ACVBP Versus ACVBP Plus Rituximab in Low Risk Localized Diffuse Large B-cell Lymphoma

Diffuse Large Cell Lymphoma Clinical Trial

Official title:

Randomized Study of ACVBP Versus ACVBP Plus Rituximab in Previously Untreated Patients Aged From 18 to 65 Years With Low-risk Localized Diffuse Large B-cell Lymphoma (Age-adjusted IPI = 0)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00140660
• Other study ID #: LNH03-1B
• Status: Terminated
• Phase: Phase 3
• First received: August 31, 2005
• Last updated: March 9, 2017
• Start date: December 2003
• Est. completion date: April 2012

Study information

• Verified date: March 2017
• Source: Lymphoma Study Association
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a multicentric randomized trial evaluating the efficacy of the combination R-ACVBP in patients 18 to 65 years with low risk localized diffuse large B-cell lymphoma.

Description:

Approximately 30 to 40% of diffuse large B cell lymphomas are localized at diagnosis (stage I-II). Until the seventies, radiotherapy was used as the single modality to treat these localized stages but no more than half of the patients were cured. From the eighties, anthracycline-based regimens combined or not with radiotherapy gave superior results in term of relapse free survival compared with radiotherapy alone. Later on Miller et al. published a randomized study showing that 3 cycles of CHOP combined with radiotherapy gave superior results in term of overall survival as compared with 8 cycles of CHOP. This study was recently updated with a follow up of more than 8 years and shows no more difference between the two arms, due to an excess of late mortality after the combined treatment.

Recently, two trials were conducted by the GELA to compare chemotherapy alone to a combined chemo-radiotherapy approach in patients with low risk localized diffuse large cell lymphoma (age-adjusted IPI = 0).

• The objective of the LNH 93-1 study was to compare, in patients aged from 18 to 60 years 3 cycles of CHOP followed by radiotherapy with chemotherapy alone consisting in 3 cycles of ACVBP. The ACVBP regimen includes a more intensive induction followed by a sequential consolidation. With a median follow up of 55 months, the results have shown a superiority of the ACVBP arm for both the 5 year event free (83% vs. 74%, p = 0.004) and overall survival (89% vs. 80%, p = 0.02).

• The LNH 93-4 study compared in patients >60 years the association of 4 cycles of CHOP + radiotherapy to the same regimen without irradiation. This study fails to demonstrate any benefit of the combined chemo-radiotherapy in term of survival, but indicates that chemotherapy alone is probably less toxic in patients older than 69 years.

Considering these two trials, we concluded that radiotherapy given after chemotherapy did not give any benefit to elderly patients treated for a low risk localized diffuse large cell lymphoma, and that ACVBP regimen was superior to 3 CHOP + radiotherapy in patients <60 years, and has to be considered as the treatment of reference in these patients.

Two other GELA trials contributed recently to improve the treatment of diffuse large B cell lymphoma and have to be considered for the elaboration of future studies:

• The objective of the LNH 98-5 study was to compare the association of CHOP + rituximab (R-CHOP) to the CHOP regimen alone in elderly patients with previously untreated large B-cell lymphoma. The analysis showed a significant superiority of the association CHOP + rituximab.

• The LNH 93-5 study compared the ACVBP regimen to the CHOP in patients aged from 61 to 69 years with aggressive lymphoma and at least one adverse prognostic factor according to the International Prognostic Index. Out of 703 patients included in this study, the results have shown the same complete response rate in the two arms, but a significantly better 3-year event free survival and overall survival in the ACVBP arm than in the CHOP arm. However, the benefit seems to be greater in patients <66 years, due to higher toxicity with the ACVBP regimen in elderly patients.

All the above-mentioned results led us to propose a randomized trial comparing ACVBP to ACVBP + rituximab (R-ACVBP) in previously untreated patients with low risk localized diffuse large B-cell lymphoma (age-adjusted IPI = 0), and to extend the upper age limit from 60 to 65 years.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 223
• Est. completion date: April 2012
• Est. primary completion date: July 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Patient with histologically proven CD20+ diffuse large B-cell lymphoma (WHO classification).

• Age from 18 to 65 years.

• Patient not previously treated.

• Ann Arbor stage I or II.

• ECOG performance status < 2.

• Normal LDH.

• Negative HIV, HBV and HCV serologies 4 weeks (except after vaccination).

• Having previously signed a written informed consent.

Exclusion Criteria:

• Any other histological type of lymphoma. vAny history of treated or non-treated indolent lymphoma. However, patients not previously diagnosed and having a diffuse large B-cell lymphoma with some small cell infiltration in lymph node may be included.

• Central nervous system or meningeal involvement by lymphoma.

• Contra-indication to any drug contained in the chemotherapy regimens.

• Poor renal function (creatinin level >150 mmol/l), poor hepatic function (total bilirubin level >30 mmol/l, transaminases >2.5 maximum normal level).

• Poor bone marrow reserve as defined by neutrophils < 1.5 G/l or platelets < 100 G/l.

• Any history of cancer during the last 5 years with the exception of non-melanoma skin tumors or stage 0 (in situ) cervical carcinoma.

• Any serious active disease (according to the investigator's decision).

• Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy and during the study.

• Pregnant or lactating women

• Adult patient under tutelage.

Related Conditions & MeSH terms

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

Intervention

Drug:
• rituximab
375 mg/m2 on D1

Locations

Country	Name	City	State
Belgium	Groupe d'Etude des Lymphomes de l'adulte	Mont-Godinne
France	Hôpital Henri Mondor	Créteil
France	Hématologie CHU de Lille	Lille
France	Hématologie Adultes - Hôpital Necker	Paris
France	Hôpital Saint Louis	Paris
France	Service d'Hématologie - Centre Hospitalier Lyon-Sud	Pierre-Bénite cedex
France	Centre Hospitalier Robert Debré	Reims
France	Centre Henri Becquerel	Rouen
France	Hématologie CHU Purpan	Toulouse
France	Institut Gustave Roussy	Villejuif
Switzerland	Centre Pluridisciplinaire d'Oncologie, CHUV	Lausanne

Sponsors (2)

Lead Sponsor	Collaborator
Lymphoma Study Association	Amgen

Countries where clinical trial is conducted

Belgium,  France,  Switzerland, 

References & Publications (4)

Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. — View Citation

Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, LeBlanc M, Carlin S, Chase E, Fisher RI. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998 Jul 2;339(1):21-6. — View Citation

Reyes F, Lepage E, Ganem G, Molina TJ, Brice P, Coiffier B, Morel P, Ferme C, Bosly A, Lederlin P, Laurent G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte (GELA).. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med. 2005 Mar 24;352(12):1197-205. — View Citation

Tilly H, Lepage E, Coiffier B, Blanc M, Herbrecht R, Bosly A, Attal M, Fillet G, Guettier C, Molina TJ, Gisselbrecht C, Reyes F; Groupe d'Etude des Lymphomes de l'Adulte.. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood. 2003 Dec 15;102(13):4284-9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival (EFS)	events defined as death from any cause, relapse for complete responders (CR) and unconfirmed complete responders (CRu), progression during and after treatment and change of therapy.	4 years
Secondary	Response rate at the end of the treatment		6 months
Secondary	Disease-free survival for complete responders		4 years
Secondary	Overall survival		4 years
Secondary	additionnal toxicities with R-ACVBP	number of SAE	4 years

External Links

•   Official site of the Groupe d'Etudes des Lymphomes de l'Adulte (In french)