A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax Combined With Chemotherapy in Participants With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL

NCT ID: NCT02055820

Last Updated: 2020-06-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 267 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-17
• Study Completion Date: 2019-06-28

Brief Summary

This is a multicenter, open-label, dose-finding study of venetoclax administered orally in combination with rituximab (R) or obinutuzumab (G) and standard doses of cyclophosphamide, doxorubicin, vincristine and oral prednisone (CHOP) in participants with Non-Hodgkin's Lymphoma (NHL). The study consisted of 2 stages: a dose-finding Phase Ib stage and a Phase II expansion stage. In the Phase I portion of the study, participants were randomized to one of 2 treatment arms venetoclax in combination with R-CHOP (Arm A) and venetoclax in combination with G-CHOP (Arm B) and explored the doses of venetoclax in combination with R-CHOP and G-CHOP. The maximum tolerated dose (MTD) of venetoclax in combination with R-CHOP and G-CHOP was determined during the dose-finding stage. For the Phase II portion of the study, the venetoclax dose for venetoclax + R-CHOP was on a non-continuous dosing schedule as determined by the Phase Ib portion of the study based on safety and tolerability observed in participants treated in the dose escalation portion of the study. On 17 July 2016, Roche/Genentech as the sponsor of Study BO21005 (Goya study), a Phase III study that evaluated G CHOP versus R-CHOP in 1L DLBCL, informed through a press release that the primary endpoint of investigator-assessed PFS was not met. Given these results, Arm B (venetoclax + G-CHOP) was not expanded in Phase II in patients who are first-line with DLBCL.

Conditions

Lymphoma, Non-Hodgkin

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Venetoclax + G-CHOP Arm

Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Venetoclax 200 to 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4-10 of Cycle 1 and Days 1-10 of Cycles 2-8 during Phase I and MTD will be administered according to the same schedule during Phase II.

Cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide 750 milligrams per square meter (mg/m\^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Obinutuzumab

Intervention Type: DRUG

Obinutuzumab will be administered by IV infusion as an absolute dose of 1000 mg on Days 1, 8, 15 of Cycle 1 and Day 1 of Cycles 2-8 (cycle length = 21 days).

Doxorubicin

Intervention Type: DRUG

Doxorubicin 50 mg/m\^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Vincristine

Intervention Type: DRUG

Vincristine 1.4 mg/m\^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Prednisone

Intervention Type: DRUG

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Venetoclax + R-CHOP Arm

Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Venetoclax 200 to 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4-10 of Cycle 1 and Days 1-10 of Cycles 2-8 during Phase I and MTD will be administered according to the same schedule during Phase II.

Cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide 750 milligrams per square meter (mg/m\^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Rituximab

Intervention Type: DRUG

Rituximab 375 mg/m\^2 dose will be administered IV on Day 1 of every 21-day cycle.

Doxorubicin

Intervention Type: DRUG

Doxorubicin 50 mg/m\^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Vincristine

Intervention Type: DRUG

Vincristine 1.4 mg/m\^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Prednisone

Intervention Type: DRUG

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Interventions

Venetoclax

Venetoclax 200 to 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4-10 of Cycle 1 and Days 1-10 of Cycles 2-8 during Phase I and MTD will be administered according to the same schedule during Phase II.

Intervention Type: DRUG

Cyclophosphamide

Cyclophosphamide 750 milligrams per square meter (mg/m\^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Intervention Type: DRUG

Obinutuzumab

Obinutuzumab will be administered by IV infusion as an absolute dose of 1000 mg on Days 1, 8, 15 of Cycle 1 and Day 1 of Cycles 2-8 (cycle length = 21 days).

Intervention Type: DRUG

Rituximab

Rituximab 375 mg/m\^2 dose will be administered IV on Day 1 of every 21-day cycle.

