A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Leukemia, Lymphocytic, Chronic, B-Cell Clinical Trial

— GLOW  

Official title:

A Randomized, Open-label, Phase 3 Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Subjects With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03462719
• Other study ID #: CR108428
• Secondary ID: 2017-004699-7754
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 17, 2018
• Est. completion date: April 5, 2027

Study information

• Verified date: April 2024
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess progression-free survival (PFS) from treatment with ibrutinib plus venetoclax (I+VEN) compared with obinutuzumab plus chlorambucil (G-Clb) as assessed by an Independent Review Committee (IRC).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 211
• Est. completion date: April 5, 2027
• Est. primary completion date: February 26, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult participants who are: (a) greater than or equal to (>=) 65 years old or, (b) 18

to 64 years old and have at least 1 of the following:

1. Cumulative Illness Rating Scale (CIRS) score > 6

2. Creatinine clearance (CrCl) estimated less than (<) 70 milliliter per minute (mL/min) using Cockcroft-Gault equation

• Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that meets International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
• Measurable nodal disease (by computed tomography [CT]), defined as at least one lymph node > 1.5 centimeter (cm) in longest diameter
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Grade less than or equal to (<=) 2
• Active CLL/SLL requiring treatment per the iwCLL criteria

Exclusion Criteria:

• Prior anti-leukemic therapy for CLL or SLL
• Presence of deletion of the short arm of chromosome 17 (del17p) or known TP53 mutation detected at a threshold of >10 percent (%) variable allele frequency (VAF)
• Major surgery within 4 weeks of first dose of study treatment
• Known bleeding disorders (example, von Willebrand's disease or hemophilia)
• Central nervous system (CNS) involvement or suspected Richter's syndrome

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Ibrutinib
Participants will receive ibrutinib 420 mg orally once daily up to 15 cycles.
• Venetoclax
Participants will receive venetoclax in combination with ibrutinib for a total of 12 cycles, beginning at Cycle 4. For the first 5 weeks of venetoclax treatment, the treatment dose will be ramped up from 20 to 400 mg.
• Chlorambucil
Participants will receive chlorambucil at a dose of 0.5 mg/kg body weight on Days 1 and 15 of Cycles 1 to 6.
• Obinutuzumab
Participant will receive obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and Day 1 of Cycles 2 to 6.
• Ibrutinib (as Subsequent Therapy)
Participants will receive ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity during the subsequent therapy phase.

