R-CHOP-14 Versus R-CHOP-21 and Darbepoetin Alpha in Patients Aged 60-80 Years With Diffuse Large B-cell Lymphoma

Diffuse Large Cell Lymphoma Clinical Trial

Official title:

Intensified CHOP Plus Rituximab (R-CHOP 14) Versus CHOP Plus Rituximab (R-CHOP 21) and Frontline/Prophylactic Darbepoetin Alfa Treatment Versus Usual Symptomatic Treatment of Anemia in Patients Aged 60 to 80 Years With Diffuse Large B-cell Lymphoma.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00144755
• Other study ID #: LNH03-6B
• Status: Completed
• Phase: Phase 3
• First received: September 2, 2005
• Last updated: September 1, 2015
• Start date: December 2003
• Est. completion date: December 2012

Study information

• Verified date: September 2015
• Source: Lymphoma Study Association
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial Summary

This study is a multicentric randomized trial evaluating the efficacy and safety of R-CHOP given every 14 days compared to R-CHOP given every 21 days in association or not with darbepoetin alfa in order to maintain hemoglobin above 13 g/dl, compared to classical symptomatic treatment of anemia in patients aged from 60 to 80 years with diffuse large B-cell lymphoma.

Description:

In patients aged 60 to 75 years with diffuse large B-cell lymphoma, the shortening of interval between the courses of CHOP combination (CHOP-14), improves the complete response rate, the progression free survival and the overall survival.

The addition of Rituximab to standard CHOP (R-CHOP) has also been shown to improve complete remission rate (CR), event-free survival (EFS) and overall survival (OS) in elderly patients with B-DLCL.

The aim of this study is to test the hypothesis that the increase of the dose intensity by shortening the interval between two courses of R-CHOP (R-CHOP-14)could further improve the results of the R-CHOP.

Anemia is frequent at diagnosis and during the treatment of aggressive lymphoma. In the previous LNH 98-5 study, 72 % of the patients had, at the diagnosis, a hemoglobin level inferior to 13 g/dl. Moreover, during the treatment, 92 % of the patients had a hemoglobin level less than 13 g/dl and 30 % were transfused. The presence of anemia at diagnosis is an indicator of poor prognosis in multivariate analysis. This prognosis impact could probably be explained at cellular level on the tumor. Tumoral hypoxia is increased by the presence of anemia. Due to this hypoxia, the expression of tumor growth factor may be increased: e.a VEGF and the induction of expression of multi drug resistance (MDR1) is observed. This resistance to treatment is also due to the inhibition of genotoxic activity of free radicals induced by ionised radiation and chemotherapy. Experimentally, the negative impact of hypoxia on the efficacy of chemotherapy has been demonstrated in sarcoma cell lines for doxorubicin, vincristine and all most cyclophosphamide. Finally, hypoxia induced over expression of apoptosis resistance genes and induced a growth advantage for apoptosis resistant tumoral lines. Improvement of survival in patients receiving erythropoetin with chemotherapy or radiotherapy was suggested in a study on patients treated with a neoadjuvant radiochemotherapy for head and neck cancer. Erythropoetin could act to protect several normal tissues during chemotherapy and thus could decrease treatment related morbidity. Darbepoetin alfa is a new recombinant protein stimulating erythropoiesis. Thus, the use of darbepoetin alfa, in association with chemotherapy, could increase CR rate, EFS and OS in patients treated for diffuse large B-cell lymphoma.

This study is a multicentric, phase III open-label, randomized trial evaluating the efficacy and safety of R-CHOP given every 14 days compared to R-CHOP given every 21 days in association or not with darbepoetin alfa in order to maintain hemoglobin above 13 g/dl, compared to classical symptomatic treatment of anemia in patients aged 66 to 80 years with not previously treated diffuse large B-cell lymphoma with at least one adverse prognostic factor of the age adjusted IPI.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 600
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 60 Years to 80 Years

Eligibility

Inclusion Criteria:

Patients with histologically proven CD20+ diffuse large B cell lymphoma (WHO Classification).

Aged 66 to 80 years old. Patients not previously treated. Ann Arbor stage II, III, IV. ECOG performance status 0 to 2. Age-adjusted IPI equal to 1, 2, or 3. With a minimum life expectancy of 3 months. Negative HIV, HBV and HCV serologies test < 4 weeks (except after vaccination for HBV).

Having signed a written informed consent.

Exclusion Criteria:

Any other histological type of lymphoma. Any 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 bone marrow or lymph node may be included.

Central nervous system or meningeal involvement by lymphoma. Contra-indication to any drug contained in the chemotherapy regimens. Any serious co-morbid active disease (according to the investigator's decision).

Poor renal function (creatinin level > 150 micromol/l), poor hepatic function (total bilirubin level > 30mmol/l, transaminases > 2.5 maximum normal level) unless these abnormalities are related to the lymphoma.

Poor bone marrow reserve as defined by neutrophils < 1.5 G/l or platelets < 100 G/l, unless related to bone marrow infiltration.

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

Uncontrolled hypertension. Known hypersensitivity to erythropoietin. Myocardial infarction during last 3 month, or unstable coronary disease, or uncontrolled cardiac insufficiency.

Venous thrombosis or pulmonary embolism during last 3 months. 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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• Darbepoetin alfa
prophylactic administration of darbepoetin alfa in experimental arm

Locations

Country	Name	City	State
Belgium	Université de Gent	Gent
Belgium	Groupe d'Etude des Lymphomes de l'adulte	Mont-Godinne
France	Polyclinique Bordeaux Nord	Bordeaux
France	Hôpital Henri Mondor	Créteil
France	Hématologie CHU de Lille	Lille
France	Centre Léon Bérard	Lyon
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	Schweirische Arbeitsgruppe fur klinische Krebsforschung	Lausanne

Sponsors (2)

Lead Sponsor	Collaborator
Lymphoma Study Association	Amgen

Countries where clinical trial is conducted

Belgium,  France,  Switzerland, 

References & Publications (2)

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. Epub 2005 May 2. — View Citation

Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, Hasenclever D, Schmitz N, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):634-41. Epub 2004 Mar 11. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy of R-CHOP 14 vs R-CHOP 21 measured by event-free survival (EFS)		8 years	No
Secondary	Efficacy of darbepoetin alfa in association with chemotherapy measured by the EFS.		8 years	No
Secondary	Efficacy and toxicity of R-CHOP 14 vs R-CHOP 21	CR rate, DFS, OS, dose intensity and additional toxicities.	8 years	Yes
Secondary	Efficacy and toxicity of Darbepoetin alfa in association with R-CHOP.	event-free survival	8 years	Yes

External Links

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