Intervention Type: DRUG

Doxorubicin

Doxorubicin 50 mg/m\^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Intervention Type: DRUG

Vincristine

Vincristine 1.4 mg/m\^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Intervention Type: DRUG

Prednisone

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Intervention Type: DRUG

Other Intervention Names

GDC-0199, ABT-199; MabThera/Rituxan

Eligibility Criteria

Inclusion Criteria

• At least one bi-dimensionally measurable lymphoma lesion on CT scan defined as > 1.5 cm in its longest dimension, which is also FDG avid by screening PET scan.
• Confirmed availability of archival or freshly biopsied tumor tissue prior to study enrollment
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Adequate hematologic function
• For female participants of childbearing potential, agreement to use highly effective forms of contraception

Dose-Escalation Portion of the Study:

• Participants must have histologically confirmed B-cell NHL, except MCL or SLL
• Participants must have never received previous R-CHOP treatment
• Any relapsed/refractory participants that are enrolled during the dose escalation should have received only a single previous treatment regimen

Expansion Portion of the Study:

• Participants must have previously untreated CD20-positive DLBCL and IPI score must be 2-5

Exclusion Criteria

• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
• Contraindication to receive any of the individual components of CHOP, rituximab or obinutuzumab
• Prior anthracycline therapy
• Participants with ongoing corticosteroid use >30 mg per day of prednisone or equivalent
• CNS lymphoma or primary mediastinal DLBCL
• Vaccination with live vaccines within 28 days prior to randomization
• Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1
• History of other malignancy that could affect compliance with the protocol or interpretation of results
• Evidence of significant, uncontrolled concomitant disease
• Significant cardiovascular disease or significant pulmonary disease
• Left ventricular ejection fraction less than (<) 50% as defined by multiple-gated acquisition (MUGA)
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, 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 Cycle 1 Day 1
• Received the following agents within 7 days prior to the first dose of venetoclax: steroid therapy for anti-neoplastic intent; strong and moderate cytochrome P450 (CYP) 3A4 inhibitors or inducers; grapefruit/grapefruit products, seville oranges or star fruit within 3 days prior to the first dose of venetoclax
• Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
• Recent major surgery
• Women who are pregnant or lactating

Dose-Escalation Portion of the Study:

• Participants with confirmed mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL)

Expansion Portion of the Study:

• Participants with transformed lymphoma (participants with discordant bone marrow involvement (i.e., low grade histology in bone marrow) may be considered after discussion with the Medical Monitor)
• Prior therapy for NHL

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AbbVie

INDUSTRY

Sponsor Role: collaborator

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

St. Jude Heritage Healthcare

Fullerton, California, United States

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, California, United States

Central Coast Medical Oncology

Santa Maria, California, United States

The West Clinici

St Louis, Missouri, United States

Hackensack University Medical Center; WFAN - Imus Pediatric Center

Hackensack, New Jersey, United States

San Juan Oncology Associates

Farmington, New Mexico, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Uni of Rochester Medical Center; Wilmot Cancer Center, Pharmacy Department