Locations

Country	Name	City	State
Belgium	Institut - Jules Bordet	Anderlecht
Belgium	ZNA Stuivenberg	Antwerpen
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Virga Jessa Ziekenhuis	Hasselt
Belgium	UZ Leuven Gasthuisberg	Leuven
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Juravinski Cancer Centre	Hamilton	Ontario
Canada	CIUSSS de l'Est-de-l'Île-de-Montréal Installation Hôpital Maisonneuve-Rosemont	Montreal	Quebec
Canada	Jewish General Hospital	Montreal	Quebec
Canada	The Ottawa Hospital - General Campus	Ottawa	Ontario
Czechia	Fakultni nemocnice Brno, Interni hematologicka a onkologicka klinika	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Fakultni nemocnice Plzen, Hemato-onkologicke oddeleni	Plzen
Czechia	Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologie	Praha 2
Denmark	Aalborg University Hospital	Aalborg
Denmark	Aarhus Universitetshospital	Aarhus
Denmark	Rigshospitalet	Copenhagen
Denmark	Odense Universitetshospital	Odense C
Denmark	Roskilde Sygehus	Roskilde
France	CHU de Clermont-Ferrand	Clermont Ferrand
France	Hopital Claude Huriez	Lille
France	CHU Montpellier	Montpellier
France	Hopital Haut Leveque Service Maladie Du Sang	Pessac
France	Centre Hospitalier Universitaire de Reims, Hôpital Robert Debré	Reims
France	Institut Universitaire du Cancer Toulouse Oncopole	Toulouse Cedex 9
France	CHU Bretonneau	Tours Cedex 9
France	CHU-Nancy	Vandoeuvre les Nancy
France	Institut Gustave Roussy	Villejuif
Israel	Bnai Zion Medical Center	Haifa
Israel	Carmel Medical Center	Haifa
Israel	Hadassah Medical Center	Jerusalem
Israel	Western Galilee Medical Center	Nahariya
Israel	Sheba Medical Center	Ramat Gan
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Netherlands	Flevoziekenhuis	Almere
Netherlands	Academic Medical Center	Amsterdam
Netherlands	OLVG	Amsterdam
Netherlands	Reinier de Graaf Gasthuis	Delft
Netherlands	MC Haaglanden	Den Haag
Netherlands	Albert Schweitzer Ziekenhuis	Dordrecht
Netherlands	Catharinaziekenhuis	Eindhoven
Netherlands	Spaarne Gasthuis	Hoofddorp
Netherlands	Zuyderland Medical Center	Sittard-Geleen
Netherlands	Antonius hospital	Sneek
Netherlands	Elisabeth zkh	Tilburg
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich	Chorzów
Poland	Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi	Lodz
Poland	Uniwersytecki Szpital Kliniczny Nr 1 w Lublinie	Lublin
Poland	Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka,	Slupsk
Poland	Instytut Hematologii i Transfuzjologii	Warszawa
Russian Federation	S.P. Botkin Moscow City Clinical Hospital	Moscow
Russian Federation	Nizhniy Novgorod Region Clinical Hospital	Nizhny Novgorod
Russian Federation	Ryazan Regional Clinical Hospital	Ryazan
Russian Federation	FSBIFederal Centre of Heart, Blood and Endocrinology named after V.A.Almazov MoH of the RF	Saint Petersburg
Russian Federation	St.-Petersburg Clinical Research Institute of Hematology and Transfusiology	St. Petersburg
Spain	Hosp. Clinic de Barcelona	Barcelona
Spain	Hosp. de La Santa Creu I Sant Pau	Barcelona
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	Hosp. Gral. Univ. Gregorio Maranon	Madrid
Spain	Hosp. Univ. de La Princesa	Madrid
Spain	Hosp. Univ. Fund. Jimenez Diaz	Madrid
Spain	Hosp. Univ. Infanta Leonor	Madrid
Spain	Hospital Ramon y Cajal	Madrid
Spain	Clinica Univ. de Navarra	Pamplona
Spain	Hospital Clinico Universitario Salamanca	Salamanca
Spain	Hosp. Virgen Del Rocio	Sevilla
Sweden	Sunderby Sjukhus Medicinkliniken	Luelå
Sweden	Karolinska Universitetssjukhuset Solna, Centrum för Hematologi, Stockholm	Stockholm
Turkey	Ankara Universitesi Tip Fakültesi Ibn-i Sina Hastanesi	Ankara
Turkey	Gazi Universitesi Tip FalKultesi	Ankara
Turkey	Ondokuz Mayis Universitesi Tip Fakultesi	Atakum
Turkey	V K V Amerikan Hastanesi	Istanbul
Turkey	Dokuz Eylul Universitesi Tip Fakultesi	Izmir
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	Addenbrookes Hospital	Cambridge
United Kingdom	Queen Mary University of London	Charterhouse Square
United Kingdom	New Victoria Hospital	Glasgow
United Kingdom	St James's Hospital	Leeds
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Barking Havering and Redbridge University Hospitals NHS Trust	Romford
United Kingdom	Royal Hallamshire Hospital	Sheffield
United States	Novant Health	Charlotte	North Carolina
United States	John Theurer Cancer Center	Hackensack	New Jersey
United States	Norton Cancer Institute	Louisville	Kentucky

