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

NCT02055820 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: GO278782013-003749-40
• Study Type: interventional
• Target: 267
• Locations: 9 countries
• Sites: 48

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

Outcome Measures

Primary Outcomes (3)

• Safety: Number of Participants With Dose-Limiting Toxicities (DLTs)

  DLTs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Decrease in B cells, lymphopenia, and leukopenia caused by lymphopenia were not considered DLTs but instead were expected outcomes of study treatment. Any Grade \>/= 3 adverse event, that was attributed to having a reasonable possibility of being related to the combined administration of venetoclax plus R-CHOP or G-CHOP, that could not be attributed by the investigator to an alternative, clearly identifiable cause such as tumor progression, concurrent illness or medical condition, or concomitant medication and that occurred during the DLT observation period (start of venetoclax treatment through end of Cycle 2) was considered a DLT for dose-escalation purposes. Grade 3 or 4 neutropenia or thrombocytopenia identified on Day 1 of Cycle 2 or 3, resulting in dose delay were considered DLTs.

  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)

• 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)

  CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake \</= mediastinum; 3) uptake \< mediastinum but \</= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy

  Baseline up to end of treatment (up to approximately 6 months)

• 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

  CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake \</= mediastinum; 3) uptake \< mediastinum but \</= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.

  Baseline up to end of treatment (up to approximately 6 months)

Secondary Outcomes (19)

• Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC)

  Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4 (cycle length = 21 days)

• Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax)

  Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)

• Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax)

  Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)

• Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval

  Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)

• Prednisone Plasma PK: AUC

  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)

Study Arms (2)

Venetoclax + G-CHOP Arm

EXPERIMENTAL

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.

Drug: Venetoclax; Drug: Cyclophosphamide; Drug: Obinutuzumab; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisone

Venetoclax + R-CHOP Arm

EXPERIMENTAL

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.

Drug: Venetoclax; Drug: Cyclophosphamide; Drug: Rituximab; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisone

Interventions

Venetoclax 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.

Also known as: GDC-0199, ABT-199

Venetoclax + G-CHOP Arm; Venetoclax + R-CHOP Arm

Cyclophosphamide 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.

Venetoclax + G-CHOP Arm; Venetoclax + R-CHOP Arm

Obinutuzumab 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).

Venetoclax + G-CHOP Arm

Rituximab DRUG

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

Also known as: MabThera/Rituxan

Venetoclax + R-CHOP Arm

Doxorubicin DRUG

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

Venetoclax + G-CHOP Arm; Venetoclax + R-CHOP Arm

Vincristine DRUG

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

Venetoclax + G-CHOP Arm; Venetoclax + R-CHOP Arm

Prednisone DRUG

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

Venetoclax + G-CHOP Arm; Venetoclax + R-CHOP Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead
• AbbVie: collaborator

Study Sites (52)

St. Jude Heritage Healthcare

Fullerton, California, 92835, United States

Location

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

Central Coast Medical Oncology

Santa Maria, California, 93454, United States

Location

The West Clinici

St Louis, Missouri, 63129, United States

Location

Hackensack University Medical Center; WFAN - Imus Pediatric Center

Hackensack, New Jersey, 07601, United States

Location

San Juan Oncology Associates

Farmington, New Mexico, 87401, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

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

Rochester, New York, 14642, United States

Location

Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

Concord Repatriation General Hospital

Concord, New South Wales, 2139, Australia

Location

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

Location

Peter MacCallum Cancer Centre-East Melbourne

Melbourne, Victoria, 3000, Australia

Location

Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

Location

LKH - Universitätsklinikum der PMU Salzburg

Salzburg, 5020, Austria

Location

Medizinische Universität Wien

Vienna, 1090, Austria

Location

Cross Cancer Institute

Edmonton, Alberta, T6G 1Z2, Canada

Location

BC Cancer Agency, CSI

Kelowna, British Columbia, V1Y 5L3, Canada

Location

BC Cancer Agency Vancouver Centre - PARENT; BC Cancer Agency

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Jewish General Hospital; Research Unit

Montreal, Quebec, H3T 1E2, Canada

Location

CHU de Quebec - Hôpital de l' Enfant Jésus

Québec, G1J 1Z4, Canada

Location

Fakultni nemocnice Brno

Brno, 613 00, Czechia

Location

Fakultni nemocnice Hradec Kralove

Hradec Králové, 500 05, Czechia

Location

Fakultni nemocnice Ostrava

Ostrava - Poruba, 708 52, Czechia

Location

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

Prague, 128 08, Czechia

Location

Hopital Henri Mondor, Unite Hemopathies lymphoides

Créteil, 94010, France

Location

Centre Hospitalier Départemental Les Oudairies

La Roche-sur-Yon, 85025, France

Location

Clinique Victor Hugo; Pharmacie

Le Mans, 72015, France

Location

Hopital Claude Huriez - CHU Lille

Lille, 59037, France

Location

Hopital Saint Eloi

Montpellier, 34295, France

Location

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

Nantes, 44093, France

Location

Hôpital Saint-Louis

Paris, 75475, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

CHU Rennes - Hopital Pontchaillou

Rennes, 35033, France

Location

Centre Henri Becquerel; Hematologie

Rouen, 76038, France

Location

Hôpital de Brabois Adultes

Vandœuvre-lès-Nancy, 54511, France

Location

Semmelweis Egyetem

Budapest, 1083, Hungary

Location

Orszagos Onkologiai Intezet

Budapest, 1122, Hungary

Location

Debreceni Egyetem; Belgyogyaszati Klinika Hematologiai Tanszek

Debrecen, 4032, Hungary

Location

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

Napoli, Campania, 80131, Italy

Location

Azienda Ospedaliero Universitaria San Martino

Genoa, Liguria, 16132, Italy

Location

Azienda Ospedaliera Città della Salute e della Scienza di Torino

Turin, Piedmont, 10126, Italy

Location

Azienda Ospedaliera Vincenzo Cervello

Palermo, Sicily, 90127, Italy

Location

Azienda Ospedaliero Universitaria Pisana; U.O. Farmaceutica

Pisa, Tuscany, 56100, Italy

Location

Amsterdam UMC Location VUMC

Amsterdam, 1081 HV, Netherlands

Location

Erasmus Medisch Centrum

Rotterdam, 3015 GD, Netherlands

Location

UMC Utrecht

Utrecht, 3508 GA, Netherlands

Location

Hospital del Mar

Barcelona, 08003, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

ICO l´Hospitalet - Hospital Duran i Reynals; Hematology

Barcelona, 08907, Spain

Location

Hospital Universitario La Paz

Madrid, 280146, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Related Publications (3)

• 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.

  PMID: 30850381 RESULT

• 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.

  PMID: 34822104 DERIVED

• 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.

  PMID: 33538797 DERIVED

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

venetoclax; Cyclophosphamide; obinutuzumab; Rituximab; Doxorubicin; Vincristine; Prednisone

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2014
• First Posted: February 5, 2014
• Study Start: November 17, 2013
• Primary Completion: June 28, 2017
• Study Completion: June 28, 2019
• Last Updated: June 11, 2020
• Results First Posted: December 20, 2018

Record last verified: 2020-05

Locations

US (9); CZ (4); CA (5); HU (3); IT (5); NL (3); FR (11); AU (2); ES (6)