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

Primary Purpose

Lymphoma, Relapse

Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Lenalidomide
Rituximab
Sponsored by
Institut Curie
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • CHU Estaing
  • CHU Bretonneau - Centre Henry Kaplan
  • Institut Bergonié
  • Hôpital de la Pitié Salpétrière
  • Institut curie - Hôpital René Huguenin
  • Chu Michallon
  • Hôpital Central
  • CHRU Lille - Hôpital Claude Huriez
  • Centre Léon Bérard
  • Centre Henri Becquerel
  • CHU Amiens -Hôpital Sud
  • Chu La Timone

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lenalidomide & Rituximab

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

Full Information

First Posted
September 24, 2013
Last Updated
December 14, 2020
Sponsor
Institut Curie
Collaborators
Centre Hospitalier Universitaire, Amiens, Institut Bergonié, University Hospital, Clermont-Ferrand, University Hospital, Lille, Central Hospital, Nancy, France, Groupe Hospitalier Pitie-Salpetriere, Centre Henri Becquerel, University Hospital, Tours, Centre Leon Berard, University Hospital, Grenoble
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1. Study Identification

Unique Protocol Identification Number
NCT01956695
Brief Title
Efficacy of Lenalidomide With Rituximab in Refractory or Relapse of Primary Central Nervous System Lymphoma
Acronym
REVRI
Official Title
Phase II Study Evaluating the Efficacy of Lenalidomide in Association With Rituximab in Refractory or Relapse of Primary Central Nervous System Lymphoma (PCNSL)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
September 18, 2013 (Actual)
Primary Completion Date
January 11, 2018 (Actual)
Study Completion Date
January 11, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut Curie
Collaborators
Centre Hospitalier Universitaire, Amiens, Institut Bergonié, University Hospital, Clermont-Ferrand, University Hospital, Lille, Central Hospital, Nancy, France, Groupe Hospitalier Pitie-Salpetriere, Centre Henri Becquerel, University Hospital, Tours, Centre Leon Berard, University Hospital, Grenoble

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma, Relapse

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
45 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lenalidomide & Rituximab
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Lenalidomide
Other Intervention Name(s)
Revlimid®
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Mabthera®
Primary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
33 months
Secondary Outcome Measure Information:
Title
The safety of the association during induction and maintenance therapy in a population of PCNSL (NCI V4)
Time Frame
56 months
Title
The duration of response
Time Frame
56 months
Title
Progressive Free Survival at one year from the date of inclusion to the date of progression of the disease or death
Time Frame
56 months
Title
Overall Survival from the date of inclusion to the date of death
Time Frame
56 months
Title
Quality of life using QLQ-C30 EORTC (European Organization for Research and Treatment of Cancer) questionnaire
Time Frame
20 months
Other Pre-specified Outcome Measures:
Title
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
Description
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
Time Frame
33 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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). Patients can have received radiotherapy or intensive chemotherapy with hematopoietic stem cell rescue as part of treatment of the PCNSL or IOL 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 Life expectancy > 2 months Able to swallow capsules (stomach tube not allowed) Adequate bone marrow function with absolute leukocytes > 2000/mm3, neutrophil count (ANC) > 1000/mm3, haemoglobin > 8 g/dl and platelets > 100 000/mm3 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) 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) Patient aged 18 years old or more and without measure of legal protection Able to understand teratogenic risks of the treatment 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. Signed inform consent Exclusion Criteria: Contraindication to any drug contained in the chemotherapy regimen or to any of their excipients T-cell lymphoma Diagnosis of any second malignancy within the last 5 years Prior history of organ transplantation or other cause of severe immunodeficiency 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). 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 Inclusion in another experimental anti-cancer drug therapy* Impossibility to follow the calendar of exams because of geographic, social or psychological reasons Patient under measure of legal protection 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carole SOUSSAIN, MD
Organizational Affiliation
Institut Curie - Hopital Rene Huguenin
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Estaing
City
Clermont-Ferrand
State/Province
Auvergne
ZIP/Postal Code
63003
Country
France
Facility Name
CHU Bretonneau - Centre Henry Kaplan
City
Tours
State/Province
Centre
ZIP/Postal Code
37044
Country
France
Facility Name
Institut Bergonié
City
Bordeaux
State/Province
Gironde
ZIP/Postal Code
33076
Country
France
Facility Name
Hôpital de la Pitié Salpétrière
City
Paris
State/Province
Ile De France
ZIP/Postal Code
75013
Country
France
Facility Name
Institut curie - Hôpital René Huguenin
City
Saint-Cloud
State/Province
Ile De France
ZIP/Postal Code
92210
Country
France
Facility Name
Chu Michallon
City
Grenoble
State/Province
Isère
ZIP/Postal Code
38043
Country
France
Facility Name
Hôpital Central
City
Nancy
State/Province
Lorraine
ZIP/Postal Code
54036
Country
France
Facility Name
CHRU Lille - Hôpital Claude Huriez
City
Lille
State/Province
Nord
ZIP/Postal Code
59037
Country
France
Facility Name
Centre Léon Bérard
City
Lyon
State/Province
Rhône-Alpes
ZIP/Postal Code
39373
Country
France
Facility Name
Centre Henri Becquerel
City
Rouen
State/Province
Seine Maritime
ZIP/Postal Code
76038
Country
France
Facility Name
CHU Amiens -Hôpital Sud
City
Amiens
State/Province
Somme
ZIP/Postal Code
80054
Country
France
Facility Name
Chu La Timone
City
Marseille
ZIP/Postal Code
13005
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
30698644
Citation
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.
Results Reference
result
Links:
URL
https://pubmed.ncbi.nlm.nih.gov/30698644/
Description
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Efficacy of Lenalidomide With Rituximab in Refractory or Relapse of Primary Central Nervous System Lymphoma

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