LOC-R01 Study of Lenalidomide and Ibrutinib in Association With Rituximab-Methotrexate Procarbazine Vincristin (R-MPV) (LOC-R01)

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

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).

Study Overview

• Status: Recruiting
• Conditions: Lymphoma, Large B-Cell, Diffuse; Central Nervous System Neoplasms, Primary
• Intervention / Treatment: Drug: Lenalidomide; Drug: Ibrutinib

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

• Study Type: Interventional
• Enrollment (Estimated): 118
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Carole SOUSSAIN, MD; Phone Number: +33 1 47 11 15 15; Email: carole.soussain@curie.fr
• Study Contact Backup: Name: LYNDA CORVI; Phone Number: +33 1 47 11 17 33; Email: drci.promotion@curie.fr

Study Locations

• France
  • Amiens, France
    • Recruiting
    • CHU Amiens
    • Contact: Caroline DELETTE, MD
    • Principal Investigator: Caroline DELETTE, MD
  • Angers, France
    • Recruiting
    • CHU Angers
    • Contact: Jérôme PAILLASSA, MD
    • Contact: Email: jerome.paillassa@chu-angers.fr
    • Principal Investigator: Jérôme PAILLASSA, MD
  • Bayonne, France, 64100
    • Not yet recruiting
    • CH Cote Basque
    • Contact: Sophie BERNARD, MD
    • Principal Investigator: Sophie BERNARD, MD
  • Besançon, France
    • Recruiting
    • CHU Besançon
    • Contact: Adrien Chauchet, MD
    • Principal Investigator: Adrien CHAUCHET, MD
  • Bordeaux, France
    • Recruiting
    • Institut Bergonie
    • Contact: Anna Schmitt, MD
    • Principal Investigator: Anna SCHMITT, MD
  • Caen, France
    • Recruiting
    • CHU Caen
    • Contact: Gandhi DAMAJ, MD
    • Principal Investigator: Gandhi DAMAJ, PhD
  • Clermont-Ferrand, France
    • Recruiting
    • CHU Clermont-Ferrand
    • Contact: Cécile MOLUCON-CHABROT, MD
    • Principal Investigator: Cécile MOLUCON-CHABROT, MD
  • Colmar, France
    • Recruiting
    • CH Colmar
    • Contact: Guido AHLE, MD
    • Principal Investigator: Guido AHLE Guido AHLE, MD
  • Créteil, France
    • Not yet recruiting
    • CHU Créteil
    • Contact: Louise ROULIN, MD
    • Principal Investigator: Louise ROULIN, MD
  • Dijon, France
    • Terminated
    • CHU Dijon
  • Grenoble, France
    • Recruiting
    • CHU Grenoble
    • Principal Investigator: Rémy GRESSIN, MD
    • Contact: Rémy Rémy GRESSIN, MD
  • Lille, France, 69000
    • Recruiting
    • CHRU Lille
    • Contact: Franck MORSCHHAUSER, PhD
    • Principal Investigator: Franck MORSCHHAUSER, PhD
  • Limoges, France
    • Recruiting
    • CHU Limoges
    • Contact: Julie Abraham, MD
    • Principal Investigator: ABRAHAM Julie, MD
  • Lyon, France
    • Recruiting
    • CHU Lyon
    • Contact: Hervé GHESQUIERES, MD
    • Principal Investigator: Hervé GHESQUIERES, Phd
  • Marseille, France
    • Recruiting
    • CHU La Timone Marseille
    • Contact: Olivier Chinot, MD
    • Principal Investigator: Olivier Chinot, MD
  • Nancy, France
    • Recruiting
    • CHU Nancy
    • Contact: Luc TAILLANDIER, PhD
    • Principal Investigator: Luc TAILLANDIER, PhD
  • Nantes, France
    • Recruiting
    • CHU Nantes
    • Principal Investigator: Thomas Gastinne, MD
    • Contact: Thomas GASTINNE, MD
  • Nice, France
    • Recruiting
    • Centre Lacassagne
    • Contact: Frédéric PEYRADE, MD
    • Principal Investigator: Frédéric PEYRADE, MD
  • Nîmes, France, 30029
    • Not yet recruiting
    • CHU Nîmes - Carémeau
    • Contact: Agathe WAULTIER-RASCALOU, MD
    • Principal Investigator: Agathe Waultier-Rascalou, MD
  • Paris, France, 75005
    • Recruiting
    • Institut Curie
    • Contact: Carole Soussain, MD
    • Principal Investigator: Carole Soussain, MD
  • Paris, France, 75006
    • Recruiting
    • Hopital Cochin
    • Contact: Lise WILLEMS, MD
    • Principal Investigator: Lise WILLEMS, MD
  • Paris, France, 75013
    • Recruiting
    • CHU Pitié-Salpêtrière
    • Contact: Caroline HOUILLIER, MD
    • Principal Investigator: Caroline HOUILLIER, MD
  • Poitiers, France
    • Not yet recruiting
    • CHU Poitiers
    • Contact: Vincent DELWAIL, MD
    • Principal Investigator: Vincent DELWAIL, MD
  • Rennes, France, 35000
    • Recruiting
    • CHU Rennes
    • Contact: Thierry LAMY De La CHAPELLE, PhD
    • Principal Investigator: Thierry Thierry LAMY De La CHAPELLE, PhD
  • Rouen, France, 76000
    • Recruiting
    • Centre Henri Becquerel
    • Contact: Fabrice JARDIN, PhD
    • Principal Investigator: Fabrice JARDIN, PhD
  • Saint Denis De La Reunion, France, 97400
    • Not yet recruiting
    • CHU de la Réunion
    • Contact: MD
    • Contact: Marie DE CHARETTE, MD
    • Principal Investigator: Marie DE CHARETTE, MD
  • Strasbourg, France, 67033
    • Not yet recruiting
    • Institut de Cancerologie de Strasbourg
    • Contact: Luc-Mathieu FORNECKER, MD
    • Principal Investigator: Luc-Mathieu FORNECKER, MD
  • Toulouse, France
    • Recruiting
    • IUCT -Oncopole
    • Contact: Lucie Obéric, MD
    • Principal Investigator: Lucie Obéric, MD
  • Tours, France
    • Recruiting
    • Chu Tours
    • Principal Investigator: Emmanuel GYAN, MD
    • Contact: Emmanuel GYAN, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A: R-MPV with Lenalidomide; Lenalidomide in association with R-MPV as a targeted induction treatment	Drug: Lenalidomide; Patients will receive 4 cycles of induction chemotherapy with R-MPV + Lenalidomide using the Maximum Tolerated Dose (MTD) of Lenalidomide and Ibrutinib as determined in the phase-Ib part of the study.; Other Names: Revlimid
Active Comparator: Arm B: R-MPV with Ibrutinib; Ibrutinib in association with R-MPV as a targeted induction treatment	Drug: Ibrutinib; Patients will receive 4 cycles of induction chemotherapy with R-MPV + Ibrutinib, using the Maximum Tolerated Dose (MTD) of Lenalidomide and Ibrutinib as determined in the phase-Ib part of the study.; Other Names: Imbruvica

