Clinical trial NCT02055820: 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
Official title: A Phase Ib/II, Open-Label Study Evaluating the Safety, Efficacy and Pharmacokinetics of GDC-0199 (ABT-199) in Combination With Rituximab (R) or Obinutuzumab (G) Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Patients With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Lymphoma, Non-Hodgkin
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: AbbVie
First posted: 2014-02-05
Enrollment: 267
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

General 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:

General 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

Primary outcomes:
measure: Safety: Number of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Start of venetoclax administration (Cycle 1 Day 4 or 3 days after first CHOP dose) up to end of Cycle 2 (cycle length = 21 days)
measure: Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Scan Using the Modified Lugano Classification Assessed by Independent Review Committee (IRC)
timeFrame: Baseline up to end of treatment (up to approximately 6 months)
measure: Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co-Expressing Both Bcl-2 and c-Myc Proteins (DE-DLBCL) Participants Assessed by IRC
timeFrame: Baseline up to end of treatment (up to approximately 6 months)
Secondary outcomes:
measure: Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC)
timeFrame: Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4 (cycle length = 21 days)
measure: Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax)
timeFrame: Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)
measure: Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)
measure: Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval
timeFrame: Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)
measure: Prednisone Plasma PK: AUC
timeFrame: Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)
measure: Prednisone Plasma PK: Tmax
timeFrame: Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)
measure: Prednisone Plasma PK: Cmax
timeFrame: Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)
measure: Rituximab PK: Cmax
timeFrame: End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
measure: Rituximab PK: Cmin Within the Dosing Interval
timeFrame: Pre-dose on Cycle 2 Day 1 (cycle length = 21 days)
measure: Obinutuzumab PK: Cmax
timeFrame: End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
measure: Cyclophosphamide PK: Cmax
timeFrame: End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
measure: Doxorubicin PK: Cmax
timeFrame: End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
measure: Vincristine PK: Cmax
timeFrame: End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
measure: Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification Assessed by IRC
timeFrame: Baseline to end of treatment (up to approximately 6 months)
measure: Percentage of Participants Who Are Alive and Without Disease Progression at Month 12
timeFrame: Month 12
measure: Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification
timeFrame: Baseline up to end of treatment (approx. 6 months)
measure: Safety: Percentage of Participants With Adverse Events
timeFrame: Baseline up to approximately 36 months
measure: Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy
timeFrame: Baseline up to Cycle 6 (cycle length = 21 days)
measure: Relative Dose Intensity of Venetoclax
timeFrame: Baseline up to Cycle 6 (cycle length = 21 days)
Other outcomes:
Locations:
city: Fullerton
country: United States
facility: St. Jude Heritage Healthcare
state: California
city: Los Angeles
country: United States
facility: UCLA Jonsson Comprehensive Cancer Center
state: California
city: Santa Maria
country: United States
facility: Central Coast Medical Oncology
state: California
city: Saint Louis
country: United States
facility: The West Clinici
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center; WFAN - Imus Pediatric Center
state: New Jersey
city: Farmington
country: United States
facility: San Juan Oncology Associates
state: New Mexico
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: Uni of Rochester Medical Center; Wilmot Cancer Center, Pharmacy Department
state: New York
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre-East Melbourne
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Salzburg
country: Austria
facility: LKH - Universitätsklinikum der PMU Salzburg
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Kelowna
country: Canada
facility: BC Cancer Agency, CSI
state: British Columbia
city: Vancouver
country: Canada
facility: BC Cancer Agency Vancouver Centre - PARENT; BC Cancer Agency
state: British Columbia
city: Montréal
country: Canada
facility: Jewish General Hospital; Research Unit
state: Quebec
city: Quebec
country: Canada
facility: CHU de Quebec - Hôpital de l' Enfant Jésus
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Ostrava - Poruba
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Praha 2
country: Czechia
facility: Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK
city: Creteil
country: France
facility: Hopital Henri Mondor, Unite Hemopathies lymphoides
city: La Roche sur Yon
country: France
facility: Centre Hospitalier Départemental Les Oudairies
city: Le Mans
country: France
facility: Clinique Victor Hugo; Pharmacie
city: Lille
country: France
facility: Hopital Claude Huriez - CHU Lille
city: Montpellier
country: France
facility: Hopital Saint Eloi
city: Nantes
country: France
facility: CHU Nantes - Hôtel Dieu; Service Assistance Medicale à la Procreation
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Pierre-Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Rennes cedex 09
country: France
facility: CHU Rennes - Hopital Pontchaillou
city: Rouen
country: France
facility: Centre Henri Becquerel; Hematologie
city: Vandoeuvre-les-nancy
country: France
facility: Hôpital de Brabois Adultes
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet
city: Debrecen
country: Hungary
facility: Debreceni Egyetem; Belgyogyaszati Klinika Hematologiai Tanszek
city: Napoli
country: Italy
facility: Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione G. Pascale
state: Campania
city: Genova
country: Italy
facility: Azienda Ospedaliero Universitaria San Martino
state: Liguria
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
state: Piemonte
city: Palermo
country: Italy
facility: Azienda Ospedaliera Vincenzo Cervello
state: Sicilia
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana; U.O. Farmaceutica
state: Toscana
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC Location VUMC
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: ICO l´Hospitalet - Hospital Duran i Reynals; Hematology
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.