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

Sponsor

The Lymphoma Academic Research Organisation (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01582776

Collaborator

(none)

317

Enrollment

Locations

Arm

121.9

Anticipated Duration (Months)

12.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Follicular Lymphoma Patients (Phase IB) Follicular and Agressive (DLBCL&MCL) B-cell Lymphoma Patients (Phase II)	Drug: Lenalidomide and GA101	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

317 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 3, 2012

Actual Primary Completion Date :

Jul 11, 2018

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Phase I part: Determination of the recommended dose of lenalidomide in combination with fixed doses of GA101 [28 days]
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.
Phase II part: Overall Response Rate (CR+CRu+PR) after 6 cycles [24 weeks]
Response rates at the end of treatment including maintenance will be expressed as percentages with their 95% Exact Clopper Pearson Confidence Interval limits

Secondary Outcome Measures

Overall survival (OS) [Up to 4.5 years]
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
Event Free survival [Up to 4.5 years]
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.
Progression free survival [Up to 4.5 years]
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.
Response duration [Up to 4.5 years]
Patients alive and free of progression will be censored at their last follow-up date
Response rate at the end of maintenance treatment [2.5 years]
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.
Complete response rate after induction [24 weeks]
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)).
Complete response rate after 3 cycles [12 weeks]
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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	ZNA Stuivenberg	Antwerpen	Belgium	2060
2	A.Z. Sint Jan AV	Bruges	Belgium	8000
3	institut Jules Bordet	Bruxelles	Belgium	1000
4	Université Catholique de Louvain Saint Luc	Bruxelles	Belgium	1200
5	AZ Groeninge - Campus Maria's Voorzienigheid	Kortrijk	Belgium	8500
6	CHU de Liège	Liège	Belgium	4000
7	Université Catholique de Louvain Mont Godinne	Yvoir	Belgium	5530
8	CHU d'Amiens	Amiens	France	80054
9	Institut Bergonié	Bordeaux	France	33076
10	Institut d'Hématologie de Basse Normandie	Caen	France	14076
11	CHU d'Estaing	Clermont-Ferrand	France	63000
12	Hôpital Henri Mondor	Créteil	France	94010
13	CHU de Dijon	Dijon	France	21034
14	CHU de Grenoble	Grenoble	France	38043
15	CHRU de Lille	Lille	France	59037
16	Centre Léon Bérard	Lyon	France	69373
17	Institut Paoli Calmette	Marseille	France	13273
18	CHU St Eloi	Montpellier	France	34295
19	CHU Brabois	Nancy	France	54511
20	CHU Hôtel Dieu	Nantes	France	44093
21	Hôpital St Louis	Paris	France	75475
22	Centre François Magendie	Pessac	France	33604
23	CH Lyon Sud	Pierre Bénite	France	69495
24	CHU Pontchaillou	Rennes	France	35003
25	Centre henri Becquerel	Rouen	France	76038

Sponsors and Collaborators

The Lymphoma Academic Research Organisation

Investigators

Principal Investigator: Franck MORSCHHAUSER, Professor, Lymphoma Study Association
Principal Investigator: Roch HOUOT, Professor, Lymphoma Study Association