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

Lymphoma, Non-Hodgkin Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02055820
• Other study ID #: GO27878
• Secondary ID: 2013-003749-40
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 17, 2013
• Est. completion date: June 28, 2019

Study information

• Verified date: May 2020
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 267
• Est. completion date: June 28, 2019
• Est. primary completion date: June 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin

Intervention

Drug:
• 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.
• 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.
• 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).
• Rituximab
Rituximab 375 mg/m^2 dose will be administered IV on Day 1 of every 21-day cycle.
• Doxorubicin
Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.
• Vincristine
Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.
• Prednisone
Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Locations

Country	Name	City	State
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	Peter MacCallum Cancer Centre-East Melbourne	Melbourne	Victoria
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Austria	LKH - Universitätsklinikum der PMU Salzburg	Salzburg
Austria	Medizinische Universität Wien	Wien
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	BC Cancer Agency, CSI	Kelowna	British Columbia
Canada	Jewish General Hospital; Research Unit	Montréal	Quebec
Canada	CHU de Quebec - Hôpital de l' Enfant Jésus	Quebec
Canada	BC Cancer Agency Vancouver Centre - PARENT; BC Cancer Agency	Vancouver	British Columbia
Czechia	Fakultni nemocnice Brno	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Fakultni nemocnice Ostrava	Ostrava - Poruba
Czechia	Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK	Praha 2
France	Hopital Henri Mondor, Unite Hemopathies lymphoides	Creteil
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-Benite
France	CHU Rennes - Hopital Pontchaillou	Rennes cedex 09
France	Centre Henri Becquerel; Hematologie	Rouen
France	Hôpital de Brabois Adultes	Vandoeuvre-les-nancy
Hungary	Orszagos Onkologiai Intezet	Budapest
Hungary	Semmelweis Egyetem	Budapest
Hungary	Debreceni Egyetem; Belgyogyaszati Klinika Hematologiai Tanszek	Debrecen
Italy	Azienda Ospedaliero Universitaria San Martino	Genova	Liguria
Italy	Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione G. Pascale	Napoli	Campania
Italy	Azienda Ospedaliera Vincenzo Cervello	Palermo	Sicilia
Italy	Azienda Ospedaliero Universitaria Pisana; U.O. Farmaceutica	Pisa	Toscana
Italy	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino	Piemonte
Netherlands	Amsterdam UMC Location VUMC	Amsterdam
Netherlands	Erasmus Medisch Centrum	Rotterdam
Netherlands	UMC Utrecht	Utrecht
Spain	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
United States	San Juan Oncology Associates	Farmington	New Mexico
United States	St. Jude Heritage Healthcare	Fullerton	California
United States	Hackensack University Medical Center; WFAN - Imus Pediatric Center	Hackensack	New Jersey
United States	UCLA Jonsson Comprehensive Cancer Center	Los Angeles	California
United States	Tennessee Oncology	Nashville	Tennessee
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	The West Clinici	Saint Louis	Missouri
United States	Central Coast Medical Oncology	Santa Maria	California

Sponsors (2)

Lead Sponsor	Collaborator
Hoffmann-La Roche	AbbVie

Countries where clinical trial is conducted

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

References & Publications (1)

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, Morschha — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	Baseline up to end of treatment (up to approximately 6 months)
Primary	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	Baseline up to end of treatment (up to approximately 6 months)
Secondary	Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC)	AUC was calculated based on measurement of venetoclax concentration in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.; Data are reported as hour*micrograms per milliliter (hr*mcg/mL)	Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4 (cycle length = 21 days)
Secondary	Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax)	Tmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.	Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)
Secondary	Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax)	Cmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.; Data are reported as micrograms per milliliter	Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)
Secondary	Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval	Cmin was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.	Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)
Secondary	Prednisone Plasma PK: AUC	AUC was determined based on measurement of Predisone concentrations in plasma over time.	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)
Secondary	Prednisone Plasma PK: Tmax	Tmax was determined based on measurement of Predisone concentrations in plasma over time.	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)
Secondary	Prednisone Plasma PK: Cmax	Cmax was determined based on measurement of Predisone concentrations in plasma over time.	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)
Secondary	Rituximab PK: Cmax	Cmax was determined using the post-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1.	End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
Secondary	Rituximab PK: Cmin Within the Dosing Interval	Cmin was determined using the pre-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose on Day 1 of Cycle 2.	Pre-dose on Cycle 2 Day 1 (cycle length = 21 days)
Secondary	Obinutuzumab PK: Cmax	Cmax was determined using the post-dose obinutuzumab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1.	End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
Secondary	Cyclophosphamide PK: Cmax	Cmax was determined using the post-dose Cyclophosphamide plasma concentrations on Cycle 1 Day 1.	End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
Secondary	Doxorubicin PK: Cmax	Cmax was determined using the post-dose Doxorubicin plasma concentrations.	End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
Secondary	Vincristine PK: Cmax	Cmax was determined using the post-dose Vincristine plasma concentrations.	End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
Secondary	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	Objective Response defined as PR (partial response) or CR (complete response) at end of treatment.; CR: Lymph nodes and extra-lymphatic sites with score 1, 2 or 3 on a 5-point scale (with a higher score being a worse outcome). 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.; PR: Lymph nodes and extralymphatic sites with score of 4 or 5 on the 5-point scale with reduced uptake compared with baseline and residual mass(es) of any size. CT-based response criteria for PR must also be met. No new lesions. In bone marrow residual uptake could be higher than in normal marrow but must be reduced compared with baseline; persistent focal changes in the marrow to be considered for further evaluation with magnetic resonance imaging (MRI) or biopsy or an interval scan. OR=PR+CR	Baseline to end of treatment (up to approximately 6 months)
Secondary	Percentage of Participants Who Are Alive and Without Disease Progression at Month 12	Progressive disease (PD) was determined using the modified Lugano classification criteria. For PET-CT-based PD: Score 4 (uptake moderately > liver) or 5 (uptake markedly higher than liver and/or new lesions) with an increase in intensity of uptake from baseline in target nodes and nodal lesions, new FDG-uptake foci of extranodal lesions consistent with lymphoma at interim or end-of-treatment assessment, no non-measured lesions, new FDG-uptake foci consistent with lymphoma, new or recurrent FDG-uptake foci in bone marrow. For CT-based PD: >/= 50% decrease in SPD of up to 6 target measureable nodes and extranodal sites; non-measured lesion should be absent/normal, have regressed, but not increased; no new lesions.	Month 12
Secondary	Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification	CR was defined as follows according to modified Lugano classification for CT-based response: Target nodes/nodal masses must have regressed to	Baseline up to end of treatment (approx. 6 months)
Secondary	Safety: Percentage of Participants With Adverse Events	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	Baseline up to approximately 36 months
Secondary	Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy	Maintenance of relative dose intensity was defined as a dose intensity of >/= 90%.	Baseline up to Cycle 6 (cycle length = 21 days)
Secondary	Relative Dose Intensity of Venetoclax	Dose intensity was categorized as < 80%, 80% to < 85%, 85% to < 90%, or >/= 90%.	Baseline up to Cycle 6 (cycle length = 21 days)