Efficacy of Lenalidomide With Rituximab in Refractory or Relapse of Primary Central Nervous System Lymphoma (REVRI)

Phase II Study Evaluating the Efficacy of Lenalidomide in Association With Rituximab in Refractory or Relapse of Primary Central Nervous System Lymphoma (PCNSL)

Because Primary Central Nervous System Lymphoma (PCNSL) are mainly diffuse large B-cell lymphoma of the activated B cells (ABC) type, the investigators hypothesize that the synergy of lenalidomide with rituximab shown in systemic non-Hodgkin's lymphoma (NHL) could be observed in PCNSL.

This study will assess the efficiency of the the combination of lenalidomide and rituximab in relapsed/refractory PCNSL, and the efficiency of a maintenance treatment with lenalidomide alone in maintaining the response.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Relapse
• Intervention / Treatment: Drug: Rituximab; Drug: Lenalidomide

Detailed Description

The investigators use a two-stage Fleming's design based on the following hypotheses under treatment: 10% (null hypothesis, minimal clinical benefit rate), 30% (alternative hypothesis, acceptable clinical benefit rate), 3% type I error rate, 5% type II error rate. Under these hypotheses, a total of 45 assessable patients will be necessary: 22 for the first stage + 23 for the second stage.

Stage 1: following the inclusion of the first 22 assessable patients, if 0 or 1 patient has an objective response (CR, Complete Response + uCR, unconfirmed Complete Response + PR, Partial Response) at the end of induction treatment, the study would be terminated early and the treatment will be considered ineffective. If 2 or more patients have an objective response at the end of induction treatment, then the treatment will be considered as effective in this indication. Otherwise, the second group of 23 patients will be recruited.

Stage 2: if at the end of recruitment, 8 or less patients have an objective response, the investigators will conclude to inefficacy, and if 9 or more patients have an objective response, then the treatment will be considered as effective and need further exploration.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Marseille, France, 13005
    • CHU La Timone
  • Auvergne
    • Clermont-Ferrand, Auvergne, France, 63003
      • CHU Estaing
  • Centre
    • Tours, Centre, France, 37044
      • CHU Bretonneau - Centre Henry Kaplan
  • Gironde
    • Bordeaux, Gironde, France, 33076
      • Institut Bergonié
  • Ile De France
    • Paris, Ile De France, France, 75013
      • Hôpital de la Pitié Salpêtrière
    • Saint-Cloud, Ile De France, France, 92210
      • Institut Curie - Hopital Rene Huguenin
  • Isère
    • Grenoble, Isère, France, 38043
      • CHU Michallon
  • Lorraine
    • Nancy, Lorraine, France, 54036
      • Hôpital Central
  • Nord
    • Lille, Nord, France, 59037
      • CHRU Lille - Hôpital Claude Huriez
  • Rhône-Alpes
    • Lyon, Rhône-Alpes, France, 39373
      • Centre Leon Berard
  • Seine Maritime
    • Rouen, Seine Maritime, France, 76038
      • Centre Henri Becquerel
  • Somme
    • Amiens, Somme, France, 80054
      • CHU Amiens -Hôpital Sud

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients over 18 years old with a refractory or relapse PCNSL and who have previously received at least high dose methotrexate (> 1.5 g/m²) and high dose cytarabine (2 g/m²).
2. Patients can have received radiotherapy or intensive chemotherapy with hematopoietic stem cell rescue as part of treatment of the PCNSL or IOL
3. Patients over 18 years old with a refractory or relapse IOL and who have received either intravenous high dose methotrexate (> 1.5 g/m2) or intraocular methotrexate
4. Life expectancy > 2 months
5. Able to swallow capsules (stomach tube not allowed)
6. Adequate bone marrow function with absolute leukocytes > 2000/mm3, neutrophil count (ANC) > 1000/mm3, haemoglobin > 8 g/dl and platelets > 100 000/mm3
7. Adequate liver function with Serum SGOT/AST or SGPT/ALT < 3.0 X Upper Limit of Normal ULN ; bilirubin < 1.5 X LNS (excepted in case of hemolytic anemia or Gilbert's syndrome)
8. Calculated creatinine clearance > 40 ml/min. Patients with calculated creatinine clearance between 40 and 50ml/min lenalidomide dose will be adjusted as follows (10mg once daily)
9. Patient aged 18 years old or more and without measure of legal protection
10. Able to understand teratogenic risks of the treatment
11. Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual contact during the following time periods related to this study for at least four weeks before starting study drug, while participating in the studyand for at least 4 weeks after discontinuation of Lenalidomide and 1 year after Rituximab.. Pregnancy tests (serum β-HCG dosage) will be negative at baseline and during the study. Men must agree not to procreate a child and use condoms if their partner can procreate, during all the treatment period, during dose interruptions and for at least 4 weeks after study drug discontinuation.
12. Signed inform consent

