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

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

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


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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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

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.




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 ]


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02329080


Locations
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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
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Study Chair: Andrés JM Ferreri, MD IELSG

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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    Key Record Dates
Last Update Posted: March 1, 2019
Last Verified: February 2019
Additional relevant MeSH terms:
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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