Study of OBINUTUZUMAB Combined to LENALIDOMIDE for the Treatment of Relapsed/Refractory Follicular and Aggressive B-cell Lymphoma

A Phase Ib/II Study of OBINUTUZUMAB Combined to LENALIDOMIDE for the Treatment of Follicular and Relapsed/Refractory Aggressive (DLBCL and MCL) B-cell Lymphoma

This study is to determine first the appropriate dose of lenalidomide to administer in combination with fixed doses of obinutuzumab in relapsed/refractory follicular lymphoma patients.

In a second step, this study aims to determine the efficacy of this combination in 3 separate populations: relapsed/refractory aggressive lymphoma (diffuse large B-cell lymphoma and mantle cell lymphoma: cohort 1), relapsed/refractory follicular lymphoma (cohort 2) and previously untreated follicular lymphoma (cohorts 3 and 4).

Study Overview

• Status: Completed
• Conditions: Follicular Lymphoma Patients (Phase IB); Follicular and Agressive (DLBCL&MCL) B-cell Lymphoma Patients (Phase II)
• Intervention / Treatment: Drug: Lenalidomide and GA101

Detailed Description

This study is an open label, multicenter study with two phases:

The Phase IB part of the study is a dose escalation study of lenalidomide (Revlimid) administered orally during on 3 weeks of every 28-day cycle, in combination with fixed doses of obinutuzumab (GA101) in relapsed/refractory follicular lymphoma patients.

The Phase II part of the study is an efficacy study of the association of the recommended dose of lenalidomide associated with GA101 in 2 separate populations of patients: relapsed/refractory aggressive lymphoma (diffuse large B-cell lymphoma and mantle cell lymphoma: cohort 1), relapsed/refractory follicular lymphoma (cohort 2) and previously untreated follicular lymphoma (cohorts 3 and 4). First, all patients will receive a combination of obinutuzumab and lenalidomide for a total of 6 cycles. Patients who achieve at least a partial response after 6 cycles will receive a maintenance treatment with obinutuzumab for 2 years and Lenalidomide for 1 year as tolerated, or until disease progression.

• Study Type: Interventional
• Enrollment (Actual): 317
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium, 2060
    • ZNA Stuivenberg
  • Bruges, Belgium, 8000
    • A.Z. Sint Jan AV
  • Bruxelles, Belgium, 1000
    • Institut Jules Bordet
  • Bruxelles, Belgium, 1200
    • Université Catholique de Louvain Saint Luc
  • Kortrijk, Belgium, 8500
    • AZ Groeninge - Campus Maria's Voorzienigheid
  • Liège, Belgium, 4000
    • CHU de Liège
  • Yvoir, Belgium, 5530
    • Universite Catholique de Louvain Mont Godinne
• France
  • Amiens, France, 80054
    • CHU D'amiens
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Caen, France, 14076
    • Institut d'Hématologie de Basse Normandie
  • Clermont-Ferrand, France, 63000
    • CHU d'Estaing
  • Créteil, France, 94010
    • Hopital Henri Mondor
  • Dijon, France, 21034
    • CHU de DIJON
  • Grenoble, France, 38043
    • Chu de Grenoble
  • Lille, France, 59037
    • CHRU de Lille
  • Lyon, France, 69373
    • Centre Léon Bérard
  • Marseille, France, 13273
    • Institut Paoli Calmette
  • Montpellier, France, 34295
    • CHU St Eloi
  • Nancy, France, 54511
    • CHU Brabois
  • Nantes, France, 44093
    • Chu Hotel Dieu
  • Paris, France, 75475
    • Hôpital St Louis
  • Pessac, France, 33604
    • Centre Francois Magendie
  • Pierre Bénite, France, 69495
    • CH Lyon Sud
  • Rennes, France, 35003
    • Chu Pontchaillou
  • Rouen, France, 76038
    • Centre Henri Becquerel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Phase IB only: Histologically documented CD20-positive follicular lymphoma (WHO grade 1, 2, or 3a) patients
• Phase II: Patients with either histologically documented CD20-positive Diffuse large-cell lymphoma or Mantle cell lymphoma (cohort 1) or follicular lymphoma, WHO grade 1, 2 or 3a (cohort 2-3-4)
• Phase IB and II:
• Relapsed/refractory NHL after ≥1 prior R-containing regimen with no curative option (cohort 2 only)
• Aged 18 years or more
• ECOG performance status 0, 1 or 2
• At least one bi-dimensionally measurable nodal or tumor lesion defined by CT scan as: greatest transverse diameter > 1.5 cm and a short axis ≥ 10mm
• Signed inform consent
• Life expectancy ≥ 3 months.
• All subjects must be able to understand and fulfill the lenalidomide Pregnancy Prevention Plan requirements (see in appendix)
• 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: 1) for at least 28 days before starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 2 months after discontinuation of all study treatments.

