Clinical trial NCT01956695: Efficacy of Lenalidomide With Rituximab in Refractory or Relapse of Primary Central Nervous System Lymphoma
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lymphoma
Relapse
Lead sponsor: Institut Curie
Sponsor class: OTHER
Collaborators: name: Centre Hospitalier Universitaire, Amiens
name: Institut Bergonié
name: University Hospital, Clermont-Ferrand
name: University Hospital, Lille
name: Central Hospital, Nancy, France
name: Groupe Hospitalier Pitie-Salpetriere
name: Centre Henri Becquerel
name: University Hospital, Tours
name: Centre Leon Berard
name: University Hospital, Grenoble
First posted: 2013-10-08
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 33 months
Secondary outcomes:
measure: The safety of the association during induction and maintenance therapy in a population of PCNSL (NCI V4)
timeFrame: 56 months
measure: The duration of response
timeFrame: 56 months
measure: Progressive Free Survival at one year from the date of inclusion to the date of progression of the disease or death
timeFrame: 56 months
measure: Overall Survival from the date of inclusion to the date of death
timeFrame: 56 months
measure: Quality of life using QLQ-C30 EORTC (European Organization for Research and Treatment of Cancer) questionnaire
timeFrame: 20 months
Other outcomes:
measure: 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
timeFrame: 33 months
Locations:
city: Clermont-Ferrand
country: France
facility: CHU Estaing
state: Auvergne
city: Tours
country: France
facility: CHU Bretonneau - Centre Henry Kaplan
state: Centre
city: Bordeaux
country: France
facility: Institut Bergonié
state: Gironde
city: Paris
country: France
facility: Hôpital de la Pitié Salpétrière
state: Ile De France
city: Saint-Cloud
country: France
facility: Institut curie - Hôpital René Huguenin
state: Ile De France
city: Grenoble
country: France
facility: Chu Michallon
state: Isère
city: Nancy
country: France
facility: Hôpital Central
state: Lorraine
city: Lille
country: France
facility: CHRU Lille - Hôpital Claude Huriez
state: Nord
city: Lyon
country: France
facility: Centre Léon Bérard
state: Rhône-Alpes
city: Rouen
country: France
facility: Centre Henri Becquerel
state: Seine Maritime
city: Amiens
country: France
facility: CHU Amiens -Hôpital Sud
state: Somme
city: Marseille
country: France
facility: Chu La Timone
Study officials:
affiliation: Institut Curie - Hopital Rene Huguenin
name: Carole SOUSSAIN, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.