Exclusion Criteria:

1. Contraindication to any drug contained in the chemotherapy regimen or to any of their excipients
2. T-cell lymphoma
3. Diagnosis of any second malignancy within the last 5 years
4. Prior history of organ transplantation or other cause of severe immunodeficiency
5. History of heart disease and/or impaired cardiac function (ECG QTc>450msec, congenital long QT syndrome, history of ventricular tachyarrhythmia, ventricular fibrillation, congestive heart failure NYHA III/IV, uncontrolled hypertension).
6. Known HIV or HTLV-1 infection, positive serology to HB surface antigen [HBsAg] or total HB core antibody [anti-HB-c]) and Hepatitis C (Hepatitis C virus [HCV] antibody) not older than 4 weeks
7. Inclusion in another experimental anti-cancer drug therapy*
8. Impossibility to follow the calendar of exams because of geographic, social or psychological reasons
9. Patient under measure of legal protection
10. No social security *For ethical reasons, the exclusion period within which the patient cannot be included in another trial will not be defined but discussed on a case to case basis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Lenalidomide & Rituximab; Induction treatment : Lenalidomide 20 mg capsule on days 1 to 21 days of a 28 days cycle for the first cycle followed by 25 mg on daily on days 1 to 21 of a 28 days cycle for cycles 2 to 8 (in the absence of hematologic toxicity. Rituximab at day 1 of each induction course 375 mg/m² intravenous. Maintenance : Lenalidomide 10 mg capsule on days 1 to 21 days of a 28 days cycle for 1 year or until progression or intolerance.

Drug: Rituximab; Other Names: Mabthera®; Drug: Lenalidomide; Other Names: Revlimid®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the efficacy of lenalidomide in combination with rituximab in relapsed/refractory PCNSL as measured by the objective response rate (CR + uCR + PR) at the end of the 8 cycles of induction therapy.	The objective response rate (CR+uCR+PR) will be evaluated according to the IPCG (International Primary CNS lymphoma Collaborative Group) recommendations. Patients will have an cerebral MRI, an ophthalmological examination and a lumbar puncture at several times.	33 months

Secondary Outcome Measures

Outcome Measure	Time Frame
The safety of the association during induction and maintenance therapy in a population of PCNSL (NCI V4)	56 months
The duration of response	56 months
Progressive Free Survival at one year from the date of inclusion to the date of progression of the disease or death	56 months
Overall Survival from the date of inclusion to the date of death	56 months
Quality of life using QLQ-C30 EORTC (European Organization for Research and Treatment of Cancer) questionnaire	20 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploration of T cells and NK (Natural Killer) cells populations in PCNSL before and after treatment to correlate possible changes of these populations with therapeutic response	Pilot exploration of T cells and NK cells populations in PCNSL before and after treatment with the combination of lenalidomide-rituximab and to correlate possible changes of these populations with therapeutic response	33 months

Collaborators and Investigators

• Sponsor: Institut Curie
• Collaborators: Centre Leon Berard; Institut Bergonié; Centre Hospitalier Universitaire, Amiens; Central Hospital, Nancy, France; Centre Henri Becquerel; University Hospital, Clermont-Ferrand; University Hospital, Grenoble; University Hospital, Lille; Groupe Hospitalier Pitie-Salpetriere; University Hospital, Tours

Publications and helpful links

General Publications

• Ghesquieres H, Chevrier M, Laadhari M, Chinot O, Choquet S, Molucon-Chabrot C, Beauchesne P, Gressin R, Morschhauser F, Schmitt A, Gyan E, Hoang-Xuan K, Nicolas-Virelizier E, Cassoux N, Touitou V, Le Garff-Tavernier M, Savignoni A, Turbiez I, Soumelis V, Houillier C, Soussain C. Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective 'proof of concept' phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)dagger. Ann Oncol. 2019 Apr 1;30(4):621-628. doi: 10.1093/annonc/mdz032.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 18, 2013
• Primary Completion (ACTUAL): January 11, 2018
• Study Completion (ACTUAL): January 11, 2018

Study Registration Dates

• First Submitted: September 24, 2013
• First Submitted That Met QC Criteria: September 30, 2013
• First Posted (ESTIMATE): October 8, 2013

Study Record Updates

• Last Update Posted (ACTUAL): December 17, 2020
• Last Update Submitted That Met QC Criteria: December 14, 2020
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Lymphoma; Recurrence; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide; Rituximab
• Other Study ID Numbers: IC 2012-05; 2012-003786-17 (EUDRACT_NUMBER)