Sponsors (2)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC	Pharmacyclics LLC.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Czechia,  Denmark,  France,  Israel,  Netherlands,  Poland,  Russian Federation,  Spain,  Sweden,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	PFS: time between date of randomization and date of disease progression, as assessed by IRC, or date of death due to any cause, whichever occurs first, regardless of use of subsequent anti-cancer therapy prior to PD or death using iWCLL2008 criteria : New enlarged lymph nodes >15 mm, new hepatomegaly or splenomegaly, or other organ infiltrates, bone lesion, ascites or pleural effusion due to CLL; >=50% increase in longest diameter (LDi) from nadir in existing lymph node (LDi >15 mm) or >=50% increase from nadir in sum of diameters of multiple nodes (and at least 1 node with LDi >15 mm); >=50% increase from nadir in enlargement of liver/spleen; >=50% increase from baseline in lymphocyte count (ALC; to >=5*10^9/L); or >=50% increase from nadir in ALC in >=2 serial assessments if ALC is >=30000*10^9/L and lymphocyte doubling time is rapid unless considered treatment-related lymphocytosis; new cytopenia attributable to CLL; transformation to more aggressive histology.	Up to 2 years 10 months
Secondary	Minimal Residual Disease (MRD) Negative Rate	MRD-negative rate is defined as the percentage of participants who achieved MRD-negative status (that is, less than [<] 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or <0.01 percentage [%]) in the bone marrow as assessed by next-generation sequencing (NGS). Participants with missing MRD data were considered MRD positive.	Up to 2 years 10 months
Secondary	Complete Response Rate (CRR)	Complete response rate is defined as the percentage of participants who achieved complete response or complete response with an incomplete marrow recovery (CRi) on or prior to initiation of subsequent anti-leukemic therapy per the IRC assessment. International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 gram per deciliter (g/dL), absolute lymphocyte count <4000/microliter (mcL) and normocellular bone marrow with <30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow.	Up to 2 years 10 months
Secondary	Overall Response Rate (ORR)	ORR: percentage of participants who achieved best overall response of either CR, CRi, nodular PR (nPR) and partial response (PR). iWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 g/dL and ALC <4000/mcL, normocellular bone marrow with <30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but bone marrow biopsy shows B-lymphoid nodules (reflecting residual disease); PR-2 of following when abnormal at baseline: >=50% decrease in ALC, >=50% decrease in sum of products of multiple nodes, >=50% decrease in enlargement of spleen or liver; and 1 of following: neutrophils >1.5*10^9/L, Platelets >100*10^9/L and Hgb>11 g/dL or >=50% improvement over baseline in any of these; 50% reduction in bone marrow infiltrates or B lymphoid nodules; no new enlarged nodes or new hepatosplenomegaly.	Up to 2 years 10 months
Secondary	Overall Survival (OS)	OS is defined as the time from date of randomization to date of death from any cause.	Up to 4 years 10 months
Secondary	Duration of Response (DOR)	DOR is defined as the interval between the date of initial documentation of a response including partial response with lymphocytosis (PRL) and the date of first documented evidence of PD or death or date of censoring per the IRC assessment. iWCLL 2008 criteria for PD: New enlarged nodes >1.5 cm, new hepatomegaly or splenomegaly, or other organ infiltrates; >= 50% increase from nadir in existing lymph node or >=50% increase from nadir in sum of product of diameters of multiple nodes; >=50% increase from nadir in enlargement of liver or spleen; >=50% increase from baseline in lymphocyte count (and to >=5*10^9/L) unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology.	Up to 2 years 10 months
Secondary	Time-to-Next Treatment	Time-to-next treatment was measured from the date of randomization to the start date of any subsequent anti-leukemic therapy.	Up to 2 years 10 months
Secondary	Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L)	Time to worsening= time interval (months) from randomization to first observation of deterioration. EQ-5D-5L consists of a 5-item descriptive system and the EuroQol visual analog scale (EQ-5D VAS). EQ-5D-VAS self-rating records respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Worsening is defined as a decrease of >= 7 points (on a 0-100 scale).; EQ-5D-5L descriptive system comprises 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe participant's current health state. Responses for 5 dimensions are combined into a 5-digit number describing respondents health state that can be converted into a single index value or utility score (using the United Kingdom weights), ranging from -1 to 1, where lower scores indicate a worse health status. Worsening is defined as a decrease of >=0.08 points (on a 0-1 scale).	Up to 2 years 10 months
Secondary	Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30)	Time to worsening= time interval from randomization to first observation of deterioration. EORTC QLQ-C30 includes 30 separate items: 5 functional scales (physical, role, emotional, cognitive, and social Functioning), 1 global health status (GHS) and QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each item, except GHS, is answered on 4-point scale (1=not at all to 4=very much) and GHS is measured on 1-7 scale: 1=very poor and 7=excellent. Scores derived using validated scoring algorithms as per EORTC QLQ-C30 Manual and linearly transformed in a range from 0-100. For functional and global QoL scales, higher scores=better level of functioning/QoL. For symptom-oriented scales, higher score=more severe symptoms. Worsening in functional and global health scores=decrease of >=10 points (on 0-100 scale) and in symptom scores=increase of >=10 points (on 0-100 scale).	Up to 2 years 10 months
Secondary	Time to Worsening and Time to Improvement as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score	Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). Time to Worsening is defined as time interval (months) from randomization to first observation of deterioration. Worsening is defined as a decrease >= 3 points (on a 0-52 scale). Time to improvement is defined as the time interval (months) from randomization to the first observation of improvement. Improvement is defined as an increase >=3 points (on a 0-52 scale).	Up to 2 years 10 months
Secondary	Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability	An adverse event (AE) is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.	Up to 4 years 10 months
Secondary	Number of Participants With Abnormal Clinical Laboratory Findings	Number of participants with abnormal clinical laboratory findings (hematology and serum chemistry) were reported.	Up to 4 years 10 months
Secondary	Percentage of Participants With Sustained Hemoglobin Improvement	Sustained hemoglobin improvement is defined as the percentage of participants who achieved an increase in hemoglobin levels from baseline by >= 2 grams per deciliter (g/dL) and lasts for at least 56 days without blood transfusion or growth factors.	Up to 2 years 10 months
Secondary	Percentage of Participants With Sustained Platelet Improvement	Sustained platelet improvement is defined as the percentage of participants who achieved an increase in platelet levels from baseline by >= 50% and lasts for at least 56 days without blood transfusion or growth factors.	Up to 2 years 10 months
Secondary	Plasma Concentration of Ibrutinib and Venetoclax	Plasma concentrations of ibrutinib and venetoclax were determined by validated liquid chromatography-tandem mass spectrometry.	Ibrutinib: Pre-dose-Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days), Venetoclax: Pre-dose-Day 1 of Cycles 5 and 6