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicity (DLT) during the first cycle of treatment for each treatment arm.	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	1 month
Complete Response (CR) rate including unconfirmed Complete Response (uCR) at the end of the 4 cycles of induction therapy	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 Central Nervous System Lymphoma Collaborative Group (IPCG)	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rates (CR + uCR) after 2 cycles of induction treatment	Assessment of response will be based on the International Primary Central Nervous System Lymphoma Collaborative Group (IPCG)	2 months
Overall response (CR + uCR + Partial Response(PR)), stable disease (SD), and primary refractory patients (PD) after 2 cycles of induction treatment	Assessment of response will be based on the International Primary Central Nervous System Lymphoma Collaborative Group (IPCG)	2 months
Overall response (CR + uCR + Partial Response(PR)), stable disease (SD), and primary refractory patients (PD) after 4 cycles of induction treatment	Assessment of response will be based on the International Primary Central Nervous System Lymphoma Collaborative Group (IPCG)	4 months
Overall Survival (OS)	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.	142 months
Progression-Free Survival (PFS)	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	142 months
The severity of the toxicity of treatment induction or ASCT	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	7 months
Patients who will receive ASCT	The percentage of patients who will receive ASCT will be presented	7 months

Collaborators and Investigators

• Sponsor: Institut Curie
• Collaborators: National Cancer Institute, France
• Investigators: Study Director: Steven Le GOUILL, PhD, Institut Curie

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2020
• Primary Completion (Estimated): January 15, 2024
• Study Completion (Estimated): January 15, 2031

Study Registration Dates

• First Submitted: June 22, 2020
• First Submitted That Met QC Criteria: June 22, 2020
• First Posted (Actual): June 25, 2020

Study Record Updates

• Last Update Posted (Actual): January 12, 2024
• Last Update Submitted That Met QC Criteria: January 10, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Lymphoma; Primary; Nervous System
• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Neoplasms by Site; Lymphoma, B-Cell; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Nervous System Neoplasms; Central Nervous System Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide
• Other Study ID Numbers: IC 2019-02; 2019-003632-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Sponsor will share de-identified data sets generated under the project will be disseminated in accordance with Institut Curie policies.
• IPD Sharing Time Frame: Data requests can be submitted starting 9 months after last article publication and will be made accessible for up to 12 months.
• IPD Sharing Access Criteria: Access to trial individual participant data can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a data sharing agreement (DSA).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No