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

Diffuse Large B-cell Lymphoma Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02329080
• Other study ID #: IELSG42
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 2014
• Est. completion date: December 2023

Study information

• Verified date: May 2023
• Source: International Extranodal Lymphoma Study Group (IELSG)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 76
• Est. completion date: December 2023
• Est. primary completion date: August 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diffuse Large B-cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• Methotrexate
methotrexate 3.5 g/m2 on day 1 courses 1, 2,3 of MATRIX regimen
• 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)
• Cytarabine
Cytarabine 2 g/m2 every 12 hours, in 3-hr infusion on days 2,3 courses 1, 2,3 (MATRIX regimen)
• 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
• 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)
• 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)
• Ifosfamide
Ifosfamide 5 g/m2 in 1.000 mL saline sol. in 24-hour infusion on day 2 courses 4,5,6 (R-ICE)
• 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.

Locations

Country	Name	City	State
Czechia	Facultni nemocnice	Brno
Czechia	FNKV (Facultni Nemocnice Kralovske Vinohrady)	Praha
Czechia	Vseobecna facultni nemocnice v Praze	Praha
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	San Raffaele H Scientific Institute	Milan
Italy	Istituto Nazionale Tumori	Milano
Italy	Ospedale Maggiore Policlinico	Milano
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
Netherlands	Erasmus MC	Rotterdam
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

Sponsors (1)

Lead Sponsor	Collaborator
International Extranodal Lymphoma Study Group (IELSG)

Countries where clinical trial is conducted

Czechia,  Italy,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	progression free survival		one year
Secondary	Complete remission rate		at the end of chemoimmunotherapy (up to 22-24 weeks from treatment start)
Secondary	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
Secondary	overall survival		from entry onto trial until death from any cause or date of the last visit of follow-up (5 years)
Secondary	number of participants with adverse events		from time informed consent is given until 30 days after end of treatment