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

• ClinicalTrials.gov Identifier: NCT03276468
• Recruitment Status: Recruiting
• First Posted: September 8, 2017
• Last Update Posted: October 10, 2018
• Sponsor: The Lymphoma Academic Research Organisation
• Information provided by (Responsible Party): The Lymphoma Academic Research Organisation

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 (Clinical Trial)
• Estimated Enrollment: 138 participants
• Intervention Model: Single Group Assignment
• Intervention Model Description: This 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: February 12, 2018
• Estimated Primary Completion Date: November 2019
• Estimated Study Completion Date: November 2021

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 Name: 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 Name: 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 Name: Venclyxto

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Progression Free Survival (PFS) [ Time Frame: 4 years ]
   time from inclusion to the first observation of progression
2. Overall Survival (OS) [ Time Frame: 4 years ]
   time from inclusion to death
3. Duration of Response (DR) [ Time Frame: 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
4. for FL and DLBCL cohorts : OMRR [ Time Frame: 4 months, 18 months ]
   According to Lugano 2014
5. for iNHL cohort : ORR [ Time Frame: 4 months, 18 months ]
   According to Lugano 2014
6. Best response [ Time Frame: 18 months ]
   Percentage of each response type according to Lugano 2014

Eligibility Criteria

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

Criteria

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

Contacts

Contact: Julie ASSEMAT; +334 72 66 93 33; julie.assemat@lysarc.org

Contact: Elise GAIRE; +334 72 66 93 33; elise.gaire@lysarc.org

Locations

France

CHU d'Angers; Active, not recruiting

Angers, France, 49933

CHU de Caen; Active, not recruiting

Caen, France, 14000

CHU de Clermont Ferrand - Estaing; Active, not recruiting

Clermont-Ferrand, France, 63000

Hopital Henri Mondor; Active, not recruiting

Créteil, France, 94010

CHU de Dijon; Recruiting

Dijon, France, 21000

Contact: Olivier CASASNOVAS, MD

CH Annecy Gennevois; Not yet recruiting

Epagny, France, 74370

Contact: Nicolas DAGUINDAU, MD

CHD de Vendée; Recruiting

La Roche-sur-Yon, France, 85925

Contact: Nadine Morineau, MD

CHU de Grenoble; Recruiting

La Tronche, France, 38700

Contact: Rémy Gressin, MD

CHRU de Lille; Recruiting

Lille, France, 59037

Contact: Franck Morschhauser, MD

Centre Léon Bérard; Active, not recruiting

Lyon, France, 69373

Institut Paoli Calmettes; Active, not recruiting

Marseille, France, 13273

CHU de Montpellier; Recruiting

Montpellier, France, 34295

Contact: Guillaume Cartron, PhD

CHU de Nancy - Brabois; Recruiting

Nancy, France, 54511

Contact: Pierre Feugier, MD

CHU de Nantes; Recruiting

Nantes, France, 44093

Contact: Steven Le Gouill, MD

CHU de Nice; Active, not recruiting

Nice, France, 62000

Hôpital Saint Louis; Active, not recruiting

Paris, France, 75010

Hôpital Necker; Active, not recruiting

Paris, France, 75015

CHU Lyon Sud; Recruiting

Pierre Bénite, France, 69495

Contact: Gilles Salles, MD

CHU de Poitiers; Not yet recruiting

Poitiers, France, 86021

Contact: Vincent Delwail, MD

CHU de Rennes - Hôpital de Pontchaillou; Active, not recruiting

Rennes, France, 35003

Centre Henri Becquerel; Recruiting

Rouen, France, 76038

Contact: Hervé Tilly, MD

Institut Curie - Hôpital René Huguenin; Active, not recruiting

Saint-Cloud, France, 92210

CHRU de Strasbourg; Not yet recruiting

Strasbourg, France, 67100

Contact: Luc-Matthieu Fornecker, MD

Institut Universitaire du Cancer de Toulouse - Oncopole; Active, not recruiting

Toulouse, France, 31100

CHRU de Tours; Active, not recruiting

Tours, France, 37044

Sponsors and Collaborators

The Lymphoma Academic Research Organisation

Investigators

• Principal Investigator: Guillaume CARTRON, PhD; Lymphoma Study Association
• Principal Investigator: Charles HERBAUX, MD; Lymphoma Study Association

More Information

• Responsible Party: The Lymphoma Academic Research Organisation
• ClinicalTrials.gov Identifier: NCT03276468 History of Changes
• Other Study ID Numbers: GATA
• First Posted: September 8, 2017
• Last Update Posted: October 10, 2018
• Last Verified: October 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by The Lymphoma Academic Research Organisation:

venetoclax; obinutuzumab; atezolizumab; lymphoma

Additional relevant MeSH terms:

Lymphoma; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large B-Cell, Diffuse; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Atezolizumab; Venetoclax; Obinutuzumab; Antibodies, Monoclonal; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents, Immunological