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

Lymphoma, Large B-Cell, Diffuse Clinical Trial

— LOC-R01  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04446962
• Other study ID #: IC 2019-02
• Secondary ID: 2019-003632-23
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 30, 2020
• Est. completion date: January 15, 2031

Study information

• Verified date: November 2023
• Source: Institut Curie
• Contact: Carole SOUSSAIN, MD
• Phone: +33 1 47 11 15 15
• Email: carole.soussain[@]curie.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 118
• Est. completion date: January 15, 2031
• Est. primary completion date: January 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Central Nervous System Neoplasms
• Central Nervous System Neoplasms, Primary
• Lymphoma
• Lymphoma, Large B-Cell, Diffuse
• Nervous System Neoplasms

Intervention

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.
• 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.

Locations

Country	Name	City	State
France	CHU Amiens	Amiens
France	CHU Angers	Angers
France	CH côte Basque	Bayonne
France	CHU Besançon	Besançon
France	Institut Bergonié	Bordeaux
France	CHU Caen	Caen
France	CHU Clermont-Ferrand	Clermont-Ferrand
France	CH Colmar	Colmar
France	CHU Créteil	Créteil
France	CHU Dijon	Dijon
France	CHU Grenoble	Grenoble
France	CHRU Lille	Lille
France	CHU Limoges	Limoges
France	CHU Lyon	Lyon
France	CHU La Timone Marseille	Marseille
France	CHU Nancy	Nancy
France	CHU Nantes	Nantes
France	Centre Lacassagne	Nice
France	CHU Nîmes - Carémeau	Nîmes
France	CHU Pitié-Salpêtrière	Paris
France	Hôpital Cochin	Paris
France	Institut Curie	Paris
France	CHU Poitiers	Poitiers
France	CHU Rennes	Rennes
France	Centre Henri Becquerel	Rouen
France	CHU de La Réunion	Saint Denis De La Reunion
France	institut de Cancérologie de Strasbourg	Strasbourg
France	IUCT -Oncopole	Toulouse
France	CHU Tours	Tours

Sponsors (2)

Lead Sponsor	Collaborator
Institut Curie	National Cancer Institute, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Patients who will receive ASCT	The percentage of patients who will receive ASCT will be presented	7 months