Rochester, New York, United States

Tennessee Oncology

Nashville, Tennessee, United States

Concord Repatriation General Hospital

Concord, New South Wales, Australia

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

Peter MacCallum Cancer Centre-East Melbourne

Melbourne, Victoria, Australia

Royal Melbourne Hospital

Parkville, Victoria, Australia

LKH - Universitätsklinikum der PMU Salzburg

Salzburg, , Austria

Medizinische Universität Wien

Vienna, , Austria

Cross Cancer Institute

Edmonton, Alberta, Canada

BC Cancer Agency, CSI

Kelowna, British Columbia, Canada

BC Cancer Agency Vancouver Centre - PARENT; BC Cancer Agency

Vancouver, British Columbia, Canada

Jewish General Hospital; Research Unit

Montreal, Quebec, Canada

CHU de Quebec - Hôpital de l' Enfant Jésus

Québec, , Canada

Fakultni nemocnice Brno

Brno, , Czechia

Fakultni nemocnice Hradec Kralove

Hradec Králové, , Czechia

Fakultni nemocnice Ostrava

Ostrava - Poruba, , Czechia

Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK

Prague, , Czechia

Hopital Henri Mondor, Unite Hemopathies lymphoides

Créteil, , France

Centre Hospitalier Départemental Les Oudairies

La Roche-sur-Yon, , France

Clinique Victor Hugo; Pharmacie

Le Mans, , France

Hopital Claude Huriez - CHU Lille

Lille, , France

Hopital Saint Eloi

Montpellier, , France

CHU Nantes - Hôtel Dieu; Service Assistance Medicale à la Procreation

Nantes, , France

Hôpital Saint-Louis

Paris, , France

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

CHU Rennes - Hopital Pontchaillou

Rennes, , France

Centre Henri Becquerel; Hematologie

Rouen, , France

Hôpital de Brabois Adultes

Vandœuvre-lès-Nancy, , France

Semmelweis Egyetem

Budapest, , Hungary

Orszagos Onkologiai Intezet

Budapest, , Hungary

Debreceni Egyetem; Belgyogyaszati Klinika Hematologiai Tanszek

Debrecen, , Hungary

Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione G. Pascale

Napoli, Campania, Italy

Azienda Ospedaliero Universitaria San Martino

Genoa, Liguria, Italy

Azienda Ospedaliera Città della Salute e della Scienza di Torino

Turin, Piedmont, Italy

Azienda Ospedaliera Vincenzo Cervello

Palermo, Sicily, Italy

Azienda Ospedaliero Universitaria Pisana; U.O. Farmaceutica

Pisa, Tuscany, Italy

Amsterdam UMC Location VUMC

Amsterdam, , Netherlands

Erasmus Medisch Centrum

Rotterdam, , Netherlands

UMC Utrecht

Utrecht, , Netherlands

Hospital del Mar

Barcelona, , Spain

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

ICO l´Hospitalet - Hospital Duran i Reynals; Hematology

Barcelona, , Spain

Hospital Universitario La Paz

Madrid, , Spain

Hospital Universitario Ramon y Cajal

Madrid, , Spain

Hospital Universitario de Salamanca

Salamanca, , Spain

Countries

United States; Australia; Austria; Canada; Czechia; France; Hungary; Italy; Netherlands; Spain

References

Zelenetz AD, Salles G, Mason KD, Casulo C, Le Gouill S, Sehn LH, Tilly H, Cartron G, Chamuleau MED, Goy A, Tam CS, Lugtenburg PJ, Petrich AM, Sinha A, Samineni D, Herter S, Ingalla E, Szafer-Glusman E, Klein C, Sampath D, Kornacker M, Mobasher M, Morschhauser F. Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial. Blood. 2019 May 2;133(18):1964-1976. doi: 10.1182/blood-2018-11-880526. Epub 2019 Mar 8.

Reference Type: RESULT

PMID: 30850381 (View on PubMed)

Samineni D, Huang W, Gibiansky L, Ding H, Zhang R, Li C, Sinha A, Rajwanshi R, Humphrey K, Bazeos A, Salem AH, Miles D. Population Pharmacokinetics and Exposure-Response Analyses for Venetoclax in Combination with R-CHOP in Relapsed/Refractory and Previously Untreated Patients with Diffuse Large B Cell Lymphoma. Adv Ther. 2022 Jan;39(1):598-618. doi: 10.1007/s12325-021-01919-z. Epub 2021 Nov 25.

Reference Type: DERIVED

PMID: 34822104 (View on PubMed)

Morschhauser F, Feugier P, Flinn IW, Gasiorowski R, Greil R, Illes A, Johnson NA, Larouche JF, Lugtenburg PJ, Patti C, Salles GA, Trneny M, de Vos S, Mir F, Samineni D, Kim SY, Jiang Y, Punnoose E, Sinha A, Clark E, Spielewoy N, Humphrey K, Bazeos A, Zelenetz AD. A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma. Blood. 2021 Feb 4;137(5):600-609. doi: 10.1182/blood.2020006578.

Reference Type: DERIVED

PMID: 33538797 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2013-003749-40

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GO27878

Identifier Type: -

Identifier Source: org_study_id