Exclusion Criteria:

• Previous treatment with obinutuzumab or lenalidomide
• Known CD20 negative status at relapse/progression. Biopsy at relapse/progression is recommended but not mandatory
• Central nervous system or meningeal involvement by lymphoma
• Contraindication to any drug contained in the study treatment regimen
• 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)
• Any serious active disease or co-morbid medical condition (such as New York Heart Association Class II or IV cardiac disease, severe arrhythmia, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm or other according to investigator's decision)

• Any of the following laboratory abnormalities unless secondary to underlying lymphoma:

  • Absolute neutrophil count (ANC) < 1,500 cells/mm3 (1.5 x 109/L).
  • Platelet count < 100,000/mm3 (100 x 109/L) unless due to lymphoma for phase II part.
  • Serum SGOT/AST or SGPT/ALT 3.0 x upper limit of normal (ULN) unless disease involvement.
  • Serum total bilirubin > 2.0 mg/dL (34 μmol/L), except if disease related or in case of Gilbert syndrome
  • Calculated creatinine clearance (Cockcroft-Gault formula or MDRD) of < 50 mL /min. For phase II part of the study, patients with calculated creatinine clearance between 30 and 50ml/min can be included and lenalidomide dose will be adjusted as follows (10mg once daily)
• Prior history of malignancies other than lymphoma unless the subject has been free of the disease for ≥ 5 years
• Any serious medical condition, laboratory abnormality (other than mentioned above), or psychiatric illness that would prevent the subject from signing the informed consent form.
• Pregnant or lactating females.
• Prior ≥ Grade 3 allergic reaction/hypersensitivity to thalidomide.
• Prior ≥ Grade 3 rash or any desquamating (blistering) rash while taking thalidomide.
• Subjects with ≥ Grade 2 neuropathy.
• Use of any standard or experimental anti-cancer drug therapy within 28 days of the initiation (Day 1) of study drug therapy
• Patients taking corticosteroids during 4 weeks before inclusion, unless administered at a dose equivalent to ≤ 10 mg/day prednisone (over these 4 weeks)
• Prior history of Progressive Multifocal Leukoencephalopathy (PML)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lenalidomide and GA101; Ga101 and lenalidomide	Drug: Lenalidomide and GA101; 1000mg of GA101 on D8, D15 and D22of cycle 1 and on D1 of cycles 2 to 6. Oral lenalidomide once daily at 10/15/20/25mg (phase I part) or at recommended dose (phase II part) on days 1 to 21 of a 28-day cycle for the first cycle and on days 2 to 22 of a 28-day cycle for cycles 2 to 6.; Other Names: Revlimid; Obinutuzumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I part: Determination of the recommended dose of lenalidomide in combination with fixed doses of GA101	The determination of the recommended dose of lenalidomide in combination with fixed doses of GA101 will be performed by a dose escalation approach. Dose Limiting Toxicities (DLTs) observed during the administration of the first 2 cycles of the study will be listed for each escalation step.	28 days
Phase II part: Overall Response Rate (CR+CRu+PR) after 6 cycles	Response rates at the end of treatment including maintenance will be expressed as percentages with their 95% Exact Clopper Pearson Confidence Interval limits	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Overall survival will be measured from the date of inclusion to the date of death from any cause. Alive patients will be censored at their last date known to be alive	Up to 4.5 years
Event Free survival	Event-Free Survival will be measured from the date of inclusion to the date of first documented disease progression, relapse, initiation of new anti-lymphoma therapy or death from any cause.	Up to 4.5 years
Progression free survival	Progression-Free Survival will be measured according to the Cheson 2007 criteria. Responding patients and patients who are lost to follow up will be censored at their last tumor assessment date.	Up to 4.5 years
Response duration	Patients alive and free of progression will be censored at their last follow-up date	Up to 4.5 years
Response rate at the end of maintenance treatment	Response rates will be evaluated at the end of maintenance phase for patients who achieve a CR/PR after induction treatment and received at least one dose of maintenance. Assessment of response will be based on the International Workshop to Standardize Response criteria for NHL (Criteria for evaluation of response in Non-Hodgkin's lymphoma (Cheson, 2007)). Patient without response assessment after maintenance treatment (due to whatever reason) will be considered as non-responder.	2.5 years
Complete response rate after induction	Disease response evaluation after 6 cycles will be used to determine the Complete Response Rate. Response after 6 cycles will be assessed only if patient completes induction phase. Assessment of response will be based on the International Workshop to Standardize Response criteria for NHL (Criteria for evaluation of response in Non-Hodgkin's lymphoma (Cheson, 1999 and 2007)).	24 weeks
Complete response rate after 3 cycles	Disease response evaluation after 3 cycles will be used to determine the Complete Response Rate. Response after 3 cycles will be assessed at the end of completion of the 3 cycles if patient received all 3 cycles or at withdrawal. Assessment of response will be based on the International Workshop to Standardize Response criteria for NHL (Criteria for evaluation of response in Non-Hodgkin's lymphoma (Cheson, 1999 and 2007).	12 weeks

Collaborators and Investigators

• Sponsor: The Lymphoma Academic Research Organisation
• Investigators: Principal Investigator: Franck MORSCHHAUSER, Professor, Lymphoma Study Association; Principal Investigator: Roch HOUOT, Professor, Lymphoma Study Association

Publications and helpful links

General Publications

• Bachy E, Houot R, Feugier P, Bouabdallah K, Bouabdallah R, Virelizier EN, Maerevoet M, Fruchart C, Snauwaert S, Le Gouill S, Marolleau JP, Molina L, Molucon-Chabrot C, Thieblemont C, Tilly H, Bijou F, Haioun C, Van den Neste E, Fabiani B, Meignan M, Cartron G, Salles G, Casasnovas O, Morschhauser F. Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study. Blood. 2022 Apr 14;139(15):2338-2346. doi: 10.1182/blood.2021013526.
• Morschhauser F, Le Gouill S, Feugier P, Bailly S, Nicolas-Virelizier E, Bijou F, Salles GA, Tilly H, Fruchart C, Van Eygen K, Snauwaert S, Bonnet C, Haioun C, Thieblemont C, Bouabdallah R, Wu KL, Canioni D, Meignin V, Cartron G, Houot R. Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study. Lancet Haematol. 2019 Aug;6(8):e429-e437. doi: 10.1016/S2352-3026(19)30089-4. Epub 2019 Jul 8.
• Morschhauser F, Salles G, Le Gouill S, Tilly H, Thieblemont C, Bouabdallah K, Fabiani B, Menard C, Tarte K, Cartron G, Houot R. An open-label phase 1b study of obinutuzumab plus lenalidomide in relapsed/refractory follicular B-cell lymphoma. Blood. 2018 Oct 4;132(14):1486-1494. doi: 10.1182/blood-2018-05-853499. Epub 2018 Aug 1.

Helpful Links

• Lymphoma Study Association

Study record dates

Study Major Dates

• Study Start (Actual): October 3, 2012
• Primary Completion (Actual): July 11, 2018
• Study Completion (Actual): May 20, 2022

Study Registration Dates

• First Submitted: April 20, 2012
• First Submitted That Met QC Criteria: April 20, 2012
• First Posted (Estimate): April 23, 2012

Study Record Updates

• Last Update Posted (Actual): March 17, 2023
• Last Update Submitted That Met QC Criteria: March 16, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide; Obinutuzumab
• Other Study ID Numbers: GALEN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO