Primary Central Nervous System Lymphoma (PCNSL) in patients aged 18 to 60, in first-line treatment MedDRA version: 21.0 Level: LLT Classification code 10036685 Term: Primary central nervous system lymphoma System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Revlimid 5 mg
Pharmaceutical Form: Capsule, hard
Trade Name: Revlimid 10 mg
Pharmaceutical Form: Capsule, hard
Trade Name: Imbruvica 140 mg
Product Name: Ibrutinib 140 mg
Pharmaceutical
Sponsors
Institut Curie
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Newly diagnosed Primary Central Nervous System Lymphoma (PCNSL). 2. Aged between 18 and 60 (=18 and = 60). 3. Histological confirmed diagnosis of Primary central nervous system lymphoma of Diffuse Large B-Cell Lymphomas (DLBCL) type OR patients with a measurable typical cerebral lesion on MRI with a diagnosis made by cytology and/or by flow cytometry on the vitreous or on the cerebral spinal fluid. 4. Measurable lesion on MRI with gadolinium enhancement. 5. Adequate hematological, renal and hepatic function (Laboratory Parameters realized within 14 days before inclusion): a. Absolute neutrophil count (ANC)=1000/mm3 b. Platelets = 100,000/mm3 independent of transfusion support c. Alanine aminotransferase and aspartate aminotransferase = 3 x Upper Limit of Normal (ULN) d. Total bilirubin = 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin e. Estimated Glomerular Filtration Rate = 60 mL/min/1.73m2. 6. Able to swallow capsules. 7. Karnofsky performance status: 40-100% for the phase IB and no restriction on the KPS for the phase II. 8. Able to understand teratogenic risks of the Lenalidomide and Ibrutinib. Patient must be able to understand and fulfill the Lenalidomide Pregnancy Prevention Plan requirements. This plan may be accepted by the person of confidence in case of impaired cognitive status of the patient. 9. Women of childbearing potential (WCBP) and men who are sexually active must be practicing a highly effective method of birth control. Women should avoid a pregnancy while taking treatment by Lenalidomide or Ibrutinib and for up to 1 month after ending treatment. Men must agree to not to father a child or donate sperm during treatment by Lenalidomide or Ibrutinib and up to 3 months after the last dose of study drug. 10. Women of childbearing potential (WCBP) must have a negative serum (beta-human chorionic gonadotropin [Beta-hCG]) or urine pregnancy test at inclusion. 11. Signed informed consent, which could be signed by a person on confidence in case the neurologic status of the patient does not allow him to understand and/or to sign. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 128 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Histology other than DLBCL. 2. Positive HIV serology. 3. Active viral infection with Hepatitis B or C virus. 4. Preexisting immunodeficiency and/or organ transplant recipient. 5. Isolated CNS relapse of systemic NHL. 6. Prior treatment for PCNSL (except corticosteroids). 7. Isolated primary vitreo-retinal lymphoma. 8. Major surgery, within 4 weeks prior to the first dose of study drug. Stereotactic biopsy and vitrectomy are not considered major surgery. 9. History of stroke or intracranial hemorrhage (except minor post biopsy hemorrhage) within 6 months prior to inclusion. 10. Requires anticoagulation with warfarin or equivalent vitamin K antagonists. 11. Requires treatment with strong CYP3A4 inhibitors. 12. Pregnancy or lactation. 13. Clinically significant cardiovascular disease. 14. Any other active malignancy, except basocellular carcinoma and non-invasive cervix cancer. 15. Inclusion in another experimental anti-cancer drug therapy*. 16. No social security affiliation. 17. Persons under legal protection.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary objective of the study: Phase IB: To determine the Maximal Tolerated Dose (MTD) and/or RP2D (Recommended Phase II Dose) of Lenalinomide and Ibrutinib when each is administered in association with R-MPV. Phase II: To assess the complete response rates after the 4 cycles of each targeted induction chemotherapy in first-line treatment of PCNSL patients. ;Secondary Objective: 1. Complete response rate (CR + uCR) after 2 cycles 2. CR + uCR + PR, Stable Disease and primary refractory patients during induction treatment, before and after ASCT 3. 2-y OS and 2-y PFS 4. Safety of the targeted induction chemotherapy 5. Correlation between induction response and overall survival and progression free survival 6. Percentage of patients who will receive ASCT 7. Efficacy of stem cell collection and tolerance of ASCT after targeted induction chemotherapy 8. Effectiveness of salvage chemotherapies after failure of the targeted induction chemotherapy 9. Long-term survivals (OS & PFS) 10. Correlation of the IL10 & IL6 levels in CSF at diagnosis and at the end of each induction treatment with response and survivals 11. Correlation between the lymphoid subpopulations at baseline and the treatment outcomes, and variations of the lymphoid subpopulations during targeted induction treatments 12. Collection of biological samples for further ancillary studies ;Primary end point(s): Phase IB: The primary endpoint is the occurrence of a Dose Limiting Toxicity (DLT) during the first cycle of treatment for each treatment arm. The phase IB is a 3+3 dose escalation design. Phase II: The primary endpoint for the phase II part of the study is the Complete Response (CR) rate including unconfirmed CR (CR+uCR) at the end of the 4 cycles of induction therapy. Assessment of response will be based on the International Primary CNS Lymphoma Collaborative Group (IPCG). ;Timepoint(s) of evaluation of this end point: Phase IB : DLT during the first cycle of traitement for each treatmen | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Response rates (CR + uCR) after 2 cycles of induction treatment as well as overall response (CR + uCR + PR), Stable Disease (SD), and primary refractory patients (PD) after 2 and 4 cycles of induction treatment, after the 2 cycles of R-Cytarabine and after the ASCT will be evaluated according to the International Primary CNS Lymphoma Collaborative Group (IPCG). 2. Overall Survival (OS) will be calculated from the date of randomization to the date of death, whatever the cause. Patients alive at the date of last contact will be censored at this date. 3. Progression-Free Survival (PFS) will be calculated from the date of randomization to the date of progression or death (if the patient does not progress). Patients alive without progression at the date of last contact will be censored at this date. 4. The severity of the toxicity of treatment induction or ASCT will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE 5.0) whenever possible and described by system organ class, preferred term. (A patient having the same event more than once will be counted only once). 5. The percentage of patients who will receive ASCT will be presented. 6. Failure of hematopoietic stem cells collection is defined as a number of collected CD34 below 3 x 106/kg. 7. Response to salvage chemotherapies after failure of the induction chemotherapy will be evaluated according to the International Primary CNS Lymphoma Collaborative Group (IPCG). 8. Incidence of second malignancies will be calculated. ;Timepoint(s) of evaluation of this end point: • First analysis (primary end-point) at the end of the induction treatment (46 months) • Second analysis (secondary end-points) 18 months after randomization of the last patient included in the phase II • Long-term events at 5 and 10 years of the last patient included in the phase II | — |
Countries
France
Contacts
Public ContactDREH Pôle Promotion
Institut Curie
Outcome results
None listed