study ID Numbers: IELSG42
• First Posted: December 31, 2014
• Last Update Posted: March 1, 2019
• Last Verified: February 2019

Additional relevant MeSH terms:

Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Rituximab; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Cytarabine; Methotrexate; Etoposide; Etoposide phosphate; Ifosfamide; Isophosphamide mustard; Thiotepa; Carmustine; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action