Evaluation of Atezolizumab-Venetoclax-Obinutuzumab Combination in Relapse/Refractory Lymphomas

Sponsor

The Lymphoma Academic Research Organisation (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03276468

Collaborator

(none)

136

Enrollment

Locations

Arm

54.3

Anticipated Duration (Months)

5.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is a multicenter phase II trial which primary objective is to assess the anti-lymphoma activity of atezolizumab associated with a BCL-2 inhibitor (GDC-199, venetoclax) and an anti-CD20 monoclonal antibody (obinutuzumab) in three separate cohorts:

relapsed/refractory follicular lymphoma (FL) patients
relapsed/refractory aggressive (DLBCL) lymphoma patients
relapsed/refractory other indolent (iNHL) lymphoma patients (MZL and MALT)

Condition or Disease	Intervention/Treatment	Phase
Follicular Lymphoma Diffuse Large B Cell Lymphoma Marginal Zone Lymphoma Mucosa Associated Lymphoid Tissue	Drug: Atezolizumab Drug: Obinutuzumab Drug: Venetoclax	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

136 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

This study is a multicentric open-label phase II trial in 3 cohorts of patientsThis study is a multicentric open-label phase II trial in 3 cohorts of patients

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Trial Evaluating Combination of Atezolizumab, With Venetoclax and Obinutuzumab for Relapsed/Refractory Lymphomas

Actual Study Start Date :

Feb 12, 2018

Actual Primary Completion Date :

Sep 19, 2019

Anticipated Study Completion Date :

Aug 22, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental Combination of venetoclax, atezolizumab and obinutuzumab	Drug: Atezolizumab 1200 mg on day 2 of each 21-day cycle during 18 months (24 cycles) Other Names: Tecentriq Drug: Obinutuzumab 1000 mg on day 1, day 8 and day 15 of cycle 1 and each day 1 from cycle 2 to cycle 8 Other Names: Gazyvaro Drug: Venetoclax 800 mg/d from day 8 of cycle 1, every day during 18 months. For MZL patients wiht lymphocytes>5 g/l : 50 mg/day: week 1 100mg/day: week 2 200mg/day: week 3 400mg/day: week 4 800mg/day: from week 5 Other Names: Venclyxto

Arm

Intervention/Treatment

Experimental: Experimental

Combination of venetoclax, atezolizumab and obinutuzumab

Drug: Atezolizumab

1200 mg on day 2 of each 21-day cycle during 18 months (24 cycles)

Other Names:

Tecentriq

Drug: Obinutuzumab

1000 mg on day 1, day 8 and day 15 of cycle 1 and each day 1 from cycle 2 to cycle 8

Other Names:

Gazyvaro

Drug: Venetoclax

800 mg/d from day 8 of cycle 1, every day during 18 months. For MZL patients wiht lymphocytes>5 g/l : 50 mg/day: week 1 100mg/day: week 2 200mg/day: week 3 400mg/day: week 4 800mg/day: from week 5

Other Names:

Venclyxto

Outcome Measures

Primary Outcome Measures

FL and DLBCL cohorts : Overall Metabolic Response Rate (OMRR) at the end of induction [8 months (8 cycles)]
Assessment of disease response according to Lugano 2014
for iNHL cohort : Overall Response Rate (ORR) at the end of induction [8 months (8 cycles)]
Assessment of disease response according to Lugano 2014

Secondary Outcome Measures

Progression Free Survival (PFS) [4 years]
time from inclusion to the first observation of progression
Overall Survival (OS) [4 years]
time from inclusion to death
Duration of Response (DR) [4 years]
from a confirmed Complete Metabolic Response / Complete Radiologic Response (CMR/CRR) or Partial Metabolic Response / Partial Radiologic Response (PMR/PRR) the first observation of progression
for FL and DLBCL cohorts : OMRR [4 months, 18 months]
According to Lugano 2014
for iNHL cohort : ORR [4 months, 18 months]
According to Lugano 2014
Best response [18 months]
Percentage of each response type according to Lugano 2014

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically documented CD20-positive follicular lymphoma (WHO grade 1, 2, or 3a) patients for cohort 1
Patients with either histologically documented CD20-positive Diffuse large-cell lymphoma (including transformations of low-grade lymphoma into DLBCL) or follicular lymphoma CD20+ grade 3b, or primary cutaneous DLBCL leg type, or primary mediastinal (thymic) large B-cell lymphoma, or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, or unclassifiable B-cell lymphoma with features intermediate between DLBCL and Hodgkin (WHO classification) for cohort 2
Patients with relapsed/refractory indolent lymphoma (marginal zone (MZL) or measurable mucosa-associated lymphoid tissue (MALT) lymphoma) for cohort 3
Relapsed/refractory NHL after ≥1 prior R-containing regimen with no curative option
Aged 18 years or more with no upper age limit
Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
Bi-dimensionally measurable disease defined by at least one single node or tumor lesion > 1.5 cm assessed by CT scan, or Positron Emission Tomography (PET) scan without IV contrast at diagnosis with at least one hypermetabolic lesion
Signed written informed consent
Life expectancy ≥ 3 months
Females of childbearing potential (FCBP) must agree to use one reliable form of contraception 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 18 months after discontinuation of all study treatments
Male patients and their partner (FCBP) must agree to use two reliable forms of contraception (condom for males and hormonal method for partners) 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 18 months after discontinuation of all study treatments
Patient covered by any social security system

