Clinical trial NCT02329080: New Combination of Chemoimmunotherapy for Systemic B-cell Lymphoma With Central Nervous System Involvement
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diffuse Large B-cell Lymphoma
Lead sponsor: International Extranodal Lymphoma Study Group (IELSG)
Sponsor class: OTHER
First posted: 2014-12-31
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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):

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

Eligibility 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.

Primary outcomes:
measure: progression free survival
timeFrame: one year
Secondary outcomes:
measure: Complete remission rate
timeFrame: at the end of chemoimmunotherapy (up to 22-24 weeks from treatment start)
measure: response duration
timeFrame: 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
measure: overall survival
timeFrame: from entry onto trial until death from any cause or date of the last visit of follow-up (5 years)
measure: number of participants with adverse events
timeFrame: from time informed consent is given until 30 days after end of treatment
Other outcomes:
Locations:
city: Brno
country: Czechia
facility: Facultni nemocnice
city: Praha
country: Czechia
facility: FNKV (Facultni Nemocnice Kralovske Vinohrady)
city: Praha
country: Czechia
facility: Vseobecna facultni nemocnice v Praze
city: Brescia
country: Italy
facility: Spedali Civili
city: Cagliari
country: Italy
facility: UO Ematologia e CTMO, PO Businco
city: Meldola
country: Italy
facility: IRST Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Mestre
country: Italy
facility: UO Ematoliga Ospedale dell'Angelo
city: Milano
country: Italy
facility: Istituto Nazionale Tumori
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico
city: Milan
country: Italy
facility: San Raffaele H Scientific Institute
city: Modena
country: Italy
facility: AOU Policlinico di Modena
city: Novara
country: Italy
facility: SCDU Ematologia
city: Padova
country: Italy
facility: Ematologia ed Immunologia Clinica - AO di Padova
city: Pagani
country: Italy
facility: UO Oncoematologia Ospedale Tortora
city: Palermo
country: Italy
facility: Villa Sofia - Cervello
city: Parma
country: Italy
facility: Ematologia AOU
city: Ravenna
country: Italy
facility: Ematologia Ospedale S.Maria delle Croci
city: Reggio Calabria
country: Italy
facility: A.O. Bianchi-Melacrino-Morelli, Divisione di Ematologia
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova, Azienda Ospedaliera di Reggio Emilia
city: Roma
country: Italy
facility: Ematologia Università La Sapienza
city: Roma
country: Italy
facility: IRCCS Istituto Regina Elena (IFO)
city: Rome
country: Italy
facility: Policlinico Universitario Campus Bio-Medico
city: San Giovanni Rotondo
country: Italy
facility: IRCCS Casa Sollievo Della Sofferenza
city: Siena
country: Italy
facility: AOU Senese
city: Terni
country: Italy
facility: AO S.Maria di Terni
city: Torino
country: Italy
facility: SC Ematologia AO Città della Salute e della Scienza
city: Tricase
country: Italy
facility: UO Ematologia Ospedale Panico
city: Udine
country: Italy
facility: AOU Santa Maria della Misericordia
city: Verona
country: Italy
facility: UOC Ematologia Policlinico Rossi
city: Vicenza
country: Italy
facility: Ematologia Ospedale S. Bortolo
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Glasgow
country: United Kingdom
facility: Beatson Cancer Center
city: Liverpool
country: United Kingdom
facility: Liverpool Aintree
city: London
country: United Kingdom
facility: UCLH University College London Hospitals NHS foundation trust
city: Manchester
country: United Kingdom
facility: The Christie Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
Study officials:
affiliation: IELSG
name: Andrés JM Ferreri, MD
role: STUDY_CHAIR
References:
citation: Ferreri AJM, Doorduijn JK, Re A, Cabras MG, Smith J, Ilariucci F, Luppi M, Calimeri T, Cattaneo C, Khwaja J, Botto B, Cellini C, Nassi L, Linton K, McKay P, Olivieri J, Patti C, Re F, Fanni A, Singh V, Bromberg JEC, Cozens K, Gastaldi E, Bernardi M, Cascavilla N, Davies A, Fox CP, Frezzato M, Osborne W, Liberati AM, Novak U, Zambello R, Zucca E, Cwynarski K; International Extranodal Lymphoma Study Group (IELSG). MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial. Lancet Haematol. 2021 Feb;8(2):e110-e121. doi: 10.1016/S2352-3026(20)30366-5.