Clinical trial NCT00140582: Primary Rituximab and Maintenance
Official title: Advanced Follicular Lymphoma Evaluating the Benefit of Maintenance Therapy With Rituximab (MabThera®) After Induction of Response With Chemotherapy Plus Rituximab in Comparison With no Maintenance Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Follicular Lymphoma
Keywords: lymphoma
follicular
maintenance
Lead sponsor: Lymphoma Study Association
Sponsor class: OTHER
Collaborators: name: HOVON - Dutch Haemato-Oncology Association
name: German Low Grade Lymphoma Study Group
name: Australasian Leukaemia and Lymphoma Group
name: Institute of Cancer Research, United Kingdom
First posted: 2005-09-01
Enrollment: 1217
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: * Objectives

  * Primary objective: To evaluate in patients with advanced follicular lymphoma the benefit of maintenance therapy with rituximab after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy
  * Secondary objective: To evaluate response rates, event driven survival endpoints (EFS, PFS, OS) and quality of life of four different chemotherapy regimens combined with rituximab, with or without maintenance with rituximab, for first line treatment of advanced stage follicular lymphoma.
* Study Design This is an international open-label, multicentre, randomized study with two treatment phases. In the induction phase patients have to respond to 1st line induction treatment in order to be eligible for randomization to the second phase of maintenance treatment or observation. After the maintenance period patients will be included in the follow up phase for 3 years.

Detailed description: Study medication

* First period: Induction of response with 8 x rituximab combined with 8 cycles of CVP or 6 cycles of CHOP in 21-day cycles or 6 cycles of FCM in 28-day cycles or 6 cycles of MCP in 28-day cycles.
* Second period: rituximab 375 mg/m2 every 8 weeks for 24 months (12 injections) or control with no treatment

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed follicular lymphoma grade 1, 2 or 3a.
* Patients previously untreated.
* Patients with at least one of the following symptoms requiring initiation of treatment:

  * Bulky disease at study entry according to the GELF criteria: nodal or extranodal mass \> 7cm in its greater diameter
  * B symptoms
  * Elevated serum LDH or beta2-microglobulin
  * involvement of at least 3 nodal sites (each with a diameter greater than 3 cm)
  * symptomatic splenic enlargement
  * compressive syndrome
  * pleural/peritoneal effusion
* Age must be \> 18 years.
* Performance status \< 2 on the ECOG scale (see appendix E).
* Adequate hematological function within 28 days prior to registration (unless those abnormalities are related to lymphoma extension), this includes:

  * Hemoglobin ≥ 8.0 g/dl (5.0 mmol/L)
  * Absolute neutrophil count (ANC) ≥ 1.5 109/L
  * Platelet count ≥ 100 109/L
* Women are not breast feeding, are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. Men agree not to father a child during participation in the trial and during the 12 months thereafter.
* Having previously signed a written informed consent form.

Exclusion Criteria:

* Transformation to high-grade lymphoma (secondary to "low-grade" follicular lymphoma).
* Grade 3b follicular lymphoma.
* Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningitis).
* Patients regularly taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to \< 20 mg/day prednisone.
* Patients with prior or concomitant malignancies except non-melanoma skin cancer or adequately treated in situ cervical cancer.
* Major surgery (excluding lymph node biopsy) within 28 days prior to registration.
* Poor renal function: Serum creatinine \> 2.0 mg/dl (197 μmol/L),
* Poor hepatic function: total bilirubin \> 2.0 mg/dl (34 μmol/L), AST (SGOT) \> 3 x the upper limit of normal unless these abnormalities are related to lymphoma.
* Known HIV infection or active HBV or HCV infection.
* Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease). Judgment is up to the investigator.
* Life expectancy \< 6 months
* Known sensitivity or allergy to murine products
* Treatment within a clinical trial within 30 days prior to trial entry
* Adult patient under tutelage.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: number of event observed driven : 344 events or 10 years
Secondary outcomes:
measure: Response rates, event driven survival endpoints (EFS, PFS, OS)
timeFrame: number of event observed driven : 344 events or 10 years
measure: Quality of life
timeFrame: number of event observed driven : 344 events or 10 years
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: Fundaleu Hospital
city: Melbourne
country: Australia
facility: Australian Leukemia and Lymphoma Group
city: Gent
country: Belgium
facility: Université de Gent
city: Mont-Godinne
country: Belgium
facility: Groupe d'Etude des Lymphomes de l'adulte
city: Sao Paulo
country: Brazil
facility: Hospital Samaritano
city: Bogota
country: Colombia
facility: Fundación Santafé de Bogotá
city: Herlev
country: Denmark
facility: Amtssygehuset i Herlev
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Lille
country: France
facility: Hématologie CHU de Lille
city: Lyon
country: France
facility: Centre Léon Bérard
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hématologie Adultes - Hôpital Necker
city: Pierre-Bénite cedex
country: France
facility: Service d'Hématologie - Centre Hospitalier Lyon-Sud
city: Reims
country: France
facility: Centre Hospitalier Robert Debré
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Toulouse
country: France
facility: Hématologie CHU Purpan
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Utrecht
country: Netherlands
facility: HOVON
city: Auckland
country: New Zealand
facility: Australia New Zealand Leukemia Lymphoma Group
city: Lima
country: Peru
facility: Instituo Nacional de Enfermedades Neoplasicas
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
Study officials:
affiliation: Lymphoma Study Association
name: Gilles A Salles, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bachy E, Seymour JF, Feugier P, Offner F, Lopez-Guillermo A, Belada D, Xerri L, Catalano JV, Brice P, Lemonnier F, Martin A, Casasnovas O, Pedersen LM, Dorvaux V, Simpson D, Leppa S, Gabarre J, da Silva MG, Glaisner S, Ysebaert L, Vekhoff A, Intragumtornchai T, Le Gouill S, Lister A, Estell JA, Milone G, Sonet A, Farhi J, Zeuner H, Tilly H, Salles G. Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. J Clin Oncol. 2019 Nov 1;37(31):2815-2824. doi: 10.1200/JCO.19.01073. Epub 2019 Jul 24.
citation: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. doi: 10.1179/1607845414Y.0000000179. Epub 2014 Jul 16.
citation: Ghesquieres H, Cartron G, Seymour JF, Delfau-Larue MH, Offner F, Soubeyran P, Perrot A, Brice P, Bouabdallah R, Sonet A, Dupuis J, Casasnovas O, Catalano JV, Delmer A, Jardin F, Verney A, Dartigues P, Salles G. Clinical outcome of patients with follicular lymphoma receiving chemoimmunotherapy in the PRIMA study is not affected by FCGR3A and FCGR2A polymorphisms. Blood. 2012 Sep 27;120(13):2650-7. doi: 10.1182/blood-2012-05-431825. Epub 2012 Aug 10.
citation: Salles G, Seymour JF, Offner F, Lopez-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Ferme C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. doi: 10.1016/S0140-6736(10)62175-7. Epub 2010 Dec 20.