Exclusion Criteria:

Lymphocytic lymphoma (LL), waldenström macroglobulinemia, unmeasurable MALT lymphoma, Mantle Cell Lymphoma (MCL) and Follicular lymphoma for cohort 3
Known CD20 negative status at last biopsy done (Biopsy at relapse/progression is mandatory)
Central nervous system or meningeal involvement by lymphoma
Prior history of Progressive Multifocal Leukoencephalopathy (PML)
Documented infection with HIV
Active Hepatitis B (HB) (positive Hepatitis B surface antigen (Ag-HBs) OR positive serology to hepatitis B (positive Ag-HBs or Hepatitis B core antibody (anti-HBc) or Polymerisation Chain Reaction (PCR) for viral DNA of HBV) Active Hepatitis C (HC) infection (patients with positive HCV serology (anti-HCV) are eligible only if PCR is negative from known HCV RNA)
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) before inclusion, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to first administration of study drug
Active immune-related disease criteria
Left Ventricular Ejection Fraction (LVEF) < 45% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan
Any serious active disease or co-morbid medical condition (such as New York Heart Association Class III or IV cardiac disease, severe arrhythmia, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including uncontrolled obstructive pulmonary disease and history of bronchospasm or other according to investigator's decision)
Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
Any of the following laboratory abnormalities:
Hemoglobin < 9 g/dL
Absolute neutrophil count (ANC) < 1,000 cells/mm3 (1.0 G/L) unless due to lymphoma
Platelet count < 75,000/mm3 (75 x 109/L) unless due to lymphoma
Serum glutamic-oxaloacetic transaminase (SGOT) / Aspartate Transaminase (AST) or Serum Glutamic-Pyruvate Transferase (SGPT) / Alanine Transaminase (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
International normalized ratio (INR) ≤ 1.5 x ULN for patients not receiving therapeutic anticoagulation
Partial thromboplastin time (PTT) or activated PTT (aPTT) > 1.5 x ULN
Prior history of malignancies other than lymphoma unless the subject has been free of the disease for ≥ 3 years. Exceptions will be allowed for patients with non-melanoma skin tumors (basal cell or squamous cell carcinoma of the skin) or any surgically removed stage 0 (in situ) carcinoma
Any serious medical condition, laboratory abnormality (other than mentioned above), or psychiatric illness that would prevent the subject from signing the informed consent form
Contraindication to any drug contained in the study treatment regimen
Previous treatment with obinutuzumab, atezolizumab or venetoclax
Use of any standard or experimental anti-cancer drug therapy within 28 days prior to first administration of study drug
Use of warfarin prior to first administration of study drug and throughout all treatment period (because of potential drug-drug interactions that may potentially increase the exposure of warfarin)
Patients taking corticosteroids within 4 weeks prior to first administration of study drug, unless administered at a cumulated dose equivalent to ≤ 3.5mg/kg (within these 4 weeks).
Use of the following agents prior to first administration of study drug: Strong and moderate CYP3A inhibitors (including grapefruit juice); Strong and moderate CYP3A inducers
Pregnant or lactating females
Person deprived of his/her liberty by a judicial or administrative decision
Adult person under legal protection
Person hospitalized without consent
Adult person unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHU d'Angers	Angers	France	49933
2	CHU de Caen	Caen	France	14000
3	CHU de Clermont Ferrand - Estaing	Clermont-Ferrand	France	63000
4	Hopital Henri Mondor	Créteil	France	94010
5	CHU de Dijon	Dijon	France	21000
6	CH Annecy Gennevois	Epagny	France	74370
7	CHD de Vendée	La Roche-sur-Yon	France	85925
8	CHU de Grenoble	La Tronche	France	38700
9	CHRU de Lille	Lille	France	59037
10	Centre Léon Bérard	Lyon	France	69373
11	Institut Paoli Calmettes	Marseille	France	13273
12	CHU de Montpellier	Montpellier	France	34295
13	CHU de Nancy - Brabois	Nancy	France	54511
14	CHU de Nantes	Nantes	France	44093
15	CHU de Nice	Nice	France	62000
16	Hôpital Saint Louis	Paris	France	75010
17	Hôpital Necker	Paris	France	75015
18	CHU Lyon Sud	Pierre Bénite	France	69495
19	CHU de Poitiers	Poitiers	France	86021
20	CHU de Rennes - Hôpital de Pontchaillou	Rennes	France	35003
21	Centre Henri Becquerel	Rouen	France	76038
22	Institut Curie - Hôpital René Huguenin	Saint-Cloud	France	92210
23	CHRU de Strasbourg	Strasbourg	France	67100
24	Institut Universitaire du Cancer de Toulouse - Oncopole	Toulouse	France	31100
25	CHRU de Tours	Tours	France	37044