Primary Rituximab and Maintenance

• ClinicalTrials.gov Identifier: NCT00140582
• Recruitment Status: Completed
• First Posted: September 1, 2005
• Last Update Posted: March 13, 2017
• Sponsor: Lymphoma Study Association
• Collaborators: HOVON - Dutch Haemato-Oncology Association; German Low Grade Lymphoma Study Group; Australasian Leukaemia and Lymphoma Group; Institute of Cancer Research, United Kingdom
• Information provided by (Responsible Party): Lymphoma Study Association

Tracking Information

• First Submitted Date: August 22, 2005
• First Posted Date: September 1, 2005
• Last Update Posted Date: March 13, 2017
• Actual Study Start Date: December 2004
• Actual Primary Completion Date: May 2007 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 1, 2015)

Progression Free Survival (PFS) [ Time Frame: number of event observed driven : 344 events or 10 years ]

defined as the time from randomization to progression, relapse, death from any cause.

• Original Primary Outcome Measures (submitted: August 31, 2005): Event Free Survival (EFS) defined as the time from randomization to progression, relapse, death from any cause, or requirement of a new treatment whatever the reason.

Current Secondary Outcome Measures (submitted: September 1, 2015)

• Response rates, event driven survival endpoints (EFS, PFS, OS) [ Time Frame: number of event observed driven : 344 events or 10 years ]
• Quality of life [ Time Frame: number of event observed driven : 344 events or 10 years ]

• Original Secondary Outcome Measures (submitted: August 31, 2005): 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.
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Follicular Lymphoma

Intervention

Drug: Rituximab

rituximab 375 mg/m2 every 8 weeks for 24 months (12 injections) or control with no treatment

Study Arms

• Experimental: A : rituximab maintenance
  Maintenance with rituximab for 2 years
  Intervention: Drug: Rituximab
• No Intervention: B : no maintenance
  No further treatment

Publications *

• 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.
• 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.
• 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.
• 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. Erratum In: Lancet. 2011 Apr 2;377(9772):1154.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 2, 2007): 1217
• Original Enrollment (submitted: August 31, 2005): 640
• Actual Study Completion Date: December 2016
• Actual Primary Completion Date: May 2007 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Colombia, Denmark, France, Netherlands, New Zealand, Peru, Spain, Thailand

Administrative Information

• NCT Number: NCT00140582
• Other Study ID Numbers: PRIMA
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Lymphoma Study Association
• Original Responsible Party: Not Provided
• Current Study Sponsor: Lymphoma Study Association
• Original Study Sponsor: Same as current

Collaborators

• HOVON - Dutch Haemato-Oncology Association
• German Low Grade Lymphoma Study Group
• Australasian Leukaemia and Lymphoma Group
• Institute of Cancer Research, United Kingdom

Investigators

• Principal Investigator: Gilles A Salles, MD PhD; Lymphoma Study Association

• PRS Account: Lymphoma Study Association
• Verification Date: March 2017