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) (GLOW)

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).

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
• Intervention / Treatment: Drug: Ibrutinib; Drug: Venetoclax; Drug: Ibrutinib (as Subsequent Therapy); Drug: Chlorambucil; Drug: Obinutuzumab

Detailed Description

The hypothesis is treatment with combination of I+VEN will result in longer PFS compared with G-Clb in participants with previously untreated chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) who meet International Workshop on CLL (iwCLL) treatment criteria. The study includes screening (30 days), treatment (from randomization until treatment discontinuation) and follow-up phase (from treatment discontinuation until Subsequent Therapy Phase [if applicable], death, lost to follow up, consent withdrawal, or study end, whichever occurs first). Participants without progression will continue disease evaluations until disease progression or death. Participants from either treatment arm that develop progressive disease may be eligible to receive single-agent ibrutinib until disease progression or unacceptable toxicity (Subsequent Therapy Phase). Participation in this phase of the study is not mandatory and is based on investigator's discretion. Study duration is approximately 6 years. Safety includes review of adverse events and laboratory tests performed over time.

• Study Type: Interventional
• Enrollment (Actual): 211
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Anderlecht, Belgium, 1070
    • Institut - Jules Bordet
  • Antwerpen, Belgium, 2060
    • ZNA Stuivenberg
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Hasselt, Belgium, 3500
    • Virga Jessa Ziekenhuis
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital - General Campus
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Montreal, Quebec, Canada, H1T 2M4
      • CIUSSS de l'Est-de-l'Île-de-Montréal Installation Hôpital Maisonneuve-Rosemont
• Czechia
  • Brno, Czechia, 625 00
    • Fakultni nemocnice Brno, Interni hematologicka a onkologicka klinika
  • Hradec Kralove, Czechia, 500 05
    • Fakultni nemocnice Hradec Kralove
  • Ostrava, Czechia, 708 52
    • Fakultni Nemocnice Ostrava
  • Plzen, Czechia, 323 00
    • Fakultni nemocnice Plzen, Hemato-onkologicke oddeleni
  • Praha 2, Czechia, 128 08
    • Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologie
• Denmark
  • Aalborg, Denmark, 9000
    • Aalborg University Hospital
  • Aarhus, Denmark, 8200
    • Aarhus Universitetshospital
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
  • Odense C, Denmark, 5000
    • Odense Universitetshospital
  • Roskilde, Denmark, DK- 4000
    • Roskilde Sygehus
• France
  • Clermont Ferrand, France, 63000
    • CHU de Clermont-Ferrand
  • Lille, France, 59000
    • Hopital Claude Huriez
  • Montpellier, France, 34295
    • CHU Montpellier
  • Pessac, France, 33604
    • Hopital Haut Leveque Service Maladie Du Sang
  • Reims, France, 51100
    • Centre Hospitalier Universitaire de Reims, Hôpital Robert Debré
  • Toulouse Cedex 9, France, 31059
    • Institut Universitaire du Cancer Toulouse Oncopole
  • Tours Cedex 9, France, 37044
    • CHU Bretonneau
  • Vandoeuvre les Nancy, France, 54511
    • CHU-Nancy
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Israel
  • Haifa, Israel, 31048
    • Bnai Zion Medical Center
  • Haifa, Israel, 34362
    • Carmel Medical Center
  • Jerusalem, Israel, 9112001
    • Hadassah Medical Center
  • Nahariya, Israel, 22100
    • Western Galilee Medical Center
  • Ramat Gan, Israel, 52621
    • Sheba Medical Center
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
• Netherlands
  • Almere, Netherlands, 1315RA
    • Flevoziekenhuis
  • Amsterdam, Netherlands, 1105 AZ
    • Academic Medical Center
  • Amsterdam, Netherlands, 1091AC
    • OLVG
  • Delft, Netherlands, 2625 AD
    • Reinier de Graaf Gasthuis
  • Den Haag, Netherlands, 2512 VA
    • MC Haaglanden
  • Dordrecht, Netherlands, 3318 AT
    • Albert Schweitzer Ziekenhuis
  • Eindhoven, Netherlands, 5623 EJ
    • Catharinaziekenhuis
  • Hoofddorp, Netherlands, 2134 TM
    • Spaarne Gasthuis
  • Sittard-Geleen, Netherlands, 6162 BG
    • Zuyderland Medical Center
  • Sneek, Netherlands, 8601 ZK
    • Antonius hospital
  • Tilburg, Netherlands, 5022 GC
    • Elisabeth zkh
• Poland
  • Chorzów, Poland, 41-500
    • Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
  • Lodz, Poland, 93-510
    • Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
  • Lublin, Poland, 20-081
    • Uniwersytecki Szpital Kliniczny Nr 1 w Lublinie
  • Slupsk, Poland, 76-200
    • Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka,
  • Warszawa, Poland, 02-776
    • Instytut Hematologii i Transfuzjologii
• Russian Federation
  • Moscow, Russian Federation, 125284
    • S.P. Botkin Moscow City Clinical Hospital
  • Nizhny Novgorod, Russian Federation, 603126
    • Nizhniy Novgorod Region Clinical Hospital
  • Ryazan, Russian Federation, 390039
    • Ryazan Regional Clinical Hospital
  • Saint Petersburg, Russian Federation, 197341
    • FSBIFederal Centre of Heart, Blood and Endocrinology named after V.A.Almazov MoH of the RF
  • St. Petersburg, Russian Federation, 193024
    • St.-Petersburg Clinical Research Institute of Hematology and Transfusiology
• Spain
  • Barcelona, Spain, 08035
    • Hosp. Univ. Vall D Hebron
  • Barcelona, Spain, 8041
    • Hosp. de La Santa Creu I Sant Pau
  • Barcelona, Spain, 08036
    • Hosp. Clinic de Barcelona
  • Madrid, Spain, 28034
    • Hospital Ramón y Cajal
  • Madrid, Spain, 28040
    • Hosp. Univ. Fund. Jimenez Diaz
  • Madrid, Spain, 28007
    • Hosp. Gral. Univ. Gregorio Maranon
  • Madrid, Spain, 28031
    • Hosp. Univ. Infanta Leonor
  • Madrid, Spain, 28006
    • Hosp. Univ. de La Princesa
  • Pamplona, Spain, 31008
    • Clinica Univ. de Navarra
  • Salamanca, Spain, 37007
    • Hospital Clinico Universitario Salamanca
  • Sevilla, Spain, 41013
    • Hosp. Virgen Del Rocio
• Sweden
  • Luelå, Sweden, 97180
    • Sunderby Sjukhus Medicinkliniken
  • Stockholm, Sweden, 171 76
    • Karolinska Universitetssjukhuset Solna, Centrum för Hematologi, Stockholm
• Turkey
  • Ankara, Turkey, 06500
    • Gazi Universitesi Tip FalKultesi
  • Ankara, Turkey, 6590
    • Ankara Universitesi Tip Fakültesi Ibn-i Sina Hastanesi
  • Atakum, Turkey, 55270
    • Ondokuz Mayis Universitesi Tip Fakultesi
  • Istanbul, Turkey, 34365
    • V K V Amerikan Hastanesi
  • Izmir, Turkey, 35340
    • Dokuz Eylul Universitesi Tip Fakultesi
• United Kingdom
  • Birmingham, United Kingdom, B9 5ST
    • Birmingham Heartlands Hospital
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrookes Hospital
  • Charterhouse Square, United Kingdom, EC1M 6BQ
    • Queen Mary University of London
  • Glasgow, United Kingdom, G42 9LF
    • New Victoria Hospital
  • Leeds, United Kingdom, LS9 7T
    • St James's Hospital
  • Plymouth, United Kingdom, PL6 8DH
    • Derriford Hospital
  • Romford, United Kingdom, RM7 0AG
    • Barking Havering and Redbridge University Hospitals NHS Trust
  • Sheffield, United Kingdom, S10 2JF
    • Royal Hallamshire Hospital
• United States
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Norton Cancer Institute
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Novant Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm A: Ibrutinib and Venetoclax (I+VEN); Participants will initially receive ibrutinib (420 mg [milligrams]/day) for 3 cycles. Venetoclax dose ramp up (from 20 to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles (each cycle is equivalent to 28 days). Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.	Drug: Ibrutinib; Participants will receive ibrutinib 420 mg orally once daily up to 15 cycles.; Drug: 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.; Drug: Ibrutinib (as Subsequent Therapy); Participants will receive ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity during the subsequent therapy phase.
Active Comparator: Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb); Participants will receive chlorambucil and obinutuzumab (G-Clb) for 6 cycles. Participants will receive obinutuzumab, 1000 mg intravenously (IV) on Days 1, 8 and 15 of Cycle 1, and on Day 1 of Cycles 2 to 6 and chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight, on Days 1 and 15 of Cycles 1 to 6. Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity.	Drug: Ibrutinib (as Subsequent Therapy); Participants will receive ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity during the subsequent therapy phase.; Drug: 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.; Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Collaborators: Pharmacyclics LLC.
• Investigators: Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2018
• Primary Completion (Actual): February 26, 2021
• Study Completion (Estimated): April 5, 2027

Study Registration Dates

• First Submitted: March 6, 2018
• First Submitted That Met QC Criteria: March 6, 2018
• First Posted (Actual): March 12, 2018

Study Record Updates

• Last Update Posted (Estimated): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Venetoclax; Obinutuzumab; Chlorambucil; Ibrutinib
• Other Study ID Numbers: CR108428; 2017-004699-77 (EudraCT Number); 54179060CLL3011 (Other Identifier: Janssen Research & Development, LLC)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes