Clinical trial NCT04446962: LOC-R01 Study of Lenalidomide and Ibrutinib in Association With Rituximab-Methotrexate Procarbazine Vincristin (R-MPV)
Official title: LOC-R01: Randomized Phase IB/II Study of Escalating Doses of Lenalidomide and Ibrutinib in Association With R-MPV as a Targeted Induction Treatment for Patients Aged 18 to 60 (up to 65 for Phase II) With a Newly Diagnosed Primary Central Nervous System Lymphoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Lymphoma, Large B-Cell, Diffuse
Central Nervous System Neoplasms, Primary
Keywords: Lymphoma
Nervous System
Primary
Lead sponsor: Institut Curie
Sponsor class: OTHER
Collaborators: name: National Cancer Institute, France
First posted: 2020-06-25
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is to improve the first-line induction chemotherapy, by combining either Ibrutinib, or Lenalidomide, to a conventional immuno- chemotherapy of R-MPV type (Rituximab-Methotrexate-Procarbazine-Vincristine). This is a randomized Phase II trial, preceded by a dose escalation phase Ib. The objective of the phase Ib is to rule out any limiting toxicity of the new treatment associations, and to determine the recommended dose of Lenalidomide and Ibrutinib to be used in the phase II. In the phase II study, patients will receive 4 cycles of R-MPV + Lenalidomide or 4 cycles of R-MPV + Ibrutinib. The therapeutic response will be evaluated after the 2nd and the 4th cycle. Patients in good therapeutic response will proceed to the consolidation phase with Autologous Stem Cell Transplantation (ASCT).

Detailed description: The objective of this proposal is to test the feasibility and efficacy of two targeted induction chemotherapies obtained by adding either Lenalidomide or Ibrutinib to a standard Rituximab-High Dose (HD) Methotrexate (MTX) based induction chemotherapy regimen. The R-MPV regimen is chosen as the backbone chemotherapy because of its wide use with robust reproducible results and a good and manageable toxicity profile

Eligibility criteria: Inclusion Criteria:

1. Newly diagnosed Primary Central Nervous System Lymphoma (PCNSL).
2. a) Aged between 18 and 60 (\>18 and \< 60) - phase IB b) Aged between 18 and 65 (≥ 18 and ≤ 65) - phase II.
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):

   1. Absolute neutrophil count (ANC) \>1000/mm3
   2. Platelets \> 100,000/mm3 independent of transfusion support
   3. Alanine aminotransferase and aspartate aminotransferase ≤ 3 x Upper Limit of Normal (ULN)
   4. Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
   5. 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 \[B-hCG\]) 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.

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 Central Nervous System (CNS) relapse of systemic Non-Hodgkin's Lymphoma.
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.

Primary outcomes:
measure: Dose Limiting Toxicity (DLT) during the first cycle of treatment for each treatment arm.
timeFrame: 1 month
measure: Complete Response (CR) rate including unconfirmed Complete Response (uCR) at the end of the 4 cycles of induction therapy
timeFrame: 4 months
Secondary outcomes:
measure: Response rates (CR + uCR) after 2 cycles of induction treatment
timeFrame: 2 months
measure: Overall response (CR + uCR + Partial Response(PR)), stable disease (SD), and primary refractory patients (PD) after 2 cycles of induction treatment
timeFrame: 2 months
measure: Overall response (CR + uCR + Partial Response(PR)), stable disease (SD), and primary refractory patients (PD) after 4 cycles of induction treatment
timeFrame: 4 months
measure: Overall Survival (OS)
timeFrame: 142 months
measure: Progression-Free Survival (PFS)
timeFrame: 142 months
measure: The severity of the toxicity of treatment induction or ASCT
timeFrame: 7 months
measure: Patients who will receive ASCT
timeFrame: 7 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens
city: Angers
country: France
facility: CHU Angers
city: Bayonne
country: France
facility: CH côte Basque
city: Besançon
country: France
facility: CHU Besançon
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: CHU Caen
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
city: Colmar
country: France
facility: CH Colmar
city: Créteil
country: France
facility: CHU Créteil
city: Dijon
country: France
facility: CHU Dijon
city: Grenoble
country: France
facility: CHU Grenoble
city: Lille
country: France
facility: CHRU Lille
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: CHU Lyon
city: Marseille
country: France
facility: CHU La Timone Marseille
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: Centre Lacassagne
city: Nîmes
country: France
facility: CHU Nîmes - Carémeau
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: CHU Pitié-Salpêtrière
city: Poitiers
country: France
facility: CHU Poitiers
city: Rennes
country: France
facility: CHU Rennes
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Strasbourg
country: France
facility: institut de Cancérologie de Strasbourg
city: Toulouse
country: France
facility: IUCT -Oncopole
city: Tours
country: France
facility: CHU Tours
Study officials:
affiliation: Institut Curie
name: Steven LE GOUILL, PhD
role: STUDY_DIRECTOR
References: