Clinical trial NCT01582776: Study of OBINUTUZUMAB Combined to LENALIDOMIDE for the Treatment of Relapsed/Refractory Follicular and Aggressive B-cell Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Follicular Lymphoma Patients (Phase IB)
Follicular and Agressive (DLBCL&MCL) B-cell Lymphoma Patients (Phase II)
Lead sponsor: The Lymphoma Academic Research Organisation
Sponsor class: OTHER
First posted: 2012-04-23
Enrollment: 317
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Phase I part: Determination of the recommended dose of lenalidomide in combination with fixed doses of GA101
timeFrame: 28 days
measure: Phase II part: Overall Response Rate (CR+CRu+PR) after 6 cycles
timeFrame: 24 weeks
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: Up to 4.5 years
measure: Event Free survival
timeFrame: Up to 4.5 years
measure: Progression free survival
timeFrame: Up to 4.5 years
measure: Response duration
timeFrame: Up to 4.5 years
measure: Response rate at the end of maintenance treatment
timeFrame: 2.5 years
measure: Complete response rate after induction
timeFrame: 24 weeks
measure: Complete response rate after 3 cycles
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: ZNA Stuivenberg
city: Bruges
country: Belgium
facility: A.Z. Sint Jan AV
city: Bruxelles
country: Belgium
facility: institut Jules Bordet
city: Bruxelles
country: Belgium
facility: Université Catholique de Louvain Saint Luc
city: Kortrijk
country: Belgium
facility: AZ Groeninge - Campus Maria's Voorzienigheid
city: Liège
country: Belgium
facility: CHU de Liège
city: Yvoir
country: Belgium
facility: Université Catholique de Louvain Mont Godinne
city: Amiens
country: France
facility: CHU d'Amiens
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Institut d'Hématologie de Basse Normandie
city: Clermont-Ferrand
country: France
facility: CHU d'Estaing
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: CHU de Dijon
city: Grenoble
country: France
facility: CHU de Grenoble
city: Lille
country: France
facility: CHRU de Lille
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli Calmette
city: Montpellier
country: France
facility: CHU St Eloi
city: Nancy
country: France
facility: CHU Brabois
city: Nantes
country: France
facility: CHU Hôtel Dieu
city: Paris
country: France
facility: Hôpital St Louis
city: Pessac
country: France
facility: Centre François Magendie
city: Pierre Bénite
country: France
facility: CH Lyon Sud
city: Rennes
country: France
facility: CHU Pontchaillou
city: Rouen
country: France
facility: Centre henri Becquerel
Study officials:
affiliation: Lymphoma Study Association
name: Franck MORSCHHAUSER, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Lymphoma Study Association
name: Roch HOUOT, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.